Neuropharm Exam 3

This set covers key vocabulary, symptoms, pathology markers, and pharmacological treatments for Parkinson's Disease, Alzheimer's Disease, Schizophrenia, Bipolar Disorder, and Clinical Depression based on the lecture notes.

Bradykinesia

A motor symptom of Parkinson's Disease characterized by slowness of movement.

Festinating gait

A walking pattern associated with Parkinson's Disease involving very small, fast steps and a stooped posture.

Micrographia

A symptom of Parkinson's Disease where the patient's handwriting becomes abnormally small.

SNpc

Substantia nigra pars compacta; the area of the midbrain where the loss of dopaminergic neurons occurs in Parkinson's Disease.

Lewy Body

Abnormal aggregates of protein, primarily alpha-synuclein, that develop inside nerve cells in Parkinson's Disease and [ ] Dementia.

Nigrostriatal pathway

The dopaminergic pathway that projects from the substantia nigra pars compacta to the striatum (caudate and putamen), which is >95\% gone in Parkinson's Disease.

MPTP

$1\text{-methyl-4-phenyl-1,2,3,6-tetrahydropyridine}$; a toxin that crosses the blood-brain barrier and is converted to $MPP^+$ by $MAO\text{-}B$, causing the degeneration of dopaminergic neurons.

Alpha-synuclein

A presynaptic protein involved in synaptic vesicle modulation that becomes a major component of Lewy Bodies when it fails to fold properly or resistant to proteasome degradation.

Tau tangles

Neurofibrillary tangles ($NFT$) formed by hyper-phosphorylated tau protein that detach from microtubules, causing microtubule destabilization and clogging the neuron's axon and dendrites.

Amyloid plaques

Extracellular deposits of $A\beta$ peptides (specifically $A\beta 42$) that result from the amyloidogenic pathway of $APP$ cleavage.

BACE

$\beta\text{-site APP Cleaving Enzyme}$ ($\beta\text{-secretase}$); an enzyme that cleaves $APP$ to begin the amyloidogenic pathway leading to $A\beta$ production.

ApoE4

An allele of the cholesterol transport protein on chromosome 19 that represents a risk factor for Late-Onset Alzheimer's by increasing risk and decreasing the age of onset.

Pittsburgh Compound-B ($PIB$)

A radioactive analog used in $PET$ scans to visualize the uptake and presence of amyloid deposits in the living brain.

Positive Symptoms (Schizophrenia)

Psychotic behaviors not generally seen in healthy people, including hallucinations, delusions, bizarre behavior, and paranoia.

Tardive dyskinesia

A severe side effect of long-term neuroleptic use characterized by involuntary, repetitive body movements.

Hypoglutamate hypothesis

A theory of schizophrenia suggesting the disorder is caused by underactivation of glutamate receptors, specifically $NMDA$ receptors.

Anhedonia

A core symptom of Major Depressive Disorder defined as the markedly diminished interest or pleasure in all, or almost all, activities.

Monoamine depletion hypothesis

A hypothesis for depression suggesting that the condition is caused by a deficiency in monoamine neurotransmitters like serotonin and norepinephrine.

Reserpine

A drug that blocks vesicle transporters in monoamine neurons, leading to reduced vesicle loading and inducing symptoms of depression.

BDNF

$\text{Brain-derived neurotrophic factor}$; a protein that supports the survival of existing neurons and encourages neurogenesis, which is often decreased during stress or depression.

BrdU

$\text{Bromodeoxyuridine}$; a synthetic nucleoside used in scientific research to measure cell proliferation (neurogenesis) by incorporating into the $DNA$ of dividing cells.

Lithium ($LiCl$)

The most common treatment for Bipolar Disorder, thought to work by modulating signaling pathways like the inositol cycle.

Cerebrum

Motor Component of the Basal Ganglia

Caudate Nucleus

Motor Component of the Basal Ganglia

Putamen

Motor Component of the Basal Ganglia

Globus Pallidus

Motor Component of the Basal Ganglia

Substantia Nigra pars compacta

Motor Component of the Basal Ganglia

Substantia Nigra pars reticulata

Motor Component of the Basal Ganglia

Dopaminergic neurons projecting from the SNpc to the striatum

95% gone in Parkinson’s Disease

L-DOPA & Carbidopa

Treatment of Parkinson’s

MAO inhibitors

Treatment of Parkinson’s

Dopamine Antagonists

Treatment of Parkinson’s

Muscarinic Cholinergic Antagonists

Treatment of Parkinson’s

Cell transplantation

Experimental approach to treat Parkinson’s

Fetal SN tissue

Experimental approach to treat Parkinson’s

xenografts (pig)

Experimental approach to treat Parkinson’s

Adrenal chromaffin cells from patient

Experimental approach to treat Parkinson’s

induced pluripotent stem cells

Experimental approach to treat Parkinson’s

embryonic stem cells

Experimental approach to treat Parkinson’s

Deep Brain Stimulation

Treatment of Parkinson’s

Exosome

How does alpha-syneuclein get from cell to cell?

Direct penetration

How does alpha-syneuclein get from cell to cell?

Trans synaptically

How does alpha-syneuclein get from cell to cell?

Membrane receptors

How does alpha-syneuclein get from cell to cell?

