Path 3 Neurode

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NEURODEGENERATIVE DISEASES - MARKESBERY AND NELSON - FRIDAY JAN 26

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ALZHEIMER'S DISEASE

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how many are affected in the US and worldwide?

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4.5 million, 25 million

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what % of individuals over 65 have it?

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10%

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what % of individuals over 85 have it?

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47%

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how many areas of cognition must one have deficits in to have alzheimers?

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two or more

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what are these areas of cognition (list)?

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memory, abstract thinking, judgment, problem solving, language, perception, praxis, and ability to learn new skills

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is there any disturbance of consciousness?

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no

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what is the range of ages that Alzheimer's can have its onset?

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40-90

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what problems occur in early stages?

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recent memory decline

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what happens next (list)?

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loss of spontaneity and initiative, poor judgment, faulty reasoning, poor decision making, and loss of insight

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what happens next (list)?

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word finding difficulties, disorientation, diminished interests, and visuospatial difficulties

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what are patients like in the late stage (list)?

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apathetic, withdrawn, lost easily, no judgment, requires assistance with simple ADLs

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what varient lipoprotein is a risk factor for Alzheimer's?

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apoprotein E - E4 allele

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what is the risk of developing late-onset AD if there is one allele, and what if there are two alleles?

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one allele - 40-45%; two alleles - 80%+

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what is the relative risk for AD for someone who has one first degree relative with AD?

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3.5

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what is the relative risk if there are two or more first degree relatives affected?

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7.5

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what is the most common inheritence pattern for AD?

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autosomal dominant

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what other genes, if mutated, are risk factors for AD (3)?

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1) amyloid precursor protein; 2) presenilin-1; 3) presenilin-2

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if the APP is mutated, what will the age of onset be?

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50s

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what if the presenilin-1 is mutated?

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40s and 50s

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what if the presenilin-2 is mutated?

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50s and later

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what will the phenotype be if the presenilin 1 or 2 is mutated?

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increased production of amyloid beta-42 (AB-42) peptides

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if the APP is mutated, what will the phenotype be (2)?

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increased production of amyloid beta (AB) peptides, or amyloid beta-42 (AB-42) peptides

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what are alterations of AD brains (3)?

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1) cortical atrophy; 2) moderately enlarged ventricles; 3) atrophy of hippocampus

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what part of the hippocampus is particularly affected?

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subiculum

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what protein misfolds in the brains of AD patients, forming plaques?

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amyloid beta protein (AB)

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besides forming neuritic plaques, where else can the AB protein cause problems?

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in the walls of vessels

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which other protein was said to form aggregates in the brain of AD patients, and what is its normal function?

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tau protein - a microtubule associated protein that stabilizes microtubules

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what abnormal form is it converted to, and by what mechanism?

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converted to PHF tau by abnormal phosphorylation

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what is the criteria for the neropathologic diagnosis of AD based on (2)?

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1) CERAD semiquantitation of neuritic plaques; 2) Braak stage

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what are the levels of neuritic plaques (3), and what number does each correllate with?

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1) sparse <6; 2) moderate <17; 3) frequent >17

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what measurements of NP and Braak stage correspond to a low likelihood of AD?

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Braak stage I-II and sparse NP

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what measurements of NP and Braak stage correspond to an intermediate likelihood of AD?

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Braak stage III-IV and moderate NP

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what measurements of NP and Braak stage correspond to a high likelihood of AD?

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Braak stage V-VI and frequent NP

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HYPOTHESES OF ALZHEIMER'S PATHOGENESIS

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what are the four hypotheses of AD pathogenesis?

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1) amyloid (amyloid cascade) hypothesis; 2) excitotoxicity hypothesis; 3) inflammatory hypothesis; 4) oxidative stress/damage hypothesis

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what does the amyloid cascade hypothesis say are the initial event in AD, and what does this initial event eventually cause to occur?

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amyloid plaques are the initial event in AD, and eventually cause neurofibrillary tangles to occur

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what cleaves the amyloid precursor protein off of the cell in the amyloid cascade hypothesis?

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B-secretase (beta)

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what cleaves the AB monomer off of the cell?

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gamma-secretase

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what can amyloid beta monomers transform into?

