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141 Cards in this Set

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NEURODEGENERATIVE DISEASES - MARKESBERY AND NELSON - FRIDAY JAN 26
ALZHEIMER'S DISEASE
how many are affected in the US and worldwide?
4.5 million, 25 million
what % of individuals over 65 have it?
10%
what % of individuals over 85 have it?
47%
how many areas of cognition must one have deficits in to have alzheimers?
two or more
what are these areas of cognition (list)?
memory, abstract thinking, judgment, problem solving, language, perception, praxis, and ability to learn new skills
is there any disturbance of consciousness?
no
what is the range of ages that Alzheimer's can have its onset?
40-90
what problems occur in early stages?
recent memory decline
what happens next (list)?
loss of spontaneity and initiative, poor judgment, faulty reasoning, poor decision making, and loss of insight
what happens next (list)?
word finding difficulties, disorientation, diminished interests, and visuospatial difficulties
what are patients like in the late stage (list)?
apathetic, withdrawn, lost easily, no judgment, requires assistance with simple ADLs
what varient lipoprotein is a risk factor for Alzheimer's?
apoprotein E - E4 allele
what is the risk of developing late-onset AD if there is one allele, and what if there are two alleles?
one allele - 40-45%; two alleles - 80%+
what is the relative risk for AD for someone who has one first degree relative with AD?
3.5
what is the relative risk if there are two or more first degree relatives affected?
7.5
what is the most common inheritence pattern for AD?
autosomal dominant
what other genes, if mutated, are risk factors for AD (3)?
1) amyloid precursor protein; 2) presenilin-1; 3) presenilin-2
if the APP is mutated, what will the age of onset be?
50s
what if the presenilin-1 is mutated?
40s and 50s
what if the presenilin-2 is mutated?
50s and later
what will the phenotype be if the presenilin 1 or 2 is mutated?
increased production of amyloid beta-42 (AB-42) peptides
if the APP is mutated, what will the phenotype be (2)?
increased production of amyloid beta (AB) peptides, or amyloid beta-42 (AB-42) peptides
what are alterations of AD brains (3)?
1) cortical atrophy; 2) moderately enlarged ventricles; 3) atrophy of hippocampus
what part of the hippocampus is particularly affected?
subiculum
what protein misfolds in the brains of AD patients, forming plaques?
amyloid beta protein (AB)
besides forming neuritic plaques, where else can the AB protein cause problems?
in the walls of vessels
which other protein was said to form aggregates in the brain of AD patients, and what is its normal function?
tau protein - a microtubule associated protein that stabilizes microtubules
what abnormal form is it converted to, and by what mechanism?
converted to PHF tau by abnormal phosphorylation
what is the criteria for the neropathologic diagnosis of AD based on (2)?
1) CERAD semiquantitation of neuritic plaques; 2) Braak stage
what are the levels of neuritic plaques (3), and what number does each correllate with?
1) sparse <6; 2) moderate <17; 3) frequent >17
what measurements of NP and Braak stage correspond to a low likelihood of AD?
Braak stage I-II and sparse NP
what measurements of NP and Braak stage correspond to an intermediate likelihood of AD?
Braak stage III-IV and moderate NP
what measurements of NP and Braak stage correspond to a high likelihood of AD?
Braak stage V-VI and frequent NP
HYPOTHESES OF ALZHEIMER'S PATHOGENESIS
what are the four hypotheses of AD pathogenesis?
1) amyloid (amyloid cascade) hypothesis; 2) excitotoxicity hypothesis; 3) inflammatory hypothesis; 4) oxidative stress/damage hypothesis
what does the amyloid cascade hypothesis say are the initial event in AD, and what does this initial event eventually cause to occur?
amyloid plaques are the initial event in AD, and eventually cause neurofibrillary tangles to occur
what cleaves the amyloid precursor protein off of the cell in the amyloid cascade hypothesis?
