Pathology of Huntington's Disease vs. Parkinson's Disease
HD: neurons in striatum itself (caudate) die (see atrophy of caudate)
PD: dopamine neurons that project to striatum (from SNc) die
Which neurons are affected early in HD?
Neurons from striatum to GPe (containing enkephalin) affected early in HD --> those neurons usually inhibit GPe --> increased activity of GPe (indirect pathway) --> increased inhibition of subthalamic nucleus --> decreased activity of subthalamic nucleus --> decreased stimulation of GPi/SNr --> decreased inhibition of VA/VL of thalamus --> increased movement
Neurons from striatum to GPi (substance P) relatively unaffected in HD
In HD, what movement disorder occurs?
Hyperkinetic disorder (too MUCH movement) due to imbalance in striatal outputs
Note: in contrast to PD where you get too LITTLE movement
General reason why you get too much movement in HD
Loss of "brake" (loss of indirect pathway) because loss of those initial neurons projecting from striatum to GPe
2 clinical situations that cause abnormal movements similar to those seen in HD
1) Lesion of subthalamic nucleus (due to stroke): hemiballismus; less stimulation of GPi/SNr (via indirect pathway) so more activity of thalamocortical
2) Long-term treatment with L-DOPA (treatment for PD): causes dyskinesia; increased effect of dopamine on D1 receptors so more inhibition of GPi/SNr so more activity of thalamocortical
Triad of clinical signs of Huntington Disease
General info on HD
Adult onset neurodegenerative disorder characterized by uncontrolled movements (chorea and dystonia), behavioral changes (depression, anxiety, psychosis, obsessive-compulsive traits), cognitive dysfunction (executive dysfunction and dementia)
Typical onset is 30s or 40s and have 15-25 year progression
Caused by CAG repeat in IT-15 gene endocing ubiquitously expressed huntingtin protein
Mechanisms of toxicity in HD
Axonal transport disruption
Cell death pathway perturbation
Juvenile onset form of HD
Only 6% present before age 20
More rapid progression
Dystonia, rigidity, bradykinesia
Paternal inheritance due to anticipation (expansion of CAG repeat)
Is there a gene test for HD?
Remember "Thirteen" (Olivia Wilde) from the show House
Can get a gene test to see if you have the huntingtin gene even before you're symptomatic
What is the "huntingtin" gene?
The gene is IT-15 on short arm of chromosome 4 and encodes the huntingtin protein
What is the mutation of IT-15 that causes HD?
Expanded CAG repeat in exon 1 is the mutation that causes HD
Normal: <26 repeats
Intermediate: 26-39 repeats
Pathologenic: >39 repeats
If you have more CAG repeats (> 39) what does that mean?
Means you are more likely to have earlier age of onset of HD
However, CAG repeat length accounts for only 50-60% of onset age variability (other factors contribute too)
Other expanded CAG repeat disorders
Spinal bulbar muscular atrophy (Kennedy's disease)
Spinocerebellar ataxias (SCA2?!)
Why is the mutant huntingtin so bad?
Cleaved to generate N-terminal polyQ fragments which aggregate
Aggregates form in cytoplasm and in nucleus (amyloid-like conformation)
Controversy over whether aggregates are toxic or protective
Gain of toxic function and/or loss of protective function
What might be transcriptionally dysregulated in HD?
Tx dysregulation of neurotrophic factors
Symptoms of HD
Motor: chorea, dystonia, abnormal eye movement, gait/balance problems, rigidity, bradykinesia, dysarthria, dysphagia
Cognitive: executive dysfunction (concentration, attention, multi-tasking), visuospatial dysfunction, memory problems
Psychiatric: depression, anxiety, obsessions, compulsions, hallucinations, delusions, apathy, impulsivity, suicidality
What are the first symptoms to appear in a person with HD?
Behavioral problems (remember "Thirteen" from show House!)
Then cognitive problems, then last motor problems
Treatment for HD
Must be individualized
Data lacking to show which treatments best
For chorea: amantadine, neuroleptics or antipsychotics (dopamine receptor blockers), reserpine (irreversible inhibitor of VMAT1 and 2 so no dopamine released from pre-synaptic terminal), tetrabenazine (reversible inhibitor of VMAT2)
For dystonia: baclofen, BoTox, DBS
For rigidity, bradykinesia: levodopa, pridopidine, baclofen, tizanidine
For gait and balance: PT, exercise, consider amantadine
For dysarthria, dysphagia: speech and swallowing therapy
For depression, anxiety, etc: SSRIs (fluoxetine), tricyclics, benzodiazepines, cognitive-behavioral therapy, counseling
For cognitive impairment: cholinesterase inhibitors, memantine, atomoxetine
How do we use tetrabenazine to treat HD
Give tetrabenazine until patient becomes a bit Parkinsonian (because you've blocked so much dopamine) then back off
Remember, tetrabenazine is a reversible inhibitor of VMAT2
In the future, how might we prevent onset or slow progression of HD?
Gene silencing to reduce amount of mutant protein produced