Neurodegenerative diseases represent a growing burden as populations age. Their diagnosis requires integration of clinical, radiological, and pathological findings. The pathological hallmarks are selective neuronal loss and accumulation of misfolded protein aggregates in specific brain regions.
Alzheimer Disease
Alzheimer disease (AD) is the most common neurodegenerative disease, accounting for 60-80% of dementia cases. The pathological diagnosis requires both amyloid-beta plaques and tau neurofibrillary tangles above age-adjusted thresholds.
Amyloid-beta (Aβ) pathology — extracellular plaques composed of 40-42 amino acid Aβ peptides. Plaques are classified as diffuse plaques (amorphous, weakly Aβ-positive — seen in aging and early AD) and neuritic plaques (compact, Aβ-positive core with dystrophic neurites, activated microglia, and reactive astrocytes — diagnostic of AD). The amyloid angiopathy of cerebral blood vessels (cerebral amyloid angiopathy, CAA) is also Aβ-positive.
Tau pathology — hyperphosphorylated tau protein aggregates as neurofibrillary tangles (NFTs) within neuronal cytoplasm, neuropil threads (dystrophic neurites in the neuropil), and dystrophic neurites in neuritic plaques. Tau pathology in AD follows a predictable progression (Braak stages I-VI): first in entorhinal cortex (I-II), then hippocampus (III-IV), then neocortex (V-VI).
IHC — Aβ (6F/3D, 4G8 clones) for plaques; phospho-tau (AT8, PHF1 clones) for tangles, threads, and dystrophic neurites. The NIA-AA diagnostic criteria require assessment of Aβ plaque score (Thal phases), NFT stage (Braak), and neuritic plaque score (CERAD), combined into an “ABC score” for the likelihood of AD.
Parkinson Disease and Lewy Body Dementia
Parkinson disease (PD) is characterized by loss of pigmented dopaminergic neurons in the substantia nigra pars compacta and accumulation of alpha-synuclein in Lewy bodies and Lewy neurites. Lewy bodies are eosinophilic, round intracytoplasmic inclusions in surviving nigral neurons. On IHC, alpha-synuclein (phosphorylated at Ser129) is the definitive marker. PD pathology follows Braak stages 1-6: first in the medulla oblongata and olfactory bulb (stage 1), then pons (2), midbrain/substantia nigra (3), basal forebrain and amygdala (4), limbic cortex (5), and neocortex (6).
Dementia with Lewy bodies (DLB) shows widespread cortical Lewy bodies and Lewy neurites, often with concurrent Alzheimer pathology. The diagnostic criteria require alpha-synuclein IHC for accurate detection — H&E alone misses cortical Lewy bodies.
Frontotemporal Lobar Degeneration (FTLD)
FTLD is a heterogeneous group of diseases characterized by focal atrophy of the frontal and temporal lobes. The major pathological subtypes are defined by the accumulating protein:
FTLD-tau — tau aggregates without Aβ plaques (Pick disease — tau-positive Pick bodies; corticobasal degeneration; progressive supranuclear palsy). FTLD-TDP (TDP-43 proteinopathy) — the most common FTLD subtype, associated with ALS in 50% of cases. FTLD-FUS — FUS protein aggregates (atypical FTLD with FUS pathology).
Other Neurodegenerative Diseases
Huntington disease — CAG repeat expansion in the HTT gene causes selective loss of medium spiny neurons in the striatum. Pathology shows striatal atrophy with reactive astrogliosis and mutant huntingtin aggregates detected by IHC (EM48 antibody).
Amyotrophic lateral sclerosis (ALS) — degeneration of upper and lower motor neurons. Pathology shows loss of Betz cells (motor cortex), loss of anterior horn cells (spinal cord), and corticospinal tract degeneration. TDP-43 cytoplasmic aggregates in motor neurons are the pathological hallmark of sporadic ALS (97% of cases). In situ hybridization can detect C9orf72 repeat expansions in familial ALS.
Prion diseases — Creutzfeldt-Jakob disease (CJD) shows spongiform vacuolation of the neuropil, neuronal loss, and astrogliosis. Prion protein (PrPSc) is detected by IHC (3F4 antibody) after formic acid pretreatment. Western blot or enzyme histochemistry for protease-resistant PrPSc confirms the diagnosis.
Brain Banking and Research
Postmortem brain donation is essential for neurodegenerative disease research. Brain banking protocols include: rapid autopsy (ideally <24 hours postmortem), standardized dissection with freezing of one hemisphere at -80°C, formalin fixation of the other hemisphere for histology, and comprehensive neuropathological assessment using standardized protocols (NIA-AA for AD, NINDS for PD, consensus criteria for FTLD). Clinical-pathological correlation with antemortem imaging and cognitive testing completes the diagnosis. Quality assurance programs include inter-laboratory comparisons of diagnostic criteria and IHC protocols.
