3 points
Neuro manifestations of PD - what happens?
- selective degeneration of dopaminergic neurons (esp in Substantia Nigra)
- formation of Lewy bodies (fibrillar cytoplasmic inclusions)
- loss of dopamine in striatum (due to neuron loss)
7
Mutations in which genes for familal PD?
and describe their uses
a-synuclein (PARK1 gene - aggregation of a-syn)
Parkin (PARK2 gene - loss of ubiquitin-protein ligase activity: responsible for protein degradation)
DJ-1 (PARK7 gene - mutation results in loss of DJ-1 protein/prevention of dimerisation: involved in cellular responses to oxidative stress)
PINK1 (PARK6 gene - for mitophagy/mitochondrial QC)
LRRK2 (PARK8 gene - cytoplasmic protein kinase and GTPase: for autophagy and vesicular trafficking)
MAPT (encoding tau)
GBA (glycolipid metabolism - deficient in Gaucher’s disease; risk for PD)
however most cases are idiopathic
other causes of PD?
- age
- drugs of abuse (MPTP) - C1 inhibitors: mitochondrial defect causes degeneration of dopaminergic neurones
- environmental conditions (eg. rotenone)
8
Symptoms of PD?
- Rhythmic Tremor (‘pill rolling’ in the hands - thumb and forefinger; decr by action/sleep, incr by emotion)
- Muscle Rigidity (stiffness in limbs felt throughout the range of movement, opposing muscle groups have similar lack; ‘cogwheeling’ - jerky resistance to passive limb movement)
- Akinesia (difficulty beginning or maintaining a body motion; bradykinesia due to rigidity, + inertia to stop motor system)
- Postural Instability (stiff falls - usual corrective righting reflexes fail)
- Appearance (characteristic stoop, shuffling gait, immobility of the face)
- Speech (monotonous, slow, weak, uncoordinated)
- Writing (small and spidery)
- Dementia (later stages - not confined to basal ganglia)
Pre-clinical symptoms?
When do they start?
(-20 years) : hyposomia, constipation, bladder disorder
(-10 years): sleep disorders, obesity, depression
Describe the Hoehn & Yahr stages of clinical onset?
- unilateral trmor, rigidity, akinesia
- bilateral symptoms
- poor balance, mild to moderate disease but still independent
- severe disability, falls, dependent, cognitive decline but still able to support themselves
- immobility, dementia
Describe Braak staging
1 - 2: peripheral and enteric NS effect (pathogens in enteric NS trigger a-syn aggregation)
3: a-syn reaches CNS via olfactory bulb and vagus nerve, spreads to SN, amygala, nucleus basalis of meynert
4: reaches temporal lobe
5: reaches prefrontal cortex
6. reaches secondary and primary motor and sensory areas
Diagnosis of PD
- cell degen (in substantia nigra pars compacta; locus coeruleus)
-> using SPECT - accumulation of Lewy bodies (same places + cerebral cortex, vagus dorsal motor nucleus)
- a-synuclein spread (misfolding of protein results in aggregation (prion-like))
does diagnosing PD in early stages help?
not rly - treatment is for symptoms, not disease; hence identifying early doesn’t mean you can treat it
define Myerson sign (what does the neurologist do + outcome?)
(aka?)
Glabellar reflex
- tapping forehead between eyebrows –> observing blinking: if it doesn’t stop it’s a sign of PD
normal: habituation after initial successive tapping, but with PD you can’t control it
what is SPECT?
not immediately diagnosed
helpful for identifying reduction of dopamine transporters –> signs of pd
drug treatment?
why give tgt with ____, and how is levodopa’s absorption
(first line) levodopa: DOPA precursor
–> give with carbidopa (for overcoming unwanted N+V side effects): occurs because of significant peripheral metabolism; decreased brain delivery
–> well absorbed from the GI tract, can cross the BBB (unwanted czt s/e?)
carbidopa: dopa decarboxylase inhibitor
limitations of current PD drug therapy?
basically problems with levodopa
- symptomatic treatment (akinesia); does not stop progression
- ‘on-off’ effects: fluctuation of efficacy
- development of dyskinesia + chorea + neuropsychiatric problems (hallucinations, confusion, psychosis)
~50% develop >/1 complications during the first 5 years of treatment
what other drugs are given concomittantly with (maindrug) to alleviate side effects? how do they work
- (first line) MAOIs (eg. selegiline) - reduction of dopamine metabolism in CNS = increases [dopa] and resultant downstream excitatory NT
- (first line) COMT inhibitors (eg. entacapone) - reduction of dopamine metabolism in periphery
- amantadine - releases dopamine (treating dyskinesia)
- ropinorole (dopa receptor agonist)
- benztropine - anticholinergic for improvement of motor function (but this leads to cognitive dysfunction issues so prob best not to give this)
what other drugs given in place of (maindrug) and why so? pros and cons
- oral dopamine receptor agonist (eg Pergolide, Lisuride)
–> lower efficacy but reduces s/e (dyskinesias and motor fluctuations) compared to levo
Pergolide has potential cardiac valvulopathy risk
2
describe stages of PD management
(early): symptomatic treatment (improving disability due to initial motor blockage)
(late): fall prevention (managing motor complications); s/e management (dyskinesias); delayed loss of autonomy (cognitive impairment)
efficacy (in motor ability) declines with year of disease progresion
dose of first-line medication
levo:carbi
1:4
(initial dosing 100/25mg) titrated upwards in 50/12.5mg increments
describe surgical intervention for PD
- deep brain stimulation - high freq electrical stimulation to either the thalamus, globus pallidus, subthalamic nucleus
- striatal grafting of dopaminergic foetal tissue
