Basal Nuclei Pathology Flashcards
What is the protein mutated in HD? What is the inheritance pattern? When is the onset, and how long does it last?
Huntingtin gene, autosomal dominant, onset 30-50 yoa, fatal in 15-20 y
What are symptoms of HD?
Brisk, jerky, uncontrollable movements, eventually athetoid (withering), then functional Parkinson’s
What is ALS/Lou Gehrig’s?
Degeneration U&LMN, fatal in 3-5 y, usually from respiratory failure
What does the only FDA approved drug for ALS do?
Decreases glutamate release, attempting to reduce glutamate excitotoxicity
What types of dystonias are there? How are the treated?
Idiopathic, genetic, acquired (CP, TBI, heavy metals), focal (e.g. writer’s cramp); Tx botox, L-dopa, muscle relaxants, PT, splints
What are usually the earliest symptoms of HD? Followed by?
Behavioral disturbance, lke depression/suicide attempt, personality change; increased saccadic eye mvmts, choreiform mvmt, dementia, PD-like
What brain regions atrophy in HD?
Dorsal striatum (C then P), frontal cortex, parts of hippocampus
How are movements, striatal DA, and subthalamic nuc glutamate affected in HD and PD?
Mvmt: increased HD, decreased PD
DA: inc HD, dec PD
Glut: dec HD, inc PD
What causes HD?
Destruction GABA dorsal striatum neurons leading to GPe in indirect pathway = unopposed direct pathway (D1+ GABA -> GPi)
What does disruptive deep brain stimulation targeting for HD? PD?
HD: GPe
PD: subthalamic nuc
How does HD cause increased saccadic eye movements?
Caudate hyperactive, inhibits SN p reticulata, which usually inhibits superior colliculus, which affects lat/vert gaze centers. Result: increased saccades toward distracting stimuli.
How does HD affect voluntary eye movements?
Less GABA from GPi, SNpr -> disinhibition frontal eye fields -> excess voluntary mvmts with abnormalities
What pharmacological treatments are there for HD?
FDA-approved drug for chorea reduces DA; antidepressants, antipsychotics, etc.
What is the biological basis of HD?
Trinucleotide polyglutamine repeat on chr 4 -> mutant long form huntingtin protein w lots glutamine. Mutant cut into small toxic pieces that misfold, aggregate
Where does the huntingtin protein accumulate?
Cytoplasm of neurons in dorsal striatum, frontal, temporal cx, and microglia around these areas
What are symptoms of juvenile HD? Who is affected?
Minority of pts (5-10%) with gene from father, greater # CAG repeats; more rapid course, usually less choreiform, more rigidity and dystonia, increased chance epilepsy (30-50%)
What syndrome does ALS commonly overlap? What symptoms?
Frontotemporal dementia; behavior/personality changes, cognitive impairment
What is the molecular basis of ALS? What about familial ALS?
Misfolded TDP-43 protein that kills UMN and LMN
Fam: autosomal dom superoxide dismutase 1 mutation (25%)
What is the target of current phase 3 clinical trials for ALS?
Increasing expression of astrocyte excitatory AA transporter to clear glutamate EAAT2 in glutamate-glutamine cycle
What are the misfolded proteins of PD and AD? Where are these proteins found?
PD: alpha-Synuclein (cytoplasm)
AD: amyloid-beta (extracellular)
What are the functions of the basal nuclei reward loop?
Interface between motor, limbic systems; activates motor fxn to reward, promotes learning/memory via reinforcement; improves mood
What is the most costly US health problem?
Substance abuse disorders (alcohol, tobacco, illicit drugs)
What are FDA-approved pharmacotherapies for tobacco?
Nicotine replacement, bupropion (Zyban; antidepressant, promotes NE, 5-HT, DA, blocks ACh)
What are the 6 components involved in reward system?
Ventral segmental area (DA), nuc accumbens (ventral striatum), ventral pallidum, MD thalamus, orbital PFC & limbic cx, PPtN (mes motor area)
What are the 3 major psychostimulants, and how do they work?
Amphetamine: promotes DA release
Cocaine: prevents DA and 5-HT reuptake
MDMA: releases 5-HT, DA, NE
How does PCP work?
NMDA glutamate receptor antagonist
What does the ventral segmental area do? Where does it project?
Makes DA; projects to ventral striatum (NA) & ventral pallidum in mesolimbic DA system (D1/2 rec), and frontal cx (cingulate, orbito-) in mesocortical DA system
What substances affect the VTA?
EtOH, nicotine (nACh receptors activate DA neurons)
What are the mesolimbic and mesocortical DA systems linked to?
Mesolimbic: natural rewards like food, sex
Mesocortical: schizophrenia
What brain areas change acutely and long-term with addiction?
Acute: VTA DA
Long: prefrontal glutamate to NA causes persistent craving
What are the possible genetic and biopsychosocial factors of addiction?
Polygenic disease affecting multiple systems; prenatal tobacco, chronic drug exposure
