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N P Neuro part > 030315 neurodegenerative dis > Flashcards

030315 neurodegenerative dis Flashcards

1
Q

what is crucial for formation of episodic memories?

A

hippocampus

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2
Q

striatum

A

caudate nucleus and putamen

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3
Q

how does dopamine facilitate movement

A

dopamine releasing cell in substantia nigra pars compact affects 2 different types of output neurons in striatum (neurons w D1 receptors that excite direct pathway, neurons with D2 receptors that inhibit indirect pathway)

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4
Q

substantia nigra is part of

A

midbrain

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5
Q

common feature of neurodegnerative dis

A

gray matter dis-progressive loss of neurons, leading to progressive decline in nerv system fxn

misfolded and/or aggregated proteins

sporadic and familial forms

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6
Q

Alzheimer’s affects

A

cerebral cortex (higher order association cortices and limbic system)

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7
Q

excitotoxicity

A

excessive glutamate can cause persistent activation of NMDA receptors (superoxide can cause this too), leading to excess intracellular Ca, which leads to ATP depletion and cell death

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8
Q

most powerful risk factor for Alzheimer’s

A

age

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9
Q

only two conditions that present predominantly with short term memory loss

A

Alzheimer’s

Lewy body dis

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10
Q

clinical definition of AD

A

gradual decline in cognitive fxn w impairments in SHORT TERM MEMORY and one additional cognitive domain that isn’t due to other medical or pscyhiatric illness and results in a functional impairment socially or occupationally

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11
Q

cognitive domains for AD

A 
memory
language
abstract thinking and judgment
visuo-spatial or perceptual skills
praxis (practicing a skill)
executive fxn
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12
Q

stage I of AD

A

memory (new, and old is mildly impaired)
visuospatial skills-topographic disorientation
language
psychiatric-depression, apathy, delusions

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13
Q

stage II of AD

A

worse memory
visuospatial skills
calculation-acalculia
pscyhiatric-delusions

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14
Q

stage III AD

A

intellectual fxn severely impaired
sphincter control-urinary and fecal
motor-limb rigidity, flexion posture

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15
Q

gross morphology of AD

A

atrophy of gyri
widening of sulci
increased size of lateral ventricles-hydrocephalus ex vacuo

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16
Q

diffuse plaque

A

in AD, extracellular accumulation of Abeta protein (from precursor APP)

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17
Q

neuritic plaque

A

in AD, extracellular accumulation of Abeta protein and tau containing neurites (neurites are axons or dendrites)

more closely associated w cognitive decline than diffuse plaque

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18
Q

congo red stain

A

can look for amyloid (stains red in cerebral amyloid angiopathy)

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19
Q

neurofibrillary tangle

A

intraneuronal accumulation of abnormally phosphorylated form of tau, a normal microtubule associated protein

looks like a cone inside cell

not unique to AD

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20
Q

inherited vs late onset AD

A

inherited-under 60-65 yrs old. often automsomal dominant mutation, highly penetrant

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21
Q

link btwn Down syndrome and AD

A

APP gene is on chromosome 21

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22
Q

most common genetic mutation in AD

A

presenilin 1 (explains 50% of familial AD)

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23
Q

genes involved in familial AD

A 
presenilin 1 (chr 14)
amyloid precurosr protein (APP) (chr 14)
presenilin 2 (chr 1)

mutations in all three of these are autosomal dominant, result in increased Abeta amyloid protein, and result in EARLY ONSET AD under 65

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24
Q

genetic risk factor for LATE ONSET AD

A

APO E4 (chr 19)

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25
Q

cholinergic signaling deficiency occurs in

A

AD
dementia w Lewy bodies
vascular dementia

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26
Q

second most common form of early dementia

A

frontotemporal degeneration

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27
Q

frontotemporal degeneration

A

causes focal degernation in frontl and anterior temporal lobes

FTLD (lobar degeneration) refers to pathologic entity

has different INITIAL symptoms from AD. AD would have memory loss. FTD has dementia later in dis progression

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28
Q

mutations involved with frontotemporal dengeration

A

tau gene (results in accumulation of tau)
progranulin (results in accumul of TDP43 protein)
C9orf72 (results in accumulation of TDP43)

all autosomal dominant

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29
Q

clinical subytpes of FTD

A

behavioral variant-50%-bifrontal lobe atrophy

primary progressive aphasia:

