NEURODEGENERATIVE DISEASES Dr. Lilian Bosire MKU Lecturer, Pathologist — OVERVIEW Definition: Progressive loss of specific neuronal groups → stereotypic si
NEURODEGENERATIVE DISEASES Dr. Lilian Bosire MKU Lecturer, Pathologist --- OVERVIEW Definition: Progressive loss of specific neuronal groups → stereotypic signs/symptoms depending on which neural system is affected. Core pathology = PROTEINOPATHY (protein aggregate accumulation) Why aggregates form: Mutations altering protein conformation Disrupted processing/clearance pathways Subtle imbalance between synthesis & clearance (genetic, environmental, stochastic) Key facts about aggregates: Resistant to degradation + aberrantly localized in neurons Large visible aggregates = NOT directly toxic → they sequester smaller oligomers Small oligomers = DIRECTLY TOXIC (this is the clinically important point) Normal protein function is also lost → adds to injury Aggregates behave prion-like → released from one cell, taken up by another → triggers more aggregation Two classification approaches: Approach Basis --- --- Symptomatic/Anatomic Region affected → symptoms (neocortex → dementia) Pathologic Type of inclusion (tau vs synuclein diseases) Clinical groups: Dementias · Hypokinetic movement disorders · Hyperkinetic movement disorders · Cerebellar ataxias · Motor neuron diseases --- 1. PRION DISEASES Definition: Rapidly progressive neurodegenerative disorders caused by aggregation and intercellular spread of misfolded prion protein (PrP) Forms: Sporadic · Familial · Transmitted Human examples: CJD · Gerstmann-Sträussler-Scheinker (GSS) · Fatal familial insomnia · Kuru Animal examples: Scrapie (sheep/goats) · BSE/mad cow (cattle) · Chronic wasting disease (deer/elk) · Mink-transmissible encephalopathy Universal hallmarks: Morphologic → spongiform change (intracellular vacuoles in neurons & glia) Clinical → rapidly progressive dementia --- Pathogenesis Normal PrP = PrPc → 30kD cytoplasmic protein · α-helix conformation · function unknown The conversion: PrPc (normal, α-helix) → PrPsc (abnormal, β-pleated sheet) ↓ Protease-resistant (survives proteinase K digestion) ↓ Accumulates in neural tissue ↓ Vacuolation + neuronal death (exact mechanism unknown) ↓ PrPsc can spread cell-to-cell → behaves like infectious agent 3 ways conversion is triggered: Type Mechanism --- --- Sporadic Spontaneous random misfolding at extremely low rate Familial Mutations in PRNP gene (encodes PrP) Transmitted Iatrogenic / inter-species Diagnosis: Immunostaining for PrP after partial proteinase K digestion → detects PrPsc (gold standard) --- Creutzfeldt-Jakob Disease (CJD) Epidemiology: Most common prion disease Incidence ~1/1,000,000/year · Sporadic = ~90% Peak: 7th decade Average survival: 7 months (uniformly fatal) Familial → mutations in PRNP Iatrogenic transmission: Corneal/dural transplantation Deep brain electrode implantation Contaminated cadaveric human growth hormone Clinical: Subtle memory & behavioral changes → rapidly progressive dementia Startle myoclonus — involuntary jerking on sudden stimulation (characteristic) Cerebellar ataxia in minority Long survivors → extensive gray matter atrophy Morphology: Feature Detail --- --- Gross Little/no atrophy (disease too rapid) Pathognomonic Spongiform transformation of cerebral cortex + deep gray matter (caudate, putamen) Microscopy Small empty vacuoles in neuropil + neuronal perikarya Advanced Neuronal loss · reactive gliosis · cystic spaces = "status spongiosus" Inflammation Absent (important distinguishing feature) Kuru plaques Extracellular PrP deposits · Congo red + PAS positive · mainly cerebellum · abundant in cortex in vCJD EM Vacuoles membrane-bound, within cytoplasm of neuronal processes --- 2. ALZHEIMER DISEASE (AD) Most common cause of dementia in older adults Epidemiology: Rarely symptomatic before age 50 Prevalence doubles every 5 years from age 60 Age 60–64 → 1% · Age 85–89 → ≥40% Familial = 5–10% · Sporadic = 90–95% Premortem diagnosis accurate in 80–90% (clinical + radiology) Definitive diagnosis = autopsy Clinical course: Insidious onset → memory impairment → visuospatial deficits → language loss → personality/judgment changes Course runs 10 years → eventually mute, immobile, incontinent Terminal event usually intercurrent pneumonia --- Pathogenesis Core = accumulation of 2 proteins: Aβ and tau Two hallmarks: Hallmark Nature Location --- --- --- Amyloid plaques Aggregated Aβ peptide Extracellular, in neuropil Neurofibrillary tangles Hyperphosphorylated tau Intracellular → extracellular after neuronal death --- A) Role of Aβ — the initiating event APP (amyloid precursor protein) = cell surface protein, single transmembrane domain Two cleavage pathways: APP ├─ α-secretase + γ-secretase → NON-AMYLOIDOGENIC → harmless soluble peptide │ (mostly at cell surface) └─ β-secretase + γ-secretase → AMYLOIDOGENIC → releases Aβ42 (endocytosed into vesicles) ↓ Small oligomers (TOXIC → synaptic dysfunction, kinase activation, cell death) ↓ Large aggregates + fibrils ↓ Amyloid plaques γ-secretase complex contains presenilin-1 or presenilin-2 + nicastrin + PEN2 + APH1 Also processes Notch rec