B-secretase (beta)
what cleaves the AB monomer off of the cell?
gamma-secretase
what can amyloid beta monomers transform into?
soluble oligomers
what effect do soluble oligomers have on neurons?
they inhibit synaptic plasticity
what can soluble oligomers transform into?
protofibrils
what is the effect of protofibrils on neurons?
they decrease neuron activity
what can protofibrils transform into?
fibrils
what is the effect of fibrils on neurons (2)?
decrease neuron activity and synaptic plasticity
what is the first step in the excitotoxic hypothesis (what is impaired, and what does it lead to)?
impaired glutamate homeostasis leads to mild activation of NMDA receptors
what does this lead to?
excess calcium influx into neurons
what does this influx lead to in neurons, and what is the result?
death of neurons and decreased memory and learning
in the inflammatory hypothesis, what type of immune response is associated with amyloid-beta deposition?
innate immune response
what other inflammatory mechanisms were said to be taking place in the immune hypothesis (4)?
1) activation of microglia; 2) complement activation; 3) secretion of proinflammatory cytokines; 4) secretion of NO; 5) expression of chemokines
in the oxidative hypothesis, what particular molecule was said to do the oxidative damage?
hydroxyl radical
what effects was it said to exert (3)?
1) DNA damage; 2) protein oxidation; 3) lipid peroxidation
SYNUCLEINOPATHIES
what synucleinopathies must we know (4)?
1) parkinson's; 2) dementia with Lewy bodies; 3) multiple system atrophy; 4) neurodegeneration with brain iron (Hallervorden-Spatz disease)
what other proteins are in the family with alpha-synuclein (3)?
beta-synuclein; gamma synuclein; synoretin
where is alpha-synuclein predominantly expressed, and where is it particularly abundant?
predominantly expressed in neurons, and abundant in presynaptic terminals
how is its expression regulated?
by post-translational mechanisms
what are its functions thought to be (2)?
1) modulate synaptic plasticity; 2) dopaminergic neurotransmission
what abnormal structure is the alpha-synuclein protein the primary component of?
Lewy bodies
what led to this discovery?
alpha-synuclein missense mutation in familial PD
DEMENTIA WITH LEWY BODIES
what are the core features of dementia with Lewy bodies?
1) fluctuating cognitive impairment with variations in attention and alertness; 2) recurrent visual hallucinations; 3) spontaneous motor features of Parkinsonism
what is required for diagnosis?
two of these three core features
what are the supportive features of dementia with Lewy bodies?
1) repeated falls; 2) syncope; 3) neuroleptic sensitivity; 4) systematized delusions; 5) non-visual hallucinations
how is the form of dementia with Lewy bodies diagnosed?
lewy bodies are counted in several areas, and a score is obtained
what areas are they counted in (5)?
1) entorhinal cortex; 2) cingulate gyrus; 3) mid-frontal cortex; 4) mid-temporal cortex; 5) inferior parietal cortex
how is a score obtained?
in each region, a count of 1-5 LBs gives a score of 1, and greater than 5 gives a score of 2
what form of dementia with LBs has a total score of 0-2?
brainstem predominant form
what form has a score of 3-6?
limbic or transitional form
what form has a score of 7-10?
neocortical form
what two diseases is dementia with Lewy bodies somewhat like (shown inbetween on a slide)?
Alzheimer's and Parkinson's
PARKINSON'S DISEASE
what is the prevalence of PD per 100,000?
100-150 per 100,000
does it occur more in males or females?
same
at what age range is the risk the greatest?
70-79 year old range
what is the mean age of onset (range)?
58-62
what is the mean duration of PD?
13-14 years
what are the neurologic manifestations of PD (5)?
1) tremor; 2) rigidity; 3) akinesia; 4) alterations in posture; 5) dysarthria
what other features are seen in some with PD (2)?
1) autonomic instability (in some); 2) dementia (in some)
what are risk factors for parkinson's disease (3)?
