Neuro - Degenerative Diseases

Front 1

Primary location and molecules involved in Alzheimer's

Back 1

Cortical
Beta-amyloid and Tau

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Primary location and hallmark in Huntington's

Back 2

Caudate
Trinucleotde repeats

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Primary location and molecules involved in Parkinson's

Back 3

Midbrain

Synuclein

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Primary location and molecules involved in ALS

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Motor system

TDP-43

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Tri-nucleotide repeats often code for...

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poly-glutamine repeats.

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Inheritance of Alzheimer's

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Small minority - autosomal dominant.
40% have some familial correlation
Most cases are sporadic.

Demential similar to AD found in pts with Down's syndrome.

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Presenile dementia

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AD before age 65.

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Clinical manifestations of AD

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Memory loss, loss of initiative, difficulty in word finding/calculations, disorientation to time/place.

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Dx of AD

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Mainly a dx of exclusion - so you must rule out other treatable causes of dementia.

Don't do biopsy bc of harm to an already compromised pt.

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Gross pathology of AD

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Cortical atrophy, enlarged ventricles, exaggerated shrinkage of the brain, sparing of the occipital cortex.

Aside from occipital, the atrophy is fairly diffuse.

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Microscopic path of AD

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Neurofibrillary tangles and senile plaques. These are especially high in the hippocampus.

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Neurofibrillary tangles

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in AD
Composed of hyperphos. tau protein (MT binding protein)

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Senile plaques

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in AD

Composed of beta amyloid (membrane protein) which is derived from cleavage of amyloid precursor protein by beta secretase then gamma secretase.

Cleavage by alpha secretase causes no real problems.

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Do beta amyloid precursor protein mutations cause AD?

Back 14

yes.

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Basal nucleus of Meynert in AD

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Involved and this supports hypothesis that a loss of cholinergic innervation of the cortex is important in pathogenesis of AD.

Front 16

Genes involved in autosomal dominant, familial, AD

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APP (beta amyloid precursor protein) - on chrom 21. This explains why Down's syndrome pts get early Alzheimer's.

Presenilin 1 (PS1) - Chrom 14

Presenilin 2 (PS2) - Chrom 1

Mutations in presenilins account for 80% of familial AD. These two genes probably play a role of post-trans modification of APP.

Front 17

Gene involved in late onset AD

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E4 isoform of apolipoprotein E - on chrom 19q.

Front 18

Mutation in tau results in...

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Not AD!!!

Another dementing illness--FTDP-17.

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Tx of AD

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Symptomatic, e.g. anticholinesterases.

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Non-AD causes of dementia

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Reversible - metabolic, infectious, psychiatric
Vascular, motor system degen, non-AD cortical degen.

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Huntington's chorea (HC) - Age of onset

Back 21

30-50

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HC - 2 clinical signs

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choreoathetosis, dementia.

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HC - inheritance

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Autosomal dominant - 100% penetrant.

Small minority of cases are sporadic - usually due to expansion of an already large but asymptomatic trinuc repeat in the father. This is called an intermediate allele.

CAG repeats in short arm of chrom 4.

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More repeats in HC leads to...

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earlier age of HC onset.

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HC - length of progression

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10-15 years.

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HC - gross pathology

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Changes in striatum

Atrophy of caudate nucleus and putamen. Secondary enlargement of anterior lateral ventricles.

Atrophy of cerebral cortex (especially frontal and parietal lobes) may also occur, but this does not correlate with extent of dementia.

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HC - microscopic path

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Loss of neurons in caudate and putamen. Preferentially among small neurons.

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HC - is genetic testing available?

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Yes.

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PD - onset of sx

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50-70

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PD - Clinical triad

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tremor (unilateral at first and a pill-rolling tremor at rest)

bradykinesia (poverty of movements or aching/stiffness.

rigidity (stooped posture, shuffling gait, mask-like face)

SENSATION REMAINS INTACT.

Front 31

PD - Gross pathology

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Loss of neuromelanin pigment from substantia nigra and locus ceruleus.

May also be cerebral atrophy and loss of brain weight.

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PD - Microscopic pathology
Principle lesion

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Degeneration of dopaminergic nigrostriatal neuronal pathway which includes...
neuronal cell bodies in zona compacta of the substantia nigra and their neurites traveling to striatum (caudate, putamen).

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PD - Microscopic pathology
Other lesions

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Degeneration of NE neurons in locus ceruleus and serotonergic neurons of dorsal raphe nucleus and cholinergic neurons in nucleus basalis.

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PD - Microscopic pathology
Result of degen of dopamine neurons

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Liberation of neuromelanin pigment into tissues and phagocytosis of pigment by macrophages.

Lewy bodies

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Lewy bodies

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PD

In the few remaining neurons. They are very round eosinophilic inclusions in the cytoplasm that displace neuromelanin.

Composed of an amorphous granular core and a filamentous periphery.

Contain synuclein.

Most often found in substantia nigra, locus ceruleus, dorsal vagal nucleus, autonomic ganglia).

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PD - Microscopic pathology
Result of degen of NE neurons of locus coeruleus.

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Similar to substantia nigra.

Liberation of neuromelanin pigment into tissues and phagocytosis of pigment by macrophages.

Lewy bodies

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PD - Microscopic pathology
Result of degen of cholinergic neurons of nucleus basalis

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These are also at risk in AD.

Formation of Lewy bodies. Less cholinergic enzymes in cerebral cortex.

Severity of these changes are much higher in PD pts WITH DEMENTIA!

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Incidence of PD

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1% of pop over age 50.

Most cases are sporadic but some familial cases are there.

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Parkonsonism

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Not Parkinson's Disease! (AKA idiopathic PD)

Sx are similar to PD but not responsive to Sinemet (carbidopa/levodopa)

Includes...
multiple system atrophy
progressive supranuclear palsy
parkinson-dementia-ALS complex of Guam
drug-induced parkinsonism
toxin-induced parkinsonism (especially MPTP)!!!

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Postencephalitis Parkinsonism

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Distinguished from idiopathic PD (commonly just known as PD) by presence of neurofibrially tangles and absesne of Lewy bodies.

Complications of an encephalitis back in the day. Not seen today.

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Pts who have PD + DEMENTIA

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Less cholinergic innervation and loss of neurons from nucleus basilis.

Also more neurofibrillary tangles and senile plaques (signs of AD)

This goes to show the importance of cholinergic input to cerebral cortex as a determinant of dementia.

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Tx of PD

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L-dopa (crosses BBB) and DOPA decarboxylase inhibitor (Sinemet)

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Mutations in synuclein can cause...

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FAMILIAL PD

(but remember, most cases are sporadic)

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Genetics of PD
Parkin and UCH-L1

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PARK2 mutation leads to levodopa-responsive parkinsonism without Lewy bodies.

Autosomal rec.

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PARK1

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Codes for synuclein

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Genetics of PD
PINK1

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PARK6 linked to autosomal rec, early onset, PD.

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Genetics of PD
DJ1

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PARK7 linked to autosomal rec, early onset, PD.

Front 48

What language problems are found in Alzheimer's disease?

Back 48

Patients often have transcortical dysphasia (can repeat complex phrases but trouble with naming objects).