ENHANCEMENT OF COGNITIVE FUNCTION.

[0001] The present invention relates medicaments for use in the treatment of various forms of dementia of mild, moderate and severe degree, including mild cognitive impairment, alcoholic dementia, vascular dementia, Alzheimer's disease, Lewy body dementia, and frontotemporal dementia. The medicament can also be used for the enhancement of cognitive function. The invention also relates to the preparation of medicaments for such treatments.

BACKGROUND OF THE INVENTION

[0002] Dementia is a degenerative disorder of the cognitive centres of the central nervous system (CNS) resulting in a progressive decline of cognitive function and memory loss. Dementia has been recognised as a major disease for centuries.

Dementia, previously known as senility is a broad category of brain diseases that cause a long term and often gradual decrease in the ability to think and remember that is great enough to affect a person's daily functioning. Other common symptoms include emotional problems, problems with language, and a decrease in motivation. A person's consciousness is largely not affected, A dementia diagnosis requires a change from a person's usual mental functioning and a greater decline than one would expect due to aging. There is no cure for dementia. Cholinesterase inhibitors such as Donepezil are often used and may be beneficial in mild to moderate disease. The overall benefit, however, may be minor.

[0003] Mild cognitive impairment (MCI) is exceedingly common in those over the age of 70 years, it basically means that the person exhibits memory or thinking difficulties, but not severe enough yet for a dementia diagnosis. He or she should score between 25-30 on the M SE, ^[4S Around 70% of people with MCI go on to develop some form of dementia. ^E4 MCI is generally divided into two categories. The first is one that is primarily memory loss (amnestic MCI). The second category is anything that is not primarily memory difficulties (non-amnestic MCI). People with primarily memory problems generally go on to develop Alzheimer's disease. People with the other type of MCI may go on to develop other types of dementia.

Diagnosis of MCI is often difficult, as cognitive testing may be normal. Often, more neuropsychological testing is necessary to make the diagnosis. The most commonly used criteria are called the Peterson criteria and include: 1) . Memory or other cognitive (thought-processing) complaint by the person or a person who knows the patient well.

2) . The person must have a memory or other cognitive problem as compared to a person of the same age and level of education,

3) . The problem must not be severe enough to affect the person's daily function.

4) . The person must not have dementia.

[0004] Alzheimer's disease accounts for up to 50% to 70% of cases of dementia. The most common symptoms of Alzheimer's disease are short-term memory loss and word-finding difficulties. People with Alzheimer's also have trouble with visual-spatial areas (for example they may begin to get lost often), reasoning, judgement, and insight. Insight refers to whether or not the person realizes he/she has memory problems. Common early symptoms of Alzheimer's include repetition, getting lost, difficulties keeping track of bills, problems with cooking especially new or complicated meals, forgetting to take medication, and word-finding problems. The part of the brain most affected by Alzheimer's is the hippocampus. Other parts of the brain that show shrinking (atrophy) include the temporal and parietal lobes. Although this pattern suggests Alzheimer's, the brain shrinkage in Alzheimer's disease is very variable, and a scan of the brain cannot actually make the diagnosis.

[0005] Vascular dementia is the cause of at least 20% of dementia cases, making it the second most common cause of dementia, it is caused by disease or injury to blood vessels that damage the brain, including strokes. The symptoms of this dementia depend on where in the brain the strokes have occurred and whether the vessels are large or small. Multiple injuries can cause progressive dementia over time, while a single injury located in an area critical for cognition (i.e. hippocampus, thalamus) can lead to sudden cognitive decline. On scans of the brain, a person with vascular dementia may show evidence of multiple different strokes of different sizes. They tend to have risk factors for artery disease.

