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Neurology > Neurodegenerative Diseases Pt. 2 > Flashcards

Neurodegenerative Diseases Pt. 2 Flashcards

1
Q

What is the second most common form of early dementia (<65 yrs) after AD?

A

Frontotemporal Degeneration (FTD)

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2
Q

What is the FTD?

What is the difference between FTD and FTLD?

A
  • FTD: Focal degeneration in frontal and anterior temporal lobes
  • FTD refers to the clinical frontotemporal dementia syndrome
  • FTLD (frontotemporal lobar degeneration) refers to the pathologic entitiy
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3
Q

What percentage of FTD are sporadic?

A

50%

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4
Q

What mutations are associated with familial cases of FTD?

A

Inherited as autosomal dominant

  • Tau gene (MAPT) – accumulation of tau
  • Progranulin (GRN) – accumulation of TDP-43 protein (DNA binding protein)
  • C9orf72: results in accumulation of TDP-43 protein
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5
Q

What are the two clinical subtypes of FTD?

A

Behavioral variant FTD (50%) - Bi frontal lobe atrophy

Primary progressive aphasia - Progressive nonfluent aphasia or Semantic variant

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6
Q

What are the characteristics of Behavioral Variant FTD?

A
  • Socially inappropriate behavior, loss of manners, careless actions
  • Early apathy or inertia
  • Early loss of sympathy or empathy
  • Early perseverative, stereotypes, or compulsive/ritualistic behavior
  • Hyperorality and dietary changes (crave sweets)
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7
Q

What are the two subtypes of Primary Progressive Aphasia and what are the characteristics associated with the disease?

A
  • Progressive nonfluent aphasia (PNFA 25%) – left peri-sylvian atrophy on scan
  • Semantic variant (20-25%) – bilateral anterior temporal lobe atrophy
  • Subtypes
    • Fluency; comprehension; repetition
    • Fluency worst in nonfluent aphasia
    • Comprehension worst in semantic variant
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8
Q

Frontotemporal lobar degeneration (FTDL)

What changes are seen in the brain?

What are the microscopic findings?

A
  • What changes are seen in the brain?
    • Frontal and temporal lobe atrophy
  • What are the microscopic findings?
    • Tauopathies - accumulation of tau protein
    • Accumulation of TDP-43 (cytoplasmic protein accumulations in frontal/temporal lobes)
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9
Q

What is Pick’s disease? What are it’s characteristics?

A

A “Tauopathy” characterized by:

  • Atrophy of frontal and temporal lobes
  • Severe neuronal loss in the frontal and temporal cortex
  • Pick bodies (round cytoplasmic inclusion in neurons containing abnormal tau filaments)
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10
Q

What are the clinical features of parkinsonism?

A
  • Rigidity
  • Bradykinesia (slowed movements)
  • Tremor
  • Mask facies, stooped posture, festinating gait (progressively shortened accelerated steps)
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11
Q

Parkinson’s Disease (PD)

What is the strongest risk factor?

What is the lifetime risk?

A
  • Age is the strongest risk factor
  • 1/40 lifetime risk
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12
Q

Is Parkinson’s Disease predominantly sporadic or familial?

A

Sporadic

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13
Q

What are the mutations described in PD familial cases?

A
  • Parkin gene: chromosome 6 - younger onset
  • α-synuclein gene: rare mutation in families with autosomal dominant familial PD (major component of Lewy bodies)
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14
Q

What environmental toxins and pesticides can cause PD?

A
  • Manganese
  • Carbon monoxide
  • Rural living (well water)
  • Paper mills
  • Hydrocarbons
  • Residential use of pesticides
    • caffeine and cigarette smoking may be protective
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15
Q

Describe a tremor in relation to PD

A
  • Most common presenting symptom
  • Typically asymmetric and low frequency
  • Pill-rolling type of movements
  • Most often affects the distal upper extremities
  • Chin tremor specific for PD
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16
Q

Describe Bradykinesia in relation to PD

A
  • Slowness or lack of movement
  • Micrographia (small cramped handwriting)
  • Hypophonia (soft speech)
  • Hypomimia (reduced racial expression)
  • Decreased blink rate
  • Decreased arm swing with walking
  • Shortened stride length
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17
Q

Describe postural instability and gait disturbance in terms of PD

A
  • Early: manifests as dragging of one leg or stooped posture
  • Later: gait problems can be severe
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18
Q

What are the nonmotor symptoms in the premotor phase of PD?

