Neurodegenerative Diseases
Pathology · CNS · lean revision notes
Neurodegenerative Diseases
Neurodegenerative diseases are a group of progressive disorders defined by the selective loss of neurons in specific anatomic and functional systems, almost always accompanied by the intracellular accumulation of abnormally folded proteins (proteinopathies). For NEET PG, the high-yield core is the histopathology — what inclusion accumulates, where, and made of which protein — plus the classic clinical-radiological correlations.
High-yield: The single most-tested concept in this topic is the protein–inclusion matching: Alzheimer = amyloid-β plaques + tau (neurofibrillary tangles), Parkinson = α-synuclein (Lewy body), Huntington = CAG/polyglutamine huntingtin, ALS = TDP-43 / SOD1. Memorise this grid first — it answers most single-best-answer questions.
Classification
Neurodegenerative diseases are best grouped by the anatomic system predominantly affected, because clinical phenotype follows topography.
| System affected | Disease | Dominant clinical syndrome |
|---|---|---|
| Cerebral cortex | Alzheimer disease, Frontotemporal dementia, Lewy body dementia | Dementia |
| Basal ganglia (substantia nigra, striatum) | Parkinson disease, Huntington disease, Wilson, PSP, MSA | Movement disorder |
| Cerebellum / spinocerebellar | Friedreich ataxia, SCAs | Ataxia |
| Motor neurons (UMN + LMN) | Amyotrophic lateral sclerosis (ALS), SMA | Weakness/wasting |
A second, mechanistically powerful classification is by the misfolded protein (the "proteinopathy" framework):
- Tauopathies: Alzheimer (also amyloid), Pick disease/FTD-tau, Progressive supranuclear palsy (PSP), Corticobasal degeneration (CBD).
- Synucleinopathies: Parkinson disease, Dementia with Lewy bodies (DLB), Multiple system atrophy (MSA — glial cytoplasmic inclusions).
- TDP-43 proteinopathies: ALS, FTD-TDP.
- Polyglutamine (CAG) expansion diseases: Huntington, several SCAs, spinobulbar muscular atrophy (Kennedy disease).
High-yield: Most neurodegenerative inclusions are ubiquitinated because the cell tags misfolded protein for proteasomal degradation but fails to clear it — this is why ubiquitin immunostain lights up plaques, tangles, Lewy bodies and ALS inclusions alike.
1. Alzheimer Disease (AD)
The commonest cause of dementia, usually presenting after age 50 with an insidious memory loss (early hippocampal/entorhinal involvement) progressing to global cognitive decline, disorientation, aphasia and finally a mute, bedbound state. Death is typically from intercurrent pneumonia.
Pathophysiology — the amyloid cascade
APP (amyloid precursor protein, chromosome 21) is cleaved by β-secretase (BACE) then γ-secretase to yield Aβ42, which is aggregation-prone. Aβ42 deposits extracellularly → activates kinases → hyperphosphorylation of tau → tau detaches from microtubules → aggregates intracellularly as paired helical filaments.
APP cleavage → Aβ42 monomers → oligomers/plaques (extracellular) → tau hyperphosphorylation → neurofibrillary tangles (intracellular) → synaptic loss & neuronal death → dementia.
Genetics
- Early-onset familial AD: APP (Chr 21), Presenilin-1 (Chr 14), Presenilin-2 (Chr 1) — all increase Aβ42.
- Late-onset/sporadic risk: ApoE ε4 is the major risk allele (ε2 protective).
- Down syndrome (trisomy 21): triple APP dosage → virtually all develop AD pathology by age 40.
Gross & microscopic pathology
- Gross: cortical atrophy with widened sulci and narrowed gyri, especially frontal/temporal/parietal; compensatory hydrocephalus ex vacuo (ventricular dilatation); medial temporal/hippocampal atrophy.
- Senile (neuritic) plaques: extracellular deposits of Aβ with a central amyloid core surrounded by dystrophic neurites; stain with Congo red (apple-green birefringence), thioflavin, silver.
