EP1521614A2 - Procedes et systemes de gestion de la maladie d'alzheimer - Google Patents

Procedes et systemes de gestion de la maladie d'alzheimer

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Publication number
EP1521614A2
EP1521614A2 EP03730451A EP03730451A EP1521614A2 EP 1521614 A2 EP1521614 A2 EP 1521614A2 EP 03730451 A EP03730451 A EP 03730451A EP 03730451 A EP03730451 A EP 03730451A EP 1521614 A2 EP1521614 A2 EP 1521614A2
Authority
EP
European Patent Office
Prior art keywords
subject
spg
nerve
odorant
stimulation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03730451A
Other languages
German (de)
English (en)
Inventor
Alon Shalev
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Brainsgate Ltd
Original Assignee
Brainsgate Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/294,310 external-priority patent/US7146209B2/en
Application filed by Brainsgate Ltd filed Critical Brainsgate Ltd
Publication of EP1521614A2 publication Critical patent/EP1521614A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36082—Cognitive or psychiatric applications, e.g. dementia or Alzheimer's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36014—External stimulators, e.g. with patch electrodes
    • A61N1/36017—External stimulators, e.g. with patch electrodes with leads or electrodes penetrating the skin

Definitions

  • 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).
  • AD Alzheimer's disease
  • Alzheimer's disease is the most common form of both senile and presenile dementia in the world and is recognized clinically as relentlessly progressive loss of memory and intellectual function and disturbances in speech (Merritt, 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
  • Alzheimer's disease is found in about 10% of
  • Alzheimer's Disease is characterized by the accumulation of insoluble, 10 n filaments containing ⁇ -amyloid (A ⁇ ) peptides, localized in the extracellular space of the cerebral cortex and vascular walls. These 40 or 42 amino acid long A ⁇ peptides are
  • the brain is driven by the presence of mutations in the ⁇ APP 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
  • the etiology of Alzheimer's disease is unknown.
  • Evidence for a genetic contribution comes from several important observations such as the familial incidence,
  • AD 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:
  • 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., J Neuropathol Exp Neurol 53:438-447, 1994; Dickson, D.W., J Neuropathol Exp Neurol 56:321-339, 1997; Hardy, J.
  • a ⁇ amyloid ⁇ protein
  • PHF paired-helical filaments
  • 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 genes, and all of them also cause FAD with 100% penetrance. In addition, in vitro and in vivo studies have demonstrated that PSI and PS2 mutations shift APP metabolism, resulting in elevated A ⁇ 42 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 ⁇ generation and amyloid deposition are the primary cause of neuronal death and synaptic loss observed in AD.
  • 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 Neurology, 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 paired helical and straight filaments in the cytoplasm of affected neurons (Oyanagei, Adv.
  • Alzheimer's disease during life is more difficult than at autopsy since the diagnosis depends upon inexact clinical observations. In the early and middle 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 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.
  • 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, acefylcholinesterase activity, and choline uptake (Davis, Brain Res. 171:319-327, 1979 and Hardy et al., Neurochem. Int.
  • Nerve cells produce nerve growth factors, proteins 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 cord 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.
  • BBB blood-brain barrier
  • 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 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: • 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.
  • 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.
  • 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.
  • 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.
  • the cerebral endothelial cell has very few pinocytic vesicles, and these vesicles are not involved in any transport function.
  • astrocyte foot processes surround the microvascular endothelium and cover more than 95 percent of its surface, therefore interposing between capillaries and cerebral neuropil.
  • 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 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 passage of ionized water-soluble compounds with a molecular weight greater than 180
  • 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% 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 are 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.
  • Silver WL "Neural and pharmacological basis for nasal irritation," in Tucker WG, Leaderer BP, M ⁇ lhave L, Cain WS (eds), Sources of Indoor Air Contaminants, Ann. NY Acad. Sci., 641, 152-163 (1992)
  • Silver W "Chemesthesis: the burning questions,” ChemoSense, Vol. 2 No. 1, 1-2 (1999)
  • 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.
  • the 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).
  • BBB blood-brain barrier
  • inventions 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.
  • 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 nerve of the pterygoid canal also called a vidian nerve
  • a nerve of the pterygoid canal also called a vidian nerve
  • a petrosal nerve a preganglionic parasympathetic nerve
  • a lesser deep petrosal nerve a postganglionic sympathetic nerve
  • a greater palatine nerve • a petrosal nerve (a preganglionic parasympathetic nerve) or a lesser deep petrosal nerve (a postganglionic sympathetic nerve); • a greater palatine nerve;
  • 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.
  • 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).
  • 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 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 allows better transport of molecules from within these blood vessels to surrounding tissue.
  • PPE plasma protein extravasation
  • 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.
  • 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.
  • similar methods for approaching the SPG are utilized, to enable the electrical stimulation or electrical blocking thereof.
  • 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 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.
  • this method can serve as a neurological drug delivery facilitator, without the sacrifices in molecular weight required by techniques of the prior art.
  • 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 other tissue.
  • this treatment is given on a long-term basis, e.g., in the chronic treatment of Alzheimer's patients.
  • 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.
  • 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.
  • odorants such as propionic acid, cyclohexanone, and amyl acetate, significantly increase cortical blood flow when presented to the nasal cavity.
  • 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.
  • 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.
  • 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.
  • 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, pipeline, gingerol, zingerone, allyl isothiocyanate, cinnamaldehyde, cuminaldehyde, 2-propenyl/2-phenylethyl isothiocyanate, thymol, and eucalyptol.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a method 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 resultant improvement in oxygen supply to neurons and other tissue.
  • this treatment is given on a long-term basis, e.g., in the chronic treatment of Alzheimer's patients.
  • 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.
  • 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.
  • 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.
  • pharmacological treatments aimed at cerebral cells for neurological and psychiatric disorders are amenable for use with these embodiments of the present invention.
  • 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.
  • 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 an increase in permeability of a blood-brain barrier (BBB) of the patient.
  • SPG sphenopalatine ganglion
  • BBB blood-brain barrier
  • 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 an increase in cerebral blood flow of the patient.
  • SPG sphenopalatine ganglion
  • 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.
  • SPG sphenopalatine ganglion
  • 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.