A
  • Sleep: REM behavior disorder
  • Olfactory loss
  • Dysautonomia
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19
Q

What are some supportive criteria in diagnosing PD?

A
  • Unilateral onset
  • Tremor
  • Excellent response to levodopa (Only confirmatory test)
  • Clinical course for 10 years or more
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20
Q

What are some changes to the brain in PD?

A
  • Pallor of substantia nigra
  • Neuronal loss and Lewy bodies in substantia nigra
  • Lewy bodies (eosinophilic cytoplasmic neuronal inclusions containing α-synuclein)
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21
Q

What are the characteristics and diagnostic clinical features of Dementia with Lewy Body (DLB)?

A

Characterized by dementia with ant two of the following three core clinical features

  1. Fluctuating cognition or level of consciousness
  2. Visual hallucinations
  3. Parkinsonian motor signs
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22
Q

What features are suggestive of DLB?

A
  • Rapid eye movement
  • Neuroleptic sensitivity
  • Low dopamine transporter uptake in the basal ganglia
23
Q

How are DLB and PD different in terms of clinical presentation?

A
  • DLB – clinical features of dementia (first sign)
  • PD – patients present with parkinsonism signs and symptoms
    • Eventually develop dementia (5x more frequent than controls)
    • Pathologic correlate of dementia is Lewy body presence in cortex
24
Q

What microscopic changes in the brain are seen in Dementia with Lewy bodies?

A
  • Neuronal loss and Lewy bodies in substantia nigra
  • Lewy bodies in the cerebral cortex
25
Q

How are dopaminergic cells reduced in Parkinson’s disease?

A
  • Dopaminergic cells of substantia nigra are selectively vulnerable because:
    • Dopamine (with MOA) → DOPAC + H2O2 → ROS (fenton reaction)
  • As cells age, the accumulation of years of free radicals reduces the number of DA cells
26
Q

What is the Mechanism of L-DOPA?

A
  • Restore levels of dopamine in the basal ganglia
  • Uses amino acid transporters to enter the brain
  • Decarboxylated to dopamine in dopamine cells and other neurons that express L-aromatic amino acid decarboxylase (L-AAAD)
27
Q

What are some pharmacokinetic considerations for L-DOPA and how can these be a problem?

A
  • At most 2% of an oral dose of L-DOPA gets into the brain
    • Most is metabolized to dopamine by peripheral L-AAAD or COMT
    • Lots of dopamine peripherally leads to side effects
28
Q

How are the issues with L-DOPA administration overcome?

A
  • L-DOPA is almost always co-administered with carbidopa (an inhibitor of L-AAAD) that does not cross the BBB
    • Results in increased dose in the CNS, decreased peripheral side effects
  • L-DOPA now co-administered with entacapone (COMT inhibitor)
    • Entacapone does cross BBB (preserves concentrations in brain)
29
Q

What is the half life of L-DOPA?

Why does it’s absorption depend upon GI contents?

A
  • Half life of L-DOPA is very short (1-3 hours)
  • Absorption is dependent on GI contents because it is taken up by amino acid transporters which may be saturated after a meal
30
Q

How effective is L-DOPA in treating Parkinson’s disease?

When is treatment started?

A

VERY EFFECTIVE - if it doesn’t help the patient probably doesn’t have Parkinson’s disease in the first place

Best results are obtained in the first few years of treatment so L-DOPA is not used until symptoms cause functional impairment

31
Q

What are some side effects of L-DOPA due to its conversion to dopamine?

A
  • CNS effects (not alleviated by carbidopa)
    • Dyskinesias (too much movement); Dementia, confusion
  • GI: nausea
  • Cardiovascular (hypotension, arrhythimas, HTN)
32
Q

What are some potential drug interactions with L-DOPA?

A
  • Pyridoxine (Vit B6: increases metabolism of dopamine in periphery)
  • MAO inhibitors (can cause hypertension)
  • Halothane (sensitizes the heart to arrhythmias)
  • Antipsychotics that are dopamine receptor antagonists
33
Q

What are some contraindications to L-DOPA use?

A
  • Glaucoma
  • Psychosis
  • Cardiac disease that involves arrythmias
  • Malignant melanoma
34
Q

What is the main reason for the use of dopamine agonists instead of L-DOPA?

A

L-DOPA treatment can result in increased oxidative stress due to its natural metabolism

35
Q

What advantages do dopamine receptor agonists have over L-DOPA?

