Neurodegenerative diseases

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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.[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]

 
 
 
 
 
 
Neurodegenerative
disorders
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amyloidoses
 
Tauopathies
 
α-synucleinopathies
 
TDP-43
 

Common diseases

Amyloidoses:

  • Alzheimer disease (Abeta).

'Pure' tauopathies:

Synucleinopathies:[2]

TDP-43 proteinopathies:

FUS proteinopathies:

Prionopathies:

  • Creutzfeldt-Jakob disease (PrP).

Table

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

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 [2]
Progressive supranuclear palsy 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
Image?
Pick disease tau 3R corticolimbic dementia + focal
cortical syndrome
Pick body ??? Image?
Parkinson disease alpha-synuclein brainstem parkinsonism Lewy bodies [3]
Dementia with
Lewy bodies
alpha-synuclein corticolimbic, brainstem dementia + parkinsonism Lewy bodies [4]
Multiple system atrophy alpha-synuclein basal ganglia, brainstem, cerebellum parkinsonism, ataxia cytoplasmic inclusion in oligodendrocytes[3] Image
Amyotrophic lateral
sclerosis (ALS)
TDP-43 motor neurons spasticity, weakness histology? Image
Frontotemporal lobar
degeneration (FTLD)
TDP-43 cortex, basal ganglia dementia, focal cortical syndromes histology? Image?

Immunohistochemistry

Alpha-synuclein

Look for:

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

Tau

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

TDP-43

  • May accumulate due to a progranulin mutation.

Microscopic

Ubiquitin

  • Marks proteins for recycling.

Microscopic

  • p62; poli-ubiquitin-binding protein p62.[4]

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:[8]

  • 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

Amyloidoses

Alzheimer disease

General

  • Onset: episodic memory loss.
  • Diagnosis is clinical & pathologic.
    • Pathologic finding alone are not diagnostic.
  • Seen in conjunction with vascular amyloid deposition; see cerebral amyloid angiopathy.

Genetics

Genes associated with Alzheimer disease:[13]

  • Amyloid precursor protein (APP).
    • On chromosome 21 - may explain why Trisomy 21 (Down syndrome) increases the risk of Alzheimer disease.[14]
  • Presenilin 1 (PSEN1).[15]
  • Presenilin 2 (PSEN2).[16]
  • Apolipoprotein E (APOE)[17] - 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):[18]

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

Images

Microscopic

Features:

  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 staging system for plaques I (mild), II (moderate), III (severe).
    • Images: senile plaques (utah.edu)[22] senile plaques - beta-APP - high mag. (WC).
  3. Neuron loss.
  4. +/-Cerebral amyloid angiopathy.

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:[23]

  • Misfolded cell-surface protein called PrPSC.
    • This is derived from the protein PrPC encoded by the PRNP gene.

Includes:

  • Creutzfeldt-Jakob disease (CJD).
  • Sporadic fatal insomnia (sFI).[23]
  • Fatal familial insomnia (FFI).[24][25]
  • Gestmann-Straussler-Scheinker syndrome (GSS) - due to PRNP gene mutations.[26]

IHC

PrPC:[24]

  • 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.[27]

Microscopic

Features:

  • Spongy appearance (cytoplasmic vacuolization[28]).

Note:

Images

Alpha-synucleinopathies

Includes the Lewy body diseases Parkinson's disease and Dementia with Lewy bodies.

Dementia with Lewy bodies

General

Clinical features:

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

Microscopic

Features:

IHC

  • Alpha-synuclein +ve.

Parkinson disease

General

  • Common - often sporadic.
  • May be genetic.

Clinical TRAP:[30]

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

Genetics:[31]

  • LRRK2 gene[32] - autosomal dominant.
  • PARK2 gene (parkin)[33] - autosomal recessive.

Gross

Features:[34]

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

Notes:

Microscopic

Features:[34]

  • 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.

IHC

  • Alpha-synuclein +ve.

Multiple system atrophy

General

Clinical findings variable:

  • Parkinsonism (stiatonigral degeneration).
  • Ataxia (olivo-panto-cerebellar degeneration).

Microscopic

Features:

  • Alpha-synuclein-rich glial cytoplasmic inclusions (finding at autopsy).[35]
    • Inclusions in oligodendrocytes.[36]


Tauopathies

Progressive supranuclear palsy

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

General

  • Diagnosis - clinical.[37]

Clinical:

  • Impaired control of gaze, esp. difficulty looking up and down (supranuclear palsy).[38]
  • Parkinsonism.[11]

Microscopic

Features:[1][37][39]

  • 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.[40][41]

Images:

Pick disease

General

  • Dementia.

Gross

  • Frontal and temporal lobe atrophy.[42]
    • May be called "walnut brain"[43] - as it resembles a walnut.

Microscopic

Features:[42]

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

Image(s):

Other

Chronic traumatic encephalopathy

  • Abbreviated CTE.

Huntington disease

General

  • Autosomal dominant inheritance.
  • Mutation in Huntington gene (HTT):[45]
    • 11-34 CAG repeat = normal.[46]
    • >42 CAG repeat = Huntington disease.

Clinical:[47]

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

Gross

  • Severe caudate atrophy.[48]
    • Prominent frontal horns of the lateral ventricles.[49]

Note:

  • A normal caudate bulges into the ventricle.

Images:

Microscopic

Features:[47]

  • 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.[50]
    • There are several subtypes of FTLD with TDP-43.

Gross

  • Frontal and temporal lobe atrophy.

Image:

Amyotrophic lateral sclerosis

  • Abbreviated ALS.

General

  • AKA Lou Gehrig's disease.
  • TDP-43 proteinopathy.
  • Characterized by motor neuron death.
  • May be familial and associated with SOD1 gene.[51]

Clinical:

  • Weakness.

Microscopic

Features:[51]

  • Motor neurons with Bunina bodies.
    • PAS positive cytoplasmic inclusions.
  • Motor neuron loss + reactive gliosis + neurogenic muscular atrophy.

Images:

Hallervorden-Spatz disease

  • AKA pantothenate kinase-associated neurodegeneration.

General

  • Uncommon.

Microscopic

Features:[53]

  • Axonal spheroids.
  • Iron deposition.

Images:

Stains

  • Prussian blue +ve.

See also

References

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