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Aging > Parkinson's > Flashcards

Parkinson's Flashcards

1
Q

What is Parkinson’s

A

Loss of dopamine neurons from substantia nigra in the basal ganglia (motor control region and key target of dopamine neurons)
Parkinson’s does not start at substantial nigra - may start in lower brain stem and olfactory bulb.
Parkinson’s px may experience loss of sense of smell and sleep disturbances before motor symptoms start

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2
Q

What is the prodromal phase of Parkinson’s

A

hyposmia, REM sleep behaviour disorder, excessvie daytime sleepiness, depression
Stable PD: non-motor fluctuations

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3
Q

What is the unstable phase of PD

A

increasing NMS burden, balance problems, drug effects wearing off

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4
Q

What is the advanced phase of PD

A

risk of pneumonia, increasing dependency. Motor: 2 hours off per day, 1 hour with troublesome dyskinesia. Levodopa over 5x a day. Dysphagia. Non-motor: mild dementia, neuropsychiatric, non-motor fluctuations, night time sleep dysfunction

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5
Q

What are the motor symptoms of PD

A

Shaking (while resting), rigidity on passive movements, bradykinesia, poverty of movement (hypokinesia), shuffling gait, freezing (feet glued to the ground)
Early PD: signs and symptoms unilateral
Progressive: bilateral

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6
Q

What are the on and off motor symptoms

A

Off: untreated, not enough dopamine, having motor symptoms
On: alleviation of symptoms on treatment

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7
Q

What is the Hoehn and Yahr Scale

A

Progression:
1 - Unilateral involvement with minimal or no functional disability
2 - bilateral or midline without impairment of balance
3 - bilateral disease: mild to moderate disability with impaired postural reflexes
4 - severely disabling disease; still able to walk to stand unassisted
5 - confined to bed

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8
Q

What is the clinical diagnosis of PD

A

bradykinesia + rigidity or 4-6 Hz resting tremor

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9
Q

How is olfactory testing done in PD

A

Olfactory dysfunction present in 70-100% of px.
Olfaction preserved in: PARK 2 (early onset genetic PD, PSP/CBD, vascular and drug induced parkinsonism, mild OD in SMA and Alzheimer’s Disease

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10
Q

What is DaTSCAN

A

DaTSCAN: SPECT imaging of membrane dopamine transporters. Detects degeneration of dopaminergic nigrostriatal pathway. Measures dopamine uptake in the basal ganglia.
Indictive but not diagnostic. Can show progressive loss of dopamine transporters

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11
Q

What are the non motor symptoms of PD

A

Neuropsychiatric (psychosis, depression, anxiety, apathy, dementia), drug induced (hallucination), sensory disorders (pain, RLS, olfaction), urinary disorders, fatigue, sexual dysfunction, sleep disorders, GI disorders (constipation), autonomic dysfunction
In prodromal stage: REM sleep disorder and loss of sense of smell

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12
Q

What is the first line treatment for PD

A

Levodopa is first line. However, it is metabolised greatly in the periphery before reaching the brain. Levodopa is given with DOPA decarboxylase inhibitor to prevent this. Excessive peripheral dopamine signalling also causes adverse side effects.

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13
Q

What COMT inhibitors are used

A

COMT inhibitors (entacapone, tolcapone, opicapone) can also be given for dual inhibition.

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14
Q

What dopamine agonists are used

A

Pramipexole, Ropinirole, Rotigotine patch) can be given to imitate the effects of dopamine

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15
Q

What MAO-B inhibitors are used

A

selegiline and rasagiline

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16
Q

What are the motor complications with levodopa

A

motor fluctuations -> on/off phenomena and wearing off, dyskinesia (involuntary movements)

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17
Q

What is the pulsatile delivery of levodopa

A

leads to pulsatile stimulation of dopamine receptors Dyskinesia can occur after over stimulation with levodopa

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18
Q

What are the non-oral ther

A

Ritigotine patch (transdermal, use for 24 hours for constant delivery, need to change site of application to prevent rashes), subcutaneous apomorphine infusion or APO-pen (dopamine agonist, 16 hours a day), duodenal carbidopa/levodopa gel infusion (PEG with duodenal tube, morning bolus dose, continuous maintenance infusion over 16 hours)

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19
Q

What genetic compo

A

encoding alpha synuclein; LRRK2; DJ-1; PINK1

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20
Q

What is the neuropathology of Parkinson’s

A

loss of pigmented cell bodies in the substantia nigra pars compacta. Marked by loss of neuromelanin (oxidation of dopamine) containing dopamine cells in mid -brain SNc

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21
Q

What are Lewy bodies

A

halo structures. Contains alpha-synuclein and ubiquitin (tags damaged proteins and transport to proteasome) clumps.

