435 Parkinson's Disease Flashcards
(190 cards)
1
Q
2nd most common age-related neurodegenerative disease (exceeded only by AD)
A
PD
2
Q
Mean age of onset of PD
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60 years old
3
Q
Classic features of PD (4)
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4
Q
hallmarks of PD (pathologically)
A
5
Q
What is BRAAK Staging
A
6
Q
Examples of OTHER MOTOR FEATURES of PD (mga non -cardinal motor features)
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7
Q
Examples of NONMOTOR features of PD
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8
Q
percentage of PD occuring sporadically
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85-90%
9
Q
only known cause of PD
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Gene mutations
10
Q
4 common gene mutations in PD
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- Alpha-synuclein (SNCA)
- GBA
- LRRK2
- PINK1/ Parkin
11
Q
HLA gene associated with PD
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Class II HLA gene DRB1
12
Q
NO environmental factor has yet been proven to cause or contribute to PD . True or false
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True
13
Q
Relationship of PD to Calcium pacing
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With aging, dopamine neurons switch from sodium to calcium pacing through calcium channels
14
Q
Genes associated with classical PD vs early onset PD vs parkinsonism
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15
Q
First PD-linked gene mutation
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Alpha-synuclein (SNCA)
16
Q
Most intensely investigated gene mutation has in PD
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Alpha-synuclein (SNCA)
17
Q
Differentiate SNCA disease from nongenetic PD in terms of disease onset
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Earlier age of disease onset than in nongenetic PD
18
Q
Differentiate SNCA disease from nongenetic PD in terms of progression of sx
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Faster progression of motor signs that are mostly levodopa-responsive
19
Q
Differentiate SNCA disease from nongenetic PD in terms of occurrence of motor fluctuations
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Early occurrence of motor fluctuations
20
Q
constitutes the major component of Lewy bodies
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SNCA
21
Q
ost important risk factor in terms of effect size for the development of PD
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GBA gene
22
Q
GBA gene encodes for what enzyme
A
glucocerebrosidase (Gcase)
23
Q
function of glucocerebrosidase (Gcase) (2)
A
- promotes lysosomal function
- Enhances the clearance of misfolded proteins like SNCA
24
Q
ASSOCIATION OF GBA AND SNCA
A
25
most common variant of LRRK2 mutation
p.G2019S
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p.G2019S is associated with what gene mutation
LRRK2
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This symptoms is a useful diagnosti clue for LRRK2 mutation
leg tremor
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Can block toxicity associated with LRRK2 mutation
kinase inhibitors
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Mutation that is the major cause of autosomal recessive and early-onset PD
Parkin mutations
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Parkin and PINK1 mutations are commonly complicated by what symptomq
Dystonia
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Neurodegeneration in Parkin and PINK1 mutations are usually restricted to what areas of the brain (2)
restricted to SNc and LC
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Lewy bodies are typically present in Parkin and PINK1 mutations. True or false
Lewy bodies typically absent
33
Explanation for pathologic findings in Parkin and PINK1 mutations
impairerd ubiquination of damaged proteins
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Refers to group pf neurodegenerative conditions that are usually assoc with MORE WIDESPREAD pathology than found in PD
Atypical Parkinsonism
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relationship of atpyical parkinsonism and speech/gait
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relationship of atpyical parkinsonism and rest tremor
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relationship of atpyical parkinsonism and levodopa response
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clinical course of atypical parkinsonism
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4 types of atypical parkinsonism
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why is neuroimaging not helpful in atypical parkinsonism
Because striatal dopamine depletion can be seen in both PD and atypical parkinsonism
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Role of metabolic imaging in atypical parkinsonism
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Combination of atypical parkinsonian features AND CEREBELLAR and AUTONOMIC features
MSA multiple system atrophy
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2 clinical syndromes of MSA (multiple system atrophy)
* MSA-p (parkinsonian)
* MSA-c (cerebellar)
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usual autonomic disturbance in MSA multiple system atrophy
orthostatic hypotension
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What type of atypical parkinsonims:
Degeneration of the SNc, striatum, cerebellum, and inferior olivary nuclei
MSA multiple system atrophy
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What type of atypical parkinsonims:
With characteristic glial cytoplasmic inclusions (GCIs)
MSA multiple system atrophy
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What type of atypical parkinsonims:
