Neurodegenerative diseases

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Neurodegenerative diseases is a big part of neuropathology. It includes some discussion of dementia.


  • Neurodegenerative disease = essentially progressive and selective neuron loss.
  • Clinically, they are not unique, e.g. dementia can be caused by several diseases (with different molecular etiologies).
    • Each syndrome (e.g. dementia, parkinsonism, ataxia) has a most common etiology and a DDx.
  • They are defined by molecular pathology.[1]
    • The diseases are due to the accumulation of abnormal protein.
      • The amino acid sequence of the protein may be completely normal. The problem may just be folding/protein conformation.

Molecular schema of neurodegenerative disorders:[1]


Common diseases


  • Alzheimer disease (Abeta).

'Pure' tauopathies:


TDP-43 proteinopathies:

FET proteinopathies:

  • Basophilic inclusion body disease (BIBD).
  • Neuronal intermediate filament inclusion disease (NIFID).
  • Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (atypical FTLD-U).


  • Creutzfeldt-Jakob disease (PrP).

Note: Some people consider α-synuclein as a prion-like protein.[3]


Disease/pathology/clinical correlation based on Dickson:[1]

Disease Deposited protein Distribution Clinical Histology Image
Alzheimer disease Abeta (mutated APP) corticolimbic, usu.
spares occipital
dementia plaques, neurofibrillary tangles [1]
Creutzfeldt-Jakob disease PrPres (mutated PrP) cortical & basal ganglia dementia (rapid progression),
movement disorder
cytoplasmic vacuolization, PrP+ve plaques, Kuru plaques (MV2 variant) [2]
Parkinson disease alpha-synuclein brainstem parkinsonism Lewy bodies in substantia nigra and locus coeruleus [3] [4]
Dementia with
Lewy bodies
alpha-synuclein corticolimbic, brainstem dementia + parkinsonism Lewy bodies brainstem and cortical, tangles [5] [6]
Multiple system atrophy alpha-synuclein basal ganglia, brainstem, cerebellum parkinsonism, ataxia Papp-Lantos inclusions (cytoplasmic deposits in oligodendrocytes)[4] [7]
Amyotrophic lateral
sclerosis (ALS)
TDP-43 motor neurons spasticity, weakness motor neuron loss, TDP-43+ve, TAF15-ve, EWS-ve inclusions in motor neurons [8]
Frontotemporal lobar
degeneration with TDP-43 (FTLD-TDP)
TDP-43 cortex, basal ganglia dementia, focal cortical syndromes histology depends on (type 1-4), ubiquitin and TDP-43+ve, tau and FUS-ve [9]
Frontotemporal lobar
degeneration with FET (FTLD-FET)
FUS/EWS/TAF15 cortex, medulla, hippocampus, and motor cells of the spinal cord dementia, cases classified as aFTLD-U, NIFID and BIBD FUS+ve, TAF15+ve, EWS+ve cytoplasmic & intranuclear inclusions, neuritic threads [10]
Progressive supranuclear palsy (FTLD-tau) tau 4R basal ganglia, brainstem atypical parkinsonism with early gait instability, falls, and supranuclear gaze palsy tau-positive globose neurofibrillary tangles
in neurons, tufted astrocytes, coiled bodies
in oligodendrocytes
Pick disease (FTLD-tau) tau 3R corticolimbic dementia + focal
cortical syndrome
Intraneuronal argyrophilic inclusions (Pick body) [12]
Corticobasal degeneration (CBD) (FTLD-tau) tau 4R cortical, basal ganglia dementia + movement disorder (Parkinson-plus syndrome) ballooned neurons, astrocytic plaques, pretangles in basal nucleus [13]
Argryophilic grain disease (AGD) (FTLD-tau) tau 4R medial temporal lobe, limbic structures late-onset amnestic syndrome Argyrophilic grains (also found unspecific in elederly) [14]



Look for:

  • Lewy bodies (seen in Parkinson's Disease (PD), Dementia with Lewy bodies (DLB)) = round cytoplasmic eosinophilic body +/- pale halo.
  • Lewy neurites(seen in PD and DLB) = abnormal neurites with filaments similar to those found in Lewy bodies.
  • Glial cytoplasmatic inclusions (Papp-Lantos bodies) seen in mutisystem atrophy (MSA).
  • Beta amyloid in vessels seen in cerebral amyloid angiopathy (CAA).


