Neurodegenerative diseases Flashcards
Alzheimers disease
- gross and microscopic pathology
2 characteristics = decline in cortical function + 2 hallmark lesions = senile plaque + neurofibrillary tangles
Gross pathology = marked, diffuse cortical atrophy
Microscopic pathology = senile plaques + neurofibrillary tangles –> both accumulate with age
- Congo red stain –> can identify beta sheets, if there are enough of them we call it amyloid
- Many different proteins can form amyloid, but in the brain its beta amyloid protein
- Neurofibrillary tangles –> major protein component is tau protein = microtubule associated protein that becomes hyperphsophorylated in disease –> dissociates from the microtubules and accumulates as insoluble inclusions = neurofibrillary tangles
Pathogenesis of AD
Genetic data support the importance of amyloid beta processing in AD pathogenesis
4 known genetic loci linked to familial disease
• Chromosome 21
–> Beta amyloid protein mutations associated with familial early onset AD
–> Down syndrome = extra chromosome produces additional beta amyloid; present with AD early
• Chromosome 14 –> familial early onset AD linked to mutations in presenilin 1 = involved in metabolism of B-APP
• Chromosome 1 –> familial early onset AD linked to presenilin 2
• Apolipoprotein E –> involved in lipid transport, several different alleles
—> E4 allele linked to susceptibility to late onset AD = very significant risk
Parkinson Disease
Pathogenesis = loss of substantia nigra dopaminergic neurons, cause of loss is unknown
- One experimental human “model” of PD is exposure to MPTP –> Mimics PD although Lewy bodies do not occur
Familial PD (much less common than sporadic PD), linked to specific - Ex = Alpha-synuclein (PARK1)
o Environmental exposure to toxins, e.g. pesticides, is implicated in etiology of sporadic PD, among other toxins.
o Cigarette smoking and caffeine are “protective”
Pathologic hallmark = lewy bodies –> major protein component is alpha synuclein
Parkinson disease is a specific condition –> parkinsonism is a set of clinical signs that can be seen in many conditions
Lewy body dementia
Dementia with lewy bodies, diffuse lewy body disease, and lewy body variant of alzheimers disease
o Second most common form of dementia
o Overlaps clinically and pathologically with parkinson’s disease and alzheimers disease
Clinical –> fluctuating cognition, visual hallucinations, personality changes + parkinsonism
Pathology –>
- Lewy bodies and Lewy neurites in the cerebral cortex and brainstem
- Lewy bodies are seen with routine stains and with alpha synuclein immunohistochemistry
- Lewy neurites require alpha synuclein immunohistochemistry for identification
- Alzheimer type pathology is also present, but variable in extent
- Clinical data is crucial in distinguishing Parkinson’s disease from Lewy body dementia
- “synucleinopathy”
Frontotemporal dementia
Characterized by frontal and temporal lobe degeneration
o Often with prominent language difficulties and personality disturbances
o The brain may have inclusions with antigenicity for various proteins (tau, ubiquitin, TDP-43), or no inclusions at all –> very heterogeneous
Two subtypes
1. Frontotemporal dementia with parkinsonism linked to chromosome-17 (FTD(P)-17)
• Form of frontotemporal dementia linked to the tau gene
• Pathologically, tau-positive neurofibrillary tangles are present, along frontotemporal degeneration, and degeneration of the substantia nigra
2. Pick disease = form of frontotemporal dementia characterized pathologically by severe frontotemporal atrophy and accumulation of numerous tau-positive Pick bodies as well as ballooned neurons (Pick cells)
Progressive supranuclear palsy
Tauopathy + movement disorder
Paralysis of upward gaze, parkinsonism + dementia
Pathology –> numerous tangles in deep locations = brainstem + deep grey matter; other tau positive inclusions
Corticobasal degeneration
Tauopathy + movement disorder
Alien limb phenomenon, parkinsonism + dementia
Pathology –> ballooned neurons, tau-positive inclusions in cortex, brainstem + deep grey matter
Vascular dementia
