Innovations In Clinical Neuroscience

JAN-FEB 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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[ V O L U M E 1 4 , N U M B E R 1 – 2 , J A N U A R Y – F E B R U A R Y 2 0 1 7 ] Innovations in CLINICAL NEUROSCIENCE 31 Since newer interventions will target the e arly stages of disease, there has been a focus on developing novel tests to detect the earliest manifestations of AD. This is because traditional neuropsychological tests were designed to detect changes a ssociated with dementing conditions and are 1) not sensitive enough to identify subtle cognitive impairment present in preclinical disease states, and 2) not designed to reliably assess meaningful change over time. Similarly, commonly employed measures of functional abilities are typically inventories completed by patients and their informants. Although there is value in this approach, subjective judgments made by both patients and informants may be prone to error and response biases. In this paper, we describe the state of the art of objective assessment of cognitive and functional impairment in AD across its early stages. We particularly focus on the following three domains: 1. Tests sensitive to early cognitive impairments 2. Performance-based assessment that provides standardized, objective, and highly portable means to assess deficits in functional capacity 3. Direct observation measures, which are now a more broadly viable strategy due to technological advances, including video observation and ecological momentary assessment with smartphone technology. WHAT ARE THE "EARLY STAGES" OF AD? There are several different populations who are treatment targets who do not meet full criteria for AD. These include individuals who meet current diagnostic criteria for mild cognitive impairment (MCI), the diagnosis of which is agreed upon to an extent. Further, there are individuals who have subtle cognitive changes that are not substantial enough to meet criteria for MCI; in some studies these individuals are designated as "pre- MCI." 2 Both MCI and pre-MCI could be viewed as conditions that are "prodromal AD" conditions, in that the risk for AD in each of these populations is empirically elevated compared to individuals without evidence of cognitive changes. 3 A final group, which can be referred to as "pre- clinical," is a group that is identified on t he basis of risk factors, including either genetic liability to AD or the presence of biomarker changes that suggest increased risk. 4 At the current time, the pre-clinical group is marked by the a ppearance of cognitive normality, 4 b ut cognitive changes can be detected in these individuals. The question is whether more sensitive tests could identify earlier impairments in some or all preclinical individuals. LIMITATIONS OF THE CURRENT STATE OF THE ART Current assessment methods used in clinical trials targeted toward cognitive and neurodegenerative disorders are limited for use in early phases of AD. In general, this is directly related to the inherent nature of the features of change that are being tracked—slow decline possibly punctuated with acute, unpredictable events—for which existing tools and methods of assessment are not optimally designed. In particular, there are two contemporary major constraints. First, clinical assessments are conducted in person at distinct spaced intervals, weeks or months apart, at the convenience of the investigator. These assessments often rely on recall of events from people whose memory may be impaired and informants whose judgments may be prone to error or memory impairments of their own. In addition, contextual aspects of a participant's daily life (e.g., sleep hygiene, medications, pain level) that might affect true real-world performance are not captured, and as a result, data collected are at best brief snapshots that do not fully reflect real-world situations. Second, in treatment studies, there is often only a modest expected difference among cognitive and/or functional test results between placebo and treatment participants, as the degree of cognitive decline prior to and during treatment is often subtle and not dramatic in early stages of AD. OVERALL GOALS OF COGNITIVE AND FUNCTIONAL ASSESSMENT IN EARLY PHASES OF AD In AD prevention research, targeted at pre-clinical and pre-MCI populations, outcomes assessments should be c apable of, at minimum, the following: 1) bi-directional sensitivity, 2) longitudinal tracking (sensitivity to change), and 3) sensitivity to impairment. Bi-directional sensitivity is r equired, because some successful interventions could eliminate progression to more advanced clinical states, relative to placebo-treated participants. Thus, measures must have the ability to detect both stability (due to a successful intervention) and worsening (due to treatment failures) in clinical trial participants who might have considerable variation in their baseline levels of performance. A critical goal for measures is to be sensitive to long-term cognitive and functional stability, which is the goal of prevention interventions. These interventions may not improve functioning from an apparently unimpaired baseline, but may prevent progression to MCI or AD. Beyond the basic requirements of test-retest stability of performance, 5 improvements in performance with testing might serve to mask subtle declines in placebo treated participants in preclinical stages, 6 ,7 thus rendering a true outcome of stability in the successfully treated pre-clinical individuals difficult to separate from retesting effects. A final goal is to be able to detect developing impairments in cognition and functioning in preclinical, pre-MCI, and MCI populations. There are two separate issues that bear on these goals. One is the level of difficulty of the assessments. Some skills that are completely intact in preclinical cases may be impaired in MCI and fully deteriorated in cases with mild-to- moderate AD. For instance, assessment of delayed recall and delayed recognition from multi-trial list learning tests with 10 items (e.g., Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychology battery) 8 may be extremely sensitive to the detection of early-stage AD; 9 however, these learning tests, while optimal in their difficulty level for MCI and mild AD populations, may be too easy for preclinical and pre-MCI populations and too challenging for moderate AD.

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