Basal Nuclei Pathology

Question 1

What is the protein mutated in HD? What is the inheritance pattern? When is the onset, and how long does it last?

Answer 1

Huntingtin gene, autosomal dominant, onset 30-50 yoa, fatal in 15-20 y

Question 2

What are symptoms of HD?

Answer 2

Brisk, jerky, uncontrollable movements, eventually athetoid (withering), then functional Parkinson’s

Question 3

What is ALS/Lou Gehrig’s?

Answer 3

Degeneration U&LMN, fatal in 3-5 y, usually from respiratory failure

Question 4

What does the only FDA approved drug for ALS do?

Answer 4

Decreases glutamate release, attempting to reduce glutamate excitotoxicity

Question 5

What types of dystonias are there? How are the treated?

Answer 5

Idiopathic, genetic, acquired (CP, TBI, heavy metals), focal (e.g. writer’s cramp); Tx botox, L-dopa, muscle relaxants, PT, splints

Question 6

What are usually the earliest symptoms of HD? Followed by?

Answer 6

Behavioral disturbance, lke depression/suicide attempt, personality change; increased saccadic eye mvmts, choreiform mvmt, dementia, PD-like

Question 7

What brain regions atrophy in HD?

Answer 7

Dorsal striatum (C then P), frontal cortex, parts of hippocampus

Question 8

How are movements, striatal DA, and subthalamic nuc glutamate affected in HD and PD?

Answer 8

Mvmt: increased HD, decreased PD
DA: inc HD, dec PD
Glut: dec HD, inc PD

Question 9

What causes HD?

Answer 9

Destruction GABA dorsal striatum neurons leading to GPe in indirect pathway = unopposed direct pathway (D1+ GABA -> GPi)

Question 10

What does disruptive deep brain stimulation targeting for HD? PD?

Answer 10

HD: GPe
PD: subthalamic nuc

Question 11

How does HD cause increased saccadic eye movements?

Answer 11

Caudate hyperactive, inhibits SN p reticulata, which usually inhibits superior colliculus, which affects lat/vert gaze centers. Result: increased saccades toward distracting stimuli.

Question 12

How does HD affect voluntary eye movements?

Answer 12

Less GABA from GPi, SNpr -> disinhibition frontal eye fields -> excess voluntary mvmts with abnormalities

Question 13

What pharmacological treatments are there for HD?

Answer 13

FDA-approved drug for chorea reduces DA; antidepressants, antipsychotics, etc.

Question 14

What is the biological basis of HD?

Answer 14

Trinucleotide polyglutamine repeat on chr 4 -> mutant long form huntingtin protein w lots glutamine. Mutant cut into small toxic pieces that misfold, aggregate

Question 15

Where does the huntingtin protein accumulate?

Answer 15

Cytoplasm of neurons in dorsal striatum, frontal, temporal cx, and microglia around these areas

Question 16

What are symptoms of juvenile HD? Who is affected?

Answer 16

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%)

Question 17

What syndrome does ALS commonly overlap? What symptoms?

Answer 17

Frontotemporal dementia; behavior/personality changes, cognitive impairment

Question 18

What is the molecular basis of ALS? What about familial ALS?

Answer 18

Misfolded TDP-43 protein that kills UMN and LMN

Fam: autosomal dom superoxide dismutase 1 mutation (25%)

Question 19

What is the target of current phase 3 clinical trials for ALS?

Answer 19

Increasing expression of astrocyte excitatory AA transporter to clear glutamate EAAT2 in glutamate-glutamine cycle

Question 20

What are the misfolded proteins of PD and AD? Where are these proteins found?

Answer 20

PD: alpha-Synuclein (cytoplasm)
AD: amyloid-beta (extracellular)

Question 21

What are the functions of the basal nuclei reward loop?

Answer 21

Interface between motor, limbic systems; activates motor fxn to reward, promotes learning/memory via reinforcement; improves mood

Question 22

What is the most costly US health problem?

Answer 22

Substance abuse disorders (alcohol, tobacco, illicit drugs)

Question 23

What are FDA-approved pharmacotherapies for tobacco?

Answer 23

Nicotine replacement, bupropion (Zyban; antidepressant, promotes NE, 5-HT, DA, blocks ACh)

Question 24

What are the 6 components involved in reward system?

Answer 24

Ventral segmental area (DA), nuc accumbens (ventral striatum), ventral pallidum, MD thalamus, orbital PFC & limbic cx, PPtN (mes motor area)

Question 25

What are the 3 major psychostimulants, and how do they work?

Answer 25

Amphetamine: promotes DA release
Cocaine: prevents DA and 5-HT reuptake
MDMA: releases 5-HT, DA, NE

Question 26

How does PCP work?

Answer 26

NMDA glutamate receptor antagonist

Question 27

What does the ventral segmental area do? Where does it project?

Answer 27

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

Question 28

What substances affect the VTA?

Answer 28

EtOH, nicotine (nACh receptors activate DA neurons)

Question 29

What are the mesolimbic and mesocortical DA systems linked to?

Answer 29

Mesolimbic: natural rewards like food, sex
Mesocortical: schizophrenia

Question 30

What brain areas change acutely and long-term with addiction?

Answer 30

Acute: VTA DA
Long: prefrontal glutamate to NA causes persistent craving

Question 31

What are the possible genetic and biopsychosocial factors of addiction?

Answer 31

Polygenic disease affecting multiple systems; prenatal tobacco, chronic drug exposure