Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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METHODS AND SYSTEMS FOR MANAGEMENT OF ALZHEIMER'S DISEASE
CROSS-REFERENCES TO RELATED APPLICATIONS
This application claims the priority of all of the following patent
applications,
which are assigned to the assignee of the present patent application and are
incorporated
herein by reference:
(a) US Provisional Patent Application 60/388,931, filed June 14, 2002,
entitled,
"Methods and systems for management of Alzheimer's disease"; and
(b) US Patent Application 10/294,310 to Gross et al., entitled, "Stimulation
for
treating eye pathologies," filed November 14, 2002, which is a continuation-in-
part of a
1 o US patent application to Shalev and Gross, filed November 8, 2002,
entitled, "Method and
apparatus for stimulating the sphenopalatine ganglion to modify properties of
the BBB
and cerebral blood flow," which is a US national phase application
corresponding to PCT
Patent Application PCT l IL O1 / 00402, filed May 7, 2001, entitled, "Method
and
apparatus for stimulating the sphenopalatine ganglion to modify properties of
the BBB
and cerebral blood flow," which claims priority from US Provisional Patent
Application
60/203,172, filed May 8, 2040, entitled, "Method and apparatus for stimulating
the
sphenopalatine ganglion to modify properties of the BBB and cerebral blood
flow." US
Patent Application 10/294,310 also claims priority from: (i) US Provisional
Patent
Application 60/400,167, filed July 31, 2002, entitled, "Delivering compounds
to the brain
2 0 by modifying properties of the BBB and cerebral circulation" and (ii) US
Provisional
Patent Application 60/364,451, filed March 15, 2002, entitled, "Applications
of
stimulating the sphenopalatine ganglion (SPG)."
FIELD OF TAE INVENTION
This invention relates to methods and systems used for therapeutic,
prophylactic
and diagnostic purposes in the management of a disease. More specifically,
this
invention relates to methods and systems used for therapeutic, prophylactic
and
diagnostic purposes in the management of Alzheimer's disease (AD).
BACKGROUND OF THE INVENTION
Alzheimer's disease (AD) is the most common form of both senile and presenile
3 0 dementia in the world and is recognized clinically as relentlessly
progressive loss of
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memory and intellectual function and disturbances in speech (Merntt, 1979, A
Textbook of
Neurology, 6th edition, pp. 484-489, Lea & Febiger, Philadelphia, which is
incorporated
herein by reference). Alzheimer's disease begins with mildly inappropriate
behavior,
uncritical statements, irritability, a tendency towards grandiosity, euphoria,
and
deteriorating performance at work; it progresses through deterioration in
operational
judgment, loss of insight, depression, and loss of recent memory; and it ends
in severe
disorientation and confusion, apraxia of gait, generalized rigidity, and
incontinence
(Gilroy & Meyer, 1979, ltledical Neurology, pp. 175-179, MacMillan Publishing
Co.,
which is incorporated herein by reference,). Alzheimer's disease is found in
about 10% of
0 the population over the age of 65 and 47% of the population over the age of
85 (Evens et
al., 1989, JAMA, 262:2551-2556, which is incorporated herein by reference).
Alzheimer's Disease is characterized by the accumulation of insoluble, 14 nm
filaments containing ~i-amyloid (A~) peptides, localized in the extracellular
space of the
cerebral cortex and vascular walls. These 40 or 42 amino acid long AJ3
peptides are
t 5 derived from the larger (3-amyloid precursor protein (~iAPP) through the
endopeptidase
action of ~3 and y secretases. In addition, the post-translational action of
putative
aminopeptidases results in a heterogeneous shortening of the 40 or 42 amino
acid long Aj3
peptides that either terminate at residue 40 or 42 and, therefore, are
designated as AJ3N-40
and AjiN-42. In familial forms of AD, the pathological appearance of the A(3
peptides in
~ 0 the brain is driven by the presence of mutations in the (3APP gene or in
the genes coding
for the proteins presenilin 1 and 2.
Sporadic AD accounts for more than 95% of the known AD cases. Its etiology,
however, remains obscure. An accepted view is that sporadic AD results from
the
interplay between an individual's genetic factors and the environment, leading
to the
2 5 deposition of A~i, neurodegeneration, and dementia. Despite this emerging
perspective,
insufficient effort has been made in identifying factors responsible for A(3
accumulation in
the brain.
The etiology of Alzheimer's disease is unknown. Evidence for a genetic
contribution comes from several important observations such as the familial
incidence,
3 0 pedigree analysis, monozygotic and dizygotic twin studies, and the
association of the
disease with Down's syndrome (for review see Baraitser, 1990, The Genetics of
Neurological Disorders, 2nd edition, pp. 85-88, which is incorporated herein
by
reference). Nevertheless, this evidence is far from definitive, and it is
clear that other
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factors are involved.
Alzheimer's Disease is a neurodegenerative disease characterized by a
progressive
decline of cognitive functions, including loss of declarative and procedural
memory,
decreased learning ability, reduced attention span, and severe impairment in
thinking
ability, judgment, and decision making. Mood disorders and depression are also
often
observed in AD patients. It is estimated that AD affects about 4 million
people in the
USA and 20 million people worldwide. Because AD is an age-related disorder
(with an
average onset at 65 years), the incidence of the disease in industrialized
countries is
expected to rise dramatically as the population of these countries ages.
AD is characterized by the following neuropathological features:
~ massive loss of neurons and synapses in the brain regions involved in higher
cognitive functions (association cortex, hippocampus, amygdala). Cholinergic
neurons are particularly affected.
~ neuritic (senile) plaques that are composed of a core of amyloid material
surrounded by a halo of dystrophic neurites, reactive type I astrocytes, and
numerous microglial cells (Selkoe, D.J., Annu Rev Neurosci 17:489-517, 1994;
Selkoe, D.J., 3 Neuropathol Exp Neurol 53:438-447, 1994; Dickson, D.W., J
Neuropathol Exp Neurol 56:321-339, 1997; Hardy, J. et al., Science 282:1075-
1079, 1998; Selkoe, D.J., Cold Spring Harb Symp Quant Biol 61:587-596, 1996,
2 0 all of which are incorporated herein by reference. The major component of
the
core is a peptide of 39 to 42 amino acids called the amyloid j3 protein, or
A(3.
Although the A~i protein is produced by the intracellular processing of its
precursor, APP, the amyloid deposits forming the core of the plaques are
extracellular. Studies have shown that the longer form of A(3 (A~i42) is much
more amyloidogenic than the shorter forms (A(340 or A~i39).
~ neurofibrillary tangles that are composed of paired-helical filaments (PHF)
(Ray et
al., Mol Med Today 4:151-157, 1998; Brion, Acta Neurol Belg 98:165-174, 1998,
both of which are incorporated herein by reference). Biochemical analyses
revealed that the main component of PHF is a hyper-phosphorylated form of the
3 0 microtubule-associated protein i. These tangles are intracellular
structures, found
in the cell body of dying neurons, as well as some dystrophic neurites in the
halo
surrounding neuritic plaques.
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Both plaques and tangles are found in the same brain regions affected by
neuronal
and synaptic loss.
Although the neuronal and synaptic loss is universally recognized as the
primary
cause of the decline of cognitive functions, the cellular, biochemical, and
molecular
events responsible for this neuronal and synaptic loss are subject to fierce
controversy.
The number of tangles shows a better correlation than the amyloid load with
the cognitive
decline (Albert, Proc Natl Acad Sci USA 93:13547-13551, 1996, which is
incorporated
herein by reference). On the other hand, a number of studies showed that
amyloid can be
directly toxic to neurons, resulting in behavioral impairment (Ma et al.,
Neurobiol Aging
1. 0 17:773-780, 1996, which is incorporated herein by reference). It has also
been shown that
the toxicity of some compounds (amyloid or tangles) could be aggravated by
activation of
the complement cascade, suggesting the possible involvement of inflammatory
process in
the neuronal death.
Genetic and molecular studies of some familial forms of AD (FAD) have recently
provided evidence that boosted the amyloid hypothesis (Ii, Drugs Aging 7:97-
109, 1995;
Price et al., Curr Opin Neurol 8:268-274, 1995; Hardy, Trends Neurosci 20:154-
159,
1997; Sellcoe, J Biol Chem 271:18295-18298, 1996, all of which are
incorporated herein
by reference). The assumption is that since the deposition of A~i in the core
of senile
plaques is observed in all Alzheimer cases, if A(3 is the primary cause of AD,
then
2 0 mutations that are linked to FAD should induce changes that, in one way or
another,
foster AJ3 deposition. There are 3 FAD genes known so far (Hardy et al.,
Science
282:1075-1079, 1998; Ray et al., Mol Med Today 4:151-157, 1998, both of which
are
incorporated herein by reference), and the activity of all of them results in
increased A(3
deposition, a very compelling argument in favor of the amyloid hypothesis.
2 5 The first of the 3 FAD genes codes for the A~3 precursor, APP (Selkoe, J
Biol
Chem 271:18295-18298, 1996, which is incorporated herein by reference).
Mutations in
the APP gene are very rare, but all of them cause AD with 100% penetrance and
result in
elevated production of either total Aj3 or A[342, both in vitro (transfected
cells) and in vivo
(transgenic animals). The other two FAD genes code for presenilin 1 and 2
(PS1, PS2)
3 0 (Hardy, Trends Neurosci 20:154-159, 1997, which is incorporated herein by
reference).
The presenilins contain 8 transmembrane domains and several lines of evidence
suggest
that they are involved in intracellular protein trafficking, although their
exact function is
still unknown. Mutations in the presenilin genes are more common than in the
APP
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genes, and all of them also cause FAD with 100% penetrance. In addition, in
vitro and in
vivo studies have demonstrated that PS1 and PS2 mutations shift APP
metabolism,
resulting in elevated AJ342 production. For a recent review on the genetics of
AD, see
Lippa, J Mol Med 4:529-536, 1999, which is incorporated herein by reference.
In spite of these compelling genetic data, it is still unclear whether A(3
generation
and amyloid deposition are the primary cause of neuronal death and synaptic
loss
observed in AD. Moreover, the biochemical events leading to Aj3 production,
the
relationship between APP and the presenilins, and between amyloid and
neurofibrillary
tangles are poorly understood. Thus, the picture of interactions between the
major
Alzheimer proteins is very incomplete, and it is clear that a large number of
novel proteins
are yet to he discovered.
The diagnosis of Alzheimer's disease at autopsy is definitive. Gross
pathological
changes are found in the brain, including low weight and generalized atrophy
of both the
gray and white matter of the cerebral cortex, particularly in the temporal and
frontal lobes
(Adams & Victor, 1977, Principles of Neurology, pp. 401-407 and Merritt, 1979,
A
Textbook of Neuf~ology, 6th edition, Lea & Febiger, Philadelphia, pp. 484-489,
both of
which are incorporated herein by reference). The histological changes include
neurofibrillary tangle (Kidd, Nature 197:192-193, 1963; Kidd, Brain 87:307-
320, 1964,
both of which are incorporated herein by reference), which consists of a
tangled mass of
2 0 paired helical and straight filaments in the cytoplasm of affected neurons
(Oyanagei, Adv.
Neurol. Sci. 18:77-88, 1979 and Grundke-Iqbal et al., Acta Neuropathol. 66:52-
61, 1985,
both of which are incorporated herein by reference).
The diagnosis of Alzheimer's disease during life is more difficult than at
autopsy
since the diagnosis depends upon inexact clinical observations. In the early
and middle
2 5 stages of the disease, the diagnosis is based on clinical judgment of the
attending
physician. In the late stages, where the symptoms are more recognizable,
clinical
diagnosis is more straightforward. But, in any case, before an unequivocal
diagnosis can
be made, other diseases, with partially overlapping symptoms, must be ruled
out. Usually
a patient must be evaluated on a number of occasions to document the
deterioration in
3 0 intellectual ability and other signs and symptoms. The necessity for
repeated evaluation is
costly, generates anxiety, and can be frustrating to patients and their
families.
Furthermore, the development of an appropriate therapeutic strategy is
hampered by the
difficulties of rapid diagnosis, particularly in the early stages where early
intervention
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could leave the patient with significant intellectual capacity and a
reasonable quality of
life. In brief, no unequivocal laboratory test specific for Alzheimer's
disease has been
reported.
Alzheimer's disease is associated with degeneration of cholinergic neurons, in
the
basal forebrain, which play a fundamental role in cognitive functions,
including memory
(Becker et al., Drug Development Research 12:163-195, 1988, which is
incorporated
herein by reference). Progressive, inexorable decline in cholinergic function
and
cholinergic markers in the brain of Alzheimer's disease patients has been
observed in
numerous studies, and includes, for example, a marked reduction in
acetylcholine
synthesis, choline acetyltransferase activity, acetylcholinesterase activity,
and choline
uptake (Davis, Brain Res. 171:319-327, 1979 and Hardy et al., Neurochem. Int.
7:545-
563, 1985, which are incorporated herein by reference). Even more, decreased
cholinergic function may be an underlying cause of cognitive decline seen in
Alzheimer's-
disease patients (Kish et al., J. Neurol., Neurosurg., and Psych. 51:544-548,
1988, which
is incorporated herein by reference). Choline acetyltransferase and
acetylcholinesterase
activities decrease significantly as plaque count rises, and, in demented
subjects, the
reduction in choline acetyl transferase activity was found to correlate with
intellectual
impairment (Perry, et al., Brit. Med. J. 25, November 1978, p. 1457, which is
incorporated
herein by reference).
2 0 Nerve cells produce nerve growth factors, pxoteins that regulate cell
maturation
during prenatal development and also play an important role in cell survival,
repair, and
regeneration during adult life. Because of their significance in cell
maintenance and
repair, these factors have attracted attention as potential treatments in
Alzheimer's
disease, stroke, spinal coxd injury, and other neurodegenerative conditions.
However,
nerve growth factors are usually too large to cross the blood-brain barrier
(BBB), a
protective shield that restricts passage of molecules to the brain.
The BBB is functionally situated at the brain capillaries endothelium layer
and
covers a surface area of 12 m2/g of brain parenchyma. The total length of this
capillary
network is 650 km. The cerebral capillary endothelial cell displays some
peculiar
3 o morphologic characteristics that form the anatomic basis of the blood-
brain barrier. It
differs from the peripheral capillary endothelial cell (referring to all non-
CNS sites) in a
number of ways:
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~ First, the CNS endothelial cell layer is not fenestrated. Cells are joined
by tight
junctions composed of 6 to 8 pentalaminar structures. They actively block
protein
movements, hydrophilic transfer and even ionic diffusion. Thus, there is very
little movement of compounds between endothelial cells from the blood to the
CNS.
~ Second, and in contrast to the peripheral capillary endothelial cell,
transcellular
movement of molecules through the non-specific mechanism of fluid-phase
endocytosis is generally absent. The cerebral vascular endothelial cell
possesses a
transcellular lipophilic pathway, allowing diffusion of small lipophilic
compounds.
1 o In addition to this route, specific receptor-mediated transport systems
are present
for given molecules, like insulin, transferrin, glucose, purines and amino
acids.
These transport systems are highly selective and asymmetric.
~ Third, the CNS endothelial cell displays a net negative charge at its
endoluminal
side and at the basement membrane. This provides an additional selective
mechanism by impeding anionic molecules to cross the membrane.
~ Fourth, the cerebral endothelial cell has very few pinocytic vesicles, and
these
vesicles are not involved in any transport function.
~ Fifth, astrocyte foot processes surround the microvascular endothelium and
cover
more than 95 percent of its surface, therefore interposing between capillaries
and
2 0 cerebral neuropil.
By virtue of this selective barrier, the CNS can preferentially regulate the
extracellular concentration of certain solutes, growth factors and
neurotransmitters; keep
certain molecules in the CNS and isolate itself from some others, and further
isolate itself
from sudden systemic homeostatic changes. It is therefore an integral
component of the
2 5 mechanisms involved in the tight regulation of the extra-cellular
homeostasis necessary to
the normal CNS function. This relatively impermeable barrier has some
drawbacks,
however, when considering the therapeutic delivery of a molecule to the CNS.
The delivery of therapeutic molecules across the BBB has proven to be a major
obstacle in treating various brain disorders. The normal blood-brain barrier
prevents
3 o passage of ionized water-soluble compounds with a molecular weight greater
than 180
Daltons. Therefore, the BBB is a major impediment to the treatment of CNS
diseases as
many drugs are unable to reach this organ at therapeutic concentrations. More
than 98%
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of the CNS-targeted drugs do not cross the BBB. Example of such disorders are:
primary
brain tumors, metastatic brain tumors, AD, addiction, ALS, head injury,
Huntington's
disease, multiple sclerosis (MS), depression, Cerebral Palsy, schizophrenia,
epilepsy,
stress and anxiety. Many new neurotherapeutic agents axe being discovered, but
because
of a lack of suitable strategies for drug delivery across the BBB, these
agents are
ineffective. Such drugs will only become effective if strategies for brain
delivery are
developed in parallel.
Apart from molecular parameters, the permeability of the BBB and active
transport mechanisms, a major determinant of molecular transport across the
BBB is their
concentration gradient - between the CNS and the cerebral circulation.
Additionally, the functioning BBB inhibits clearance of neurotoxic compounds,
such as ~i-Amyloid, tau, PS 1, and PS2, from the CNS into the systemic
circulation. These
neurotoxic compounds are therefore not metabolized and removed from the body
to the
extent desired, and therefore continue to have undesired effects in the CNS.
US Patent 5,752,515 to Jolesz et al., which is incorporated herein by
reference,
describes apparatus for image-guided ultrasound delivery of compounds through
the
blood-brain barrier. Ultrasound is applied to a site in the brain to effect in
the tissues
and/or fluids at that location a change detectable by imaging. At least a
portion of the
brain in the vicinity of the selected location is imaged, e.g., via magnetic
resonance
2 0 imaging, to confirm the location of that change. A compound, e.g., a
neuropharmaceutical, in the patient's bloodstream is delivered to the
confirmed location
by applying ultrasound to effect opening of the blood-brain barrier at that
location and,
thereby, to induce uptake of the compound there.
The following references, which are incorporated herein by reference, may be
2 5 useful:
Delepine L, Aubineau P, "Plasma protein extravasation induced in the rat dura
mater by
stimulation of the parasympathetic sphenopalatine ganglion," Experimental
Neurology,
147, 389-400 (1997)
Hara H, Zhang QJ, Kuroyanagi T, Kobayashi S, "Parasympathetic cexebxovascular
3 0 innervation: An anterograde tracing from the sphenopalatine ganglion in
the rat,"
Neurosurgery, 32, 822-827 (1993)
Jolliet-Riant P, Tillement JP, "Drug transfer across the blood-brain barrier
and
8
CA 02489341 2004-12-13
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improvement of brain delivery," Fundam. Clin. Pharmacol., 13, 16-25 (1999)
Kroll RA, Neuwelt EA, "Outwitting the blood brain barrier for therapeutic
purposes:
Osmotic opening and other means," Neurosurgery, 42, 1083-1100 (1998)
Sanders M, Zuurnlond WW, "Efficacy of sphenopalatine ganglion blockade in 66
patients
suffering from cluster headache: A 12-70 month follow-up evaluation," Journal
of
Neurosurgery, 87, 876-880 (1997)
Syelaz J, Hara H, Pinard E, Mraovitch S, MacKenzie ET, Edvinsson L, "Effects
of
stimulation of the sphenopalatine ganglion on cortical blood flow in the rat,"
Journal of
Cerebral Blood Flow and Metabolism," 8, 875-878 (1988)
Van de Waterbeemd H, Camenisch G, Folkers G, Chretien JR, Raevsky OA,
"Estimation
of blood brain barrier crossing of drugs using molecular size and shape and h
bonding
descriptors," Journal of Drug Targeting," 6, 151-165, (1998)
Suzuki N, Hardebo JE, Kahrstrom J, Owman C, "Selective electrical stimulation
of
postganglionic cerebrovascular parasympathetic nerve fibers originating from
the
sphenopalatine ganglion enhances cortical blood flow in the rat," Journal of
Cerebral
Blood Flow and Metabolism, 10, 383-391 (1990)
Suzuki N, Hardebo JE, Kahrstrom J, Owman CH, "Effect an cortical blood flow of
electrical stimulation of trigeminal cerebrovascular nerve fibres in the rat,"
Acta Physiol.
Scand., 138, 307-315 (1990)
2 0 Major A, Silver W, "Odorants presented to the rat nasal cavity increase
cortical blood
flow," Chem. Senses, 24, 665-669 (1999)
Fusco BM, Fiore G, Gallo F, Martelletti P, Giacovazzo M, "'Capsaicin-
sensitive' sensory
neurons in cluster headache: pathophysiological aspects and therapeutic
indications,"
Headache, 34, 132-137 (1994)
,2 5 Lambert GA, Bogduk N, Goadsby PJ, Duckworth JW, Lance JW, "Decreased
carotid
arterial resistance in cats in response to trigeminal stimulation," Journal of
Neurosurgery,
61, 307-315 (1984)
Silver WL, "Neural and pharmacological basis for nasal irritation," in Tucker
WG,
Leaderer BP, Mr~lhave L, Cain WS (eds), Sources of Indoor Air Contaminants,
Ann. NY
30 Acad. Sci., 641, 152-163 (1992)
9
CA 02489341 2004-12-13
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Silver W, "Chemesthesis: the burning questions," ChemoSense, Vol. 2 No. 1, 1-2
(1999)
Asaba H, Hosoya K, Takanaga H, Ohtsuki S, Tamura E, Takizawa T, Terasaki T,
"Blood
Brain barrier is involved in the efflux transport of a neuroactive steroid,
dehydroepiandrosterone sulfate, via organic anion transporting polypeptide 2,"
J.
Neurochem. 75(5):1907-1916 (2000)
Isakovica AJ, Segalb MB, Milojkovica BA, Dacevica MP, Misirlica ST, Rakicc ML,
Redzicb ZB, "The efflux of purine nucleobases and nucleosides from the rat
brain,"
Neuroscience Letters 318:65-68 (2002)
Kakee A, Terasaki T, Sugiyama Y, "Brain efflux index as a novel method of
analyzing
efflux transport at the blood- brain barrier," J. Pharmacol. Exp. Ther.
277:1550-1559
(1996)
Kakee A, Terasaki T, Sugiyama Y, "Selective brain to blood efflux transport of
para-
aminohippuric acid across the blood brain barrier: in vivo evidence by use of
the brain
efflux index method," J. Pharmacol. Exp. Ther. 283:1018-1025 (1997)
Takasawa K, Terasaki T, Suzuki H, Sugiyama Y, "In vivo evidence for carrier-
mediated
efflux transport of 39-azido-39-deoxythymidine and 29,39-dideoxyinosine across
the
blood-brain baxrier via a probenecid-sensitive transport system," J.
Pharmacol. Exp. Ther.
281:369-375 (1997)
Hosoya K, Sugawara M, Asaba H, Terasaki T, "Blood-brain barrier produces
significant
2 0 efflux of L-aspartic acid, but not D-aspartic acid: in vivo evidence using
the brain efflux
index method," J. Neurochem. 73:1206-1211 (1999)
Boado RJ, "Antisense delivery through the blood brain barrier," Adv. Drug.
Del. Rev.
15:73-107 (1995)
SUMMARY OF THE INVENTION
It is an object of some aspects of the present invention to provide improved
methods and apparatus for delivery of compounds to the brain, particularly
through the
BBB.
It is also an object of some aspects of the present invention to provide such
methods and apparatus as can be employed to deliver such compounds through the
BBB
3 0 with a minimally invasive approach.
It is a further object of some aspects of the present invention to provide
such
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methods and apparatus as can facilitate delivery of large molecular weight
compounds
through the BBB.
It is yet a further object of some aspects of the present invention to provide
cost-
effective methods and apparatus for delivery of compounds through the BBB.
It is still a further object of some aspects of the present invention to
provide
improved methods and apparatus for remedying or modifying neurological
activities and
disorders via delivery of compounds through the BBB.
It is also a further object of some aspects of the present invention to
modulate
cerebral blood flow.
It is an additional object of some aspects of the present invention to provide
improved methods and apparatus for treating and/or preventing neurological
diseases,
whose prognosis and evolution of pathological symptoms are influenced .by
cerebral
blood flow.
It is still an additional object of some aspects of the present invention to
provide
improved methods and apparatus for treating andlor preventing Alzheimer's
disease.
It is also an object of some aspects of the present invention to provide
improved
methods and apparatus for diagnosing neurological diseases.
It is a further object of some aspects of the present invention to provide
improved
methods and apparatus for diagnosing Alzheimer's disease.
2 o It is yet a further object of some aspects of the present invention to
provide
implantable apparatus which affects a properly of the brain, without actually
being
implanted in the brain.
It is still a further object of some aspects of the present invention to
provide
methods which affect a property of the brain without the use of implantable
apparatus.
