Neurodegenerative Disease (Lec 12)

Question 1

Neurodegenerative Disease. . . what is it? Pathogenesis?

Answer 1

 Progressive dysfunction & death of neurons
› Usually excludes diseases of known vascular, toxic, metabolic, infective or autoimmune cause
› Loss of movement & coordination
.
 Pathogenesis
› Genetic susceptibility, environmental factors, aging
› Abnormal protein accumulation in neurons is typical feature (below)
 Parkinson’s Disease: Lewy bodies contain ubiquitan & synuclein
 Alzheimer’s Disease: Neuritic plaques (outside neuron) & neurofibrillary tangles (inside neuron)

Question 2

Degeneration of brain . . .

Answer 2

• Degeneration often affects specific systems implying selective vulnerability
• Neurodegenerative diseases such as Alzheimer’s disease (AD), Frontotemporal
  Lobar Degeneration (FTD), Lewy Body disease (LBD), Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS) ALL exhibit PROTEIN AGGREGATES that
  represent pathological hallmark lesions

Question 3

Parkinson’s Disease . . . general

Answer 3

 Cell loss in substantia nigra (DA neurons)
› Decreased number of dopaminergic neurons 10-20% of normal
 Idiopathic, vascular disease, head trauma, tumors, drug induced parkinsonism, environmental agents
 Lewy bodies: normal brain protein (alphasynuclein) that is “misfolded” and forms
aggregates that are associated with cell
death

Question 4

Issues with neurons in Parkinson’s Disease (PD)

Answer 4

 SN neuron loss may be the result of normal DA metabolism by MAO-B which produces toxic hydroxyl radicals
 DA undergoes auto-oxidation to semiquinones and quinones, also producing superoxide radicals
 Reactive oxygen species (ROS) released from mitochondria & the accumulation of stray lipids may play a role in lysosomal damage. Improperly functioning lysosomes create cellular waste product (α−synuclein) which is left to accumulate inside the cell.

Question 5

Pathophysiology with Parkinson’s Disease

Answer 5

Question 6

Treatment target of Parkinson’s Disease

Answer 6

 DA is not being synthesized in SN
› Treatments target:
1. Replenishing DA levels
2. Mimicking DA activity
3. Antagonizing effects of cholinergic neurons

Question 7

Treatment: Levodopa (PD)

Answer 7

 Mechanism of action is to increase DA in the remaining nigrostriatal neurons of
caudate nucleus
.
 95% of PO L-dopa is converted to DA in the periphery by L-AAD
› Major cause of levodopa peripheral toxicity
————— Orthostatic hypotension: increased NE = central α2 receptors, reduces sympathetic outflow
————— Cardiac stimulation: tachycardia/arrhythmia due to dopaminergic activation of β adrenergic receptors
————— Vomiting: peripheral DA –> activates CTZ –> N/V

Question 8

Treatment: Carbidopa (PD)

Answer 8

 Peripheral Dopamine decarboxylase inhibitor
 Does NOT cross BBB –> decreases peripheral conversion of L-dopa to DA
› Carbidopa + Levodopa (Sinemet) combination routinely used
——–To allow for lower doses of L-dopa
——– To decrease peripheral toxicity

Question 9

Central Toxicity of L-dopa (PD)

Answer 9

1. Dyskinesia: involuntary chorieform movements
2. Behavioral effects: hallucinations, confusion anxiety, agitation, insomnia, delirium, psychotic reactions
3. “ON-OFF” syndrome (long-term l-dopa tx >3 y)
   › Off – rapid loss of therapeutic effect between doses
   › “on-off” syndrome: rapid fluctuations between therapeutic effect and no effect after a single dose of levodopa

Question 10

Treatment: Dopamine agonists (general) (PD)

Answer 10

 Monotherapy or + L-dopa
 Upregulation of D2 receptors in striatum due to low levels of DA release –> increased # of receptors –> greater response to D2 agonists
› Adverse effects: somnolence, N/V, Orthostatic hypotension
› Abrupt withdrawal  anxiety, panic attacks, depression, sweating, nausea, fatigue, dizziness, drug cravings
› Low risk of dyskinesias

Question 11

Treatment: Dopamine agonist - drugs and highlights (PD)

Answer 11

Question 12

Treatment: Selective MAO-B inhibitor (PD)

Answer 12

 Selegiline (Eldepryl, Emsam)
› Selective MAO-B inhibitor at low doses (<10 mg/d)
› Nonselective MAO-A and –B inhibitor (> 10mg/d)
› Potential drug interactions: tyramine containing foods, sympathomimetic compounds, antidepressants, tramadol, meperidine, methadone, dextromethorphan
› Used as adjunct levodopa therapy (Specifically reduces DA metabolism in the SN without the problems seen with tyramine & MAO-A inhibitors)
› May be neuroprotective
.
 Rasagiline (Azilect)
› Selective MAO-B inhibitor @ 0.5 mg/day

Question 13

Treatment: COMT Inhibitor (general) (PD)

