Albert Chen

May 5th 2011 PFIZER SEMINAR

Nothing

to Disclose!

 OVERVIEW ASSESS

OF NEUROTRANSMITTER SYSTEMS

NEUROTRANSMITTER CHANGES IN VARIOUS DEMENTING CONDITIONS. HYPOTHETICAL TREATMENT

DEVELOP

MODELS

ALZHEIMERS DISEASE
PARKINSONS DISEASE, Lewy Body Disease Fronto-temporal Degeneration

CVD & STROKE

Small Vessel Disease

Subcortical Disease

DEMENTIA
OTHER nonCNS DISEASES
Chen A.W (2008)

Unknown Factors

Dementia Type

Various

Rabins

Barker et al.

AD

60-70 %

66%

42%

LBD

20-30%

8-15%

8%

Vascular

15-30%

15-20%

3%

FTD

13.3-21.9%

5%

4%

Mixed

42%

AAGP 2008

 ALZHEIMERS

DEMENTIA accounts for 65% of

all cases.

VaD FTD
AAGP (2008)

LBD

 When

heterologous tissues are transplanted into the CNS, they were spared from immunological rejection ( Medawar, 1948).

Pathways of metabolism of sphingomyelin, ceramide, and cholesterol, their modulation by oxidative stress, and their possible roles in neuronal death in AD.

Cutler R G et al. PNAS 2004;101:2070-2075

2004 by National Academy of Sciences

B-Amyloid plaques

Parkinsons disease Fronto-temporal dementia

Tau
Picks bodies Ubiquitin

LEWY BODY DISEASE

Alzheimers disease

Lewy Bodies -synuclein

GLUTAMATE GABA SEROTONIN DOPAMINE NOREPINEPHRINE ACETYLCHOLINE

(7)

(5)

Chen A.W (2010).

Neurotransmitter

Place of formation in brain

Acetylcholine

In the brainstem from pontomesencephalotegmental complex. In the basal forebrain, it originates from the basal optic neucleus of Meynert and medial septal nucleus
Locus Ceruleus in brainstem hippocampus, amygdala, & basal ganglia substantia nigra & globus pallidus nuclei of the basal ganglia, the hypothalamus, the periaqueductal grey matter ("central grey") and the hippocampus. 1. the nigrostriatial tract from the substantia nigra to the striatum accounts for most of the brain's dopamine 2 the tuberoinfundibular tract from the arcuate nucleus of the hypothalamus to the pituitary stalk, 3 the mesolimbic tract from the ventral tegmental area to many parts of the limbic system and 4 the mesocortical tract from the ventral tegmental area to the neocortex, particularly the prefrontal area. Dopamine cells project topographically to the areas they innervate
Chen A.W. (2010) The neurons of the raphe nuclei are the principal source

Norepinephrine Glutamate GABA

Dopamine

Serotonin 5-HT

 LEARNING
MEMORY ATTENTION PLASTICITY,

and reward. C7H16NO2 Principal inducer of REM sleep The enhancement of sensory perceptions when we wake up and in sustaining attention. basal optic neucleus of Meynert and medial septal nucleus
arousal
Chen A.W. (2009).

Control Sleep,

of appetite,

Memory and learning,

depression, aggression, anxiousness, and elevated pain sensitivity.
.......... Impulsivity ....sexual & hallucinogenic

Mood, ... Behavior

Cardiovascular

functions Muscle contraction Endocrine regulation Temperature regulation.

Raphe nucleus

5 HT (1-7)

 Studies

of postmortem brains & CSF of AD patients= reduced serotonin activity.

Reduced

5-HT correlates with greater neuronal loss & greater NFT-burden (Yamamoto & Hirano, 1985).
et al., (1996) identified reduced 5-HT & 5HIAA levels in brain and CSF. et al., (1985) identified reduced cortical 5HT1, 5-HT2 receptor level. serotonergic activity linked to ~ behavior
Chen A.W. (2008)

Chen

Cross

Low

 Behavior

and Cognition. Attention & Working memory. Learning Voluntary movement, Motivation & Drive Punishment & Reward Inhibition of prolactin. Sexual Gratification Sleep and Mood Control information flow to and within frontal lobes
(DR 1-5)

 30%

of AD patients develop EPS Cytopathology (Cross et al., 1984) CSF & Brain dopamine metabolites. Tyrosine hydrolase activity Substantia negra cell death D-1receptor unaffected D-2 receptor---severe loss with altered motor function in some

Associated

patients

Processing speed Personality Judgment Mental flexibility Planning Sequencing Decision-making Working memory Behavioral regulation, self-monitoring Motivation, drive, interest

Most prominent neurotransmitter in the body.

