Neurodegenerative diseases

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

Overview

• 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.
  • 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:

Neurodegenerative disorders

Amyloidoses

Tauopathies

α-synucleinopathies

TDP-43

FUS

Common diseases

Amyloidoses:

• Alzheimer disease (Abeta).

'Pure' tauopathies:

• Progressive supranuclear palsy.
• Pick's disease.
• Corticobasal degeneration.
• FTDP-17.
• Dementia pugilistica.

Synucleinopathies:

• Parkinson disease.
• Dementia with Lewy bodies.
• Multiple system atrophy.

TDP-43 proteinopathies:

• Amyotrophic lateral sclerosis.
• Frontotemporal lobar degeneration with TDP-43 (FTLD-TDP).

FUS proteinopathies:

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

Prionopathies:

• Creutzfeldt-Jakob disease (PrP).

Table

Disease/pathology/clinical correlation based on Dickson:

Disease	Mutated 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)	[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 FUS (FTLD-FUS)	FUS	cortex, medulla, hippocampus, and motor cells of the spinal cord	dementia, cases classified as FTLD-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	[11]
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]

Immunohistochemistry

Alpha-synuclein

Look for:

• Lewy bodies (seen in Parkinson's d., Dementia with Lewy bodies) = round cytoplasmic eosinophilic body +/- pale halo.
• Glial cytoplasmatic inclusions (Papp-Lantos bodies) seen in MSA.

Tau

• AT8 = stains phosphorylated tau.
  • AT = anti-tau.
  • Stains tau 4R and tau 3R.

TDP-43

• May accumulate due to a progranulin mutation.

Microscopic

• TDP-43 - normally in the nucleus.
  • Pathologic: Micrograph (label B) - neurites, skein-like formations (ama-assn.org)
    • Fibrillar or skein-like formations = cytoplasmic staining.
      • "Skein" = yarn or thread wound on a reel or flock of birds in flight.
    • Neurites = "squiggly appearance"; "worm-like appearance".

Ubiquitin

• Marks proteins for recycling.

Microscopic

• p62; poli-ubiquitin-binding protein p62.

Look for:

• Lewy bodies. (???)

Clinical perspective

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.

Mnemonic

Dementia mnemonic VITAMIN D VEST:

• 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

• Parkinson's disease
• Dementia with Lewy bodies.
• Multiple system atrophy (MSA).
• Progressive supranuclear palsy (PSP).
• Drug induced (valproic acid, MPTP).
• Vascular.
• Postencephalitic.
• Tramuatic (Dementia pugilistica).

Amyloidoses

Alzheimer disease

General

• 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.
• Seen in conjunction with vascular amyloid deposition; see cerebral amyloid angiopathy.
• Evidence of possible iatrogenic transmission by cadaver-sourced growth hormone batches.

Genetics

Genes associated with Alzheimer disease:

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

Gross

Features:

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

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

• 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

Images

• 

  Alzheimer's brain. (WC/NIH)

• 

  Alzheimer's brain macroscopy (top) vs control (bottom). (WC/Hersenbank)

• 

  Alois Alzheimer provided a first description of the pathology. (NLM)

Microscopic

Features:

1. Neurofibrillary tangles.
   • Consists of tau.
   • Location: hippocampus, cerebral cortex, hypothalamus.
   • Dementia severity correlates better with NF tangles number than senile plaque number.
   • Six-tiered scoring method to assess tangle load
   • Images: tangles - schematic (pakmed.net), tangle (washington.edu).
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).
   • Images: senile plaques (utah.edu) senile plaques - beta-APP - high mag. (WC).
3. Neuron loss.
4. +/-Cerebral amyloid angiopathy.

Images

• 

  Neuritic plaques with amyloid core in HE. (WC/jensflorian)

• 

  Neuritic plaques in Gallays silver impregnation. (WC/jensflorian)

• 

  Neuritic plaques with amyloid core in Bodian stain. (WC/KGH)

• 

  Plaques with Abeta IHC. (WC/Nephron)

• 

  Neurofibrillary tangles in HE. (WC/Patho)

• 

  Tau IHC highlighting tangles. (WC/Patho)

• 

  Tangles in Gallays silver impregnation.(WC/Patho)

• 

  HE stain with ghost tangles and Hirano bodies in AD. (WC/Patho)

• 

  HE stain with granulovaculolar degeneration in AD. (WC/Patho)

Classification

NIA/AA Guidelines: "ABC" scoring method

• (A) assessment of amyloid b deposits
• (B) staging of neurofibrillary tangles
• (C) scoring of neuritic plaques

(A) abeta plaques (Thal phase)	(B) Neurofibrillary tangles (Braak stage)	(C) neuritic plaques (CERAD)
(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.

Notes:

• 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

General

Etiology:

• Misfolded cell-surface protein called PrP^SC.
  • This is derived from the protein PrP^C encoded by the PRNP gene.

Includes:

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

IHC

PrP^C:

• Congo red +ve.
• PAS +ve.

Creutzfeldt-Jakob disease

• Commonly abbreviated as CJD.

General

• 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.

General

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

Microscopic

Features:

• Spongy appearance (cytoplasmic vacuolization).

Note:

• Spongiform changes may be seen in ALS, Alzheimer's disease and Lewy body disease (e.g. Parkinson disease); however, the changes are only in the upper cortex and not diffuse.

• 

  CJD. (WC/DRdoubleB)

• 

  Spongiform changes in CJD. (CDC/ Teresa Hammett)

• 

  Florid plaques in vCJD. (WC/Sbrandner)

• 

  Florid plaques in vCJD - low mag. (WC/CDC.gov)

• 

  vCJD - prion protein immunostain tonsil. (WC/Sbrandner)

• 

  sCJD - prion protein immunostain cortex. (WC/jensflorian)

• 

  sCJD - prion protein immunostain cerebellum. (WC/jensflorian)

• CJD - several cases (upmc.edu).