  • progressive nonfluent aphasia (25%)-L peri Sylvian atrophy
  • semantic variant (25%)-bilateral anterior temporal lobe atrophy. trouble finding the word or comprehending the meaning of a word
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30
Q

behavioral variant of FTD

A

socially inappropriate behavior, loss of manners or impulsive actions

early apathy or inertia

early loss of sympathy or empathy

early compulsive behavior

hyperorality and dietary changes

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31
Q

microscopic findings for FTLD

A

vary by subtype

tauopathies:
-Pick’s disease (atrophy of frontal and temporal lobes). Pick bodies (round cytoplasmic inclusions in neurons containing abnormal TAU FILAMENTS)

FTLD-TDP43 accumulation:
-cytoplasmic protein accumulations in frontal or temporal lobes

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32
Q

pick bodies

A

ROUND cytoplasmic inclusions in neurons containing hyerphosphorylated TAU filaments

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33
Q

resting tremor is specific for

A

PD, not Parkinsonian syndromes

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34
Q

Parkinsonism

A

clinical syndrome: rigidity, bradykinesia, resting tremor, mask facies, stooped posture, festinating gait

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35
Q

genes involved w PD

A 
Parkin gene (chr 6)
alpha synuclein gene (very rare)
36
Q

clinical features of PD

A

resting tremor
rigidity
bradykinesia
gait

37
Q

nonmotor symptoms in premotor phase of PD

A

REM behavior disorder (kicking and screaming in sleep)
olfactory loss
dysautonomia (ANS dysfxn)

38
Q

excellent response to levodopa

A

PD

it’s uncharacteristic of any other parkinsonian symptom disease

39
Q

PD pathology

A

pallor of substantia nigra

neuronal loss and LEWY BODIES in substantia nigra

40
Q

Lewy bodies

A

eosinophilic cytoplasmic neuronal inclusions, contain alpha synuclein

41
Q

dementia w Lewy body

A

dementia associated w any 2 of 3 core clinical features

  • fluctuating cognition or level of sconsioucness
  • visual hallucinations (pleasant and non-threatening)
  • Parkinsonian motor signs
42
Q

dementia being early onset in disease

A

dementia w Lewy body

AD

43
Q

dementia with Lewy body pts have no problems w

A

episodic memory or language

44
Q

compare and contrast dementia w Lewy body and PD

A

both have substantia nigra degeneration and Lewy bodies

however, CLINIAL PRESENTATIONS are diff

45
Q

clinical presentations of dementia w Lewy body and PD

A

dementia w Lewy body:
-clinical features of dementia at onset

PD:

  • pts present w PARKINSONISM SIGNS
  • most EVENTUALLY develop dementia
  • pathological correlate of dementia is Lewy body presence in cortex
46
Q

pathologic findings in dementia w Lewy bodies

A

neuronal loss and Lewy bodies in substantia nigra
AND
Lewy bodies in cerebral cortex

47
Q

what cells are vulnerable in PD?

A

dopaminergic cells of substantia nigra

48
Q

MOA of levodopa

A

uses amino acid transporters to enter brain (dopamine itself would not be able to cross BBB)

49
Q

levodopa is converted to dopamine by

A

L-AAAD

50
Q

how do you get levodopa to not affect other tissues outside of brain?

A

adminiter L-DOPA w CARBIDOPA, an inhibitor of L-AAAD that doesn’t cross BBB

51
Q

entacapone

A 
COMT inhibitor (COMT metabolizes dopamine)
gets into brain and periphery
52
Q

best results of L-dopa are obtained when?

A

in first few years of tx (effectiveness is not as good afterwards) so L-dopa is NOT USED UNTIL symptoms cause functional impairment

53
Q

side effects of L-dopa

A

due to conversion to dopamine:
wearing off effect
dyskinesias (too much mvmt)
dementia, confusion-can look psychotic

54
Q

what’s used more instead of levodopa for PD?

A

dopamine receptor agonists

55
Q

why are dopamine receptor agonists better than L-DOPA?

A

no enzymatic conversion needed
selectivity for receptor subtypes
longer half life
less dopamine-dependent oxidative stress possibly

56
Q

dopamine receptor agonists-name them?