Answer 13

 Inhibit catechol-O-methyltransferase (COMT) thereby suppressing metabolism of
L-dopa to 3-OMD. Augments L-dopa availability to brain.
.
 Tolcapone (Tasmar) & Entacapone (Comtan)
› Only as adjunct therapy to carbidopa/levodopa
› Ineffective by themselves
› Toxicity: N/V, orthostatic hypotension, hallucinations, confusion

Question 14

Treatment: COMT Inhibitor (drugs/ highlights) (DP)

Answer 14

Question 15

Treatment: Apomorphine (PD)

Answer 15

 Apokyn, Kynmobi
› “end-of-dose wearing-off” and unpredictable “on-off” episodes for patients with
severe/advanced disease
.
› ADE:
 Severe N/V pretreat & continue trimethobenzamide NMT ~2 months
 Falling asleep during activities of daily life
 Hypotension (potentiated by alcohol, antihypertensive medications, and vasodilators), QTc prolongation
 Falls, psychotic-like behavior, dyskinesias, intense urges
 WARNING: Contraindicated with comcomitant 5HT3 antagonists (ondansetron): profound hypotension and loss of consciousness

Question 16

Treatment: Anticholinergics (PD)

Answer 16

 Initial monotherapy or adjunct therapy
 Overcome the cholinergic overactivity in the caudate due to imbalance/lack of DA
› Targets tremor in mild, early stages of PD
› Also used to treat pseudoparkinsonism from 1st generation antipsychotic administration
› ADE: mental confusion, constipation, urinary
retention, blurred vision

Question 17

Other treatment options for PD . . .

Answer 17

 Amantadine (Symmetrel)
› Weak, non-competitive antagonist of the NMDA receptor, which increases dopamine release and prevents dopamine reuptake.
› Adjunct therapy with levodopa during “onoff” periods
› Used early to delay L-dopa administration & as adjunct with L-dopa during “on-off”
› Livedo reticulari

Question 18

Switching to Alzheimer’s Disease (AD) . . .general and it’s 3 stages

Answer 18

• Most common cause of dementia
• Neuronal cell loss and dysfunction in the medial temporal lobe: responsible for language, memory
  .
  3 stages:
  1. “preclinical”: accumulation of β-amyloid & tau proteins
  2. MCI stage with episodic memory loss; not severe enough to impair daily function
  3. Dementia stage with progressive loss of functional abilities
  ….. Death usually ensues within 6-12 years of onset
  › Pneumonia or pulmonary embolis

Question 19

Alzheimer’s Disease stages . . . Picture

Answer 19

Question 20

Pathophysiology of AD . . . 3 different hypotheses

Answer 20

1.) Cholinergic hypothesis
› Decreased Ach in forebrain –> problems with memory/learning
.
2.) Amyloid hypothesis
› Cell membrane amyloid precursor protein (APP) sits across neuronal membranes, helps neuron grow & repair after injury
› β amyloid (Aβ) metabolic waste product present in fluid between brain cells
› Aβ “plaque” accumulates outside neurons –> inflammation, decrease in communication between neurons
.
3.) Tau Hypothesis (in later slides)

Question 21

β amyloid (AD) . . . roles and importance when it comes to AD

Answer 21

• Over time it gets broken down & recycled
• Broken down by alpha & gamma secretase
  › cut APP into pieces that are soluble, and can be excreted.
• IF beta & gamma secretase “team up” instead
  › cuts APP into insoluble pieces, namely a monomer (amyloid β)
  › Amyloid b is “sticky” and clumps together forming plaques outside/in between neurons
  › Plaques interfere with neuron to neuron signaling, impairing brain function
  › Also may cause inflammation which might damage surrounding neurons.

Question 22

AD . . . Tau Hypothesis

Answer 22

Question 23

AD . . . “plaques & tangles”

Answer 23

Cause brain atrophy:
› gyri get narrower
› sulci (grooves) get wider
› Ventricles enlarge

Question 24

Genetic component of AD

Answer 24

Question 25

Familial Alzheimer’s Disease

Answer 25

Question 26

Treatment of AD

Answer 26

Donepezil (Aricept), Rivastigmine (Exelon [transdermal patch]), Galantamine (Razadyne)
› Acetylcholinesterase inhibitor –> increases ACh available –> improves cholinergic transmission
› Indicated for mild/moderate AD
› High incidence of peripheral cholinergic effects
› Ineffective against agitation or aggressive behaviors

Question 27

Treatment of AD: Memantine (Namenda)

Answer 27

 Memantine (Namenda)
› Lack of ACh allows excessive glutamate activation of NMDA receptors (contributes to AD symptoms)
› Uncompetitive NMDA receptor antagonist
› Prevents or slows rate of memory loss in vasculature associated with Alzheimer’s dementias
› Indicated for patients with moderate/severe AD
› ADE: relatively well tolerated… confusion, agitation, restlessness; may be indistinguishable from disease symptoms
› Overdose symptoms resemble ketamine (confusion, hallucinations, stupor)
 Memantine/Donepezil (Namzaric)