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Case 7- Parkinson's Flashcards

1
Q

Where is the primary somatosensory cortex and primary motor cortex found?

A

Primary somatosensory = postcentral gyrus (behind central sulcus)
Primary motor cortex= precentral gyrus (anterior to central sulcus)

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2
Q

What forms the striatum?

A

Caudate nucleus
Putamen

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3
Q

What forms the Lentiform nucleus?

A

Globus pallidus
Putamen

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4
Q

What are the structures of the basal ganglia?

A

Thalamus
Striatum (caudate nucleus + putamen)
Globus pallidus - internal and external parts
Subthalamic nucleus
Substantia nigra

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5
Q

What pathways provide input to the striatum? What neurotransmitter do they release?

A

Corticostriatal: from whole cerebral cortex to striatum = glutamergic

Nigrostriatal: from substantia nigra (pars compacta) to the striatum = dopaminergic

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6
Q

What is the basic motor function of the basal ganglia?

A

communicates back and forth with the cerebral cortex to initiate, inhibit and modulate movement, before information is sent from the cortex to the muscles via the corticospinal tract

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7
Q

What neuropeptides do the direct and indirect pathways contain?

A

Direct= dynorphin
Indirect= enkephalin

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8
Q

List the steps in the direct pathway

A

1- Corticostriatal pathway releases glutamate onto putamen to stimulate movement
2- Putamen releases glutamate to globus pallidus internus (GPI)
3- GPI releases GABA onto its own neurones, inhibiting them
4- These neurones release GABA and project to the thalamus, but since they’re inhibited by self neurones this is reduced (IPSP)
5- Thalamus is released from inhibition so is stimulated
6- Increased action potentials sent to cortex, this initiates wanted movements

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9
Q

What are the steps to the indirect pathway?

A

1: Corticostriatal pathway sends glutamate to the putamen
2- Putamen releases GABA to the globus pallidus externus (GPE)
3- Since the GPE normally inhibits the subthalamic nucleus (STN), inhibiting GPE releases the STN from inhibition
4- STN releases glutamate to GPI
5- GPI releases GABA onto thalamus
6- Thalamus is inhibited
7- Less action potentials sent to cortex, inhibits unwanted movements

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10
Q

What substrate do D2 and D1 receptors effect and what is its role?

A

Adenylyl cyclase; which is responsible for conversion of ATP into cAMP (cAMP= stimulatory)

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11
Q

Explain how dopamine affects the direct pathway

A

Dopamine binds to D1 receptors which is associated with G-stimulatory protein, therefore increases action potentials down neurone (potentiates effect of glutamate onto putamen)
= More intense action potentials sent to cortex

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12
Q

Explain how dopamine affects the indirect pathway

A

Dopamine binds to D2 receptors associated with G-inhibitory protein, this inhibits the putamen which is also being stimulated by glutamate, therefore less GABA is sent to GPE= STN is stimulated, this sends GABA to GPI, which is inhibited so less GABA is sent to thalamus overall = excitatory to cortex
= More excitatory signals to the cortex

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13
Q

What is the overall effect of dopamine on the direct and indirect pathways?

A

It increases movement:
- Stimulates direct pathway to facilitate desired movement
- Stimulates indirect pathway to inhibit unwanted movement
= Overall more powerful contractions (less inhibition)

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14
Q

How does the cerebellum project to the brainstem?

A

Superior cerebellar peduncle= connects to midbrain
Middle cerebellar peduncle = connects to pons
Inferior cerebellar peduncle = connects to medulla

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15
Q

What is the role of the archicerebellum (vestibulocerebellum)?

A

Connects cerebellum to vestibular system: involved in balance, posture and ocular reflexes, mainly fixation on a target

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16
Q

What is the role of the paleocerebellum (spinocerebellum)?

A

Connected to spinocerebellar tracts: regulates body movements and receives proprioceptive information

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17
Q

What is the role of the neocerebellum (cerebrocerebellum)?

A

Connected to the cortex via the pons: Involved in planning movements and motor learning, role in muscle activation and visually guided movements

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18
Q

List the 4 deep cerebellar nuclei

A

Dentate nuclei = largest
Globose
Emboliform
Fastigal

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19
Q

What divisions do the cerebellar nuclei connect to?

A

Dentate nucleus: neocerebellum (cerebro)
Emboliform and globose: paleocerebellum (spino)
Fastigal: archiocerebellum (vestibulo)

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20
Q

What are the inputs to the cerebellum?

