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Most influential paper In imaging and biomarkers… Metabolic network as a progression biomarker of premanifest Huntington's disease J Clin Invest. 2013 Sep 3;123(9):4076-88. doi: 10.1172/JCI69411. Epub 2013 Aug 29. By: Tang CC, Feigin A, Ma Y, Habeck C, Paulsen JS, Leenders KL, Teune LK, van Oostrom JC, Guttman M, Dhawan V, Eidelberg D (Summary by Chris C. Tang, MD, PhD) The need for sensitive and accurate measurements of preclinical disease progression in at-risk individuals has been a major roadblock in the development of effective treatment for neurodegenerative disorders. In this fluorodeoxyglucose positron emission tomography (FDG-PET) study, we used a novel computational approach to identify and validate a brain network biomarker of disease progression in premanifest HD carriers. The subjects, who underwent longitudinal metabolic imaging in the rest state, exhibited a significant linear increase in network activity over seven years, continuing even as clinical manifestations emerged. The progression rate of network activity in this cohort was nearly identical to that measured prospectively in an independent cohort of premanifest HD carriers scanned longitudinally over a 2.3 ± 0.3 – year period. Moreover, this rate was found to be faster than the corresponding rates of conventional single-region measurements (i.e. caudate D 2 binding and tissue volume) acquired in the same subjects. Thus, the metabolic network can provide a sensitive and reliable means of assessing systems-level changes in the progression of premanifest HD. This network biomarker is currently undergoing further validation in a multicenter longitudinal trial as part of the PREDICT-HD study. The results will help determine its utility in future clinical trials on new treatments targeted at slowing the progression of HD in the premanifest period. Image: An example of the FDG-PET imaging – based brain metabolic network biomarker identified in premanifest HD gene carriers. Copyright © Huntington Study Group 2014. All rights reserved. Clinical and biomarker changes in premanifest Huntington disease show trial feasibility: A decade of the PREDICT-HD study Front Aging Neurosci. 2014; 6: 78. Published online Apr 22, 2014. doi: 10.3389/fnagi.2014.00078 By: Paulsen JS, Long JD, Johnson HJ, Aylward EH, Ross CA, Williams JK, Nance MA, Erwin CJ, Westervelt HJ, Harrington DL, Bockholt HJ, Zhang Y, McCusker EA, Chiu EM, Panegyres PK; PREDICT-HD Investigators and Coordinators of the Huntington Study Group (Summary by Christina Colletta, BA) Clinical trials to test novel therapies in individuals with premanifest HD have been limited by the scarcity of proven outcome measures and objective measures of disease progression. PREDICT-HD, a thirteen year study, aims to identify markers of HD- related change in individuals with premanifest and early HD needed to determine whether HD treatments are effective early in the disease process. This year's analysis of the PREDICT-HD data found changes occurring in 36 of 39 potential outcome measures examined over a ten year period in individuals with premanifest HD, which could potentially be used as outcome measures in future therapeutic trials. Specifically, outcome measures of imaging based on regional brain volumes had the largest effect sizes. A motor assessment showed the next highest effect size, followed by a cognitive assessment of working memory, complex scanning and processing speed. Measures of function related to health and disability and measures of psychiatric symptoms such as obsessive-compulsive disorder were also found to show significant change over time. Using these and other outcome measures, clinical trials could be initiated seven to twelve years before motor diagnosis. Research Round-Up: Insights, cont... (continued on Page 8...) H D I N S I G H T S HD Insights, Vol. 9 7