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Neurosciences > Exam3Lec4IntrotoMovementDisorders (HD/PD) > Flashcards

Exam3Lec4IntrotoMovementDisorders (HD/PD) Flashcards

1
Q

What is Huntington’s disease?

A

Neurodegenerative disease known for its prominent clinical feature of chorea

Behavioral and Cognitive Changes are also prominent

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2
Q

What is the pattern of inhertance for HD and the mutation?

A

Autosomal dominant pattern of inheritance
Mutation on chromosome 4 is an expansion of a polyglutamine repeat (>39 repeats of CAG) on HTT gene

only 1 mutatuted gene passed on=can get disease

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3
Q

What are 3 characteristics of HD in terms of movement?

A
  1. Often: hyperkinetic, choreiform
  2. Later in disease: Dystonia, rigidity, akinesia
  3. Juvenile onseit (<20 yrs old): Rigidity, bradykinesia, tremor

looks like PD when young
dystonia: abnoral posture due to sustained muscle contraction or going from 1 abnormal posture to anothert in a slower writing twisting manner. Slower and stiffer movement

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4
Q

What is the average age onset and avg age survival for HD?

A

Average age onset = 40 years
Average survival 15-20 years although varies

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5
Q

What is the prognosis for HD in early, middle, and advances stages?

A
  1. Early: mood changes and subtle cognitive issues
  2. Middle stage: Chorea
  3. Advanced stages: dementia and parkinsonism
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6
Q

What are 4 additional clinical features present with HD?

A
  1. Motor sequencing- fine motor ( all motr fxn messed up, not just chorea)
  2. Bradykinesia- slow movements
  3. Dysarthria/Dysphagia- speech/swallow
  4. Gait instability and falls

Leading cause of nursing home placement
More difficult to treat (PT/OT/ST)

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7
Q

What are 3 psyhiatric issues present with HD?

A
  1. Mood disurbances: depresseion, anxiety, mania
  2. OCD: Mild obessiveness can be seen
  3. Psychosis: Hallucination rare, Delusion more common but still rare
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8
Q

What percentage of HD patients experience depression? These patients with depression also have what risk?

A

40%. Suicidal attempt is at 7.3%-12%,
which is greater than average risk

depression is not correlated with disease severity

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9
Q

What are 6 behaviors seen with HD?

A
  1. Outbursts of temper
  2. Fits of despondency
  3. Jealousy
  4. Promiscuity/Paraphilias
  5. Alcholism
  6. Smoking

lots of impulsivity

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10
Q

Neuropathology of HD

A

thin ribbon of caudate and deep sulci
marked atrophy of the caudate and putamen (striatum)

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11
Q

Which neurons are the 1st to degenerate and result in chorea early on in HD?

ON EXAM

A

Striatal, medium sized neurons, that are gabaergic and enkelaphenergic than project from the putamen (striatum) to the GPexternal.

ON EXAM

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12
Q

Early chorea in HD is associated with loss of ___ ___ spiny neurons

A

striatal GABA/Enk

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13
Q

Pathological examination of a case of early chorea in HD showed loss of projection from ____ to ____+

A

putamen to GPex

early in diseae, loose proj to GPex

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14
Q

a case of juvenile HD (with rigidity and dystonia) showed loss of projections from ____ to ____

A

putamen to both GPex and GPint

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15
Q

Genetics of HD (3 points)

A
  1. Autosomal dominant
  2. Each child has 50% chance inheritance
  3. CAG repeat or expansion-> leads to excessive glutamine in Huntington protein
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16
Q

What is the normal, borderline low abnomal, and abnormal amount of CAG repeats?

A
  1. Normal: CAG 10-35
  2. Borderline (intermediate zone): CAG 27-35
  3. Low abnormal: CAG 35-39
  4. Abnormal: CAG >40

for the borderline zone it can expand if passed by male. so they can pass it on to their child and expand the number of repeats, this is not necessarily a mutation

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17
Q

You are more likely to develop HD with how many CAG repeats?

A

39 or more

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18
Q

Expansion of CAG repeats can be seen in what?

A

spermatogenesis
* Greatest expansion was seen in DNA from sperm (> 80 repeats)
* The process of meiosis during spermatogenesis is associated with instability in the repeat length

top=HD bottom=normal chromosome smear= expansion/repeats.

for picture: Analysis of number of repeats in sperm DNA was compared to repeats in lymphoblasts in 5 HD carriers

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19
Q

CAG repeats may expand in ____ via meiosis during ____

A

paternal transmission, spermatogenesis

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20
Q

What are 4 sympotomatic therapeutics used for HD?

A
  1. Anti-depressants (serontonin uptake inhibitors, tricyclics)
  2. Carbamazepine for aggressive outbursts
  3. Neuroleptics (butryophenones-haloperidol or phenothiazines-chlorpromazine) for control of chorea
  4. Monoamine depletors (tetrabenazine)

neuroleptics are dop receptor antags

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21
Q

What are neuroprotective agent therapeutics used for HD, but was later shown to be futile?

A

CoQ10,creatine

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22
Q

Has cell-based therapy for HD been successful?