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22
Q

When do halo structures start to appear

A

when striatal DA reduced by 60-80%

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23
Q

What does 18F dopa do

A

show reduced number of DA nerve terminals, through dopamine transporters on the terminal of neurons.

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24
Q

How does mitchondrial dysfunction occur in PD

A

: complex 1 in respiratory chain not working properly. Leads to reduction in ATP generation and free radical generation. Increase in reactive oxygen species and therefore oxidative stress.

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25
Q

What does activated microglial do in PD

A

infiltration of microglia in the substantial nigra to release inflammatory markers

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26
Q

What does increased glutamate transmission do in PD

A

receptor operated ion channel. This increases intracellular Ca2+
Increased operation of Ca.1,3 channels leading to more intracellular Ca2+
These cause excitotoxic pathways to be triggered

27
Q

Why does the SNc have a high basal free radical production

A

Auto-oxidation of dopamine to form neuromelanin -> H2O2 (high reactive and enters the Fenton reaction)
Dopamine metabolism by mono-amine oxidase í H2O2
Fenton reaction: H2O2 combines with iron to produce hydroxyl radicals í cause damage to biomolecules: lipds, proteins, and DNA bases

28
Q

How are free radicals elevated in PD

A

Elevated levels of Fe2+ in SNc reflecting the infiltration of microglial cells
Impairment of mitochondrial complex I activity in px SNC due to H2O2: leaky electron transport chain, electrons combine with water to form more hydrogen peroxide

29
Q

How is there reduced anti-oxidant capacity

A 
Reduced GSH (major anti-oxidant enzyme system clearing ROS in SNc)
GSH capacity is reduced in PD px
30
Q

What does alpha-sync clump cause

A

cause inclusions. These oligomers deposit inside of Lewy bodies, causing neurons to die

31
Q

What happens in PINK-1 mutations

A

protects mitochondrial function - mutation leads to leaky electrons

32
Q

What happens with Parkin mutations

A

loss of function (involved with juvenile onset), involved with ubiquitin tagging

33
Q

WHat happens with LRRK2 mutation

A

enhance phosphorylation of proteins leads to UPS impairment

34
Q

What happens with SYNCA gene mutation

A

increased production of alpha-syn that can clump and lead to Lewy body formation

35
Q

What is the caudate + putamen

A

Striatum

36
Q

What is the substantia nigra

A

pars compacta has dopamine containing neurons and pars reticulata forms the output of the basal ganglia

37
Q

What is GPe/i

A

globus pallidus externus/internus

38
Q

What is Snc/r

A

substantia nigra pars compacta/reticulata

39
Q

What does GABA do

A

act on GABA-A receptors to hyperpolarise and inhibit firing of pathway

40
Q

What does the activation of the thalamocortical pathway do

A

facilitates movement

41
Q

What is the striatum area

A

input area: motor cortex and SNc

42
Q

What is the Gpi/SNr

A

output area as they receive all the information to relay to areas outside basal ganglia

43
Q

What is the direct pathway

A

SNc->striatum->GPe->GPi/SNr->thalamic relay nuclei

44
Q

What happens in the direct pathway

A

Cortical striatal pathway fires, sending glutamate to striatum. Glutamate excite direct pathway neurons as it has AMPA receptors. In turn, GABA receptors are released, inhibiting firing from GPe. Thalamic relay nuclei are therefore receiving less GABA. Glutamate feedback to motor cortex increased, facilitating movement.

45
Q

What does dopamine do in the direct pathway

A

SNc fires, release dopamine in the striatum. Dopamine in the striatum will act on D1 receptors (Gs coupled), causing excitation of GABA pathway to GPe. Same pathway as cortical striatal glutamate pathway.

46
Q

What is the indirect pathway

A

Activation of cortical striatal pathway, releasing glutamate in the striatum. This activates AMPA receptors, which activates GABA in GPe. This inhibits pathway to STN. This removes inhibitory influence on STN, which floods GPi/SNr with glutamate. This inhibits the thalamocortical pathway back to motor cortex - causes conflicting message to direct pathway

47
Q

What does dopamine do in the indirect pathway

A

SNc activates and releases dopamine in the striatum, which acts on the D2R (Gi/o coupled). They inhibit firing of first GABA pathway to GPe. More firing of GABA to STN. STN is inhibited and less output to GPi/SNr. Thalamic relay nuclei free to fire. This overrides glutamate from motor cortex.