1) rural environment; 2) genetics; 3) age
what reduces the risk of parkinson's disease?
smoking
FRONTOTEMPORAL DEMENTIA
what forms of frontotemporal dementia are there (6)?
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
what type of intellectual defects are seen with FTD (list)?
behavioral and personality changes, disinhibition, emotional instability, lack of insight and judgment, language dissolution, memory decline later
is FTD ever familial?
yes, frequently
what is seen on MR scans of those with FTD (2)?
frontal and temporal atrophy
what gene do familial forms have a mutation in?
tau gene (chromosome 17)
what structures are seen in the brain of those with Pick's disease (2)?
1) Pick bodies; 2) balloon neurons
what type of inclusion is shown in FTD with motor neuron disease?
ubiquitin positive inclusion
HUNTINGTON'S DISEASE
what is the normal onset age of HD, and what is the range?
onset age 35-40 normally, range 5 to 70
what is the mean duration of HD?
15 years
what are the clinical findings of HD (3)?
1) chorea/choreathetoid movements; 2) dementia (mild); 3) personality disorders
what are the major biochemical alterations in HD (3)?
1) decreased GABA; 2) decreased GAD (glutamic acid decarboxylase); 3) decreased CAT (choline acetyl transferase)
what leads to disease in HD?
a polymorphic trinucleotide repeat that results in a polyglutamate expansion
how many CAG repeats do normal individuals have, and how many CAG repeats to HD individuals have?
normal: 11 to 30 repeats; HD: 36 to 121 repeats
what protein does this gene code for and what is its function?
codes for huntingtin, whose function is unknown
how is huntingtin useful to us?
provides a simple specific genetic test for rapid confirmation of the diagnosis of HD and for asymptomatic individuals at risk
where can inclusions be located in HD (2)?
1) cytoplasmic; 2) intranuclear
what do accumulations of these inclusions lead to?
neurodegeneration and cell death
in what locations are there other brain changes in advanced cases of HD (3)?
1) neocortex; 2) hippocampus; 3) globus pallidus
what happens to the neocortex (2)?
1) atrophy; 2) neuron loss
what happens to the hippocampus?
reduced neuron density in CA1
what happens to the globus pallidus (2)?
1) atrophy; 2) neuron loss
what was shown to happen in the caudate in HD (2)?
1) astrocytosis; 2) neuron loss
AMYOTROPHIC LATERAL SCLEROSIS
what are the five forms of ALS?
1) clasiscal; 2) progressive bulbar palsy; 3) progressive muscular atrophy; 4) primary lateral sclerosis; 5) familial ALS (many forms)
what happens in ALS related to lower motor neurons (3)?
1) muscle atrophy; 2) fasciculations; 3) loss of reflexes
what happens in ALS related to upper motor neurons (3)?
1) spasticity; 2) hyperreflexia; 3) pathological reflexes (extensor plantar responses - Babinski sign)
SPINOCEREBELLAR ATAXIAS
what are the two main classes of spinocerebellar ataxias?
1) sporadic; 2) hereditary
what is the sporadic form of SCA called?
cerebellar cortical atrophy
what autosomal recessive SCA is there?
Friedreich's ataxia
what are the three forms of autosomal dominant spinocerebellar ataxia?
1) type 1-17; 2) dentatorubropallidolusian atrophy; 3) episodic ataxia (type 1 and 2)
what was shown to degenerate in Friedreich's ataxia?
tract and posterior root
MULTIPLE SYSTEM ATROPHY
what types of multiple system atrophy are there (3)?
1) olivopontocerebellar atrophy; 2) striatonigral degeneration; 3) Shy-Drager syndrome
what type of clinical feature does olivopontocerebellar atrophy have?
predominately cerebellar clinical feature
what type of features does striatonigral degeneration have?
parkinsonism feature
what type of disease is Shy-Drager syndrome?
autonomic failure