Endocytosis

How does alpha-syneuclein get from cell to cell?

Acetylcholinesterase

Treatment of Alzheimer’s

NMDA antagonoists

Treatment of Alzheimer’s

Statins

Treatment of Alzheimer’s

NSAIDs

Treatment of Alzheimer’s

Anti-oxidants

Treatment of Alzheimer’s

Estrogen

Treatment of Alzheimer’s

Y-secretase

Presenilin

Increased kinase activity and decreased phosphotase activity

How do tau tangles form?

Missense mutation in APP or Presenilin 1 or 2 gene

Dominant Inherited forms of Alzheimer’s Disease

Failure of AB clearance mechanisms

Nondominant forms of Alzheimer’s Disease

Early Onset Alzheimer’s Disease

Before age 65, autosomal dominant mutation on chromosome 21 (APP, PSEN1 or PSEN2)

ApoE2

Protective allele that alters extracellular AB levels in Alzheimer’s Disease

Negative symptoms of Schizophrenia

Loss of touch w/ reality, reduced speech, lack of grooming, intellectual impairment, social isolation

Cognitive symptoms of Schizophrenia

attention problems, working memory, executive functions

Disorganized symptoms of Schizophrenia

speech/thoughts, repetitive gestures

Neuroleptics: Chlorpromazine (Thorazine)

Treatment of Schizophrenia

Side effect of neuroleptics

Sedation

Side effect of neuroleptics

autonomic nervous system side effects (due to antagonising cholinergic receptors) include: rapid HR, dizziness, hypotension

Side effect of neuroleptics

neuroendocrine (lactation)

Side effect of neuroleptics

neuroleptic malignant syndrome (NMS)

neuroleptic malignant syndrome (NMS)

a rare, life-threatening neurological emergency caused by a reaction to dopamine-receptor antagonist medications (antipsychotics) or rapid withdrawal of dopaminergic drugs

Symptoms of NMS

Hyperthermia, muscle rigidity (& muscle wasting), confusion & agitation, autonomic instability (rapid HR), elevated creatine phosphokinase (CPK)

Atypical Neuroleptic

Aripiprazole (Abilify), partial DA & 5-HT(1A) agonist, 5-HT(2A) antagonist

anti-NMDAR encephalitis

a severe autoimmune disease where antibodies target NMDA receptors, causing rapid-onset psychiatric symptoms, memory deficits, seizures, and movement disorders, often triggered by ovarian tumors

5-HT(1A) receptor

inhibitory receptor located in the limbic system, responsible for promoting anxiety reduction, resilience, and passive coping

5-HT(2A) receptor

excitatory receptor found in the cortex, enhancing cognitive flexibility, creativity, and active coping. overactivation of this receptor linked to hallucinations and psychosis

Manic Symptoms (Bipolar)

High energy, elevated mood, elevated creativity

Depressive Symptoms (Bipolar)

low energy, low motivation, loss of interest, suicidal thoughts

GABA modulators (valproate, carbamazepine)

Treatment of Bipolar Disorder

Depressed mood most of the day, almost every day (sadness, emptiness, hopelessness)

DSM-V Criteria of Major Depressive Disorder

Anhedonia

DSM-V Criteria of Major Depressive Disorder

Fluctuations in weight when not intended (weight gain/weight loss)

DSM-V Criteria of Major Depressive Disorder

Fluctuations in Sleep (insomnia/oversleeping)

DSM-V Criteria of Major Depressive Disorder

Psychomotor agitation or retardation nearly every day

DSM-V Criteria of Major Depressive Disorder

Psychomotor agitation

a state of intense, unintentional, and restless physical movement: pacing, hand-wringing, rapid talking, and, in severe cases, aggressive outbursts

Fatigue or loss of energy nearly every day

DSM-V Criteria of Major Depressive Disorder

Feelings of worthlessness of excessive/inappropriate guilt nearly every day

DSM-V Criteria of Major Depressive Disorder

Diminished ability to think or concentrate or indecisiveness, nearly every day

DSM-V Criteria of Major Depressive Disorder

Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a plan for committing suicide

DSM-V Criteria of Major Depressive Disorder

Phenelzine, Tranylcypromine

MAO inhibitors

The beer-wine-and-cheese problem

If someone is on a MAO inhibitor, they cannot eat fermented foods (tyramine presence) or else they risk a hypertensive crisis

Tricyclic antidepressants (TCAs)

Imipramine, Amitriptyline, Desipramine (block 5-HT & NE reuptake)

Selective Serotonin Reuptake Inhibitors (SSRIs)

Fluoxetine, Sertraline, Paroxetine

Why are SSRIs preferred over TCAs?

Fewer side effects

HPA & hippocampus dysregulation theory

Chronic stress causes a loop of hypercortisolism, which impairs the hippocampus (& response needed for wakefulness & sleep), and damages its ability to turn off the stress response, leading to the development of MDD

Impairment of neurotropic mechanisms

Depleted levels of BDNF decrease neurogenesis, reduce synaptic plasticity, and cause atrophy in key brain regions involved in mood regulation leading to MDD

How do we test for cortisol dysregulation?

Dexamethasone challenge shows non suppressed plasma cortisol in depressed patients