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soluble oligomers

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what effect do soluble oligomers have on neurons?

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they inhibit synaptic plasticity

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what can soluble oligomers transform into?

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protofibrils

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what is the effect of protofibrils on neurons?

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they decrease neuron activity

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what can protofibrils transform into?

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fibrils

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what is the effect of fibrils on neurons (2)?

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decrease neuron activity and synaptic plasticity

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what is the first step in the excitotoxic hypothesis (what is impaired, and what does it lead to)?

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impaired glutamate homeostasis leads to mild activation of NMDA receptors

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what does this lead to?

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excess calcium influx into neurons

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what does this influx lead to in neurons, and what is the result?

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death of neurons and decreased memory and learning

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in the inflammatory hypothesis, what type of immune response is associated with amyloid-beta deposition?

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innate immune response

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what other inflammatory mechanisms were said to be taking place in the immune hypothesis (4)?

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1) activation of microglia; 2) complement activation; 3) secretion of proinflammatory cytokines; 4) secretion of NO; 5) expression of chemokines

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in the oxidative hypothesis, what particular molecule was said to do the oxidative damage?

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hydroxyl radical

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what effects was it said to exert (3)?

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1) DNA damage; 2) protein oxidation; 3) lipid peroxidation

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SYNUCLEINOPATHIES

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what synucleinopathies must we know (4)?

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1) parkinson's; 2) dementia with Lewy bodies; 3) multiple system atrophy; 4) neurodegeneration with brain iron (Hallervorden-Spatz disease)

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what other proteins are in the family with alpha-synuclein (3)?

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beta-synuclein; gamma synuclein; synoretin

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where is alpha-synuclein predominantly expressed, and where is it particularly abundant?

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predominantly expressed in neurons, and abundant in presynaptic terminals

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how is its expression regulated?

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by post-translational mechanisms

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what are its functions thought to be (2)?

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1) modulate synaptic plasticity; 2) dopaminergic neurotransmission

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what abnormal structure is the alpha-synuclein protein the primary component of?

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Lewy bodies

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what led to this discovery?

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alpha-synuclein missense mutation in familial PD

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DEMENTIA WITH LEWY BODIES

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what are the core features of dementia with Lewy bodies?

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1) fluctuating cognitive impairment with variations in attention and alertness; 2) recurrent visual hallucinations; 3) spontaneous motor features of Parkinsonism

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what is required for diagnosis?

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two of these three core features

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what are the supportive features of dementia with Lewy bodies?

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1) repeated falls; 2) syncope; 3) neuroleptic sensitivity; 4) systematized delusions; 5) non-visual hallucinations

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how is the form of dementia with Lewy bodies diagnosed?

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lewy bodies are counted in several areas, and a score is obtained

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what areas are they counted in (5)?

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1) entorhinal cortex; 2) cingulate gyrus; 3) mid-frontal cortex; 4) mid-temporal cortex; 5) inferior parietal cortex

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how is a score obtained?

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in each region, a count of 1-5 LBs gives a score of 1, and greater than 5 gives a score of 2

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what form of dementia with LBs has a total score of 0-2?

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brainstem predominant form

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what form has a score of 3-6?

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limbic or transitional form

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what form has a score of 7-10?

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neocortical form

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what two diseases is dementia with Lewy bodies somewhat like (shown inbetween on a slide)?

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Alzheimer's and Parkinson's

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PARKINSON'S DISEASE

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what is the prevalence of PD per 100,000?

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100-150 per 100,000

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does it occur more in males or females?

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same

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at what age range is the risk the greatest?

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70-79 year old range

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what is the mean age of onset (range)?

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58-62

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what is the mean duration of PD?

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13-14 years

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what are the neurologic manifestations of PD (5)?

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1) tremor; 2) rigidity; 3) akinesia; 4) alterations in posture; 5) dysarthria

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what other features are seen in some with PD (2)?

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1) autonomic instability (in some); 2) dementia (in some)

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what are risk factors for parkinson's disease (3)?

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1) rural environment; 2) genetics; 3) age

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what reduces the risk of parkinson's disease?

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smoking

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FRONTOTEMPORAL DEMENTIA

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what forms of frontotemporal dementia are there (6)?

