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Parkinson disease, parkinsonism (mechanism of disease)

This is a mechanism of disease flowchart for Parkinson disease and other types of parkinsonism, covering the etiologies, pathophysiology, and manifestations of these diseases. ADDITIONAL TAGS: Pharmacology / toxicity Infectious / microbial Biochem / molecular bio Neurotransmitter imbalance Signs / symptoms Labs / tests / imaging results Parkinson disease Core concepts Social determinants of health / risk factors Neuron malfunction Genetics / hereditary Inflammation Pathophysiology Etiology Manifestations Dopaminergic neuron degeneration (50%) in substantia nigra Dopamine deficiency at the striatum Interrupted transmission to thalamus and motor cortex Serotonin and norepinephrine depletion in the raphe nuclei Acetylcholine excess in the nucleus basalis of Meynert Dyskinesia (jerking, twitching, tics) Idiopathic Mutations (including duplication / triplication) of α-synuclein (SCNA) → Lewy bodies Dardarin (LRRK2) mutation (dominant) Parkin (PARK2) mutation (recessive) Glucocerebrosidase (GBA) mutation (most common) Altered phosphorylation of target proteins and lysosomal dysfunction Impaired turnover and clearance of mitochondria altered autophagy and lysosomal function Impairment of α-synuclein clearance Viral (HSV, HIV) Bacterial (T pallidum, M tuberculosis) Parasites (T gondii, Plasmodium) Prion (Creutzfeldt-Jakob disease) Antidopaminergic meds: haloperidol, metoclopramide, amiodarone, valproate, Li Illicit drug MPTP → metabolite MPP+ Toxins: CO, carbon disulfide, manganese Secondary parkinsonism Advanced Huntington disease Wilson disease Hemochromatosis Niemann Pick Cardio- / cerebrovascular risk factors Subcortical arteriosclerotic encephalopathy Lewy body deposits in the autonomic nervous system Apathy Impulsive, irritable Fatigue Poor sleep ↓ sense of smell Depression ↓ attention ↓ concentration ↓ memory ↓ executive function Neuropsych Urinary urgency → incon Orthostatic hypotension Oily skin Impaired sex function Autonomic Motor Early symptoms: -constipation -sleep problem: REM disorder, daytime sleepiness, RLS -low sense of smell -mood: depress, anxiety, apathy Syndrome of parkinsonism (TRAP) Tremor: resting (4-6Hz), pill-rolling, ↓ w voluntary movements, ↑ w stress Rigidity: high and persistent resistance to passive joint movement. Tremor + tonus = cogwheel rigidity Akinesia: no or ↓ movement; freezing; low arm swing → short steps with shuffling gait (5-8 to turn around) → parkinsonian gait Postural instability: imbalance + impaired righting reflex → tendency to fall; + pull test Dystonia: sustained muscle contraction → involuntary fixed posture Increased axial muscle flexion → stooped posture Shrinking handwriting (micrographia) Decreased facial expressions (hypomimia) ↑ Upwards Arrow 24 ↓ Downwards Arrow 25 → Rightwards Arrow 26 ← Leftwards Arrow 27 ↔ Left-Right Arrow 29 ↕ Up-Down Arrow 18