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Neuroscience: Exam 3 > Lecture 4: Huntington's Disease & Parkinson's Disease > Flashcards

Lecture 4: Huntington's Disease & Parkinson's Disease Flashcards

1
Q

What is Huntington’s Disease?

A

Neurological disorder characterized by spasmodic involuntary movements of the limbs or facial muscles (Chorea)

Chorea→dance like

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2
Q

What are the clinical features of Huntington’s Disease (3)?

A
  • Chroea → spasmodic involuntary movements of the limbs or facial muscles
  • Autosomal dominant pattern of inheritance → mutation on chromosome (chromosome 4 exon 1) is an expansion of a polyglutamine repeat (≥ 39 repeats of CAG)
  • Behavioral and Cognitive changes
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3
Q

What are the clinical features/characteristics of Huntington’s Disease (3)? What clinical feature is prominent in juvenile-onset of HD (3)?

A
  • Most often hyperkinetic, choreiform (jerking/writhing movements)
  • Dystonic, rigidity, and akinesia supervene later in the course
  • Rigidity, bradykinesia (slow movements), and tremors can be prominent in juvenile-onset HD (<20 years of age)
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4
Q

What are the clinical features of incoordination in HD (4)?

A
  • Motor sequencing → fine motor
  • Bradykinesia → slow movements
  • Dysarthria/Dysphagia → speech/swallow
  • Gait instability and falls

Dysarthria → disorder of speech
Dysphasia → disorder of language

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5
Q

What is the average onset age of HD? and average survivial length?

A
  • 40 years
  • 15-20 years although varies

10% <20, 10% >60

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6
Q

What are the psychiatric conditions associated with HD (3)?

A
  • Mood disturbances → depression, anxiety, mania
  • OCD → mild obsessiveness can be seen
  • Psychosis → hallucination rare, delusion more common but still rare
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7
Q

What is the suicidal attempt rate from depression associated with HD?

A
  • Suicidal attempt → 7.3% - 12%
  • Greater than average risk
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8
Q

What part of the brain does dementia from HD cause cognition to decline?

A

Subcortical

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9
Q

What are the factors that contribute to changes in behavior from HD (2)? What are the clinical presentations of behavior in HD (4)?

A

Factors

  • Outbursts of temper → hunger, thirst, pain, inability to communicate, frustration with failing abilities, boredom, changes in routine
  • Fits of despondency

Clinical Presentations

  • Jealously
  • Promiscuity/Paraphilias → voyeriusm, exhibitionism
  • Alcoholism → 17% males, 6% females
  • Smoking → high cardiovascular mortality
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10
Q

How does a brain affected by HD appear?

A

Marked atrophy of the caudate and putamen (striatum)

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11
Q

Which striatial neurons are the 1st to degenerate with HD?

A

Spiny I: GABA/Enk medium spiny neurons that project from putamen (striatum) to external globus pallidus

ON EXAM

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12
Q

What is the clinical presentation of a brain with early chorea in HD?

A

Loss of projections from putamen to external globus pallidus (GPex)

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13
Q

What is the clinical presentation of a brain with juvenile HD (rigidity and dystonia)?

A

Loss of projections from the putamen to both external (GPex) and internal globus pallidus (GPint)

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14
Q

What can cause sudden onset hemichorea-hemiballismus?

A

lesion in the brain from a stroke in subthalamic nucleus

ON EXAM

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15
Q

What genetically causes HD?

A

Mutation of chromosome 4 → causes an expansion of a polyglutamine repeat (≥ 39 repeats of CAG) on the Huntingtin protein (HTT gene)

Excessive glutamine in Huntington protein

CAG repeats may expand in paternal transmission via meiosis during spermatogenesis → instability in the repeat length

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16
Q

What is the normal, borderline, low abnormal, and abnormal levels of CAG?

A
  • Normal: CAG 10-35
  • Borderline: CAG 27-35 (may expand if passed by male)
  • Low abnormal: CAG 35-39 (may develop disease)
  • Abnormal: CAG >40 (will develop disease)

  • Up to 26→normal never get the illness
  • Up tp 36→most likely to get when older
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17
Q

What types of drugs are used for symptomatic therapy to treat HD (4)?

A
  • Anti-depressants → serotonin uptake inhibitors, tricyclics
  • Carbamazepine for aggressive outbursts
  • Neuroleptics → eg butyrophenones-haloperidol or phenothiazines-chlorpromazine for control of chorea
  • Monoamine depleters → tetrabenazine
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18
Q

What neuroprotective agents are used as therapy for HD (2)?