It is also a further object of some aspects of the present invention to affect
a
property of the brain by using the neuroexcitatory and/or neuroinhibitory
effects of
odorants on nerves in the head.
These and other objects of the invention will become more apparent from the
description of preferred embodiments thereof provided hereinbelow.
3 o In preferred embodiments of the present invention, an electrical
stimulator drives
current into the sphenopalatine ganglion (SPG) or into related neuroanatomical
structures,
including neural tracts originating or reaching the SPG, including outgoing
and incoming
parasympathetic and sympathetic tracts and other parasympathetic centers.
Typically, the
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stimulator drives the current in order to control and/or modify SPG-related
behavior, e.g.,
in order to induce changes in cerebral blood flow and/or to modulate
permeability of the
blood-brain barrier (BBB). These embodiments may be used in many medical
applications, such as, by way of illustration and not limitation, (a) the
treatment of
cerebrovascular disorders such as stroke, (b) the treatment of migraine,
cluster and other
types of headaches, or (c) the facilitation of drug transport across the BBB.
In the specification of the present patent application, unless indication to
the
contrary is stated, stimulation of the SPG is to be understood to
alternatively or
additionally include stimulation of one or more of the following nerves or
ganglions:
~ an anterior ethmoidal nerve;
~ a posterior ethmoidal nerve;
~ a communicating branch between the anterior ethmoidal nerve and the
SPG (retro orbital branch);
~ a communicating branch between the posterior ethmoidal nerve and
the SPG (retro orbital branch)
~ a nerve of the pterygoid canal (also called a vidian nerve), such as a
greater superficial
~ a petrosal nerve (a preganglionic parasympathetic nerve) or a lesser
deep petrosal nerve (a postganglionic sympathetic nerve);
2 0 ~ a greater palatine nerve;
~ a lesser palatine nerve;
~ a sphenopalatine nerve;
~ a communicating branch between the maxillary nerve and the
sphenopalatine ganglion;
2 5 ~ a nasopalatine nerve;
~ a posterior nasal nerve;
~ an infraorbital nerve;
~ an otic ganglion;
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~ an afferent fiber going into the otic ganglion; and/or
~ an efferent fiber going out of the otic ganglion.
It is to be appreciated that, whereas some preferred embodiments of the
present
invention are described with respect to driving current into the SPG or into
neural
structures directly xelated thereto, the scope of the present invention
includes driving
current into other sites in the brain which upon stimulation modulate cerebral
blood flow
or modulate permeability properties of the BBB, as appropriate for a given
application.
It is also to be appreciated that electrical "stimulation," as provided by
preferred
embodiments of the present invention, is meant to include substantially any
form of
current application to designated tissue, even when the current is configured
to block or
inhibit the activity of nerves.
It is further to be appreciated that implantation and stimulation sites,
methods of
implantation, and parameters of stimulation are described herein by way of
illustration
and not limitation, and that the scope of the present invention includes other
possibilities
which would be obvious to someone of ordinary skill in the art who has read
the present
patent application.
It is yet further to be appreciated that while preferred embodiments of the
invention are generally described herein with respect to electrical
transmission of power
and electrical stimulation of tissue, other modes of energy transport may be
used as well.
2 0 Such energy includes, but is not limited to, direct or induced
electromagnetic energy, RF
transmission, ultrasonic transmission, optical power, and low power laser
energy {via, for
example, a fiber optic cable).
It is additionally to be appreciated that whereas preferred embodiments of the
present invention are described with respect to application of electrical
currents to tissue,
2 5 this is to be understood in the context of the present patent application
and in the claims as
being substantially equivalent to applying an electrical field, e.g., by
creating a voltage
drop between two electrodes.
The SPG is a neuronal center located in the brain behind the nose. It consists
of
parasympathetic neurons innervating the middle cerebral and anterior cerebral
lumens, the
3 o facial skin blood vessels, and the lacrimal glands. Activation of this
ganglion is believed
to cause vasodilation of these vessels. A second effect of such stimulation is
the opening
of pores in the vessel walls, causing plasma protein extravasation {PPE). This
effect
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allows better transport of molecules from within these blood vessels to
surrounding tissue.
The middle and anterior cerebral arteries provide the majority of the blood
supply
to the cerebral hemispheres, including the frontal and parietal lobes in their
entirety, the
insula and the limbic system, and significant portions of the following
structures: the
temporal lobes, internal capsule, basal ganglia and thalamus. These structures
are
involved in many of the neurological and psychiatric diseases of the brain,
and preferred
embodiments of the present invention are directed towards providing improved
blood
supply and drug delivery to these structures.
There is also animal evidence for the presence of SPG-originated
parasympathetic
innervation in the posterior cerebral and basilar arteries. Consistent with
the assumption
that this is also the case in humans, many regions of the human brain are
within the reach
of treatments provided by preferred embodiments of the present invention, as
described
hereinbelow.
Currently the SPG is a target of manipulation in clinical medicine, mostly in
attempted treatments of severe headaches such as cluster headaches. The
ganglion is
blocked either on a short-term basis, by applying lidocaine, or permanently,
by ablation
with a radio frequency probe. In both cases the approach is through the
nostrils. In some
preferred embodiments of the present invention, similar methods for
approaching the SPG
are utilized, to enable the electrical stimulation or electrical blocking
thereof.
2 0 According to a preferred embodiment of the instant invention, a method and
apparatus are provided to enhance delivery of therapeutic molecules across the
BBB by
stimulation of the SPG and/or its outgoing parasympathetic tracts and/or
another
parasympathetic center. The apparatus typically stimulates the parasympathetic
nerve
fibers of the SPG, thereby inducing the middle and anterior cerebral arteries
to dilate, and
2 5 also causing the walls of these cerebral arteries to become more permeable
to large
molecules. In this manner, the movement of large pharmaceutical molecules from
within
blood vessels to the cerebral tissue is substantially increased. Preferably,
therefore, this
method can serve as a neurological drug delivery facilitator, without the
sacrifices in
molecular weight required by techniques of the prior art.
3 0 Advantageously (and even in the absence of BBB permeability changes),
patients
with these and other disorders are generally helped by the vasodilation
secondary to
stimulation of the SPG, and the resultant improvement in oxygen supply to
neurons and
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other tissue. For some applications, this treatment is given on a long-term
basis, e.g., in
the chronic treatment of Alzheimer's patients. For other applications, the
treatment is
performed on a short-term basis, e.g., to minimize the damage following an
acute stroke
event and initiate neuronal and therefore functional rehabilitation.
Alternatively or additionally, the changes induced by electrical stimulation
as
described hereinabove are achieved by presenting odorants to an air passage of
a patient,
such as a nasal cavity or the throat. There is animal evidence that some
odorants, such as
propionic acid, cyclohexanone, and amyl acetate, significantly increase
cortical blood
flow when presented to the nasal cavity. This has been interpreted by some
researchers
as evidence that these odorants (e.g., environmental pollutants) may be
involved in the
formation of various headaches by increasing cerebral blood flow. The temporal
profile
and other quantitative characteristics of such odorant stimulation are
believed by the
present inventors to have a mechanism of action that has a neuroanatomical
basis
overlapping with that of the electrical stimulation of the SPG. Furthermore,
experimental
animal evidence collected by the inventors and described in a US provisional
patent
application to Shalev and Gross entitled, "SPG stimulation," filed March 28,
2002, which
is assigned to the assignee of the present invention and is incorporated
herein by
reference, suggest a correlation between the mechanisms of increasing cerebral
blood
flow and increased cerebrovascular permeability. It is hypothesized that such
increased
2 0 cerebral blood flow caused by odorants is a result of stimulation of
parasympathetic
andlor trigeminal fibers. These fibers may mediate cerebral blood flow changes
directly,
by communicating with the SPG, or by some other mechanism. It is also
hypothesized
that these odorants stimulate via reflex arcs the SPG or other autonomic
neural structures
that innervate the cerebrovascular system. Therefore, the inventors
hypothesize, odorant
2 5 "stimulation" may increase cerebral blood flow in general, and cortical
blood flow in
particular, by some or all of the same mechanisms as electrical stimulation,
as described
hereinabove. Alternatively or additionally, odorants may cause increased
cortical blood
flow by other mechanisms, such as by entering the blood stream and reaching
the affected
blood vessels in the brain or by parasympathetic stimulation via the olfactory
nerve. In
3 0 addition to the effect on cerebral blood flow, the introduction of
odorants into an air
passage is also believed by the inventors to induce an increase in the
permeability of the
anterior two thirds of the cerebrovascular system to circulating agents of
various sizes,
i.e. to increase the permeability of the BBB. Similarly, presenting certain
other odorants
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to an air passage decreases cerebral blood flow and decreases the permeability
of the
BBB.
Odorants that may increase or decrease cerebral blood flow and/or the
permeability of the BBB include, but are not limited to, propionic acid,
cyclohexanone,
amyl acetate, acetic acid, citric acid, carbon dioxide, sodium chloride,
ammonia, menthol,
alcohol, nicotine, piperine, gingerol, zingerone, allyl isothiocyanate,
cinnamaldehyde,
cuminaldehyde, 2-propenyl/2-phenylethyl isothiocyanate, thymol, and
eucalyptol.
According to a preferred embodiment of the instant invention, a method is
provided to enhance delivery of therapeutic molecules across the BBB by
presenting an
odorant to an air passage of a patient, such as a nasal cavity or the throat.
In a preferred
application, this method serves as a neurological drug delivery facilitator.
The odorant is
preferably presented using apparatus known in the art, such as aqueous spray
nasal
inhalers; metered dose nasal inhalers; or air-dilution olfactometers.
Alternatively or
additionally, the odorant is presented by means of an orally-dissolvable
capsule that
releases the active odorants upon contact with salivary liquids. The odorants
reach the
appropriate neural structures and induce vasodilatation, vasoconstriction
and/or
cerebrovascular permeability changes. Delivery of a drug can be achieved by
mixing the
drug with the odorant; by intravenously, intraperitoneally, or intramuscularly
administering the drug, or by other delivery methods known in the art. For
some
2 0 applications, it is desirable to combine a local analgesic with the
odorant in order to
diminish any possible sensation of pain or discomfort that may directly or
indirectly (e.g.,
via a reflex arc) accompany the odorant action upon nerves in the head. For
example,
preventing neural transmission in the neighboring pain fibers may be performed
as a "pre-
odorant" treatment, by topical administration of capsaicin together with a
local analgesic
for several days prior to the use of odorant stimulation. In this manner, the
odorants
typically induce the SPG-related response with a reduced or eliminated
sensation of pain
or discomfort.
Alternatively or additionally, a method is provided for increasing or reducing
cortical blood flow and/or inducing or inhibiting vasodilation (even in the
absence of
3 0 BBB permeability changes) by presenting an odorant to an air passage of a
patient, such
as a nasal cavity or the throat, for treatment of a condition. Patients with
the
aforementioned disorders and other disorders are generally helped by
vasodilation and the
resultant improvement in oxygen supply to neurons and other tissue. For some
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applications, this treatment is given on a long-term basis, e.g., in the
chronic treatment of
Alzheimer's patients. For other applications, the treatment is performed on a
short-term
basis, e.g., to minimize the damage following an acute stroke event and
initiate neuronal
and therefore functional rehabilitation. Alternatively or additionally, the
method
provided above can be used for diagnostic purposes or in conjunction with
other
diagnostic methods and/or apparatus known in the art, in order to enhance
diagnostic
results, reduce procedure risk, reduce procedure time, or otherwise improve
such
diagnostic procedures and/or diagnostic results. For example, methods and
apparatus
described herein may be used to increase the uptake into the brain of a radio-
opaque
material, in order to facilitate a CT scan.
In general, it is believed that substantially all pharmacological treatments
aimed at
cerebral cells for neurological and psychiatric disorders are amenable for use
with these
embodiments of the present invention. In particular, these embodiments may be
adapted
for use in the treatment of disorders such as brain tumors, epilepsy,
Parkinson's disease,
Alzheimer's disease, multiple sclerosis, schizophrenia, depression, stress,
anxiety,
disorders requiring the administration of various growth factors, and other
CNS disorders
that are directly or indirectly affected by changes in cerebral blood flow or
by BBB
permeability changes.
There is therefore provided, in accordance with a preferred embodiment of the
2 0 present invention, apparatus for modifying a property of a brain of a
patient, including:
one or more electrodes, adapted to be applied to a site selected from a group
of
sites consisting of a sphenopalatine ganglion (SPG) of the patient and a
neural tract
originating in or leading to the SPG; and
a control unit, adapted to drive the one or more electrodes to apply a current
to the
2 5 site capable of inducing an increase in permeability of a blood-brain
barrier (BBB) of the
patient.
There is also provided, in accordance with a preferred embodiment of the
present
invention, apparatus for modifying a property of a brain of a patient,
including:
one or more electrodes, adapted to be applied to a site selected from a group
of
3 0 sites consisting of a sphenopalatine ganglion (SPG) of the patient and a
neural tract
originating in or leading to the SPG; and
a control unit, adapted to drive the one or more electrodes to apply a current
to the
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site capable of inducing an increase in cerebral blood flow of the patient.
There is further provided, in accordance with a preferred embodiment of the
present invention, apparatus for modifying a property of a brain of a patient,
including:
one or more electrodes, adapted to be applied to a site selected from a group
of
sites consisting of: a sphenopalatine ganglion (SPG) of the patient and a
neural tract
originating in or leading to the SPG; and
a control unit, adapted to drive the one or more electrodes to apply a current
to the
site capable of inducing a decrease in cerebral blood flow of the patient.
There is still further provided, in accordance with a preferred embodiment of
the
present invention, apparatus for modifying a property of a brain of a patient,
including:
one or more electrodes, adapted to be applied to a site selected from a group
of
sites consisting of: a sphenopalatine ganglion (SPG) of the patient and a
neural tract
originating in or leading to the SPG; and
a control unit, adapted to drive the one or more electrodes to apply a current
to the
site capable of inhibiting parasympathetic activity of the SPG.
Preferably, the one or more electrodes are adapted for a period of
implantation in
the patient greater than about one month.
In a preferred embodiment, the apparatus includes a wire, adapted to connect
the
control unit to the one or more electrodes, wherein the control unit is
adapted to drive the
one or more electrodes from a position external to the patient.
Alternatively or additionally, the control unit is adapted to drive the one or
more
electrodes by wireless communication from a position external to the patient.
In a
preferred embodiment, the apparatus includes an electromagnetic coupling,
adapted to
couple the control unit and the one or more electrodes. Alternatively or
additionally, the
2 5 control unit is adapted to be in electro-optical communication with the
one or more
electrodes. Further alternatively or additionally, the control unit is adapted
to be in
electro-acoustic communication with the one or more electrodes. Still further
alternatively or additionally, the control unit is adapted to be implanted in
a nasal cavity
of the patient.
3 o Preferably, the one or more electrodes are adapted to be implanted in a
nasal
cavity of the patient. For some applications, at least one of the one or more
electrodes
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includes a flexible electrode, adapted for insertion through a nostril of the
patient and to
extend therefrom to the site.
The apparatus preferably includes at least one biosensor, adapted to measure a
physiological parameter of the patient and to generate a signal responsive
thereto. The
control unit, in turn, is preferably adapted to modify a parameter of the
applied current
responsive to the signal. As appropriate, the biosensor may include one or
more of the
following:
~ a blood flow sensor.
~ a temperature sensor.
~ a chemical sensor.
~ an ultrasound sensor.
~ transcranial Doppler (TCD) apparatus.
~ laser-Doppler apparatus.
~ a systemic blood pressure sensor.
~ an intracranial blood pressure sensor.
~ a detecting element adapted to be fixed to a cerebral blood vessel, and
wherein the
control unit is adapted to analyze the signal to detect an indication of a
change in
blood pressure indicative of a clot.
~ a kinetics sensor (in this case, the control unit is typically adapted to
analyze the
2 0 signal to detect an indication of a change in body disposition of the
patient).
~ an electroencephalographic (EEG) sensor.
~ a blood vessel clot detector.
In a preferred embodiment, the control unit is adapted to configure the
current so
as to facilitate uptake of a drug through the BBB when the permeability of the
BBB is
2 5 increased.
Alternatively or additionally, the control unit is adapted to configure the
current so
as to increase a diameter of a blood vessel and allow an embolus that is
located at a site in
the blood vessel to move from the site in the blood vessel.
Further alternatively or additionally, the control unit is adapted to drive
the one or
3 o more electrodes to apply the current responsive to an indication of
stroke.
Still further alternatively or additionally, the control unit is adapted to
drive the
one or more electrodes to apply the current responsive to an indication of
migraine of the
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patient.
There is also provided, in accordance with a preferred embodiment of the
present
invention, a method for modifying a property of a brain of a patient,
including:
selecting a site from a group of sites consisting of: a sphenopalatine
ganglion
(SPG) of the patient and a neural tract originating in or leading to the SPG;
and
applying a current to the site capable of inducing an increase in permeability
of a
blood-brain barrier (BBB) of the patient.
There is additionally provided, in accordance with a preferred embodiment of
the
present invention, a method for modifying a property of a brain of a patient,
including:
selecting a site from a group of sites consisting of: a sphenopalatine
ganglion
(SPG) of the patient and a neural tract originating in or leading to the SPG;
and
applying a current to the site capable of inducing an increase in cerebral
blood
flow of the patient.
There is yet additionally provided, in accordance with a preferred embodiment
of
the present invention, a method for modifying a property of a brain of a
patient,
including:
selecting a site from a group of sites consisting of a sphenopalatine ganglion
(SPG) of the patient and a neural tract originating in or leading to the SPG;
and
applying a current to the site capable of inducing a decrease in cerebral
blood flow
2 0 of the patient.
There is still additionally provided, in accordance with a preferred
embodiment of
the present invention, a method for modifying a property of a brain of a
patient,
including:
selecting a site from a group of sites consisting of: a sphenopalatine
ganglion
2 5 (SPG) of the patient and a neural tract originating in or leading to the
SPG; and
applying a current to the site capable of inhibiting parasympathetic activity
of the
SPG.
For some applications, the one or more electrodes are adapted for a period of
implantation in the patient less than about one week.
3 0 There is further provided, in accordance with a preferred embodiment of
the
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present invention, vascular apparatus, including:
a detecting element, adapted to be fixed to a blood vessel of a patient and to
generate a signal responsive to energy coming from the blood vessel; and
a control unit, adapted to analyze the signal so as to determine an indication
of an
embolus in the blood vessel.
Preferably, the detecting element includes an energy transmitter and an energy
receiver. For example, the energy transmitter may include an ultrasound
transmitter or a
transmitter of electromagnetic energy.
There is yet further provided, in accordance with a preferred embodiment of
the
present invention, a method for detecting, including:
fixing a detecting element to a blood vessel of a patient;
generate a signal responsive to energy coming from the blood vessel; and
analyzing the signal so as to determine an indication of an embolus in the
blood
vessel.
There is still further provided, in accordance with a preferred embodiment of
the
present invention, a method for treating Alzheimer's disease (AD), including
stimulating a
sphenopalatine ganglion (SPG) of a subject so that the concentration of a
substance in a
brain of the subject changes.
In a preferred embodiment, the stimulation causes increased clearance of the
2 0 substance from the brain. As appropriate, the substance may be one or more
of the
following:
~ amyloid;
~ tau protein;
~ PS1;
~ PS2;
~ RNA fragments;
~ cytokine;
~ a marker of neuronal death;
~ a marker of neuronal degeneration;
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~ a marker of an inflammatory process; and
~ a neurotoxic substance.
Alternatively or additionally, the substance may include DNA.
In another preferred embodiment, the stimulation causes increased clearance of
the
substance from cerebrospinal fluid (CSF). As appropriate, the substance may be
one or
more of the following:
~ amyloid;
~ tau protein;
~ PS1;
~ PS2;
~ RNA fragments;
~ cytokine;
~ a marker of neuronal death;
~ a marker of neuronal degeneration;
~ a marker of an inflammatory process; and
~ a neurotoxic substance.
Alternatively or additionally, the substance may include DNA.
There is additionally provided, in accordance with a preferred embodiment of
the
present invention, a method for treating Ahheimer's disease (AD), including:
2 0 supplying a pharmaceutical agent to blood of a subject; and
stimulating a sphenopalatine ganglion (SPG) of the subject so that the
concentration of the pharmaceutical agent in a brain of the subject increases.
As appropriate, the pharmaceutical agent may be one or more of the following:
~ a glutamate receptor antagonist;
2 5 ~ a (3-amyloid inhibitor;
~ an NMDA-receptor blocker;
~ a combination of an AD vaccine and an anti-inflammatory drug;
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~ a microglial activation modulator;
~ a cholinesterase inhibitor;
~ a stimulant of nerve regeneration;
~ a nerve growth factor;
~ a compound that stimulates production of nerve growth factor;
~ an antioxidant;
~ a hormone;
~ an inhibitor of protein tyrosine phosphatases;
~ medium chain triglycerides;
~ an endogenous protein;
~ a gene therapy agent;
~ an anti-inflanunatory drug;
~ a non-steroidal anti-inflammatory drug; and
~ an AD vaccine. More specifically, the AD vaccine may contain antibodies
against a specific protein that is characteristic of AD. Still more
specifically, the AD vaccine may contain antibodies against ~3-amyloid
andlor antibodies against tau protein.
Alternatively, the pharmaceutical agent is adapted to have an inhibitory
effect on
the derivation of (3-amyloid from amyloid precursor protein.
2 0 There is yet additionally provided, in accordance with a preferred
embodiment of
the present invention, a method for diagnosing Alzheimer's disease (AD),
including
stimulating a sphenopalatine ganglion (SPG) of a subject so that molecular
passage
increases between a central nervous system (CNS) of the subject and another
body
compartment of the subject.
2 5 Preferably, the method includes measuring a constituent of the other body
compartment. As appropriate, the other body compartment may be one of the
following:
~ blood of the subject;
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~ plasma of the subject;
~ serum ofthe subject; and
~ ascites of the subject.
There is still additionally provided, in accordance with a preferred
embodiment of
the present invention, a method for diagnosing Alzheimer's disease (AD),
including
stimulating a sphenopalatine ganglion (SPG) of a subject so that molecular
passage
increases between cerebrospinal fluid (CSF) of the subject and another body
fluid of the
subject.
Preferably, the method includes measuring a constituent of the other body
fluid.
More preferably, the method includes correlating an abnormal concentration of
the
constituent to a pathology of AD. As appropriate, the constituent may be
selected from
the group consisting of the following: a protein, a hormone, an antibody, an
electrolyte, a
neuropeptide, and an enzyme.
Alternatively or additionally, the measurement is performed by sampling a
fluid
selected from the group consisting of the following: whole blood, plasma,
serum, and
ascites. Further alternatively or additionally, the measurement is performed
by extracting
the fluid from tissue of the subject.
Optionally, the measurement may be performed by measuring more than one
constituent. In this case, a diagnostic result may be determined according to
the
2 0 interrelation between concentrations of the constituents.
There is also provided, in accordance with a preferred embodiment of the
present
invention, a method for diagnosing Alzheimer's disease (AD), including
stimulating a
sphenopalatine ganglion (SPG) of a subject so that molecular passage increases
between
cerebrospinal fluid (CSF) ofthe subject and a tissue of the subject.
2 5 Preferably, the method includes measuring a constituent of the tissue.
More
preferably, the method includes correlating an abnormal concentration of the
constituent
to a pathology of AD. As appropriate, the constituent may be selected from the
group
consisting of the following: a protein, a hormone, an antibody, an
electrolyte, a
neuropeptide, and an enzyme.
3 o Optionally, the measurement may be performed by measuring more than one
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constituent. In this case, a diagnostic result may be determined according to
the
interrelation between concentrations of the constituents.
There is further provided, in accordance with a preferred embodiment of the
present invention, a system for treating Alzheimer's disease (AD), including a
stimulator
for stimulating the sphenopalatine ganglion (SPG) of a subject, so that the
concentration
of a substance in a brain of the subject changes.
There is yet further provided, in accordance with a preferred embodiment of
the
present invention, a pharmaceutical agent delivery system for treating
Alzheimer's disease
(AD), including:
a pharmaceutical agent supplied to a body of a subject for delivery to a brain
of the
subject via blood of said subject; and
a stimulator for stimulating a sphenopalatine ganglion (SPG) of the subject,
so that
the concentration of the pharmaceutical agent in the brain increases.
There is still further provided, in accordance with a preferred embodiment of
the
present invention, a system for diagnosing Alzheimer's disease (AD), including
a
stimulator for stimulating a sphenopalatine ganglion (SPG) of a subject, so
that molecular
passage increases between a CNS of the subject and another body compartment of
the
subject.
There is additionally provided, in accordance with a preferred embodiment of
the
2 0 present invention, a system for diagnosing Alzheimer's disease (AD),
including a
stimulator for stimulating a sphenopalatine ganglion (SPG) of a subject, so
that molecular
passage increases between cerebrospinal fluid (CSF) of the subject and another
body fluid
of the subject.