Pathologic iron accumulation in the striatum (T2weighted)
MSA multiple system atrophy
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What type of atypical parkinsonims:
MRI showing putaminal rim
MSA-p
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What type of atypical parkinsonims:
MRI showing Pontine " hot cross bun" sign
MSA-c
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What is putaminal rim
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What is Pontine " hot cross bun" sign
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What type of atypical parkinsonism...:
no established Gene mutation
MSA multiple system atrophy
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Parkinsonism with
* Slow ocular saccades
* Eyelid apraxia
* Restricted vertical eye movements with particular impairment of downward gaze
PSP - progressive supranuclear palsy
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What type of atypical parkinsonism:
Hyperextension of the neck with early gait disturbance and falls
PSP - progressive supranuclear palsy
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2 clinical forms of PSP - progressive supranuclear palsy
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differentiate Parkinson form vs Richardson form in terms of response to levodopa
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What type of atypical parkinsonism:
MRI : hummingbird sign
PSP - progressive supranuclear palsy
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What is hummingbird sign
MRI finding showing Atrophy of the midbrain with relative preservation of the pons on midsagittal images (seen in PSA)
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What type of atypical parkinsonism:
degeneration of the SNc, striatum, STN, midline thalamic nuclei, and pallidum
PSP - progressive supranuclear palsy
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What type of atypical parkinsonism:
(+) mutation for MAPT gene which encodes tau protein
PSP - progressive supranuclear palsy
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TAU protein is seen in which type of atypical parkinsonism
both PSP and CBS
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What type of atypical parkinsonism:
Asymmetric dystonic contractions and clumsiness of one hand
CBS - corticobasal syndrome
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What type of atypical parkinsonism:
alien limb phenomenon
CBS - corticobasal syndrome
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What is alien limb phenomenon
Limb assumes a position in space without the patient being aware of its location or recognizing that the limb belongs to them
Seen in CBS
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MRI findings of corticobasal syndrome
* Asymmetric cortical atrophy
* May not be obvious to casual inspection
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PAtho findings of Corticobasal syndrome
* Achromatic neuronal degeneration with tau deposits
* may overlap with PSP pathologically
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"Historical" diagnosis of PD
PD diagnosed based on presence of 2 out of 3 parkinsonian features ( tremor, rigidity, bradykinesia)
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UK Brain Bank Criteria for diagnosis of PD
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MDS Clinical Diagnostic Criteria for Parkinson's disease ---- CLinicially PROBABLE PD
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MDS Clinical Diagnostic Criteria for Parkinson's disease ---- Clinically ESTABLISHED PD
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Major input region of basal ganglia
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Major output region of basal ganglia
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Part of basal ganglia which Provides inhibitory (GABAergic) tone to thalamic and brainstem neurons
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Effect of decreased vs increased activity of GPi
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Pathophy of parkinsonism based from Fig 435-5
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Pathophy of dyskinesia based from Fig 435-5
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Mainstay of therapy for PD / GOLD standard
Levodopa
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Most effective symptomatic treatment for PD
LEvodopa
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Levodopa is Routinely given in combination with what type of drug
PERIPHERAL DECARBOXYLASE INHIBITOR
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Role of PERIPHERAL DECARBOXYLASE INHIBITOR
To prevent peripheral metabolism of levodopa to dopamine
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Primary source of disability in PD (2)
falls and dementia
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Main reason for hospitalization and nursing home placement (2)
falls and dementia
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Acute dopaminergic side effects of levodopa (3)
Nausea , Vomiting , Orthostatic hypotension
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first thing to do if there is occurrence of acute dopaminergic side effects with use of levodopa
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next things to do if there is persistence of acute dopaminergic side effects with use of levodopa after doing the first line action (3)
86
How does dyskinesia develop with levodopa use
CURRENTLY, it is now thought that dyskinesia results from alteration in the GPi/SNr neuronal firing pattern and not simply the firing frequency alone
This leads to transmission of misinformation from pallidum to thalamus/cortex leading to dyskinesia
87
dyskinesia with levodopa use most likely occurs in this subset of population (4)