A
  • CoQ10, creatine → recently shown to be futile as neuroprotective agents
  • Other agents have been tried but failed as neuroprotectants → Remacemide, riluzole, minocycline
19
Q

What is RNA interference as a therapy for HD?

A

a natural gene silencing mechanism mediated by double-stranded RNA

20
Q

How was RNA interference clinically demonstrated as an option for therapy for HD (proof of concept)?

A
  • The silencing of mutant HTT expression was demonstrated in a tetracycline-regulated conditional mouse mode of HD 10 years ago
  • HD gene could be turned on and off in mice
  • When the gene was on → cellular inclusions of HTT protein and motor dysfunction developed
  • When the gene was off → inclusions disappeared and behavioral changes improved
21
Q

How was the siRNA directed against the HD gene administered in animal experiments (2)?

A
  • Direct infusion into the brain
  • By infusion into the cerebrospinal fluid at the lower spine
22
Q

What are the obstacles to human gene silencing in HD (4)?

A
  • Find a non-invasive way to deliver drugs so that they reach all levels of the brain (not just the striatum) and can be used for decades
  • Need for continuous expression of the siRNA against htt
  • Requires direct infusion to stratum via a pump to deliver the gene for anti-htt siRNA or infusion into the CSF at the lower spine (intrathecal infusion pump)
  • Avoid “off-target” effects → anti-htt siRNA may affect the normal HD allele
23
Q

What was the Nanoparticles for “Direct Nose-to-Brain delivery of Gene Therapy” experiment?

A

C57/BL mice were given intranasal manganese-nanoparticles (Mn-NPs) loaded with a transgene (dsDNA encoding red fluorescent protein (RFP) )

24
Q

What was the result of the Nanoparticles for “Direct Nose-to-Brain delivery of Gene Therapy” experiment?

A

Mouse brain sections showed expression of RFP (red fluorescent protein) in neurons of the olfactory bulb (OB), striatum (ST), and hypothalamus (HT) after 48 hours

25
Q

What is Parkinson’s Disease? What causes it?

A
  • Chronic, progressive, neurodegenerative disease
  • Caused by loss of dopaminergic projections from the substantia nigra pars compacta onto the striatum
26
Q

What are the motor symptoms of Parkinson’s Disease?

A
  • Tremor at rest
  • Bradykinesia/Akinesia
  • Rigidity
  • Postural instability (occurs at later stages & not associated with dopamine loss)
  • Micrographia – small handwriting
  • Hypophonia – low talking
  • Slow, shuffling gait
  • Stooped posture
  • Decreased arm swinging when walking
27
Q

What is the main therapy for Parkinson’s Disease? What are the 3 methods?

A

Symptoms improve when dopamine replacement therapy is instituted

  • Levodopa/carbidopa (Sinemet)
  • Levodopa/carbidopa/comtan (Stalevo)
  • Dopamine agonists (Pramipexole, Ropinirole)

Primary treatment includes Levadopa (precursor) + Carbidopa

  • In the absence of carbidopa, levodopa is converted into dopamine peripherally which can lead to nausea
  • Carbidopa inhibits peripheral decarboxylase which allows levodopa to be transported into the brain
28
Q

What is the 2nd most common neurodegenerative disorder?

A

Parkinson’s Disease

29
Q

What part of the brain is affected by PD?

A
  • Dopaminergic neurons in the substania nigra degenerate gradually
  • Substantia nigra → component of neuronal circuits required for the control of movement

PD pathology is not restricted to neruons that control movement → may explain the presence of the nonmotor symptoms of PD

30
Q

Where are lewy bodies found in a brain affected by PD? What are they?

A
  • Deposits begin in brainstem and olfactory bulb and spreads gradually
  • Presence of lewy bodies (intracellular eosinophilic occulusion) containing misfolded, aggregated proteins
31
Q

What are the 3 therapies that have been used to treat PD?

A
  • Symptomatic Therapy → Anti-cholinergic drug, doapmine replacement (levadopa, DA agonists), Amantadine
  • Neuroprotective therapy → hasn’t been shown to be effective
  • Azilect (has been shown to slow progression, but there are some issues to be resolved) → rotigone, an MAO-B inhibitor
32
Q

When should treatment begin in the early stages of PD? What drugs would be used (3)?

