Term
| what is the pathophysiology of parkinson's disease? |
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Definition
| loss of D2 inhibition in the putamen, which results in augmented inhibition of the globus pallidum externa on the subthalamic nucleus (indirect pathway). consequently, the subthalamic nucleus overstimulates the globus pallidum interna w/exaggerated inhibition of the thalamus w/inhibition rather than stimulation of the motor cortex = bradykinesia. (*augmented inhibition of inhibitory sytem w/bradykinesia*) |
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Term
| what is huntington's disease? |
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Definition
| destruction of the inhibitory GABAergic *caudate w/increased motor activity; loss of ACh stimulation of the cognitive cortex. |
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Term
| what is primary parkinson's disease defined by? |
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Definition
| bradykinesia, tremor, muscle rigidity - responding to levodopa tx |
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Term
| what are some parkinson's-like diseases? |
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Definition
| progressive supranuclear palsy, multiple system atrophy (shy-drager), corticobasal ganglionic degeneration, familial frontotemporal dementia, and diffuse lewy body disease |
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Term
| what is the epidemiology of parkinson's disease? |
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Definition
| parkinson's usually affects pts 55-65 y/o and female:male::2:3. ashkenazi jews = 7x risk. low incidence among african americans and asians. smoking/caffeine reduces risk. |
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Term
| what can lead to secondary parkinsonism? |
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Definition
| postencephalitis, toxins (MPTP, CO, ethanol, methanol), antipsychotic drugs (dopamine receptor blockers: risperdal, zyprexa = repetitive chewing, fly catcher toungue, body rocking, piano playing), head trauma-dementia pugisistica, multi-infarct "biswanger's disease" (of white matter), wilson's disease, huntington's, and normal pressure hydrocephalus |
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Term
| how can MPTP lead to secondary parkinsonism? |
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Definition
| MPTP (contaminant of synthetic heroin) inhibits NADH-ubiquinone oxidoreductase of the mitochondrial electron transport chain -> leading to apoptosis of dopaminergic neurons. in primary parkinson's disease there also happens to be a 30-40% reduction in this mitochondrial enzyme (clue to pathophysiology of primary disease). |
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Term
| what are some processes which have been linked to the pathophysiology of parkinson's? |
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Definition
| autooxidation of dopamine to quinone (rotenone a pesticide can also cause this) and other ROS (fenton rxn: iron w/hydrogen peroxide = hydroxyl radicals, reduced glutathione peroxidase), mitochondrial dysfunction, excitotoxicity, immune mechanisms, and mutation of synuclein and parkin genes |
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Term
| how does the substantia nigra appear grossly when the brain is affected by parkinson's? |
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Definition
| the normally dark substantia nigra appears washed out b/c the dopaminergic neuromelanin cells die and are phagocytized by macrophages |
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Term
| what are the stages of parkinson's disease? |
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Definition
| 1) lewy body formation in the IX/X nuclei and subependymal 4th ventricle. 2) lewy bodies in intermediate reticular zone and caudal raphe nuclei. 3) beginning loss of melanin in SN. 4) severe SN melanin loss and lewy bodies in the hypothalamus. 5) neuronal loss in olfactory region. 6) neocortical lewy bodies. |
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Term
| what parts of the brain other than the substantia nigra (dopaminergic) are affected by parkinson's? |
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Definition
| locus ceruleus (catecholaminergic), nucleus basalis of meynert (cholinergic), dorsal motor nucleus of CN X (cholinergic - depression), brain stem raphe nuclei (seratoninergic), olfactory bulb, amygdala, and the cingulate gyrus (limbic system: affects emotions, memory) |
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Term
| how is protein folding the essence of parkinsons's pathophysiology? |
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Definition
| either environmental or genetic (LRRK2, DJ-1, alpha-synuclein, parkin, UCH-L1 mutaions) factors lead to damage of proteins which affect different processes in the cells which focus on the folding of protein = aggregation of misfolded protein w/in damaged cells and inability to clear them (either by the lysosomal system, ubiquitin-proteosomal system, or mitochondrial system), which leads to autoapoptosis. |
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Term
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Definition
| aggregated protein (predominately alpha synuclein which formes beta-pleated sheets [amyloid] as it complexes w/itself = very hard to break down) in a dopaminergic neuron |
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Term
| what are all the proteins found in lewy bodies? |
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Definition
| alpha synuclein (predominant, made in that cells and typically associates w/vesicles containing NTs in the synapse - aids their release), ubiquitin (usually gets rid of abnormal proteins), neurofilament protein, alpha B crystalin (chaperone protein), beta amyloid precursor protein (also seen in alzheimer's), and synaptic proteins |
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Term
| are lewy bodies specific to parkinson's disease? |
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Definition
| no, they are also seen in parkinsonism including lewy body dementia (found in cortex), multiple system atrophy, progressive supranuclear palsy, and parkinsonian-dementia complex of guam |
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Term
| what are the clinical criteria for parkinson's disease? |
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Definition
| akinesia (poverty of movement), bradykinesia (slowness of movement), muscle rigidity, postural instability, tremor, and positive response to L-dopa |
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Term
| what are other clinical findings seen in parkinson's disease? |
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Definition
| hypomimia (masked face), loss of arm swing, stooped posture, propulsive gait, micrographia (small handwriting), freezing, constipation, dysphagia, ED, sweating, drooling, depression, anxiety, dementia, and sleep disorders. |
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Term
| what is the prevalence of dementia in parkinson's disease? |
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Definition
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Term
| how many parkinson's pts also have alzheimer's? |
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Definition
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Term
| what characterizes dementia w/lewy bodies? |
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Definition