  • SPG sphenopalatine ganglion
  • the one or more electrodes are adapted for a period of implantation in the patient greater than about one month.
  • 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.
  • the control unit is adapted to drive the one or more electrodes by wireless communication from a position external to the patient.
  • the apparatus includes an electromagnetic coupling, adapted to couple the control unit and the one or more electrodes.
  • the control unit is adapted to be in electro-optical communication with the one or more electrodes.
  • the control unit is adapted to be in electro-acoustic communication with the one or more electrodes.
  • the control unit is adapted to be implanted in a nasal cavity of the patient.
  • the one or more electrodes are adapted to be implanted in a nasal cavity of the patient.
  • at least one of the one or more electrodes 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 is preferably adapted to modify a parameter of the applied current responsive to the signal.
  • the biosensor may include one or more of the following:
  • TCD transcranial Doppler
  • 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.
  • control unit is typically adapted to analyze the signal to detect an indication of a change in body disposition of the patient.
  • 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 increased.
  • 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.
  • control unit is adapted to drive the one or more electrodes to apply the current responsive to an indication of stroke.
  • control unit is adapted to drive the one or more electrodes to apply the current responsive to an indication of migraine of the patient.
  • 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.
  • SPG sphenopalatine ganglion
  • BBB blood-brain barrier
  • 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 spinal pressure regulation
  • a neural tract originating in or leading to the SPG
  • applying a current to the site capable of inducing an increase in cerebral blood flow of the patient.
  • 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 of the patient.
  • SPG sphenopalatine ganglion
  • 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 inhibiting parasympathetic activity of the SPG.
  • SPG sphenopalatine ganglion
  • the one or more electrodes are adapted for a period of implantation in the patient less than about one week.
  • 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.
  • the detecting element includes an energy transmitter and an energy receiver.
  • the energy transmitter may include an ultrasound transmitter or a transmitter of electromagnetic energy.
  • 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.
  • 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.
  • AD Alzheimer's disease
  • SPG sphenopalatine ganglion
  • the stimulation causes increased clearance of the substance from the brain.
  • the substance may be one or more of the following:
  • the substance may include DNA.
  • the stimulation causes increased clearance of the substance from cerebrospinal fluid (CSF).
  • CSF cerebrospinal fluid
  • the substance may be one or more of the following: amyloid; tau protein;
  • RNA fragments RNA fragments; cytokine; a marker of neuronal death; a marker of neuronal degeneration; • a marker of an inflammatory process; and a neurotoxic substance.
  • the substance may include DNA.
  • a method for treating Alzheimer's disease including: 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.
  • AD Alzheimer's disease
  • SPG sphenopalatine ganglion
  • the pharmaceutical agent may be one or more of the following:
  • 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 ⁇ -amyloid and/or antibodies against tau protein.
  • the pharmaceutical agent is adapted to have an inhibitory effect on the derivation of ⁇ -amyloid from amyloid precursor protein.
  • a method for diagnosing Alzheimer's disease 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.
  • the method includes measuring a constituent of the other body compartment.
  • the other body compartment maybe one of the following:
  • AD Alzheimer's disease
  • SPG sphenopalatine ganglion
  • 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.
  • 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.
  • 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.
  • the measurement may be performed by measuring more than one constituent.
  • a diagnostic result may be determined according to the interrelation between concentrations of the constituents.
  • a method for diagnosing Alzheimer's disease including 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.
  • 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.
  • 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.
  • the measurement may be performed by measuring more than one constituent. In this case, a diagnostic result may be determined according to the interrelation between concentrations of the constituents.
  • a system for treating Alzheimer's disease 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.
  • AD Alzheimer's disease
  • SPG sphenopalatine ganglion
  • a pharmaceutical agent delivery system for treating Alzheimer's disease 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.
  • AD Alzheimer's disease
  • SPG sphenopalatine ganglion
  • a system for diagnosing Alzheimer's disease 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.
  • AD Alzheimer's disease
  • SPG sphenopalatine ganglion
  • a system for diagnosing Alzheimer's disease 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.
  • AD Alzheimer's disease
  • SPG sphenopalatine ganglion
  • a system for diagnosing Alzheimer's disease 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.
  • AD Alzheimer's disease
  • SPG sphenopalatine ganglion
  • a method for treating Alzheimer's disease 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 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.
  • SPG sphenopalatine ganglion
  • CNS central nervous system
  • a method for treating Alzheimer's disease 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.
  • SPG sphenopalatine ganglion
  • CNS central nervous system
  • a method for treating Alzheimer's disease 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 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.
  • SPG sphenopalatine ganglion
  • CNS central nervous system
  • CSF cerebrospinal fluid
  • a method for treating Alzheimer's disease 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 cerebrospinal fluid (CSF) of the subject to a systemic blood circulation of the subject, so as to treat the AD.
  • stimulating the SPG-related tissue includes directly stimulating the SPG.
  • the AD-related constituent includes an inflammatory- related constituent, tau protein, PSI, 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
  • configuring the stimulation includes configuring the stimulation so as to cause the increase in the clearance of the inflammatory-related constituent, tau protein, PSI, 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 am
  • a method for treating Alzheimer's disease 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
  • AD Alzheimer's disease
  • a method for treating Alzheimer's disease including: supplying a pharmaceutical agent to a systemic blood circulation of a subject; 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.
  • SPG sphenopalatine ganglion
  • 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.
  • the pharmaceutical agent includes a glutamate receptor antagonist, an NMDA receptor blocker, an agent having an inhibitory effect on derivation of ⁇ -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 ⁇ - amyloid inhibitor, an endogenous protein, an anti-inflammatory agent, a non-steroidal anti-inflammatory drug (NSAID), 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 ⁇ -amyloid, or (d) antibodies against tau protein
  • supplying the pharmaceutical agent includes administering the pharmaceutical agent for inhalation by the subject.
  • administering the pharmaceutical agent for inhalation by the subject may include administering the pharmaceutical agent mixed with the odorant.
  • a method for treating Alzheimer's disease including: 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
  • a method for treating Alzheimer's disease including: 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 cerebral blood flow (CBF) of the subject, so as to treat the AD.
  • configuring the stimulation includes configuring the stimulation so as to cause an improvement in a metabolic state of a central nervous system (CNS) of the subject.