There is yet additionally provided, in accordance with a preferred embodiment
of
the present invention, a system for diagnosing Alzheimer's disease (AD),
including a
stimulator for stimulating a sphenopalatine ganglion (SPG) of a subject, so
that molecular
passage increases between cerebrospinal fluid (CSF) of the subject and a
tissue of the
subject.
There is therefore provided, in accordance with an embodiment of the present
3 0 invention, a method for treating Alzheimer's disease (AD), including:
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stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by
applying
an electrical signal to the SPG-related tissue, the SPG-related tissue
selected from: an
SPG of the subject and nerve fibers of the subject which are directly
anatomically
connected to the SPG; and
configuring the stimulation so as to cause an increase in clearance of an AD-
related constituent of a central nervous system (CNS) of the subject, from a
brain of the
subject to a systemic blood circulation of the subject, so as to treat the AD.
There is further provided, in accordance with an embodiment of the present
invention, a method for treating Alzheimer's disease (AD), including:
stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by
presenting an odorant to an air passage of the subject, the SPG-related tissue
selected
from: an SPG of the subject and nerve fibers of the subject which are directly
anatomically connected to the SPG; and
configuring the stimulation so as to cause an increase in clearance of an AD-
related constituent of a central nervous system (CNS) of the subject, from a
brain of the
subject to a systemic blood circulation of the subject, so as to treat the AD.
There is still further provided, in accordance with an embodiment of the
present
invention, a method for treating Alzheimer's disease (AD), including:
stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by
applying
2 0 an electrical signal to the SPG-related tissue, the SPG-related tissue
selected from: an
SPG of the subject and nerve fibers of the subject which are directly
anatomically
connected to the SPG; and
configuring the stimulation so as to cause an increase in clearance of an AD-
related constituent of a central nervous system (CNS) of the subject, from
cerebrospinal
fluid (CSF) of the subject to a systemic blood circulation of the subject, so
as to treat the
AD.
There is yet further provided, in accordance with an embodiment of the present
invention, a method for treating Alzheimer's disease (AD), including:
stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by
3 0 presenting an odorant to an air passage of the subject, the SPG-related
tissue selected
from: an SPG of the subject and nerve fibers of the subject which are directly
anatomically connected to the SPG; and
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configuring the stimulation so as to cause an increase in clearance of an AD-
related constituent of a central nervous system (CNS) of the subject, from
cerebrospinal
fluid (CSF) of the subject to a systemic blood circulation of the subject, so
as to treat the
AD.
In an embodiment, stimulating the SPG-related tissue includes directly
stimulating
the SPG.
For some applications, the AD-related constituent includes an inflammatory-
related constituent, tau protein, PS1, PS2, a DNA fragment, an RNA fragment, a
cytokine, a marker of neuronal death or degeneration, a marker of an
inflammatory
process, a neurotoxic substance, amyloid protein, an amyloid protein selected
from the list
consisting of wild amyloid protein and mutated amyloid protein, and/or an
amyloid
protein selected from the list consisting of: fragmented amyloid protein and
whole
amyloid protein, and configuring the stimulation includes configuring the
stimulation so
as to cause the increase in the clearance of the inflammatory-related
constituent, tau
protein, PS l, PS2, DNA fragment, RNA fragment, cytokine, marker of neuronal
death or
degeneration, marker of an inflammatory process, neurotoxic substance, amyloid
protein,
amyloid protein selected from the list consisting of: wild amyloid protein and
mutated
amyloid protein, and/or amyloid protein selected from the list consisting of:
fragmented
amyloid protein and whole amyloid protein.
2 0 There is also provided, in accordance with an embodiment of the present
invention, a method for treating Alzheimer's disease (AD), including:
supplying a pharmaceutical agent to a systemic blood circulation of a subject;
stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by
applying an electrical signal to the SPG-related tissue, the SPG-related
tissue selected
from: an SPG of the subject and nerve fibers of the subject which are directly
anatomically connected to the SPG; and
configuring the stimulation so as to cause an increase in passage of the
pharmaceutical agent from the systemic blood circulation into a central
nervous system
(CNS) of the subj ect, so as to treat the AD.
3 0 There is additionally provided, in accordance with an embodiment of the
present
invention, a method for treating Alzheimer's disease (AD), including:
supplying a pharmaceutical agent to a systemic blood circulation of a subject;
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stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by
presenting an odorant to an air passage of the subject, the SPG-related tissue
selected
from: an SPG of the subject and nerve fibers of the subject which are directly
anatomically connected to the SPG; and
configuring the stimulation so as to cause an increase in passage of the
pharmaceutical agent from the systemic blood circulation into a central
nervous system
(CNS) of the subject, so as to treat the AD.
In an embodiment, supplying the pharmaceutical agent includes administering
the
pharmaceutical agent to the systemic blood circulation using a technique
selected from the
list consisting of per-oral administration, intravenous administration, infra-
arterial
administration, intraperitoneal administration, subcutaneous administration,
and
intramuscular administration.
For some applications, the pharmaceutical agent includes a glutamate receptor
antagonist, an NMDA receptor blocker, an agent having an inhibitory effect on
derivation
of j3-amyloid from amyloid precursor protein, a cholinesterase inhibitor, a
stimulant of
nerve regeneration, a nerve growth factor, a compound that stimulates
production of nerve
growth factor, a microglial activation modulator, an antioxidant, a hormone,
an inhibitor
of protein tyrosine phosphatases, a medium chain triglyceride, a gene therapy
agent, a (3-
amyloid inhibitor, an endogenous protein, an anti-inflammatory agent, a non-
steroidal
2 0 anti-inflammatory drug (NSA>I7), or a pharmaceutical agent selected from
the list
consisting of an AD vaccine, a component of an AD vaccine, and a derivative of
an AD
vaccine (for example, the selected pharmaceutical agent including (a) an anti-
inflammatory drug, (b) antibodies against a specific protein that is
characteristic of AD,
(c) antibodies against (3-amyloid, or (d) antibodies against tau protein), and
configuring
2 5 the stimulation includes configuring the stimulation so as to cause the
increase in the
passage of the pharmaceutical agent.
In an embodiment, supplying the pharmaceutical agent includes administering
the
pharmaceutical agent for inhalation by the subject. For example, administering
the
pharmaceutical agent for inhalation by the subject may include administering
the
3 0 pharmaceutical agent mixed with the odorant.
There is still additionally provided, in accordance with an embodiment of the
present invention, a method for treating Alzheimer's disease (AD), including:
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stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by
applying an electrical signal to the SPG-related tissue, the SPG-related
tissue selected
from: an SPG of the subject and nerve fibers of the subject which are directly
anatomically connected to the SPG; and
configuring the stimulation so as to cause an increase in cerebral blood flow
(CBF) of the subject, so as to treat the AD.
There is yet additionally provided, in accordance with an embodiment of the
present invention, a method for treating Alzheimer's disease (AD), including:
stimulating sphenopalatine ganglion (SPG)-related tissue of the subject by
presenting an odorant to an air passage of the subject, the 5PG-related tissue
selected
from: an SPG of the subject and nerve fibers of the subject which are directly
anatomically connected to the SPG; and
configuring the stimulation so as to cause an increase in cerebral blood flow
(CBF) of the subject, so as to treat the AD.
In an embodiment, configuring the stimulation includes configuring the
stimulation so as to cause an improvement in a metabolic state of a central
nervous system
(CNS) ofthe subject.
There is also provided, in accordance with an embodiment of the present
invention, a method for diagnosing Alzheimer's disease (AD), including:
2 0 stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by
applying
an electrical signal to the SPG-related tissue, the SPG-related tissue
selected from: an
SPG of the subject and nerve fibers of the subject which are directly
anatomically
connected to the SPG; and
configuring the stimulation so as to cause an increase in molecular passage
between a central nervous system (CNS) of the subject and another body
compartment of
the subject, so as to facilitate a diagnosis of the AD.
There is additionally provided, in accordance with an embodiment of the
present
invention, a method for diagnosing Alzheimer's disease (AD), including:
stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by
3 0 presenting an odorant to an air passage of the subject, the SPG-related
tissue selected
from: an SPG of the subject and nerve fibers of the subject which are directly
anatomically connected to the SPG; and
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configuring the stimulation so as to cause an increase in molecular passage
between a central nervous system (CNS) of the subject and another body
compartment of
the subject, so as to facilitate a diagnosis of the AD.
In an embodiment, the method includes measuring a constituent of the other
body
compartment.
For some applications, the other body compartment includes a systemic blood
circulation of the subject, and configuring the stimulation includes
configuring the
stimulation so as to cause the increase in molecular passage between the CNS
and the
systemic blood circulation. Alternatively or additionally, the other body
compartment
includes plasma of the subject, and configuring the stimulation includes
configuring the
stimulation so as to cause the increase in molecular passage between the CNS
and the
plasma. Further alternatively or additionally, the other body compartment
includes serum
of the subject, and configuring the stimulation includes configuring the
stimulation so as
to cause the increase in molecular passage between the CNS end the serum.
Still further
alternatively or additionally, the other body compartment is ascites of the
subject, and
configuring the stimulation includes configuring the stimulation so as to
cause the
increase in molecular passage between the GNS and the ascites.
There is yet additionally provided, in accordance with an embodiment of the
present invention, a method for diagnosing Alzheimer's disease (AD),
including:
stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by
applying
an electrical signal to the SPG-related tissue, the SPG-related tissue
selected from: an
SPG of the subject and nerve fibers of the subject which are directly
anatomically
connected to the SPG; and
configuring the stimulation so as to cause an increase in molecular passage
2 5 between cerebrospinal fluid (CSF) of the subject and another body fluid of
the subject, so
as to facilitate a diagnosis of the AD.
There is still additionally provided, in accordance with an embodiment of the
present invention, a method for diagnosing Alzheimer's disease (AD),
including:
stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by
3 0 presenting an odorant to an air passage of the subject, the SPG-related
tissue selected
from: an SPG of the subject and nerve fibers of the subject which are directly
anatomically connected to the SPG; and
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configuring the stimulation so as to cause an increase in molecular passage
between cerebrospinal fluid (CSF) of the subject and another body fluid of the
subject, so
as to facilitate a diagnosis of the AD.
In an embodiment, the method includes measuring a constituent of the other
body
fluid.
In an embodiment, the method includes correlating an abnormal concentration of
the constituent to a pathology of AD.
For some applications, the constituent is selected from the group consisting
of: a
protein, a hormone, an antibody, an electrolyte, a neuropeptide, and an
enzyme, and
measuring the constituent includes measuring the selected constituent.
Alternatively or
additionally, the other body fluid is selected from the list consisting of
whole blood,
plasma, serum, and ascites, and measuring the constituent includes sampling
the selected
fluid.
Measuring the constituent typically includes extracting the other body fluid
from
tissue of the subject, and, for some applications, measuring a plurality of
constituents. In
an embodiment, the method includes determining a diagnostic result according
to the
interrelation between concentrations of the constituents.
There is also provided, in accordance with an embodiment of the present
invention, a method for diagnosing Alzheimer's disease (AD), including:
2 0 stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by
applying
an electrical signal to the SPG-related tissue, the SPG-related tissue
selected from: an
SPG of the subject and nerve fibers of the subject which are directly
anatomically
connected to the SPG; and
configuring the stimulation so as to cause an increase in molecular passage
between cerebrospinal fluid (CSF) of the subject and a tissue of the subject,
so as to
facilitate a diagnosis of the AD.
There is further provided, in accordance with an embodiment of the present
invention, a method for diagnosing Alzheimer's disease (AD), including:
stimulating sphenopalatine ganglion (SPG)-related tissue of a subject by
3 0 presenting an odorant to an air passage of the subject, the SPG-related
tissue selected
from: an SPG of the subject and nerve fibers of the subject which are directly
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anatomically connected to the SPG; and
configuring the stimulation so as to cause an increase in molecular passage
between cerebrospinal fluid (CSF) of the subject and a tissue of the subject,
so as to
facilitate a diagnosis of the AD.
For some applications, the method includes measuring a constituent of the
tissue
and/or correlating an abnormal concentration of the constituent to a pathology
of AD.
In accordance with an embodiment of the present invention, the constituent is
selected from the group consisting of a protein, a hormone, an antibody, an
electrolyte, a
neuropeptide, and an enzyme, and measuring the constituent includes measuring
the
selected constituent.
In an embodiment, measuring the constituent includes measuring a plurality of
constituents of the tissue. In this case, for some applications, the method
includes
determining a diagnostic result according to the interrelation between
concentrations of
the constituents of the tissue.
There is still further provided, in accordance with an embodiment of the
present
invention, a method for treating Alzheimer's disease (AD), including:
applying an electrical signal to at least one site of a subject, the site
selected from
the Iist consisting of a sphenopalatine ganglion (SPG) of the subject, an
anterior
ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a
2 0 communicating branch between an anterior ethmoidal nerve and a retro-
orbital branch of
an SPG of the subject, a communicating branch between a posterior ethmoidal
nerve and
a retro-orbital branch of an SPG of the subject, a greater palatine nerve of
the subject, a
lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a
communicating branch between a maxillary nerve and an SPG of the subject, a
nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an
infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent fiber going
into the otic
ganglion of the subject, an efferent fiber going out of the otic ganglion of
the subject, a
vidian nerve of the subject, a greater superficial petrosal nerve of the
subject, and a lesser
deep petrosal nerve of the subject; and
3 0 configuring the signal so as to cause an increase in clearance of an AD-
related
constituent of a central nervous system (CNS) of the subject, from a brain of
the subject to
a systemic blood circulation of the subject, so as to treat the AD.
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There is yet further provided, in accordance with an embodiment of the present
invention, a method for treating Alzheimer's disease (AD), including
presenting an
odorant to an air passage of a subject, the odorant having been selected for
presentation to
the air passage because it is such as to cause an increase in clearance of an
AD-related
constituent of a central nervous system (CNS) of the subject from
cerebrospinal fluid
(CSF) of the subject to a systemic blood circulation of the subject, so as to
treat the AD.
There is also provided, in accordance with an embodiment of the present
invention, a method for treating Alzheimer's disease (AD), including:
supplying a pharmaceutical agent to a systemic blood circulation of a subject;
applying an electrical signal to at least one site of a subject, the site
selected from
the list consisting of a sphenopalatine ganglion (SPG) of the subject, an
anterior
ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a retro-orbital
branch of
an SPG of the subject, a communicating branch between a posterior ethmoidal
nerve and
a retro-orbital branch of an SPG of the subject, a greater palatine nerve of
the subject, a
lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a
communicating branch between a maxillary nerve and an SPG of the subject, a
nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an
infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent fiber going
into the otic
2 0 ganglion of the subject, an efferent fiber going out of the otic ganglion
of the subject, a
vidian nerve of the subject, a greater superficial petrosal nerve of the
subject, and a lesser
deep petrosal nerve of the subject; and
configuring the signal so as to cause an increase in passage of the
pharmaceutical
agent from the systemic blood circulation into a central nervous system (CNS)
of the
subject, so as to treat the AD.
There is additionally provided, in accordance with an embodiment of the
present
invention, a method for treating Alzheimer's disease (AD), including:
supplying a pharmaceutical agent to a systemic blood circulation of a subject;
and
presenting an odorant to an air passage of the subject, the odorant having
been
3 o selected for presentation to the air passage because it is such as to
cause an increase in
passage of the pharmaceutical agent from the systemic blood circulation into a
central
nervous system (CNS) of the subject, so as to treat the AD.
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There is still additionally provided, in accordance with an embodiment of the
present invention, a method for treating Alzheimer's disease (AD), including:
applying an electrical signal to at least one site of a subject, the site
selected from
the list consisting of a sphenopalatine ganglion (SPG) of the subject, an
anterior
ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a retro-orbital
branch of
an SPG of the subject, a communicating branch between a posterior ethmoidal
nerve and
a retro-orbital branch of an SPG of the subject, a greater palatine nerve of
the subject, a
lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a
communicating branch between a maxillary nerve and an SPG of the subject, a
nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an
infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent fiber going
into the otic
ganglion of the subject, an efferent fiber going out of the otic ganglion of
the subject, a
vidian nerve of the subject, a greater superficial petrosal nerve of the
subject, and a lesser
deep petrosal nerve of the subject; and
configuring the signal so as to cause an increase in cerebral blood flow (CBF)
of
the subject, so as to treat the AD.
There is yet additionally provided, in accordance with an embodiment of the
present invention, a method for treating Alzheimer's disease (AD), including
presenting
2 0 an odorant to an air passage of the subject, the odorant having been
selected for
presentation to the air passage because it is such as to cause an increase in
cerebral blood
flow (CBF) of the subject, so as to treat the AD.
There is also provided, in accordance with an embodiment of the present
invention, a method for diagnosing Alzheimer's disease (AD), including:
2 5 applying an electrical signal to at least one site of a subject, the site
selected from
the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an
anterior
ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a retro-orbital
branch of
an SPG of the subject, a communicating branch between a posterior ethmoidal
nerve and
3 0 a retro-orbital branch of an SPG of the subject, a greater palatine nerve
of the subject, a
lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a
communicating branch between a maxillary nerve and an SPG of the subject, a
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nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an
infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent fiber going
into the otic
ganglion of the subject, an efferent fiber going out of the otic ganglion of
the subject, a
vidian nerve of the subject, a greater superficial petrosal nerve of the
subject, and a lesser
deep petrosal nerve of the subject; and
configuring the signal so as to cause an increase in molecular passage between
a
central nervous system (CNS) of the subject and another body compartment of
the
subject, so as to facilitate a diagnosis of the AD.
There is further provided, in accordance with an embodiment of the present
invention, a method for diagnosing Alzheimer's disease (AD), including
presenting an
odorant to an air passage of the subject, the odorant having been selected for
presentation
to the air passage because it is such as to cause an increase in molecular
passage between
a central nervous system (CNS) of the subject and another body compartment of
the
subject, so as to facilitate a diagnosis of the AD.
There is still further provided, in accordance with an embodiment of the
present
invention, a method for diagnosing Alzheimer's disease (AID), including:
applying an electrical signal to at least one site of a subject, the site
selected from
the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an
anterior
ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a
2 0 communicating branch between an anterior ethmoidal nerve and a retro-
orbital branch of
an SPG of the subject, a communicating branch between a posterior ethmoidal
nerve and
a retro-orbital branch of an SPG of the subject, a greater palatine nerve of
the subject, a
lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a
communicating branch between a maxillary nerve and an SPG of the subject, a
nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an
infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent fiber going
into the otic
ganglion of the subject, an efferent fiber going out of the otic ganglion of
the subject, a
vidian nerve of the subject, a greater superficial petrosal nerve of the
subject, and a lesser
deep petrosal nerve of the subject; and
3 0 configuring the signal so as to cause an increase in molecular passage
between
cerebrospinal fluid (CSF) of the subject and another body fluid of the
subject, so as to
facilitate a diagnosis of the AD.
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There is yet further provided, in accordance with an embodiment of the present
invention, a method for diagnosing Alzheimer's disease (AD), including
presenting an
odorant to an air passage of the subject, the odorant having been selected for
presentation
to the air passage because it is such as to cause an increase in molecular
passage between
cerebrospinal fluid (CSF) of the subject and another body fluid of the
subject, so as to
facilitate a diagnosis of the AD.
There is also provided, in accordance with an embodiment of the present
invention, a method for diagnosing Alzheimer's disease (AD), including:
applying an electrical signal to at least one site of a subject, the site
selected from
the list consisting of: a sphenopalatine ganglion (SPG) of the subject, an
anterior
ethmoidal nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch between an anterior ethmoidal nerve and a retro-orbital
branch of
an SPG of the subject, a communicating branch between a posterior ethrnoidal
nerve and
a retro-orbital branch of an SPG of the subject, a greater palatine nerve of
the subject, a
lesser palatine nerve of the subject, a sphenopalatine nerve of the subject, a
communicating branch between a maxillary nerve and an SPG of the subject, a
nasopalatine nerve of the subject, a posterior nasal nerve of the subject, an
infraorbital
nerve of the subject, an otic ganglion of the subject, an afferent fiber going
into the otic
ganglion of the subject, an efferent fiber going out of the otic ganglion of
the subject, a
2 o vidian nerve of the subject, a greater superficial petrosal nerve of the
subject, and a lesser
deep petrosal nerve of the subject; and
configuring the signal so as to cause an increase in molecular passage between
cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to
facilitate a
diagnosis of the AD.
2 5 There is additionally provided, in accordance with an embodiment of the
present
invention, a method for diagnosing Alzheimer's disease (AD), including
presenting an
odorant to an air passage of the subject, the odorant having been selected for
presentation
to the air passage because it is such as to cause an increase in molecular
passage between
cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to
facilitate a
3 0 diagnosis of the AD.
In an embodiment, the method includes presenting in association with the
odorant
an analgesic in a dosage configured to reduce a sensation associated with the
presenting of
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the odorant. For some applications, the air passage includes a nasal cavity or
a throat of
the patient, and presenting the odorant includes presenting the odorant to the
nasal cavity
or the throat.
For some applications, the odorant is selected from the list consisting of
propionic
acid, cyclohexanone, and amyl acetate, and presenting the odorant includes
presenting the
selected odorant.
Alternatively or additionally, the odorant is selected from the list
consisting of:
acetic acid, citric acid, carbon dioxide, sodium chloxide, and ammonia, and
presenting the
odorant includes presenting the selected odorant.
Further alternatively or additionally, the odorant is selected from the list
consisting
of: menthol, alcohol, nicotine, piperine, gingerol, zingerone, allyl
isothiocyanate,
cinnamaldehyde, curninaldehyde, 2-propenyl/2-phenylethyl isothiacyanate,
thymol, and
eucalyptol, and presenting the odorant includes presenting the selected
odorant.
In an embodiment, presenting the odorant includes presenting a capsule for
placement within a mouth of the patient, the capsule being configured to
dissolve upon
contact with salivary liquids of the patient, whereupon the odorant is
presented to the air
passage.
There is yet additionally provided, in accordance with an embodiment of the
present invention, apparatus for treating Alzheimer's disease (AD), including
a stimulator
2 0 adapted to:
stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by
applying an
electrical signal to the SPG-related tissue, the SPG-related tissue selected
from: an SPG of
the subject and nerve fibers of the subject which are directly anatomically
connected to
the SPG, and
2 5 configure the stimulation so as to cause an increase in clearance of an AD-
related
constituent of a cenfiral nervous system (CNS) of the subject, from a brain of
the subject to
a systemic blood circulation of the subject, so as to treat the AD.
There is still additionally provided, in accordance with an embodiment of the
present invention, apparatus for treating Alzheimer's disease (AD), including
a stimulator
3 0 adapted to:
stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by
presenting
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an odorant to an air passage of the subject, the SPG-related tissue selected
from: an SPG
of the subject and nerve fibers of the subject which are directly anatomically
connected to
the SPG, and
configure the stimulation so as to cause an increase in clearance of an AD-
related
constituent of a central nervous system (CNS) of the subject, from a brain of
the subject to
a systemic blood circulation of the subject, so as to treat the AD.
There is also provided, in accordance with an embodiment of the present
invention, apparatus for treating Alzheimer's disease (AD), including a
stimulator adapted
to:
stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by
applying an
electrical signal to the SPG-related tissue, the SPG-related tissue selected
from: an SPG of
the subject and nerve fibers of the subject which are directly anatomically
connected to
the SPG, and
configure the stimulation so as to cause an increase in clearance of an AD-
related
constituent of a central nervous system (CNS) of the subject, from
cerebrospinal fluid
(CSF) of the subject to a systemic blood circulation of the subject, so as to
treat the AD.
There is further provided, in accordance with an embodiment of the present
invention, apparatus for treating Alzheimer's disease (AD), including a
stimulator adapted
to:
2 0 stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by
presenting
an odorant to an air passage of the subject, the SPG-related tissue selected
from: an SPG
of the subject and nerve fibers of the subject which are directly anatomically
connected to
the SPG, and
configure the stimulation so as to cause an increase in clearance of an AD-
related
constituent of a central nervous system (CNS) of the subject, from
cerebrospinal fluid
(CSF) of the subject to a systemic blood circulation of the subject, so as to
treat the AD.
In an embodiment, the stimulator is adapted to directly stimulate the SPG.
There is still further provided, in accordance with an embodiment of the
present
invention, apparatus for treating Alzheimer's disease (AD), including a
stimulator adapted
3 0 to:
stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by
applying
an electrical signal to the SPG-related tissue, the SPG-related tissue
selected from: an
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SPG of the subject and nerve fibers of the subject which are directly
anatomically
connected to the SPG, and
configure the stimulation so as to cause an increase in passage from a
systemic
blood circulation of the subject into a central nervous system (CNS) of the
subject, of a
pharmaceutical agent supplied to the systemic blood circulation, so as to
treat the AD.