* Younger individuals
* Women
* Those using higher doses of levodopa
* Those with more severe disease
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Difference between ON vs OFF episodes
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What is on-off phenomenon
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What is wearing off effect
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What is peak-dose dyskinesia
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What is diphasic dyskinesia
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Consist of transient stereotypic rhythmic movements that predominantly involve the lower extremities asymmetrically
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treatment for diphasic dyskinesia
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How to Minimize risk of developing motor complications in px using levodopa (2)
* Using the lowest dose of levodopa that provides satisfactory benefit
* Use of polypharmacy
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Location of absorption of levodopa
Duodenum
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Px craving for levodopa and take frequent and unnecessary doses in an addictive manner
Dopamine dysregulation syndrome
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Purposeless, stereotyped behaviors like the assembly or disassembly or collection and sorting of objects
Punding
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LEVODOPA has neither beneficial nor deleterious effect on disease progression. True or False
TRUE. LEVODOPA has neither beneficial nor deleterious effect on disease progression. It is used solely to provide symptomatic relief balanced by the risk of causing motor complications and other side effects
100
PET or SPECT findings in PD
Shows REDUCED and ASYMMETRIC uptake of striatal dopaminergic biomarkers particularly in the posterior putamen with relative sparing of the caudate nucleus
These findings reflect the degeneration of nigrostriatal dopaminergic neurons and the loss of their striatal terminals
101
Most common genetic association with PD
Genetic variants of GBA (glucocerebrocidase)
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Responsible for 1% of typical sporadic cases of PD
Genetic variants of LRRK2 gene
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Most common cause of secondary parkinsonism
Neuroleptics (dopamine-blocking agents)
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Region of basal ganglia affected by carbon monoxide
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Region of basal ganglia affected by manganese
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Region of basal ganglia affected by stroke or tumor
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Disease that Results from mutation in the GTP-cyclohydrolase 1 gene
Dopa-responsive dystonia
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Should be considered in patients <20 years old who present with parkinsonism particularly if there are dystonic features
Dopa-responsive dystonia
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Can be prevented with the use of copper chelators
Wilson's disease
110
Has Westphal variant (juvenile form)
Huntington's disease
111
Formerly known as Hallervorden-Spatz disease
PANK-associated neurodegeneration
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Neurodegenerartive disorder assoc with parkinsonism that is associated with brain iron accumulation
PANK-associated neurodegeneration
113
Alternative diagnosis to consider if there is:
early speech and gait impairment (no tremor, no motor asymmetry, with early falls
114
Alternative diagnosis to consider if there is:
exposure to neuroleptics
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Alternative diagnosis to consider if there is:
onset prior to 40 years old (3)
116
Alternative diagnosis to consider if there is:
liver disease (2)
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Alternative diagnosis to consider if there is:
diplopia, impaired vertical gaze
118
Alternative diagnosis to consider if there is:
poor or no response to an adequate trial of levodopa (2)
119
Alternative diagnosis to consider if there is:
dementia as first or early feature
120
Alternative diagnosis to consider if there is:
prominenty orthostatic hypotension
121
Alternative diagnosis to consider if there is:
prominent cerebellar signs
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Alternative diagnosis to consider if there is:
slow saccades with impaired downward gaze
123
Alternative diagnosis to consider if there is:
high frequency 6-10Hz symmetric postural tremor with a prominent kinetic component
124
Unlike levodopa,
they do not require metabolic conversion
and Do not undergo oxidative metabolism
Dopamine agonists
125
Adverse effects
Unwanted sleep episodes
Impulse-control disorder
dopamine agonists
126
That is why some doctors initiate this type of drug in YOUNGER patients who are more prone to develop motor complications because they are less prone to dyskinesia
Dopamine agonists
127
Side effect of dopamine agonists (ergot derivates)
128
Non-ergot dopamine agonists (3)
129
How to administer the following dopamine agonists :
* Ronipinirole
* Pramipexole
* Rotigotine
* Apomorphine
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Dopamine agonist with efficacy comparanble with Levodopa
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Careful while driving . Should not drive when tired when using this drug class
Dopamine agonists
132
Leg edema as chronic side effect of this drug class
Dopamine agonist
133
Drug class that blocks central dopamine metabolism
MAO-B inhibitor
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Examples of MAO-B inhibitors (3)
Selegiline, Rasagiline, Safinamide
135
2 drugs that....