| dementia w/lewy bodies comprises 10% of dementias and is a progressive but fluctuating cognitive decline w/variations in attention and alertness. pts experience visual hallucinations, systematized delusions, spontaneous features of parkinsonism, and *atrophy of the putamen (vs that in the temporal lobe-hippocampus as seen in alzheimer's dz). |
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Term
| can ubiquitin be stained for in lewy body disease (such as diffuse lewy bosy disease or parkinson's)? |
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Definition
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Term
| what are the distinguishing characteristics of diffuse lewy body dementia? |
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Definition
| prominent early extrapyramidal motor signs, postural instability, paranoid behavior w/visual hallucinations and delusions, and undue sensitivity to neuroleptic drugs. |
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Term
| what is progressive supranuclear palsy (steele-richardson-olszewski syndrome)? |
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Definition
| a tauopathy (problem w/the tau protein - which binds microtubules together) where proteins accumulate w/in neurons + astrocytes in neurofibrillary tangles in the globus pallidum, substantia nigra, subthalamic nucleus. |
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Term
| what are the clinical features of progressive supranuclear palsy (steele-richardson-olszewski syndrome)? |
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Definition
| there is a vertical supranuclear palsy (absence of downward gaze) w/postural instability, and frequent falls. it shares symmetric akinesia or rigidity w/parkinson's. pts may also experience retrocolis (throwing head back), facial dystonia (furrowed brow), dysphagia, dysarthria, early onset cognitive impairment (affecting abstract thought/verbal fluency) and apathy. |
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Term
| what is multiple system atrophy? |
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Definition
| a simultaneous collection of 1) levodopa-ineffective parkinsonism (bradykinesia, rigidity, postural instability), 2) cerebellar dysfunction (gait ataxia, "slurring" dysarthria, nystagmus), 3) autonomic dysfunction (orthostatic hypotension, urinary incontinence, ED), and 4) *absence of dementia |
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Term
| how does the brain appear grossly in multiple system atrophy? |
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Definition
| there is a green-brown coloration of the putamen and GP |
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Term
| what are the clinical subset syndromes associated w/multiple system atrophy? |
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Definition
| 1) pure parkinsonism (striatonigral degeneration), 2) autonomic dysfunction (shy-drager syndrome), 3) ataxia (olivopontocerebellar atrophy), and 4) amyotrophy (amyotrophic parkinsonism) |
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Term
| what is corticobasal degeneration? |
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Definition
| this consists of *striatal signs (asymmetric akinesia [useless arm], rigidity, athetosis [trying to extend finger - but get flexion], postural instability, orolingual dyskinesias) and *cortical signs (cortical sensory loss, dementia, apraxia, "alien limb", and hyperreflexia). |
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Term
| what are the stages of corticobasal degeneration? |
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Definition
| early (1-3 yrs): asymmetric clumsiness/stiffness. mid (3-5 yrs): dystonic rigidity, akinesia, pyramidal deficits. late (5-8 yrs): frontotemporal dementia (FTD) - behavioral and cognitive. |
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Term
| how does a brain affected by corticobasal degeneration appear grossly? |
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Definition
| there is asymmetrical atrophy in the frontal and parietal regions and a loss of pigmented neurons in the substantia nigra. ballooned cells w/tau+ neurofibrillary tangles in the cortex, SN, and brain stem. |
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Term
| what is the genetic association for huntington's? |
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Definition
| the mutation of the huntington protein is found on chr 4. huntington's disease is transmitted paternally. the more CAG (encode glutamine) repeats (create polyglutamine proteins) there are in the mutation, the younger age of onset. |
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Term
| what is the age of huntington's onset? |
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Definition
| variable (childhood - adulthood) |
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Term
| what are the early symptoms of huntington's? |
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Definition
| altered coordination (clumsy), chorea, grimacing, shoulder shrugging, and dysphoria |
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Term
| what are the middle symptoms of huntington's? |
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Definition
| severe chorea, dysarthria, dysphagia, and psychosis |
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Term
| what are the late/juvenile onset symptoms of huntington's? |
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Definition
| rigidity, bradykinesia, and dementia (crossover w/parkinsonism) |
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Term
| what is the range of neuropsychiatric presentations in huntington's pts? |
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Definition
| dysphoria, agitation, irritability, apathy, anxiety, and disinhibition |
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Term
| what is the pathogenesis of huntington's disease? |
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Definition
| when CAG repeats of the huntington protein on chr 4 number greater than 36 (<27 is WNL) the resultant polyglutamine undergoes proteolysis w/toxic fragments, injuring neuronal mitochondria and initiating aspartic protease (caspase) induced apoptosis. there is then associated excitotoxicity and possible nuclear penetration of the toxic fragments = altered gene transcription. |
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Term
| what is seen histologically in huntington's disease? what location? |
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Definition
| intranuclear inclusions of abnormal "huntington" proteins in neurons - which eventually lead to cell death, principally in the *caudate nucleus*. |
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Term
| what is the pathology associated w/huntington's? |
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Definition
| progressive atrophy of the caudate and putamen. neuronal intranuclear inclusions+ubiquitin (trying to eradicate inclusions). loss of GABA-producing medium size spiny neurons w/associated gliosis (crossover w/parkinsonism). *later atrophy of the globus pallidus and subthalamic nucleus (crossover w/parkinsonism). *end stage atrophy of the cerebral cortex, cerebellum, and brain stem (due to resultant lack of interconnections). |
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Term
| what happens specifically in the caudate nucleus in huntington's? |
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Definition
| spongiosis w/neuron loss and gliosis |
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Term
| why might a huntington's pt resemble a hydrocephalic pt on MRI? |
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Definition
| the lateral ventricles widen b/c the caudate shrinks |
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