[0006] Lewy body dementia (LBD) is a dementia that has the primary symptoms of visual hallucinations and "Parkinsonism," Parkinsonism. Symptoms of this includes tremor, rigid muscles, and a face without emotion. The visual hallucinations in LBD are generally very vivid hallucinations of people and/or animals and they often occur when someone is about to fall asleep or just waking up. Other prominent symptoms indude problems with attention, organization, problem solving and planning (executive function) and difficulty with visual-spatial function. Again, imaging studies cannot necessarily make the diagnosis of DLB, but some signs are particularly common. A person with LBD often shows occipital hypoperfusion on a SPECT scan or occipital hypometabolism on a PETscan

[0007] Frontotemporal dementia (FTD) is a dementia that is characterized by drastic personality changes and language difficulties. In all FTD, the person has a relatively early social withdrawal and early lack of insight into the disease. Memory problems are not a main feature of this disease. There are three main types of FTD. The first has major symptoms in the area of personality and behavior. This is called behavioral variant FTD (bv-FTD) and is the most common. In bv~FTD, the person shows a change in personal hygiene, becomes rigid in their thinking, and rarely recognize that there is a problem, they are socially withdrawn, and often have a drastic increase in appetite. They may also be socially inappropriate. For example, the may make inappropriate sexual comments, or may begin using pornography openly when they had not before. One of the most common signs is apathy, or not caring about anything. Apathy, however, is a common symptom in many different dementias.

[0008] The other two types of FTD feature language problems as the main symptom. The second type is called semantic dementia or temporal variant dementia (TV-FTD). The main feature of this is the loss of the meaning of words. It may begin with difficulty naming things. The person eventualiy may also lose the meaning of objects as well. For example, a drawing of a bird, dog, and an airplane in someone with FTD may ail appear just about the same. ^E4S in a classic test for this, a patient is shown a picture of a pyramid and below there is a picture of both a palm tree and a pine tree. The person is asked to say which one goes best with the pyramid, in TV-FTD the person would not be able to answer that question.

[0009] Another type of FTD is called progressive non-fluent aphasia (PNFA).

This is mainly a problem with producing speech. They have trouble finding the right words, but mostly they have a difficulty coordinating the muscles they need to speak. Eventualiy, someone with P FA only uses one-syllabie words or may become totally mute. With both TV-FTD and P FA the symptoms of behaviour may be present, but milder and later than in bv-FTD. Imaging studies show shrinking of the frontal and temporal lobes of the brain. [0010] The parts of the central nervous system (CNS), that affects dementia are distinct from peripheral nervous system, which by definition lays outside the CNS. The forms of dementia concerned are characterised by degeneration of the cognitive parts of the central nervous system. Dementia can be also be contrasted with disorders such as multiple sclerosis (MS), which are entirely different neurological disorders. ^{1 2} Dementia is a degenerative disease which affects the body of the neuron in the cognitive parts of the brain, which leads to cognitive dysfunction. ¹ MS is an autoimmune disorder which affect s the myelin sheath that surrounds the axon of the neuron and leads to demyelination of the long tracts with reduced motor function. ² The effects of dementia in Alzheimer's disease, the commonest form of dementia, occur in the body of the neuron where there is an excess of plaques of beta-amyloid protein. This specifically prevents the normal function of areas like the frontal lobes and the memory centres, including the hippocampus. The neuronal centres in dementia are both entirely pathologically distinct and distinct in location from the parts which are affected in MS.

[0011] WO 98/001 157 discloses treatment of peripheral neuropathies using combinations of antidepressant or a monoamine oxidase inhibiter, vitamin B1 and C a precursor or inducer of a neurotransmitter. WO 96/1 1009 discloses treatment of multiple sclerosis, by some of the combinations of components employed in the present invention. Vitamin B12 has been proposed for the treatment of B12- deficiency associated neuropathy and cognitive dysfunction, in those with known B12 deficiency.

DISCLOSURE OF THE INVENTION

[0012] The present inventor has surprisingly found that a combination of two or more of vitamin B12, Vitamin B1 or Vitamin B9 (folic acid); a noradrenaline or a serotonin reuptake inhibitor; or a precursor of a neurotransmitter, such as L- phenylalanine with or without L-tyrosine, can be effective in the treatment of moderate and severe dementia. The components of this medicament may be presented as a combined preparation for simultaneous separate or sequential use in the treatment of various forms of dementia. It has also been observed that a parallel or simultaneous administration of vitamin B12 treatment, the latter by injection, may further enhance the therapeutic effect of this combination. [0013] It has also been found that a combinations of vitamin B12, Vitamin B1 , or Vitamin B9 (folic acid) with L-Phenylalanine with or without L-Tyrosine is effective in the treatment of mild cognitive impairment and mild dementia.