  • AT8 = stains phosphorylated tau.[5]
    • AT = anti-tau.
    • Stains tau 4R and tau 3R.[6]


  • May accumulate due to a progranulin mutation.



  • Marks proteins for recycling.
  • Stains Barr bodies in hippocampal granule cells[9]


  • p62; poli-ubiquitin-binding protein p62.[5]


Look for:

  • Lewy bodies and extracellular pigment in neuromelanin-containing nuclei (SN, LC, DVN) -> PD.
  • Spongiform vacuolation in the neuropil (seen in Prion disease and FTLD-TDP).
  • Neurofibrillar tangles (pyramidal layer of dentate gyrus).
  • Granulovacuolar degeneration (granules within cytoplasmic vacuoles, mainly in the hippocampal pyramidal neurons, seen in AD).
  • Cores of amyloid plaqyes.
  • Cotton wool plaques (seen in familiar AD).
  • Pick cells (balloned neurons in frontal cortex).
  • Pick bodies (granular layer of dentate gyrus).
  • Extensive astrogliosis (striatonigral degeneration, hepatic encephalopathy).
  • Corpora amylacea in the cornu ammonis may be increased in neurodegenerative diseases. [10]

Clinical perspective

  • Correlations between clinical signs and molecular can be poor.
    • Example: The MAPT A152T gene mutation may cause clinical symptoms matching AD, CBD, PSP and LBD.[11]

Dementia general (mostly useless) DDx

  • Alzheimer's dementia - most common.
  • Vascular.
    • Multi-infarct dementia.
  • Parkinson's associated dementia.
  • Lewy body dementia.
  • Alcohol-related dementia.
  • Fronto-temporal dementia (Pick disease).
  • Multisystem atrophy.


Dementia mnemonic VITAMIN D VEST:[12]

  • Vitamin deficiency (B12, folate, thiamine).
  • Infection (HIV).
  • Trauma.
  • Anoxia.
  • Metabolic (Diabetes).
  • Intracranial tumour.
  • Normal pressure hydrocephalus.
  • Degenerative (Alzheimer's, Huntington's, CJD).
  • Vascular.
  • Endocrine.
  • Space occupying lesion (chronic subdural hematoma).
  • Toxins (alcohol).

Functional anatomy of dementia

  • Hippocampus (essential for forming new memories).
  • Frontal lobe (essential for retrieval of memories).

Parkinsonism causes


Alzheimer disease


  • Onset: episodic memory loss.
  • Diagnosis is clinical & pathologic.
    • Pathologic finding alone are not diagnostic.
    • Onset, rate of progression and the development of pathology are highly variable.
  • Defined by:
    • Pathological accumulation of amyloid β (Aβ) into extracellular plaques.
    • Abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs).
    • Clinicopathological correlation better for NFT than for Aβ.[21]
  • Seen in conjunction with vascular amyloid deposition; see cerebral amyloid angiopathy.
  • Evidence of possible iatrogenic transmission by cadaver-sourced growth hormone batches.[22][23]


Genes associated with Alzheimer disease:[24]

  • Amyloid precursor protein (APP).
    • On chromosome 21 - may explain why Trisomy 21 (Down syndrome) increases the risk of Alzheimer disease.[25]
  • Presenilin 1 (PSEN1).[26]
  • Presenilin 2 (PSEN2).[27]
  • Apolipoprotein E (APOE)[28] - specifically the epsilon-4 allele.