A

Spinocerebellar tracts: from spinal cord
Vestibular nuclei: in medulla at level of inferior olivary nucleus
Cerebral cortex: via pontine nuclei

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21
Q

What are the outputs from the cerebellum?

A

Outputs - to deep cerebellar nuclei (mostly dentate) then goes to brainstem, specifically:
- Vestibular nuclei
- Reticular nuclei
- Red nuclei
Some bypass the nucleu and go straight to thalamus (ventral lateral)

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22
Q

What is the motor pathway of the archicerebellum (vestibulo)?

A

1- input from vestibular nerve - to vestibular nuclei
2- Projects to cerebellar cortex via inferior peduncle
3- Purkenje cells project into fastigal nucleus
4- Fastigal nucleus projects back to vestibular nucleus and reticular nucleus
5- Forms vestibulospinal and reticulospinal tracts
6- Influences posture and movement

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23
Q

What is the motor pathway of the paleocerebellum (spino)?

A

1- Input from the spinocerebellar tracts, enters cerebellum via inferior peduncle
2- Purkenje fibres project to globose and emboliform nuclei
3- Fibres project to brainstem via superior peduncle
4- Fibres enter red nucleus
5- Forms rubrospinal tract, which descends down spinal cord= regulates movement

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24
Q

What is the motor pathway of the neocerebellum (cerebro)?

A

1- Input from cerebral cortex, via pontine nuclei
2- Nucleus gives rise to pontocerebellar fibres, enter cerebellum at middle peduncle
3- Purkenje fibres -> to dentate nucleus
4- Fibres project out at superior peduncle
5- Fibres go to ventrolateral nucleus of thalamus
6- Influences movement via corticospinal tracts