Brain injury from vascular insufficiency/ischemia –> correlation between clinical diagnosed vascular dementia and pathologic findings is poor
Multiple infarct dementia –> stepwise deterioration in cortical function
- pathology = multiple infarcts
Binswanger’s disease –> hypertension, progressive neurological decline
- pathology = white matter degeneration + infarcts
CADASIL = Cerebral, Autosomal, Dominant, Angiopathy with Subcortical Infarcts and Leukoencephalopathy
- autosomal dominant, notch3 mutation, no hypertension
- pathology –> white matter degeneration, infarcts, vascular sclerosis with PAS positive granular grunge in media; vascular changes outside of CNS in skin (skin biopsy for dx)
- -> gross and micro similar to Binswanger’s except for PAS positive grunge
Multiple system atrophy
Characterized by parkinsonism (damage to substantia nigra + striatum), atiaxia (damage to cerebellum) + autonomic failure (damage to SNS) –> affects glial cells rather than neurons
Encompasses three systems degenerations
- Striatonigral degeneration –> parkinsonism
- Olivopontocerebellar atrophy –> ataxia
- Shy-Drager syndrome –> autonomic failure due to degeneration of the intermediolateral cell column of the spinal cord)
- The systems degenerations may occur alone, or in combination
Pathology
- Neuronal loss and gliosis in affected systems
- Alpha-synuclein positive oligodendroglial inclusions
- MSA is a “synucleinopathy.”
ALS – Lou Gehrig’s disease = amytrophic lateral sclerosis
Degeneration of both upper and lower motor neurons
- Lower motor neuron degeneration leads to atrophy of the skeletal muscle = amytrophic sclerosis
- Upper motor neuron loss leads to wallerian degeneration of lateral columns of the spinal cord = lateral sclerosis
- Motor neuron loss, Bunina bodies, other inclusions microscopically
- Progressive and fatal
- Small percentage of Cu-Zn superoxide dismutase germline mutation (SOD1)
- No treatment/cure
Prion disease
Rare, heterogeneous group of neurological disorders that affect humans and animals
o Prion = proteinaceous infectious particle
o Roughtly 1-2 person per million per year affected
o Prion diseases are unique among human disease, in being comprised of familial, sporadic and transmitted forms
o Accumulation of protease-resistant isoforms of the host-encoded prion protein - PrPsc.
—> PrPsc is thought by some to be the infectious agent and cause of cytotoxicity.
oPrion diseases are transmissible
o PrPsc is difficult to inactivate (e.g. requires bleech, 2N NaOH, formic acid); however, infectivity is very low.
Human forms:
- Creutzfeldt-Jakob disease (sporadic, familial, and iatrogenic/transmitted);
- Variant Creutzfeldt-Jakob disease (subtype linked to ingestion of beef contaminated by BSE)
- Fatal insomnia - both familial and sporadic forms
- Gerstmann-Straussler-Scheinker syndrome (entirely familial disease so far);
- Kuru (entirely transmitted).
Animal forms
- Bovine spongiform encephalopathy (BSE, mad cow disease).
- Scrapie in sheep and goats
- Chronic wasting disease in deer and elk (occurs only in US)
Creutzfedlt-Jakob disease + variant CJD
Creutzfedlt-Jakob disease
- Rapidly progressive dementia
- Startle myoclonus
- Periodic sharp waves by EEG.
- Usually middle age or older at presentation
- Median survival about 3 to 4 months.
- Neuropathology Spongiform degeneration of gray matter.
- Codon 129 (prion protein gene) polymorphism associated with susceptibility and phenotypic variability
Variant CJD = subtype of prion disease linked to BSE; majority of cases occurred in the UK - Differences from sporadic CJD • Younger age at onset • Slightly longer disease duration • “Florid plaques” in brain tissue • Detectable PrPsc in lymphoid tissue
Chronic traumatic encephalopathy
Loosely associated, poorly understood process involving contact sports clinically, variable tau accumulation pathologically, ill-defined functional symptoms, and cognitive impairment in some cases
o Progressive tauopathy that occurs as a consequence of repetitive mild traumatic brain injury
o Clinically associated with symptoms of irritability, impulsivity, aggression, depression, short term memory loss, and heightened suicidality, usually beginning 8-10 years after the injury
