Metabolic network as a progression biomarker of premanifest Huntington’s disease
Chris C. Tang, … , Vijay Dhawan, David Eidelberg
Chris C. Tang, … , Vijay Dhawan, David Eidelberg
Published August 29, 2013
Citation Information: J Clin Invest. 2013;123(9):4076-4088. https://doi.org/10.1172/JCI69411.
View: Text | PDF
Clinical Research and Public Health Neuroscience

Metabolic network as a progression biomarker of premanifest Huntington’s disease

Abstract

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.

Authors

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

×

Figure 4

HD metabolic progression pattern: regional changes.

Options: View larger image (or click on image) Download as PowerPoint
HD metabolic progression pattern: regional changes. In the premanifest H...
In the premanifest HD1 cohort, progressive declines (black lines) in regional metabolic activity (P < 0.005, RMANOVA) were present in (A) the caudate nucleus and anterior putamen, (B) the mediodorsal thalamus, and (C) the prefrontal cortex. In these regions, metabolic activity at all time points was lower for the subjects who phenoconverted at a later point in the study (red) as compared with those who remained clinically premanifest at follow-up (blue). Regional metabolic activity concurrently increased in several regions (Table 1), including (D) the pons (P < 0.001), in which the subsequent phenoconverters exhibited higher values than their nonphenoconverting counterparts at each time point. For each region, MNI coordinates at the peak voxel are given in parentheses. The y axes denote regional metabolic activity ratio-normalized to the global mean. Error bars represent 1 SE above or below the mean of the HD subjects. The broken line represents mean metabolic activity for the HC1 healthy control group; the dotted lines represent 1 SE above and below the normal mean.