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
(A) This spatial covariance pattern was characterized by progressive loss of tissue volume (blue) in several brain regions (see text). The pattern is displayed as a reliability map thresholded at z = 2.33, P < 0.01 (1-tailed) using a bootstrap resampling procedure (ICV = –8.78, 6.81, P < 0.0001; 1,000 iterations). (B) All premanifest HD1 subjects exhibited a monotonic increase in pattern expression (P < 0.005; permutation test) across the first 3 time points. (C) In the HD1 longitudinal cohort, pattern expression increased linearly with disease progression (P < 0.0001; IGM) at a rate of 0.16/year (95% CI = 0.12, 0.21). (D) In the HD3 cohort, however, longitudinal changes in the expression of the volume-loss pattern were not significant (P = 0.40). Red lines denote the initially premanifest HD1 subjects who subsequently phenoconverted. Blue lines denote their counterparts who did not phenoconvert by the end of the study. Post-phenoconversion values are represented by filled symbols. The horizontal broken line represents the mean (equal to 0) for the healthy control group; the dotted lines represent 2 SD above and below the normal mean. In C and D, the solid line represents the best fit according to the model; the broken curves represent the 95% CI of the fitted line.