Novel approaches to measuring neurocognitive functions in Alzheimer's disease clinical trials

Abstract

Purpose of reviewWe comprehensively examined recent advancements in developing novel cognitive measures that could significantly enhance detection of outcome changes in Alzheimer's disease clinical trials. Previously established measures were largely limited in their ability to detect subtle cognitive declines in preclinical stages of Alzheimer's disease, particularly due to weak psychometric properties (including practice effects and ceiling effects) and requirement of in-person visits that impacted ascertainment.Recent findingsWe present novel cognitive measures that were designed to exhibit reduced practice effects and stronger correlations with Alzheimer's disease biomarkers. In addition, we summarized some recent efforts in developing remote testing measures protocols that are aimed to overcome the limitations and inconvenience of in-person testing, and digital phenotyping, which analyses subtle forms of digital behaviour indicative of cognitive phenotypes. We discuss each measure's prognostic accuracy and potential utility in Alzheimer's disease research while also commenting on their limitations. We also describe our study, the Development of Novel Measures for Alzheimer's Disease Prevention Trials (NoMAD), that employed a parallel group design in which novel measures and established measures are compared in a clinical trials armature.SummaryOverall, we believe that these recent developments offer promising improvements in accurately detecting clinical and preclinical cognitive changes in the Alzheimer's disease spectrum; however, further validation of their psychometric properties and diagnostic accuracies is warranted before reliably implementing these novel measures in Alzheimer's disease clinical trials.

Rationale for the selection of dual primary endpoints in prevention studies of cognitively unimpaired individuals at genetic risk for developing symptoms of Alzheimer’s disease

“…The lack of sensitivity and limitations of existing composite cognitive scales in the early stages of AD have also been put forward by Schneider and Goldberg [ 25 ]. These authors propose novel cognitive measures that may be more reliable and sensitive to very subtle changes, and thereby yield evidence of impairment and progression unseen in the analyzed historical cohorts; these, however, still need to be validated [ 26 , 27 ].…”

The future of psychopharmacology: a critical appraisal of ongoing phase 2/3 trials, and of some current trends aiming to de‐risk trial programmes of novel agents

“…More than one outcome in a trial is desirable, as one outcome only can hardly provide a comprehensive clinical picture, yet adjusting for multiple comparisons in the statistical analyses is needed in case that more than one primary outcome is be­ing assessed or in case that inferential statistical testing is desired even of key secondary outcomes. For secondary and exploratory, hypothesis‐generating outcomes and those requiring a lot of multidimensional data, such as for functioning, modern tools including digital phenotyping and ecological momentary assessment can be of great value and should be progressively introduced in assessment of trials 218‐228 . Digital phenotyping and ecological momentary assessments can be repeated mul­tiple times, and can be even continuous in case of passive monitoring.…”

Reliability of the NACC Telephone‐administered Neuropsychological Battery (T‐cog) and Montreal Cognitive Assessment for participants in the USC ADRC

“…In the context of older participant samples, telephone administration is also attractive, given their broad access to phones in addition to their, sometimes-compromised, ability to use technology for video conferences or smartphone test administration. 2 However, it should not be assumed once appropriate tests are selected, given the nature of telephone communication, that the reliability of telephone test administration follows reliability in face-to-face administration. Environmental variables, usually controlled for in a laboratory setting, for example distractors, hearing impairments due to poor signal and the absence of lip reading, play a significant role in comprehension of everyday face-to-face conversation 3 and may negatively impact participant scoring.…”

“…Telephone administration is a feasible form of remote administration, with the American Psychological Association, and other organizations around the world, publishing guidelines 1 to move toward tele‐assessment while restrictions limited face‐to‐face testing. In the context of older participant samples, telephone administration is also attractive, given their broad access to phones in addition to their, sometimes‐compromised, ability to use technology for video conferences or smartphone test administration 2 …”