Huntington’s disease: Learning from Extremes Abstract: Huntington's disease (HD) is a fatal genetic neurodegenerative disorder characterized by progressive 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 is the 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 environmental factors. Variable progression is not explained by the CAG expansion length since the vast majority of individuals with HD fall in a limited range of CAG lengths spanning 41-47 yet have ages of clinical onset from childhood to the 8th decade of life. Genome-wide association studies (GWAS) have uncovered some potential and very limited contributions from other genes and do not explain the extremes observed clinically. We have studied non-juvenile HD subjects matched for CAGn and disease duration and having early and late onset and find that earlier onset is associated with more rapid cerebral atrophy and older onset with slower cerebral atrophy, 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 previously identified altered metabolomic, genetic, and transcriptomic markers from the blood and in HD subjects 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 targeted studies of blood and csf markers to seek distinguishing clues to the variance in progression.