Neurodegenerative Disorders

Overview & Classification - Brains Fading Fast

• Definition: Insidious onset, progressive loss of specific neuronal populations, leading to characteristic clinical syndromes.
• Core Mechanisms:
  • Proteinopathies: Misfolding & aggregation of proteins (Aβ, Tau, α-synuclein, TDP-43).
  • Shared pathways: Oxidative stress, mitochondrial dysfunction, neuroinflammation, excitotoxicity.
• Classification (Protein-based):
  • Tauopathies: Alzheimer's (AD), Pick's disease, Progressive Supranuclear Palsy (PSP).
  • α-Synucleinopathies: Parkinson's Disease (PD), Lewy Body Dementia (LBD), Multiple System Atrophy (MSA).
  • Amyloidopathies: AD (Aβ component).
  • TDP-43 Proteinopathies: Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Lobar Degeneration (FTLD-TDP).

⭐ Huntington's disease is an autosomal dominant trinucleotide repeat disorder, distinct from most common proteinopathies but also a key neurodegenerative condition.

Alzheimer's Disease - Memory's Thief

• Pathology: Extracellular amyloid-β (Aβ) plaques & intracellular Tau neurofibrillary tangles (NFTs).
• Genetics:
  • Early-onset: APP (Chr 21), PSEN1 (Chr 14), PSEN2 (Chr 1).
  • Late-onset risk: APOE ε4 allele.
• Clinical: 📌 4 A's: Amnesia (anterograde first), Aphasia, Apraxia, Agnosia. Executive dysfunction.
• Diagnosis:
  • Clinical criteria (e.g., NINCDS-ADRDA).
  • CSF: ↓Aβ42, ↑Total Tau, ↑Phosphorylated Tau.
  • Imaging: Medial temporal lobe (hippocampal) atrophy. PET for amyloid/tau.
  • MMSE score <24/30 indicates cognitive impairment.
• Management:
  • Cholinesterase inhibitors: Donepezil, Rivastigmine, Galantamine (mild-moderate).
  • NMDA receptor antagonist: Memantine (moderate-severe).

⭐ APOE ε4 is the most significant genetic risk factor for late-onset Alzheimer's disease.

Parkinson's Disease - Shakes & Slows

• Progressive loss of dopaminergic neurons (substantia nigra pars compacta) → ↓ striatal dopamine.
• Pathology: Lewy bodies (α-synuclein).
• Motor Symptoms (📌 TRAP):
  • Tremor: Resting, pill-rolling (4-6 Hz), unilateral onset.
  • Rigidity: Cogwheel or lead-pipe.
  • Akinesia/Bradykinesia: Slow movement, micrographia, masked facies.
  • Postural instability: Shuffling gait, festination (late).
• Non-motor: Anosmia, constipation, REM sleep behavior disorder, depression.
• Staging: Hoehn & Yahr (Stage 1-5).
• Rx: Levodopa/Carbidopa, Dopamine agonists, MAO-B inhibitors. Deep Brain Stimulation (DBS) for advanced.

⭐ Asymmetric onset of motor symptoms is a key feature distinguishing PD from other parkinsonian syndromes.

LBD, FTD, HD, Prions - Diverse Decline

⭐ LBD: Core feature is visual hallucinations; REM Sleep Behavior Disorder (RBD) is a strong early indicator.

Motor Neuron Disease - Muscles Wasting

• Progressive neurodegenerative disorder affecting upper motor neurons (UMN), lower motor neurons (LMN), or both, leading to muscle weakness and wasting.
• UMN Signs:
  • Spasticity, hyperreflexia, ↑muscle tone.
  • Babinski sign positive.
  • Weakness pattern: Pyramidal.
• LMN Signs:
  • Flaccidity, hyporeflexia/areflexia, ↓muscle tone.
  • Muscle atrophy (wasting), fasciculations.
  • Weakness pattern: Segmental/focal.
• Bulbar involvement (dysphagia, dysarthria) common.

⭐ Amyotrophic Lateral Sclerosis (ALS) is the most common form, characterized by combined UMN and LMN signs. No sensory or cognitive (usually) impairment initially. Riluzole may offer modest survival benefit (2-3 months).

High‑Yield Points - ⚡ Biggest Takeaways

• Alzheimer's Disease: Amyloid plaques, tau tangles; ApoE4 risk; most common dementia.
• Parkinson's Disease: Dopamine loss (substantia nigra); Lewy bodies (α-synuclein); tremor, rigidity, bradykinesia.
• Huntington's Disease: Autosomal Dominant, CAG repeats (Chr 4); chorea, dementia.
• ALS: Combined UMN & LMN signs; progressive weakness; SOD1 mutations (familial).
• Frontotemporal Dementia (FTD): Early behavioral/language changes; Pick bodies (tau) or TDP-43.
• Lewy Body Dementia (LBD): Fluctuating cognition, visual hallucinations, parkinsonism; REM sleep disorder.
• Creutzfeldt-Jakob Disease (CJD): Rapidly progressive dementia, myoclonus; prions; spongiform changes.