(present in over 50% (70%) of nervous tissue.)

Major functions of glutamate receptors appears to be the modulation of synaptic plasticity, neural development & neuro-degeneration.
(vital for memory and learning.)

Neural

communication, Memory formation, learning, and regulation. Glutamate receptors are implicated in most neurodegenerative diseases by evoking excitotoxicity.

Dominant excitatory neurotransmitter in CNS

AD

severe loss of cortical, hippocampal and striatal glutamate (Gsell et al.,1997).

Severe

AD- elevated CSF glutamate. Gazulla J, Cavero-Nagore M. Glutamate and Alzheimer's disease. Rev Neurol. 2006 Apr 115;42(7):427-32. Glutamatergic dysfunction plays an important role in the pathogenesis of this illness......

Timothy Greenamyre, William F. Maragos, Roger L. Albin, John B. Penney and Anne B. Young.: Glutamate transmission and toxicity in alzheimer's disease.. Progress in Neuro-Psychopharmacology and Biological Psychiatry. Vol 12, Issue 4, 1988, Pages 421-430, IN3-IN4

Alzheimers disease

AIDS Dementia Complex

Amyotrophic Lateral Sclerosis

neuropathic pain syndromes (e.g. causalgia or painful peripheral neuropathies) Mitochondrial abnormalities

Multiple Sclerosis
Schizophrenia

Vit. B12 Defeciency Dementia Hepatic encephalopathy Lead encephalopathy Rett Syndrome Parkinsons disease Hungtintons disease

Chen A.W. (2008)

Non-ketotic hyperglycaemia
Olivopontocerebellar atrophy

Second most abundant neurotransmitter in the human brain, occurring in 30-40% of all synapses.

Chief

inhibitory neurotransmitter in the central nervous system. Balances chemical processes that regulate our mood and other factors. Reduce anxiety and induces relaxation and sleep. Improve memory, mental performance and alleviates the symptoms of cerebral palsy.

most highly concentrated in the substantia nigra & globus pallidus nuclei of the basal ganglia, followed by the hypothalamus, the periaqueductal grey matter ("central grey") and the hippocampus. The GABA concentration in the brain is 2001000 times greater than that of the monoamines or acetylcholine.

 Predominant

inhibitory neurotransmitter in cortex & hippocampus. cortical concentration and symatosome uptake of GABA in AD (Lowe et al., 1988). of GABA receptors (Reisine et al., 1987). loss of GABAergic neurones in late stages of

Reduced

Loss

Greater

AD.

Tranquilizers & alcohol inhibits

Caffeine & PCP inhibits

Caffeine & PCP stimulates

Tranquilizers & alcohol stimulates

GABA and glutamate regulate action potential traffic. GABA, an inhibitory neurotransmitter, stops action potentials. Glutamate, an excitatory neurotransmitter, starts action potentials or keeps them going.
Chen A.W (2010)

Locus

ceruleus In midbrain Attention Motivation Focus Memory Arousal

 Locus

Ceruleus neuronal loss in AD

Reduced
Reduced

CSF norepinephrine levels

brain norepinephrine levels level of metabolites in CSF

Increased

Linked

to Agitation and Aggression. Zubenko, 1992

Acetylcholine: 90% Serotonin: 50-70%

Norepinephrine: 30-70%
GABA: 50% Glutamate 30-50% Dopamine ?
Chen A.W. (2005)

Neuro-Chemical Deficit

Mechanism of interaction DELAY BRAKEDOWN OF ACETYLCHOLINE IN SYNAPTIC CLEFT BY INHIBITING ACETYL- AND BUTYL CHOLINESTERASE

Proposed Treatment TACRINE DONEPEZIL RIVASTIGMINE REMINYL

ACETYLCHOLINE DEFICIT

SEROTONIN DEFICIT NOREPINEPHRINE GABA GLUTAMATE

INHIBIT REUPTAKE OF 5HT INHIBIT ACTION OF NOREPINEPHRINE STABILIZE LEVELS OF GABA NMDA- RECEPTOR INHIBITION

SSRIS BETA-BLOCKERS MOOD STABILIZERS MEMANTINE HCL

Chen A.W (2009)

 SSRIs

as a group gives mixed results shows no benefit ( Tariot & Schnieder,

Fluoxetine

1998).
Citalopram,

Fluvoxamine, and Sertraline gives positive

results.