  • Temporal atrophy, esp. hippocampus.
  • Dilation of:
    • Lateral ventricles.
    • Third ventricle.

Gross/microscopic - disease spread by NF tangles (staging):[29]

  • Alzheimer "spreads" in a reproducible pattern:
    • Stage I-II: entorhinal cortex.
    • Stage III-IV: inferior aspect of brain.
    • Stage V-VI: limbic system.

Minimal sampling:

  • Frontal, parietal & temporal lobe
  • Hippocampus and entorhinal cortex

Additional sampling:

  • Basal ganglia
  • Cerebellum
  • Midbrain (including substantia nigra)
  • Occipital cortex




  1. Neurofibrillary tangles.
  2. Senile plaques (AKA neuritic plaques).
    • Consists of two components:
      1. Centre - radiates.
        • Consists of Abeta amyloid
      2. Neurites - swollen axons.
    • Considered to be more specific for Alzheimer's than NF tangles.
      • How to remember: senile plaques = specific.
    • There is a CERAD staging system for senile plaque load: 0 (none), I (mild), II (moderate), III (severe).[34]
    • Images: senile plaques ([35] senile plaques - beta-APP - high mag. (WC).
  3. Neuron loss.
  4. +/-Cerebral amyloid angiopathy.



NIA/AA Guidelines: "ABC" scoring method [36]

  • (A) assessment of amyloid b deposits
  • (B) staging of neurofibrillary tangles
  • (C) scoring of neuritic plaques
(A) abeta plaques (Thal phase)[37] (B) Neurofibrillary tangles (Braak stage) [38] (C) neuritic plaques (CERAD) [39]
(A0) 0 (B0) 0 (C0) none
(A1) 1 (temporal),2 (+frontal, +CA1) (B1) I,II (transentorhinal) (C1) sparse (1–5 neuritic plaques/1 mm2)
(A2) 3 (+diencephalon, +striatum) (B2) III,IV (limbic) (C2) moderate(6–19 neuritic plaques/1 mm2)
(A3) 4 (+brainstem),5 (+cerebellum, +pons) (B3) V,VI (neocortical) (C3) frequent(>20 neuritic plaques/1 mm2)

The ABC score is a good indicator for the likelihood of dementia.

Example: Cerebellar abeta deposits (A3) + tangles in entorhinal cortex and few temporal (B2), + 15 neuritic plaques per 1 mm2 (C2) -> (A3, B3, C2): intermediate AD level change.


  • Abeta amyloid:
    • Derived from amyloid precursor protein (APP).
      • APP:
        • Rapid axonal transport - useful as a marker of axonal injury.
        • Function currently not known.
  • Tau:
    • Important in microtubule assembly.

Prion diseases



  • Misfolded cell-surface protein called PrPSC.
    • This is derived from the protein PrPC encoded by the PRNP gene.
  • Different genetics strains are associated with varying clinical phenotype.[41]


  • Creutzfeldt-Jakob disease (CJD).
  • Sporadic fatal insomnia (sFI).[40]
  • Fatal familial insomnia (FFI).[42][43]
  • Gestmann-Straussler-Scheinker syndrome (GSS) - due to PRNP gene mutations.[44]



  • Congo red +ve.
  • PAS +ve.

Creutzfeldt-Jakob disease

  • Commonly abbreviated as CJD.


  • Rare.
  • Incurable disease.

Usually diagnosed clinically:

  • Characteristic findings:
    • Very rapid decline (3-4 months).
    • Characteristic (cortex findings on) neuroradiology.

Variant Creutzfeldt-Jakob disease

  • Abbreviated vCJD.
  • Associated with bovine spongiform encephalopathy (AKA mad cow disease).
  • Should sample: spleen, lymph nodes, tonsils.[45]



  • Spongy appearance (cytoplasmic vacuolization[46]).



