030315 neurodegenerative dis Flashcards
what is crucial for formation of episodic memories?
hippocampus
striatum
caudate nucleus and putamen
how does dopamine facilitate movement
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)
substantia nigra is part of
midbrain
common feature of neurodegnerative dis
gray matter dis-progressive loss of neurons, leading to progressive decline in nerv system fxn
misfolded and/or aggregated proteins
sporadic and familial forms
Alzheimer’s affects
cerebral cortex (higher order association cortices and limbic system)
excitotoxicity
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
most powerful risk factor for Alzheimer’s
age
only two conditions that present predominantly with short term memory loss
Alzheimer’s
Lewy body dis
clinical definition of AD
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
cognitive domains for AD
memory language abstract thinking and judgment visuo-spatial or perceptual skills praxis (practicing a skill) executive fxn
stage I of AD
memory (new, and old is mildly impaired)
visuospatial skills-topographic disorientation
language
psychiatric-depression, apathy, delusions
stage II of AD
worse memory
visuospatial skills
calculation-acalculia
pscyhiatric-delusions
stage III AD
intellectual fxn severely impaired
sphincter control-urinary and fecal
motor-limb rigidity, flexion posture
gross morphology of AD
atrophy of gyri
widening of sulci
increased size of lateral ventricles-hydrocephalus ex vacuo
diffuse plaque
in AD, extracellular accumulation of Abeta protein (from precursor APP)
neuritic plaque
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
congo red stain
can look for amyloid (stains red in cerebral amyloid angiopathy)
neurofibrillary tangle
intraneuronal accumulation of abnormally phosphorylated form of tau, a normal microtubule associated protein
looks like a cone inside cell
not unique to AD
inherited vs late onset AD
inherited-under 60-65 yrs old. often automsomal dominant mutation, highly penetrant
link btwn Down syndrome and AD
APP gene is on chromosome 21
most common genetic mutation in AD
presenilin 1 (explains 50% of familial AD)
genes involved in familial AD
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
genetic risk factor for LATE ONSET AD
APO E4 (chr 19)
cholinergic signaling deficiency occurs in
AD
dementia w Lewy bodies
vascular dementia
second most common form of early dementia
frontotemporal degeneration
frontotemporal degeneration
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
mutations involved with frontotemporal dengeration
tau gene (results in accumulation of tau)
progranulin (results in accumul of TDP43 protein)
C9orf72 (results in accumulation of TDP43)
all autosomal dominant
clinical subytpes of FTD
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
behavioral variant of FTD
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
microscopic findings for FTLD
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
pick bodies
ROUND cytoplasmic inclusions in neurons containing hyerphosphorylated TAU filaments
resting tremor is specific for
PD, not Parkinsonian syndromes
Parkinsonism
clinical syndrome: rigidity, bradykinesia, resting tremor, mask facies, stooped posture, festinating gait
genes involved w PD
Parkin gene (chr 6) alpha synuclein gene (very rare)
clinical features of PD
resting tremor
rigidity
bradykinesia
gait
nonmotor symptoms in premotor phase of PD
REM behavior disorder (kicking and screaming in sleep)
olfactory loss
dysautonomia (ANS dysfxn)
excellent response to levodopa
PD
it’s uncharacteristic of any other parkinsonian symptom disease
PD pathology
pallor of substantia nigra
neuronal loss and LEWY BODIES in substantia nigra
Lewy bodies
eosinophilic cytoplasmic neuronal inclusions, contain alpha synuclein
dementia w Lewy body
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
dementia being early onset in disease
dementia w Lewy body
AD
dementia with Lewy body pts have no problems w
episodic memory or language
compare and contrast dementia w Lewy body and PD
both have substantia nigra degeneration and Lewy bodies
however, CLINIAL PRESENTATIONS are diff
clinical presentations of dementia w Lewy body and PD
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
pathologic findings in dementia w Lewy bodies
neuronal loss and Lewy bodies in substantia nigra
AND
Lewy bodies in cerebral cortex
what cells are vulnerable in PD?
