Measuring cognition and function in the preclinical stage of Alzheimer's disease.

The Alzheimer's Association's Research Roundtable met in November 2016 to explore how best to measure changes in cognition and function in the preclinical stage of Alzheimer's disease. This review will cover the tools and instruments currently available to identify populations for prevention trials, and measure subtle disease progression in the earliest stages of Alzheimer's disease, and will include discussions of suitable cognitive, behavioral, functional, composite, and biological endpoints for prevention trials. Current prevention trials are reviewed including TOMMOROW, Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease Trial, the Alzheimer's Prevention Initiative Generation Study, and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's to compare current approaches and tools that are being developed.

Clinically Meaningful Outcomes in Early Alzheimer Disease: A Consortia-Driven Approach to Identifying What Matters to Patients.

BACKGROUND: Numerous statistically derived composite measures have recently been proposed as clinical outcome assessments (COAs) for clinical trials in the early stages of Alzheimer disease. Critical Path Institute's Coalition Against Major Diseases (CAMD) advanced a proposed statistically derived composite measure to regulatory agencies with the goal of qualifying it as a COA for pre-dementia trials. In response to FDA's requirement to demonstrate that proposed COAs are meaningful to patients, this project aimed to identify the most important cognition-related concerns patients and informants report early in the disease and determine how this information maps to what is assessed by several statistically derived composite measures. METHODS: Leveraging qualitative research completed by Critical Path Institute's Patient-Reported Outcome Consortium, CAMD utilized a summary report that included frequency grids of reported concerns of amnestic mild cognitive impairment patients and their informants, as well as the narrative transcripts from focus groups. Transcripts were reviewed and analyzed to identify which cognitive domains the patient- and informant-reported concerns mapped onto. The results were then compared to see how well these cognitive domains were represented in various statistically derived composite measures. RESULTS: The patient- and informant-reported concerns primarily mapped to the cognitive domains of episodic memory and, secondarily, orientation and language. Depending on the specified composite, there were varying levels of alignment between their subcomponents and these cognitive domains. CONCLUSION: Through secondary analyses of existing qualitative data, this study examined several statistically derived composite measures and found that they generally capture cognitive domains that reflect aspects of day-to-day functioning that patients and informants consider meaningful.

Novel Statistically-Derived Composite Measures for Assessing the Efficacy of Disease-Modifying Therapies in Prodromal Alzheimer's Disease Trials: An AIBL Study.

BACKGROUND: There is a growing consensus that disease-modifying therapies must be given at the prodromal or preclinical stages of Alzheimer's disease (AD) to be effective. A major unmet need is to develop and validate sensitive measures to track disease progression in these populations. OBJECTIVE: To generate novel statistically-derived composites from standard scores, which have increased sensitivity in the assessment of change from baseline in prodromal AD. METHODS: An empirically based method was employed to generate domain specific, global, and cognitive-functional novel composites. The novel composites were compared and contrasted with each other, as well as standard scores for their ability to track change from baseline. The longitudinal characteristics and power to detect decline of the measures were evaluated. Data from participants in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study characterized as mild cognitively impaired with high neocortical amyloid-ß burden were utilized for the study. RESULTS: The best performing standard scores were CDR Sum-of-Boxes and MMSE. The statistically-derived novel composites performed better than the standard scores from which they were derived. The domain-specific composites generally did not perform as well as the global composites or the cognitive-functional composites. CONCLUSION: A systematic method was employed to generate novel statistically-derived composite measures from standard scores. Composites comprised of measures including function and multiple cognitive domains appeared to best capture change from baseline. These composites may be useful to assess progression or lack thereof in prodromal AD. However, the results should be replicated and validated using an independent clinical sample before implementation in a clinical trial.

The NAB shape learning subtest as a predictor of lateralized seizure onset.

This study presents the first empirical evaluation of the predictive value of the Neuropsychological Assessment Battery Shape Learning (NAB-SL) subtest in a sample of patients with unilateral temporal lobe epilepsy. Stimulus characteristics of the NAB-SL may improve predictive ability over other commonly used visual memory tests. Forty-nine patients with unilateral temporal lobe epilepsy were compared on measures of non-verbal and verbal memory (NAB-SL and Wechsler Memory Scale-III subtests). Univariate and forward conditional logistic regressions identified predictive values for each memory test individually and in combination. The NAB-SL delayed memory demonstrated consistently stronger predictive power over visual reproduction at the univariate and multivariate levels. The NAB-SL was a good predictor (80% range) of lateralized seizure onset when combined with a verbal memory measure. These preliminary results provide support for the use of the NAB-SL in preoperative epilepsy evaluations as a predictor of non-dominant temporal lobe dysfunction. Potential benefits of this test are discussed.

The influence of cognitive reserve on neuropsychological functioning following coronary artery bypass grafting (CABG).

Neuropsychological impairment is common, yet variable, after coronary artery bypass grafting (CABG). Similar variability has been observed in other CNS-related diseases. Empirical findings in Alzheimer's disease and HIV, among other areas, suggest cognitive reserve (CR) may mediate the cognitive impact of these diseases. The present study examined whether CR mediates neuropsychological outcome after CABG. Participants were 42 (N=42) individuals who underwent elective, normothermic CABG. Each was placed in high (n=22) or low (n=20) CR groups based on estimated premorbid intelligence and occupational attainment. All were administered neuropsychological tests preoperatively and at discharge. The total incidence of neuropsychological decline (66.7%) was not significantly different between CR groups. However, on working memory and executive function tests, specifically, the high CR group demonstrated greater post-operative decline compared to the low CR group. These data are considered in the context of a threshold model of CR theory.

Preliminary examination of cognitive reserve theory in closed head injury.

This investigation was designed to provide preliminary support for cognitive reserve theory in closed head injury (CHI), and demonstrate the effectiveness of using the Oklahoma premorbid intelligence estimate (OPIE) in research and clinical activities. Out of a possible 124 consecutive referrals, 26 patients (N=26) who underwent neuropsychological assessment following brain injury met study inclusion/exclusion criteria. Participants were included if they had exited post-traumatic amnesia (PTA), demonstrated uncompromised upper extremity use, displayed adequate verbal communication, and were judged capable of completing a full neuropsychological evaluation. Participants were divided into a closed head injury-negative premorbid history (CHI-) or closed head injury-positive premorbid history (CHI+) group based upon premorbid variables (e.g., history of alcoholism). Groups did not differ in terms of demographic variables or premorbid IQ. Despite having less severe head injuries, the CHI+ group had a greater pre-post difference for PIQ, and a significantly larger VIQ/PIQ discrepancy than the CHI- group. In conclusion, these findings suggest that the CHI+ group had diminished cognitive reserve secondary to the aggregate effects of premorbid insult, which resulted in greater cognitive decline following an additional stressor (i.e., CHI) than what might otherwise be expected from the head injury alone.