Residency · Residency · Pathology
Neurodegenerative Disease Neuropathology
Overview
Neurodegenerative diseases are characterized by progressive neuronal loss and accumulation of misfolded proteins. Definitive diagnosis often requires postmortem neuropathologic examination. Modern classification emphasizes the specific proteinopathy (amyloid-beta, tau, alpha-synuclein, TDP-43) and its anatomic distribution. Overlap between proteinopathies is common, particularly in elderly patients.
Alzheimer Disease (AD)
Pathologic Hallmarks
Amyloid (Senile) Plaques
Amyloid plaques are extracellular deposits of amyloid-beta (Abeta) peptide, primarily the Abeta42 species. Diffuse plaques are amorphous Abeta deposits without neuritic changes that may be pre-pathologic and are common with aging. Neuritic plaques consist of a dense core of fibrillar Abeta surrounded by dystrophic neurites (swollen, tau-positive axons) and are associated with clinical disease. Detection methods include Abeta immunohistochemistry (4G8, 6E10 antibodies), thioflavin S fluorescence, and Congo red birefringence. The Thal phases describe Abeta distribution: Phase 1 (neocortex), Phase 2 (allocortex), Phase 3 (diencephalon/striatum), Phase 4 (brainstem), and Phase 5 (cerebellum).
Neurofibrillary Tangles (NFTs)
NFTs are intracellular accumulations of hyperphosphorylated tau protein (both 3R and 4R tau). They appear flame-shaped in pyramidal neurons and globose in subcortical neurons. Ghost tangles are extracellular tangles remaining after the neuron has died. Detection uses phospho-tau IHC (AT8), Gallyas silver stain, or thioflavin S. Braak staging describes the anatomic progression of tau pathology: Stages I-II (transentorhinal) involve the entorhinal cortex and hippocampus; Stages III-IV (limbic) involve the hippocampus, temporal cortex, and amygdala; Stages V-VI (neocortical) show widespread neocortical involvement. Only stages V-VI typically correlate with clinical dementia.
Other Features
Neuropil threads are tau-positive dystrophic neurites in the neuropil. Cerebral amyloid angiopathy (CAA) results from Abeta deposition in walls of leptomeningeal and cortical vessels, associated with lobar hemorrhages. Granulovacuolar degeneration (GVD) appears as small intracytoplasmic vacuoles with dense granules in hippocampal pyramidal neurons. Hirano bodies are eosinophilic rod-shaped actin-related inclusions in the hippocampus.
NIA-AA Criteria (ABC Score)
The current standard for AD neuropathologic evaluation uses the ABC score: A score (Amyloid/Thal phase, A0-A3), B score (Braak NFT stage, B0-B3), and C score (Neuritic plaque density/CERAD, C0-C3). The combined ABC score determines the likelihood of AD neuropathologic change contributing to cognitive impairment: Not, Low, Intermediate, or High.
| Component | Score | Basis |
|---|---|---|
| A (Amyloid) | A0–A3 | Thal phase of Aβ plaque distribution |
| B (Braak stage) | B0–B3 | NFT topographic staging (I–VI) |
| C (CERAD) | C0–C3 | Neuritic plaque density (none to frequent) |
Lewy Body Disease
Alpha-Synuclein Pathology
Classic brainstem Lewy bodies are intracytoplasmic, eosinophilic, round inclusions with a dense core and pale peripheral halo found in pigmented brainstem neurons. Cortical Lewy bodies are pale, poorly circumscribed, and lack the halo, occurring in cortical neurons. Lewy neurites are alpha-synuclein-positive dystrophic neurites. Detection relies on alpha-synuclein IHC (most sensitive), H&E for brainstem Lewy bodies, and ubiquitin IHC.
Parkinson Disease (PD)
PD predominantly involves the substantia nigra pars compacta with neuronal loss and depigmentation, showing brainstem-predominant Lewy body pathology. Braak PD staging progresses from Stage 1 (dorsal motor nucleus of vagus/olfactory bulb) through Stage 2 (lower brainstem), Stage 3 (substantia nigra), and Stages 4-6 (cortical spread).
