Pathology

Pathology/C/107

Neurodegenerative and prion diseases

神経変性疾患・プリオン病

1. Overview

  • Neurodegenerative diseases are characterized by progressive cellular degeneration of neurons, astrogliosis, and deposition of abnormal protein aggregates.
  • Dementia = development of memory impairment and loss of other cognitive functioning (thinking, reasoning, problem-solving).
  • Selective vulnerability: functionally related neuronal groups are preferentially affected.
Region affected Disease
Hippocampus + cortex Dementia (Alzheimer’s)
Basal ganglia (hypokinetic) Parkinson’s disease
Basal ganglia (hyperkinetic) Huntington’s disease
Cerebellum Ataxias
Motor system (anterior horn + corticospinal tract) ALS
  • Prion diseases are infective protein-misfolding disorders that overlap clinically with neurodegenerative dementia (rapidly progressive).

2. Alzheimer’s Disease (AD)

  • Most common cause of dementia in the elderly; incidence ↑ with age.
  • Begins as slow loss of higher intellectual function + mood/behavior changes.
  • Progresses to disorientation, memory loss, aphasia.

A) Pathogenesis

1. Aβ accumulation → neuritic (amyloid) plaques (extracellular)

  • Amyloid core = Aβ, derived from amyloid precursor protein (APP), cleaved by β-secretase and γ-secretase.
  • Mutations in APP or γ-secretase → early-onset hereditary AD (↑ rate of Aβ accumulation).
  • Effects:
    • Small aggregates → altered neurotransmission, neuronal toxicity.
    • Larger plaques → neuronal death via local inflammatory response.

2. Tau accumulation → neurofibrillary tangles (NFTs) (intracellular)

  • Composed of hyperphosphorylated tau (normally a microtubule-associated protein).
  • Eventually displace the nucleus.
  • Braak stages (post-mortem): Transentorhinal (I/II) → Limbic (III/IV) → Neocortical (V/VI).

3. Genetic risk factors

  • APOE gene polymorphisms (APOE ε4 allele → ↑ risk).

3. Parkinson’s Disease (PD)

  • Degenerative CNS disorder caused by loss of dopaminergic neurons in the substantia nigra.
  • Manifests as parkinsonism syndrome:
    • Diminished facial expression, stooped posture, bradykinesia (slowness), rigidity, resting tremor, postural instability.
  • Idiopathic PD is the most common neurodegenerative disease associated with parkinsonism.
  • Parkinsonism can also be induced by dopamine antagonists or neurotoxins (MPTP, etc.).
  • Mostly sporadic, but familial forms exist.
  • Loss of dopaminergic neurons → pallor of the substantia nigra and locus ceruleus.

A) Pathogenesis

  • Lewy bodies = intraneuronal inclusions of aggregated α-synuclein (a synaptic protein).
  • Suggests a defect in proteasomal degradation of α-synuclein.

B) Clinical features

  • Progresses over 10–15 years.
  • End-stage: severe motor slowing → near immobility, dementia, death.
  • L-DOPA (dopamine precursor) = effective symptomatic treatment, but does not alter disease progression.
  • Diagnostic criteria: (1) progressive parkinsonism without toxic cause + (2) responsiveness to L-DOPA.

4. Huntington Disease (HD)

  • Inherited autosomal dominant neurodegenerative disorder.
  • Clinically: progressive movement disorder + dementia.
  • Degeneration of the striatum (caudate nucleus + putamen).

A) Pathogenesis

  • Mutation: CAG trinucleotide repeat expansion in the gene encoding huntingtin.
  • Normal allele: 11–34 repeats; disease: up to hundreds.
  • Mechanisms:
    • Mutant huntingtin binds and sequesters transcription factors → ↓ synthesis of critical proteins.
    • Causes mitochondrial dysfunction → neurodegeneration.

B) Morphology

  • Marked atrophy of the caudate nucleus, ventricular dilation.
  • Intranuclear inclusions of ubiquitinated huntingtin.

C) Clinical features

  • Huntington’s chorea: involuntary, jerky movements of the extremities.
  • Cognitive decline, dementia.
  • Progressive, intractable; fatal after ~15 years.

