HD-CAB: a cognitive assessment battery for clinical trials in Huntington's disease 1,2,3

Cognitive dysfunction is central to Huntington's disease (HD) and undermines quality of life. Clinical trials are now targeting cognitive outcomes in HD; however, no cognitive battery has been optimized for HD clinical trials. We evaluated 16 cognitive tests in a 20-site, five-country, observational study designed to mimic aspects of a clinical trial (e.g., data collection managed by a contract research organization, repeated testing, prespecified statistical analyses). Fifty-five early HD, 103 premanifest HD (pre-HD), and 105 controls were tested at visit 1, visit 2 (1-3 days later), and visit 3 (5-7 weeks after visit 1). For inclusion in a recommended battery, tests were evaluated for sensitivity, practice effects, reliability, domain coverage, feasibility, and tolerability. Most tests differentiated controls from pre-HD and early HD and showed excellent psychometric properties. We selected six tests to constitute the Huntington's Disease Cognitive Assessment Battery (HD-CAB): Symbol Digit Modalities Test, Paced Tapping, One Touch Stockings of Cambridge (abbreviated), Emotion Recognition, Trail Making B, and the Hopkins Verbal Learning Test. These tests demonstrated sensitivity to disease status (Cohen's d effect sizes: early HD= -1.38 to -1.90 and pre-HD= -0.41 to -0.78), and acceptable reliability (r's 0.73-0.93). A composite score yielded large effect sizes (early HD = -2.44 and pre-HD = -0.87) and high reliability (r = 0.95). HD-CAB is the first cognitive battery designed specifically for use in late premanifest and early HD clinical trials. Adoption of the HD-CAB will facilitate evaluation of treatments to improve cognition in HD.