Provide antiparkinsonian benefits when used as monotherapy in early disease
Reduce "off" time when used as adjunct to levodopa
Selegiline and Rasagiline
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Relatively selective suicide inhibitors of the MAO-B isoform of the enzyme
Selegiline and Rasagiline
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Inhibition of MAO-A isoform prevents metabolism of tyramine in the gut leading to a potentially fatal hypertensive reaction
Cheese effect
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Reversible MAO-B inhibitor
Safinamide
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Also acts on SODIUM CHANNELS and inhibit glutamine release
Potential to provide antiparkinsonian as well as anti dyskinetic effect
Safinamide
140
What STUDY:
Selegiline significantly delayed the time till the emergence of disability necessitating the introduction of levodopa
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What STUDY:
Early treatment with RASAGILINE 1mg/d provided benefits that could not be achieved when treatment with same drug was initiated at a later time point
142
* Increase the elimination half life of levodopa and enhances it brain availability
* Reduces "off" time
* Prolongs "on" time
COMT INHBITORS
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Metabolizes levodopa in the peripehery
Catechol-O-methlytransferase (COMT) enzyme
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Examples of COMT inhibitors (3)
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COMT inhibitor that has fatal hepatic toxicity
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most effective COMT inhibitor
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COMT inhibitors that cause severe diarrhea
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Stalevo is a combination of what 3 drugs
149
differentiate the 3 COMT inhibitors in terms of timing and frequency of administration
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Urine discoloration is seen in what PD drug class
COMT inhibitors
151
Drug class that decreases the excessive activation of the indirect pathway in PD
Adenosine A2A receptor antagonists
152
Drug class that:
* Restores the balance in the basal ganglia -thalamocortical circuit
* Providing a dopaminergic effect without the need to increase levodopa doses
Adenosine A2A receptor antagonists (Istradefylline)
153
Only Adenosine A2A receptor antagonist that is approved for use
Istradefylline
154
Drinking coffee is associated with reduced frequency of PD . True or False
True. Coffee is A2a antagonist
155
Introduced initially as antiviral agent but noticed to have antiparkinsonian effect (due to NMDA receptor antagonism effect)
Amantadine
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Role of amantadine in early vs late PD
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ONLY oral agent able to reduce dyskinesia WITHOUT worsening parkinsonian features
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SIDE EFFECTS
* Cognitive impairment
* Livedo reticularis
* Weight gain
* Withdrawal-like symptoms (hence should be discontinued gradually)
Amantadine
159
PD drug class whose Major clinical effect is addressing tremors
CENTRAL-ACTING ANTICHOLINERGICS
Example: Benztropine and Trihexypenidyl
160
SIDE EFFECTS particularly in the elderly
* Urinary dysfunction
* Glaucoma
* Cognitive impairment
CENTRAL-ACTING ANTICHOLINERGICS
Example: Benztropine and Trihexypenidyl
161
An anticonvulsant which also has antiparkinsonian effect
Zonisamide
162
ON-DEMAND THERAPIES FOR "OFF" PERIODS (3)
* Inhaled Levodopa
* SQ Apomorphine
* SL Apomorphine
163
indication for Deep brain stimulation (2)
Primarily indicated for px
* who suffer disability resulting from levodopa-induced motor complications
* With severe tremors
164
Simulates the effects of a lesion without needing to make a brain lesion
Deep Brain Stimulation
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parts of basal ganglia targeted by deep brain stimulation (2)
Targets STN or GPi
166
stimulation of what part of basal ganglia is assoc with decreased frequency of depression
GPi
167
* Persists after lowering or even stopping levodopa
* Postulated to be related to suboptimal release of dopamine from grafted cells leading to a sustained form of diphasic dyskinesia
GRAFT-INDUCED DYSKINESIA
168
2 examples of proteins that enhance neuronal growth and restore function to damaged neurons
Trophic factors : GDNF (glial-derived neurotrophic factor) and Neurturin
169
virus most often used in gene therapy for PD
AAV2 virus
170
Difference between gene therapy and gene delivery
171
Drug that may be helpful for both PD motor features and depression
Pramipexole
172
Harbinger of developing dementia
PSychosis
173
Drugs for anxiety in PD
Short-acting benzodiazepines
174
severe side effect of clozapine
agranulocytosis
175
differs from other atypical neuroleptics in that it is also an inverse agonist of the serotonin receptor
Pimavanserin
176
In contrast to AD, this disease primarily affects executive functions and attention with relative sparing of language, memory, and calculation domains
Dementia in PD (PDD)
177
if dementia precedes, develops, coincident with, or occurs within 1 yea
DLB (not PDD)
178
* Drugs used to treat PD can worsen cognitive function. They are discontinued in the following sequence
179
what to give if PD px develops sexual dysfunction
Sildenafil or Tadalafil
180
What to give if PD px develops sleep disturbancews
Clonazepam 0.5 to 1mg at bedtime
181
EXERCISE - generally recommended for ALL PD patients .. True or False
True
182
Major cause of falling
Freezing
183
Treatment of FREEZING during ON vs OFF periods
184
Dopamine terminal degeneration
May be complete within ________years of diagnosis
4 years
185
Premotor features of PD (3)
Constipation, RBD, anosmia
186
Met all 3 prespecified primary endpoints consistent with a disease-modifying effect
Rasagiline 1mg per day
187
ideal subsets of population wherein levodopa, MAO B inhibitor, or Dopamine agonist should be started
188
Only drug that has been demonstrated to TREAT dyskinesia WITHOUT worsening parkinsonism
Amantadine
189
What is Duodopa
Continuous intraintestinal infusion of levodopa/carbidopa intestinal gel
190
Drug Associated with skin nodules
Apomorphine continuous infusion