  • The CJD phenotype is associated with a PRNP D178N mutation and valine polymorphism at codon 129 (D178N-129V).
    • Note: A Met129 polymorphism will cause Fatal familiar insomnia in the setting of the same PRNP D178N mutation. [48]


Without clincial information Parkinson's disease and Dementia with Lewy bodies cannot separated in histology.

Dementia with Lewy bodies


Clinical features:

  • Parkinsonian features.
  • Hallucinations (visual).
  • Progressive cognitive decline with fluctuations.



Note: Cortical Lewy bodies are easily missed in HE.


  • Alpha-synuclein +ve.


Parkinson disease


  • Common - often sporadic.
  • May be genetic.

Clinical TRAP:[49]

  • Tremor.
  • Rigidity.
  • Akinesia.
  • Postural instability.


  • LRRK2 gene[51] - autosomal dominant.
  • PARK2 gene (parkin)[52] - autosomal recessive.



  • Abnormally pale substantia nigra.
    • Pigmentation increases with age.
  • Pale locus ceruleus.




  • Loss of pigmented (catecholaminergic) neurons in the substantia nigra and locus ceruleus.
  • Gliosis - due to neuron loss.
  • Lewy bodies (in remaining neurons) - key feature.
    • Eosinophilic cytoplasmic inclusion with "dense" (darker) core and pale (surrounding) halo.
      • Consist of filaments composed of alpha-synuclein.
  • Lewy neurites - alpha-synuclein positive processes.


  • Alpha-synuclein +ve.



  • Hereditary forms in less than 10% of the cases
    • Involved genes are consecutively labeled PARK1, PARK2....

Multiple system atrophy

Multiple system atrophy is a neurodegenerative disease of the parkinsonism-plus disorder group.


Clinical findings variable:

  • Parkinsonism (stiatonigral degeneration, MSA-P).
  • Ataxia (olivo-ponto-cerebellar degeneration, MSA-C).
  • Autonomic dysfunction (Shy-Drager syndrome, depreceated).
  • Clinical onset between 40-60 years.
  • Progedient tremor, atxia, laryngeal paresis, wakness, cognitive decline.
  • Patients usually succumb after 6 years from aspiration pneumonia.





  • Inclusions cerebral, subcortical white matter, cerebellar.
  • Neuronal loss and gliosis (absent in minimal-change MSA).
  • Alpha-synuclein-rich glial and neuronal cytoplasmic inclusions in white matter (finding at autopsy).[54]
    • Inclusions in oligodendrocytes (triangular, flame-like or sickle-shaped) are definitive diagnostic for MSA.[55][56]
    • Inclusions usu. abundant in basal ganglia, substantia nigra, pontine nuclei, medulla and cerebellum.
  • Pons and Putamen:
    • Nuclear inclusions (sparse in most cases).
    • Neuropil threads (alpha-synuclein).
  • Loss of myelinated fibers from external capsule, striatum and pallidum.



  • No known alpha-synuclein mutation.
  • Genetic variants of SNCA gene assoicated with MSA. [57]


More than 20 different degenerative disorders can be classified as tauopathies.[58] FTLD-tau is an umbrella term used for tauopathies including PSP, CBD, PiD and GGT. [59]

Argyrophilic grain disease

Corticobasal degeneration

  • AKA CBD.
  • Symptoms may vary:
    • Progressive asymmetrical rigidity and apraxia, progressive aphasia or dementia.
  • Neuronal and glial Tau-positive inclusions.[60]
    • Astrocytic plaques.
    • Thread-like lesions and coiled bodies.
    • Ballooned neurons +/-.
  • Pathology is cortical and striatal and Gallyas-positive.
  • Neuronal loss in the substantia nigra.

DD: PSP (widespread neurofibrillary degeneration, with characteristic globose NFT).

Globular glial tauopathies

  • Commonly abbreviated GGT.
  • AKA sporadic multiple system tauopathy.
  • Rare disease.[61]
  • Combination of frontotemporal dementia and motor neuron disease or only part thereof.
  • 4-repeat tauopathy.