Tariot & Schneider, 1998

 SSRIs:

setraline & fluoxatine= long 1/2t.

Paroxetine blocks muscarinic receptors. phenylpiperazine agent phenylpiperazine agent

Trazodone:

Nefazodone: Buspirone: Lithium:

arylpiperazine derivitive

increases tryptophan levels

1.

5-HT1A receptor antagonists

Lecozotan is a potent and selective 5-HT1A receptor antagonist.

It promotes release of glutamate and acetylcholine as well as inhibiting serotonin reuptake.

Lecozotan has pro-cognitive properties

Schechter LE et al, J of Pharmacol and Exper Therapeutics 2005

 ALZHEIMERS

DEMENTIA accounts for 65% of

all cases.

VaD FTD
AAGP (2008)

LBD

The acetylcholine (ACh) concentration in the cerebrospinal fluid was investigated in patients with vascular dementia of the Binswanger type (VDBT) or multiple small infarct type (MSID) as compared with patients with Alzheimer-type dementia (ATD). The ACh concentration in patients with ATD was found to be significantly lower than in controls (73%, p < 0.0001), and showed a significant positive correlation with dementia scale scores (rs=0.63, p < 0.03). In VDBT/MSID patients, the ACh concentration was significantly lower than in controls (p < 0.001), also showing a significant positive correlation with dementia scale scores (rs=0.62, p < 0.02), but was significantly higher than in ATD patients (p < 0.001 Conclusion: These results suggest that simultaneous determination of ACh and Ch concentrations in CSF may be useful for differentiating VDBT/MSID from ATD and that increasing the ACh level using cholinergic agents may be a beneficial therapeutic strategy for the treatment of ATD as well as VDBT/MSIT, and is worthy of further investigation.

Neurotransmitter Abnormalities in Vascular Dementia Jenny A. Court and Elaine K. Perry

Joint MRC/Newcastle University Centre Development in Clinical Brain Ageing, Newcastle General Hospital, Newcastle upon Tyne, UK A number of neurotransmitters, including acetylcholine, serotonin, noradrenaline, and dopamine, modulate cerebral perfusion. In vascular dementia, reductions in markers of cholinergic innervation are consistently reported, and there are some indications that the serotonergic and dopaminergic systems may also be affected. Limited data indicate that the numbers of nucleus basalis, locus coeruleus, and dorsal raph neurons and the density of neurotransmitter receptors are not reduced in the majority of cases. These data suggest neurotransmitter systems as a potential therapeutic target in vascular dementia.

 Grantham

C, Geerts H. The rationale behind cholinergic drug treatment for dementia related to cerebrovascular disease. J Neurol Sci. 2002; 203 204:131136. CG, Blennow K, Karlsson I, Wallin A. The neurochemistry of vascular dementia. Dementia. T. Cerebrovascular dementia: pathophysiology, diagnosis and treatment. CNS Drugs. 1999; 12: 3548.

Gottfries

Erkinjuntti

 Wilcock

G, Mobius HJ, Stoffler A. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol. 2002; 17: 297305.

Orgogozo JM, Rigaud AS, Stoffler A, Mobius HJ, Forette F. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke. 2002; 33: 18341839.
Its benefit seems to be at least comparable to the effect of ACEI

Conclusion:

 Acetylcholine Serotonin Glutamate GABA Norepinephrine Dopamine

metabolite in CSF

Metabolites in CSF

 N=

1219 mild to moderate cognitive decline due to probable or possible vascular dementia (according to the NINCDS/AIREN criteria and the Hatchinski Ischemia Scale) . Donepezil, at doses of 5 or 10 mg a day was compared with placebo for 24 weeks. For each outcome measure, mean change from baseline at weeks 12 and 24, using a last observation carried forward analysis, was calculated.

The donepezil groups showed statistically significantly better performance than the placebo groups on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) at 12 and 24 weeks.
The donepezil groups produced statistically significantly better scores than the placebo groups on the Mini-Mental State Examination (MMSE) at 12 and 24 weeks.