Alpha-synucleinopathies

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

Dementia with Lewy bodies

General

Clinical features:

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

Microscopic

Features:

• Lewy bodies.
• Lewy neurites.

Note: Cortical Lewy bodies are easily missed in HE.

IHC

• Alpha-synuclein +ve.

Images

• 

  Lewy bodies in frontal cortex of DLB. (WC/jensflorian)

• 

  Alpha-synculein IHC showing cortical Lewy bodies. (WC/jensflorian)

• 

  Alpha-synculein IHC showing Lewy Neurites in DLB. (WC/jensflorian)

Parkinson disease

General

• Common - often sporadic.
• May be genetic.

Clinical TRAP:

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

Genetics:

• LRRK2 gene - autosomal dominant.
• PARK2 gene (parkin) - autosomal recessive.

Gross

Features:

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

Notes:

• Substantia nigra is a midbrain structure.
  • Image: Midbrain - schematic (WC).

Microscopic

Features:

• 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.

IHC

• Alpha-synuclein +ve.

Images

• 

  Schematic progression of PD (PLOSone/Jubault et al.).

• 

  Lewy body (HE, left) and Lewy neurite (aSyn IHC, right).

• 

  Alpha-synculein positive Lewy body (WC/Marvin101).

• 

  Lewy body and Lewy neurites (WC/Suraj Rajan).

Molecular

• 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.

General

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.

DDx:

• Spinocerebellar ataxia.
• Parkinson disease.
• Motor-neuron disease.
• Lewy-Body disease.

Macroscopy

• Cerebral (mild) & cerebellar atrophy.
• greenish putamen.
• Discoloration Substantia nigra and Locus coeruleus

Microscopic

Features:

• 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).
  • Inclusions in oligodendrocytes (triangular, flame-like or sickle-shaped) are definitive diagnostic for MSA.
  • 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.

Images

• 

  Gray-brown discoloration in putamen of a striatonigral-type MSA (WC/jensflorian).

• 

  Gallays silver stain showing MSA-typic inclusions (WC/jensflorian).

• 

  a-synuclein IHC showing Glial and neuronal cytoplasmic inclusion in the pons of a MSA case (WC/jensflorian).

Molecular

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

Tauopathies

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

Corticobasal degeneration

• AKA CBD.
• Symptoms may vary:
  • Progressive asymmetrical rigidity and apraxia, progressive aphasia or dementia.
• Neuronal and glial Tau-positive inclusions.
  • 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.
• Combination of frontotemporal dementia and motor neuron disease or only part thereof.
• 4-repeat tauopathy.

Microscopic

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

Progressive supranuclear palsy

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

General

• Diagnosis - clinical.

Clinical:

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

Microscopic

Features:

• 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.

Images:

• PSP - several images (upmc.edu).

Pick disease

General

• Dementia.

Gross

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

Microscopic

Features:

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

Image(s):

• Pick body (nature.com).

FTLD-FET

• 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

• Neuronal cytoplasmic inclusions in hippocampus and frontotemporal lobes.

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).
• TAF15+ve
• alpha-Internexin+ve.

Neuronal Intermediate Filament Inclusion Disease

• AKA: NIFID.
• Hyaline conglomerates (brightly eosinophilic branching fibrillar structures embedded in a round, well-delineated, glassy vacuole).
• FUS+ve (heterogenous).
• Ubiquitin +/-ve.
• NF +ve (some subunits).
• p62 +/-ve.
• TDP43-ve.
• Tau-ve.
• α-synuclein-ve.

Other

Chronic traumatic encephalopathy

• Abbreviated CTE.

Main article: Chronic traumatic encephalopathy

Huntington disease

General

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

Clinical:

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

Gross

• Severe caudate atrophy.
  • Prominent frontal horns of the lateral ventricles.

Note:

• A normal caudate bulges into the ventricle.

Images:

• Huntington's disease (ouhsc.edu).
• Prominent frontal horns of the lateral ventricles (upmc.edu).

Microscopic

Features:

• Neuron loss.
• Gliosis.

Binswanger disease

General

• 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.

Microscopic

Features:

• Subcortical lesions that replace the myelin consisting of macrophages.

Frontotemporal lobar degeneration with ubiquitinated inclusions

Abbreviated FTLD with ubiquitinated inclusions or FTLD-TDP43.

General

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

Gross

• Frontal and temporal lobe atrophy.

Image:

• FTLD (WC).

Amyotrophic lateral sclerosis

• Abbreviated ALS.

General

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

Clinical

• 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).

Microscopic

Features:

• 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.
• TDP-43 proteinopathy in motor neurons (90% of all sporadic ALS cases).
  • SOD1-mutant cases are TDP-43-ve.
• C9orf72 expansion cases: p62+ve, TDP-43-ve inclusions in the dentate gyrus, neocortex, and cerebellum.
  • FUS-mutant cases show FUS+ve, p62+ve (few) and TDP-43-ve inclusions.

Images:

• Bunina body (umin.ac.jp).
• Bunina body (duke.edu).
• ALS - several images (upmc.edu).

• 

  Motor neuron loss in ALS-TDP. (WC)

• 

  pTDP-43 positive inclusions in neurons. (WC)

DDx:

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

Hallervorden-Spatz disease

• AKA pantothenate kinase-associated neurodegeneration.

General

• Uncommon.

Microscopic

Features:

• Axonal spheroids.
• Iron deposition.

Images:

• HSD - several images (upmc.edu).

Stains

• Prussian blue +ve.

See also

• Neuropathology.
• Neurohistology.