[0014] It has additionally been found that a combination of Vitamin B12,

Vitamin B1 , or Vitamin B9 (folic acid) with L-Phenylalanine with or without L-Tyrosine, is effective in the enhancement of cognitive function, including normal cognitive function. In particular a combination of Vitamin B12, Vitamin B1 and Vitamin B9 (folic acid) with L-Phenylalanine with or without L-Tyrosine is effective.

[0015] Accordingly, in a first aspect the present invention provides a combination comprising:

A and B; or

A and C; or

B and C; or

A, B and C,

for use in the treatment of a patient suffering from dementia

wherein

A is an antidepressant or a monoamine oxidase inhibiter,

B is selected from Vitamin B12, Vitamin B1 or Vitamin B9 (Folic acid) or a combination thereof and

C is a precursor of a neurotransmitter,

with at least one pharmaceutically acceptable component or vehicle to prepare a medicament suitable for administration to a patient.

[0016] The components A, B and C may be administered simultaneously or separately, in amounts which in combination have the effect of ameliorating dementia. The components A, B and C may be admixed for simultaneous administration.

[0017] In some embodiments, C is L-phenylalanine with or without L-tyrosine.

Optionally, when C is L-phenylalanine with or without L-tyrosine I a monoamine oxidase inhibitor is not used.

[0018] In some embodiments, the combination is a combination of B and C or

A and B.

[0019] In some embodiments B is vitamin B12. [0020] In a further aspect the present invention provides a combination comprising:

A and B; or

A and C; or

B and C; or

A, B and C,

for use in the enhancement of cognitive ability

wherein

A is an antidepressant or a monoamine oxidase inhibiter,

B is selected from Vitamin B12, Vitamin B1 or Vitamin B9 (Folic acid) or a combination thereof and

C is a precursor of a neurotransmitter,

with at least one pharmaceutically acceptable component or vehicle to prepare a medicament suitable for administration to a patient.

[0021] The components A, B and C may be administered simultaneously or separately, in amounts which in combination have the effect of enhancing cognitive ability. The components A, B and C may be admixed for simultaneous administration.

[0022] In some embodiments, C is L-phenylalanine with or without L-tyrosine.

Optionally, when C is L-phenylalanine with or without L-tyrosine I a monoamine oxidase inhibitor is not used.

[0023] In some embodiments B is vitamin B12, Vitamin B1 and Vitamin B9

(folic acid).

[0024] In some embodiments, the combination is a combination of B and C.

[0025] In a further aspect the invention provides a method of treating a patient with dementia or to enhance normal cognitive ability by administering to the patient any one of the combination of the present invention. The combination of components may be administered simultaneously or separately, in amounts which in combination have the effect of ameliorating dementia or enhancing normal cognitive ability. [0025] In a further aspect the invention provides a method of making a medicament for the treatment of a patient suffering from dementia or for the enhancement of normal cognitive ability, comprising admixing any one of the following combinations of components:

A and B,

A and C,

B and C,

A, B and C,

wherein

A is an antidepressant or a monoamine oxidase inhibiter,

B is Vitamin B12, Vitamin B1 or Vitamin B9 (Folic acid) or a combination thereof and

C is a precursor of a neurotransmitter,

with at least one pharmaceutically acceptable component

or vehicle to prepare a medicament suitable for administration to a patient.

[0027] In some embodiments, C is L-phenylalanine with or without L-tyrosine.

Optionally, when C is L-phenylalanine with or without L-tyrosine I a monoamine oxidase inhibitor is not used.

[0028] In some embodiments B is vitamin B12, Vitamin B1 and Vitamin B9

(folic acid)

[0029] In a further aspect the invention provides a pharmaceutical composition containing as the only pharmaceutically active components vitamin B12, and a precursor or inducer of a neurotransmitter for the enhancement of normal cognitive function. In some embodiments the precursor or inducer of a

neurotransmitter.is L-phenylalanine with or without L-tyrosine for the enhancement of normal cognitive function.