Clinical Dementia Rating (CDR-SB) showed at 24 weeks a statistically significant benefit of 10 mg donepezil daily over both placebo and a 5 mg daily dosage.
CIBIC-plus showed improved global function of participants taking 5 mg of donepezil daily compared with the placebo group but this was not seen in the higher dose

IADL scale, there was no statistically significant difference between the groups taking donepezil 5 mg per day donepezil and placebo, but the group taking 10 mg of donepezil a day showed benefit compared with placebo There were statistically significant benefit for donepezil at either dosage compared with placebo on the Alzheimer's Disease Functional Assessment and Change Scale (ADFACS).
Broad range of adverse events were reported in the studies and data confirmed that donepezil was well tolerated, and most of the side effects were transient and were resolved by stopping the medication. Some of these events, especially nausea, diarrhoea, anorexia and cramp appeared more frequently on the 10 mg dose where there was a statistically significant difference compared with placebo. The drop-out rate was similar between the groups, 84.2% (330) patients completed the studies. The withdrawal rate was low and due mainly to side effects.

Neuro-Chemical Deficit

Mechanism of interaction DELAY BRAKEDOWN OF ACETYLCHOLINE IN SYNAPTIC CLEFT BY INHIBITING ACETYL- AND BUTYL CHOLINESTERASE INHIBIT REUPTAKE OF 5HT INHIBIT ACTION OF NOREPINEPHRINE STABILIZE LEVELS OF GABA

Proposed Treatment TACRINE DONEPEZIL RIVASTIGMINE REMINYL

ACETYLCHOLINE DEFICIT

SEROTONIN DEFICIT NOREPINEPHRINE GABA

SSRIS BETA-BLOCKERS MOOD STABILIZERS

GLUTAMATE

NMDA- RECEPTOR INHIBITION ANTICOAGULANT ANTIPLATELET STATIN Chen A.W (2009)

MEMANTINE HCL AGGRENOX ASPIRIN CLOPIDOGREL

Dementia similar to that of Alzheimers.

Onset same age or a bit earlier than AD.

Progresses faster in most cases.

Significantly greater fluctuation in condition from day to day, compared to AD.

81% have periods of marked unexplained confusion, mimicking delirium. Twice as common in men. (1.6-2:1) Generally non-familial, but a few autosomal dominant cases reported

DEMENTIA

FLUCTUATING COGNITION LBD

PARKINSONISM
Chen A W 2009

Heyman A et al. Neurology. 1999;52:1839-1844. Ballard CG et al. Dement Geriatr Cogn Disord. 1999;10:104-108. Barber R et al. Neurology. 1999;52:1153-1158.

VISUAL HALLUCINATIONS

James E. Gavin et. a. 2008. Current Issues in Lewy Body Dementia

AcetylCholine 90-95%

Dopamine 30-50% No serotonergic deficit.

Ach 5HT

Chen A.W (2008).

Neuro-Chemical Deficit/ Syndromic ACETYLCHOLINE DEFICIT

Mechanism of interaction

Proposed Treatment

DELAY BRAKEDOWN OF ACETYLCHOLINE IN SYNAPTIC CLEFT BY INHIBITING ACETYL- AND BUTYL CHOLINESTERASE

TACRINE DONEPEZIL RIVASTIGMINE REMINYL

PARKINSONISM Reduced Dopamine NO SEROTONIN DEFICIT REM SLEEP BEHAVIOR DISORDER PSYCHOSIS/HALLUCINATIO N GLUTAMATE

INCREASE DOPAMINE LEVEL INHIBIT REUPTAKE OF 5HT SYNUCLEOPATHIES BENIGN NELECT CAREGIVER TRAINING NMDA- RECEPTOR INHIBITION Chen A.W (2009)

?? ?? SSRIS NOT NEEDED MELATONIN CLONAZEPAM SEROQUEL MEMANTINE HCL

Benzatropine/ Benztropine (cogentin) Wellbutrin Ketamine Methylphensidate (Ritalin)

Clinical Syndromes
Fronto-Temporal Dementia
Tactlessness & Disinhibition Impulsiveness Loss of social ability & control, self schemata

Primary Progressive Aphasia

Non-Fluent Verbal output. Economy of speech Early Mutism . Echolalia. Perseveration

Semantic Aphasia Visual Agnosia

Miller BL, Cummings JL, et al: Neurology 41:1374-1382, 1991

in Frontal/Temporal areas.