A

NO, Grafting of human fetal striatal cells to patients with HD has been disappointing

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23
Q

What type of research has opened new avenues for therapeutic applications in the treatment of HD?

A

RNA Interference (RNAi)

RNA interference is a natural gene silencing mechanism mediated by double-stranded RNA

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24
Q

What research was done to prove RNA Interference as a promising therapeutic therapy?

A

mutant HTT expression was silenced in mice.
1. HD gene could be turned on and off
2. When the gene was “on” cellular inclusions of Htt protein and motor dysfunction developed
3. When the gene was “turned off” inclusions disappeared and behavioral changes improved.

silence the gene=prevent the disease from occuring

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25
Q

____ and ____ are two new ways to silence the HD gene to prevent the expression of the HD gene in mice and monkeys

A

siRNA and anti-sense oligonucleotides

26
Q

There were animal experiements where the siRNA directed against the HD gene. How was this administered?

A

It was given by direct infusion into brain or by infusion into the cerebrospinal fluid at the lower spine.

27
Q

What are 3 obstacles to human Gene Silencing in HD?

A
  1. Need for continuous expression of the siRNA against htt and need to deliver the siRNA to all levels of brain, not only striatum
  2. At present requires direct infusion to striatum via a pump to deliver the gene for anti-htt siRNA or infusion into the CSF at the lower spine (intrathecal infusion pump) (invasive)
  3. Need to cvoid “off-target” effects Anti-htt siRNA may affect the normal HD allele
28
Q

What was the goal of Dr. Sanchez-Ramos research to overcome the major obstacle to fulfilling the therapeutic promise of gene silencing technology ?

A

The goal was to design and test a nanocarrier for non-invasive delivery to brain of molecules useful for gene therapy.

29
Q

What were the results of Dr. Sanchez-Ramos nanoparticles research?

A
  1. Mn T1 signal levels were significantly increased in olfactory bulb, hippocampus, corpus striatum and frontal cerebral cortex
  2. GFP silencing in OB, ST and HI, even when NPs did not contain Mn (grey bars); FC (frontal cortex) was silenced only when Mn-containing NPs were used

OB, Hippocampus, Cerebral cortex, and Corpus striatum all had high lvls of maganese

30
Q

What was the result of Dr. R-S research?

from TA

A

Mouse brain sections show expression of RFP in neurons of olfactory bullb (OB), striatum (ST) and hypothalamus (HT) after 48 hrs.

RFP was used to visualize distribution of transgene within the brain. Results indicate even distribution of transgene across various portions of the brain which was a large concern with this therapeutic method.

31
Q

What are 3 processes where nanoparticles can be transported and if successful, will have a significant impact on disease-modifying therapeutics of neurodegenerative diseases?

A

1.CN 1 and 5 innervation of mouse nasal epithelium.
2.Transport of NPs via perineural and perivascular channels to OFB and CSF.
3.Mn and the divalent metal transporter (DMT1) in the active uptake by olfactory nerves.

32
Q

A pt had a very small stroke that caused a lesion in a specific part of the brain. This lesion caused hemichorea/hemiballismus (movements are quick and sudden). What is the lxn of this pt’s lesion?

on exam

A

Subthalamic nucleus

on exam

damage to subthalamic nucleus= hemi-chorea

33
Q

If you stimulate the Subthalamic nucelus, what can occur?

A

You get attenuation of hemi chorea and motor fxn. So you can smooth complex motor fluctation

34
Q

Chorea can be caused by what 3 things?

A
  1. Drugs
  2. Strokes
  3. Hereditary disorders
35
Q

What is PD?

A

Progressive disorder of unknown cause that results in degeneration of dopaminergic neurons and loss of dopamine

hypokinetic moving disorder

36
Q

What is the hallmark of PD?

A

Loss of dopaminergic neurons/projections from Substansia nigra onto striatum. So there is a lack of dopamine to striatum

37
Q

PD begins on which side of the body?

A

Begin gradually, typically on one side of the body first, then both sides. (unilaterally then becomes bilateral)

38
Q

What are 3 different types of dopamine replacement therapy given to help improve symptoms?

A
  1. Levodopa/carbidopa (Sinemet)
  2. Levodopa/carbidopa/comtan (Stalevo)
  3. Dopamine agonists (Pramipexole, Ropinirole)
39
Q

Name 10 motor sx of PD

A
  1. Tremor at rest
  2. Bradykinesia/Akinesia
  3. Rigidity
  4. Postural instability (later stages)
  5. Decreased arm swing when walking
  6. Micrographia
  7. Hypophonia
  8. Masked face
  9. Slow, shuffling gait
  10. Stooped posture

bradykinesia and rigidity dampens motor fxn and causes sx 4-10.
Micrographia: small handwriting
Hypophonia: low voice volume

40
Q

What are 6 cognitive psychiatric sx associated with PD?

A
  1. Anxiety
  2. Depression
  3. Fatigue
  4. Slow thinking
  5. Hallucinations
  6. Sleep dysfunction

REM disorder are usually seen before degradoing motor fxns alot of times. Although motor symptoms are a key feature of PD, nonmotor symptoms are common and can cause significant disability.