[0030] In a further aspect the invention provides a pharmaceutical composition containing as the only pharmaceutically active components vitamin B12, vitamin B1 and Vitamin B9 (folic acid) and a precursor or inducer of a

neurotransmitter for the enhancement of normal cognitive function. In some embodiments the precursor or inducer of a neurotransmitter.is L-phenylalanine with or without L-tyrosine for the enhancement of normal cognitive function. [0031] In a further aspect the invention provides a pharmaceutical composition containing as the only pharmaceutically active components vitamin B12, and a precursor or inducer of a neurotransmitter for the treatment of dementia, in particular for the treatment of MCI and alcoholic dementia. In some embodiments the precursor or inducer of a neurotransmitter.is L-phenylalanine with or without L- tyrosine for the enhancement of normal cognitive function.

[0032] In a further aspect the invention provides a combination comprising

A and B,

A and C,

B and C, or

A, B and C,

wherein

A is an antidepressant or a monoamine oxidase inhibiter,

B is Vitamin B12, Vitamin B1 and Vitamin B9 (Folic acid) or a combination thereof and

C is a precursor of a neurotransmitter,

with at least one pharmaceutically acceptable component or vehicle.

[0033] In a further aspect the invention provides a pharmaceutical composition containing as the only pharmaceutically active components vitamin B12, vitamin B1 and Vitamin B9 (folic acid) and a precursor or inducer of a

neurotransmitter for the treatment of dementia, in particular for the treatment of MCI and alcoholic dementia. In some embodiments the precursor or inducer of a neurotransmitter.is L-phenylalanine with or without L-tyrosine for the enhancement of normal cognitive function.

[0034] In the pharmaceutical compositions of the invention, there may be included at least one pharmaceutically acceptable component or vehicle such as an incipient, carrier, buffer, stabiliser or other material, as discussed below.

[0035] Also provided is a kit or pack containing components:

A and B, or

A and C, or

A and B and C, or

B and C, wherein the components are formulated for simultaneous, separate or sequential delivery in the treatment of dementia or for the enhancement of cognitive ability. Particularly components A and C may be combined, and component B separate.

[0036] In some embodiments, C is L-phenylalanine with or without L-tyrosine.

Optionally, when C is L-phenylalanine with or without L-tyrosine I a monoamine oxidase inhibitor is not used.

[0037] In some embodiments B is vitamin B12, Vitamin B1 and Vitamin B9

(folic acid). In some embodiments B is vitamin B12.

[0038] In addition to the dementias presented here, the present invention is applicable to any and all forms of dementia, also including but not restricted to HIV related dementia, dementia in Parkinson's disease, hypothyroidism related dementia, chronic traumatic encephalopathy (dementia pugilistica), Wernicke's encephalopathy and Korsakoff's syndrome amongst others.

[0039] Preferred antidepressants for use in the present invention include noradrenaline reuptake inhibitors and tetracyclic antidepressants such as

lofepramine and selected serotonin re-uptake inhibitors (SSRI). Lofepramine and certain noradrenaline reuptake inhibitors also show some monoamine oxidase inhibitor (MAOI) activity. Other suitable antidepressants and MAOIs also including but not restricted to mianserin, trimipramine, imipramine, clomipramine, amitriptyline, protriptyline, nortriptyline, trazadone, fluvoxamine, fluoxetine, maprotiline, sertraline, venlaflaxine, isocarbazid, pargyline, triazolopyridine, phenelzine, tranylcypromine, desipramine, moclobemide, dothiepin, doxepin, paroxetine, oxazine, viloxazine, citalopram, escitalopram, agomelatine, duloxetine, ruboxetine flupentixol and mirtazapine amongst others.

[0040] A neurotransmitter inducer or precursor is a component which enhances or triggers production of a neurotransmitter.

[0041] A preferred neurotransmitter precursor for use in the present invention is L-phenylalanine (LPA).This can be used with or without L-tyrosine. However L- tryptophan may also find use in the present invention. [0042] Other amino acids such as L-tyrosine or other compounds such as tyramine may also find use in the present invention as a neurotransmitter, inducer or precursor.

[0043] Compounds may be provided as a metabolite of a precursor. For example, L-phenylalanine may be provided as a metabolite of aspartame.