There is yet further provided, in accordance with an embodiment of the present
invention, apparatus for treating Alzheimer's disease (AD), including a
stimulator adapted
to:
stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by
to presenting an odorant to an air passage of the subject, the SPG-related
tissue selected
from: an SPG of the subject and nerve fibers of the subject which are directly
anatomically connected to the SPG, and
configure the stimulation so as to cause an increase in passage from a
systemic
blood circulation of the subject into a central nervous system (CNS) of the
subject, of a
pharmaceutical agent supplied to the systemic blood circulation, so as to
treat the AD.
There is also provided, in accordance with an embodiment of the present
invention, apparatus for treating Alzheimer's disease (AD), including a
stimulator adapted
to:
stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by
applying
2 0 an electrical signal to the SPG-related tissue, the SPG-related tissue
selected from: an
SPG of the subject and nerve fibers of the subject which are directly
anatomically
connected to the SPG, and
configure the stimulation so as to cause an increase in cerebral blood flow
(CBF)
of the subject, so as to treat the AD.
2 5 There is additionally provided, in accordance with an embodiment of the
present
invention, apparatus for treating Alzheimer's disease (AD), including a
stimulator adapted
to:
stimulate sphenopalatine ganglion (SPG)-related tissue of the subject by
presenting an odorant to an air passage of the subject, the SPG-related tissue
selected
3 0 from: an SPG of the subject and nerve fibers of the subject which are
directly
anatomically connected to the SPG, and
configure the stimulation so as to cause an increase in cerebral blood flow
(CBF)
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of the subject, so as to treat the AD.
There is still additionally provided, in accordance with an embodiment of the
present invention, apparatus for diagnosing Alzheimer's disease (AD),
including a
stimulator adapted to:
stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by
applying an
electrical signal to the SPG-related tissue, the SPG-related tissue selected
from: an SPG of
the subject and nerve fibers of the subject which are directly anatomically
connected to
the SPG, and
configure the stimulation so as to cause an increase in molecular passage
between
a central nervous system (CNS) of the subject and another body comparhnent of
the
subject, so as to facilitate a diagnosis of the AD.
There is yet additionally provided, in accordance with an embodiment of the
present invention, apparatus for diagnosing Alzheimer's disease (AD),
including a
stimulator adapted to:
stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by
presenting
an odorant to an air passage of the subject, the SPG-related tissue selected
from: an SPG
of the subject and nerve fibers of the subject which are directly anatomically
connected to
the SPG, and
configure the stimulation so as to cause an increase in molecular passage
between
2 0 a central nervous system (CNS) of the subject and another body comparhnent
of the
subject, so as to facilitate a diagnosis of the AD.
There is also provided, in accordance with an embodiment of the present
invention, apparatus for diagnosing Alzheimer's disease (AD), including a
stimulator
adapted to:
stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by
applying an
electrical signal to the SPG-related tissue, the SPG-related tissue selected
from: an SPG of
the subject and nerve fibers of the subject which are directly anatomically
connected to
the SPG, and
configure the stimulation so as to cause an increase in molecular passage
between
3 o cerebrospinal fluid (CSF) of the subject and another body fluid of the
subject, so as to
facilitate a diagnosis of the AD.
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There is further provided, in accordance with an embodiment of the present
invention, apparatus for diagnosing Alzheimer's disease (AD), including a
stimulator
adapted to:
stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by
presenting
an odorant to an air passage of the subject, the SPG-related tissue selected
from: an SPG
of the subject and nerve fibers of the subject which are directly anatomically
connected to
the SPG, and
configure the stimulation so as to cause an increase in molecular passage
between
cerebrospinal fluid (CSF) of the subject and another body fluid of the
subject, so as to
facilitate a diagnosis of the AD.
There is still further provided, in accordance with an embodiment of the
present
invention, apparatus for diagnosing Alzheimer's disease (AD), including a
stimulator
adapted to:
stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by
applying an
electrical signal to the SPG-related tissue, the SPG-related tissue selected
from: an SPG of
the subject and nerve fibers of the subject which are directly anatomically
connected to
the SPG, and
configure the stimulation so as to cause an increase in molecular passage
between
cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to
facilitate a
2 0 diagnosis of the AD.
There is yet further provided, in accordance with an embodiment of the present
invention, apparatus for diagnosing Alzheimer's disease (AD), including a
stimulator
adapted to:
stimulate sphenopalatine ganglion (SPG)-related tissue of a subject by
presenting
an odorant to an air passage of the subject, the SPG-related tissue selected
from: an SPG
of the subject and nerve fibers of the subject which are directly anatomically
connected to
the SPG, and
configure the stimulation so as to cause an increase in molecular passage
between
cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to
facilitate a
3 0 diagnosis of the AD.
There is also provided, in accordance with an embodiment of the present
invention, apparatus for treating Alzheimer's disease (AD), including a
stimulator adapted
41
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to:
apply an electrical signal to at least one site of a subject, the site
selected from the
list consisting of: a sphenopalatine ganglion (SPG) of the subject, an
anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch
between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of
the subject, a
communicating branch between a posterior ethmoidal nerve and a retro-orbital
branch of
an SPG of the subject, a greater palatine,nerve of the subject, a lesser
palatine nerve of the
subject, a sphenopalatine nerve of the subject, a communicating branch between
a
maxillary nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior
nasal nerve of the subject, an infraorbital nerve of the subject, an otic
ganglion of the
subject, an afferent fiber going into the otic ganglion of the subject, an
efferent fiber going
out of the otic ganglion of the subject, a vidian nerve of the subject, a
greater superficial
petrosal nerve of the subject, and a lesser deep petrosal nerve of the
subject, and
configure the signal so as to cause an increase in clearance of an AD-related
constituent of a central nervous system (CNS) of the subject, from a brain of
the subject to
a systemic blood circulation of the subject, so as to treat the AD.
There is also provided, in accordance with an embodiment of the present
invention, apparatus for treating Alzheimer's disease (AD), including a
stimulator adapted
to present an odorant to an air passage of a subject, the odorant having been
selected for
2 0 presentation to the air passage because it is such as to cause an increase
in clearance of an
AD-related constituent of a central nervous system (CNS) of the subject from
cerebrospinal fluid (CSF) of the subject to a systemic blood circulation of
the subject, so
as to treat the AD.
There is additionally provided, in accordance with an embodiment of the
present
2 5 invention, apparatus for treating Alzheimer's disease (AD), including a
stimulator adapted
to apply an electrical signal to at least one site of a subject, the site
selected from the list
consisting of: a sphenopalatine ganglion (SPG) of the subject, an anterior
ethmoidal nerve
of the subject, a posterior ethmoidal nerve of the subject, a communicating
branch
between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of
the subject, a
3 0 communicating branch between a posterior ethmoidal nerve and a retro-
orbital branch of
an SPG of the subject, a greater palatine nerve of the subject, a lesser
palatine nerve of the
subject, a sphenopalatine nerve of the subject, a communicating branch between
a
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maxillary nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior
nasal nerve of the subject, an infraorbital nerve of the subject, an otic
ganglion of the
subject, an afferent fiber going into the otic ganglion of the subject, an
efferent fiber going
out of the otic ganglion of the subject, a vidian nerve of the subject, a
greater superficial
petrosal nerve of the subject, and a lesser deep petrosal nerve of the
subject, and
configure the signal so as to cause an increase in passage from a systemic
blood
circulation of the subject into a central nervous system (CNS) of the subject,
of a
pharmaceutical agent supplied to the systemic blood circulation, so as to
treat the AD.
There is still additionally provided, in accordance with an embodiment of the
present invention, apparatus for treating Alzheimer's disease (AD), including
a stimulator
adapted to present an odorant to an air passage of the subject, the odorant
having been
selected for presentation to the air passage because it is such as to cause an
increase in
passage from a systemic blood circulation of the subject into a central
nervous system
(CNS) of the subject, of a pharmaceutical agent supplied to the systemic blood
circulation, so as to treat the AD.
There is yet additionally provided, in accordance with an embodiment of the
present invention, apparatus for treating Alzheimer's disease (AD), including
a stimulator
adapted to:
apply an electrical signal to at least one site of a subject, the site
selected from the
2 0 list consisting of: a sphenopalatine ganglion (SPG) of the subject, an
anterior ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch
between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of
the subject, a
communicating branch between a posterior ethmoidal nerve and a retro-orbital
branch of
an SPG of the subject, a greater palatine nerve of the subject, a lesser
palatine nerve of the
subject, a sphenopalatine nerve of the subject, a communicating branch between
a
maxillary nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior
nasal nerve of the subject, an infraorbital nerve of the subject, an otic
ganglion of the
subject, an afferent fiber going into the otic ganglion of the subject, an
efferent fiber going
out of the otic ganglion of the subject, a vidian nerve of the subject, a
greater superficial
3 0 petrosal nerve of the subject, and a lesser deep petrosal nerve of the
subject, and
configure the signal so as to cause an increase in cerebral blood flow (CBF)
of the
subject, so as to treat the AD.
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There is also provided, in accordance with an embodiment of the present
invention, apparatus for treating Alzheimer's disease (AD), including a
stimulator adapted
to present an odorant to an air passage of the subject, the odorant having
been selected for
presentation to the air passage because it is such as to cause an increase in
cerebral blood
flow (CBF) of the subject, so as to treat the AD.
There is further provided, in accordance with an embodiment of the present
invention, apparatus for diagnosing Alzheimer's disease (AD), including a
stimulator
adapted to:
apply an electrical signal to at least one site of a subject, the site
selected from the
list consisting of a sphenopalatine ganglion (SPG) of the subject, an anterior
ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch
between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of
the subject, a
communicating branch between a posterior ethmoidal nerve and a retro-orbital
branch of
an SPG of the subject, a greater palatine nerve of the subject, a lesser
palatine nerve of the
subject, a sphenopalatine nerve of the subject, a communicating branch between
a
maxillary nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior
nasal nerve of the subject, an infraorbital nerve of the subject, an otic
ganglion of the
subject, an afferent fiber going into the otic ganglion of the subject, an
efferent fiber going
out of the otic ganglion of the subject, a vidian nerve of the subject, a
greater superficial
2 0 petrosal nerve of the subject, and a lesser deep petrosal nerve of the
subject, and
configure the signal so as to cause an increase in molecular passage between a
central nervous system (CNS) of the subject and another body compartment of
the
subject, so as to facilitate a diagnosis of the AD.
There is still further provided, in accordance with an embodiment of the
present
2 5 invention, apparatus for diagnosing Alzheimer's disease (AD), including a
stimulator
adapted to present an odorant to an air passage of the subject, the odorant
having been
selected for presentation to the air passage because it is such as to cause an
increase in
molecular passage between a central nervous system (CNS) of the subject and
another
body compartment of the subject, so as to facilitate a diagnosis of the AD.
3 0 There is yet further provided, in accordance with an embodiment of the
present
invention, apparatus for diagnosing Alzheimer's disease (AD), including a
stimulator
adapted to:
44
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WO 03/105658 PCT/IL03/00508
apply an electrical signal to at least one site of a subject, the site
selected from the
list consisting of a sphenopalatine ganglion (SPG) of the subject, an anterior
ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch
between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of
the subject, a
communicating branch between a posterior ethmoidal nerve and a retro-orbital
branch of
an SPG of the subject, a greater palatine nerve of the subject, a lesser
palatine nerve of the
subject, a sphenopalatine nerve of the subject, a communicating branch between
a
maxillary nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior
nasal nerve of the subject, an infraorbital nerve of the subject, an otic
ganglion of the
subject, an afferent fiber going into the otic ganglion of the subject, an
efferent fiber going
out of the otic ganglion of the subject, a vidian nerve of the subject, a
greater superficial
petrosal nerve of the subject, and a lesser deep petrosal nerve of the
subject, and
configure the signal so as to cause an increase in molecular passage between
cerebrospinal fluid (CSF) of the subject and another body fluid of the
subject, so as to
facilitate a diagnosis of the AD.
There is also provided, in accordance with an embodiment of the present
invention, apparatus for diagnosing Alzheimer's disease (AD), including a
stimulator
adapted to present an odorant to an air passage of the subject, the odorant
having been
selected for presentation to the air passage because it is such as to cause an
increase in
molecular passage between cerebrospinal fluid (CSF) of the subject and another
body
fluid of the subject, so as to facilitate a diagnosis of the AD.
There is additionally provided, in accordance with an embodiment of the
present
invention, apparatus for diagnosing Alzheimer's disease (AD), including a
stimulator
adapted to:
apply an electrical signal to at least one site of a subject, the site
selected from the
list consisting of a sphenopalatine ganglion (SPG) of the subject, an anterior
ethmoidal
nerve of the subject, a posterior ethmoidal nerve of the subject, a
communicating branch
between an anterior ethmoidal nerve and a retro-orbital branch of an SPG of
the subject, a
communicating branch between a posterior ethmoidal nerve and a retro-orbital
branch of
3 0 an SPG of the subject, a greater palatine nerve of the subject, a lesser
palatine nerve of the
subject, a sphenopalatine nerve of the subject, a communicating branch between
a
maxillary nerve and an SPG of the subject, a nasopalatine nerve of the
subject, a posterior
CA 02489341 2004-12-13
WO 03/105658 PCT/IL03/00508
nasal nerve of the subject, an infraorbital nerve of the subject, an otic
ganglion of the
subject, an afferent fiber going into the otic ganglion of the subject, an
efferent fiber going
out of the otic ganglion of the subject, a vidian nerve of the subject, a
greater superficial
petrosal nerve of the subject, and a lesser deep petrosal nerve of the
subject, and
configure the signal so as to cause an incxease in molecular passage between
cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to
facilitate a
diagnosis of the AD.
There is still additionally provided, in accordance with an embodiment of the
present invention, apparatus for diagnosing Alzheimer's disease (AD),
including a
stimulator adapted to present an odorant to an air passage of the subject, the
odorant
having been selected for presentation to the air passage because it is such as
to cause an
increase in molecular passage between cerebrospinal fluid (CSF) of the subject
and a
tissue of the subject, so as to facilitate a diagnosis of the AD.
There is yet additionally provided, in accordance with an embodiment of the
present invention, apparatus for treating Alzheimer's disease (AD), including:
an odorant-storage vessel;
an odorant for storage within the odorant-storage vessel, the odorant being
capable
of increasing clearance of an AD-related constituent of a central nervous
system (CNS) of
the subject from cerebrospinal fluid (CSF) of the subject to a systemic blood
circulation of
2 o the subject; and
an odorant-delivery element, adapted to present the odorant to an air passage
of
the patient, so as to treat the AD.
There is also provided, in accordance with an embodiment of the present
invention, apparatus for treating Alzheimer's disease (AD), including:
an odorant-storage vessel;
an odorant for storage within the odorant-storage vessel, the odorant being
capable
of increasing passage, from a systemic blood circulation of a subject into a
central
nervous system (CNS) of the subject, of a pharmaceutical agent supplied to the
systemic
blood circulation; and
3 0 an odorant-delivery element, adapted to present the odorant to an air
passage of
the patient, so as to treat the AD.
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There is further provided, in accordance with an embodiment of the present
invention, apparatus for treating Alzheimer's disease (AD), including:
an odorant-storage vessel;
an odorant for storage within the odorant-storage vessel, the odorant being
capable
of increasing cerebral blood flow (CBF) of the subject; and
an odorant-delivery element, adapted to present the odorant to an air passage
of
the patient, so as to treat the AD.
There is still further provided, in accordance with an embodiment of the
present
invention, apparatus for diagnosing Alzheimer's disease (AD), including:
an odorant-storage vessel;
an odorant for storage within the odorant-storage vessel, the odorant being
capable
of increasing molecular passage between a central nervous system (CNS) of the
subject
and another body compartment of the subject; and
an odorant-delivery element, adapted to present the odorant to an air passage
of
the patient, so as to facilitate a diagnosis of the AD.
There is yet further provided, in accordance with an embodiment of the present
invention, apparatus for diagnosing Alzheimer's disease (AD), including:
an odorant-storage vessel;
an odorant for storage within the odorant-storage vessel, the odorant being
capable
2 0 of increasing molecular passage between cerebrospinal fluid (CSF) of the
subject and
another body fluid of the subject; and
an odorant-delivery element, adapted to present the odorant to an air passage
of
the patient, so as to facilitate a diagnosis of the AD.
There is also provided, in accordance with an embodiment of the present
' 2 5 invention, apparatus for diagnosing Alzheimer's disease (AD), including:
an odorant-storage vessel;
an odorant for storage within the odorant-storage vessel, the odorant being
capable
of increasing molecular passage between cerebrospinal fluid (CSF) of the
subject and a
tissue of the subject; and
3 0 an odorant-delivery element, adapted to present the odorant to an air
passage of
the patient, so as to facilitate a diagnosis of the AD.
In an embodiment, the odorant-storage vessel in combination with the odorant-
47
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delivery element includes an aqueous spray nasal inhaler.
In an embodiment, the odorant-storage vessel in combination with the odorant-
delivery element includes a metered dose nasal inhaler.
In an embodiment, the odorant-storage vessel in combination with the odorant-
delivery element includes an air-dilution olfactometer.
The present invention will be more fully understood from the following
detailed
description of preferred embodiments thereof, taken together with the
dxawings, in which:
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a schematic pictorial view of a fully implantable stimulator for
l0 stimulation of the SPG, in accordance with a preferred embodiments of the
present
invention;
Fig. 2 is a schematic pictorial view of another stimulator for stimulation of
the
SPG, in accordance with a preferred embodiment of the present invention;
Fig. 3 is a schematic block diagram illustrating circuitry for use with the
stimulator shown in Fig. 1, in accordance with a preferred embodiment of the
present
invention;
Fig. 4 is a schematic block diagram illustrating circuitry for use with the
stimulator shown in Fig. 2, in accordance with a preferred embodiment of the
present
invention;
2 0 Figs. SA and SB are schematic illustrations depicting different modes of
operation
of stimulators such as those shown in Figs. 1 and 2, in accordance with
preferred
embodiments of the present invention;
Fig. 6 is a schematic illustration of a mode of operation of the stimulators
shown
in Figs. 1 and 2, synchronized with a drug delivery system, in accordance with
a preferred
2 5 embodiment of the present invention;
Fig. 7 is a schematic block diagram illustrating circuitry for use with the
stimulator shown in Fig. l, where the stimulator is driven by an external
controller and
energy source using a modulator and a demodulator, in accordance with a
preferred
embodiment of the present invention;
3 0 Fig. 8 depicts sample modulator and demodulator functions for use with the
circuitry of Fig. 7, in accordance with a preferred embodiment of the present
invention;
Figs. 9, 10A, and lOB are schematic diagrams illustrating further circuitry
for use
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CA 02489341 2004-12-13
WO 03/105658 PCT/IL03/00508
with implantable stimulators, in accordance with respective preferred
embodiments of the
present invention;
Figs. 11 and 12 are bar graphs showing experimental data collected in
accordance
with a preferred embodiment of the present invention;
Fig. 13 is a schematic illustration of a sensor for application to a blood
vessel, in
accordance with a preferred embodiment of the present invention;
Fig. I4 is a schematic sectional illustration of a nasal inhaler, for use in
presenting
an odorant to a subject, in accordance with a preferred embodiment of the
present
invention; and
1 o Figs. 15-17 are graph showing the results from SPG stimulation experiments
carried out in accordance with embodiments of the present invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Fig. 1 is a schematic pictorial view of a fully-implantable stimulator 4, for
stimulation of the sphenopalatine ganglion (SPG) 6 or other parasympathetic
site of a
patient, in accordance with a preferred embodiments of the present invention.
In Fig. l, a
human nasal cavity 2 is shown, and stimulator 4 is implanted adjacent to SPG
6.
Branches of parasympathetic neurons coming from SPG 6 extend to the middle
cerebral
and anterior cerebral arteries (not shown). Preferably, one yr more relatively
short
electrodes 7 extend from stimulator 4 to contact or to be in a vicinity of SPG
6 or of
2 0 nerves innervating SPG 6 (e.g., postganglionic parasympathetic trunks
thexeof).
For some applications, stimulator 4 is implanted on top of the bony palate, in
the
bottom of the nasal cavity. Alternatively or additionally, the stimulator is
implanted at
the lower side of the bony palate, at the top of the oral cavity. In this
instance, one or
more flexible electrodes 7 originating in the stimulator are passed through
the palatine
bone or posterior to the soft palate, so as to be in a position to stimulate
the SPG or its
parasympathetic tracts. Further alternatively or additionally, the stimulator
may be
directly attached to the SPG and/or to its postganglionic parasympathetic
trunlc(s).
For some applications, stimulator 4 is delivered to a desired point within
nasal
cavity 2 by removably attaching stimulator 4 to the distal end of a rigid or
slightly
3 0 flexible introducer rod (not shown) and inserting the rod into one of the
patient's nasal
passages until the stimulator is properly positioned. As appropriate, the
placement
process may be facilitated by fluoroscopy, x-ray guidance, fine endoscopic
surgery (FES)
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techniques or by any other effective guidance method known in the art, or by
combinations of the aforementioned. Preferably, the ambient temperature and/or
cerebral
blood flow is measured concurrently with insertion. The cerebral blood flow
may be
measured with, for example, a laser Doppler unit positioned at the patient's
forehead or
transcranial Doppler measurements. Verification of proper implantation of the
electrodes
onto the appropriate neural structure may be performed by activating the
device, and
generally simultaneously monitoring cerebral blood flow.
The passage of certain molecules from cerebral blood vessels into the brain is
hindered by the BBB. The endothelium of the capillaries, the plasma membrane
of the
2 0 blood vessels, and the foot processes of the astrocytes all impede uptake
by the brain of
the molecules. The BBB generally allows only small molecules (e.g.,
hydrophilic
molecules of molecular weight less than about 200 Da, and lipophilic molecules
of less
than about 500 Da) to pass from the circulation into the brain.
In accordance with a preferred embodiment of the present invention,
parasympathetic activation induced by current from stimulator 4 overcomes the
resistance
to traps-BBB molecular movement generated by the endothelium of the cerebral
capillaries and the plasma membrane. For some applications, therefore,
stimulator 4 may
be used to transiently remove a substantial obstacle to the passage of drugs
from the
blood to the brain. For example, the stimulator may cyclically apply current
for about
2 0 two minutes, and subsequently have a rest period of between about 1 and 20
minutes.
It is hypothesized that two neurotransmitters play an important role in this
change
in properties of the BBB -- vasoactive intestinal polypeptide (VIP) and nitric
oxide (NO).
(Acetylcholine may also be involved.) VIP is a short peptide, and NO is a
gaseous
molecule. VIP is believed to be a major factor in facilitating plasma protein
extravasation
2 5 (PPE), while NO is responsible for vasodilation. For some applications,
stimulator 4 is
adapted to vary parameters of the current applied to the SPG, as appropriate,
in order to
selectively influence the activity of one or both of these neurotransmitters.
For example,
stimulation of the parasympathetic nerve at different frequencies can induce
differential
secretion -- low frequencies cause secretion of NO, while high frequencies
(e.g., above
3 0 about 10 Hz) cause secretion of peptides (VIP).
For other applications, a constant level DC signal, or a slowly varying
voltage
ramp is applied, in ~rder to block parasympathetic neural activity in affected
tissue.
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Alternatively, similar results can be obtained by stimulating at a xate higher
than about 10
Hz, because this tends to exhaust neurotransmitters. Thus, stimulator 4 may be
configured to induce parasympathetic electrical block, in order to cause
vasoconstriction
by mimicking the overall effect of chemical block on the SPG. This
vasoconstrictive
effect may be used, for example, to controllably prevent or reverse the
formation of
migraine headaches. This technique of electrical treatment of migraines stands
in contrast
to methods of the prior art, in which pharmacological agents such as lidocaine
are used to
induce SPG block.
Fig. 2 is a schematic illustration of a stimulator control unit 8 positioned
external
to a patient's body, in accordance with a preferred embodiment of the present
invention.
At least one flexible electrode 10 preferably extends from control unit 8,
through a nostril
12 of the patient, and to a position within the nasal cavity I4 that is
adjacent to SPG 6.
It is to be understood that electrodes 7 (Fig. 1) and 10 may each comprise one
or
more electrodes, e.g., two electrodes, or an array of microelectrodes. For
applications in
which stimulator 4 comprises a metal housing that can function as an
electrode, then
typically one electrode 7 is used, operating in a monopolar mode. Regardless
of the total
number of electrodes in use, typically only a single or a double electrode
extends to SPG
6. Other electrodes 7 or 10 or a metal housing of stimulator 4 are preferably
temporarily
or permanently implanted in contact with other parts of nasal cavity 2.
