Paulsen, Jane S.

Decades of research on biomarker identification and integration in Alzheimer’s disease (AD) have helped to advance biologically driven disease models, disease subtypes, and disease-modifying treatments. Key lessons learned from AD biomarker development include the need for integration of new biological insights, investment in large cross-sectional and longitudinal studies, a multicomponent biomarker approach, and recruitment of clinical trial cohorts and biosamples that are representative of the target population. We describe how these lessons are being applied in Parkinson’s disease, Huntington’s disease, multiple sclerosis, and psychotic disorders as use cases to inform biomarker-based approaches across central nervous system disorders.

Background: “Practice effects” (PE), or performance improvements due to prior exposure to testing, are known to confound cognitive test results, particularly when short intervals occur between two test sessions. Objective: We examined two subsamples with short or long re-test intervals from a recent clinical trial. Methods: Thirty-four non-depressed adults with mild Huntington Disease (HD) participated. Three cognitive tests were administered at screening and again at baseline, before active treatment randomization. Half the sample had a 24-hour retest interval while the other half was >6-days. Results: The two groups differed on demographic/clinical factors (age, Total Motor Score and Total Functional Capacity). After controlling for age and motor score, PE differences were found on three of the five UHDRS cognitive tests: the longer interval group showed larger PE on Symbol-Digit Modalities and Stroop color, while the rapid interval group had larger PE on Stroop interference. Controlling for screening cognitive performance yielded similar results. Conclusions: Length of interval between screening and baseline visits and level of disease severity may influence stability of UHDRS cognitive test results in clinical trials in HD.

Abstract Background: In Huntington disease (HD), cognitive changes due to disease-progression or treatment are potentially confounded by “practice effects” (PE) — performance improvement from prior exposure to test materials. Objective: A practice run-in (“dual baseline”) was used in an HD cognitive trial to determine if PE could be minimized and evaluate performance trajectories over multiple visits. Methods: Non-depressed adults ( N = 36) with mild to moderate HD-related cognitive deficits participated in a clinical trial to examine the efficacy of citalopram to enhance cognition. Cognitive tests were administered at three visits (2 weeks separating each visit), before active treatment randomization. Some tests were also administered at screening. Therefore 3–4 pre-treatment repetitions were available. We examined test improvement using repeated-measures ANOVAs with planned pairwise comparisons. Results: Despite the practice run-in and use of alternate test forms, results indicated ongoing improvements over at least three test sessions on all three UHDRS cognitive tests. Trails A and B showed improvements between the third and fourth session, which suggests that one pre-baseline visit may not be effective in reducing practice on this important and commonly used test. Conclusions: Overall, 7 out of 13 variables showed some degree of short-term PE, even after multiple sessions and alternate forms. Tests assessing processing speed and memory may be particularly confounded by ongoing PE across at least 2–3 sessions. Practice run-in periods and alternate forms may help minimize the impact of such effects in HD clinical trials but awareness of which tests are most susceptible to PE is important in clinical trial design.

ABSTRACTBackgroundThe objective of this study was to evaluate citalopram for executive functioning in Huntington's disease (HD).MethodsThe study was randomized, double‐blind, and placebo‐controlled. Thirty‐three adults with HD, cognitive complaints, and no depression (Hamilton Depression [HAM‐D] rating scale ≤12) were administered citalopram 20 mg or placebo (7 visits, 20 weeks), with practice and placebo run‐ins. The primary outcome was change in executive functioning.ResultsThe intent to treat analysis was controlled for practice effects, comparing visits 1 and 2 to visits 5 and 6 for citalopram versus placebo. There were no significant benefits on the executive function composite (treatment‐placebo mean difference −0.167; 95% confidence interval [CI], −0.361 to 0.028; P = .092). Citalopram participants showed improved clinician‐rated depression symptoms on the HAM‐D (t = −2.02; P = 0.05). There were no group differences on motor ratings, self‐reported executive functions, psychiatric symptoms, or functional status.ConclusionsThere was no evidence that short‐term treatment with citalopram improved executive functions in HD. Despite excluding patients with active depression, participants on citalopram showed improved mood, raising the possibility of efficacy for subsyndromal depression in HD. © 2013 International Parkinson and Movement Disorder Society