[0044] If the combination for treatment includes vitamin B12, this may be in the form of cyanocobalamin or hydroxycobalamin, to be administered orally or intramuscularly. Vitamin B1 in the form of thiamine and vitamin B9 in the form of folic acid,

[0045] The compositions provided herein may comprise an antidepressant or a monoamine oxidase inhibitor (MAOI) and a neurotransmitter precursor or inducer, or any other combination of components disclosed herein, as combined

(simultaneous or sequential) actives. However, compounds may be employed which mimic a given active in improving diagnostic status and/or ameliorating one or more symptoms of dementia (mimetics). Such compounds and their use are within the scope of the present invention. Also within the scope of the present invention are derivatives or analogues of the antidepressant or MAOI which retain the

noradrenaline/serotonin reuptake inhibitor or MAOI activity, respectively.

[0046] In accordance with the present invention, compositions provided may be administered to individuals. Administration is preferably in a "therapeutically effective amount", this being sufficient to show benefit to a patient. In the case of enhancement of normal cognitive function this would normally constitute the administration of B vitamins and neurotransmitter precursors in the form of combinations of B and C. In the treatment of dementia such benefit may be at least amelioration of at least one symptom. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, eg decisions on dosage etc, is within the responsibility of general practitioners and other medical doctors.

[0047] In moderate and severe dementias the dose regimens for the noradrenaline/serotonin reuptake inhibitor or MAOI antidepressants may be within the range used for the treatment of depression (for which the standard starting dose of lofepramine is 140mg per day). With the proviso that the prescribing physician will be able to decide suitable and safe dosage levels, a possible range for administration of antidepressants is 10-210mg per day, although 50-70mg per day may be suitable. For the neurotransmitter precursors or inducers, a range of 100mg to 5g per day, preferably 500-2000mg/d (mg per day) may be employed, the dose increasing in proportion to the level of antidepressant or MAOI employed.

[0048] As an example, a 70mg dose of lofepramine may be combined with

500mg of L-phenylalanine given in the morning, this being supplemented with a further 50mg of L-phenylalanine given in the afternoon.

[0049] In the treatment of dementia when vitamin B compounds are used these may be greater than that recommended for daily intake. For Vitamin B1 the optimum therapeutic dosage is up to 50-400mg BD administered orally. With folic acid the recommended is the daily dose but may rise to 5-10 mg daily. When B12 is co-administered, the amounts may be greater than that recommended for daily use. The preferred average dosage range for vitamin B12 as an IM injection in the invention is from 1 mg every month up to 1 mg every 3 days. When symptoms are severe, this may be 1 mg intramuscular hydroxycobalamin per week in an 10 week course at the start of treatment, perhaps reduced to 1 mg every 10 days as treatment progresses. The desired dosage level of vitamin B12 may conveniently be given by weekly intramuscular injection. Intramuscular injection, but doses ranging from 5mg to 10mg may be given daily orally. Wth the addition of L-Tyrosine the dose is 2g - 20g daily.

[0050] In the enhancement of cognitive function, in particular the

enhancement of normal cognitive function, intermittent dosing of compounds B and C are recommended. Such doses should only be used once daily intermittently such as twice weekly, or on alternate days. When vitamin B compounds are used these may be greater than that recommended for daily intake. For Vitamin B1 the therapeutic dosage is up to 50- 400 mg OD administered orally. Wth folic acid the recommended is the daily dose up to 5-10 mg OD. When B12 is co-administered, the amounts may be greater than that recommended for daily use. Doses ranging from 500μg to 10mg may be given daily orally. Wth the addition of L- phenylalanine 500 - 2,000 mg OD, with or without L-Tyrosine 2g -20g daily.

[0051] Pharmaceutical compositions according to the present invention, and for use in accordance with the present invention, may comprise, in addition to active ingredient, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration,

which may be oral, or by injection, e.g. cutaneous, subcutaneous or intravenous.

[0052] Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form. A tablet may comprise a solid carrier such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.

[0053] For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection. Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required. L-tryptophan and L-phenylalanine are available in 500mg tablets.

[0054] A combined oral preparation in single tablet form, containing all these components A, B and C, or for example components B and C, is feasible.

Alternatively, a treatment pack may contain the components separately.