A

pramipexole, ropinerole (selective D2)-most commonly used currently

apomorphine (high affinity D4, moderate affinity D2/D3/D5)

57
Q

initial therapy in young pts

A

direct dopamine agonists (pramipexole, ropinerole)

58
Q

why avoid DA agonists in elderly pts?

A

confusion side effect is worse than that of L-DOPA

59
Q

side effects of direct DA agonists

A 
CNS toxicity
nausea
fatigue
sudden attack of daytime sleep
apomorphine-increased QT prolongation
60
Q

why are MAO-B inhibitors preferred over MAO-A?

A

MAO-A is a form found in liver, so would inhibit metabolism of tyramine

61
Q

rationale of MAO-B inhibitors

A

prolong action of dopamine and may reduce oxidative stress on neurons

62
Q

MAO-B inhibitors-list them

A

selegiline

rasagiline

63
Q

effectiveness of MAO-B inhibitors

A

mild
usually prescribed as soon as dis is diagnosed
also an anti-depressant

64
Q

rationale for COMT inhibitors

A

COMT metabolizes dopamine so inhibition will prolong the action of dopamine. COMT inhibition also decreases L-DOPA metabolism to non-dopamine metabolites

65
Q

list the COMT inhibitors

A

tolcapone (signif hepatotoxicity)

entacapone

66
Q

rationale for antimuscarinics

A

cholinergic interneurons in striatum are normally inhibited by dopamine. loss of dopamine results in overactivity of these excitatory neurons

67
Q

MOA of antimuscarinics

A

antagonists of striatal muscarinic receptors

68
Q

rationale for amantadine

A

discovered by serendipity

least effec of the agents

69
Q

MOA of amantadine

A

increases dopamine release
mildly anticholinergic
blocks NMDA receptors (to reduce Ca toxicity)

70
Q

Huntington dis

A

autosomal dominant

progressive motor, cognitive, and behavioral domains:

  • motor symptoms predominant at onset in many cases
  • cognitive symptoms may occur at or before onset of motor symptoms (as dis progresses, pts become demented eventually)
  • neuropsychiatric symptoms are exhibited in most pts
71
Q

when do symptoms present for HD?

A

4-5th decade

72
Q

gene mutation for HD

A

in huntington gene (chr 4)–expanded CAG repeat

73
Q

what does huntington gene mutation cause

A

intranuclear inclusions in basal ganglia

74
Q

pathology of HD

A

loss of medium striatal neurons in the caudate and putamen (these modulate motor activity), resulting in chorea. loss of striatal inhibition of thalamic drive

neuronal loss in cerebral cortex-cognitive changes

75
Q

HD-imaging

A

usually, caudate nucleus makes bump into lateral ventricles. in HD, this is absent

76
Q

gross pathology of HD

A

atrophy of caudate and putamen, ventricular enlargement

mild to moderate atrophy of gyri

77
Q

mechanism of HD

A

loss of striatal excitation and inhibition of pathways results in thalamus exciting cerebral cortex

78
Q

ALS

A

widespread degeneration of upper and lower motor neurons

lower motor neuron-degeneration of anterior horn cells and axons

upper motor neuron-degernation of corticospinal tracts in lateral column of spinal cord

bulbar dysfxn (involvement of brainstem motor cranial nerves)-dysarthria, dysphagia

79
Q

most common mutation in ALS

A

superoxide dismutase 1 gene (SOD1)

in subset of ALS, TDP43 gene mutation, causing TDP43 accumulation

80
Q

pathology of ALS

A

anterior roots of spinal cord are atrophic
primary motor cortex (cerebrum) may show atrophy
reduced number of anterior horn cells
loss of corticospinal tract axons and myelin
brainstem motor cranial nerves may be affected

81
Q

drugs for AD

A

donepezil
rivastigmine
galantamine

memantine

82
Q

riluzole

A

used for ALS

NMDA channel blocker (increases life span by 2-3 months)

83
Q

neuritic plaques

A

extracellular Abeta and tau, seen in AD

84
Q

neurofibrillary tangles

A

intraneuronal phosphorylated tau

85
Q

where do you see neurofibrillary tnagles in AD?

A

hippocampus and neocortex

86
Q

dementia w Lewy bodies

A

early dementia, later motor disorder

N P Neuro part (18 decks)

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