  • CNS central nervous system
  • a method for diagnosing Alzheimer's disease 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 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.
  • SPG sphenopalatine ganglion
  • a method for diagnosing Alzheimer's disease 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 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.
  • SPG sphenopalatine ganglion
  • the method includes measuring a constituent of the other body compartment.
  • 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.
  • 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.
  • 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 and the serum.
  • 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 CNS and the ascites.
  • a method for diagnosing Alzheimer's disease 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 between cerebrospinal fluid (CSF) of the subject and another body fluid of the subject, so as to facilitate a diagnosis of the AD.
  • SPG sphenopalatine ganglion
  • a method for diagnosing Alzheimer's disease 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 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.
  • SPG sphenopalatine ganglion
  • the method includes measuring a constituent of the other body fluid.
  • the method includes correlating an abnormal concentration of the constituent to a pathology of AD.
  • 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.
  • 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.
  • the method includes determining a diagnostic result according to the interrelation between concentrations of the constituents.
  • a method for diagnosing Alzheimer's disease 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 between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate a diagnosis of the AD.
  • SPG sphenopalatine ganglion
  • a method for diagnosing Alzheimer's disease 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 molecular passage between cerebrospinal fluid (CSF) of the subject and a tissue of the subject, so as to facilitate a diagnosis of the AD.
  • the method includes measuring a constituent of the tissue and/or correlating an abnormal concentration of the constituent to a pathology of AD.
  • 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.
  • measuring the constituent includes measuring a plurality of constituents of the tissue, i this case, for some applications, the method includes determining a diagnostic result according to the interrelation between concentrations of the constituents of the tissue.
  • a method for treating Alzheimer's disease 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 gang
  • SPG sphenopalatine ganglion
  • a method for treating Alzheimer's disease 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.
  • CNS central nervous system
  • CSF cerebrospinal fluid
  • a method for treating Alzheimer's disease 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
  • a method for treating Alzheimer's disease 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 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.
  • AD Alzheimer's disease
  • a method for treating Alzheimer's disease 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 gang
  • SPG sphenopalatine ganglion
  • AD Alzheimer's disease
  • a method for treating Alzheimer's disease 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 cerebral blood flow (CBF) of the subject, so as to treat the AD.
  • CBF cerebral blood flow
  • a method for diagnosing Alzheimer's disease 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 gang
  • SPG sphenopalatine ganglion
  • a method for diagnosing Alzheimer's disease 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.
  • AD Alzheimer's disease
  • a method for diagnosing Alzheimer's disease 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 sphenopalatine ganglion (SPG) of the subject, an anterior
  • a method for diagnosing Alzheimer's disease 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.
  • AD Alzheimer's disease
  • a method for diagnosing Alzheimer's disease 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 gang
  • SPG sphenopalatine ganglion
  • a method for diagnosing Alzheimer's disease 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 diagnosis of the AD.
  • AD Alzheimer's disease
  • the method includes presenting in association with the odorant an analgesic in a dosage configured to reduce a sensation associated with the presenting of the odorant.
  • 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.
  • the odorant is selected from the list consisting of: propionic acid, cyclohexanone, and amyl acetate, and presenting the odorant includes presenting the selected odorant.
  • the odorant is selected from the list consisting of: acetic acid, citric acid, carbon dioxide, sodium chloride, and ammonia, and presenting the odorant includes presenting the selected odorant.
  • the odorant is selected from the list consisting of: menthol, alcohol, nicotine, pipeline, gingerol, zingerone, allyl isothiocyanate, cinnamaldehyde, cuminaldehyde, 2-propenyl/2-phenylethyl isothiocyanate, thymol, and eucalyptol, and presenting the odorant includes presenting the selected odorant.
  • 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.
  • apparatus for treating Alzheimer's disease 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 a brain of the subject to a systemic blood circulation of the subject, so as to treat the AD.
  • SPG sphenopalatine ganglion
  • CNS central nervous system
  • apparatus for treating Alzheimer's disease 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 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.
  • SPG sphenopalatine ganglion
  • CNS central nervous system
  • apparatus for treating Alzheimer's disease 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.
  • SPG sphenopalatine ganglion
  • CNS central nervous system
  • CSF cerebrospinal fluid
  • apparatus for treating Alzheimer's disease 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 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.
  • SPG sphenopalatine ganglion
  • the stimulator is adapted to directly stimulate the SPG.
  • apparatus for treating Alzheimer's disease including a stimulator adapted 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 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 cenfral nervous system (CNS) of the subject, of a pharmaceutical agent supplied to the systemic blood circulation, so as to treat the AD.
  • SPG sphenopalatine ganglion
  • CNS cenfral nervous system
  • apparatus for treating Alzheimer's disease 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 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.
  • SPG sphenopalatine ganglion
  • CNS central nervous system
  • apparatus for treating Alzheimer's disease including a stimulator adapted 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 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.
  • SPG sphenopalatine ganglion
  • apparatus for treating Alzheimer's disease 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 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.
  • SPG sphenopalatine ganglion
  • apparatus for diagnosing Alzheimer's disease 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 compartment of the subject, so as to facilitate a diagnosis of the AD.
  • SPG sphenopalatine ganglion
  • apparatus for diagnosing Alzheimer's disease 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 a central nervous system (CNS) of the subject and another body compartment of the subject, so as to facilitate a diagnosis of the AD.
  • SPG sphenopalatine ganglion
  • apparatus for diagnosing Alzheimer's disease 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 another body fluid of the subject, so as to facilitate a diagnosis of the AD.
  • SPG sphenopalatine ganglion
  • apparatus for diagnosing Alzheimer's disease 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.
  • SPG sphenopalatine ganglion
  • apparatus for diagnosing Alzheimer's disease 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 diagnosis of the AD.
  • SPG sphenopalatine ganglion
  • apparatus for diagnosing Alzheimer's disease 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 diagnosis of the AD.
  • SPG sphenopalatine ganglion
  • apparatus for treating Alzheimer's disease 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
  • apparatus for treating Alzheimer's disease including a stimulator adapted to present 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.
  • a stimulator adapted to present 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.
