unravelling the neurochemistry of the dementias 5-2011

7/29/2019 Unravelling the Neurochemistry of the Dementias 5-2011

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Albert ChenMay 5th 2011PFIZER SEMINAR
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Nothing to Disclose!
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OVERVIEW OF NEUROTRANSMITTER SYSTEMS

ASSESS NEUROTRANSMITTER CHANGES IN

VARIOUS DEMENTING CONDITIONS.

DEVELOP HYPOTHETICAL TREATMENT

MODELS


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DEMENTIA

PARKINSONS DISEASE,

Lewy Body Disease

Fronto-temporalDegeneration

Subcortical Disease

ALZHEIMERS

DISEASE

CVD & STROKESmall Vessel Disease

Chen A.W (2008)

OTHER non-CNS DISEASES

UnknownFactors


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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


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ALZHEIMERS DEMENTIA accounts for 65% of

all cases.

AAGP (2008)

LBD

FTD

VaD


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When heterologous tissues are transplantedinto the CNS, they were spared from

immunological rejection ( Medawar, 1948).
http://en.wikipedia.org/wiki/File:Peter_Brian_Medawar.jpg


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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


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B-Amyloid plaques

Tau

Picks bodies

Ubiquitin

Lewy Bodies

Alzheimers disease

Parkinsons disease

Fronto-temporal dementia

-synuclein

LEWY BODY DISEASE


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GLUTAMATE GABA

SEROTONIN(7)

DOPAMINE (5)

NOREPINEPHRINE ACETYLCHOLINE

Chen A.W (2010).
http://www.publicjournalist.com/userimages/user3399_1168847394a.jpg


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N i Pl f f i i b i


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Neurotransmitter Place of formation in brain

Acetylcholine In the brainstem from pontomesencephalotegmentalcomplex. In the basal forebrain, it originates from thebasal optic neucleus of Meynert and medial septal nucleus

Norepinephrine Locus Ceruleus in brainstem

Glutamate hippocampus, amygdala, & basal ganglia

GABA substantia nigra & globus pallidus nuclei of the basal

ganglia, the hypothalamus, the periaqueductal greymatter ("central grey") and the hippocampus.

Dopamine 1. the nigrostriatial tract from the substantia nigra to thestriatum accounts for most of the brain's dopamine2 the tuberoinfundibular tract from the arcuate nucleus

of the hypothalamus to the pituitary stalk,3 the mesolimbic tract from the ventral tegmental areato many parts of the limbic system and4 the mesocortical tract from the ventral tegmental area

to the neocortex, particularly the prefrontal area.Dopamine cells project topographically to the areas they

innervateSerotonin 5-HT The neurons of the ra he nuclei are the rinci al sourceChen A.W. (2010)
http://upload.wikimedia.org/wikipedia/en/8/88/Dopamineseratonin.png


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http://upload.wikimedia.org/wikipedia/en/8/88/Dopamineseratonin.png


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LEARNING

MEMORY

ATTENTION

PLASTICITY, arousal and reward.

Principal inducer of REM sleep

The enhancement of sensory perceptions

when we wake up and in sustainingattention.

basal optic neucleus of Meynert and medialseptal nucleus

Chen A.W. (2009).

C7H16NO2
http://en.wikipedia.org/wiki/File:Acetylcholine.svghttp://en.wikipedia.org/wiki/File:ACh-stick.png


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http://www.cnsforum.com/content/pictures/imagebank/hirespng/hrl_Neuro_path_ACH_AD.png


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Control of appetite,

Sleep, Memory and learning,

Mood, ... depression, aggression, anxiousness, and elevated pain sensitivity.Behavior.......... Impulsivity ....sexual & hallucinogenicCardiovascular functions

Muscle contraction

Endocrine regulation Temperature regulation.

Raphe nucleus

5 HT (1-7)


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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).

Chen et al., (1996) identified reduced 5-HT & 5-HIAA levels in brain and CSF.

Cross et al., (1985) identified reduced cortical 5-

HT1, 5-HT2 receptor level.

Low serotonergic activity linked to ~ behavior

Chen A.W. (2008)


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http://www.cnsforum.com/content/pictures/imagebank/hirespng/Neuro_path_SN.png


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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)
http://en.wikipedia.org/wiki/File:Dopamine-3d-CPK.png


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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

Associated with altered motor function in somepatients


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Processing speed

Personality Judgment

Mental flexibility

Planning Sequencing

Decision-making

Working memory Behavioral regulation, self-monitoring

Motivation, drive, interest


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Most prominent neurotransmitter in the body.

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

Major functions of glutamate receptors appears to bethe 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.


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Dominant excitatory neurotransmitter in CNS

AD severe loss of cortical, hippocampal andstriatal glutamate (Gsell et al.,1997).

