Neurodegenerative Diseases Pt. 2 Flashcards Preview

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Flashcards in Neurodegenerative Diseases Pt. 2 Deck (53):

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

Frontotemporal Degeneration (FTD)


What is the FTD?

What is the difference between FTD and FTLD?

  • 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


What percentage of FTD are sporadic?



What mutations are associated with familial cases of FTD?

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


What are the two clinical subtypes of FTD?

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

Primary progressive aphasia - Progressive nonfluent aphasia or Semantic variant


What are the characteristics of Behavioral Variant FTD?

  • 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)


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

  • 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


Frontotemporal lobar degeneration (FTDL)

What changes are seen in the brain?

What are the microscopic findings?

  • 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)


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

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)


What are the clinical features of parkinsonism?

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


Parkinson's Disease (PD)

What is the strongest risk factor?

What is the lifetime risk?

  • Age is the strongest risk factor
  • 1/40 lifetime risk


Is Parkinson's Disease predominantly sporadic or familial?



What are the mutations described in PD familial cases?

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


What environmental toxins and pesticides can cause PD?

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


Describe a tremor in relation to PD

  • 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


Describe Bradykinesia in relation to PD

  • 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


Describe postural instability and gait disturbance in terms of PD

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


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

  • Sleep: REM behavior disorder
  • Olfactory loss
  • Dysautonomia


What are some supportive criteria in diagnosing PD?

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


What are some changes to the brain in PD?

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


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

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


What features are suggestive of DLB?

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


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

  • 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


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

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


How are dopaminergic cells reduced in Parkinson's disease?

  • 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


What is the Mechanism of L-DOPA?

  • 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)


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

  • 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


How are the issues with L-DOPA administration overcome?

  • 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)


What is the half life of L-DOPA?

Why does it's absorption depend upon GI contents?

  • 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


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

When is treatment started?


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


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

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


What are some potential drug interactions with L-DOPA?

  • 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


What are some contraindications to L-DOPA use?

  • Glaucoma
  • Psychosis
  • Cardiac disease that involves arrythmias
  • Malignant melanoma


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

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


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

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


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

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


What is an "off episode" and how is it dealt with?

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

Treated with subcutaneous injection of amorphine


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

Direct agonists are the initial therapy in young patients

L-DOPA in the elderly


What are the side effects of dopamine agonists?

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


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

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


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

MAO-A is found in the GI tract and liver

MAO-B in brain


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

Selegilline and Rasagiline

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


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

  • 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)


What are the side effects of MAO inhibitors?

  • 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)


What are some adverse drug interactions associated with MAO inhibitors?

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


What are the COMT inhibitors?

What is their clinical usefulness?

  • 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


What side effects are associated with COMT inhibitors?

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


What are the antimuscarinics? How do they work?

  • 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”)


How effective are the antimuscarinics? When are they used?

  • 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


What are the side effects of the anti-muscarinics?

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


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

Anti-viral agent

In PD, increases dopamine release and is mildly anticholinergic

Blocks NMDA receptors


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

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


What are some side effects of Amantadine?

When is it contraindicated?

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