  • CNS central nervous system
  • CSF cerebrospinal fluid
  • apparatus for treating Alzheimer's disease 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 refro-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,
  • SPG sphenopalatine ganglion
  • apparatus for freating Alzheimer's disease 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 cenfral nervous system (CNS) of the subject, of a pharmaceutical agent supplied to the systemic blood circulation, so as to treat the AD.
  • 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 cenfral nervous system (CNS) of the subject, of a pharmaceutical agent supplied to the systemic blood circulation, so as to treat the AD.
  • CNS cenfral nervous system
  • apparatus for treating Alzheimer's disease 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,
  • SPG sphenopalatine ganglion
  • apparatus for freating Alzheimer's disease 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.
  • CBF cerebral blood flow
  • apparatus for diagnosing Alzheimer's disease 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,
  • SPG sphenopalatine ganglion
  • apparatus for diagnosing Alzheimer's disease 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.
  • 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.
  • CNS central nervous system
  • apparatus for diagnosing Alzheimer's disease 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
  • SPG sphenopalatine ganglion
  • apparatus for diagnosing Alzheimer's disease 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.
  • AD Alzheimer's disease
  • apparatus for diagnosing Alzheimer's disease 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,
  • SPG sphenopalatine ganglion
  • apparatus for diagnosing Alzheimer's disease 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.
  • AD Alzheimer's disease
  • apparatus for treating Alzheimer's disease 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 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.
  • CNS central nervous system
  • CSF cerebrospinal fluid
  • apparatus for treating Alzheimer's disease 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 an odorant-delivery element, adapted to present the odorant to an air passage of the patient, so as to treat the AD.
  • AD Alzheimer's disease
  • apparatus for treating Alzheimer's disease 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.
  • AD Alzheimer's disease
  • apparatus for diagnosing Alzheimer's disease 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.
  • AD Alzheimer's disease
  • apparatus for diagnosing Alzheimer's disease 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 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.
  • AD Alzheimer's disease
  • apparatus for diagnosing Alzheimer's disease 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 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.
  • AD Alzheimer's disease
  • the odorant-storage vessel in combination with the odorant- delivery element includes an aqueous spray nasal inhaler.
  • the odorant-storage vessel in combination with the odorant- delivery element includes a metered dose nasal inhaler.
  • the odorant-storage vessel in combination with the odorant- delivery element includes an air-dilution olfactometer.
  • Fig. 1 is a schematic pictorial view of a fully implantable stimulator for 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
  • Figs. 5A and 5B 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 embodiment of the present invention
  • Fig. 7 is a schematic block diagram illustrating circuitry for use with the stimulator shown in Fig. 1, 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
  • 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 10B are schematic diagrams illustrating further circuitry for use 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. 14 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
  • Figs. 15-17 are graph showing the results from SPG stimulation experiments carried out in accordance with embodiments of the present invention.
  • 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.
  • SPG sphenopalatine ganglion
  • 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).
  • one or more relatively short electrodes 7 extend from stimulator 4 to contact or to be in a vicinity of SPG 6 or of nerves innervating SPG 6 (e.g., postganglionic parasympathetic trunks thereof).
  • stimulator 4 is implanted on top of the bony palate, in the bottom of the nasal cavity.
  • the stimulator is implanted at the lower side of the bony palate, at the top of the oral cavity, i 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.
  • the stimulator may be directly attached to the SPG and/or to its postganglionic parasympathetic trunk(s).
  • 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 flexible introducer rod (not shown) and inserting the rod into one of the patient's nasal passages until the stimulator is properly positioned.
  • the placement process may be facilitated by fluoroscopy, x-ray guidance, fine endoscopic surgery (FES) techniques or by any other effective guidance method known in the art, or by combinations of the aforementioned.
  • FES fine endoscopic surgery
  • 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 endotheliu-n of the capillaries, the plasma membrane of the 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.
  • stimulator 4 may be used to transiently remove a substantial obstacle to the passage of drugs from the blood to the brain.
  • the stimulator may cyclically apply current for about two minutes, and subsequently have a rest period of between about 1 and 20 minutes.
  • VIP vasoactive intestinal polypeptide
  • NO nitric oxide
  • 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 about 10 Hz) cause secretion of peptides (VIP).
  • a constant level DC signal, or a slowly varying voltage ramp is applied, in order to block parasympathetic neural activity in affected tissue.
  • 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 prefe ⁇ ed 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 14 that is adjacent to SPG 6.
  • electrodes 7 (Fig. 1) and 10 may each comprise one or more electrodes, e.g., two electrodes, or an a ⁇ ay of microelectrodes.
  • stimulator 4 comprises a metal housing that can function as an electrode
  • 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.
  • 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.
  • a physiologically-acceptable material such as silver, iridium, platinum, a platinum iridium alloy, titanium, nitinol, or a nickel-chrome alloy.
  • 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.
  • 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.
  • the distal tip may be porous platinized.
  • 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 prefe ⁇ ed 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 elecfromagnetic 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 override signal, entered by the patient or a healthcare provider to terminate stimulation or to modify it in accordance with a predetermined program.
  • Microprocessor 32 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 override signal, entered
  • microprocessor 32 preferably processes control signal 34 and feedback signal 36 so as to determine one or more parameters of the electric cu ⁇ ent to be applied through electrodes 24. Responsive to this determination, microprocessor 32 typically generates an electromagnetic control signal 42 that is conveyed by elecfromagnetic coupler 28 to electromagnetic coupler 26. Control signal 42 preferably co ⁇ esponds to a desired cu ⁇ ent or voltage to be applied by electrodes 24 to SPG 6, and, in a prefe ⁇ ed embodiment, inductively drives the electrodes.
  • 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 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 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 cu ⁇ ent to the SPG.
  • the waveform applied by one or more of electrodes 24 to designated tissue 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.
  • the waveform comprises one or more bursts of short shaped or square pulses — each pulse preferably less than about 1 ms in duration.
  • appropriate waveforms and parameters thereof are determined during an initial test period of external unit 30 and implanted unit 20.
  • 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) period.
  • Fig. 4 is a schematic block diagram of circuitry for use, for example, in conjunction with confrol unit 8 (Fig. 2), in accordance with a prefe ⁇ ed 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 groimd 56.
  • Microprocessor 52 preferably receives confrol 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.
  • feedback signal 68 comprises electrical feedback measured by one or more of electrodes 66 and/or feedback from other 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.