dopaminergic cells of substantia nigra
MOA of levodopa
uses amino acid transporters to enter brain (dopamine itself would not be able to cross BBB)
levodopa is converted to dopamine by
L-AAAD
how do you get levodopa to not affect other tissues outside of brain?
adminiter L-DOPA w CARBIDOPA, an inhibitor of L-AAAD that doesn’t cross BBB
entacapone
COMT inhibitor (COMT metabolizes dopamine) gets into brain and periphery
best results of L-dopa are obtained when?
in first few years of tx (effectiveness is not as good afterwards) so L-dopa is NOT USED UNTIL symptoms cause functional impairment
side effects of L-dopa
due to conversion to dopamine:
wearing off effect
dyskinesias (too much mvmt)
dementia, confusion-can look psychotic
what’s used more instead of levodopa for PD?
dopamine receptor agonists
why are dopamine receptor agonists better than L-DOPA?
no enzymatic conversion needed
selectivity for receptor subtypes
longer half life
less dopamine-dependent oxidative stress possibly
dopamine receptor agonists-name them?
pramipexole, ropinerole (selective D2)-most commonly used currently
apomorphine (high affinity D4, moderate affinity D2/D3/D5)
initial therapy in young pts
direct dopamine agonists (pramipexole, ropinerole)
why avoid DA agonists in elderly pts?
confusion side effect is worse than that of L-DOPA
side effects of direct DA agonists
CNS toxicity nausea fatigue sudden attack of daytime sleep apomorphine-increased QT prolongation
why are MAO-B inhibitors preferred over MAO-A?
MAO-A is a form found in liver, so would inhibit metabolism of tyramine
rationale of MAO-B inhibitors
prolong action of dopamine and may reduce oxidative stress on neurons
MAO-B inhibitors-list them
selegiline
rasagiline
effectiveness of MAO-B inhibitors
mild
usually prescribed as soon as dis is diagnosed
also an anti-depressant
rationale for COMT inhibitors
COMT metabolizes dopamine so inhibition will prolong the action of dopamine. COMT inhibition also decreases L-DOPA metabolism to non-dopamine metabolites
list the COMT inhibitors
tolcapone (signif hepatotoxicity)
entacapone
rationale for antimuscarinics
cholinergic interneurons in striatum are normally inhibited by dopamine. loss of dopamine results in overactivity of these excitatory neurons
MOA of antimuscarinics
antagonists of striatal muscarinic receptors
rationale for amantadine
discovered by serendipity
least effec of the agents
MOA of amantadine
increases dopamine release
mildly anticholinergic
blocks NMDA receptors (to reduce Ca toxicity)
Huntington dis
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
when do symptoms present for HD?
4-5th decade
gene mutation for HD
in huntington gene (chr 4)–expanded CAG repeat
what does huntington gene mutation cause
intranuclear inclusions in basal ganglia
pathology of HD
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
HD-imaging
usually, caudate nucleus makes bump into lateral ventricles. in HD, this is absent
gross pathology of HD
atrophy of caudate and putamen, ventricular enlargement
mild to moderate atrophy of gyri
mechanism of HD
loss of striatal excitation and inhibition of pathways results in thalamus exciting cerebral cortex
ALS
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
most common mutation in ALS
superoxide dismutase 1 gene (SOD1)
in subset of ALS, TDP43 gene mutation, causing TDP43 accumulation
pathology of ALS
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
drugs for AD
donepezil
rivastigmine
galantamine
memantine
riluzole
used for ALS
NMDA channel blocker (increases life span by 2-3 months)
neuritic plaques
extracellular Abeta and tau, seen in AD
neurofibrillary tangles
intraneuronal phosphorylated tau
where do you see neurofibrillary tnagles in AD?
hippocampus and neocortex
dementia w Lewy bodies
early dementia, later motor disorder