- Neurofibrillary tangles (NFTs): intracellular bundles of paired helical filaments of hyperphosphorylated tau; flame-shaped, silver-positive; persist as "ghost tangles" after the neuron dies.
- Other: amyloid angiopathy (Aβ in vessel walls → lobar haemorrhage risk), granulovacuolar degeneration and Hirano bodies (actin) in hippocampal neurons.
| Feature | Senile plaque | Neurofibrillary tangle |
|---|---|---|
| Location | Extracellular | Intracellular |
| Composition | Amyloid-β (Aβ42) | Hyperphosphorylated tau |
| Stain | Congo red, thioflavin, silver | Silver, tau immunostain |
| Significance | Aβ cascade trigger | Correlates better with dementia severity |
High-yield: NFT burden (Braak staging) correlates with cognitive decline better than plaque load. Plaques are extracellular Aβ; tangles are intracellular tau — never mix these up.
Diagnosis & investigation
- Clinical diagnosis (DSM/NIA-AA criteria); definitive diagnosis is histological (autopsy).
- MRI: medial temporal/hippocampal atrophy.
- CSF biomarkers: ↓ Aβ42, ↑ total tau and ↑ phospho-tau (the "AD signature").
- Amyloid PET (Pittsburgh compound B) shows cortical Aβ.
Management
- Mild–moderate: acetylcholinesterase inhibitors — donepezil, rivastigmine, galantamine (cholinergic deficit from nucleus basalis of Meynert loss).
- Moderate–severe: memantine (NMDA antagonist).
- Disease-modifying: anti-amyloid monoclonal antibodies (lecanemab, aducanumab) clear plaques — watch for ARIA (amyloid-related imaging abnormalities/oedema).
2. Parkinson Disease (PD)
A hypokinetic movement disorder from loss of dopaminergic neurons in the substantia nigra pars compacta, leading to dopamine deficiency in the nigrostriatal pathway.
Clinical features — TRAP
Tremor (resting, 4–6 Hz, "pill-rolling"), Rigidity (cogwheel/lead-pipe), Akinesia/bradykinesia, Postural instability. Also masked facies, micrographia, festinant (shuffling) gait, hypophonia. Resting tremor that decreases with movement distinguishes it from cerebellar/essential tremor.
Pathophysiology
α-synuclein misfolds and aggregates → Lewy bodies. Neuronal loss in SNpc → depigmentation of substantia nigra (loss of neuromelanin). Motor symptoms appear once ~60–80% of nigral dopaminergic neurons are lost.
Pathology
- Gross: pallor (depigmentation) of the substantia nigra and locus ceruleus.
- Lewy body: intracytoplasmic, round, eosinophilic inclusion with a dense core and pale halo, composed chiefly of α-synuclein (also ubiquitin). Found in surviving SNpc neurons.
- Lewy neurites and cortical Lewy bodies underlie dementia with Lewy bodies (DLB).
High-yield: Lewy body = α-synuclein. This is the single most repeated histology MCQ in this topic. The substantia nigra appears depigmented/pale on gross.
Diagnosis & management
- Clinical diagnosis; supportive: DaT-SPECT (reduced striatal dopamine transporter), good response to levodopa.
- Drug of choice: Levodopa + carbidopa (carbidopa = peripheral dopa-decarboxylase inhibitor, reduces peripheral side effects, doesn't cross BBB). Long-term → on-off fluctuations and dyskinesias.
- Others: dopamine agonists (pramipexole, ropinirole), MAO-B inhibitors (selegiline, rasagiline), COMT inhibitors (entacapone), amantadine, anticholinergics (for tremor). Deep brain stimulation of the subthalamic nucleus for advanced disease.
High-yield: MPTP (a pethidine analogue contaminant) destroys SNpc neurons via its metabolite MPP+ (complex I inhibition) → drug-induced parkinsonism — a classic toxicology link.
3. Huntington Disease (HD)
An autosomal dominant, hyperkinetic movement disorder of midlife (30–50 yrs) with the triad of chorea, behavioural/psychiatric disturbance, and dementia.
Genetics
- CAG trinucleotide repeat expansion in the huntingtin (HTT) gene on chromosome 4p16.3.