Severe AD- elevated CSF glutamate. Gazulla J, Cavero-Nagore M. Glutamate and

Alzheimer's disease. Rev Neurol. 2006 Apr 1-15;42(7):427-32. Glutamatergic dysfunctionplays 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 inalzheimer's disease.. Progress in Neuro-Psychopharmacology and BiologicalPsychiatry. Vol 12, Issue 4, 1988, Pages 421-430, IN3-IN4


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Alzheimers disease

AIDS Dementia Complex

Amyotrophic Lateral

Sclerosis

Vit. B12 DefeciencyDementia

Hepatic encephalopathy

Lead encephalopathy

Rett Syndrome

Parkinsons disease

Hungtintons disease

neuropathic pain syndromes(e.g. causalgia or painfulperipheral neuropathies)

Mitochondrial abnormalities

Multiple Sclerosis

Schizophrenia

Non-ketotic hyperglycaemia

Olivopontocerebellar atrophy

Chen A.W. (2008)


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http://www.cnsforum.com/content/pictures/imagebank/hirespng/Neuro_path_GLUT_SCH.png


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

Chief inhibitory neurotransmitter in the centralnervous system.

Balances chemical processes that regulate our moodand other factors.

Reduce anxiety and induces relaxation and sleep.

Improve memory, mental performance and alleviatesthe symptoms of cerebral palsy.
http://en.wikipedia.org/wiki/File:GABA.pnghttp://en.wikipedia.org/wiki/File:GABA.png


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most highly concentrated in the substantia

nigra & globus pallidus nuclei of the basalganglia, followed by the hypothalamus, theperiaqueductal grey matter ("central grey")

and the hippocampus.

The GABA concentration in the brain is 200-

1000 times greater than that of themonoamines or acetylcholine.


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Predominant inhibitory neurotransmitter in cortex &

hippocampus.

Reduced cortical concentration and symatosomeuptake of GABA in AD (Lowe et al., 1988).

Loss of GABA receptors (Reisine et al., 1987).

Greater loss of GABAergic neurones in late stages ofAD.


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http://www.cnsforum.com/content/pictures/imagebank/hirespng/Neuro_path_GABA.png


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Tranquilizers& alcoholinhibits

Tranquilizers& alcohol

stimulates

Caffeine &PCPstimulates

Caffeine &PCP inhibits

Chen A.W (2010)

GABA and glutamate regulate actionpotential traffic. GABA, an inhibitoryneurotransmitter, stops actionpotentials. Glutamate, an excitatoryneurotransmitter, starts actionpotentials or keeps them going.


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Locus ceruleus In midbrainAttention

MotivationFocus

MemoryArousal


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http://www.cnsforum.com/content/pictures/imagebank/hirespng/Neuro_path_N.png


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Locus Ceruleus neuronal loss in AD

Reduced CSF norepinephrine levels

Reduced brain norepinephrine levels

Increased level of metabolites in CSF

Linked to Agitation and Aggression.

Zubenko, 1992


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Acetylcholine: 90%

Serotonin: 50-70%

Norepinephrine: 30-70%

GABA: 50%

Glutamate 30-50%

Dopamine ?

Chen A.W. (2005)
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Neuro-Chemical Deficit Mechanism of interaction Proposed Treatment

ACETYLCHOLINEDEFICIT

DELAY BRAKEDOWN OFACETYLCHOLINE INSYNAPTIC CLEFT BY

INHIBITING ACETYL- ANDBUTYL CHOLINESTERASE

TACRINEDONEPEZIL

RIVASTIGMINEREMINYL

SEROTONIN DEFICIT INHIBIT REUPTAKE OF 5HT SSRIS

NOREPINEPHRINE INHIBIT ACTION OF

NOREPINEPHRINE

BETA-BLOCKERS

GABA STABILIZE LEVELS OFGABA

MOOD STABILIZERS

GLUTAMATE NMDA- RECEPTOR

INHIBITION

MEMANTINE HCL

Chen A.W (2009)
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Tariot & Schneider, 1998

SSRIs as a group gives mixed results

Fluoxetine shows no benefit ( Tariot & Schnieder,1998).

Citalopram, Fluvoxamine, and Sertraline gives positiveresults.


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SSRIs: setraline & fluoxatine= long 1/2t.

Paroxetine blocks muscarinic receptors.

Trazodone: phenylpiperazine agent

Nefazodone: phenylpiperazine agent

Buspirone: arylpiperazine derivitive

Lithium: increases tryptophan levels


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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 serotoninreuptake.

Lecozotan has pro-cognitive properties

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


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ALZHEIMERS DEMENTIA accounts for 65% of

all cases.

AAGP (2008)

LBD

FTD

VaD


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The acetylcholine (ACh) concentration in the cerebrospinal fluidwas investigated in patients with vascular dementia of the

Binswanger type (VDBT) or multiple small infarct type (MSID) ascompared with patients with Alzheimer-type dementia (ATD).

The ACh concentration in patients with ATD was found to besignificantly lower than in controls (73%, p < 0.0001), andshowed 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 significantpositive correlation with dementia scale scores (rs=0.62, p

unravelling the neurochemistry of the dementias 5-2011

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