  • electrodes 66 are temporarily implanted in the patient (e.g., following a stroke), and are directly driven by wires connecting the external unit to the implanted unit.
  • Fig. 5 A 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 prefe ⁇ ed embodiment of the present invention.
  • 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.
  • a step (ON/OFF) mode of stimulation stimulation of the SPG or related tissue is initiated at a time Tl, and this is reflected by a measurable rise in temperature (due to increased blood flow).
  • Fig. 5B 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 prefe ⁇ ed embodiment of the present invention.
  • the amplitude of the waveform applied to the SPG is varied among a continuous set of values (SI), or a discrete set of values (S2), responsive to the measured temperature, in order to achieve the desired performance.
  • SI continuous set of values
  • S2 discrete set of values
  • other feedback parameters measured in the head e.g., intracranial pressure and/or cerebral blood flow
  • measured systemic parameters e.g., heart rate
  • 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.
  • 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 prefe ⁇ ed embodiment of the present invention.
  • 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 Tl.
  • this prior generation of heightened concentrations of the drug in the 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.
  • combined administration and stimulation schedules are determined by the patient's physician based on the biochemical properties of each drug 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 prefe ⁇ ed 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 confrol 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.
  • microprocessor 82 Responsive to signals 88 and 108, microprocessor 82 preferably generates a display signal 89 which drives a display 90, as described hereinabove.
  • 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 cu ⁇ ent through an electromagnetic coupler 96, which inductively drives an electromagnetic coupler 98 of implanted unit 100.
  • a demodulator 102 coupled to elecfromagnetic coupler 98, in turn, generates a signal 103 which drives at least one electrode 104 to apply cu ⁇ ent to the SPG or to other tissue, as appropriate.
  • biosensor 106 comprises implantable or external medical apparatus including, for example, one or more of the following:
  • TCD transcranial Doppler
  • laser-Doppler apparatus • a systemic or intracranial blood pressure sensor (e.g., comprising a piezoelectric crystal fixed to a major cerebral blood vessel, capable of detecting a sudden blood pressure increase indicative of a clot),
  • a systemic or intracranial blood pressure sensor e.g., comprising a piezoelectric 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
  • Fig. 8 is a schematic illustration showing operational modes of modulator 94 and/or demodulator 102, in accordance with a prefe ⁇ ed 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 prefe ⁇ ed embodiment of the present invention.
  • 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.
  • microprocessor 112 and controller 122 are operative to communicate via electromagnetic couplers 126 and 124, in order to exchange data or to change parameters.
  • battery 114 is inductively rechargeable by electromagnetic coupling.
  • Fig. 10A is a schematic illustration of a stimulator 150, in accordance with a prefe ⁇ ed embodiment of the present invention.
  • substantially all of the elecfronic components are encapsulated in a biocompatible metal case 154.
  • An inductive coil 156 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. 10B is a schematic illustration of another configuration of an implantable stimulator, in accordance with a prefe ⁇ ed embodiment of the present invention.
  • substantially all of the electronic components are encapsulated in a biocompatible metal case 174.
  • One or more feed-throughs are preferably provided to enable coupling between at least one elecfrode 182 and the electronic circuit, as well as between inductive coil 176 and another inductive coil (not shown) in communication therewith.
  • the energy source for electronic circuits 158 and 178 may comprise, for example, a primary battery, a rechargeable battery, or a super capacitor.
  • 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 energy converter that converts the kinetics of the patient movement into electrical charge.
  • an external light source e.g., a simple LED, a laser diode, or any other light source
  • ultrasound energy is directed onto the implanted unit, and transduced to drive battery charging means.
  • Figs. 11 and 12 are bar graphs showing experimental results obtained during rat experiments performed in accordance with a prefe ⁇ ed 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 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 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.
  • 99Tc-DTPA DTPA molecule conjugated to a 99-Technetium isotope
  • 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.
  • 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 confrol and test hemispheres.
  • Fig. 13 is a schematic illustration of acoustic or optical clot detection apparatus
  • 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 acoustic or optical transmitter/receiver 206, and an optional reflecting surface 204.
  • a major blood vessel 200 e.g., the internal carotid artery or aorta
  • a detecting element comprising an acoustic or optical transmitter/receiver 206, and an optional reflecting surface 204.
  • Natural physiological liquids may serve as a mediating fluid between the device and the vessel.
  • the transmitter/receiver generates an ultrasound signal or elecfromagnetic signal which is reflected and returned, and a processor evaluates changes in the returned signal to detect indications of a newly-present clot.
  • 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.
  • 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.
  • odorants such as propionic acid, cyclohexanone, and amyl acetate
  • 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.
  • 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.
  • 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.
  • 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 cerebrovascular system to circulating agents of various sizes, i.e. to increase the permeability of the BBB.
  • 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, pipeline, gingerol, zingerone, allyl isothiocyanate, cinnamaldehyde, cuminaldehyde, 2-propenyl/2-phenylethyl isothiocyanate, thymol, and eucalyptol.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 presenting an odorant to a subject, in accordance with a prefe ⁇ ed 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 nasal passage using an odorant-delivery element 304, such as a nasal piece.
  • 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.
  • 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).
  • Rats were anesthetized by infraperitoneal administration of Pentobarbital, and then mounted on a stereotaxic frame.
  • a bun 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.
  • 0.50 ml of [3H]PNA (150,000 disintegrations per minute (dpm), .5'-CCGCTCCG- 3', MW.
  • ECF extracellular fluid
  • 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, 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 elecfrode, both poles of the electrode being inserted slightlyinto 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 e ⁇ or 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.
  • Four 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.
  • a solution of 10 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 cycling between on-periods, lasting 90 seconds, and off-periods, lasting for 60 seconds.
  • 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. 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 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 confrol group.
  • the high concentration of the dextran tracer 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 confrol groups, in a non-SPG-regulated brain tissue, and
  • the inventor additionally assessed the concenfration 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 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
  • CBF cerebral blood flow
  • Fig. 17 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 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).
  • this embodiment may be adapted for use in the freatment 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.
  • 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.
  • a method 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 freatment 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.
  • this treatment is given on a long-term basis, e.g., in the chronic treatment of Alzheimer's patients.
  • 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.
  • 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.
  • 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.