  • Globular oligodendroglial and astrocytic Tau inclusions.
  • Absence of tufted astrocytes.
  • Mostly Gallyas-negative.

Progressive supranuclear palsy

  • Commonly abbreviated PSP.
  • AKA Steele-Richardson-Olszewski syndrome.


  • Diagnosis - clinical.[62]


  • Impaired control of gaze, esp. difficulty looking up and down (supranuclear palsy).[63]
  • Parkinsonism.[15]



  • Globose neurofibrillary tangles in neurons.
  • Coiled bodies in oligodendrocytes.
    • Wire coil-like structure around the nucleus.
  • Tufted astrocytes.
    • Near impossible to see without IHC - specifically AT8.
    • Cellular processes filled with crap.
    • Star-like appearance; looks like a road network where all the roads lead to one place (Parisian star).
  • Grumose degeneration of the cerebellar dentate nucleus.
    • Granular eosinophilic material adjacent to nuclei; once thought to be pathognomonic for PSP.[65][66]


Pick disease


  • Dementia.


  • Frontal and temporal lobe atrophy.[67]
    • May be called "walnut brain"[68] - as it resembles a walnut.



  • Pick cells = large ballooned neurons.
  • Pick bodies = round, homogenous, intracytoplasmic inclusions, size ~10 micrometers.


TDP Proteinopathies


  • Accounts for about 50% of all FTLD cases.
  • Degeneration of frontal and temporal lobes.
  • Inclusions not seen in HE or silver stains.
  • TDP43-positive
    • Neuronal cytoplasmic inclusions.
    • Neuronal intranuclear inclusions.
    • Dystrophic neurites.
  • Ubiquitin+ve.
  • p62+ve.
  • aSynculein-ve.
  • Tau-ve.
  • FUS-ve.
  • Four FTLD-TDP subtypes
    • Type A: compact nuclear/cytoplasmatic inclusions, associated with GRN mutations.
    • Type B: diffuse nuclear/cytoplasmatic inclusions most often seen in C9orf72 expansion.
    • Type C: dystrophic neurites.
    • Type D: Lentiform nuclear inclusions, only in cases with VCP mutations.
  • C9orf72 mutated show additional DPR+ve staining of TDP‐43‐ve inclusions.
    • These addtional inclusions are ubiquitin+ve and p62+ve


  • Clinical manifestations depend on the distribution of the pathologic alterations in the CNS
  • Currently 3 disorders among the FTLD-FET subgroup.
  • In contrast to ALS-FUS, no genetic alterations of FUS have been reported to date for cases within the FTLD-FUS group.
  • 5–10% of all FTLD cases
  • Deposited Proteins: FUS, EWS, TAF-15.
  • FUS‐positive inclusions in FTLD cases show co‐aggregation of TAF15 and EWS
    • (Different from ALS-FUS)

DDx (also FUS+ve):

  • Spinocerebellar Ataxia (SCA)
  • Huntington Disease (SD)

Atypical FTLD‐U

  • Early onset frontotemporal dementia, rapidly progressive psycho‐behavioural changes.
  • Neuronal cytoplasmic inclusions in hippocampus and frontotemporal lobes.
  • Ubiquitin+ve, tau/TDP‐ve.
  • FET+ve inclusions
    • Unique vermiform filamentous neuronal nuclear inclusions.
  • Caudate nucleus head degeneration and hippocampal sclerosis.

Basophilic inclusion body disease

  • AKA: BIBD.
  • Variable clinic (behavioral, cognitive alterations, parkinsonism, motor neuron diseases, ALS-like).
  • Age of onset: 35-70 years.
  • Intraneuronal cytoplasmic basophilic inclusion bodies.
  • FUS+ve (universally).
  • EWS+ve.
  • TAF15+ve.
  • alpha-Internexin+ve.

