Association of CAG Repeat Length in the Huntington Gene With Cognitive Performance in Young Adults

Abstract

Objective: To investigate the relationships between CAG repeat length in the huntingtin gene and cognitive performance in participants above and below the disease threshold for Huntington disease (HD), we performed a cross-sectional analysis of the Enroll-HD database.

Methods: We analyzed data from young, developing adults (≤30 years of age) without a history of depression, apathy, or cognitive deficits. We included participants with and without the gene expansion (CAG ≥36) for HD. All participants had to have a Total Functional Capacity Score of 13, a diagnostic confidence level of zero, and a total motor score of <10 and had to be >28.6 years from their predicted motor onset. We performed regression analyses to investigate the nonlinear relationship between CAG repeat length and various cognitive measures controlling for age, sex, and education level.

Results: There were significant positive relationships between CAG repeat length and the Symbol Digit Modalities, Stroop Color Naming, and Stroop Interference test scores. There were significant negative relationships between CAG repeat length and scores on Parts A and B of the Trails Making Test (p < 0.05), indicating that longer CAG repeat lengths were associated with better performance.

Discussion: An increasing number of CAG repeats in the huntingtin gene below disease threshold and low pathologic CAG ranges were associated with some improvements in cognitive performance. These findings outline the relationship between CAG repeats within the huntingtin gene and cognitive development.

Classification of evidence: This study provides Class IV evidence that CAG repeat length is positively associated with cognitive function across a spectrum of CAG repeat lengths.

Figure 1. Flowchart of Patient Exclusions

This flowchart shows how many participants were excluded on the basis of the exclusionary criteria outlined in the text. DCL = diagnostic confidence level; TFC = Total Functional Capacity Score; TMS = total motor score; YTO = years to onset.

Figure 2. CAG Relationship With Cognitive Tests

Thick black regression lines represent the nonlinear relationship across all CAG repeat lengths and the cognitive tasks. This line was produced from the individual models described. Dashed lines represent the 95% confidence interval of those models. For panels A–H, the y-axis represents the total correct of the listed cognitive tasks. Category VF = Category Verbal Fluency Task; Letter VF = Letter Verbal Fluency Task; SCNT = Stroop Color Naming Test; SDMT = Symbol Digit Modalities Test; SIT = Stroop Interference Test; SWRT = Stroop Word Reading Test; Trails A = Part A of the Trail Making Test; Trails B = Part B of the Trail Making Test.