Background. The evaluation of effective disease-modifying therapies for neurodegenerative disorders relies on objective and accurate measures of progression in at-risk individuals. Here we used a computational approach to identify a functional brain network associated with the progression of preclinical Huntington’s disease (HD).
Methods. Twelve premanifest HD mutation carriers were scanned with [18F]-fluorodeoxyglucose PET to measure cerebral metabolic activity at baseline and again at 1.5, 4, and 7 years. At each time point, the subjects were also scanned with [11C]-raclopride PET and structural MRI to measure concurrent declines in caudate/putamen D2 neuroreceptor binding and tissue volume. The rate of metabolic network progression in this cohort was compared with the corresponding estimate obtained in a separate group of 21 premanifest HD carriers who were scanned twice over a 2-year period.
Results. In the original premanifest cohort, network analysis disclosed a significant spatial covariance pattern characterized by progressive changes in striato-thalamic and cortical metabolic activity. In these subjects, network activity increased linearly over 7 years and was not influenced by intercurrent phenoconversion. The rate of network progression was nearly identical when measured in the validation sample. Network activity progressed at approximately twice the rate of single region measurements from the same subjects.
Conclusion. Metabolic network measurements provide a sensitive means of quantitatively evaluating disease progression in premanifest individuals. This approach may be incorporated into clinical trials to assess disease-modifying agents.
Trial registration. Registration is not required for observational studies.
Funding. NIH (National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering) and CHDI Foundation Inc.
Chris C. Tang, Andrew Feigin, Yilong Ma, Christian Habeck, Jane S. Paulsen, Klaus L. Leenders, Laura K. Teune, Joost C.H. van Oostrom, Mark Guttman, Vijay Dhawan, David Eidelberg
109 participants (47 HD gene carriers and 62 age-matched healthy control [HC] subjects) were enrolled. A metabolic progression pattern was identified from the FDG PET scans obtained in a longitudinal cohort (HD1) comprising 12 premanifest HD carriers. Pattern expression was prospectively validated in a crosssectional validation cohort (HD2) comprising 9 premanifest carriers (for the evaluation of test-retest reliability) and 5 early-stage symptomatic HD subjects. The rate of network progression was validated in an independent longitudinal cohort (HD3) comprising 21 premanifest carriers. Metabolic network values were computed in a control group (HC1) comprising 12 healthy subjects and were used to standardize pattern expression in each subject. A second control group (HC2) comprising 20 healthy subjects was used to prospectively evaluate pattern expression in gene-negative individuals. A volume-loss progression pattern was identified in the structural MRI scans obtained in the longitudinal HD1 subjects. Progression rates for this pattern were assessed in both the HD1 and HD3 longitudinal cohorts. Individual scores of the volume-loss pattern were standardized with reference to values computed from a control group (HC4) comprising 18 healthy subjects. In the longitudinal HD1 cohort, the rates of network progression were compared with analogous regional measurements obtained in the caudate and putamen with [11C]-raclopride (RAC) PET (D2 receptor binding) and structural MRI (tissue volume). These regional values were standardized with reference to the corresponding HC3 (comprising 12 healthy subjects) and HC4 control groups.