A
  • Mild symptoms, no disability
  • Delay L-dopa
  • Dopamine agonists
  • MAO-B inhibitors
33
Q

When should treatment begin in the moderate stages of PD? What drugs would be used (3)?

A
  • Moderate symptoms with some disability
  • MAO-B inhibitors
  • Dopamine agonists
  • CD/LD
34
Q

When should treatment begin in the advanced stages of PD (5)?

A
  • Worsening symptoms and disability
  • Need for CD/LD ± adjunctive therapy
  • Increasing disability
  • Bedridden/wheelchair
  • Motor complications from treatment possible
35
Q

What are the 2 types of complications of medication (levodopa therapy) used to treat PD?

A
  • Motor fluctuations
  • Dyskinesias
36
Q

Motor fluctuations are one of the complications of levodopa therapy to treat PD. What are the symptoms (4)?

A
  • End of dose →”wearing off”
  • Unpredictable motor fluctuations → “ON-OFF” phenomenon
  • Dose failures → “no-ON” phenomenon
  • Freezing episodes
37
Q

Dyskinesias is one of the complications of levodopa therapy to treat PD. What are the symptoms (3)?

A
  • Peak dose dyskinesia → occurs at the maximum concentration of L-dopa dose
  • Diphasic dyskinesia → occurs at the beginning or end of the L-dopa dose
  • Dystonia → mostly occurs during the early morning, before the first dose of L-dopa
38
Q

How is deep brain stimulation used to treat PD?

A

Direct electrical stimulation of the subthalamic nucleus can diminish bradykinesia/rigidity (improving parkinsonism)

39
Q

When should deep brain stimulation be considered as a treatment for PD (4)?

A
  • Motor complications with dyskinesia are not responding to optimal treatment with medication
  • Good acute response to a trial dose of levodopa
  • No existing problems with cognitive function (i.e. no dementia)
40
Q
  1. A 53-year-old man is rushed to the ED following the sudden onset of strange neurological symptoms. Upon physical exam, physicians note continuous involuntary movements on one side of the body which are suggestive of hemichorea likely caused by a stroke. If so, which of the following structures are likely affected?
    A. Subthalamic Nucleus
    B. Substantia Nigra Pars Compacta
    C. VA/VL Complex
    D. Frontal Cortex
A

A. Subthalamic Nucleus

41
Q
  1. Neuroscientists at the Morsani College of Medicine are studying the association between genetic mutations on Chromosome 4 and the age of onset of Huntington’s Disease (HD). Which of the following study participants is at greatest risk for developing HD?
    A. Participant 1: Age 54, 33 CAG Repeats
    B. Participant 2: Age 24, 29 CAG Repeats
    C. Participant 3: Age 70, 55 CAG Repeats
    D. Participant 3: Age 32, 67 CAG Repeats
A

D. Participant 3: Age 32, 67 CAG Repeats

42
Q
  1. In animal studies, RNA interference (RNAi) therapy has been shown to be effective against Huntington’s Disease (HD). Which of the following best describes the study methods?
    A. Magnesium-nanoparticles (mNP’s) infused with siRNA are delivered intranasally
    B. Uptake of mNP’s is mediated by olfactory nerve divalent metal transporters (DMT1)
    C. Direct infusion of siRNA upregulates HTT gene on chromosome 4
    D. dsDNA expression of red fluorescent protein (RFP) within the striatum alone
A

B. Uptake of mNP’s is mediated by olfactory nerve divalent metal transporters (DMT1)

43
Q
  1. All of following are clinical features associated with Parkinson’s Disease EXCEPT:
    A. Loss of dopaminergic projections
    B. Accumulation of Lewy bodies within the brainstem
    C. Atrophy of the putamen and caudate
    D. Hypokinetic symptoms such as Akinesia
A

C. Atrophy of the putamen and caudate

44
Q
  1. A 67-year-old woman presents to her neurologist after the gradual onset of bradykinesia. Although her symptoms are relatively mild, further testing suggests early-stage Parkinson’s Disease which may progress over time. What is the best course of treatment at this time?
    A. Levodopa alone
    B. Levodopa & Carbidopa
    C. Levodopa, Carbidopa, & Adjunctive Therapy
    D. Dopamine Agonists
A

D. Dopamine Agonists

Neuroscience: Exam 3 (9 decks)

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