- Normal <27 repeats; disease ≥36–40.
- Anticipation: repeats expand across generations (more with paternal transmission) → earlier onset, more severe disease.
- Expanded polyglutamine huntingtin → toxic gain of function and intranuclear ubiquitinated inclusions.
Pathology
- Atrophy of the caudate nucleus and putamen (striatum) — loss of GABAergic medium spiny neurons (those expressing enkephalin in the indirect pathway are lost first).
- Gross: caudate atrophy → flattening/"box-car" enlargement of the lateral ventricles (loss of the normal caudate bulge).
High-yield: HD = CAG repeat, chromosome 4, caudate atrophy, chorea. Loss of indirect-pathway striatal neurons disinhibits movement → chorea (opposite of Parkinson's hypokinesia).
Diagnosis & management
- Genetic testing (CAG repeat count) is confirmatory; MRI shows caudate atrophy.
- No cure. Chorea managed with tetrabenazine/deutetrabenazine (VMAT2 inhibitors) or antipsychotics; SSRIs for mood.
4. Amyotrophic Lateral Sclerosis (ALS / Motor Neuron Disease)
Progressive degeneration of both upper motor neurons (cortex/corticospinal tract) and lower motor neurons (anterior horn, brainstem motor nuclei), producing combined UMN + LMN signs with sensory sparing.
Clinical features
- LMN signs: muscle weakness, wasting, fasciculations, hyporeflexia.
- UMN signs: spasticity, hyperreflexia, extensor plantar (Babinski).
- Asymmetric limb weakness, bulbar involvement (dysarthria, dysphagia), tongue fasciculations.
- Spared: sensation, eye movements, sphincters (until late). Cognition usually preserved (overlap with FTD in some).
High-yield: ALS = UMN + LMN signs together with NO sensory loss. Anterior horn cell loss (LMN) + corticospinal tract degeneration (UMN). Most cases are sporadic; SOD1 mutation is the classic familial cause, and TDP-43 is the inclusion protein.
Pathology
- Loss of anterior horn cells and Betz cells; degeneration of corticospinal tracts.
- Skeletal muscle: neurogenic (denervation) atrophy.
- Inclusions: TDP-43 positive, ubiquitinated cytoplasmic inclusions; Bunina bodies.
Diagnosis & management
- EMG/NCS: denervation (fibrillations, fasciculations) with normal sensory conduction; El Escorial criteria.
- Drug of choice / only survival-prolonging drugs: Riluzole (glutamate antagonist) and edaravone (free-radical scavenger). Supportive: non-invasive ventilation, PEG feeding.
Comparative grid (the master table)
| Disease | Protein / inclusion | Site / gross | Genetics | Clinical |
|---|---|---|---|---|
| Alzheimer | Aβ plaques (extracell.) + tau NFTs (intracell.) | Cortical atrophy, hydrocephalus ex vacuo | APP, PSEN1/2, ApoE4 | Dementia (memory first) |
| Parkinson | α-synuclein (Lewy body) | Depigmented substantia nigra | SNCA, LRRK2, Parkin | TRAP — hypokinetic |
| Huntington | Polyglutamine huntingtin (intranuclear) | Caudate/putamen atrophy | AD, CAG repeat Chr 4 | Chorea, dementia |
| ALS | TDP-43 / SOD1 | Anterior horn + corticospinal tract | SOD1 (familial) | UMN + LMN, no sensory |
Complications
- Alzheimer: aspiration pneumonia (commonest cause of death), falls, lobar haemorrhage from amyloid angiopathy.
- Parkinson: aspiration, falls/fractures, levodopa-induced dyskinesias, autonomic dysfunction, depression/dementia.
- Huntington: suicide (psychiatric burden), aspiration, cachexia.
- ALS: respiratory failure (commonest cause of death), aspiration, communication loss.
Key differentials
High-yield: Distinguish Parkinson disease from "Parkinson-plus" syndromes — these respond poorly to levodopa.
- Progressive supranuclear palsy (PSP): vertical gaze palsy, early falls, tauopathy.
