Parkinson's Disease

Question 1

Describe the prevalence, age of onset and gender bias of parkinon’s disease

Answer 1

2nd most common ND disease
80,000 Aus (1/350), 8-10 million worldwide
57yrs avg age onset
men 1.5x more likely

Question 2

what are the cardinal symptoms of PD

Answer 2

tremor at rest
rigidity
akinesia (loss mvm)
bradykinesia
postural instability/gait change
must have at least 2, including resting tremor or bradykinesia

Question 3

what are some non-motor symptom categories of PD

Answer 3

personality and behaviour
cognition and mental
sensory
autonomic
sleep problems
fatigue

Question 4

describe cognitive impairment in parkinson’s

Answer 4

range from mild cognitive impairment -> dementia
25% have cognitive impairment
80% develop parkinson’s disease dementia within 20 years diagnosis

Question 5

diagnosis of parkinson’s disease

Answer 5

no definitive test
clinical symptoms, ruling our other disorders, levadopa
neuroimaging can look at dopamine uptake

Question 6

course of parkinsons disease progression

Answer 6

symptoms can begin insiduously and gradually worsen
avg survival time = 12 yrs

Question 7

early warning signs of PD

Answer 7

loss of smell
REM sleep behavioural disorder
neuropsychiatric changes
GI changes
by the time you get motor symptoms, already lost 60% dopaminergic neurons

Question 8

what is the etioogly of PD

Answer 8

familial PD = 5-10%
idiopathic PD: 90-95% (environmental = gene combo probably, env= history TBI, pesticide/herbicide exposure)
tea + coffee antioxidants (caffeine and theobromine = adenosine antagonists) cam improve PD symptoms

Question 9

describe the basal ganglia

Answer 9

group of nuclei deep within the brain
voluntary motor control, procedural learning, eye mvm, cognitive an emotional function
caudata nucleus, putamen (striatum) globus pallidus, subthalamic nucleus, substantia nigra (where degeneration starts)

Question 10

role of basal ganglia in mvm

Answer 10

gating proper initiation of mvm -> motor cortex
fine motor control
inhibition of what you don’t need, excitation of what you do need

Question 11

summarise the circuitry of the basal ganglia

Answer 11

direct pathway promotes execution of planned motor action by exciting cortical neurons
indirect inhibits motor action by inhib cortical neurons
pathways balanced or smooth execution of mvm

Question 12

describe the circuitry of the direct pathway

Answer 12

cerebral cortex -> planning mvm sends excitatory signal via glut -> striatum -> secretion of dopamine binds to D1 GABA-yn receptors in the striatum -> inc inhibition (GABA release) on the globus pallidus interna/substantia nigra reticulata (inhibits these inhibitors) => reduce inhibition on thalamus to increase glutamate excitation on cortex rom thalamus

Question 13

describe the circuitry of the indirect pathway

Answer 13

substantia nigra -> dopamine binds to D2 GABA-3nk receptors -> reduce inhibition on globus pallidus externa (normally inhibits subthalamic nucleus) -> excites globus pallidus interna/substantia nigra reticula -> more inhibition of thalamus -> less excitation from thalamus to cortex -> reduces motor mvm

Question 14

effect of globus pallidus interna/substantia nigra reticula

Answer 14

decrease the effect of the thalamus to decrease excitation of the cortex
so direct pathway must inhibit these inhibitors to cause thalamus excitation
and the indirect pathway must excite the inhibitors to cause thalamus inhibition

Question 15

whats the balance between the direct and indirect pathways in PD

Answer 15

severe loss dopamine in SNc, hypokinetic
reduced execution of mvm means that direct pathway is more affected
increased inhibition of mvm for indirect

Question 16

what happens when dopamine is lost

Answer 16

output nuclei become overactive (Gpe, SNr)
no dopamine = unchecked effects of cortical input => basal ganglia = imbalanced
output nuclei over inhibit thalamus (normally excitatory relays to cerebral cortex)
also oscillatory neuronal discharge (tremor) + altered output to brainstem (rigidity)

Question 17

describe the degeneration of other neuronal populations in PD

Answer 17

noradrenaline neurons in locus coeruleus (motor, depression, adhd)
ACH neurons in nucles basalis of meynery (plasticity, arousal, memory)
serotonin (5-HT) neurons of the dorsal raphe nucleus (regulation of mood, appetite, sleep muscle contraction)

Question 18

what are lewy bodies ad why do they suck

Answer 18

pathological hallmark of PD
protein, alpha-synuclein abnormally deposits, leading to formation intracellular lewy bodies (core + halo)
secreted by damaged neurons and can be taken up by surrounding neurons + structures (like microglia)
spreads in ascending direction

Question 19

describe the Braak stages

Answer 19

1+2 => autonomic and olfactory disturbance (olfactory bulb, vagus nerve => premotor symptoms)
3+4 => sleep and motor disturbances (motor symptoms)
5+6 => emotional and cognitive disturbances

Question 20

describe the braak staging of lewy bodies

Answer 20

spread of lewy bodies from lower brainstem up to cortex
parallels clinical progression of the disease

Question 21

describe pathological transmission of a-synuclein

Answer 21

EC space -> taken up by health neurons, causing normal a-syn to misfold -> secretes damaged a-syn

Question 22

prion-like hypothesis

Answer 22

a-syn spread along anatomical regions similar manner to prion proteins in prion disease (Creutzfeldt-Jacob)

Question 23

treatments of PD

Answer 23

no cure
treatments slow down progression + symptoms
levadopa

Question 24

details about levadopa

Answer 24

prodrug = metabolic precursor of dopamine
levadopa cross BBB (dopamine cant)
enzymatically converted to dopamnie in CNS
1-3% enters brain bc extracerebral metabolism = reduced by coupling with dopa-decarboxylase inhibitor to prevent peripheral conversion of dopamine

Question 25

effectiveness of levadopa

Answer 25

best results in first few years
80% = improvement
20% virtually normal motor function
levadopa therapy = less effective over time
progressive loss of dopaminergic neurons