Dementia with Lewy Bodies (DLB)
DLB shows cortical-predominant alpha-synuclein pathology with concurrent Alzheimer pathology common (mixed dementia). Clinically it presents with fluctuating cognition, visual hallucinations, parkinsonism, and REM sleep behavior disorder.
Multiple System Atrophy (MSA)
MSA is defined by alpha-synuclein-positive glial cytoplasmic inclusions (GCIs) in oligodendrocytes rather than neuronal Lewy bodies. MSA-C (cerebellar) shows cerebellar and pontine atrophy (olivopontocerebellar atrophy pattern). MSA-P (parkinsonian) shows striatonigral degeneration. GCIs are the defining pathologic feature and distinguish MSA from Lewy body diseases.
Frontotemporal Lobar Degeneration (FTLD)
Classification by Proteinopathy
FTLD-Tau
Pick disease is a 3R tauopathy featuring Pick bodies (round, well-circumscribed, tau-positive inclusions in cortical neurons), frontal and temporal atrophy, and balloon cells (achromatic neurons). Corticobasal degeneration (CBD) is a 4R tauopathy with astrocytic plaques, thread-like tau pathology, corticobasal inclusions, and asymmetric cortical atrophy with substantia nigra involvement. Progressive supranuclear palsy (PSP) is a 4R tauopathy featuring tufted astrocytes and globose NFTs in subcortical structures (subthalamic nucleus, substantia nigra, pontine nuclei, dentate nucleus). Chronic traumatic encephalopathy (CTE) is a 3R+4R tauopathy with perivascular tau deposits at the depths of cortical sulci, associated with repetitive head trauma.
FTLD-TDP (TDP-43)
FTLD-TDP is the most common molecular subtype of FTLD, classified into types based on inclusion morphology and distribution. Type A shows neuronal cytoplasmic inclusions (NCIs) and dystrophic neurites in upper cortical layers, associated with GRN mutations. Type B shows diffuse granular NCIs across all cortical layers, associated with C9orf72 expansion. Type C shows long dystrophic neurites in sporadic semantic variant PPA. Type D shows lentiform neuronal intranuclear inclusions with VCP mutations. Type E shows granulofilamentous inclusions with a rapidly progressive course. TDP-43 pathology is also found in ALS motor neurons, hippocampal sclerosis of aging (LATE), and approximately 50 percent of Alzheimer disease cases.
FTLD-FUS
This is a rare form with FUS (fused in sarcoma) protein inclusions, including neuronal intermediate filament inclusion disease (NIFID), basophilic inclusion body disease, and atypical FTLD-U.
Prion Diseases
Creutzfeldt-Jakob Disease (CJD)
CJD is characterized by spongiform change (fine vacuolation of the neuropil in grey matter), neuronal loss and gliosis, and the absence of significant inflammatory infiltrate. PrPSc (misfolded prion protein) is detected by PrP IHC, which shows synaptic, perivacuolar, or plaque-like patterns.
CJD Subtypes
Sporadic CJD (sCJD) is the most common form (approximately 85 percent), presenting as rapidly progressive dementia with MRI showing cortical ribboning and caudate/putamen signal abnormality. Variant CJD (vCJD) is linked to bovine spongiform encephalopathy and shows florid plaques (PrP-positive amyloid plaques with spongiform halo) in younger patients. Familial CJD results from PRNP mutations. Iatrogenic CJD is transmitted through dura mater grafts, corneal transplants, pituitary hormones, or surgical instruments.
Safety Considerations
Brain, spinal cord, and eye are high-risk tissues, and standard formalin fixation does not inactivate prions. Formic acid treatment (96 percent, 1 hour) is recommended before tissue processing. Instruments should be single-use or decontaminated with 1N NaOH or bleach followed by autoclaving at 134 degrees Celsius.
Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE)
LATE is a TDP-43 proteinopathy predominantly affecting elderly patients over 80 years. It manifests as hippocampal sclerosis (severe neuronal loss and gliosis in CA1 and subiculum). Staging progresses from Stage 1 (amygdala) through Stage 2 (hippocampus) to Stage 3 (middle frontal gyrus). It is common co-pathology with AD and may contribute to dementia independently. Despite involving TDP-43, it is not associated with the FTLD clinical phenotype.