A
  • No enzymatic conversion is needed
  • Selectivity for receptor subtypes
  • Longer half-life
  • Less DA-dependent oxidative stress
36
Q

What are the two types of dopamine agonists and which receptors do they activate?

A
  • Pramipexole and Ropinerole: selective D2 agonists; most commonly used
  • Apomorphine – high affinity D4 agonist – moderate affinity for D2, D3, D5
37
Q

What is an “off episode” and how is it dealt with?

A

An “off” episode occurs when your Parkinson symptoms still exist, even though you take medicines to control them

Treated with subcutaneous injection of amorphine

38
Q

Which treatment (L-DOPA or dopamine agonists) are the initial therapy in young patients? Which is used in the elderly?

A

Direct agonists are the initial therapy in young patients

L-DOPA in the elderly

39
Q

What are the side effects of dopamine agonists?

A
  • Nausea
  • Fatigue
  • Sudden attacks of daytime sleep
  • CNS toxicity (confusion)
  • Amorphine can cause increased QT prolongation and injection site reactoins
40
Q

Why are MAO inhibitors not as effective as other drugs in the treatment of Parkinson’s disease?

A

MAO in the liver is essential to metabolize tyramine that is injested; tyramine is a sympathomimetic

41
Q

What are the two forms of MAO and where are they found?

A

MAO-A is found in the GI tract and liver

MAO-B in brain

42
Q

What are the MAO-B inhibitors and how are they effective against PD?

A

Selegilline and Rasagiline

  • MAO inhibition will prolong the action of dopamine; and may also reduce oxidative stress on neurons
43
Q

What is the clinical usefulness of a MAO inhibitor and when is it prescribed?

A
  • Usually prescribed as soon as the disease is diagnosed (may reduce progression – benefit is modest)
  • In more advanced disease, used together with L-DOPA to prolong its effective half life
  • Anti-depressant (increases NE)
44
Q

What are the side effects of MAO inhibitors?

A
  • Generally well tolerated
  • In advanced disease – worsens side effects of L-DOPA
  • Metabolized to amphetamine and methamphetamine (can cause anxiety and insomnia)
  • Reduced SE when administered as an orally disintegrating tablet or as patch (avoid 1st pass metabolism)
45
Q

What are some adverse drug interactions associated with MAO inhibitors?

A
  • When administered in combo with meperidine
  • Tricyclic antidepressants
  • Serotonin reuptake inhibitors (MAO inhibitors can ↑ serotonin)
  • Can lead to serotonin syndrome (stupor, rigidity, agitation, hyperthermia)
46
Q

What are the COMT inhibitors?

What is their clinical usefulness?

A
  • Tocapone (causes hepatotoxicity) – Has a relatively long half life and inhibits both peripheral and central COMT
  • Entacapone – has a short half life and does not get into the CNS well; therefore is usually co-administered with L-DOPA to eliminate peripheral metabolism
47
Q

What side effects are associated with COMT inhibitors?

A
  • Common due to increased dopamine:
    • nausea
    • orthostatic hypotension
    • vivid dreams
    • confusion, hallucinations
48
Q

What are the antimuscarinics? How do they work?

A
  • Cholinergic interneurons in the striatum are normally inhibited by dopamine; loss of dopamine → overactivity of these neurons; this effect is blunted by antimuscarinics (Antagonist of striatal muscarinic receptors)
  • Trihexyphenidyl; Benztropine
  • Diphenhydramine (anti-histamine with anti-muscarinic “side effects”)
49
Q

How effective are the antimuscarinics? When are they used?

A
  • Modest effectiveness: not good against bradykinesia
  • 3rd choice – used when dopaminergic therapy is contraindicated (early disease; elderly)
  • Can be used in combination with L-DOPA agonists so that their dose can be lower
50
Q

What are the side effects of the anti-muscarinics?

A
  • Sedation; mental confusion
  • Atropine-like side effects in the periphery
51
Q

What is Amantadine? How does it work in PD treatment?

A

Anti-viral agent

In PD, increases dopamine release and is mildly anticholinergic

Blocks NMDA receptors

52
Q

What is the effectiveness of Amantadine and when is it used?

A
  • Less effective (short-lived benefits)
  • Often given with L-DOPA or with anticholinergics
  • Not useful when L-DOPA is ineffective
53
Q

What are some side effects of Amantadine?

When is it contraindicated?

A
  • Dizziness, lethargy, sleep disturbances
  • Can cause peripheral edema
  • Sympathomimetic effects due to effects on catecholamine release
  • Contradindicated in patients with congestive heart failure

Neurology (26 decks)

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