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25
Define Parkinson's disease
Progressive degeneration of dopaminergic neurones within the substantia nigra (pars compacta), leading to reduced dopamine and thus, altered motor movement. It is a progressive disorder without remission, and presents with asymmetrical symptoms
26
What is found to accumulate in the brainstem, spinal cord and cortical regions in Parkinson's disease?
Alpha-synuclein, which forms Lewy bodies as it accumulates
27
Which part of the substantia nigra contains dopaminergic neurones and dopamine?
Pars compacta
28
What is the effect of pars compacta nigral cell loss?
Decreased dopamine release going to D1 and D2, which normally help enhance movement in direct pathway and increase inhibition of unwanted movement in indirect pathway
29
Explain how reduced dopamine can lead to akinesia/ dyskinesia in PD
Overall basal ganglia output is increased, which is inhibitory so increased inhibition of motor regions in thalamus = reduced motor signals to cortex. > Direct pathway: less dopamine = less stimulatory input, it is underactive (less movement) > Indirect pathway: less dopamine = less inhibitory input of putamen so its just being stimulated (by glutamate), it is overactive (too much inhibition of movement) = Muscles have significantly less input, the primary cause of akinesia/ dyskinesia
30
When are symptoms of PD seen?
Once levels of dopamine are 20-40% of normal
31
What is the classic triad of features with PD?
1: Resting tremor 2: Rigidity (increased muscle tone) 3: Bradykinesia/ akinesia
32
What is an early sign of PD?
Impairment of dexterity (fine motor skill), i.e. coordination of muscles in eyes, hands and fingers
33
What other signs/ symptoms can akinesia and dyskinesia lead to?
- Micrographia: handwriting gets smaller - Shuffling gait: small steps when walking, reduced arm swing - Difficulty initiating movement, i.e. turning around - Hypomimia: reduced facial expression ('mask-like')
34
What causes tremor and rigidity in PD?
Imbalance between dopaminergic and cholinergic neurons; cholinergic neurons usually act to oppose dopamine, so with dopamine lowering, ACh is going to increase (inhibits D1 and excites D2)
35
What type tremor is usually present in PD? When is it more pronounced?
Pill-rolling tremor (unilateral) - looks like they're rolling a pill between their thumb and finger More pronounced at rest, improves with voluntary movement
36
What type of rigidity is usually present in PD?
Cogwheel rigidity: constant resistance to passive movement of the joints, which gives away in small increments and causes a jerky movement. Usually in upper limbs Lead pipe: resistance to any movement, usually in lower limbs
37
For the limbs, is ridigity in PD worse on flexion or extension of the joints?
Lower limbs: worse on flexion Upper limbs: worse on extension
38
Other than the classic triad of signs, what else may PD patients present with?
- Depression - Insomnia - Loss of sense of smell (anosmia) - Postural instability: hunched over posture, difficulty standing in one place - Cognitive impairment and memory problems - Constipation
39
What signs/symptoms may be present in late-stage PD?
- Problems with chewing and swallowing - Monotonous speech (hypophonic) - Slightly slurred speech
40
Whats the difference between primary and secondary Parkinsonism?
Primary= idiopathic PD (main) Secondary= either: - vascular Parkinsonism - developed after a stroke, have problems with memory, sleep, mood and movement - Drug-induced Parkinsonism - by neuroleptic drugs, but symptoms reside in a few months
41
Name the 3 Parkinson's plus syndromes
Multiple system atrophy Dementia with Lewy bodies Progressive supranuclear palsy
42
What is multiple system atrophy and how does it present?
Neurons in multiple systems degenerate, affects the basal ganglia and other areas. Degeneration of the basal ganglia = PD symptoms, and degeneration in other areas can lead to autonomic dysfunction (urinary continence, postural hypotension, abnormal sweating) and cerebellar dysfunction (ataxia)
43
What is Dementia with Lewy bodies and how does it present?
Progressive cognitive decline (dementia) with features of PD. Has other symptoms such as visual hallucinations, dellusions, disorders of REM sleep and fluctuating consciousness.
44
Explain the presentation of progressive supranuclear palsy and give its typical age of onset
Affects eye movement, balance, mobility, cognitive impairment, speech and swallowing. Age of onset = 60-65 years
45
What is the epidemiology of PD?
Mean age of onset = 45-60 years Prevalence: 0.5-1% of over 60's in the UK 2nd common neurodegenerative disorder (after Alzheimer's)
46
What is the main risk factor for PD?
Age
47
What genes are associated with PD?
- Parkin: associated with substantia nigra degeneration but no Lewy bodies - PINK1 - DJ-1 - A-synuclein - LRRK-2: associated with Lewy bodies - SNCA - GBA: Lewy bodies
48
What environmental factors are associated with PD?
Toxins, i.e. MPTP (mitochondrial toxin, wipes out dopamine neurons), paraquat (pesticide)
49
Why do some symptoms of PD occur later?
The degree of cell loss and akinesia is correlated, thus the more dopaminergic neurones that are destroyed = high symptom severity or more symptoms
50
What symptom/sign is thought to indicate that someone may develop PD in the future?
REM sleep behaviour disorder - physically acting out your dreams while you're sleeping (highly correlated to PD) Decreased smell
51
What is the UK PD Society Brain Bank Clinical Diagnostic Criteria for diagnosing PD?
1- Bradykinesia with either 4-6 Hz rest tremor and/or rigidity 2- Absence of red flags indicating another diagnosis, including history of strokes 3- Supportive criteria of symptoms, i.e. unilateral onset, good response to levodopa, olfactory loss, progressive disorder etc.
52
