Neurodegenerative Disease (Lec 12) Flashcards
Neurodegenerative Disease. . . what is it? Pathogenesis?
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)
Degeneration of brain . . .
- 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
Parkinson’s Disease . . . general
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
Issues with neurons in Parkinson’s Disease (PD)
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.
Pathophysiology with Parkinson’s Disease
Treatment target of Parkinson’s Disease
DA is not being synthesized in SN › Treatments target: 1. Replenishing DA levels 2. Mimicking DA activity 3. Antagonizing effects of cholinergic neurons
Treatment: Levodopa (PD)
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
Treatment: Carbidopa (PD)
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
Central Toxicity of L-dopa (PD)
- Dyskinesia: involuntary chorieform movements
- Behavioral effects: hallucinations, confusion anxiety, agitation, insomnia, delirium, psychotic reactions
- “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
Treatment: Dopamine agonists (general) (PD)
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
Treatment: Dopamine agonist - drugs and highlights (PD)
Treatment: Selective MAO-B inhibitor (PD)
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
Treatment: COMT Inhibitor (general) (PD)
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
Treatment: COMT Inhibitor (drugs/ highlights) (DP)
Treatment: Apomorphine (PD)
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
Treatment: Anticholinergics (PD)
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
Other treatment options for PD . . .
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
Switching to Alzheimer’s Disease (AD) . . .general and it’s 3 stages
- 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
Alzheimer’s Disease stages . . . Picture
Pathophysiology of AD . . . 3 different hypotheses
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)
β amyloid (AD) . . . roles and importance when it comes to AD
- 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.
AD . . . Tau Hypothesis
AD . . . “plaques & tangles”
Cause brain atrophy:
› gyri get narrower
› sulci (grooves) get wider
› Ventricles enlarge
Genetic component of AD
