CAG Repeat Length Predicts Huntington Disease Decline

August 13, 2019

Using principal component analysis, the findings suggest that CAG repeat length strongly predict the rate of cognitive-motor decline in patients with Huntington disease, with higher CAG resulting in earlier and faster decline.

Douglas R. Langbehn, MD, PhD

New study findings suggest that concise summary measures of function and brain loss can characterize Huntington disease progression across a wide disease span, with CAG repeat length strongly predicting the rate of cognitive-motor decline.

Investigators used principal component analysis (PCA) to derive summary measures separately for non-imaging and imaging variables, with the first principal component (PC) score being the focus. Ultimately, 2065 visits from 443 participants were analyzed, and motor-cognitive measures were greatly associated and had comparable CAG repeat length-dependent links with patient age. A composite summary score accounted for 67.6% of their combined variance.

“This work aids understanding of the association between brain changes and clinical manifestation in Huntington disease and their dependence on age and CAG repeat length, which may have utility in disease-modifying clinical trials,” Douglas R. Langbehn, MD, PhD, professor of psychiatry, Carver College of Medicine, University of Iowa, and colleagues wrote.

The PCA score was approximated by combining 3 facets of the Unified Huntington’s Disease Rating Scale (UHDRS): total motor score, Symbol Digit Modalities Test (SDMT) score, and Stroop word reading score. As the 6 brain volume measures could not be condensed into a single summary score due to their distinct patterns of dependence on age and CAG repeat length, Langbehn and colleagues only combined those measures which had similar patterns. Although, whole-brain, ventricular, and white matter volumes were found to be consistent in age and CAG repeat length dependencies.

Additionally, the group also demonstrated 3 distinct patterns—basal ganglia, gray matter, and a combination of whole-brain, ventricular, and white matter volumes—of CAG repeat length-dependent progression.

Using quadratic models, the investigators were able to estimate CAG-repeat length-specific ages for the mean age at which they can predict worsening motor-cognitive scores. With 40 CAG repeats, the estimated age of initial score change is 42.46 (standard error [SE], 2.82). For 45, it is 26.65 (SE, 1.38), and for 50, it is 18.49 (SE, 2.08).

“The estimates are almost identical for the motor-cognitive and UHDRS motor-cognitive scores but are younger for the white matter—ventricle score,” Langbehn and colleagues wrote. “However, nonnegligible brain volume loss is also occurring in healthy controls. Adjusting for this, the white matter–ventricle estimates are much closer to those of the clinical measures.”

The investigators noted that there was no sign of distinct motor-cognitive phenotypes in early Huntington disease, though they admitted that the extent of which this apparent unidimensional decline is due to motor impairment impact on cognitive testing is unknown. “Such potential confounding remains an ongoing challenge in the study of HD cognitive decline,” they wrote.

They also found that the association with UHDRS motor-cognitive score and Total Functioning Capacity (TFC) score is essentially linear once daily function declines, which is a justification for the addition of the TFC to the UHDRS motor-cognitive score in the instance of early-stage, diagnosed patients.

“By characterizing these CAG repeat length-dependent disease trajectories, we provide insights into disease progression that may guide future therapeutic approaches and identify the most appropriate intervention ages to prevent clinical decline,” Langbehn and colleagues concluded.


Langbehn DR, Stout JC, Gregory S, et al. Association of CAG repeats with long-term progression in Huntington disease. JAMA Neurol. Published online August 12, 2019. doi: 10.1001/jamaneurol.2019.2368.