5. Amyotrophic Lateral Sclerosis (ALS)

  • Neurodegenerative disease characterized by degeneration of motor neurons in the ventral (anterior) horn of the spinal cord.
  • ↓ Anterior horn neurons throughout the cord.
  • → Degeneration of descending corticospinal tracts in the lateral spinal cord = “lateral sclerosis”.
  • Also neuronal loss in motor nuclei of cranial nerves (sparing oculomotor nuclei).
  • Causes: 90% sporadic, 10% hereditary (e.g. SOD1, TDP-43).

A) Clinical features

  • Manifests in the 5th decade or later.
  • Atrophy of skeletal muscles from denervation; fasciculations (involuntary contractions of single motor units).
  • Early: asymmetric weakness of the hands (dropping objects, fine-motor difficulty), cramping, spasticity of arms/legs.
  • Dementia may occur.
  • End-stage: involvement of respiratory muscles → respiratory failure = most common cause of death.

6. Comparison Table — Neurodegenerative Diseases

Disease Region Aggregated protein Key inclusion Clinical hallmark
Alzheimer’s Hippocampus, cortex Aβ + tau Neuritic plaques + NFTs Progressive dementia
Parkinson’s Substantia nigra α-synuclein Lewy bodies Resting tremor, rigidity, bradykinesia
Huntington’s Striatum (caudate + putamen) Mutant huntingtin (CAG) Intranuclear inclusions Chorea + dementia (AD inheritance)
ALS Anterior horn + corticospinal tracts SOD1 / TDP-43 aggregates — UMN + LMN signs, fasciculations

7. Prion Diseases

  • Prions = infectious agents composed of misfolded proteins (protein-only infectivity).
  • Prion diseases = group of infective diseases affecting the structure of the brain and other neural tissue.
  • Include Creutzfeldt-Jakob disease (CJD) with subtypes:
    • sCJD (sporadic), fCJD (familial), iatrogenic CJD, variant CJD (vCJD).

A) Pathogenesis

  • Due to misfolded abnormal forms of the normal prion protein PrP^C.
  • PrP^C undergoes conformational change to PrP^Sc:
    • PrP^C: many α-helices.
    • PrP^Sc: many β-sheets.
  • PrP^Sc interacts with PrP^C → induces further misfolding (self-propagating).
  • Causes: acquired (inoculation), genetic, or idiopathic.
  • Accumulation of PrP^Sc in neural tissue → cytoplasmic vacuoles + neuronal death.

8. Creutzfeldt-Jakob Disease (CJD)

  • Degenerative brain disorder leading to dementia.
  • Peak incidence above 70 yrs; 85% sporadic (fCJD in younger patients).
  • Clinical: subtle changes in memory and behavior → rapidly progressive dementia.

A) Morphology

  • Spongiform transformation of cerebral cortex and deep nuclei.
  • Vacuoles within the neuropil and perikarya.
  • No inflammatory infiltrate.
  • Advanced: severe neuronal loss + gliosis.

B) Prognosis

  • Median survival ~7 months.

9. Variant CJD (vCJD)

  • CJD-like disease that appeared in the UK in 1995; same pathogenesis as CJD.

Differences from classic CJD

Feature Classic CJD vCJD
Age >70 yrs Young adults
Early features Memory/behavior Dominant behavioral changes
Progression Rapid (~7 mo) Slower neurological progression
Histology Spongiform only Several amyloid plaques
Spread Sporadic/genetic/iatrogenic Beef (mad cow disease) or transfusion

High-yield:

  • Alzheimer’s = Aβ plaques (extracellular) + hyperphosphorylated tau NFTs (intracellular); APP/γ-secretase mutations → early onset; APOE ε4 risk.
  • Parkinson’s = loss of dopaminergic neurons in substantia nigra + Lewy bodies of α-synuclein; L-DOPA treats symptoms only.
  • Huntington’s = AD CAG repeat in huntingtin → striatal (caudate) atrophy → chorea + dementia, fatal in ~15 yrs.
  • ALS = anterior horn + corticospinal degeneration (UMN + LMN, oculomotor spared); 90% sporadic, SOD1/TDP-43; death from respiratory failure.
  • Prions: PrP^C (α-helix) → PrP^Sc (β-sheet), self-propagating; spongiform cortex without inflammation.
  • CJD: elderly, 85% sporadic, median survival ~7 months.
  • vCJD: young adults, slower progression, amyloid plaques, spread by mad cow beef / transfusion.