2 0 Each of electrodes 7 and/or 10 preferably comprises a suitable conductive
material, for example, a physiologically-acceptable material such as silver,
iridium,
platinum, a platinum iridium alloy, titanium, nitinol, or a nickel-chrome
alloy. For some
applications, one or more of the electrodes have lengths ranging from about 1
to 5 mm,
and diameters ranging from about 50 to 100 microns. Each electrode is
preferably
insulated with a physiologically-acceptable material such as polyethylene,
polyurethane,
or a co-polymer of either of these. The electrodes are preferably spiral in
shape, for better
contact, and may have a hook shaped distal end for hooking into or near the
SPG,
Alternatively or additionally, the electrodes may comprise simple wire
electrodes, spring-
loaded "crocodile" electrodes, or adhesive probes, as appropriate.
3 0 In a preferred embodiment of the invention, each one of electrodes 7
and/or 10
comprises a substantially smooth surface, except that the distal end of each
such electrode
is configured or treated to have a large surface area. For example, the distal
tip may be
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porous platinized. Alternatively or additionally, at least the tip of
electrode 7 or 10,
and/or a metal housing of stimulator 4 includes a coating comprising an anti
inflammatory drug, such as beclomethasone sodium phosphate or beclomethasone
phosphate. Alternatively, such an anti-inflammatory drug is injected or
otherwise
applied.
Fig. 3 is a schematic block diagram illustrating circuitry comprising an
implanted
unit 20 and an external unit 30, for use with stimulator 4 (Fig. 1), in
accordance with a
preferred embodiment of the present invention. Implanted unit 20 preferably
comprises a
feedback block 22 and one or more sensing or signal application electrodes 24.
Implanted unit 20 typically also comprises an electromagnetic coupler 26,
which receives
power and/or sends or receives data signals to or from an electromagnetic
coupler 28 in
external unit 30.
External unit 30 preferably comprises a microprocessor 32 which receives an
external control signal 34 (e.g., from a physician or from the patient), and a
feedback
signal 36 from feedback block 22. Control signal 34 may include, for example,
operational parameters such as a schedule of operation, patient parameters
such as the
patient's weight, or signal parameters, such as desired frequencies or
amplitudes of a
signal to be applied to the SPG. If appropriate, control signal 34 can
comprise an
emergency overnde signal, entered by the patient or a healthcare provider to
terminate
2 0 stimulation or to modify it in accordance with a predetermined program.
Microprocessor
32, in turn, preferably processes control signal 34 and feedback signal 36 so
as to
determine one or more parameters of the electric current to be applied through
electrodes
24. Responsive to this determination, microprocessor 32 typically generates an
electromagnetic control signal 42 that is conveyed by electromagnetic coupler
28 to
2 5 electromagnetic coupler 26. Control signal 42 preferably corresponds to a
desired current
or voltage to be applied by electrodes 24 to SPG 6, and, in a preferred
embodiment,
inductively drives the electrodes. The configuration of couplers 26 and 28
and/or other
circuitry in units 20 or 30 may determine the intensity, frequency, shape,
monophasic or
biphasic mode, or DC offset of the signal (e.g., a series of pulses) applied
to designated
3 0 tissue.
Power for microprocessor 32 is typically supplied by a battery 44 or,
optionally,
another DC power supply. Grounding is provided by battery 44 or a separate
ground 46.
If appropriate, microprocessor 32 generates a display signal 38 that drives a
display block
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40 of external unit 30. Typically, but not necessarily, the display is
activated to show
feedback data generated by feedback block 22, or to provide a user interface
for the
external unit.
Implanted unit 20 is preferably packaged in a case made of titanium, platinum
or
an epoxy or other suitable biocompatible material. Should the case be made of
metal,
then the case may serve as a ground electrode and, therefore, stimulation
typically is
performed in a monopolar mode. Alternatively, should the case be made of
biocompatible plastic material, two electrodes 24 are typically driven to
apply current to
the SPG.
For some applications, the waveform applied by one or more of electrodes 24 to
designated tissue (e.g., the SPG) comprises a waveform with an exponential
decay, a
ramp up or down, a square wave, a sinusoid, a saw tooth, a DC component, or
any other
shape known in the art to be suitable for application to tissue. Alternatively
or
additionally, the waveform comprises one or more bursts of short shaped or
square pulses
-- each pulse preferably less than about 1 ms in duration. Generally,
appropriate
waveforms and parameters thereof are determined during an initial test period
of external
unit 30 and implanted unit 20. For some applications, the waveform is
dynamically
updated according to measured physiological parameters, measured during a
period in
which unit 20 is stimulating the SPG, and/or during a non-activation (i.e.,
standby)
2 0 period.
Fig. 4 is a schematic block diagram of circuitry for use, for example, in
conjunction with control unit 8 (Fig. 2), in accordance with a preferred
embodiment of
the present invention. An external unit 50 comprises a microprocessor 52
supplied by a
battery 54 or another DC power source. Grounding may be provided by battery 54
or by
a separate ground 56. Microprocessor 52 preferably receives control and
feedback
signals 58 and 68 (analogous to signal 34 and 36 described hereinabove), and
generates
responsive thereto a stimulation signal 64 conveyed by one or more electrodes
66 to the
SPG or other tissue. Typically, but not necessarily, feedback signal 68
comprises
electrical feedback measured by one or more of electrodes 66 and/or feedback
from other
3 0 sensors on or in the patient's brain or elsewhere coupled to the patient's
body. If
appropriate, microprocessor 52 generates a display signal 60 which drives a
display block
62 to output relevant data to the patient or the patient's physician.
Typically, some or all
of electrodes 66 are temporarily implanted in the patient (e.g., following a
stroke), and are
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directly driven by wires coimecting the external unit to the implanted unit.
Fig. SA is a graph schematically illustrating a mode of operation of one or
more of
the devices shown in Figs. 1-4, in accordance with a preferred embodiment of
the present
invention. Preferably, the effect of the applied stimulation is monitored by
means of a
temperature transducer at the SPG or elsewhere in the head, e.g., in the nasal
cavity. As
shown in Fig. SA for a step (ON/OFF) mode of stimulation, stimulation of the
SPG or
related tissue is initiated at a time T1, and this is reflected by a
measurable rise in
temperature (due to increased blood flow). Once the temperature rises to a
predetermined
or dynamically-varying threshold (e.g., 37 oC), stimulation is terminated
(time TZ),
responsive to which the temperature falls. As appropriate, when the
temperature drops to
a designated or dynamically-determined point, the stimulation is reinitiated
(time T3).
Preferably, suitable temperatures or other physiological parameters are
determined fox
each patient so as to provide the optimal treatment. If appropriate, control
instructions
may also be received from the patient.
Fig. SB is a graph schematically illustrating a mode of operation of one or
more of
the devices shown in Figs. 1-4, in accordance with another preferred
embodiment of the
present invention. In this embodiment, the amplitude of the waveform applied
to the SPG
is varied among a continuous set of values (S1), or a discrete set of values
(S2),
responsive to the measured temperature, in order to achieve the desired
performance. It
2 0 will be appreciated that other feedback parameters measured in the head
(e.g., intracranial
pressure and/or cerebral blood flow), as well as measured systemic parameters
(e.g., heart
rate) and subjective patient inputs may be used in conjunction with or
separately from
temperature measurements, in order to achieve generally optimal performance of
the
implanted apparatus.
2 5 Fig. 6 is a graph schematically illustrating a mode of operation of one or
more of
the devices shown in Figs. 1-4, in accordance with a preferred embodiment of
the present
invention. In this embodiment, a drug is administered to the patient at a
constant rate,
e.g., intravenously, prior to the initiation of stimulation of the SPG at time
T1.
Advantageously, this prior generation of heightened concentrations of the drug
in the
3 0 blood tends to provide relatively rapid transfer of the drug across the
BBB and into the
brain, without unnecessarily prolonging the enhanced permeability of the BBB
while
waiting for the blood concentration of the drug to reach an appropriate level.
Alternatively, for some applications it is desirable to give a single
injection of a bolus of
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the drug shortly before or after initiation of stimulation of the SPG.
Typically, combined
administration and stimulation schedules are determined by the patient's
physician based
on the biochemical properties of each dxug targeted at the brain.
Fig. 7 is a schematic block diagram showing circuitry for parasympathetic
stimulation, which is particularly useful in combination with the embodiment
shown in
Fig. 1, in accordance with a preferred embodiment of the present invention. An
external
unit 80 preferably comprises a microprocessor 82 that is powered by a battery
84 and/or
an AC power source. Microprocessor 82 is grounded through battery 84 or
through an
optional ground 86.
In a typical mode of operation, an external control signal 88 is input to
microprocessor 82, along with a feedback signal 108 from one or more
biosensors 106,
which are typically disposed in a vicinity of an implanted unit 100 or
elsewhere on or in
the patient's body. Responsive to signals 88 and 108, microprocessor 82
preferably
generates a display signal 89 which drives a display 90, as described
hereinabove. In
addition, microprocessor 82 preferably processes external control signal 88
and feedback
signal 108, to determine parameters of an output signal 92, which is modulated
by a
modulator 94. The output therefrom preferably drives a current through an
electromagnetic coupler 96, which inductively drives an electromagnetic
coupler 98 of
implanted unit 100. A demodulator 102, coupled to electromagnetic coupler 98,
in turn,
2 0 generates a signal 103 which drives at least one electrode 104 to apply
current to the SPG
or to other tissue, as appropriate.
Preferably, biosensor 106 comprises implantable or external medical apparatus
including, for example, one or moxe of the following:
~ a blood flow sensor,
2 5 ~ a temperature sensor,
~ a chemical sensor,
~ an ultrasound sensor,
~ transcranial Doppler (TCD~ apparatus,
~ laser-Doppler apparatus,
3 0 ~ a systemic or intracranial blood pressure sensor (e.g., comprising a
piezoelectric
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crystal fixed to a major cerebral blood vessel, capable of detecting a sudden
blood
pressure increase indicative of a clot),
~ a kinetics sensor, comprising, for example, an acceleration, velocity, or
level
sensor (e.g., a mercury switch), for indicating body dispositions such as a
sudden
change in body attitude (as in collapsing),
~ an electroencephalographic (EEG) sensor comprising EEG electrodes attached
to,
or implanted in, the patients head, for indicating changes in neurological
patterns,
such as symptoms of stroke or migraine,
~ a blood vessel clot detector (e.g., as described hereinbelow with reference
to Fig.
13), or
~ other monitors of physiological quantities suitable for carrying out the
objects of
this or other embodiments of the present invention.
Fig. 8 is a schematic illustration showing operational modes of modulator 94
and/or demodulator 102, in accordance with a preferred embodiment of the
present
invention. The amplitude and frequency of signal 92 in Fig. 7 can have certain
values, as
represented in the left graph; however, the amplitude and frequency are
modulated so that
signal 103 has different characteristics.
Fig. 9 is a schematic illustration of further apparatus for stimulation of the
SPG, in
accordance with a preferred embodiment of the present invention. In this
embodiment,
2 0 substantially all of the processing and signal generation is performed by
circuitry in an
implanted unit 110 in the patient, and, preferably, communication with a
controller 122 in
an external unit 111 is performed only intermittently. The implanted unit 110
preferably
comprises a microprocessor 112 coupled to a battery 114. Microprocessor 112
generates
a signal 116 that travels along at least one electrode 118 to stimulate the
SPG. A
feedback signal 120 from a biosensor (not shown) and/or from electrode 118 is
received
by microprocessor 112, which is adapted to modify stimulation parameters
responsive
thereto. Preferably, microprocessor 112 and controller 122 are operative to
communicate
via electromagnetic couplers 126 and 124, in order to exchange data or to
change
parameters. Further preferably, battery 114 is inductively rechargeable by
3 o electromagnetic coupling.
Fig. l0A is a schematic illustration of a stimulator 150, in accordance with a
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preferred embodiment of the present invention. Preferably, substantially all
of the
electronic components (including an electronic circuit 158 having a
rechargeable energy
source) are encapsulated in a biocompatible metal case 154. An inductive coil
I56 and at
least one electrode 162 are preferably coupled to circuit 158 by means of a
feed-through
coupling 160. The inductive coil is preferably isolated by an epoxy coating
152, which
allows for higher efficiency of the electromagnetic coupling.
Fig. lOB is a schematic illustration of another configuration of an
implantable
stimulator, in accordance With a preferred embodiment of the present
invention.
Preferably, substantially all of the electronic components (including an
inductive coil 176
and an electronic circuit 178 having a rechargeable energy source) are
encapsulated in a
biocompatible metal case 174. One or more feed-throughs are preferably
provided to
enable coupling between at least one electrode I82 and the electronic circuit,
as well as
between inductive coil 176 and another inductive coil (not shown) in
communication
therewith.
With reference to Figs. l0A and IOB, the energy source for electronic circuits
158
and 178 may comprise, for example, a primary battery, a rechargeable battery,
or a super
capacitor. For applications in which a rechargeable battery or a super
capacitor is used,
any kind of energizing means may be used to charge the energy source, such as
(but not
limited to) standard means for inductive charging or a miniature
electromechanical
2 0 energy converter that converts the kinetics of the patient movement into
electrical charge.
Alternatively, an external light source (e.g., a simple LED, a laser diode, or
any other
light source) may be directed at a photovoltaic cell in the electronic
circuit. Further
alternatively, ultrasound energy is directed onto the implanted unit, and
transduced to
drive battery charging means.
2 5 Figs. I 1 and 12 are bar graphs showing experimental results obtained
during rat
experiments performed in accordance with a preferred embodiment of the present
invention. A common technique in monitoring bio-distribution of materials in a
system
includes monitoring the presence and level of radio-labeled tracers. These
tracers are
unstable isotopes of common elements (e.g., Tc, In, Cr, Ga, and Gd),
conjugated to target
3 o materials. The chemical properties of the tracer are used as a predictor
for the behavior of
other materials with similar physiochemical properties, and are selected based
on the
particular biological mechanisms that are being evaluated. Typically, a
patient or
experimental animal is placed on a Gamma camera, or target tissue samples can
be
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harvested and placed separately into a well counter. For the purpose of the
present set of
experiments which were performed, the well counter method was chosen due to
its higher
sensitivity and spatial resolution. A series of experiments using 99Tc-DTPA
(DTPA
molecule conjugated to a 99-Technetium isotope) were performed. The molecular
weight
of 99Tc-DTPA is 458 Da, its hipophihicity is negative, and its electric charge
is +1. These
parameters are quite similar with pharmacological agents used in standard
chemotherapy,
such as tamoxifen, etoposide and irinotecan.
Figs. 11 and 12 show results obtained using 99Tc-DTPA penetration assays using
ordinary brain sampling techniques (Fig. 11) and peeled brain techniques (Fig.
12). The
x-axis of each graph represents different experimental runs, and the y-axis of
each graph
is defined as: [(hemisphere radioactivity) / (hemisphere weight)] / [(total
injected
radioactivity) / (total animal weight)]. The results obtained demonstrate an
average 2.5-
fold increase in the penetration of 99Tc-DTPA to the rat brain. It is noted
that these
results were obtained by unilateral stimulation of the SPG. The inventors
believe that
bilateral SPG stimulation will approximately double drug penetration, relative
to
unilateral SPG stimulation.
In both Fig. 11 and Fig. 12, some animals were designated as control animals,
and
other animals were designated as test animals. In each group, the left and
right
hemispheres were tested separately, and the height of each bar represents, for
a given
2 0 anirnah and a given hemisphere, the normalized level of radioactivity as
defined above.
Thus, Fig. 11 shows results from a total of four test hemispheres and four
control
hemispheres. Fig. 12 shows results from six test hemispheres and fourteen
control
hemispheres. The juxtaposition of control and test bars in the bar graphs is
not meant to
imply pairing of control and test hemispheres.
Fig. 13 is a schematic illustration of acoustic or optical clot detection
apparatus
202, for use, for example, in providing feedbaclc to any of the
microprocessors or other
circuitry described hereinabove, in accordance with a preferred embodiment of
the
present invention. The detection is preferably performed by coupling to a
major blood
vessel 200 (e.g., the internal carotid artery or aorta) a detecting element
comprising an
3 0 acoustic or optical transmitter/receiver 206, and an optional reflecting
surface 204.
Natural physiological liquids rnay serve as a mediating fluid between the
device and the
vessel. Preferably, the transmitterlreceiver generates an ultrasound signal or
electromagnetic signal which is reflected and returned, and a processor
evaluates changes
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in the returned signal to detect indications of a newly-present clot.
Alternatively, a
transmitter is placed on side of the vessel and a receiver is placed on the
other side of the
vessel. In either case, for some applications, more than one such apparatus
202 are
placed on the vessel, in order to improve the probability of successful clot
detection for
possible estimation of the clot's direction of motion within the vessel, and
to lower the
false alarm (i.e. false detection) rate.
Alternatively or additionally, the changes induced by electrical stimulation
as
described hereinabove axe achieved by presenting odorants to an air passage of
a patient,
such as a nasal cavity or the throat. There is animal evidence that some
odorants, such as
propionic acid, cyclohexanone, and amyl acetate, significantly incxease
cortical blood
flow when presented to the nasal cavity. This has been interpreted by some
researchers
as evidence that these odorants (e.g., environmental pollutants) may be
involved in the
formation of various headaches by increasing cerebral blood flow. The temporal
profile
and other quantitative characteristics of such odorant stimulation are
believed by the
present inventors to have a mechanism of action that has a neuroanatomical
basis
overlapping with that of the electrical stimulation of the SPG. Furthermore,
experimental
animal evidence collected by the inventors and described in a US provisional
patent
application to Shalev and Gross entitled, "SPG stimulation," filed March 28,
2002, which
is assigned to the assignee of the present invention and is incorporated
herein by
2 0 reference, suggest a correlation between the mechanisms of increasing
cerebral blood
flow and increased cerebrovascular permeability. It is hypothesized that such
increased
cerebral blood flow caused by odorants is a result of stimulation of
parasympathetic
and/or trigeminal fibers. These fibers may mediate cerebral blood flow changes
directly,
by communicating with the SPG, or by some other mechanism. It is also
hypothesized
2 5 that these odorants stimulate via reflex arcs the SPG or other autonomic
neural structures
that innexvate the cerebrovascular system. Therefore, the inventors
hypothesize, odorant
"stimulation" may increase cerebral blood flow in general, and cortical blood
flow in
particular, by some or all of the same mechanisms as electrical stimulation,
as described
hereinabove. Alternatively, odorants may cause increased cortical blood flow
by other
3 0 mechanisms, such as by entering the blood stream and reaching the affected
blood vessels
in the brain or by parasympathetic stimulation via the olfactory nerve. In
addition to the
effect on cerebral blood flow, the introduction of odorants into an air
passage is also
expected to induce an increase in the permeability of the anterior two thirds
of the
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cerebrovascular system to circulating agents of various sizes, i.e. to
increase the
permeability of the BBB. Similarly, presenting certain other odorants to an
air passage
decreases cerebral blood flow and decreases the permeability of the BBB.
Odorants that may increase or decrease cerebral blood flow and/or the
permeability of the BBB include, but are not limited to, propionic acid,
cyclohexanone,
amyl acetate, acetic acid, citric acid, carbon dioxide, sodium chloride,
ammonia, menthol,
alcohol, nicotine, piperine, gingerol, zingerone, allyl isothiocyanate,
cinnamaldehyde,
cuminaldehyde, 2-propenyl/2-phenylethyl isothiocyanate, thymol, and
eucalyptol.
According to a preferred embodiment of the instant invention, a method is
provided to enhance delivery of therapeutic molecules across the BBB by
presenting an
odorant to an air passage of a patient, such as a nasal cavity or the throat.
In a preferred
application, this method serves as a neurological drug delivery facilitator.
The odorant is
preferably presented using apparatus known in the art, such as aqueous spray
nasal
inhalers; metered dose nasal inhalers; or air-dilution olfactometers.
Alternatively or
additionally, the odorant is presented by means of an orally-dissolvable
capsule that
releases the active odorants upon contact with salivary liquids. The odorants
reach the
appropriate neural structures and induce vasodilatation, vasoconstriction
and/or
cerebrovascular permeability changes. Delivery of a drug can be achieved by
mixing the
drug with the odorant; by intravenously, intraperitoneally, or intramuscularly
2 0 administering the drug, or by other delivery methods known in the art. For
some
applications, it is desirable to combine a local analgesic with the odorant in
order to
diminish any possible sensation of pain or discomfort that may directly or
indirectly (e.g.,
via a reflex arc) accompany the odorant action upon nerves in the head. For
example,
preventing neural transmission in the neighboring pain fibers may be performed
as a "pre-
odorant" treatment, by topical administration of capsaicin together with a
local analgesic
for several days prior to the use of odorant stimulation. In this manner, the
odorants
typically induce the SPG-related response with a reduced or eliminated
sensation of pain
or discomfort.
Fig. 14 is a schematic sectional illustration of a nasal inhaler 300, for use
in
3 0 presenting an odorant to a subject, in accordance with a preferred
embodiment of the
present invention. Nasal inhaler 300 preferably comprises apparatus known in
the art,
such as an aqueous spray nasal inhaler, a metered dose nasal inhaler, or an
air-dilution
olfactometer. The odorant is stored in an odorant-storage vessel 302, and is
delivered to a
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nasal passage using an odorant-delivery element 304, such as a nasal piece.
Alternatively
or additionally, the odorant is presented by means of an orally-dissolvable
capsule that
releases the active odorants upon contact with salivary liquids. The odorants
reach the
appropriate neural structures and induce vasodilatation, vasoconstriction
andlor
cerebrovascular permeability changes.
Fig. 15 is a graph showing the results of an efflux study, performed in
accordance
with an embodiment of the present invention. Techniques described in the
following two
articles, which are incorporated herein by reference, were applied for use
with this
embodiment:
Asaba et al., "Blood brain barrier is involved in the efflux transport of a
neuroactive steroid, dehydroepiandrosterone sulfate, via organic anion
transporting polypeptide 2." J. Neurochem. 75, pp. 1907-1916, (2000).
Isakovic et al., "The efflux of purine nucleobases and nucleosides from the
rat brain." Neuroscience Letters 318, pp. 65-68, (2002) .
Male Wistar rats (280-300 g; Harlan) were used. Six rats were in an
experimental
group, and six rats were in a control group. A BEI (brain efflux index) study
was
performed according to the method described in an article by Kakee et al.,
"Brain efflux
index as a novel method of analyzing efflux transport at the blood brain
barrier." J.
Pharmacol. Exp. Ther. 277, 1550-1559. (1996), which is incorporated herein by
2 0 reference. Rats were anesthetized by intraperitoneal administration of
Pentobarbital, and
then mounted on a stereotaxic frame. A burr hole was made 5.5 mm lateral and
0.2 mm
anterior to the bregma, and a fine injection needle was advanced to a depth of
4.5 mm.
Then, 0.50 ml of [3H~PNA (150,000 disintegrations per minute (dpm), .5'-
CCGCTCCG-
3', MW. 2122) dissolved in extracellular fluid (ECF) buffer (122 mM NaCI, 25
mM
2 5 NaHC03, 10 mM D-glucose, 3 mM KCI, 1.4 mM CaCl2, 1.2 mM MgSO4, 0.4 mM
K2HP04, 10 mM HEPES, pH 7.4) was administered over 1 min using a 5.0-ml
microsyringe (Hamilton, Reno, NE, U.S.A.) fitted with a fme needle at a depth
of 4.5 mm
from the surface of the scalp (that is, in the parietal cortex area Z (Par2)
region). At the
end of the experiment (60 min), an aliquot of CSF was collected from the
cisterns magna,
3 0 using techniques described in Kakee et al., 1996. The whole brain was
subsequently
isolated, and the left cerebrum, right cerebrum, and cerebellum were isolated.
After
weighing, tissue samples were dissolved in 1 ml of 2 M NaOH at 50°C for
3 h and then
were mixed with 4 ml of scintillation cocktail. The associated radioactivity
was measured
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in a liquid scintillation counter equipped with an appropriate crossover
correction of 3H
(LS-6500; Beckman, Fullerton, CA, U.S.A.).
The SPG stimulation protocol included cycling between on-periods, lasting 90
seconds, and off periods, lasting for 60 seconds. During each on-period, a 5
volt, IO Hz
signal was applied to the SPG, each pulse having a pulse width of 1 ms. The
signal was
applied using a concentric bipolar electrode, both poles of the electrode
being inserted
slightly into the SPG.
Fig. 15 clearly shows the increased clearance of the injected tracer from the
animals that received electrical SPG stimulation, compared to the clearance in
the non-
stimulated (i.e., control) animals. The error bars represent one standard
deviation. No
electrodes were inserted into the SPG of the control animals.