What are some red flags for PD diagnosis (indicating a differential diagnoses)?
- Absent tremor or symmetrical onset (PD = always asymmetrical) - Early gait abnormality and falls - Poor levodopa response - Supranuclear gaze palsy (struggle looking up and down) - Early dementia
53
What scan might be performed to check for differential diagnoses of PD?
Single photo emission CT (SPECT), specifically dopamine transporter SPECT scans
54
How is SPECT used for diagnosing PD?
Dopamine transporter SPECT can differentiate PD from disorders that aren't associated with nigrostriatal dysfunction, i.e. used if essential tremor cannot be differentiated from PD: - Normally have a tadpole appearance on the scan (represents caudate nucleus) - In PD you lose the tail of the putamen so then it appears more like a full stop
55
What other scans may be used for diagnosing PD or differentials of Parkinsons?
PET - not used for differentials but used for diagnosis MRI - not used for diagnosing PD, but may be used for differentials
56
How can PD affect cognitive function and why does this occur?
- Cognitive disturbance: Lewy bodies in cortex - Impulsive disorder: gambling, hypersexuality, compulsive eating. Linked to severe dopaminergic deficit in ventral (limbic) striatal areas - Depression and anxiety: monoamine loss in brainstem
57
How does a Positron Emission Tomography (PET) scan work?
Produces a 3D image map of functional processes in the body. It detects 2 gamma rays emitted indirectly by a positron emitting radionuclide (at 180 degrees), which is introduced onto the body on a biologically active molecule. It is detected by static ring of detectors.
58
What are some pros/ cons of PET scans?
Pros= Better resolution Cons= higher cost, shorter half life so has to be injected instantly (= less user friendly)
59
How does a SPECT scan work?
Uses a gamma camera to acquire 2D images, known as projections, from different angles (rotating camera). A computer converts these projections into a 3D data set. Can be manipulated to show thin slices of the body
60
What are some pros/ cons of SPECT scans?
Pros= low cost, longer tracer half life, easier to perform (radioisotope more readily available) Cons= low resolution
61
How does a dopamine transporter SPECT scan work? What is its sensitivity and specificity?
Identifies presynaptic dopamine neuronal dysfunction by demonstrating reduced uptake of a radioactive tracer than binds to dopamine receptors in the basal ganglia. Highly accurate: 98-100% sensitivity and specificity in detecting nigrostriatal cell loss
62
What marker may be used in PET scans for PD diagnosis? What would it show if a patient had PD?
18F-Flurodopa: in PD, would show decreased levels of dopamine in the substantia nigra
63
What marker may be used for PET scans to assess metabolic activity?
18F-flurodeoxyglucose (FDG): indirectly measures glucose activity, i.e. in cancer diagnosis
64
Which PET marker may show the putamen and caudate nucleus as a full-stop shape in PD patients?
18F-DOPA
65
What is the most effective treatment for PD?
Levodopa, but is less effective over time so is reserved for when other treatments cannot manage symptoms
66
How do MAO-B inhibitors work to treat PD? What is its aim?
Inhibits monoamine oxidase B, the enzyme responsible for breaking down dopamine in the CNS. - Helps slow disease progression (early PD) - Used to delay use of levodopa - Used in combination with levodopa to reduce the dose required.
67
Give examples of MAO-B inhibitors used for PD
Selegiline, Rasagiline, Safinamide
68
What are the side effects of MAO-B inhibitors?
Lacks the same side effects as MAO-A inhibitors in depression (as its selective for MAO-B), but can cause postural hypotension and atrial fibrillation (potentially serious)
69
What is levodopa? What is the typical dosage for PD patients?
Synthetic dopamine used to boost levels 800mg/ 24hours, but increase to this dose gradually
70
What drugs may be given to prevent the breakdown of levodopa before it reaches the brain?
Peripheral decarboxylase inhibitors, i.e. carbidopa and benserazide
71
What is co-beneldopa and co-careldopa?
Co-beneldopa= levodopa with benserazide Co-careldopa= levodopa with carbidopa
72
When is levodopa typically given?
When PD starts to adversely affect activities of daily living, usually 10-12 months after diagnosis
73
What are some side effects of levodopa?
Nausea GI upset Dyskinesias Hypotension Arrythmia Psychosis Confusion Impulsive behaviours On-off effect
74
What are dyskinesias?
Abnormal movements associated with excessive motor activity, i.e. dystonia, chorea, athetosis -
75
What is dystonia?
Excessive muscle contraction leads to abnormal postures or exaggerated movements
76
What is chorea?
Abnormal involuntary movements that can be jerking or random movements
77
What is athetosis?
involuntary twisting or writhing movements, usually in fingers, hands or feet
78
What is the prevalence of impulsive behaviours in PD patients and what are the risk factors for displaying them?
13.6% - Dopamine agonist use - Smoking - Males - Depression - novelty-seeking behaviour
79
What is the on-off effect?
The fluctuating plasma concentration of levodopa, seen the longer the drug has been used. Has occasions where the drug is effective vs where it isn't at all and symptoms dramatically return
80
How do dopamine agonists work? When are they given?
Mimic dopamine in the basal ganglia and stimulates dopamine receptors. Less effective in reducing symptoms but are given to delay use of levodopa or with levodopa to reduce dose required
81
Give 2 examples of dopamine agonists
Pergolide, Carbergoline
82
What are the side effects of dopamine agonists?
Serious one= pulmonary fibrosis Also can cause nausea, postural hypotension
83
Give an example of a selective D2 agonist and its side effects
Bromocryptine Hallucinations, hypotension, nausea