  • Decreasing cerebral blood flow by presenting certain odorants to an air passage is used in accordance with some prefe ⁇ ed embodiments of the present invention to treat or prevent various types of headaches, especially with an autonomic nervous system (ANS) etiology, such as migraine and cluster headaches.
  • ANS autonomic nervous system
  • 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.
  • the better delivery of drugs is an important factor in the treatment of various disorders, such as Parkinson's disease, Alzheimer's disease, and other neurological diseases.
  • various disorders such as Parkinson's disease, Alzheimer's disease, and other neurological diseases.
  • 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 prefe ⁇ ed 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).
  • cholinomimetic medications typically, at most, slow down the deterioration of cognitive function in patients.
  • SPG stimulation typically increases blood flow and oxygen supply to the brain, and therefore help these patients.
  • permanent stimulators may be implanted in the nasal cavity, for long-term intermittent stimulation.
  • the delivery of cholinomimetic medications is facilitated by SPG stimulation.
  • 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.
  • opening of the BBB preferably, but not necessarily, using techniques described herein leads to an increased net fransport of that compound from the CNS into the circulation.
  • 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.
  • 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.
  • AD is diagnosed.
  • such a testing procedure is minimally invasive.
  • molecular passage is increased to another body compartment and/or fluid, such as plasma, serum, ascites, or cerebrospinal fluid.
  • 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 ⁇ -Amyloid, tau, PSI, and PS2, from the CNS into the systemic circulation.
  • neurotoxic compounds such as ⁇ -Amyloid, tau, PSI, and PS2
  • 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.
  • 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 demonstrative purposes.
  • Excitotoxicity is related to excessive activation of glutamate receptors which results in neuronal cell death.
  • the physiological function of glutamate receptors is the mediation of ligand-gated cation 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., Behav. Brain Res. 83:225-228, 1997; Roesler, R. et al., Neurology 50:1195, 1998; Wheal, H. V. et al., Prog. Neurobiol.
  • 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 AIDS dementia, epilepsy, focal ischemia (Coyle, J.T. et al., Science 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.
  • a potential freatment modality for AD is the systemic administration of a JNK (c- Jun amino-terminal kinase) or MLK (Mixed lineage kinase) apoptosis inhibitor as a means for preventing AD-related apoptosis of brain cells.
  • JNK c- Jun amino-terminal kinase
  • MLK Mated lineage kinase
  • achieving a therapeutic concenfration of such an inhibitor in the CNS may be accompanied by undesired dose-related side effects.
  • 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.
  • 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.
  • methods for treatment of Alzheimer's disease target the formation of ⁇ -amyloid through the enzymes involved in the proteolytic processing of ⁇ -amyloid precursor protein.
  • Compounds that inhibit ⁇ or ⁇ secretase activity are used, in accordance with this embodiment, to confrol the production of ⁇ -amyloid.
  • compounds that specifically target ⁇ secretases could control the production of ⁇ -amyloid.
  • such inhibition of ⁇ or ⁇ secretases reduces production of A ⁇ , which, in turn, reduces or prevents the neurological disorders associated with A ⁇ protein.
  • a ⁇ is an internal polypeptide derived from a type 1 integral membrane protein, termed b amyloid precursor protein (APP).
  • APP amyloid precursor protein
  • ⁇ 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 ⁇ APP by as yet unknown enzyme (protease) system(s), collectively termed secretases.
  • proteolytic activities include ⁇ secretase(s), generating the N-terminus of A ⁇ , a secretase(s) cleaving around the 16/17 peptide bond in A ⁇ , and y secretases, generating C-terminal A ⁇ fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.
  • a ⁇ is the major protein found in amyloid plaques.
  • a ⁇ is neurotoxic and may be causally related to neuronal death observed in AD patients.
  • missense DNA mutations at position 717 in the 770 isoform of ⁇ APP can be found in affected members but not unaffected members of several families with a genetically determined (familiar) form of AD. i addition, several other ⁇ APP mutations have been described in familiar forms of AD.
  • Similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human ⁇ APP.
  • individuals with Down's syndrome have an increased gene dosage of ⁇ APP and develop early-onset AD. Taken together, these observations strongly suggest that A ⁇ depositions may be causally related to the AD.
  • a ⁇ inhibits neurological degeneration by controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with A ⁇ production.
  • One method of treatment prefe ⁇ ed by the inventors is based on drugs that inhibit the formation of A ⁇ in vivo, administered in combination with techniques for SPG stimulation described herein.
  • Methods of treatment preferably target the formation of A ⁇ through the enzymes involved in the proteolytic processing of ⁇ amyloid precursor protein.
  • Compounds that inhibit ⁇ or ⁇ secretase activity could control the production of A ⁇ .
  • compounds that specifically target ⁇ secretases could confrol the production of A ⁇ .
  • Such inhibition of ⁇ or ⁇ secretases could thereby reduce production of A ⁇ , which, in turn, could reduce or prevent the neurological disorders associated with A ⁇ protein.
  • US Patent Application Publication 20020055501 to Olson et al. describes pharmaceutical compositions and methods of use of such compounds, which inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of A ⁇ -peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein.
  • efficacy of administration of pharmaceutical agents that inhibit the processing of amyloid precursor protein into ⁇ -amyloid is typically substantially increased when used in conjunction with the techniques of SPG stimulation described herein.
  • the therapeutic or prophylactic administration of such compounds targeting production of A ⁇ 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 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 NMDA 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 the NMDA receptor (compared to the inhibitory glycine receptor and other receptors), or a glycine uptake inhibitor (e.g., N-methylglycine).
  • a partial agonist such as D-cycloserine
  • a full agonist e.g., D-serine or D-alanine
  • a glycine uptake inhibitor e.g., N-methylglycine
  • disorders that can be treated by the methods they describe include schizophrenia, Alzheimer's disease, autism, depression, benign forgetfulness, childhood learning disorders, closed head injury, and 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 for (a) the glycine site of the NMDA receptor, compared with (b) the inhibitory glycine receptor and other receptors.
  • the pharmaceutical composition may include, for example, (i) a therapeutically effective amount of D-alanine (wherein the pharmaceutical composition is substantially free of D-cycloserine) and/or (ii) a therapeutically effective amount of D- serine, and/or (iii) D-cycloserine in an amount of 105-500 mg, and/or (iv) a therapeutically effective amount of N-methylglycine.