41
Q

What are 6 autonomic sx associated with PD?

A
  1. Drenching sweats
  2. Dyspnea
  3. Orthostatic hypotension
  4. Sexual dysfunction
  5. Seborrhea
  6. Constipation
42
Q

What are 4 sensory/pain sx associated with PD?

A
  1. Tingling sensation
  2. Akathisia
  3. Olfactory deficit
  4. Diffuse pain

akathisia: a state of agitation, distress, and restlessness

43
Q

What is the second most common neurodegenerative disorder?

hy

A

PD

hy

*Alzheimer’s disease is the most prevalent.(#1)

44
Q

What parts of brain are affected with PD?

A
  • Dopaminergic neurons in the substantia nigra degenerate gradually

The substantia nigra is a component of the neuronal circuits required for the control of movement
* PD pathology is not restricted to neurons that control movement, which may explain the presence of the nonmotor symptoms of PD

45
Q

What is the the cause of the classic motor symptoms observed in PD?

A

Degeneration of dopaminergic neurons in the substantia nigra pars compacta

the substantia nigra pigment diminishes

46
Q

A common feature of degenerating neurons is the presence of what?

A

Lewy bodies, which are cellular occlusions containing misfolded, aggregated proteins.

Lewy bodies are cellular occlusions containing misfolded, aggregated proteins and serves as a pathological hallmark for PD

47
Q

Where do lewy body deposits begin?

A

Lewy Body Deposits begins in brainstem and olfactory bulb and spreads gradually

48
Q

What are the different symptomatic therapies used to treat PD?

A
  1. Anti-cholinergic drugs
  2. Dopamine replacement (levodopa, DA agonists)
  3. Amantadine (endog dopamine action)
49
Q

Are anti-cholinergic drugs for PD good for patients >60 and does it work well for slowness and rigidity?

A

NO to both. It’s not good for patients greater than 60 because is can cause memory and cognitive issues and it works well for tremors but not slwoness and rigidity

50
Q

What are different neuroprotective therapies used for PD?

A
  1. Anti-oxidants (vitamin E)
  2. Mitochondrial enhancers (CoQ10)
  3. Anti-apoptotic agents

none are effective

51
Q

How can azilect be helpful for PD?

A

called rotigotine and it’s an MAO-B inhibitor and has been shown to slow progression

there are some issues to be resolved

52
Q

In the early stage of PD with mild symptoms, no disability, how should treatment start?

A
  1. Delay L-dopa
  2. Dopamine agonists
  3. MAO-B inhibitors

dont usually start with l-dopa early on bc the longer you use it, the more likely you get l-dopa indusced dyskinesia (chorea movement caused by l-dopa)

53
Q

In the moderate stage of PD with moderate symptoms and some disability, how should treatment start?

A
  1. MAO-B inhibitors, dopamine agonists
  2. CD/LD

CD=carbidopa; LD=levodopa

54
Q

In the advanced stage of PD with worsening symptoms and disability, how should treatment start?

A
  1. Need for CD/LD ± adjunctive therapy

advanced stages: Increasing disability, Bedridden/wheelchair
Motor complications from treatment possible

55
Q

How does Levodopa work?

A
  • Enzyme tyrosine hydroxylase (TH) converts Tyrosine to DOPA, which is then changed to dopamine by DOPA decarboxylase (also called AADC) and is stored in a vesicle
  • Dopamine is released and post-synaptic receptors are activated.
  • Released DA is removed from the synaptic cleft by reuptake into the presynaptic neuron and recycled into vesicles for further release.
  • Dopamine that is not taken back into the presynaptic neuron is primarily metabolized by MAO-B into DOPAC.
  • COMT also metabolizes Dopamine to 3-MT
56
Q

Does Levodopa Lose its Benefits?

A

Yes, Basically it starts out with a large therapeutic window and low efficacy threshold. However, as the disease advacenes, you see a smaller therapeutic window and higher efficacy threshold. So this means that the 1/2 life if Levodopa decreases alot and you would need to be given L-dopa more frequently. This can lead to L-dopa induced dyskinesia

57
Q

What are 2 main complications of L-dopa medication?

A

Motor fluctuations
Dyskinesia

58
Q

Explain 3 types of dyskenesias that can occur with L-dopa depending on the dose of L-dopa

A
  1. Maxium concentration of an L-dopa dose: Peak-dose dyskinesia
  2. Beginning or end of L-dopa dose: Diphasic dyskinesia
  3. early morning, Before the 1st dose of L-dopa: Dystonia
59
Q

Direct electrical stimulation of ____ can diminish bradykinesia/rigidy (improving parkinsonism)

A

subthalamic nucleus

60
Q

When should a patient with PD consider deep brain stimulation (DBS)

A

1.Motor complications with dyskinesias are not responding to optimal treatment with medication
2.Good acute response to a trial dose of levodopa
3.No existing problems with cognitive function (no dementia)
4.No other significant medical problems

Neurosciences (28 decks)

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