48
Q

What are the pathophysiological changes in pathways in PD

A

Thalamocortical feedback is reduced, evoking motor deficits
SNc pathway to striatum is lost. Direct pathway less active (no stimulation of D1R, less release of GABA in output regions). Indirect pathway is more active (no inhibition from D2R, flooding GPe with GABA, inhibiting GABA pathway to STN, therefore STN is overactive, over release of glutamate in the GPi/SNr). Overall, output region is overactive with increase in glutamate. Massive increase of GABA to thalamic relay nuclei, switching off thalamocortical glutamate pathway back to the motor cortex.
Need to lose 60-80% of SNc pathway. There can be compensation.

49
Q

What is the role of cholinergic interneurons in the pathway

A

Cholinergic interneurons have D2R. When dopamine arrives at striatum, it will activate D2R receptors on cholinergic interneurons and inhibits it. Lack of dopamine causes disinhibition of cholinergic receptors and increase ACh levels in the striatum.

50
Q

What happens in Gq-coupled receptors on the indirect pathway

A

. Increased ACh can lead to increased stimulation of muscarinic receptors (PLC activation) and can exacerbate activity of indirect pathway, which adds to movement problems.

51
Q

What do muscarinic receptor antagonist do

A

benzhexol, benzatropine)
Increase in ACh contributes to symptoms of tremor
Muscarinic antagonists are only effective against tremor. Minimal effect against bradykinesia and rigidity

52
Q

What are the side effects of muscarinic antagonists

A

Central e.g. confusion, mood changes

Peripheral e.g. constipation, blurred vision, dry mouth (useful if sialorrhea is a problem)

53
Q

How does Levodopa work

A

Levodopa: cross BBB
L-DOPA->dopa decarboxylase to DA
Raises striatal DA levels. Activity normalise in direct and indirect pathways. Improves rigidity, bradykinesia, facial expression, speech and handwriting

54
Q

What is L-DOPA administered with

A

CO-administered with peripherally acting DDC inhibitor such as Carbidopa or benserazide
L-DOPA is metabolised by COMT. COMT inhibitor, entacapone, may be used as adjunct
Conversion by DDC happens inside DA and 5-HT neurones

55
Q

What are the acute side effects of L-DOPA

A 
Nausea - due to remaining peripheral dopamine receptor activation (domperidone given as adjunct)
Postural hypotension (esp. in px on anti-hypertensive drugs)
Psychological - hallucinations, confusion, insomnia, or nightmares
56
Q

What are the chronic side effects of L-DOPA

A

Motor fluctuations: rapid fluctuations in clinical state. Freezing may last minutes or hours. Related to plasma fluctuations in L-Dopa or storage of dopamine
Levodopa-induced dyskinesia: excessive, hyperkinetic involuntary movements (choreic or dystonic). Thalamocortical feedback is increased above normal. Face and limbs most affected. Amantadine (NMDA-type glutamate receptor blocker): only drug providing relief

57
Q

What are dopaminergic drug interventions

A

Levodopa - synthesis
MAO-B inhibitor and COMT inhbitors - degradation prevention
Amantadine - release
Dopamine agonist - receptor
No dopamine reuptake inhibitors clinically

58
Q

What MAO-B inhibitors are used

A

MAO-B is principle route of DA metabolism in DA rich brain regions
MAO-B inhibitors block DA metabolism. Used as adjuncts to lower L-DOPA.

59
Q

What are the side effects of MAO-B inhibitors

A

unlike non-selective MAO inhibitors, selegiline does not inhibit peripheral tyramine metabolism so no cheese reaction

60
Q

What dopamine receptor agonists are used

A

lysuride, ropinirole
Produce effects mainly through activation of striatal D2 receptors, not affected by progressive neurodegeneration
Used as adjunct to lower L-DOPA

61
Q

What is Rotigotine

A

dopamine agonist patch: effective as monotherapy in early PD

62
Q

What are the surgical options for PD

A

Thalamotomy (tremor dominant)
Pallidotomy (improves rigidity and bradykinesia)
Subthalamotomy (improves rigidity, bradykinesia and LIDs)

63
Q

What is the chronology of therapy for PD

A
  1. Levodopa to start if px elderly
  2. Muscarinic receptor antagonist (Benzhexol, benzatropine)
  3. MAO-B inhibitor
  4. Levodopa

Aging (8 decks)

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