Neurodegenerative Neuropathology
What You'll Learn
- To classify neurodegeneration by the misfolded protein — tau, α-synuclein, TDP-43, polyQ, prion
- The signature inclusion, stain, and regional atrophy for each disease
- How to separate the overlapping dementias and parkinsonisms on tissue
The neuropathology view — inclusions, stains, distribution. Clinical diagnosis/treatment lives in the Dementia and Movement Disorders notes.
- Alzheimer: extracellular neuritic (Aβ) plaques + intracellular neurofibrillary tangles (tau); plaques shown with Bielschowsky/silver, thioflavin-S, Aβ IHC (Congo red highlights amyloid cores & CAA). Tangle spread follows Braak staging.
- Synucleinopathies: PD = nigral Lewy bodies; DLB requires limbic/cortical Lewy bodies; MSA = oligodendroglial cytoplasmic inclusions (Papp-Lantos). All α-synuclein+.
- ALS / FTLD-TDP: ubiquitin+, TDP-43+ cytoplasmic inclusions; ALS shows motor-neuron loss + Bunina bodies + corticospinal-tract degeneration.
- Huntington: caudate (medium spiny neuron) atrophy → “box-car” frontal horns; intranuclear huntingtin/ubiquitin inclusions.
- Prion (CJD): spongiform vacuolation + neuronal loss + gliosis, no inflammation; PrPSc immunostain.
Alzheimer Disease & Tauopathies
| Disease | Pathology | Stain / distribution |
|---|
| Alzheimer | Neuritic Aβ plaques + neurofibrillary tangles (paired helical tau); neuropil threads; granulovacuolar degeneration & Hirano bodies (hippocampus); CAA | Bielschowsky/thioflavin/Aβ IHC; tau IHC; Braak tangle + Thal amyloid staging; hippocampal & temporoparietal atrophy |
| PSP | Globose tangles, tufted astrocytes, coiled bodies; midbrain/pallidum/subthalamic | 4R-tau; midbrain atrophy (“hummingbird”) |
| Corticobasal degeneration | Astrocytic plaques, ballooned achromatic neurons; asymmetric frontoparietal | 4R-tau |
| Pick disease (FTLD-tau) | Pick bodies (round argyrophilic), ballooned Pick cells; knife-edge frontotemporal atrophy | 3R-tau; silver+ |
Synucleinopathies
| Disease | Pathology | Clue |
|---|
| Parkinson disease | Nigral Lewy bodies (eosinophilic, halo) & Lewy neurites; loss of pigmented dopaminergic neurons | Depigmented substantia nigra; α-synuclein+; Braak PD staging (ascending) |
| Dementia with Lewy bodies | Limbic + neocortical Lewy bodies/neurites (cortical LBs less distinct) | α-synuclein IHC required to see cortical LBs |
| Multiple system atrophy | Glial cytoplasmic inclusions (Papp-Lantos bodies) in oligodendrocytes; striatonigral & olivopontocerebellar degeneration | α-synuclein+; putaminal/pontine (“hot cross bun”) atrophy |
TDP-43 Proteinopathies & Motor Neuron Disease
| Disease | Pathology | Inclusion |
|---|
| ALS | Loss of anterior-horn & upper motor neurons; corticospinal tract degeneration; neurogenic muscle atrophy | Cytoplasmic TDP-43 skein-like / ubiquitin inclusions; Bunina bodies (cystatin C+, eosinophilic) |
| FTLD-TDP | Frontotemporal neuronal loss, superficial spongiosis | TDP-43+ cytoplasmic inclusions (ubiquitin+, tau-negative) |
C9orf72 hexanucleotide expansion links familial ALS & FTLD and adds p62+/TDP-43-negative inclusions.
Polyglutamine & Prion Disease
| Disease | Pathology | Signature |
|---|
| Huntington | Atrophy of caudate > putamen (medium spiny neuron loss) → ex-vacuo “box-car” frontal horns | Intranuclear huntingtin/ubiquitin inclusions; CAG expansion |
| Creutzfeldt-Jakob (prion) | Spongiform vacuolation, neuronal loss, astrogliosis, no inflammatory infiltrate | PrPSc IHC (protease-resistant); vCJD shows florid kuru plaques |
| Friedreich ataxia | Degeneration of dorsal columns, spinocerebellar & corticospinal tracts, dorsal root ganglia | GAA expansion (frataxin) |
| Inclusion / finding | Protein | Disease |
|---|
| Neurofibrillary tangles + Aβ plaques | Tau + Aβ | Alzheimer |
| Tufted astrocytes | 4R-tau | PSP |
| Astrocytic plaques | 4R-tau | CBD |
| Pick bodies | 3R-tau | Pick disease |
| Lewy body | α-synuclein | PD / DLB |
| Glial cytoplasmic inclusions (Papp-Lantos) | α-synuclein | MSA |
| Skein-like inclusions (TDP-43) + Bunina bodies (cystatin C) | TDP-43 / cystatin C | ALS |
| Spongiform change, no inflammation | PrPSc | CJD |
References
- Love S, et al. Greenfield's Neuropathology. 9th ed. 2015.
- Kovacs GG. Molecular pathological classification of neurodegenerative diseases. Int J Mol Sci. 2016.
🔒
Continue reading — sign in
The full note has more clinical pearls, tables, and board-focused tips. Free account, no fee.