- Multiple system atrophy (MSA): autonomic failure + cerebellar/parkinsonism; glial cytoplasmic inclusions of α-synuclein.
- Corticobasal degeneration: alien limb, asymmetric apraxia (tau).
- Dementia vs Alzheimer: vascular dementia (stepwise, infarcts), Lewy body dementia (fluctuating cognition + visual hallucinations + parkinsonism + neuroleptic sensitivity), Pick disease/FTD (behaviour/language, Pick bodies = round tau inclusions), Creutzfeldt-Jakob (rapid dementia + myoclonus + 14-3-3 protein + spongiform change).
- Chorea differentials of HD: Sydenham chorea (post-streptococcal), Wilson disease, drug-induced, SLE.
| Dementia type | Distinguishing clue |
|---|---|
| Alzheimer | Gradual memory loss; plaques + tangles |
| Vascular | Stepwise, focal deficits, infarcts |
| Lewy body | Fluctuating cognition, visual hallucinations, parkinsonism |
| Frontotemporal (Pick) | Personality/behaviour or language first; Pick bodies (tau) |
| Creutzfeldt-Jakob | Rapid course, myoclonus, spongiform, 14-3-3 |
Recently asked / exam angle
- "Lewy body is composed of?" → α-synuclein (classic single-line MCQ).
- "Neurofibrillary tangles are made of?" → hyperphosphorylated tau; senile plaques → amyloid-β.
- "Which correlates best with dementia severity in AD?" → neurofibrillary tangle (Braak stage), not plaque load.
- CAG repeat / chromosome 4 / caudate atrophy → Huntington; anticipation strongest with paternal transmission.
- "Depigmentation of substantia nigra" image/gross → Parkinson.
- UMN + LMN signs with intact sensation → ALS; familial gene = SOD1; inclusion = TDP-43; drug = riluzole.
- MPTP → MPP+ → complex I inhibition → parkinsonism (pharmacology/toxicology crossover).
- Down syndrome develops AD by 40 (APP gene dosage, Chr 21).
- Congo red apple-green birefringence for amyloid plaques and amyloid angiopathy.
- Hirano bodies (actin) and granulovacuolar degeneration in hippocampus — AD associations.
- Glial cytoplasmic inclusions of α-synuclein → MSA (a synucleinopathy, not PD).
Mnemonics:
- Parkinson clinical → TRAP (Tremor, Rigidity, Akinesia, Postural instability).
- Huntington → "Hunting 4 a CAG in the Caudate" (chromosome 4, CAG repeat, caudate atrophy).
- AD inclusions → "Plaques are Aβ, Tangles are Tau" (P-A, T-T pairing).
Rapid revision
- Senile plaque = extracellular amyloid-β42; neurofibrillary tangle = intracellular hyperphosphorylated tau (paired helical filaments).
- NFT burden correlates with dementia severity better than plaque load.
- AD genetics: APP (Chr 21), PSEN1/2; ApoE ε4 risk, ε2 protective; Down syndrome → AD by 40.
- AD drugs: donepezil/rivastigmine/galantamine (mild-mod) + memantine (severe); CSF shows ↓Aβ42, ↑p-tau.
- Lewy body = α-synuclein (eosinophilic, core + halo); Parkinson = depigmented substantia nigra.
- Parkinson symptoms appear after ~60–80% nigral dopaminergic loss; DOC = levodopa + carbidopa.
- MPTP → MPP+ → complex I inhibition causes parkinsonism.
- Huntington = autosomal dominant CAG repeat, HTT gene, chromosome 4, caudate/putamen atrophy, chorea; anticipation worse with paternal inheritance.
- Huntington loses GABAergic medium spiny (indirect pathway) neurons; treat chorea with tetrabenazine.
- ALS = UMN + LMN signs, sensation spared; familial SOD1, inclusions TDP-43, DOC riluzole (+ edaravone).
- Parkinson-plus (PSP — vertical gaze palsy; MSA — autonomic + glial α-synuclein inclusions) respond poorly to levodopa.
- Pick bodies = tau (FTD); Creutzfeldt-Jakob = rapid dementia + myoclonus + spongiform + 14-3-3 protein.