Tag: neurodegenrative disease

Etiopathologenesis

Loss of Dopaminergic neurons from SUBSTANTIA NIGRA (Parkinson disease).

Destruction of SN neurons due to exposure to MPTP (1 METHYL 4 PHENYL 1,2,3,6 TRIHYDRO PYRIDINE) – contaminant of illicit opioids. (Acute Parkinsonian syndrome)

Gut-Brain hypothesis (enteric NS to medulla)

Clinical features

  • Triad (all motor – due to SN involvement)
    • Tremor (pill rolling tremor)
    • Rigidity
    • Bradykinesia
  • Responds to L-Dopa.
  • Appearance:
    • Masked face – less expression
    • Stooped posture
    • Slowing of voluntary movement (Bradykinesia)
    • FESTINATING gait

Pathology

Protein accumulation in cytoplasm, mitochondrial damage, lysosomal dysfunction (a/w Gaucher disease).

Diagnostic hallmark: Alpha Synuclein: Major component of Lewy body.
Encoded by SCNA gene.
Effect like Alzheimer’s (ABeta) – forms deposits.
Propogates like Prion (PrPsc).
Other proteins: DJ1, PINK1, PARKIN. These are involved in Mitochondrial dysfunction.

Morphology

SN – Pallor. (White)
Neuronal loss + reactive gliosis
Lewy bodies – eosinophilic irregular multiple cytoplasmic inclusions with halo.
Densely packed filaments of alpha synucelin.

Histological sample of Substantia nigra in Parkinson's disease

Autosomal dominant.

HTT gene of Chromosome 4p16.3, coding for huntingtin.

Trinucleotide repeat disease of poly–glutamine. [CAG]
Neurodegenerative disease.

Expansion of trinucleotide starts from spermatogenesis of father -> Early onset in child.

Clinical features

  • 30s – 40s. Onset and severity depends on HTT gene repeat amount.
  • Progressive movement disorder (Motor – 1st)
    • Chorea – Jerky hyperkinetic dystonic movement of whole body
    • Choreo-athetosis
  • Dementia (Cognitive – 2nd)
  • Death due to pneumonia and suicide (no cure).

Morphology

Intranuclear huntingtin inclusions. (neuroprotective mechanism of the neuron).
Stained with IHC for Ubiquitin.

Affects Striatum and Cortex neurons nearer to the ventricle. (tail of caudate nucleus)

Small brain. Atrophy of Caudate and Putamen.
Dilated lateral and third ventricles.

Affected neurons:

Medium sized spiny neurons containing these neurotransmitters:
GABA, enkephalin, dynorphin, substance-P.

What?

Progressive loss of a group of neurons having same function.

All are Proteinopathies.
Caused due to accumulation of insoluble proteins.
Tangle / plaque / lewy body.

List:

  • Prion disease
  • Alzheimers disease
  • Fronto-temporal lobar degeneration (FTLD)
  • Parkinson disease
  • Atypical Parkinson disease
  • Huntington disease
  • Spinocerebellar generation
  • Amyotrophic lateral sclerosis (ALS)
    • LMN and UMN Palsy with Bulbar involvement. (Swallowing)
  • Other motor neuron diseases

Which are the prion diseases?

  • Creutz feldt Jakob Disease (CJD) and variants
  • Kuru (human) or Scrapie (sheep)
  • Fatal familial insomnia
  • Gerstmann Straussler Scheinker disease
  • Milk transmissible encephalopathy
  • Chronic wasting disease in deer and elk
  • Bovine spongiform encephalopathy

Etiology

Sporadic:

Infectious protein particle from contaminated food.
Misfolded protein particles that causes other protein particles to misfold.

PrPc is an alpha-helix brain protein with no function. Becomes abnormal by misfolding into beta-pleated sheet isoform PrPsc. This resists protease digestion.

Results in Neurodegeneration.

Familial:

PRNP gene mutation in chromosome 20.

Clinical features

CJD:

  • Rapidly progressing dementia (0-6 month) in an old patient.
  • Slow progressing dementia in young (Familial CJD).
  • Jerking on stimuli or Startle myoclonus (Cerebellar involvement).
  • Death within 7 months.
  • Subtle behavioral changes.
  • Age: Young or Old depending on variant of CJD.

Morphology (Deep grey matter)

  • Kuru plaques = extracellular PrPsc deposits.
    • Positive with PAS, Congo red.
  • STATUS SPONGIOSUS = Collection of vacuoles in Glial and Neuronal tissue (Spongiform change).

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