2: Parkinson Flashcards
Hallmark Features
• bradykinesia: slowness of movement, fatigueing and decrement or repetive movements
• tremor: shaking; in particular: rest tremor
• rigidity: muscle stiffness
Other main clinical signs/symptoms of PD:
• Hypomimia: masked face
• Lack of global spontaneous body movements
• Difficulties with fine motor skills (e.g., buttoning up a shirt; handwriting)
• Difficulties turning in bed
Epidemiology
• Global prevalence: 0.3%
• >3% bei ≥ 80yrs
• Age-related increase
• Men twice as often
• Genetic factors (but most idiopathic)
• Environmental factors (smoking, caffeine -> protective // pesticides, brain injury -> risk)
Clinical Course
- Prodromal Phase
- Non-motor symptoms (REM sleep, Depression, Hyposomnia, Fatigue, Pain, Apathy)
- motor symptoms (bradykinesia, rigidity, tremor, dyskinesia, gait disorder)
Differential diagnosis:
• Drug-induced parkinsonism (dopamine receptor blockers)
• Other neurodegenerative diseases (Progressive supranuclear palsy, multisystem atrophy, corticobasal degeneration, frontotemporal dementia with parkinsonism)
• Vascular parkinsonism (in basalganglia)
• Non-degenerative tremor disorders
• Normal pressure hydrocephalus
• Rare genetic disorders
Investigations
Imaging:
• DaTscan: to distinguish from mimics without presynaptic striatal denervation
• MRI: to differentiate from other causes of parkinsonism
Polysomnography
• detects REM sleep behaviour disorder (supportive of αSNC pathology)
Genetic testing
• When YOPD (young onset) or positive family history Pathophysiology
Pathology
• Neuronal loss -> starting in ventrolateral parts of substantia nigra
• intracellular α- synuclein (αSNC) aggregation (Lewy bodies)
• Braak hypothesis: αSNC spread from cholingergic&monaminergic lower brainstem neurons
Molecular mechanisms:
• αSNC proteostasis (misfolded = toxic)
• Mitochondrial function
• Oxidative stress (Subst. Nigra very susceptible)
• Calcium homeostasis
• Neuroinflammation (second step -> microglia gets infected)
Motor circuits:
• Decreased dopaminergic neurotransmission in motor region of striatum
• Increased GABAergic inhibition (inhibition of movement)
Treatment of motor symptoms:
Pharmacological:
• L-Dopa (Vorversion von Dopamin) (continuous duodopa pump)
• COMT inhibitors
• MAO B inhibitors (Blockiert Abbau von Dopamin)
• Dopamine agonists
• Amantadine
Surgical:
- Deep brain stimulation (DBS) (of subthalamic nucleus)
(-> in patients with excellent L- Dopa response but complications of long-term L-dopa therapy, allows reduction of L-Dopa by ~60%)
- Focused ultrasound (of STN)
(-> For very asymmetric PD, patients who can ́t have DBS)
Gold Standard:
• Levodopa (since 50 years!)
+: relief from motor symptoms
-: only symptomatic, only some of the symptoms, behavioral fluctuations, side effects (dyskinesias)…
• Deep brain stimulation (since 20 years!)
+: relief from motor symptoms
-: only symptomatic, only some of the symptoms, invasive
Complications of long-term L-Dopa therapy:
• Motor fluctuations (early wearing-off, slow time to on, sudden OFF periods)
• L-dopa induced dyskinesias
Treatment of non-motor symptoms
• Depression -> antidepressants
• Dementia -> cholinesterase inhibitors
• Hallucinations/psychosis -> atypical neuroleptics
• Sialorrhoea (excessive drooling) -> botulinum toxin
• Orthostatic hypotension -> conservative measures like support stockings; fludrocortisone, adrenergic agents
• Urinary incontinence -> anti-muscarinergics
• Erectile dysfunction -> sidenafil
• Constipation -> pro-kinetic drugs
Treatment: multidisciplinary approach
• Physio
• Speech/language therapy
• Occupational therapy (work/home)
PD mysteries
• Kinesis paradoxica (plötzlich doch ganz schnell)
• REM sleep behaviour movements in PDs have normal speed movements
• Cueing (different strategies to walk)
Outlook
• Prodromal PD: window of opportunity for preventive treatments
• Biomarkers
• Experimental therapies (gene therapies, fetal cell transplantation, stem cells; active/passive immunization, drug- repurposing)
A-Synuclein
• long chains accumulate in cell -> Lewy Bodies
• Neuron disappears in SN
• Dopamin Mangel
• Sleepdisorder/Hyposomnia/Dementia (Motor & Nonmotor Problems)
-> Extracellular a-synuclein propagation -> Wiederaufnahme, prionlike mechanism, like cells that get infected
Braakstaging
• 1&2: autonomic & olfactory
• 3&4: sleep & motor
• 5&6: emotional & cognitive
Causes of PD
• Genetic (familial) < 10%: Parkin (PARK2), PARK?
• Toxins environment, lifestyle, unkown (sporadic) > 90%