Neuronal Intermediate Filament Inclusion Disease

  • Sporadic early‐onset frontotemporal dementia, motor neuron disease, extrapyramidal motor symptoms.
  • Hyaline conglomerates (brightly eosinophilic branching fibrillar structures embedded in a round, well-delineated, glassy vacuole).
  • Deposits in cerebral cortex, hippocampus, basal ganglia, thalamus, cerebellar dentate, numerous brainstem nuclei and lower motor neurons.
  • FUS+ve/EWS+ve/TAF15+ve (heterogenous).
    • FET+ve filamentous nuclear inclusions in the hippocampus.
  • Ubiquitin +/-ve.
  • NF +ve (some subunits).
  • p62 +/-ve.
  • TDP43-ve.
  • Tau-ve.
  • α-synuclein-ve.


Chronic traumatic encephalopathy

  • Abbreviated CTE.

Huntington disease


  • Autosomal dominant inheritance.
  • Mutation in Huntington gene (HTT):[70]
    • 11-34 CAG repeat = normal.[71]
    • >42 CAG repeat = Huntington disease.


  • Early onset dementia.
  • Involuntary movements (chorea) - both arms and legs.
  • Behaviour changes, e.g. grimacing.
  • Speech changes.


  • Severe caudate atrophy.[73]
    • Prominent frontal horns of the lateral ventricles.[74]


  • A normal caudate bulges into the ventricle.




  • Neuron loss.
  • Gliosis.

Binswanger disease


  • Multi-infarct dementia affecting subcortical white matter.
  • Waste-basket diagnosis; diagnosed if CADASIL and amyloidosis have been excluded.
  • Diagnosis has been controversial -- most with this entity (in the past) were diagnosed with Alzheimer's disease.



  • Subcortical lesions that replace the myelin consisting of macrophages.

Frontotemporal lobar degeneration with ubiquitinated inclusions

Abbreviated FTLD with ubiquitinated inclusions or FTLD-TDP43.


  • There are several forms of frontotemporal dementia.
  • Related to amyotrophic lateral sclerosis (ALS); also a TDP-43 pathology.[75]
    • There are several subtypes of FTLD with TDP-43.


  • Frontal and temporal lobe atrophy.


Amyotrophic lateral sclerosis

  • Abbreviated ALS.


  • AKA Lou Gehrig's disease.
  • Characterized by motor neuron death.
  • May be familial and associated with C9orf72 expansion, or SOD1, FUS and TARDBP mutations.[76][77]
  • Pathological protein aggregates cause dysfunction of RNA-binding proteins.


  • Peak incidence: 50-60yrs.
  • 2-5 per 100,000 individuals worldwide.
  • Dead after disease onset: Usu. 2-5yrs.
  • Weakness (Progressive bulbar, limb, thoracic, and abdominal muscle atrophy).
  • About 20% of ALS cases develop frontotemporal lobar degeneration (FTLD).
  • Environmental toxins are discussed (Guam ALS).[78]



  • Loss of the giant cells of Betz.
  • Motor neurons with eosinophilic inclusions (Bunina bodies).
    • PAS positive cytoplasmic inclusions.
  • Motor neuron loss + reactive gliosis + neurogenic muscular atrophy.
    • Loss of myelinated axons in the lateral and anterior columns of the spinal cord.
  • Ubiquitinated cytoplasmic inclusions.[80]
  • TDP-43 proteinopathy in motor neurons (90% of all sporadic ALS cases).
  • C9orf72 expansion cases: p62+ve, TDP-43-ve inclusions in the dentate gyrus, neocortex, and cerebellum.[82]
    • FUS-mutant cases show FUS+ve, p62+ve (few) and TDP-43-ve inclusions.[83]



  • Spinal muscular atrophy.
  • Primary Lateral Sclerosis.
  • Hereditary Spastic Paraparesis (HSP).

Hallervorden-Spatz disease

  • AKA pantothenate kinase-associated neurodegeneration.


  • Uncommon.



  • Axonal spheroids.
  • Iron deposition.



  • Prussian blue +ve.

See also


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