Huntington?sdisease:LearningfromExtremes Abstract:Huntington'sdisease(HD)isafatalgeneticneurodegenerativedisordercharacterizedbyprogressive motor, psychiatric and cognitive decline. It is caused by a genetic mutation leading to the global cellular expression of the mutant huntingtin protein (mtHtt), which is particularly toxic to the CNS. Disease modifying treatments are not yet available for this devastating and lethal disease. One of the challenges for designing efficient clinical trials isthe tremendous clinical variability that is observed. Much of that variability is contained in the markedly different rates of progression between subjects, which are likely caused by both genetic and environmentalfactors.VariableprogressionisnotexplainedbytheCAGexpansionlengthsincethevastmajority ofindividualswithHDfallinalimitedrangeofCAGlengthsspanning41-47yethaveagesofclinicalonsetfrom childhoodtothe8thdecadeoflife.Genome-wideassociationstudies(GWAS)haveuncoveredsomepotential and very limited contributions from other genes and do not explain the extremes observed clinically. We have studiednon-juvenileHDsubjectsmatchedforCAGnanddiseasedurationandhavingearlyandlateonsetand findthatearlieronsetisassociatedwithmorerapidcerebralatrophyandolderonsetwithslowercerebralatrophy, suggesting that age-of-onset is a strong predictor of the slope of progression. Understanding the biological factors that underlie divergent ages of onset and rates of progression may uncover correlates that enable understanding and predicting rates of progression and may help identify new treatment targets. We have previouslyidentifiedalteredmetabolomic,genetic,andtranscriptomicmarkersfromthebloodandinHDsubjects that represent pathways that could influence progression. We propose to expand our cohort of early and late onset subjects, evaluate their progression clinically and by neuroimaging, and to perform both unbiased and targetedstudiesofbloodandcsfmarkerstoseekdistinguishingcluestothevarianceinprogression.

Public Health Relevance

HuntingtonDisease(HD)isadevastating,fatal,andsofaruntreatableneurodegenerativediseasewith considerablevariabilitybetweenpatients.Wehaveobservedthatearlieronsetisassociatedwithmorerapid brainatrophyandolderonsetwithsloweratrophy,suggestingthatage-of-onsetstronglypredictstherateof progression.Weproposetostudyyoungandoldonsetsubjectsusingadvancedneuroimagingmethods,and toseekgeneticandmolecularcluesintheirbloodthatcouldhelpexplainthedifferentagesofonsetandrates ofprogressioninhumanHDandsuggestnewtreatmentsandbiomarkers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS106384-02
Application #
9775463
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Miller, Daniel L
Project Start
2018-09-15
Project End
2023-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114