<image>A medical illustration of Alzheimer disease neuropathology. Panel A: Low-power view of neocortex showing multiple neuritic plaques (dark deposits on Abeta IHC) scattered throughout the grey matter. Panel B: High-power view of a neuritic plaque showing a dense amyloid core surrounded by dystrophic neurites highlighted by phospho-tau IHC (AT8), with a neurofibrillary tangle-bearing neuron nearby showing a flame-shaped intracellular tau accumulation. Panel C: Congo red stain under polarized light showing apple-green birefringence of amyloid in a senile plaque. Panel D: Cerebral amyloid angiopathy (CAA) showing Abeta deposition in the walls of leptomeningeal and cortical arteries, with vessel wall thickening and loss of smooth muscle cells.</image>
<image>A medical illustration of Lewy body disease and synucleinopathies. Panel A: Substantia nigra showing neuronal loss with depigmentation, a surviving neuron containing a classic brainstem Lewy body (eosinophilic round inclusion with a dense core and pale peripheral halo). Panel B: Alpha-synuclein IHC highlighting a cortical Lewy body (pale, poorly defined inclusion in a cortical neuron) and Lewy neurites (dystrophic neurites with beaded alpha-synuclein aggregates). Panel C: Multiple system atrophy showing glial cytoplasmic inclusions (GCIs) in oligodendrocytes highlighted by alpha-synuclein IHC, showing crescentic or triangular inclusions adjacent to the nucleus. Panel D: Comparison diagram showing Lewy body (neuronal, round, cored) versus GCI (oligodendroglial, flame-shaped, no halo).</image>
<image>A medical illustration of frontotemporal lobar degeneration subtypes and prion disease. Panel A (Pick disease): Round, well-circumscribed Pick bodies in cortical neurons highlighted by 3R-tau IHC, with a balloon cell (enlarged achromatic neuron) nearby. Panel B (PSP): Tufted astrocyte in the striatum highlighted by 4R-tau IHC, showing radiating tau-positive processes. Panel C (FTLD-TDP Type A): TDP-43 IHC showing neuronal cytoplasmic inclusions and short dystrophic neurites in upper cortical layers. Panel D (Creutzfeldt-Jakob disease): Spongiform change (fine neuropil vacuolation) in the cortex with PrP IHC inset showing synaptic pattern of prion protein deposition.</image>
Clinical Pearls
The NIA-AA "ABC" scoring system is the current standard for AD neuropathologic evaluation at autopsy. The B score (Braak stage for tau/NFTs) correlates most strongly with clinical cognitive decline, while amyloid burden alone does not predict dementia severity. Incidental Lewy body pathology is found in approximately 10 percent of autopsies in individuals over 60 without clinical parkinsonism; its clinical significance is debated and it may represent preclinical PD.
Glial cytoplasmic inclusions (GCIs) in oligodendrocytes are the hallmark of MSA and distinguish it from PD and DLB, which have neuronal Lewy bodies; alpha-synuclein IHC is essential for this distinction. When prion disease (CJD) is suspected, the pathology laboratory must be notified before tissue processing due to infection control requirements; standard formalin fixation does not inactivate prions, and formic acid treatment is required.
Co-pathology is the rule rather than the exception in elderly patients. Combined AD plus Lewy body disease, AD plus LATE (TDP-43), and AD plus vascular disease are all common, and each may contribute independently to cognitive decline. CTE can only be diagnosed at autopsy; its defining feature is perivascular tau deposits at the depths of cortical sulci, which is distinct from the distribution of tau in AD.
References
- Montine TJ, et al. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement. 2012;8(1):1-13.
- McKeith IG, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report. Neurology. 2017;89(1):88-100.
- Mackenzie IR, et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol. 2011;122(1):111-113.
- Nelson PT, et al. Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain. 2019;142(6):1503-1527.
- Budka H, et al. Neuropathological diagnostic criteria for Creutzfeldt-Jakob disease and other human spongiform encephalopathies. Brain Pathol. 1995;5(4):459-466.
