CNS I Path - Neurodegenerative Diseases Flashcards
Alzheimer’s Disease Overview
BETA AMYLOID and TAU mutations
Affects the hippocampus, language areas and frontal regions of the cortex
PYRAMIDAL LAYER of the hippocampus affected –> AMYLOID PLAQUES and NEUROFIBRILLARY TANGLES
Beta Amyloid Plaques
Extracellular inclusions composed of a central, amorphous area made up of the beta-amyloid protein surround by dystrophic neuritis and microglial cells
Plaque may also contain MACROPHAGES digesting the protein - plaques release pro-inflammatory cytokines that are damaging to the surrounding tissue
Neurfibrillary Tangles
Abnormal accumulation of TAU PROTEINS within the neuronal cytoplasm
Appear as Flame-Like tails on histology
Gene Mutations and Familial AD
Beta Amyloid Precursor Protein (APP) –> improper cleaving of APP increases the ability to aggregate –> plaques! Problem with cleavage enzymes – target for treatment?
PRESENILIN 1 and 2
ApoE –> Unique as it DICTATES RISK OF ACQUIRING AD –> 3 possible alleles (2, 3, 4) –> 2 seems to be protective, 4 not so much (2/3, 2/4, 3/3 low risk) but (3/4 and 4/4 HIGHER RISK!)
TAU
Progression AD
Affects hippocampus, language areas, and frontal regions of the cortex
Brain is SHRIVELED with GYRI ATROPHY and SULCI ENLARGEMENT
Staged from I to VI, with each stage marking increased cortical atrophy and amyloid/tau accumulation
DEGENERATION STARTS IN THE HIPPOCAMPUS AND SPREADS TO MORE DIFFUSED AREAS OF THE CORTEX – a disease of spread!
Beta amyloid and Tau progression
Begin to accumulate WELL BEFORE patients develop neurological symptoms
May have “pre-clinical” stage where the patient develops plaques with no impairment
PET scans can be utilized to see beta amyloid plauqes – allows for a real-time view of the pathologic accumulation before autopsy
Presence of plaques and tangles are NOT diagnostic for AD – all elderly patients have some plaque
What are the Tauopathies?
ALZHEIMERS
FTDP-17
Corticobasal Degeneration
Pick’s Disease
Progressive Supranuclear Palsy
Progressive Supranuclear Palsy
Can present with: depression, gait disturbance, diplopia, memory problems, UPWARD GAZE PARALYSIS (specific), DEMENTIA
Grossly –> Hypopigmented Substantia Nigra and Locus Ceruleus in the midbrain
Microscopically –> Extraceullar neuronal MELANIN (neuronal rupture) and TAU INCLUSIONS
What are common areas affected by TAUOPATHIES?
Mibrain (SUBSTANTIA NIGRA, periaqueductal gray, red nucleus)
PONS - Locus ceruleus
MEDULLA - cranial nerves
HIPPOCAMPUS, GLOBUS PALLIDUS, STN
Cerebellum, Cortex
Pick’s Disease
Almost identical presentation to AD!
Dramatic FRONTOTEMPORAL DEGENERATION
Pick Cells (large, swollen neurons) and accumulation of pink material within the cells (Tau?) –> mimic reactive astrocytes/red dead neurons
TAUOPATHY
Corticobasal Degeneration
Characterized by LOBAR ATROPHY but located in the frontoparietal lobes
Patients usually present around 60 y.o. with asymmetric clumsiness, jerking movements, and often an “alien” limb…what?
Swollen neurons - similar to Pick Cells
Huntington’s Disease
Autosomal Dominant –> 100% penetrance
Presents with CHOREA (abnormal movements) and DEMENTIA, AGGRESSION
TRINUCLEOTIDE REPEATS!!!!! CAG-CAG-CAG… on 4p chromosome
9-37 repeats OK, 38-86 disease state
More repeats, the eraly the onset of symptoms
30-50 y.o. with subtle fidgeting and personality changes that dramatically progress over the next decade or so
Primarily affects the CAUDATE nucleus (degeneration)
Parkinson’s
Triad of Symptoms –> Tremor, Akinesia, Rigidity
Onset is INSIDIOUS and PROGRESSIVE (initially present with pill rolling tremor, stooped posture, and facial grimace)
Histology -> LEWY BODIES in DA neurons, round EOSINOPHILIC CYTOPLASMIC INCLUSIONS (alpha-synuclein)
Gross –> DEGENERATION OF SUBSTANTIA NIGRA (just like Progressive Supranuclear Palsy!)
Diseases by Mutations
Beta Amyloid? ALZHEIMERS
Tau? ALZHEIMERS, Pick’s, PSP, Frontotemporal Dementia, Corticobasalr Degeneration
Synuclein? PARKINSONS
TDP-43? ALS/Frontotemporal Lobar Degeneration
Trinucleotide Repeats? HUNTINGTON’S