  • 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.
  • US Patent Application Publication 20020028834 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 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 neurofransmitter 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 the brain. They also discuss the efficacy of three known acetylcholinesterase inhibitors, physostigmine, metrifonate, and tefrahydroaminoacridine.
  • 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, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
  • Example 5 Therapeutics (direct stimulation of neural regeneration.
  • NGF Nerve Growth Factor
  • BDNF Nerve Growth Factor
  • IGF IGF
  • GDNF active stimulants of neural regeneration.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 brain processes.
  • 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, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
  • AD Alzheimer's disease
  • synaptophysin decreases in neurodegenerative disorders along with a decline in neurofransmission.
  • 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: 893-897, 1995).
  • a combination of neurofrophic factors is most effective in providing optimal trophic support for compromised neuron functions, including neurofransmission (Rathbone M.P. et al., "AIT-082 as a potential neuroprotective and regenerative agent in stroke and central nervous system injury,” Exp. Opin. Invest. Drugs. 8:1255-12652, 1999).
  • Multiple neurofrophic factors may synergistically regulate synaptophysin levels in a manner that can lead to increased neurofransmission and improved neuronal function.
  • Pharmaceutical agents that increase 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 neurodegenerative 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/or secretion of 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.
  • the purine moiety can be guanine or hypoxanthine. Therefore, there exists a need for methods that can stimulate the synthesis and/or 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 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.
  • neurological diseases including neurodegenerative diseases such as AD and neurodevelopmental disorders such as Down's syndrome
  • 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.
  • US Patent Application Publication 20020019519 to Bingham et al. describes the use of KIAA0551 polypeptides and polynucleotides in the design of protocols for the treatment of various neurological disorders, among which is AD.
  • 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 .
  • a number of diseases and disorders are thought to be caused by or to be associated with alterations in mitochondrial metabolism and/or inappropriate induction or suppression of mitochondria-related functions leading to apoptosis.
  • diseases and disorders 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 mitochondrial structural abnormalities, fatal infantile myopathy with severe mtDNA depletion and benign "later-onset" myopathy with moderate reduction in mtDNA, MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke) and MIDD (mitochondrial diabetes and deafness); MERFF (myoclonic epilepsy ragged red fiber syndrome); arthritis; NARP (Neuropathy; Ataxia; Retinitis Pigmentosa); MNGIE (Myopathy and external ophthalmoplegi
  • ETC respiratory activity requires maintenance of an electrochemical potential (ATm) in the inner mitochondrial membrane by a coupled chemiosmotic mechanism.
  • ATm electrochemical potential
  • 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 mitochondrial activity may also result in a catastrophic mitochondrial collapse that has been termed "mitochondrial permeability transition" (MPT).
  • MPT mitochondrial permeability transition
  • mitochondrial proteins such as cytochrome c and "apoptosis inducing factor” may dissociate or be released from mitochondria due to MPT (or the action of mitochondrial 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 mitochondrial 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.
  • ROS reactive oxygen species
  • oxygen free radical induced lipid peroxidation is a well established pathogenetic mechanism in cenfral nervous system (CNS) injury such as that found in a number of degenerative diseases, and in ischemia (i.e., stroke).
  • CNS cenfral nervous system
  • ischemia i.e., stroke
  • free radical mediated damage may inactivate one or more of the myriad proteins of the ETC.
  • free radical mediated damage may result in catastrophic mitochondrial collapse that has been termed "transition permeability.”
  • transition permeability According to generally accepted theories of mitochondrial function, proper ETC respiratory activity requires maintenance of an electrochemical potential in the inner mitochondrial membrane by a coupled chemiosmotic mechanism. Free radical oxidative activity may dissipate this membrane potential, thereby preventing ATP biosynthesis and/or triggering mitochondrial events in the apoptotic cascade.
  • AD Alzheimer's disease
  • Mitochondrial 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 mitochondrial 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 mitochondrial function may initiate the apoptotic cascade (Ausserer et al., Mol. Cell.
  • ROS reactive oxygen species
  • Oxidatively-sfressed 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).
  • members of the Bcl-2 family of anti- apoptosis gene products are located within the outer mitochondrial membrane (Monaghan 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).
  • AD Alzheimer's disease
  • 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).
  • ROS reactive oxygen species
  • the therapeutic or 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
  • Example 8 Therapeutics ( ⁇ -amyloid inhibitors) 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 ⁇ or its release from cells, or of reducing the activity of A ⁇ 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 6,211,235 to Wu et al describes compounds which inhibit ⁇ -amyloid peptide release and/or its synthesis, and, accordingly, may have utility in treating Alzheimer's disease. It also describes pharmaceutical compositions comprising a compound which may inliibit ⁇ -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 prefe ⁇ ed, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs. Latentiation is generally achieved through 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.
  • the delivery of hydrophilic drugs may be enhanced by infra-arterial infusion of hypertonic solutions which may transiently open the BBB to some extent.
  • 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.
  • the permeability of the BBB 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, in order to permit ⁇ -amyloid polymerization inhibitors naturally occurring in the blood, particularly albumin, to pass from the blood into the CNS.
  • Example 10 Therapeutics (microglial activation modulators)
  • Acute and chronic brain injuries can activate resident microglia (resident macrophage-like cells found in the cenfral nervous system) as well as recruit peripheral immune cells to injured 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 co ⁇ elated with significant neuronal protection in pre-clinical studies of ischemia, fraumatic brain injury, spinal cord injury and Alzheimer's disease.
  • microglia activation comprising the administration of a compound capable of inhibiting 5-LOX, FLAP, attenuating degradation of I ⁇ B ⁇ or inhibiting nuclear translocation of the NF- ⁇ B active complex for the treatment of various disorders associated with excessive production of inflammatory mediators in the brain, among which is Alzheimer's disease.
  • 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 neuroanatomical structures, by using electrical stimulation, odorant presentation, and/or other means for stimulating the SPG or for modulating permeability of the BBB.
  • the anti-inflammatory 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 to the placebo treated confrol group.
  • Alzheimer's patients with moderate cognitive impairment treated with indomethacin also exhibit a reduction in cognitive decline.