84
Give an example of a selective D3 agonist and its benefits
Ropinirole and pramipexole Less side effects than levodopa and less risk of causing dyskinesias
85
When might ropinirole or pramipexole be used?
First line treatment for PD in younger patients (as efficacy doesnt decrease)
86
What condition can abrupt withdrawal of Antiparkinsonism medications lead to?
Neuroleptic malignant syndrome
87
What drug might be given to reduce motor symptoms of PD?
Anticholinergics, i.e. atropine As many motor symptoms are due to overactivity of ACh and its imbalance with dopamine
88
What type of drug is entecapone and when might it be used?
COMT inhibitor; the COMT enzyme metabolises levodopa so it is used to increase dopamine levels May be given with levodopa and a decarboxylase inhibitor to slow breakdown of levodopa
89
Why do dopaminergic medications need to be reduced later in advanced PD?
The brain finds it increasingly difficult to handle dopamine and levodopa, so you get the 'wearing off' effect, which leads to motor complications.
90
When might the wearing off effect and its associated motor complications occur?
4-6 years after treatment, occurs in 50% of patients
91
Where are leads placed during deep brain stimulation?
Intracranially, on subthalamic nucleus or globus pallidus internus Then leads attached to a battery in the chest
92
What finding is DBS based upon?
That high-frequency (100-200 Hz) electrical stimulation of specific brain targets can mimic the effect of a lesion without the need for destroying brain tissue.
93
What factors are associated with worse DBS outcomes?
- Older age (>75) - Cognitive impairment, i.e. dementia - Presence of levodopa-resistant symptoms, i.e. gait disturbance
94
What factors would indicate an ideal candidate for DBS?
- Idiopathic PD - Excellent L-DOPA response (at least 30%) - Motor complications due to long-term medical treatment (on-off fluctuations, dyskinesia’s) - Younger, below age 69 (but may be older) - Little to no dysfunction
95
Define Health-related Quality of Life (HR-QoL)
The impact of a disease or illness on key aspects of physical, social or psychological functioning: - Physical = pain, fatigue - Social = relationships, life roles - Psychological = thoughts, feelings, self-esteem, identity
96
What is a Quality-Adjusted Life Year (QALY)?
A measure of the state or health of a person or group in which the benefits in terms of length of life are adjusted to reflect the QoL.
97
What is 1 QALY equal to?
1 year of life in perfect health
98
How is a QALY calculated?
Calculated by estimating the years of life remaining for a patient following a treatment or intervention, then waiting each year with a QoL score on a scale of 0-1. Often measured in terms of a person’s ability to carry out: - Activities of daily living (ADLs) - Freedom from pain - Mental ill health and wellbeing
99
How might health status be measured?
Subjectively by QoL or HR-QoL Objectively by: - Mortality rates= number of deaths in one year, compared to other years - Morbidity rates= information at the level of the population, important when defining health (not just an absence of disease or death) - Measures of functioning = ADL
100
What are patient reported outcome measures (PROMS)?
Standardised, validated questionnaires that are completed by patients to ascertain: - Perceptions of health status - Perceived level of impairment - Disability - HR-QoL
101
Name the 6 measures of QoL
Illness-specific Generic Unidimensional Multidimensional Individualised Standardised
102
Give an example of an illness-specific and generic measure of QoL
Illness-specific = AIMS-2, simplified psoriasis index Generic= SF-36
103
Give a criticism for both illness-specific and generic measures of QoL
Illness-specific = too narrow, may miss some factors Generic = too vague
104
What is a uni-dimensional measure of QoL? Give examples
Focuses on 1 particular aspect of health - General Health Questionnaire: focus=mood - Hospital Anxiety and Depression Scale= mood - McGill pain questionairre = pain
105
What is a multi-dimensional measure of QoL?
Assesses health in a broad sense, i.e. could be a single item - 'how would you say your health is'? = good/ excellent/ bad, or 'how would you rate your health on a scale from 1-10?'
106
What is an individualised measure of QoL? Give an example
Schedule for Evaluating Individual Quality of Life (SEIQoL): asks individuals to select 5 areas of their life that are important to them, and rate them in importance and how satisfied they are currently.
107
What is a standardised measure of QoL? Give an example
Barthel index: Looks at how independent the patient is, asks the staff but the patient may have a different view of their mobility.
108
Explain Ferran's (2015) revised HR-QoL model
Characteristics of the individual and characteristics of the environment influence 5 factors, which are placed in consecutive order: 1- biologic function, which affects: 2- Symptoms, which affects: 3- Functional status, which affects: 4- General health perceptions, which affects: 5- Overall QoL
109
How can someones QoL change without their health status changing?
Depends on 3 appraisals: - Frame of reference: helps us understand the question and what words mean to us - Standards of comparison: could be off our own self-history of QoL or against other people - Sampling strategy: choosing what part of your life/ health to assess
110
How can a resting tremor (i.e. in Parkinson's) be distinguished from an essential tremor (intention tremor)?
Resting tremor= asymmetrical, 4-6Hz, worse at rest but improves with movement, present with other PD symptoms, no change with alcohol Intention tremor= symmetrical, 5-8 Hz (faster), better at rest and worse with movement, no PD symptoms, better with alcohol

PBL Y2 S3 (10 decks)

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