Neurodegenerative Diseases

Neurodegenerative Diseases - Brain's Protein Glitches

Definition: Progressive, often age-related, loss of neuron structure and/or function. Common mechanisms:

• Protein misfolding & aggregation (proteinopathies)
• Oxidative stress
• Neuroinflammation
• Impaired proteostasis

⭐ Most neurodegenerative diseases involve intracellular or extracellular aggregates of misfolded proteins.

Key Proteinopathies & Associated Diseases:

Neurodegenerative Diseases - Memory's Missing Pages

• Alzheimer's Disease (AD): Most common dementia.
  • Etiopathogenesis: Extracellular Aβ plaques (from Amyloid Precursor Protein - APP); Intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated Tau protein.
  • Gross: Cortical atrophy (frontal, temporal, parietal lobes), widened sulci, hydrocephalus ex vacuo.
  • Microscopic: Neuritic plaques, NFTs, amyloid angiopathy, neuronal loss.
  • Genetic Factors:
    • Early-onset (familial): APP, PSEN1, PSEN2.
    • Late-onset (sporadic):

      ⭐ APOEε4 is the major genetic risk factor for sporadic AD.

    • 📌 Mnemonic: Old APPs Play Songs 1 & 2 Every 4ever (APP, PSEN1, PSEN2, APOEε4).
  • Association: ↑ risk in Down syndrome (Trisomy 21; APP gene on Chr 21).
  • Clinical: Progressive memory loss, cognitive decline, dementia features develop over years (e.g., disorientation, mood changes).

Neurodegenerative Diseases - Synuclein's Shaky Saga

• Parkinson's Disease (PD):
  • Pathology: Loss of dopaminergic neurons in substantia nigra pars compacta → ↓ dopamine.
  • Hallmark: Intracytoplasmic Lewy bodies (α-synuclein aggregates).
  • Clinical: 📌 TRAP mnemonic: Tremor (resting, "pill-rolling"), Rigidity ("cogwheel"), Akinesia/Bradykinesia, Postural instability.

⭐ Lewy bodies containing α-synuclein are the hallmark of Parkinson's disease.

• Other α-Synucleinopathies:
  • Lewy Body Dementia (LBD): Fluctuating cognition, visual hallucinations (early), Parkinsonism. Lewy bodies in cortex & brainstem.
  • Multiple System Atrophy (MSA): Parkinsonism (poor L-dopa response), autonomic failure (e.g., orthostatic hypotension), cerebellar ataxia. α-synuclein in oligodendroglial cytoplasm (Papp-Lantos bodies).

Neurodegenerative Diseases - Genetic Repeats & Motor Retreats

• Huntington's Disease (HD): Autosomal Dominant (AD); CAG repeats (HTT gene, Chr 4). >40 repeats = full penetrance; 36-39 = reduced penetrance. Exhibits anticipation.
  • Pathophysiology: Caudate atrophy, ↓GABAergic neurons. 📌 "Hunting for GABA in the Caudate with CAGs".
  • 

⭐ Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, exhibiting anticipation.

• Amyotrophic Lateral Sclerosis (ALS): Combined Upper Motor Neuron (UMN) & Lower Motor Neuron (LMN) signs.
  • Pathophysiology: TDP-43 proteinopathy (most common); SOD1 gene mutations (familial cases).
  • Histology: Bunina bodies (characteristic intracytoplasmic inclusions in LMNs).
  • 

Neurodegenerative Diseases - Spongy Scare & Frontal Flare

• Prion Diseases (Spongy Scare):
  • Pathogenesis: Accumulation of abnormal prion protein (PrPSc).
  • Key CNS finding: Spongiform encephalopathy (neuronal loss, gliosis, vacuolation).
  • Creutzfeldt-Jakob Disease (CJD): Rapidly progressive dementia, myoclonus, ataxia, visual disturbances. 📌 Mnemonic: Can't Jog Daily (ataxia, rapid).

  ⭐ Spongiform encephalopathy (vacuolation) is the characteristic CNS finding in Creutzfeldt-Jakob disease.

• Frontotemporal Dementia (FTD) (Frontal Flare):
  • Pathology: Progressive frontotemporal lobar atrophy.
  • Key proteinopathies: Tau (e.g., Pick bodies) or TDP-43.
  • Clinical Variants:
    • Behavioral (bvFTD): Early personality/behavioral changes (disinhibition, apathy).
    • Primary Progressive Aphasia (PPA): Language deficits (semantic, nonfluent, logopenic).

High‑Yield Points - ⚡ Biggest Takeaways

• Alzheimer's: Aβ plaques (extracellular), tau tangles (intraneuronal); ApoE4 major genetic risk.
• Parkinson's: α-synuclein Lewy bodies in substantia nigra; marked dopamine loss.
• Huntington's: Autosomal dominant CAG repeats (HTT gene); progressive caudate atrophy.
• ALS: UMN & LMN degeneration; common proteinopathies include TDP-43 or SOD1.
• Prion Diseases (CJD): PrPSc induces spongiform encephalopathy; rapidly fatal dementia.
• FTD: Frontal/temporal lobar atrophy; characteristic tau (Pick bodies) or TDP-43 inclusions.