NEURODEGENERATIVE DISEASES Dr. Lilian Bosire MKU Lecturer, Pathologist --- OVERVIEW Definition: Progressive loss of specific neuronal groups → stereotypic signs
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 receptors → explains why PS mutations have wide effects - Aβ42 most prone to aggregation (clinically important) Why Aβ is the initiating event: Diseases with tau alone (FTLD, PSP, CBD) have NO Aβ deposits → NO full AD. MAPT mutations (tau gene) → cause FTLD, not AD. --- B) Role of Tau - Tau = microtubule-associated protein, normally in axons - In AD → shifts to somatic-dendritic distribution - Becomes hyperphosphorylated → loses ability to bind microtubules - Forms tangles → eventually becomes independent of Aβ burden 2 injury mechanisms: 1. Tau aggregates elicit cellular stress response 2. Loss of tau function destabilizes microtubules --- C) Genetic risk factors Gene/Factor Chromosome Effect --- --- --- APP 21 Increased Aβ production; trisomy 21 → early onset AD Presenilin-1 (PS-1) 14 Most common familial AD; alters γ-secretase cleavage Presenilin-2 (PS-2) 1 Similar to PS-1, rarer ApoE ε4 19 Strongest sporadic risk factor; promotes Aβ deposition + tau neurodegeneration; lowers age of onset ApoE ε2 19 Protective ApoE note: 3 alleles exist (ε2, ε3, ε4). ε4 dosage = increased risk + earlier onset. ε4 promotes Aβ generation AND Aβ-independent tau-mediated neurodegeneration. --- Morphology Gross: - Cortical atrophy → gyral narrowing + sulcal widening - Most affected: frontal, temporal, parietal lobes - Medial temporal lobe (hippocampus, entorhinal cortex, amygdala) → earliest + most severely affected - Hydrocephalus ex vacuo → compensatory ventricular enlargement Microscopic: Feature Detail --- --- Neuritic (senile) plaques Focal spherical collections of dystrophic neurites around central Aβ core · 20–200 μm · microglial cells + reactive astrocytes at periphery Neurofibrillary tangles Tau filament bundles in neuronal cytoplasm · "flame-shaped" in pyramidal neurons · "globose" in rounder cells Neuronal loss Progressive, severe; same regions as plaques/tangles Reactive gliosis Accompanies neuronal loss Staining: - Amyloid core → Congo red + β-amyloid immunostain - Tangles → basophilic on H&E · best seen with Bielschowsky silver stain + tau immunohistochemistry - Dystrophic neurites → contain tau aggregates biochemically similar to tangles Current treatment targets: - Clearing Aβ via immunologic approaches - Secretase inhibitors to block Aβ generation - Preventing tau alterations --- 3. PARKINSON DISEASE (PD) Most common hypokinetic movement disorder Core lesion: Loss of dopaminergic neurons from substantia nigra → reduced striatal dopamine Clinical triad: 1. Tremor (resting, "pill-rolling") 2. Rigidity 3. Bradykinesia Other features: - Masked facies · stooped posture · festinating gait - Diagnosis confirmed by symptomatic response to L-DOPA - Similar syndrome can be caused by dopaminergic antagonists or toxins Important: Degeneration of substantia nigra = midstage disease. Disease begins in medulla → brainstem → limbic → neocortex → cognitive impairment Treatment: - L-DOPA (does not revers