No Cholinergic Deficit Loss of Serotonin receptors Serotonergic Deficit Dopaminergic Deficit GABA? Glutamate?
Alonso-Navarro et. al., 2006

ACTYLCHOLINE

NO DEFICIT (AChEI)

SEROTONIN
DOPAMINE GABA GLUTAMATE

SSRI?
DOPAMINERGIC? MOOD STABILIZERS? MEMANTINE HCL?

NEUROCHEMICAL STATUS

TREATMENT OPTIONS

CHEN A.W (2009)

Free Radicals

Inflammation

AGE & Disease

Homocysteine

Anti-oxidants

Anti Inflammatory Diet

AGE & Health

B,
6

B B B Folate
1
2 12

Pro-inflammatory agents

Anti-inflammatory agents

Omega-6-fatty acids
Corn Oil Processed Foods Simple sugars vegetable oils (e.g., corn, soy, and safflower oils).

Omega-3-fatty acids
Olive oil, Fish Oil Unprocessed foods Fruits & vegetables Nuts, pumpkin seeds
Chen A. W., 2011.

Omega-3

essential fatty acids in cold water oily fish, walnuts, flax and pumpkin seeds Olive oil canola oil, grapeseed oil, walnut oil.
Chen A. W., 2011.

mackerel, herring, sardines, tuna, anchovies, whitefish, and sablefish.

Chen A. W., 2011.

1.

Salmon 2. Herring 3. Sardines 4. Trout 5. Pollock

Chen A. W., 2011.

. Curry spice curcumin

active ingredient in turmeric, (member of ginger family) metal chelator antioxidant anti-inflammatory agent & COX inhibitor
Ringman JM et al, Current Alz Research Zhang H-Y, Science Direct 2005

1. 2.

Zingiberaceae ginger family

Chen A. W., 2011.

 Antioxidant

action Anti-inflammatory action Anti-carcinogenic Anti-mutagenic Anti- thrombotic action Hepatoprotectective action Antimicrobial action Antiviral action Antiparasitic action
Srinivasan, K.R. (1953) Chromatographic study of the curcuminoids in Curcuma longa. J. Pharm. Pharmacol. 5.448.

Chen A. W., 2011.

 Ginger

protects the stomach lining from alcohol damage. Ginger improves digestions and activates peristalsis Ginger is a good source of scavengers of free radicals thus protecting the body from toxins. Ginger warms the lungs, and resolves phlegm and accumulated fluid. Ginger is used for those with symptoms of abdominal pains, vomiting and diarrhea. It lowers blood cholesterol by inhibiting the cholesterol production of the liver. It inhibits cytokines production and inflammation
Chen A. W., 2011.

Anti-inflammatory Anti-Fungal reducing fevers stomach cramps flatulence and colic easing arthritic pain general digestive aid Aromatherapy Antioxidant

Chen A. W., 2011.

 Full

of flavonoids. Anti-oxidant Anti-inflammatory Reduces cholesterol Reduces triglycerides Diuretic properties. Adjunct to weight loss
Chen A. W., 2011.

 Vitamin

C Beta carotene Vitamin E Bioflavonoids

vegetables
Carotenoids Selenium Manganese

fruits, vegetables carrots, mangoes nuts, grains, fish

coloured fruits &

yellow coloured foods

zinc and Lycopenes alpha lipoic acid.

Chen A. W., 2011.

Tomato

Chen A. W., 2011.

Vitamin B2 Vitamin B6 Vitamin B 12 Folic Acid Almonds Whole grains Wild rice Soybeans Fish Green beans Field salad Bananas Daily supp. Of 100 mg Liver, beef. Leafy green
vegetables

Trout Salmon

Tuna Eggs Daily supp. Broccoli 50-300 mcg.

Chen A. W., 2011.

Fruits (citrus/juice s) Avacardo

 Clinical

presentation of Alzheimers disease and other forms of dementia hinges on the neuro-chemical changes.

Clinical

management should follow the same thread.

Comprehensive

management of dementia should reflect all the detectable changes & imbalances and the current state of KNOWLEDGE.

THE END

Neurotransmitter

Decreased Function

Increased Function

Acetylcholine

Memory impairment, delirium, delusions

Aggression, depression

Dopamine

Dementia, depression

Psychosis, anxiety, confusion, aggression

Serotonin

Depression, aggression

Anxiety

Norepinephrine

Depression, dementia

Anxiety, aggression

GABA

Anxiety

Reduce anxiety and aggression