Pathology of Alzheimer & Other Neurodegenerative Diseases Flashcards
(27 cards)
What are the common features of neurodegenerative diseases?
Progressive - gradual progressive loss of neurologic function
Symmetrical, and involving a particular cell population in CNS / PNS -> will not be regional or focal damage on one side, as would be with a vascular cause.
Associated with neuronal loss and gliosis in the area affected
What degeneration is seen in Fredreich ataxia and what causes it?
Caused by GAA(it) expansion in frataxin gene on chromosome 9 which is an iron binding protein in mitochondria -> free radial damage of neurons
Causes degeneration of cerebellum -> ataxia
Degeneration of dorsal root ganglia -> loss of vibratory sense and proprioception
degeneration of spinal cord in general -> frequent falling
What does Fredreich ataxia present and what is the cause of death?
Presents in childhood with kyphoscoliosis
Cause of death is hypertrophic cardiomyopathy
What are the Tauopathies?
Disorders of tau protein accumulation
Alzheimer’s, Pick disease, progressive supranuclear palsy
What are the synucleinopathies?
Disorders of alpha-synuclein accumulation
Parkinson, diffuse Lewy body disease
What are the two forms of Alzheimer’s and its major risk factors (outside of genetics)?
Presenile dementia
Senile dementia
Risk factors: Risk factors for atherosclerosis + cerebrovascular disease (statins are protective)
Others: History of depression, low education levels, hypothyroidism
What diseases are associated with Alzheimer’s disease?
Trisomy 21 - most get it after age 50
Parkinson and DLBD - 50% have AD
Cerebral amyloid angiopathy - amyloid plaques in blood vessels
What are the early and late changes seen in Alzheimer’s disease?
Early - memory changes with difficulty finding words and impaired visuospatial memory
Late changes - nonfluent speech, agitation / aggression, severe rigidity
How does the course of vascular dementia vs diffuse Lewy body disease vs Alzheimer’s differ?
Alzheimer’s - steady decline
Vascular dementia - Stepwise decline
Lewy body disease - waxes and wanes on its way down
What does MRI of Alzheimer’s show ? Where are neurons lost?
Cortical atrophy (with loss of brain weight) with narrowing of gyri and widening of sulci
- > medial temporal lobe (affects hippocampus)
- > loss of neurons in frontal cortex (nucleus basalis in basal forebrain)
- > loss of neurons in limbic system -> especially posterior cingulate gyrus
Hydrocephalus ex vacuo
What are neurofibrillary tangles? How do they appear on electron microscopy? Does this cause the cell death?
Intracellular, hyperphosphorylated tau protein (a microtubule-associated protein) in association with other neurofilaments in the cytoplasm of neurons.
Appear as paired helical filaments on EM
Unclear if this causes cell death or is just associated with it.
What are neuritic plaques?
Also called senile plaques, they are extracellular zones of disrupted neuropil containing axons and dendrites with a Beta-amyloid core.
How is diagnosis of Alzheimer disease made?
Can only be done pathologically post-mortem
-> assess numbers of neurofibrillary tangles and senile plaques in affected brain areas, comparing it to the standard at that age (always increases with age)
-> patient must also have a clinical history of dementia
What are three other common changes seen in elderly patients with or without diagnosis of Alzheimer’s disease?
- Hirano bodies - crystalloid, rod-like structures made of actin alongside hippocampal neurons
- Granulovacuolar degeneration - intracytoplasmic vesicles with tau core
- Amyloid angiopathy - deposition of beta-amyloid in walls of leptomeningeal and intracortical blood vessels
How is A-beta amyloid formed? How is it usually cleared?
APP is normally cut by alpha-secretases
If APP is cut by beta-secretases -> Amyloid-beta fragments stay in the cell membrane and can form aggregates. This can be further processes by gamma secretases.
It is neurotoxic and usually degraded and cleared by proteosomes of astrocytes
What are the familial forms of Alzheimer’s caused by? What are the inherited risk factors for the sporadic form?
Risk modifiers for sporadic form: ApoE4 increased risk, ApoE2 decreased risk
Familial forms:
Presenilin-1, presenilin-2 mutations which are part of gamma-secretase
What is the normal function of tau protein? What form is seen in Pick disease vs AD?
Microtubule-associated protein with multiple phosphorylation sites
Pick disease - 3 repeat isoform (3R)
AD - 3R or 4R, associated with amyloid-beta.
What is Pick disease? What are the symptoms?
Frontotemporal dementia
Frontal lobe effects - behavioral symptoms, especially disinhibition
Temporal lobe - aphasia (language effects)
What is seen pathologically in Pick disease?
Frontotemporal atrophy “knife-blade atrophy”
Microscopic - “Pick bodies” - round aggregates of tau protein in neurons of the cortex
What drives amyloid formation in sporadic vs familial forms of Alzheimer’s?
Sporadic - environmental factors such as metal ions, free radicals, and oxidative stress
-> antioxidants may be of some benefit
Familial - mutations induce misfolding of amyloid
What is the function of prion protein and how does it lead to CJD / other dysfunction?
Signal transducer and regulator of cleavage of amyloid precursor protein
- > PrPsc is resistant to protease cleavage
- > toxic to neurons when it accumulates
- > can form fibrils and amyloid aggregates as well as causing other prion proteins to assume B-pleated sheet conformation
What are the causes of iatrogenic CJD?
Patients receiving human pituitary-derived growth hormone supplements, dural / corneal grafts, and contaminated neurosurgery instruments
What is variant CJD?
Bovine spongiform encephalopathy
-> as opposed to sporadic CJD, which is the most common form
What are the characteristic physical exam findings and EEG findings of CJD?
Physical exam - rapidly progressive dementia with startle myoclonus
EEG findings - periodic sharp waves
