380.3 🏥 內科專科考前版

380.3.1 Mechanistic Deep Dive

380.3.1.1 α-Synuclein

  • 140-AA protein
  • Normally in synaptic vesicles
  • Misfolds → aggregates → Lewy bodies + neurites
  • Prion-like spread (cell to cell)

380.3.1.2 Dopamine Loss

  • Loss in nigrostriatal pathway
  • Loss of inhibition on indirect pathway
  • ↑ Output of GPi → ↓ thalamocortical drive → bradykinesia

380.3.1.3 Levodopa Pharmacology

  • Crosses BBB
  • Converted to dopamine in CNS
  • Carbidopa blocks peripheral conversion (less nausea)
  • Short half-life (1-2 hr) — wearing off

380.3.2 Recent Trials & Updates

380.3.2.1 Foslevodopa-Foscarbidopa (Vyalev) FDA 2024

  • Continuous SC pump (24/7)
  • For advanced PD with motor fluctuations
  • Alternative to LCIG (less invasive)
  • M15-741 trial positive

380.3.2.2 LRRK2 Inhibitors (Trials)

  • For LRRK2-PD
  • Multiple in trials

380.3.2.3 GLP-1 Agonists

  • Exenatide (Lixisenatide)
  • Lixisenatide trial (LIXIPARK 2024) some neuroprotection signal
  • Larger trials planned

380.3.2.4 Anti-α-synuclein Antibodies

  • Prasinezumab (PASADENA) — negative
  • Cinpanemab — negative
  • BIIB101 (PADOVA) — pending

380.3.2.5 GBA-Directed Therapies

  • For GBA-associated PD (more aggressive cognitive decline)
  • Ambroxol increases GCase activity
  • Limited evidence

380.3.2.6 Focused Ultrasound Pallidotomy

  • FDA 2021
  • For dyskinesias

380.3.2.7 Sublingual Apomorphine (Kynmobi)

  • For OFF period rescue

380.3.2.8 Inhaled Levodopa (Inbrija)

  • For OFF period rescue
  • Self-administered

380.3.2.9 Skin Biopsy for α-Synuclein

  • Phosphorylated α-synuclein in peripheral nerves
  • Diagnostic accuracy high

380.3.2.10 CSF + Plasma α-Synuclein RT-QuIC

  • Emerging diagnostic biomarker
  • Distinguishes synucleinopathies

380.3.3 High-Yield Specialist Points

380.3.3.1 Early-Onset PD (< 50)

  • Genetic more likely
  • PARKIN, PINK1, DJ-1, LRRK2, GBA
  • Different management considerations

380.3.3.2 PD vs Atypical Parkinsonism

  • Atypical: poor levodopa response, early falls, autonomic failure, bulbar, cerebellar, supranuclear gaze, etc.
  • MSA, PSP, CBD, DLB
  • See Ch380

380.3.3.3 REM Behavior Disorder Prodrome

  • 80% develop synucleinopathy in 15 yr
  • Counsel patients
  • Polysomnography for confirmation
  • Treat with melatonin or clonazepam + safety

380.3.3.4 Vascular Parkinsonism

  • Lower body more affected (“lower body parkinsonism”)
  • Stepwise progression
  • Vascular risk factors
  • Normal DaT-SCAN
  • Poor levodopa response
  • Treatment: vascular risk factor modification

380.3.3.5 Drug-Induced Parkinsonism

  • Antipsychotics, antiemetics (metoclopramide, prochlorperazine), VPA
  • Reversible mostly
  • Normal DaT-SCAN

380.3.3.6 Hemiparkinsonism-Hemiatrophy

  • Childhood injury
  • Asymmetric atrophy + parkinsonism

380.3.3.7 Wilson Disease

  • Young (< 40) with parkinsonism
    • dystonia, tremor, dysarthria, psychiatric
  • KF rings
  • Low ceruloplasmin
  • Chelators or zinc

380.3.3.8 Acquired Hepatocerebral Degeneration

  • Cirrhosis + parkinsonism + cognitive
  • T1 bright basal ganglia (manganese accumulation)

380.3.3.9 Manganism

  • Welders, miners
  • Parkinsonism + behavioral
  • Less levodopa response

380.3.3.10 Genetic PD Testing

  • Considered:
    • Early onset (< 50)
    • Family history
    • Specific phenotypes
  • LRRK2, GBA, PARK panels
  • Genetic counseling

380.3.3.11 Camptocormia + Pisa Syndrome

  • Severe truncal flexion (camptocormia)
  • Lateral flexion (Pisa)
  • Treatment difficult
  • Surgical/orthotic options

380.3.3.12 Pharmacogenomics

  • COMT polymorphisms may affect response
  • Limited clinical utility currently

380.3.4 Pearls

  • TRAP + non-motor (RBD, hyposmia, constipation)
  • α-synuclein pathology
  • Levodopa gold standard
  • DA agonist ICDs — counsel!
  • Pimavanserin for psychosis
  • Rivastigmine for PDD
  • DBS for motor fluctuations
  • LCIG, foslevodopa SC (Vyalev 2024), focused ultrasound advanced therapies
  • DaT-SCAN distinguishes from non-PD parkinsonism
  • No disease-modifying therapy yet — many trials ongoing