EXAMPLES

Case 1

[0055] A 58 year old male, with mild alcoholic dementia presented with difficulty remembering names and the recollection of events particularly during and after drinking bouts. He was commenced on components B and C, taken

intermittently. Within days his cognitive function and memory returned even during drinking bouts.

Case 2

[0056] A 24 year old male graduate with a 1st class masters degree in physics, volunteered for a study of combinations B and C. A standardised complex puzzle was used to test his cognitive ability. He was tested before and 90 minutes after taking the combination. The results of the test showed that he averaged 19 minutes and 20 sees before and 13 minutes and Usees after taking the combination. Thus a significant improvement was noted in normal cognitive ability.

Case 3

[0057] A 42 year old male doctor was tested with a combination of B and C taken intermittently. He also had with a lifelong interest in physics. Prior to the test his comprehension of physics was limited by his inability to understand the equations involved. He began intermittently taking compounds B and C. Since that time his comprehension of physics was no longer problematic. He now has 17 publications in physics including published journal papers on gravitational physics, quantum electrodynamics, particle physics and thermodynamics. He also has 3 published textbooks in physics.

Case 4

[0058] A 48 year old male, diagnosed non-insulin dependent diabetic when aged 28, showed symptoms of mild cognitive impairment (MCI) as evidenced by his failure to remember to take his medication. He also had diabetic neuropathy which commenced approximately 8 years ago. The onset of neuropathy was thought to be due to poor compliance and poor control of diabetes. His neuropathic symptoms had increased in severity over several years. Treatment with tricyclic antidepressants alone or with carbemazepine was ineffective. A regime of 70mg lofepramine and 500mg LPA, each administered with informed consent twice daily, with weekly 1 mg vitamin B12 injections, significantly improved his cognitive impairment and his diabetic neuropathy. Almost complete clinical resolution of clinical signs of MCI had occurred after one week of the combined therapy.

Case 5

[0059] A male in his fifth decade was HIV positive and had moderate HIV related dementia and complained of mild peripheral neuropathy. Clinically his dementia and neuropathy was diagnosed as that related to HIV. He had been previously commenced on amitriptyline 75 mg daily with some mild beneficial effects. He was additionally commenced on L-phenylalanine 500 mg twice daily, where after he reported an approximate further 50% improvement in the symptoms of his painful neuropathy and his dementia improved considerably.

Case 6

[0060] A 72 year old male with vitamin B12 neuropathy and mild alcoholic and B12 dependant dementia was studied. Clinical progress with vitamin B12 injections alone was insignificant. The addition of lofepramine to the medication enabled the patient to retain his balance, and within 3 days ambulate and function almost normally. Previously he required the assistance of another person to function in his daily living.

Case 7

[0061] A male in his fourth decade had mild alcoholic dementia and peripheral alcoholic neuropathy of six months duration with increasing severity over the past two months. In addition he complained of a compressive neuropathy involving the C6 nerve root. He was commenced on vitamin B12 orally 200μg daily and L-phenylalanine 500mg twice daily with a considerable improvement on dementia and reduction in overall symptomatology whilst on therapy.

Case 8

[0062] A female in her sixth decade had mild dementia and severe diabetic peripheral neuropathy and resultant Charcot foot joints. She was initially placed on tricyclic anti-depressants in the form of dothiepin 150 mg once daily with a mild beneficial effect in neuropathy. The subsequent addition of vitamin B12 injections 1 mg weekly, resulted in improvement in painful symptomatology, and improvement in dementia. Further clinical benefit was gained by the addition of L-phenylalanine 500 mg twice daily. Her pain has subsided and she has noted no further recurrence of her dementia to date. [0063] It will be apparent to those skilled in the art that variations and modifications to the specific embodiments disclosed herein may be made without departing from the scope of the invention.

REFERENCES

IMerritt's Neurology, Chapter 107, Dementia and Alzheimer's Disease. Ed. .L.P. Rowland. 1 1 ^th Edition Lippincott, Williams & Wilkins (2005).

2. Merritt's Neurology, Chapter 134, Multiple Sclerosis. Ed. .L.P. Rowland. 1 1 ^th Edition Lippincott, Williams & Wlkins (2005).