Fig. 16 is a graph showing the results of an experiment performed in
accordance
with an embodiment of the present invention. Foux beagles were in a control
(non-
stimulated) group, and four beagles were in a stimulated group. No electrodes
were
applied to the SPG of the animals of the control group. At time zero, a
solution of I O kDa
FITC-dextran tracer was administered intravenously, and, at the same time, SPG
stimulation was initiated. Administration of the dextran was performed
continuously over
a 20 minute period, and SPG stimulation continued for 30 minutes (i.e., for 10
minutes
after termination of the dextran administration). The SPG stimulation protocol
included
2 0 cycling between on-periods, lasting 90 seconds, and off periods, lasting
for 60 seconds.
During each on-period, a 6 volt, 10 Hz signal was applied to the SPG, each
pulse having a
pulse width of 1 ms. The signal was applied using a concentric bipolar
electrode, both
poles of the electrode being inserted slightly into the SPG.
After termination of the SPG stimulation (or equivalent time period in the
control
2 5 group), each animal was sacrificed. Concentrations of dextran in various
parts of each
beagle's brain were measured. In the control group, concentrations in the left
half and the
right half were measured separately, such that the control results shown in
Fig. 16
represent n = 8, from four animals. In the experimental group, four animals
were used.
For each experimental animal, only one sample was taken from each brain
region,
3 o ipsilateral to the stimulation (thus n = 4).
Fig. 16 shows results from six brain regions known to be regulated to some
extent
by the SPG (the frontal cortex, the temporal cortex, frontal white matter, the
olfactory
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bulb, the striatum, and the hippocampus). Fig. 16 also shows dextran
concentrations
measured in the pons, a portion of the brain regulated by the otic ganglion
(and
substantially not by the SPG). Notably, the results of this experiment show
that dextran
concentrations in each of the six regions regulated by the SPG were
significantly higher in
the SPG-stimulated group than in the control group. The high concentration of
the
dextran tracer (a large molecule), indicates that BBB permeability was
substantially
increased as a result of the SPG stimulation, in the brain regions regulated
by the SPG.
Also notable is the almost exact equivalence between the dextran levels in the
pons of the
SPG-stimulated animals and in the pons of the control animals. The contrast
between:
(a) the equivalence of the experimental and control groups, in a non-SPG-
regulated brain
tissue, and
(b) the significant differences between the experimental and control groups in
the
SPG-regulated brain tissues,
is a strong indication that the displayed significant effect of the
experimental
protocol shown in Fig. 16 is a result of modulating the functioning of the SPG
and its
control over BBB permeability in certain portions of the brain.
In addition to the results shown in Fig. 16 and described hereinabove, the
inventox
additionally assessed the concentration of the dextran tracer in temporal
muscle of the
animals in the SPG-stimulated group and in the control group. It is noted that
temporal
2 0 muscle, being outside of the brain, has no protection from the BBB. The
results show that
the dextran concentrations rose to high and essentially equivalent values in
the temporal
muscle of the animals in both the SPG-stimulated group and the control group.
This, in
combination with the pons data, shows that SPG stimulation as provided herein
only
produced a measured effect on brain tissue that is regulated by the SPG.
Fig. 17 shows results from an experiment which included one hour of continuous
SPG stimulation in five rats, in accordance with an embodiment of the present
invention.
Prior to the initiation of SPG stimulation, cerebral blood flow (CBF) was
measured, and
this measurement provided a baseline for subsequent CBF measurements. CBF was
continuously recorded throughout the hour of SPG stimulation, and continued to
be
3 0 recorded for 30 minutes after the stimulation ceased. SPG stimulation
protocols were
identical to those described hereinabove with reference to Fig. 15.
Three bars are shown in Fig. 17. The left bar represents the average blood
flow
change 20 minutes after SPG stimulation was initiated. The middle bar shows
average
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blood flow change 40 minutes after stimulation was initiated, and the right
bar shows
average blood flow change 20 minutes after the termination of SPG stimulation.
From
this figure, it is evident that during SPG stimulation, a CBF increase of
around 50% (i.e.
150% of original blood flow level) is measured. This increase in cerebral
blood flow is
believed to be associated with improved metabolic state of brain tissue
supplied by the
CBF, as supported by other data collected by the inventor (not shown).
In general, it is believed that substantially all pharmacological treatments
aimed at
cerebral cells for neurological and psychiatric disorders are amenable for use
with these
embodiments of the present invention. In particular, this embodiment may be
adapted for
use in the treatment of disorders such as brain tumors, epilepsy, Parkinson's
disease,
Alzheimer's disease, multiple sclerosis, schizophrenia, depression, stress,
anxiety,
disorders requiring the administration of various growth factors, and other
CNS disorders
that are directly or indirectly affected by changes in cerebral blood flow or
by BBB
permeability changes.
Alternatively or additionally, a method is provided for increasing or reducing
cortical blood flow and/or inducing or inhibiting vasodilation (even in the
absence of
BBB permeability changes) by presenting an odorant to an air passage of a
patient, such
as a nasal cavity or the throat, for treatment of a condition. Patients with
the
aforementioned disorders and other disorders are generally helped by
vasodilation and the
2 0 resultant improvement in oxygen supply to neurons and other tissue. For
some
applications, this treatment is given on a long-term basis, e.g., in the
chronic treatment of
Alzheimer's patients. For other applications, the treatment is performed on a
short-term
basis, e.g., to minimize the damage following an acute stroke event and
initiate neuronal
and therefore functional rehabilitation. Alternatively or additionally, the
method
2 5 provided above can be used for diagnostic purposes or in conjunction with
other
diagnostic methods and/or apparatus known in the art, in order to enhance
diagnostic
results, reduce procedure risk, reduce procedure time, or otherwise improve
such
diagnostic procedures and/or diagnostic results. For example, methods and
apparatus
described herein may be used to increase the uptake into the brain of a radio-
opaque
3 D material, in order to facilitate a CT scan.
Decreasing cerebral blood flow by presenting certain odorants to an air
passage is
used in accordance with some preferred embodiments of the present invention to
treat or
prevent various types of headaches, especially with an autonomic nervous
system (ANS)
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etiology, such as migraine and cluster headaches.
In a preferred embodiment of the present invention, stimulation of the SPG may
be performed using direct galvanic contact, indirect electromagnetic
induction, photonic
excitation, chemical excitation, mechanical excitation and other methods or
combinations
thereof, which are known in the art of neural stimulation. Stimulation of the
SPG may be
performed directly on the SPG, or the nerves connected directly or indirectly
with the
SPG, e.g., via reflex arc.
In a preferred embodiment of the present invention, techniques described
herein
are applied in combination with methods and apparatus described in PCT
Application IL
01/00402, filed May 7, 2001, entitled, "Method and apparatus for stimulating
the
sphenopalatine ganglion to modify properties of the BBB and cerebral blood
flow," US
Provisional Patent Application 60/364,451, filed March I5, 2002, entitled,
"Applications
of stimulating the sphenopalatine ganglion (SPG)," US Provisional Patent
Application
60/368,657, filed March 28, 2002, entitled, "SPG stimulation," and/or US
Provisional
Patent Application 60/376,048, filed April 25, 2002, entitled, "Methods and
apparatus for
modifying properties of the BBB and cerebral circulation by using the
neuroexcitatory
and/or neuroinhibitory effects of odorants on nerves in the head," all of
which are
assigned to the assignee of the present invention and are incorporated herein
by reference.
The better delivery of drugs, as provided in accordance with preferred
2 0 embodiments of the present invention, is an important factor in the
treatment of various
disorders, such as Parkinson's disease, Alzheimer's disease, and other
neurological
diseases. For some applications, the trans-BBB delivery of various growth
factors is
facilitated using the techniques described herein. Growth factors are
typically large
molecules that stimulate the growth of neurons, and, in accordance with a
preferred
embodiment of the present invention, are used to treat degenerative disorders,
such as
Parkinson's disease, Alzheimer's disease, and Motor Neuron Diseases (e.g., Lou
Gehrig's
disease).
Alzheimer's disease is becoming a major source of disability and financial
load
with the increase in life expectancy. In recent years, vascular factors have
been
3 0 considered prominent in the pathophysiology of the disease. Current
therapy is generally
concentrated along one line -- cholinomimetic medications, which typically, at
most, slow
down the deterioration of cognitive function in patients. SPG stimulation, as
provided in
accordance with preferred embodiments of the present invention, typically
increases
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blood flow and oxygen supply to the brain, and therefore help these patients.
For this use,
permanent stimulators may be implanted in the nasal cavity, for long-term
intermittent
stimulation. In a preferred embodiment, the delivery of cholinomimetic
medications is
facilitated by SPG stimulation.
Apart from molecular parameters, the permeability of the BBB and active
transport mechanisms, a major determinant of molecular transport across the
BBB is their
concentration gradient - between the CNS and the cerebral circulation. In
cases where a
compound has a higher concentration in the brain than in the cerebral
circulation, opening
of the BBB, preferably, but not necessarily, using techniques described herein
leads to an
increased net transport of that compound from the CNS into the circulation. In
a
preferred embodiment, this technique is used to facilitate a diagnosis, e.g.,
by enhancing
permeability of the BBB, taking a blood sample, and testing the blood sample
for
increased levels of the compound.
In a preferred embodiment of the present invention, parasympathetic fibers
associated with the SPG are stimulated, preferably by using electrical
stimulation and/or
odorant presentation techniques described herein, thereby rendering the BBB
permeable
to certain compounds in the CNS. One or more of such compounds are then
analyzed by
analyzing the blood of the patient. By testing such compounds that are
indicative of the
presence of AD, AD is diagnosed. Advantageously, such a testing procedure is
2 0 minimally invasive. Alternatively or additionally, molecular passage is
increased to
another body compartment and/or fluid, such as plasma, serum, ascites, ox
cerebrospinal
fluid.
Moreover, in accordance with a preferred embodiment of the present invention,
a
controlled, reversible suppression of the impedance of the BBB is useful as a
stand-alone
treatment, when said suppression facilitates clearance of neurotoxic
compounds, such as
j3-Amyloid, tau, PS 1, and PS2, from the CNS into the systemic circulation.
Once in the
systemic circulation, these neurotoxic compounds may be metabolized and
removed from
the body with greater ease and with fewer side effects, compared to effects
that
accompany their presence in the CNS.
3 0 The following examples demonstrate selected therapeutic and diagnostic
applications of SPG stimulation in the management of Alzheimer's disease. It
should be
appreciated by those of skill in the art, that the following examples are set
forth for
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demonstrative purposes. Howevex, those of skill in the art should, in light of
the present
disclosure, appreciate that many changes can be made in the specific
embodiments
disclosed and still obtain a like or similar result without departing from the
spirit and
scope of the invention. The following description relates to specific
embodiments for
stimulation of the SPG and related neural structures, possible system
configurations for
the stimulator device, variations or combinations of the therapeutic and
diagnostic
modalities that accompany SPG stimulation and complementary explanation for
the
various mechanisms of actions of such a system for AD management. Furthermore,
the
methods described herein may be either directly, or indirectly applicable for
the
management of other CNS disorders, such as Parkinson's disease, epilepsy, ALS,
MS and
more. All references cited herein, including articles, patents, and published
patent
applications, are incorporated herein by reference.
Example 1: Therapeutics (glutamate inhibitors)
Excitotoxicity is related to excessive activation of glutamate receptors which
results in neuxonal cell death. The physiological function of glutamate
receptors is the
mediation of ligand-gated canon channels with the concomitant influx of
calcium, sodium
and potassium through this receptor-gated channel. The influx of these cations
is
essential for maintaining membrane potentials and the plasticity of neurons
which in itself
plays a pivotal role in cognitive function of the central nervous system (Li,
H. B. et al.,
2 0 Behav. Brain Res. 83:225-228, 1997; Roesler, R. et al., Neurology 50:1195,
1998; Wheal,
H. V. et al., Prog. Neurobiol. 55:611-640, 1998; Wangen, K et al., Brain Res.
99:126-130,
1997). Excitotoxicity plays an important role in neuronal cell death following
acute
insults such as hypoxia, ischemia, stroke and trauma, and it also plays a
significant role in
neuronal loss in AmS dementia, epilepsy, focal ischemia (Coyle, J.T. et al.,
Science
2 5 262:689-695, 1993). Neurodegenerative disorders, such as Huntington's
disease (HD),
Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral
sclerosis
(ALS), are characterized by the progressive loss of a specific population of
neurons in the
central nervous system. Growing evidence suggests that glutamate-mediated
excitotoxicity may be a common pathway which contributes to neuronal cell
death in a
3 o wide range of neurological disorders (Coyle, J.T. et aL, Science 262:689-
695, 1993). The
molecular mechanisms of excitotoxicity-mediated neuronal cell death remains
obscure.
Over-production of free radicals that lead to impairment of mitochondria)
function is the
most widely held hypothesis (Seal, M.F. et al., Ann. Neurol. 38:357-366, 1995;
Coyle,
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J.T. et al., Science 262:689-695, 1993). However, it is unclear in the
literature whether
the increase of free radicals is the precursor that initiates neuronal
degeneration or, rather,
a subsequent consequence of neuronal degeneration. Interestingly,
administration of
antioxidants is reported as having little neuroprotective effect in patients
suffering from
various neurodegenerative diseases (Shults, C.W. et al., Neurology 50:793-795,
1998).
Thus, some other mechanisms) must exist for excitotoxicity-induced neuronal
cell death.
A potential treatment modality for AD is the systemic administration of a JNK
(c-
Jun amino-terminal kinase) or MLI~ (Mixed lineage kinase) apoptosis inhibitor
as a
means fox preventing AD-related apoptosis of brain cells. However, without the
use of
the techniques described herein, achieving a therapeutic concentration of such
an
inhibitor in the CNS may be accompanied by undesired dose-related side
effects.
Advantageously, the use of techniques described herein for enhancing drug
delivery to
the CNS typically enables the achievement of therapeutic results at lower
dosages, which,
in turn, lowers the risk of dose-related side effects.
In a preferred embodiment of the present invention, the therapeutic or
prophylactic administration of such inhibitors is enhanced by stimulation of
the SPG
and/or its related neuroanatomical structures, by using electrical
stimulation, odorant
presentation, and/or other means for stimulating the SPG or for modulating
permeability
of the BBB.
2 0 Example 2: Therapeutics J.iL/~y secretase inhibitors
In a preferred embodiment of the present invention, methods for treatment of
Alzheimer's disease target the formation of j3-amyloid through the enzymes
involved in
the proteolytic processing of ~i-amyloid precursor protein. Compounds that
inhibit (3 or y
secretase activity, either directly or indirectly, are used, in accordance
with this
2 5 embodiment, to control the production of (3-amyloid. Advantageously,
compounds that
specifically target y secretases, could control the production of ~i-amyloid.
Typically,
such inhibition of (3 or Y secretases reduces production of A~i, which, in
turn, reduces or
prevents the neurological disorders associated with A~3 protein.
Compelling evidence accumulated during the last decade revealed that A(3 is an
3 0 internal polypeptide derived from a type 1 integral membrane protein,
termed b amyloid
precursor protein (APP). J3 APP is normally produced by many cells both in
vivo and in
cultured cells, derived from various animals and humans. AP is derived from
cleavage of
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~i APP by as yet unknown enzyme (protease) system(s), collectively termed
secretases.
The existence of at least four proteolytic activities has been postulated.
They
include ~i secretase(s), generating the N-terminus of A~i, a secretase(s)
cleaving around
the 16117 peptide bond in Aj3, and y secretases, generating C-terminal A~i
fragments
ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended
precursors
which are subsequently truncated to the above polypeptides.
Several Lines of evidence suggest that abnormal accumulation of A(3 plays a
key
role in the pathogenesis of AD. First, A(3 is the major protein found in
amyloid plagues.
Second, A(3 is neurotoxic and may be causally related to neuronal death
observed in AD
patients. Third, missense DNA mutations at position 717 in the 770 isoform of
(3 APP
can be found in affected members but not unaffected members of several
families with a
genetically determined (familiar) form of AD. In addition, several other (3
APP mutations
have been described in familiar forms of AD. Fourth, similar neuropathological
changes
have been observed in transgenic animals overexpressing mutant forms of human
J3 APP.
Fifth, individuals with Down's syndrome have an increased gene dosage of (3
APP and
develop early-onset AD. Taken together, these observations strongly suggest
that AJ3
depositions may be causally related to the AD.
It is hypothesized by the inventors that inhibiting the production of A(3
inhibits
neurological degeneration by controlling the formation of amyloid plaques,
reducing
2 0 neurotoxicity and, generally, mediating the pathology associated With A(3
production.
One method of treatment preferred by the inventors is based on drugs that
inhibit the
formation of A(3 in vivo, administered in combination with techniques for SPG
stimulation described herein.
Methods of treatment preferably target the formation of A~i through the
enzymes
2 5 involved in the proteolytic processing of j3 amyloid precursor protein.
Compounds that
inhibit ~i or 'y secretase activity, either directly or indirectly, could
control the production
of A(3. Advantageously, compounds that specifically target y secretases could
control the
production of A(3. Such inhibition of (3 or y secretases could thereby reduce
production of
A~i, which, in turn, could reduce or prevent the neurological disorders
associated with A~i
3 0 protein.
US Patent Application Publication 20020055501 to Olson et al. describes
pharmaceutical compositions and methods of use of such compounds, which
inhibit the
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processing of amyloid precursor protein and, more specifically, inhibit the
production of
A~i-peptide, thereby acting to prevent the formation of neurological deposits
of amyloid
protein.
The efficacy of administration of pharmaceutical agents that inhibit the
processing
of amyloid precursor protein into (3-amyloid is typically substantially
increased when
used in conjunction with the techniques of SPG stimulation described herein.
In a preferred embodiment of the present invention, the therapeutic or
prophylactic administration of such compounds targeting production of AJ3 is
enhanced
by stimulation of the SPG and/or its related neuroanatomical structures, by
using
electrical stimulation, odorant presentation, and/or other means for
stimulating the SPG or
for modulating permeability of the BBB.
Example 3: Therapeutics~,NMDA-receptor blocker)
US Patent Application Publication 20020035145 to Tsai et al., describes a
method
to treat various neuropsychiatric disorders, including Alzheimer's disease.
Their
description relates that neuropsychiatric disorders characterized by a deficit
in
neurotransmission via the NMDA receptor can be alleviated by a compound that
acts as
an agonist of the glycine site on the N1VIDA receptor or an inhibitor of
glycine uptake.
The compound is either a partial agonist such as D-cycloserine, which can be
used at a
dosage of 105-500 mg, or a full agonist (e.g., D-serine or D-alanine) that is
selective for
2 0 the NMDA receptor (compared to the inhibitory glycine receptor and other
receptors), or
a glycine uptake inhibitor (e.g., N-methylglycine). They describe methods for
treating
neuropsychiatxic disorders in patients (i.e., humans). Examples of disorders
that can be
p treated by the methods they describe include schizophrenia, Alzheimer's
disease, autism,
depression, benign forgetfulness, childhood learning disorders, closed head
injury, and
2 5 attention deficit disorder. The methods entail administering to a patient
diagnosed as
suffering from such a neuropsychiatric disorder a pharmaceutical composition
that
contains a therapeutically-effective amount of an agonist of the glycine site
of the NMDA
receptor or a glycine uptake inhibitor, which agonist is relatively selective
far (a) the
glycine site of the NMDA receptor, compared with (b) the inhibitory glycine
receptor and
3 0 other receptors. The pharmaceutical composition may include, for example,
(i) a
therapeutically effective amount of D-alanine (wherein the pharmaceutical
composifiion is
substantially free of D-cycloserine) and/or (ii) a therapeutically effective
amount of D-
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serine, and/or (iii) D-cycloserine in an amount of 105-500 mg, and/or (iv) a
therapeutically effective amount of N-methylglycine.
US Patent Application Publication 20010051633 to Bigge et al., describes a
subtype-selective NMDA receptor ligands and the use thereof for treating or
preventing
neuronal loss associated with neurodegenerative diseases including Alzheimer's
disease
by treating or preventing the adverse consequences of the overstimulation of
the
excitatory amino acids.
US Patent Application Publication 20010047014 to Alanine et al., describes a
compound of the formula 1 its R,R-, S,S-enantiomers and racemic mixtures, also
suitable
for the treatment of Alzheimer's disease.
In a preferred embodiment of the present invention, the therapeutic or
prophylactic administration of such compounds described in this example
(Example 3),
and/or the diagnostic use thereof, is enhanced by stimulation of the SPG
and/or its related
neuroanatomical structures, by using electrical stimulation, odorant
presentation, and/or
other means for stimulating the SPG or for modulating permeability of the BBB.
Example 4: Therapeutics~cholinesterase inhibitors
US Patent Application Publication 20020028534 to Villalobos et al., describes
the
use of cholinesterase inhibitors for enhancing memory in patients suffering
from
dementia and Alzheimer's disease. It is known that acetylcholinesterase
inhibitors are
2 o effective in enhancing cholinergic activity and useful in improving the
memory of
Alzheimer's patients. By inhibiting acetylcholinesterase enzyme, these
compounds
increase the level of the neurotransmitter acetylcholine in the brain and thus
enhance
memory. Becker et al., cited hereinabove, report that behavioral changes
following
cholinesterase inhibition appear to coincide with predicted peak levels of
acetylcholine in
2 5 the brain. They also discuss the efficacy of three known
acetylcholinesterase inhibitors,
physostigmine, metrifonate, and tetrahydroaminoacridine.
In a preferred embodiment of the present invention, the therapeutic or
prophylactic administration of such cholinesterase inhibitors is enhanced by
stimulation
of the SPG and/or its related neuroanatomical structures, by using electrical
stimulation,
3 0 odorant presentation, and/or other means for stimulating the SPG or for
modulating
permeability of the BBB.
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Example 5: Therapeutics direct stimulation of neural regeneration)
There are continuous efforts to use a Nerve Growth Factor (NGF) as a stimulant
of neural regeneration, thus potentially slowing degenerative processes, or
even reversing
neural damage. (NGF belongs to a large family of neural growth factors,
including
BDNF, IGF, GDNF and other active stimulants of neural regeneration. However,
for the
purpose of the present patent application, the term NGF shall be used to
represent any
such compound, or combinations thereof). Therefore, growth factor therapy for
AD is
considered a potentially curative approach of disease management. However,
such an
approach still has to overcome the challenge of administering growth factor in
adequate
amounts, preferably over a continuous period of time, into the CNS. In the
prior art, the
BBB is generally considered impermeable to high molecular weight compounds,
and thus
systemic administration of growth factor, without using the techniques
described herein,
is not generally considered a treatment option for a patient with a functional
BBB.
Because the BBB is generally considered in the prior art to be impermeable to
high molecular weight compounds, invasive methods have been developed to
enable
NGF to reach a patient's brain. For example, a possible method for AD therapy,
currently being tested in clinical trials, uses gene therapy techniques for
the in-situ
production of growth factors. This method involves brain surgery, where a
patient's own
cells are genetically modified to produce the NGF. The patient's cells, called
2 0 "fibroblasts," are obtained from skin biopsies. The fibroblasts are
genetically modified in
vitro and are then implanted into either 5 or 10 locations in the patient's
brain. The
eventual goal of this research effort is to determine whether NGF produced by
the cells
implanted into the brain can prevent the death of some nerve cells that are
affected in
Alzheimer's disease, and enhance the function of some remaining brain cells.
In animal studies, fibroblasts genetically modified to produce NGF have been
shown to prevent the death of certain nerve cells in the brain. This
effectiveness has been
shown in both the rat brain and the monkey brain. The genetically-modified
cells prevent
cell death after injury, and prevent cell atrophy that is a natural
consequence of aging in
primates.
3 0 A straightforward approach to circumventing the BBB would be to pierce the
meninges and directly administer growth factors into the CNS. This technique,
however,
has several drawbacks. First, it puts the patient in a continuous risk of
inflammatory
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brain processes. Second, direct infusion into the brain is usually very
localized, and
therefore its effectiveness is limited to the close vicinity of the
administration tip,
especially where the active molecule is of high molecular weight, making it
less mobile.
It is therefore clear that a relatively safe method of transiently opening the
BBB to large
molecular weight molecules, such as that described herein, could make nerve
growth
factors a compound of choice for the treatment of AD.
In a preferred embodiment of the present invention, the therapeutic or
prophylactic administration of nerve growth factor is enhanced by stimulation
of the SPG
and/or its related neuroanatomical structures, by using electrical
stimulation, odorant
presentation, andlor other means for stimulating the SPG or for modulating
permeability
of the BBB.
US Patent Application Publication 20020040052 to Ito et al., describes a
method
for extending neurites of neurocytes without any side effects, and a method
for preventing
and/or treating neurodegeneration diseases using compositions having neurite
extending
Z 5 effect. This invention is described as being necessary because the more
direct method of
administering NGF directly suffers from several limitations: "However, an NGF
is a
protein having a molecular weight of 13000 in the form of monomer and 26000 in
the
form of dimer, so that it cannot pass through the blood-brain barrier.
Therefore, in order
to treat disorders of central function, NGFs are required to be administrated
2 0 intraventricularly. Moreover, it is difficult to prepare NGFs in large
quantities. In these
respects, there are many problems about the use of NGF itself. As a result, it
is very
difficult to use NGF itself clinically."