  • patients treated with oral indomethacin developed drug related adverse effects that required their treatment to be discontinued and their removal from the study.
  • US Patent Application Publication 20010027309 to Elsberry describes a method for freating 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) freatment of AD.
  • NSAIDs indomethacin or nonsteroidal anti- inflammatory drugs 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) freatment of AD.
  • a vaccine made by Elan Corporation (Dublin, Ireland) and known by its code name AN- 1792, was tested in a clinical trial.
  • NSAIDs are known to be very extensively protein bound (>99%). 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.
  • the therapeutic or prophylactic administration of NSAIDs 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 other means for stimulating the SPG or for modulating permeability of the BBB.
  • the administration of a vaccine 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 20020009445 to Du et al discusses the use of an anti-A ⁇ antibody for diagnosing and/or freating amyloid associated diseases, especially Alzheimer's disease. They indicate that naturally-occurring A ⁇ 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 freatment of amyloid associated diseases and especially of Alzheimer's disease. In the context of this application, the terms "anti-A ⁇ antibodies” and "A ⁇ antibodies” are used interchangeably to designate the antibody of their invention. An embodiment of their diagnostic method uses lumbar CSF samples, on which A ⁇ antibody levels were determined utilizing an ELISA assay in which the A ⁇ peptide was used as the capture ligand.
  • the therapeutic or prophylactic administration of anti-A ⁇ antibodies, 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 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.
  • relaxin a polypeptide hormone, whose molecular weight is between 5,700 to 6,500 Da
  • Neurodegenerative dysfunctions potentially amenable to freatment 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 bloodsfream. 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.
  • the therapeutic or prophylactic adminisfration 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.
  • PTPase's Protein Tyrosine Phosphatases
  • PTP1B Protein Tyrosine Phosphatases
  • CD45 Protein Tyrosine Phosphatases
  • SHP-1 protein Tyrosine Phosphatases
  • SHP-2 protein Tyrosine Phosphatases
  • PTP ⁇ LAR and HePTP or the like
  • 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.
  • the therapeutic or prophylactic adminisfration of medium chain triglycerides, 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 14 Diagnostics 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 (Motter et al, Ann. Neurol. 38, 643-648, 1995).
  • CSF cerebrospinal fluid
  • 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 co ⁇ esponding 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 statistically-significant co ⁇ elation 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-Macroglobulin variant proteins. Finally, kits for nucleic acid analysis or protein analysis are described.
  • 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 procedure.
  • US Patent Application Publication 20020019519 to Bingham et al describes the use of KIAA0551 polypeptides and polynucleotides in the design of protocols for 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 ⁇ 4Q/A ⁇ 42 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 describes the use of an anti-A ⁇ antibody for diagnosing and/or treating amyloid associated diseases, especially Alzheimer's disease.
  • 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 ⁇ -amyloid ⁇ -42 or A ⁇ 3pE is completely or nearly completely (i.e., thoroughly) dissociated from binding proteins prior to the analysis of the levels of ⁇ -amyloid - or A ⁇ 3pE.
  • 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, for diagnosing Alzheimer's Disease, and also describes treatments of these Ags that enhance their reactivity with autoantibodies directed against A68. These treatments include 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 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.
  • 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 polymerization of tubulin (Weingarten, M.D. et al, Proc. Natl. Acad. Sci.
  • Tau protein is also the major constituent of paired helical filaments (PHF), characteristic structures found as neurofibrillary tangles in tissue sections of the brain of Alzheimer patients (Greenberg, S. et al, Proc.
  • 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, 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).
  • tau protein as predicted from 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 _S!H2"i ermma - part of the molecules (Goedert, M. 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 alkaline phosphatase treatment, have been detected exclusively in brain areas showing neurofibrillary tangles and senile plaques (Flament, S. et al, A., J. Neurol. Sci. 92, 133-141, 1989; Flament,
  • the Alz50 epitope has recently been mapped to the NH2-terminal part of the tau molecule (Ksiezak-Reding, H. et al, J. Neurosci. Res., 25, 412-419, 1990; Goedert, M. et al, Neurosci. Lett., 126, 149-154, 1991).
  • this antibody 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;
  • monoclonal antibodies have been developed to recognize tau protein.
  • monoclonal antibody 5E2 was raised by immunization with human fetal heat-stable microtubule-associated proteins and recognizes an epitope spanning amino acids 156-175 which is present in normal and abnormally phosphorylated tau (Kosik, K. S. et al, Neuron., 1, 817-825, 1988).
  • US Patent Application Publication 20010014670 to Balin et al describes a method of treating Alzheimer's disease in a mammal comprising administering to the 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 the CNS, or to be able to evaluate presence of diagnostic agents (e.g. C. Pneumoniae) in a minimally invasive method.
  • diagnostic agents e.g. C. Pneumoniae
  • Inducing changes in BBB permeability 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.
  • 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.
  • 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 acetylcholinesterase to pass therethrough, it is quickly in the systemic bloodsfream 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 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 concentration of acetylcholinesterase or other compounds of diagnostic value in the brain.
  • 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 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.
  • 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 BBB 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 prefe ⁇ ed embodiment of the present invention.
  • the diagnostic techniques described in this example 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.
  • apparatus for communication and power transmission which are shown to be coupled in a wireless fashion may be, alternatively, coupled in a wired fashion
  • apparatus for communication and power transmission which are shown to be coupled in a wired fashion may be, alternatively, coupled in a wireless fashion.

Abstract

L'invention porte sur un procédé de traitement de la maladie d'Alzheimer (AD). Ce procédé consiste à stimuler un ganglion sphéno-palatin (SPG) d'un sujet afin de modifier la concentration d'une substance dans le cerveau du sujet.
EP03730451A 2002-06-14 2003-06-13 Procedes et systemes de gestion de la maladie d'alzheimer Withdrawn EP1521614A2 (fr)

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US38893102P 2002-06-14 2002-06-14
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US10/294,310 US7146209B2 (en) 2000-05-08 2002-11-14 Stimulation for treating eye pathologies
US294310 2002-11-14
PCT/IL2003/000508 WO2003105658A2 (fr) 2002-06-14 2003-06-13 Procedes et systemes de gestion de la maladie d'alzheimer

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