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1) Pick's disease; 2) FTD with tau positive deposition in neurons and glia; 3) FTD and parkinsonism linked to tau gene mutation; 4) FTD with motor neuron disease; 5) FTD with ubiquitin-only immunoreactive changes; 6) FTD with no distinctive histopathological feature

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what type of intellectual defects are seen with FTD (list)?

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behavioral and personality changes, disinhibition, emotional instability, lack of insight and judgment, language dissolution, memory decline later

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is FTD ever familial?

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yes, frequently

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what is seen on MR scans of those with FTD (2)?

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frontal and temporal atrophy

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what gene do familial forms have a mutation in?

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tau gene (chromosome 17)

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what structures are seen in the brain of those with Pick's disease (2)?

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1) Pick bodies; 2) balloon neurons

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what type of inclusion is shown in FTD with motor neuron disease?

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ubiquitin positive inclusion

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HUNTINGTON'S DISEASE

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what is the normal onset age of HD, and what is the range?

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onset age 35-40 normally, range 5 to 70

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what is the mean duration of HD?

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15 years

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what are the clinical findings of HD (3)?

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1) chorea/choreathetoid movements; 2) dementia (mild); 3) personality disorders

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what are the major biochemical alterations in HD (3)?

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1) decreased GABA; 2) decreased GAD (glutamic acid decarboxylase); 3) decreased CAT (choline acetyl transferase)

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what leads to disease in HD?

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a polymorphic trinucleotide repeat that results in a polyglutamate expansion

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how many CAG repeats do normal individuals have, and how many CAG repeats to HD individuals have?

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normal: 11 to 30 repeats; HD: 36 to 121 repeats

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what protein does this gene code for and what is its function?

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codes for huntingtin, whose function is unknown

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how is huntingtin useful to us?

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provides a simple specific genetic test for rapid confirmation of the diagnosis of HD and for asymptomatic individuals at risk

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where can inclusions be located in HD (2)?

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1) cytoplasmic; 2) intranuclear

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what do accumulations of these inclusions lead to?

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neurodegeneration and cell death

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in what locations are there other brain changes in advanced cases of HD (3)?

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1) neocortex; 2) hippocampus; 3) globus pallidus

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what happens to the neocortex (2)?

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1) atrophy; 2) neuron loss

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what happens to the hippocampus?

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reduced neuron density in CA1

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what happens to the globus pallidus (2)?

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1) atrophy; 2) neuron loss

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what was shown to happen in the caudate in HD (2)?

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1) astrocytosis; 2) neuron loss

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AMYOTROPHIC LATERAL SCLEROSIS

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what are the five forms of ALS?

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1) clasiscal; 2) progressive bulbar palsy; 3) progressive muscular atrophy; 4) primary lateral sclerosis; 5) familial ALS (many forms)

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what happens in ALS related to lower motor neurons (3)?

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1) muscle atrophy; 2) fasciculations; 3) loss of reflexes

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what happens in ALS related to upper motor neurons (3)?

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1) spasticity; 2) hyperreflexia; 3) pathological reflexes (extensor plantar responses - Babinski sign)

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SPINOCEREBELLAR ATAXIAS

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what are the two main classes of spinocerebellar ataxias?

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1) sporadic; 2) hereditary

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what is the sporadic form of SCA called?

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cerebellar cortical atrophy

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what autosomal recessive SCA is there?

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Friedreich's ataxia

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what are the three forms of autosomal dominant spinocerebellar ataxia?

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1) type 1-17; 2) dentatorubropallidolusian atrophy; 3) episodic ataxia (type 1 and 2)

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what was shown to degenerate in Friedreich's ataxia?

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tract and posterior root

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MULTIPLE SYSTEM ATROPHY

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what types of multiple system atrophy are there (3)?

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1) olivopontocerebellar atrophy; 2) striatonigral degeneration; 3) Shy-Drager syndrome

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what type of clinical feature does olivopontocerebellar atrophy have?

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predominately cerebellar clinical feature

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what type of features does striatonigral degeneration have?

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parkinsonism feature

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what type of disease is Shy-Drager syndrome?

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autonomic failure