In our final issue for 2014, the HD Insights team wanted to recognize the most influential papers in HD research in the 2013–2014 year. Our staff, Editorial Board, and leading HD researchers nominated the eleven papers below in three categories: lab research, clinical research, and imaging and biomarkers. The HD Insights Editorial Board then voted to select the three most influential papers, one in each category. The authors of the winning papers will present their research in a panel discussion at the Huntington Study Group meeting on November 7, 2014. Congratulations to all the nominees and winners!
Metabolic network as a progression biomarker of premanifest Huntington’s disease
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 D2 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.
Clinical and biomarker changes in premanifest Huntington disease show trial feasibility: A decade of the PREDICT-HD study
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.
HTRF analysis of soluble huntingtin in PHAROS PBMCs
By: Moscovitch-Lopatin M, Goodman RE, Eberly S, Ritch JJ, Rosas HD, Matson S, Matson W, Oakes D, Young AB, Shoulson I, Hersch SM; Huntington Study Group PHAROS Investigators (Summary by Steven M. Hersch, MD, PhD and Miriam Moscovitch-Lopatin, PhD, PMP)
Mutant huntingtin (mHTT) is a target of many treatments currently being developed for HD. Therefore, the ability to measure levels of mHTT in humans will be crucial to future research efforts. Measuring mHTT has been very technically challenging. In our study of white blood cell samples from the PHAROS study, we used a sophisticated fluorescent assay to detect higher relative values of soluble mHTT in gene carriers (CAG≥37) prior to symptoms, and relatively lower values in symptomatic HD subjects.
The study demonstrated that soluble mHTT can be usefully detected in blood, and that HD may influence its levels. Since then, we have used this same assay in blood from early HD subjects participating in the HSG’s Reach2HD trial of PBT2 (PRANA Biotechnology), and found that the treatment can affect soluble mHTT levels. Currently, we are developing an assay that can also measure mHTT aggregates in clinical samples, which we believe will also prove useful for developing treatments that target huntingtin.
Multi-modal neuroimaging in premanifest and early Huntington’s disease: 18 month longitudinal data from the IMAGE-HD study
By: Domínguez D JF, Egan GF, Gray MA, Poudel GR, Churchyard A, Chua P, Stout JC, Georgiou-Karistianis N (Summary by Nellie Georgiou-Karistianis, PhD)
IMAGE-HD is an Australia-based longitudinal multimodal biomarker development study that followed individuals with HD, and healthy controls, over 30 months. Results from IMAGE-HD have made significant contributions to biomarker discovery and to understanding of the impact of HD neuropathology on brain structure, microstructure, connectivity, and function during both the premanifest and early symptomatic stages.
However, much remains to be discovered about the contribution of specific brain regions and/or networks to the phenotypic heterogeneity of HD, and whether these decline at different rates. Such knowledge will be essential for well-targeted disease management strategies and therapeutic interventions. It will be important in the future to investigate the heterogeneity of HD in terms of brain endophenotypes and their relationships with cognitive, psychiatric and motor exophenotypes. Understanding how genetic and/or environmental factors modify these relationships and influence their development will be key to this endeavor. This will require a range of innovative approaches and novel analytical techniques, such as high throughput connectomics and predictive computational models.
There is also growing evidence for the potential benefit of cognitive and physical training in forestalling further worsening of HD symptoms. Such non-pharmaceutical interventions offer new and exciting possibilities to explore disease-modifying potential and to determine their neural mechanisms of action.
The new CAVE2™ at Monash University will provide state-of-the art capacity for high-throughput neuroimaging data for visualization and sorting of brain images based on pre-defined characteristics, which will enable imaging data to be visualized in new and exciting ways.