Examale 6: Therapeutics (indirect stimulation of neural regeneration)
One of the characteristics of Alzheimer's disease (AD) is loss of presynaptic
2 5 markers such as synaptophysin. Synaptophysin decreases in
neurodegenerative disorders
along with a decline in neurotransmission. Synaptophysin: (i) is a synaptic
vesicle-
associated integral membrane protein (molecular weight about 38 kDa), (ii)
acts as a
specific marker for the presynaptic terminal, and (iii) is involved in
neuronal transmission
(Scheller, R.H., "Membrane Trafficking in the Presynaptic Nerve Terminal,"
Neuron 14:
3 0 893-897, 1995). A combination of neurotrophic factors is most effective in
providing
optimal trophic support for compromised neuron functions, including
neurotransmission
(Rathbone M.P. et al., "AIT-082 as a potential neuroprotective and
regenerative agent in
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stroke and central nervous system injury," Exp. Opin. Invest. Drugs. 8:1255-
12652,
1999). Multiple neurotrophic factors may synergistically regulate
synaptophysin levels in
a maimer that can lead to increased neurotransmission and improved neuronal
function.
Pharmaceutical agents that incxease synaptophysin synthesis and/or secretion,
decrease its metabolism, increase its release or improve its effectiveness may
also be of
benefit in reversing the course of neurological diseases including
neuxodegenerative
diseases, such as Alzheimer's disease, and improve function in
neurodevelopmental
disorders, such as Down's syndrome. US Patent Application Publication
0020040032 to
Glasky et al. describes a method of increasing the synthesis and/ox secretion
of
1 o synaptophysin, comprising administering to a patient with a neurological
disease or a
patient at risk of developing a neurological disease an effective quantity of
a purine
derivative or analogue, a tetrahydroindolone derivative or analogue, or a
pyrimidine
derivative or analogue. If the compound is a purine derivative, the purine
moiety can be
guanine ox hypoxanthine.
Therefore, there exists a need for methods that can stimulate the synthesis
andlor
secretion of synaptophysin in patients with neurological diseases, including
neurodegenerative diseases such as AD and neurodevelopmental disorders such as
Down's syndrome, in order to preserve, restore or improve neuronal
transmission
capability in such patients. Preferably, these methods are combined with
methods that
2 0 enable active compounds to cross the BBB, making combined therapy more
efficient.
These methods are suitable for use with compounds or pharmaceutical
compositions that
can stimulate nerve growth or regeneration in patients with neurological
diseases,
including neurodegenerative diseases such as AD and neurodevelopmental
disorders such
as Down's syndrome, thus reversing the course of the disease.
2 5 In a preferred embodiment of the present invention, the therapeutic or
prophylactic administration of compounds affecting synaptophysin, and/or the
diagnostic
use thereof, is enhanced by stimulation of the SPG and/or its related
neuroanatomical
structures, by using electrical stimulation, odorant presentation, and/or
other means for
stimulating the SPG or for modulating permeability of the BBB.
3 0 US Patent Application Publication 20020019519 to Bingham et al. describes
the
use of KIA.A0551 polypeptides and polynucleotides in the design of protocols
for the
treatment of various neurological disorders, among which is AD.
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In a preferred embodiment of the present invention, the therapeutic or
prophylactic administration of KIAA0551 polypeptides and polynucleotides,
and/or the
diagnostic use thereof, is enhanced by stimulation of the SPG its related
neuroanatomical
structures, by using electrical stimulation, odorant presentation, and/or
other means for
stimulating the SPG or for modulating permeability of the BBB.
Example 7: Therapeutics ~antioxidantsl
A number of diseases and disorders are thought to be caused by or to be
associated with alterations in mitochondria) metabolism and/or inappropriate
induction or
suppression of mitochondria-related functions leading to apoptosis. These
include, by
way of example and not limitation, chronic neurodegenerative disorders such as
Alzheimer's disease (AD) and Parkinson's disease (PD); auto-immune diseases;
diabetes
mellitus, including Type I and Type II; mitochondria associated diseases,
including but
not limited to congenital muscular dystrophy with mitochondria) structural
abnormalities,
fatal infantile myopathy with severe mtDNA depletion and benign "later-onset"
myopathy
with moderate reduction in mtDNA, MELAS (mitochondria) encephalopathy, lactic
acidosis, and stroke) and MIDD (mitochondria) diabetes and deafness); MERFF
(rnyoclonic epilepsy ragged red fiber syndrome); arthritis; NARP (Neuropathy;
Ataxia;
Retinitis Pigmentosa); MNGTE (Myopathy and external ophthalinoplegia;
Neuropathy;
Gastro-Intestinal; Encephalopathy), LHON (Leber's; Hereditary; Optic;
Neuropathy),
Kearns-Sayre disease; Pearson's Syndrome; PEO (Progressive External
Ophthalmoplegia); Wolfram syndrome DIDMOAD (Diabetes Tnsipidus, Diabetes
Mellitus, Optic Atrophy, Deafness); Leigh's Syndrome; dystonia; schizophrenia;
and
hyperproliferative disorders, such as cancer, tumors and psoriasis.
According to generally accepted theories of mitochondria) function, proper ETC
2 5 respiratory activity requires maintenance of an electrochemical potential
(ATm) in the
inner mitochondria) membrane by a coupled chemiosmotic mechanism. Conditions
that
dissipate or collapse this membrane potential, including but not limited to
failure at any
step of the ETC, may thus prevent ATP biosynthesis and hinder or halt the
production of
a vital biochemical energy source. Altered or defective mitochondria) activity
may also
3 0 result in a catastrophic mitochondria) collapse that has been termed
"mitochondria)
permeability transition" (MPT). In addition, mitochondria) proteins such as
cytochrome c
and "apoptosis inducing factor" may dissociate or be released from
mitochondria due to
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MPT (or the action of mitochondria) proteins such as Bax), and may induce
proteases
known as caspases and/or stimulate other events in apoptosis (Murphy, Drug
Dev. Res.
46:18-25, 1999).
Defective mitochondria) activity may alternatively or additionally result in
the
generation of highly-reactive free radicals that have the potential of
damaging cells and
tissues. These free radicals may include reactive oxygen species (ROS) such as
superoxide, peroxynitrite and hydroxyl radicals, and potentially other
reactive species that
may be toxic to cells. For example, oxygen free radical induced lipid
peroxidation is a
well established pathogenetic mechanism in central nervous system (CNS) injury
such as
that found in a number of degenerative diseases, and in ischemia (i.e.,
stroke).
(Mitochondria) participation in the apoptotic cascade is believed to also be a
key event in
the pathogenesis of neuronal death.)
There are, moreover, at least two deleterious consequences of exposure to
reactive
free radicals arising from mitochondria) dysfunction that adversely impact the
mitochondria themselves. First, free radical mediated damage may inactivate
one or
more of the myriad proteins of the ETC. Second, free radical mediated damage
may
result in catastrophic mitochondria) collapse that has been termed "transition
permeability." According to generally accepted theories of mitochondria)
function,
proper ETC respiratory activity requires maintenance of an electrochemical
potential in
2 0 the inner rnitochondrial membrane by a coupled chemiosmotic mechanism.
Free radical
oxidative activity rnay dissipate this membrane potential, thereby preventing
ATP
biosynthesis and/or triggering mitochondria) events in the apoptotic cascade.
There is evidence that defects in oxidative phosphorylation within the
mitochondria are at least a partial cause of sporadic AD. The enzyme
cytochrorne c
2 5 oxidase (COX), which makes up part of the mitochondria) electron transport
chain (ETC),
is pxesent in normal amounts in AD patients; however, the catalytic activity
of this
enzyme in AD patients and in the brains of AD patients at autopsy has been
found to be
abnormally low. This suggests that the COX in AD patients is defective,
leading to
decreased catalytic activity that in some fashion causes or contributes to the
symptoms
3 0 that are characteristic of AD.
One hallmark pathology of AD is the death of selected neuronal populations in
discrete regions of the brain. Cell death in AD is presumed to be apoptotic
because signs
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of programmed cell death (PCD) are seen and indicators of active gliosis and
necrosis are
not found (Smale et al., Exp. Neurolog. I33:225-230, 1995; Cotman et aL,
Molec.
Neurobiol. 10:19-4S, 1995). The consequences of cell death in AD, neuronal and
synaptic loss, are closely associated with the clinical diagnosis of AD and
are highly
correlated with the degree of dementia in AD (DeKosky et al., Ann. Neurology
2757-464,
1990).
Mitochondria) dysfunction is thought to be critical in the cascade of events
leading to apoptosis in various cell types (Kroemer et al., FASEB J 9:1277-
1287, 1995),
and may be a cause of apoptotic cell death in neurons of the AD brain. Altered
mitochondria) physiology may be among the earliest events in PCD (Zamzami et
al., J.
Exp. Med. 182:367-77, 1995; Zamzami et al., J. Exp. Med. 181:1661-72, 1995)
and
elevated reactive oxygen species (ROS) levels that result from such altered
mitochondria)
function may initiate the apoptotic cascade (Ausserer et al., Mol. Cell. Biol.
14:5032-42,
1994). In several cell types, including neurons, reduction in the
mitochondria) membrane
potential (8yrm) precedes the nuclear DNA degradation that accompanies
apoptosis. In
cell-free systems, mitochondria), but not nuclear, enriched fractions are
capable of
inducing nuclear apoptosis (Newmeyer et al., Cell 70:353-64, 1994).
Perturbation of
mitochondria) respiratory activity leading to altered cellular metabolic
states, such as
elevated intracellular ROS, may occur in mitochondria associated diseases and
may
2 0 further induce pathogenetic events via apoptotic mechanisms.
Oxidatively-stressed mitochondria may release a pre-formed soluble factor that
can induce chromosomal condensation, an event preceding apoptosis (Marchetti
et al.,
Cancer Res. 56:2033-38, 1996). In addition, members of the Bcl-2 family of
anti-
apoptosis gene products are located within the outer mitochondria) membrane
(Monaghan
2 5 et al., J. Histochem. Cytochem. 40:1819-25, 1992) and these proteins
appear to protect
membranes from oxidative stress (Korsmeyer et al, Biochim. Biophys. Act.
1271:63,
1995). Localization of Bcl-2 to this membrane appears to be indispensable for
modulation of apoptosis (Nguyen et al., J. Biol. Chem. 269:16521-24, 1994).
Thus,
changes in mitochondria) physiology may be important mediators of apoptosis.
To the
3 0 extent that apoptotic cell death is a prominent feature of neuronal loss
in AD,
mitochondria) dysfunction may be critical to the progression of this disease
and may also
be a contributing factor in other mitochondria associated diseases.
Focal defects in energy metabolism in the mitochondria, with accompanying
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increases in oxidative stress, may be associated with AD. It is well-
established that
energy metabolism is impaired in AD brain (Palmer et aL, Brain Res. 645:338-
42, 1994;
Pappolla et al., Am. J. Pathol. 140:621-28, 1992; Jeandel et al., Gerontol.
35:275, 1989;
Balazs et al., Neurochem. Res. 19:1131-37, 1994; Mecocci et al., Ann. Neurol.
36:747-
751, 1994; Gsell et al., J. Neurochem. 64:1216-23, 1995). For example,
regionally
specific deficits in energy metabolism in AD brains have been reported in a
number of
positron emission tomography studies (Kuhl, et al., J. Cereb. Blood Flow
Metab. 7:5406,
1987; Grady, et al., J. Clin. Exp. Neuropsychol. 10:576-96, 1988; Haxby et
al., Arch.
Neurol. 4:753-60, 1990; Azari et al., J. Cereb. Blood Flow Metab. 13:438-47,
1993).
Metabolic defects in the temporoparietal neocortex of AD patients apparently
presage
cognitive decline by several years. Skin fibroblasts from AD patients display
decreased
glucose utilization and increased oxidation of glucose, leading to the
formation of
glycosylation end products (Yan et al., Proc. Nat. Acad. Sci. U.S.A. 91:7787-
91, 1994).
Cortical tissue from postmortem AD brain shows decreased activity of the
mitochondrial
enzymes pyruvate dehydrogenase (Sheu et al., Ann. Neurol. 17:444-49, 1985) and
a-
ketoglutarate dehydrogenase (Mastrogiacomo et al., J. Neurochem. 6:2007-2014,
1994),
which are both key enzymes in energy metabolism. Functional magnetic resonance
spectroscopy studies have shown increased levels of inorganic phosphate
relative to
phosphocxeatine in AD brain, suggesting an accumulation of precursors that
arises from
2 0 decreased ATP production by mitochondria (Pettegrew et al., Neurobiol. of
Aging
15:117-32, 1994; Pettigrew et al., Neurobiol. of Aging 16:973-75, 1995). In
addition, the
levels of .pyruvate, but not of glucose or lactate, are reported to be
increased in the
cerebrospinal fluid of AD patients, consistent with defects in cerebral
mitochondrial
electron transport chain (ETC) activity (Parnetti et al., Neurosci. Lett
199:231-33, 1995).
2 5 Signs of oxidative injury are prominent features of AD pathology and, as
noted
above, reactive oxygen species (ROS) are critical mediators of neuronal
degeneration.
Indeed, studies at autopsy show that markers of protein, DNA and lipid
peroxidation are
increased in AD brain (Palmer et al., Brain Res. 645:338-42, 1994; Pappolla et
al., Am. J.
Pathol. 140:621-28, 1992; Jeandel et al., Gerontol. 35:275-82, 1989; Balazs et
al., Arch.
3 0 Neurol. 4:864, 1994; Mecocci et al., Ann. Neurol. 36:747-751, 1994; Smith
et al., Proc.
Nat. Acad. Sci. U.S.A. 88:10540-10543, 1991). In hippocampal tissue from AD
but not
from controls, carbonyl formation indicative of protein oxidation is increased
in neuronal
cytoplasm, and nuclei of neurons and glia (Smith et al., Nature 382:120-21,
1996).
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Neurofibrillary tangles also appear to be prominent sites of protein oxidation
(Schweers
et al., Proc. Nat. Acad. Sci. U.S.A. 92:8463, 1995; Blass et aL, Arch. Veurol.
4:864,
1990). Under stressed and non-stressed conditions incubation of cortical
tissue from AD
brains taken at autopsy demonstrate increased free radical production relative
to non-AD
controls. In addition, the activities of critical antioxidant enzymes,
particularly catalase,
are reduced in AD (Gsell et al., J. Neurochem. 64:1216-23, 1995), suggesting
that the AD
brain is vulnerable to increased ROS production. Thus, oxidative stress may
contribute
significantly to the pathology of mitochondria associated diseases such as AD,
where
mitochondria) dysfunction and/or elevated ROS may be present.
Increasing evidence points to the fundamental role of mitochondria)
dysfunction
in chronic neurodegenerative diseases (Beat, Biochim. Biophys. Acta 1366: 211-
223,
1998), and recent studies implicate mitochondria for regulating the events
that lead to
necrotic and apoptotic cell death (Susin et al., Biochim. Biophys. Aeta 1366:
151-168,
1998). Stressed (by, e.g., free radicals, high intracellular calcium, Ioss of
ATP, among
others) mitochondria may release pre-formed soluble factors that can initiate
apoptosis
through an interaction with apoptosomes (Marchetti et al., Cancer Res. 56:2033-
38, 1996;
Li et al., Cell 91: 479-89, 1997). Release of preformed soluble factors by
stressed
mitochondria, like cytochrome c, may occur as a consequence of a number of
events. In
any event, it is thought that the magnitude of stress (ROS, intracellular
calcium levels,
2 0 etc.) influences the changes in mitochondria) physiology that ultimately
determine
whether cell death occurs via a necrotic or apoptotic pathway. To the extent
that
apoptotic cell death is a prominent feature of degenerative diseases,
mitochondria)
dysfunction may be a critical factor in disease progression.
In a preferred embodiment of the present invention, the therapeutic or
2 5 prophylactic administration of antioxidant compounds, and/or the
diagnostic use thereof,
is enhanced by stimulation of the SPG and/or its related neuroanatomical
structures, by
using electrical stimulation, odorant presentation, and/or other means for
stimulating the
SPG or for modulating permeability ofthe BBB.
Example 8: Therapeutics (~3-amyloid inhibitors)
3 0 US Patent Application Publication 20020042420 to Briem et. al., describes
a
method to prepare compounds which may be capable of interfering (preferably in
an
inhibitory capacity) in the process of the formation of A[3 or its release
from cells, or of
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reducing the activity of A(3 by inhibiting it. Their description has the
further objective of
preparing compounds which can be used effectively for the prevention or
treatment of
Alzheimer's disease.
US Patent Application Publication 20020025955 to Han et al., describes the
potential use of lactams that inhibit the processing of amyloid precursor
protein and, more
specifically, inhibit the production of Aj3-peptide, thereby potentially
acting to prevent the
formation of neurological deposits of amyloid protein.
US Patent Application Publication 20020022621 to Chaturvedula et al.,
describes
a series of arylacetamidoalanyl derivatives of benzodiazepinones, which axe
inhibitors of
~i-amyloid peptide production and may be useful in the treatment of
Alzheimer's disease
and other conditions characterized by aberrant extract cellular deposition of
amyloid.
US Patent Application Publication 20010020097 to Audia et al., describes
compounds Which inhibit (3-amyloid peptide release and/or its synthesis, and,
accordingly,
may have utility in treating Alzheimer's disease both prophylactically and
therapeutically.
Introduction of the compounds into the brain, for therapeutic purposes, or out
of the brain,
for diagnostic purposes, may require crossing the BBB.
US Patent 6,211,235 to Wu et al., describes compounds which inhibit (3-amyloid
peptide release and/or its synthesis, and, accordingly, may have utility in
treating
Alzheimer's disease. It also describes pharmaceutical compositions comprising
a
2 0 compound which may inhibit (3-amyloid peptide release and/or its synthesis
when
introduced either directly or indirectly into the brain. Direct techniques
usually involve
placement of a drug delivery catheter into the host's ventricular system to
bypass the
blood-brain barrier. One such implantable delivery system used for the
transport of
biological factors to specific anatomical regions of the body is described in
US Patent
5,011,472 to Aebischer et al. Indirect techniques, which are generally
preferred, usually
involve formulating the compositions to provide for drug latentiation by the
conversion of
hydrophilic drugs into lipid-soluble drugs. Latentiation is generally achieved
thxough
blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present
on the drug
to render the drug more lipid soluble and amenable to transportation across
the BBB.
3 0 Alternatively, the delivery of hydrophilic drugs may be enhanced by infra-
arterial
infusion of hypertonic solutions which may transiently open the BBB to some
extent,
However, without using the techniques described herein, no general method is
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known to controllably open the BBB for the efficient delivery of large-
molecular weight
pharmaceutical compounds, or compounds with high plasma protein binding.
In a preferred embodiment of the present invention, the therapeutic or
prophylactic administration of the compounds described in this example
(Example 8),
and/or the diagnostic use thereof, is enhanced by stimulation of the SPG
and/or its related
neuroanatomical structures, by using electrical stimulation, odorant
presentation, and/or
other means for stimulating the SPG or for modulating permeability of the BBB.
Example 9: Therapeutics~~3-amyloid polymerization inhibitors)
Bernd Bohrmann et aI. reported (J Bio1 Chem, Vol. 274, Issue 23, 15990-15995,
June 4, 1999) that certain plasma proteins, at physiological concentrations,
are potent
inhibitors of /3-amyloid peptide polymerization. These proteins are also
present in
cerebrospinal fluid, but at low concentrations having little or no effect on
(3-amyloid.
Thirteen proteins representing more than 90% of the protein content in plasma
and
cerebrospinal fluid were studied. Quantitatively, albumin was the most
important protein,
representing 60% of the total amyloid inhibitory activity, followed by ocl-
antitrypsin and
immunoglobulins A and G. Albumin suppressed amyloid formation by binding to
the
oligomeric or polymeric beta-amyloid, blocking a further addition of peptide.
The results of Bohrmann et al. suggest that several endogenous proteins are
negative regulators of amyloid formation. Plasma contains at least 300 times
more
2 0 amyloid inhibitory activity than cerebrospinal fluid. These endings may
provide one
explanation as to why j3-amyloid deposits are not found in peripheral tissues
but are only
found in the central nervous system. Moreover, the data suggest that some
drugs that
display an affinity for albumin may enhance (3-amyloid formation and promote
the
development of AD.
2 5 Increased penetration of plasma proteins into the CNS may, on the other
hand,
have an inhibitory effect on ~i-amyloid polymerization, consequently slowing,
or
reversing, AI) progression.
In a preferred embodiment of the present invention, the permeability of the
BBB
is enhanced by stimulation of the SPG and/or its related neuroanatomical
structures, by
3 0 using electrical stimulation, odorant presentation, and/or other means for
stimulating the
SPG or for modulating permeability of the BBB, in order to permit (i-amyloid
polymerization inhibitors naturally occurring in the blood, particularly
albumin, to pass
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from the blood into the CNS.
Example 10: Therapeutics (micro~lial activation modulators)
Acute and chronic brain injuries can activate resident microglia (resident
macrophage-like cells found in the central nervous system) as well as recruit
peripheral
immune cells to injuxed brain regions that can exacerbate neuronal damage.
Inflammatory processes can induce cell death by (a) the release of proteases
and free
radicals that induce lipid peroxidation, (b) direct cytotoxic effects or (c)
the phagocytosis
of sublethally-injured neurons. The attenuation of microglia and peripheral
immune cell
activation has been correlated with significant neuronal protection in pre-
clinical studies
of ischemia, traumatic brain injury, spinal cord injury and Alzheimer's
disease. US Patent
Application Publication 20020022650 to Posmantur et al. describes methods of
modulating or inhibiting microglia activation comprising the administration of
a
compound capable of inhibiting 5-LO~', FLAP, attenuating degradation of IxBa
or
inhibiting nuclear translocation of the NF-~cB active complex fox the
treatment of various
disorders associated with excessive production of inflammatory mediators in
the brain,
among which is Alzheimer's disease.
In a preferred embodiment of the present invention, the therapeutic or
prophylactic administration of the compounds described in this example
(Example 10),
and/or the diagnostic use thereof, is enhanced by stimulation of the SPG
and/or its related
2 0 neuroanatomical structures, by using electrical stimulation, odorant
presentation, and/or
other means for stimulating the SPG or for modulating permeability of the BBB.
Example 11: Therapeutic~SAID)
Studies support an inverse relationship between anti-inflammatory medications
used for treating patients with rheumatoid arthritis and an associated low
prevalence of
Alzheimer's disease (Rich, J.B. et al., Neurology 45:51-55, 1995). Controlled
studies of
twin pairs having Alzheimer's disease onset greater than 3 years apart provide
additional
support that prior treatment with anti-inflammatory medications serves a
protective role
in Alzheimer's disease (Breitner, J.C.S. et al., Neurology 44:227-232, 1994).
Specifically, controlled double-blinded studies have found that the anti-
inflammatory
3 0 agent "indomethacin" administered orally has a therapeutic benefit for
mild to moderately
cognitively-impaired Alzheimer's disease patients, and treatment with
indomethacin
during early stages of the disease has a retarding effect on disease
progression compared
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to the placebo treated control group. (Rogers, J. et al., Neurology 43:1609-
1612, 1993).
Alzheimex's patients with moderate cognitive impairment treated with
indomethacin also
exhibit a reduction in cognitive decline. However, patients treated with oral
indomethacin developed drug related adverse effects that xequired their
treatment to be
discontinued and their removal from the study.
US Patent Application Publication 20010027309 to Elsberry describes a method
for treating Alzheimer's disease, comprising delivering indomethacin or
nonsteroidal anti-
inflammatory drugs (NSAIDs) having cyclooxygenase inhibitor action directly to
the
hippocampus or the lateral ventricle through an implanted catheter.
It may also be advantageous to allow NSAID and other anti-inflammatory drugs
into the CNS in combination with immunological (vaccine) treatment of AD. A
vaccine,
made by Elan Corporation (Dublin, Ireland) and known by its code name AN-1792,
was
tested in a clinical trial. In the trial, twelve volunteers were reported to
have fallen
seriously ill with brain inflammation, forcing the vaccine's manufacturer to
halt the trial
and raising doubts about the product's clinical potential. The AN-1792 vaccine
had
generated unusually intense enthusiasm among scientists and patient advocates
during the
past two years, as experiments in mice suggested it could halt the progression
of
Alzheimer's and pexhaps even cure the deadly disease.
In general, NSAlDs are known to be very extensively protein bound (>99%).
2 0 This characteristic makes the penetration of NSAID into the CNS very
scarce, since they
are usually bound to plasma proteins having molecular weights of around 70
kDa.
Therefore, allowing macromolecules into the CNS is expected to allow the
introduction of anti-inflammatory drugs. These, on their own, or in
conjunction with
immunological or other therapeutic approaches, can serve as an effective
treatment for
2 5 AD.
In a preferred embodiment of the present invention, the therapeutic or
prophylactic administration of NSA~s and other anti-inflammatory agents,
and/or the
diagnostic use thereof, is enhanced by stimulation of the SPG and/or its
related
neuroanatomical structures, by using electrical stimulation, odorant
presentation, and/or
3 0 other means for stimulating the SPG or for modulating permeability of the
BBB.
In another preferred embodiment of the present invention, the administration
of a
vaccine is enhanced by stimulation of the SPG and/or its related
neuroanatomical
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structures, by using electrical stimulation, odorant presentation, and/or
other means for
stimulating the SPG or for modulating permeability of the BBB.
Example 12: Therapeutics (vaccine)
US Patent Application Publication 20020009445 to Du et al., discusses the use
of
an anti-A(3 antibody for diagnosing and/or treating amyloid associated
diseases, especially
Alzheimer's disease. They indicate that naturally-occurring A(3 antibodies
exist in
biologically relevant fluids, i.e., CSF and plasma, and that levels of these
antibodies differ
between normal age-matched healthy controls and AD patients. Based on these
findings
it was concluded and then supported by experiments that these antibodies can
be used for
diagnosis and treatment of amyloid associated diseases and especially of
Alzheimer's
disease. In the context of this application, the terms "anti-A(3 antibodies"
and "A(3
antibodies" are used interchangeably to designate the antibody of their
invention. An
embodiment of their diagnostic method uses lumbar CSF samples, on which A~i
antibody
levels were determined utilizing an ELISA assay in which the A~i peptide was
used as the
capture ligand.
In a preferred embodiment of the present invention, the therapeutic or
prophylactic administration of anti-A(3 antibodies, andlor the diagnostic use
thereof, is
enhanced by stimulation of the SPG and/or its related neuroanatomical
structures, by
using electrical stimulation, odorant presentation, and/or other means for
stimulating the
2 0 SPG or for modulating permeability of the BBB.
Example 13: Therapeutics other approaches)
US Patent Application Publication 20020022593 to Yue describes a method of
treating neurodegenerative dysfunctions and aging symptoms by administering a
therapeutically-effective amount of relaxin (a polypeptide hormone, whose
molecular
weight is between 5,700 to 6,500 Da) to a patient. Neurodegenerative
dysiunctions
potentially amenable to treatment with relaxin include Alzheimer's, attention
deficit
disorder, Parkinson's, and others. The aforementioned method is based on the
recognition
that some of the symptoms associated with aging and/or neurodegenerative
dysfunctions
can be alleviated by relaxin, and may in fact be caused by a decrease of
relaxin in the
3 o bloodstream. This lack of relaxin in the blood stream may be congenital or
the result of
another mechanism which suppresses the normal production or action of relaxin.
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In a preferred embodiment of the present invention, the therapeutic or
prophylactic administration of relaxin, and/or the diagnostic use thereof, is
enhanced by
stimulation of the SPG and/or its related neuroanatomical structures, by using
electrical
stimulation, odorant presentation, and/or other means for stimulating the SPG
or for
modulating permeability of the BBB.
US Patent Application Publication 20020019412 to Andersen et al., describes
novel inhibitors of Protein Tyrosine Phosphatases (PTPase's) such as PTP1B,
CD45,
SHP-1, SHP-2, PTPa, LAR and HePTP or the like, for treatment of various
systemic and
CNS-related disorders, including Alzheimer's disease.
In a preferred embodiment of the present invention, the therapeutic or
prophylactic administration of PTPase's, and/or the diagnostic use thereof, is
enhanced by
stimulation of the SPG and/or its related neuroanatomical structures, by using
electrical
stimulation, odorant presentation, and/or other means for stimulating the SPG
or for
modulating permeability of the BBB.
US Patent Application Publication 20020006959 to Henderson describes a method
of potentially treating or preventing dementia of Alzheimer's type, or other
loss of
cognitive function caused by reduced neuronal metabolism, comprising
administering an
effective amount of medium chain triglycerides to a patient in need thereof.
In a preferred embodiment of the present invention, the therapeutic or
2 0 prophylactic administration of medium chain triglycerides, andlor the
diagnostic use
thereof, is enhanced by stimulation of the SPG and/ox its related
neuroanatomical
structures, by using electrical stimulation, odorant presentation, and/or
other means for
stimulating the SPG or for modulating permeability of the BBB.
Example 14: Dia n~tics
2 5 Accurate diagnosis of AD during life is highly desirable. However,
clinical
evaluation is at best only about 80% accurate. Therefore, there exists a need
to identify
specific biochemical markers of AD. So far, analysis of blood or cerebrospinal
fluid
(CSF) has not yielded a biochemical marker of sufficient diagnostic value
(Blass et al.,
1998), although detectable differences are reported in the levels of certain
proteins
3 0 (Motter et al., Ann. Neurol. 38, 643-648, 1995).
Although recent reports of using positron-emission tomography (PET) (Reiman,
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E.M., et al., New Eng. J Med., 334:752-758, 1996), determining the genotype of
an
individual's ApoE, or measuring the levels of ~i-arnyloid protein in cerebral
spinal fluid
may be promising, diagnosis of AD is currently confirmed only upon autopsy to
determine the presence of (3-amyloid senile plaques.
Moreover, recent studies have shown that damage to CNS neurons due to
Alzheimer's disease begins years before clinical symptoms are evident (Reiman,
E.M. et
al., New Eng. J Med., 334:752-758, 1996), suggesting that therapy could begin
in the pre-
symptomatic phase of the disease if a sensitive diagnostic test and targeted
therapies were
available. There exists a great need to determine the physiological mechanisms
involved
with the disease and for an accurate and easy to perform assay to evaluate the
risk of
developing Alzheimer's disease.
US Patent Application Publication 20020042121 to Riesner et al., describes a
method for the diagnostic detection of diseases associated with protein
depositions
(pathological protein depositions) by measuring an association of
substructures of the
pathological protein depositions, structures forming pathological protein
depositions,
structures corresponding to pathological protein depositions and/or
pathological protein
depositions as a probe or a target.
US Patent Application Publication 20020028462 to Tanzi et al., describes a
diagnostic method for AD based on genotyping the Alpha-2-Macroglobulin locus.
A
2 0 statistically-significant correlation was found between inheritance of
particular alleles of
the Alpha-2-Macroglobulin gene and the occurrence of AD. The diagnostic method
involves the isolation of nucleic acid from an individual and subsequent
genotyping by
means such as sequencing or restriction fragment length polymorphism analysis.
The
invention also describes a means for genotype analysis through protein
isotyping Alpha-
2 5 2-Macroglobulin variant proteins. Finally, kits for nucleic acid analysis
or protein
analysis are described.
US Patent Application Publication 20020022242 to Small et al., describes a
method for the diagnosis of AD in a patient by detecting the presence of BuChE
with an
altered glycosylation pattern in an appropriate body fluid sample. It has been
established
3 0 that on average approximately 93.6% of the BuChE in the CSF of AD patients
binds to
Concanavalin (Con A). All embodiments of this method are described as using
either
CSF or brain tissue as the sample, thereby adding a risk factor to the
diagnostic
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procedure.
US Patent Application Publication 20020019519 to Bingham et al., describes the
use of KIAA0551 polypeptides and polynucleotides in the design of protocols
fox the
treatment of and also for diagnostics assays of AD.
US Patent Application Publication 20010044126 to Holtzman et al., describes a
diagnostic method for identifying individuals at risk for developing
Alzheimer's disease,
which relies on elevated levels of the ratio of A(340/A(342 associated with
lipoproteins in
the cerebrospinal fluid of individuals at risk as compared to this ratio in
the overall
population. It is based on the assessment that the lipoprotein fraction of CSF
in such
individuals has such increased ratios.
US Patent Application Publication 20020019016 to Vanmechelen et al., describes
a method for the differential diagnosis of an individual suffering from AD
versus an
individual suffering from another neurological disease (dementia with Lewy
bodies,
Parkinson's disease without dementia, . multi-system atrophy and/or
progressive
supranuclear palsy), where phospho-tau is used as a neurological marker, the
Level of
which is measured in a CSF sample.
US Patent Application Publication 20020009445 to Du et al., cited and
sununarized hereinabove, describes the use of an anti-A(3 antibody for
diagnosing and/or
treating amyloid associated diseases, especially Alzheimer's disease.
2 0 US Patent Application Publication 20020006627 to Reitz et al., describes a
method for diagnosing Alzheimer's disease involving analysis of a test sample
in such a
way that (3-amyloidl_42 or Aj33pE is completely or nearly completely (i.e.,
thoroughly)
dissociated from binding proteins prior to the analysis of the levels of (3-
amyloidl-42 or
Aji3pE.
US Patent Application Publication 20020002270 to Zinkowski et al., describes a
preparation comprising Alzheimer's disease antigen (A68), as well as methods
of
obtaining this purified antigen (Ag), and methods using the purified Ag, for
instance, fox
diagnosing Alzheimer's Disease, and also describes treatments of these Ags
that enhance
their reactivity with autoantibodies directed against A68. These treatments
include
3 0 treatment with hypericin, free fatty acids, and/or hydroxynonenal or other
advanced
glycation end products.
US Patent Application Publication 20010026916 to Ginsberg et al., describes a
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method of identifying senile plaques, neurofibrillary tangles and neuropil
threads in brain
tissue which comprises contacting brain tissue with a fluorescent dye capable
of
intercalating selectively into nucleic acids and detecting any fluorescence in
the brain
tissue indicative of senile plaques, neurofibrillary tangles and neuropil
threads in the brain
tissue.
US Patent 6,238,892 to Mercken et al., describes the use of a monoclonal
antibody
which forms an immunological complex with a phosphorylated epitope of an
antigen
belonging to human abnormally phosphorylated tau protein. The tau protein can
be
obtained from a brain homogenate, itself isolated from the cerebral cortex of
a patient
having Alzheimer's disease. Methods for in-vivo diagnosis of AD using the
latter mAb,
should preferably employ techniques that leaves the meninges intact. Such
methods are
described in this patent as being yet undeveloped.
The '892 patent provides an overview of tau (complete references have been
provided):
Tau is a microtubule-associated protein which is synthesized in the
neurons (Kosik, K.S. et al., Ann. Neurol. 26, 352-361, 1989) of several
species, including humans, and which is abundantly present in the axonal
compartment of these neurons (Binder, L.I. et al., J. Cell Biol., 101:1371-
1378, 1985). Functionally the tau protein is involved in the
2 0 polymerization of tubulin (Weingarten, M.D. et al., Proc. Natl. Acad. Sci.
U.S.A. 72, 1868-1862, 1975) and presumably in reducing microtubule
instability (Bre, M.H. et al., Cell Motil. Cytoskeleton 15, 88-98, 1990).
Tau protein is also the major constituent of paired helical filaments
(PHF), characteristic structures found as neurofibrillary tangles in tissue
2 5 sections of the brain of Alzheimer patients (Greenberg, S. et al., Proc.
Natl. Acad. Sci. U.S.A., 87, 5827-5831, 1990; Lee, V. M.-Y. et al.,
Science, 251, 675-678, 1991). The protein exists as a family of different
isoforms of which 4 to 6 isoforms are found in normal adult brain but only
1 isoform is detected in fetal brain (Goedert, M. et al., Neuron 3, 519-526,
3 0 1989). The diversity of the isoforms is generated from a single gene by
alternative mRNA splicing (Himmler, A., Mol. Cell. Biol., 9, 1389-1396,
1989). The most striking feature of tau protein as predicted from
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molecular cloning is a stretch of 31 or 32 amino acids occurring in the
carboxy-terminal part of the molecule that is repeated 3 or 4 times.
Additional diversity is generated through 29 or 58 amino acid long
insertions in the NH2-terminal part of the molecules (Goedert, IVI, et al.,
Neuron 3, 519-526, 1989).
Tau variants of 64 and 69 kDa, which are abnormally
phosphorylated as revealed by the decrease in their molecular mass
observed after allcaline phosphatase treatment, have been detected
exclusively in brain areas showing neurofibrillary tangles and senile
plaques (Flament, S. et al., A., J. Neuxol. Sci. 92, 133-141, 1989; Flament,
S. et al., Brain Res. 516, 15-19, 1990; and Flament, S. et al., Nature 346,
6279, 1990). The sites of phosphorylation by 4 different kinases have
been mapped in the C-terminal microtubule-binding half of tau and it
could be shown that the action of a calcium calmodulin-dependent kinase
on bacterially expressed tau resulted in a phosphorylation of Ser(405)
which induced a lower electrophoretical mobility (Steiner, B. et al., The
EMBO Journal 9, 3539-3544, 1990).
Several antibodies are reported that show reactivity to human tau
either because they are directed to nonspecific phosphorylated epitopes
2 0 present on neurofilament and subsequently shown to cross-react with
normal and abnormally phosphorylated tau (Nuking, N. et al., Proc. Natl.
Acad. Sci. U.S.A. 84, 3415-3419, 1987; Ksiezak-Reding et al., Proc. Natl.
Acad. Sci. U.S.A., 84, 3410-3414, 1987) or because they recognized
specific epitopes on normal and abnormally phosphorylated tau.
The A1z50 monoclonal antibody (Wolozin, B.L. et al., Science 232,
648-650, 1986; Nuking et al., Neurosci. Lett 87, 240-246, 1988)
recognizing a phosphate-independent epitope present on tau variants of
bovine origin and of normal and abnormally phosphorylated tau from
human origin (Ksiezak-Reding, H. et al., J. Biol. Chem., 263, 7943-7947,
3 0 1988, Flament, S. et al., Brain Res. 516, 15-I9, 1990; and Flament, S. et
al., Nature 346, 6279, 1990) belongs to the latter class of antibodies. The
epitope recognized by this monoclonal is specifically expressed in the
somatodendritic domain of degenerating cortical neurons during
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Alzheimer disease (Delacourte, A. et al., Acta Neuropathol. 80, 111-117,
1990).
The A1z50 epitope has recently been mapped to the NH2-terminal
part of the tau molecule (Ksiezak-Reeling, H. et al., J. Neurosci. Res., 25,
4I2-4I9, 1990; Goedert, M. et al., Neurosci. Lett., 126, 149-I54, 1991).
Due to its cross-reactivity with normal tau, this antibody is only able to
discriminate normal from abnormally phosphorylated tau by the use of
Western blotting detection of brain homogenates or by ammonium sulfate-
concentrated CSF, or also by using a sandwich immunoassay on brain
homogenates (Ghanbari et al., J. Clin. Laboratory Anal. 4, 189-192, 1990;
Wolozin, B. et al, Ann. Neurol. 22, 521-526, 1987; European Patent
Application Publication EP 0 444 856 to Ghanbari et al.). A CSF-based
assay using antibodies directed against PHF was first described by Mehta
et al., The Lancet, July, 35, 1985, but shows considerable overlap between
Alzheimer CSF and CSF from controls. The epitope recognized by this
antibody was identified as part of ubiquitin (Perry et al., J. Neurochem. S2,
1523-1528, 1989).
Other monoclonal antibodies have been developed to recognize tau
protein. For instance, monoclonal antibody 5E2 was raised by
2 0 immunization with human fetal heat-stable microtubule-associated
proteins and recognizes an epitope spanning amino acids I56-175 which is
present in normal and abnormally phosphorylated tau (Kosik, K. S. et al.,
Neuron., 1, 817-825, 1988).
Other antibodies such as tau 1 and several others were raised by
2 5 immunization with bovine tau, bovine heat-stable microtubule-associated
protein, or rat brain extracts (Binder, L. I. et al., J. Cell Biol. 101, 1371-
1378, 1985; Kosik, K.S. et al., Neuron., l, 817-825, 1988), and most of the
antibodies recognize the normal and the abnormally phosphorylated tau
(Ksiezak-Reeling, H. et al., J. Neurosci. Res., 25, 412-419, 1990).
3 0 An antibody named "423", raised against the core of PHF, reacted
specifically with a 9.5 and 12-kDa fragment of the tau protein, localized in
the repetitive elements of tau, but recognized neither normal human tau
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nor the abnormally phosphorylated tau in Alzheimer's brain (Wischik,
C.H. et al., Proc. Natl. Acad. Sci. U.S.A., 85, 4884-4888, 1988). This
antibody has been used to discriminate Alzheimer PHF pathology from
normal controls in brain homogenates (Harrington, C.R, et al., J. Immunol.
Methods 134, 261-271, 1990; PCT Publication W089/03993 to Wischik et
al.).
Thus far, none of all the antibodies described heretofore has had an
absolute specificity for the abnormally phosphorylated tau either by
immunohistology, Western blotting, or ELISA. Quantitative
measurements of normal and abnormally phosphorylated tau have until
now only been able to detect tau in brain homogenates, in brain extracts
containing PHF, or in concentrated CSF samples after Western blotting
(Ghanbari H.A. et al., J. Clin. Laboratory Anal. 4, 189-192, 1990;
Harrington C.R. et al., J. Immunol. Methods 134, 261-271, 1990,
Wisniewski, H.M. et al., Biologieal lvlarkers ~f Alzheime~~'s Disease,
Boiler, Katzman, Rascol, Signoret & Christian eds., 23-29, 1989; Wolozin,
B. et al., Ann. Neurol. 22, 521-526, 1987).
US Patent Application Publication 20010018191 to Mercken et al., describes
monoclonal antibodies which are described as specifically able to detect only
abnormally-
2 0 phosphorylated tau present in brain tissue sections, in brain extracts, or
in body fluids
such as cerebrospinal fluid. It is required that a method for bypassing the
BBB be
employed in order to introduce the monoclonal antibodies into the CNS.
US Patent Application Publication 20010014670 to Balin et al., describes a
method of treating Alzheimer's disease in a mammal comprising administering to
the
2 5 mammal an anti-microbial agent having anti-Chlamydia pneumoniae activity.
The
description also relates to a method of diagnosing Alzheimer's disease in a
mammal
comprising measuring the serum anti-Chlamydia pneumoniae antibody titer in a
patient
suspected of having Alzheimer's disease. It is required that a method for
bypassing the
BBB be employed in order to communicate the therapeutic compounds, antibodies,
into
3 0 the CNS, or to be able to evaluate presence of diagnostic agents (e.g. C.
Pneumoniae) in a
minimally invasive method.
US Patent 6,287,793 to Schenk et al., describes methods for the identification
of
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key diagnostic antibodies, antigens, diagnostic kits and methods for diagnosis
for AD,
where the diagnostic procedure uses a biological fluid from a subject - most
preferred are
plasma and CSF sample.
Inducing changes in BBB permeability, as provided by preferred embodiments of
the present invention, is useful for detecting acetylcholinesterase in human
patients. Loss
of acetylcholinesterase in humans is associated with brain disorders, such as
dementia and
epilepsy, muscle disorders, and disorders of the digestive system. The methods
of some
embodiments' of the present invention are particularly useful for detecting
acetylcholinesterase in the brain of a patient suspected of suffering from a
dementia, such
as Alzheimer's disease, thereby allowing the diagnosis, estimating the
severity of, and
monitoring the progression of the dementia. Certain brain disorders and
dementia,
including Alzheimer's disease, are known to be accompanied by a decrease in
acetylcholinesterase concentration in the brain. Thus, monitoring the
concentration of
acetylcholinesterase in the brain of a patient suspected of suffering from a
brain disorder
or dementia typically allows diagnosis of the disorder or dementia, monitoring
its
progression, and/or estimating its severity. Advantageously, this diagnosis
and
monitoring is simply performed, for example, by stimulating the SPG using
techniques
described herein, and, simultaneously or shortly thereafter, extracting a
blood sample
using standard lab techniques. Since the increase in BBB permeability allows
the
2 0 acetylcholinesterase to pass therethrough, it is quickly in the systemic
bloodstream and
detectable in the blood sample. It is to be understood that other compounds of
diagnostic
value can be extracted using essentially the same technique.
The methods of some embodiments of the present invention can be used to
provide a brain image that shows the distribution and relative concentrations
of
2 5 acetylcholinesterase (or other compounds of diagnostic value) in a
patient's brain, thereby
allowing diagnosis, estimating the severity of, and analysis of the
progression of a
disorder or dementia in a patient. The methods of some embodiments of the
invention can
therefore be used to diagnosis, estimate the severity, and monitor the
progression of any
dementia, known or to be discovered, that is accompanied by a detectable
change in
3 0 concentration of acetylcholinesterase or other compounds of diagnostic
value in the brain.
In a preferred embodiment, a molecule such as an antibody which is attracted
to
acetylcholinesterase is injected, swallowed, or otherwise introduced
systemically, and its
passage into the CNS is facilitated by techniques described herein for
increasing
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permeability of the BBB. Imaging techniques which are able to detect the
introduced
molecule are then utilized to determine the locations or quantities of
acetylcholinesterase
or other diagnostic compounds to which the molecule is attached.
Some of the diagnostic techniques mentioned above indicate to the inventors
that
there is a need for performing diagnostic tests on certain bio-chemical
characteristics of
the CSF by using a simple blood test. Other diagnostic techniques mentioned
above
indicate to the inventors that there is a need for increasing the permeability
of the 8BB
using techniques described herein in order to facilitate the passage of
diagnostic
molecules into the CNS, where the molecules can be detected, such as by
imaging.
Diagnostic procedures, which are on one hand highly accurate and on the other
minimally
invasive, typically substantially improve the management of AD, when applied
in
accordance with a preferred embodiment of the present invention. In a
preferred
embodiment of the present invention, the diagnostic techniques described in
this example
(Example 14) are enhanced and/or enabled by stimulation of the SPG and/or its
related
neuroanatomical structures, by using electrical stimulation, odorant
presentation, and/or
other means for stimulating the SPG or for modulating permeability of the BBB.
Techniques described in the present patent application may be practiced in
combination with methods and apparatus described in one or moxe of the
following patent
applications, which are assigned to the assignee of the present patent
application and are
2 0 incorporated herein by reference:
~ PCT Publication WO 01/85094, filed May 7, 2001, entitled, "Method and
apparatus for stimulating the sphenopalatine ganglion to modify properties
of the BBB and cerebral blood flow"
~ US Provisional Patent Application 60/364,451, filed March 15, 2002,
2 5 entitled, "Applications of stimulating the sphenopalatine ganglion (SPG)"
~ US Provisional Patent Application 60/368,657, filed March 28, 2002,
entitled, "SPG Stimulation"
~ US Provisional Patent Application 60/376,048, filed April 25, 2002,
entitled, "Methods and apparatus for modifying properties of the BBB and
3 0 cerebral circulation by using the neuroexcitatory andlor neuroinhibitory
effects of odorants on nerves in the head"
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~ US Provisional Patent Application 60/388,931, filed June 14, 2002,
entitled "Methods and systems for management of Alzheimer's disease"
~ US Provisional Patent Application 60/400,167, filed July 31, 2002,
entitled, "Delivering compounds to the brain by modifying properties of
the BBB and cerebral circulation"
~ a US Provisional Patent Application, filed November 14, 2002, entitled,
"Surgical tools and techniques for sphenopalatine ganglion stimulation"
~ a US Provisional Patent Application, filed November 14, 2002, entitled,
"Stimulation circuitry and control of electronic medical device"
~ a US Patent Application, filed November 14, 2002, entitled, "SPG
stimulation for treating eye pathologies"
~ a US Patent Application, filed November 14, 2002, entitled,
"Administration of anti-inflammatory drugs into the CNS"
~ a US Provisional Patent Application, filed November 14, 2002, entitled,
"Stimulation for treating ear pathologies"
~ a US Provisional Patent Application, filed February 20, 2003, entitled,
"Stimulation for treating autoimmune-related disorders ofthe CNS"
~ a US Provisional Patent Application to Gross et al., filed April 8, 2003,
entitled, "Treating abnormal conditions of the mind and body by
2 0 modifying properties of the blood-brain barrier and cephalic blood flow"
~ a PCT patent application to Shalev, filed April 25, 2003, entitled,
"Methods and apparatus for modifying properties of the BBB and cerebral
circulation by using the neuroexcitatory and/or neuroinhibitory effects of
odorants on nerves in the head"
It will be appreciated by persons skilled in the art that the present
invention is not
limited to what has been particularly shown and described hereinabove. Rather,
the scope
of the present invention includes both combinations and subcornbinations of
the various
features described hereinabove, as well as variations and modifications
thereof that are
not in the prior art, which would occur to persons skilled in the art upon
reading the
3~0 foregoing description. For example, elements which are shown in a figure
to be housed
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within one integral unit may, for some applications, be disposed in a
plurality of distinct
units. Similarly, apparatus for communication and power transmission which are
shown
to be coupled in a wireless fashion may be, alternatively, coupled in a wired
fashion, and
apparatus for communication and power transmission which are shown to be
coupled in a
wired fashion may be, alternatively, coupled in a wireless fashion.
