Innovations In Clinical Neuroscience

JAN-FEB 2017

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

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Page 31 of 63

Innovations in CLINICAL NEUROSCIENCE [ 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 ] 32 A second question regarding s ensitivity to decline is whether the same aspects of cognitive and functional impairment are even relevant in preclinical and pre-MCI states as in AD. It may be that different assessment p aradigms must be used to detect cognitive or functional changes early in the course of MCI. There are elements of memory impairment, discussed below, that define pre-MCI and could provide predictive utility for identifying cases at risk for progression to more severe impairments. Similarly, performance-based functional assessments, if feasible at all, will need to be aimed at very subtle aspects of impairment in preclinical and pre-MCI cases. An example could be measuring highly complex instrumental activities of daily living (ADLs) such as internet-based banking or bill paying. Incipient signs of these deficits might not be visible to observers or even accessible to the awareness of the participant. As suggested below, ecologically valid direct observation strategies may also yield information that might not be easily observable, particularly in a cross-sectional context. In contrast, in mild-to-moderate AD, even basic ADLs may be performed only with difficulty and be readily detected even by untrained or themselves impaired observers. SENSITIVITY TO IMPAIRMENT AND SENSITIVITY TO CHANGE If a cognitive or functional assessment is not sufficiently sensitive to detect impairment, it will not be sensitive to improvement with treatment. A caveat is that the impairments detected must be related to the incipient illness and not lifelong premorbid limitations in functioning. 10 In the case of the minimal impairments associated with pre-MCI, detection of impairments with historical measures such as the ADAS-COG is challenging due to ceiling effects, 11 and detection of improvements with such measures may not be possible. If preclinical study participants enter a trial performing at a level equivalent to their lifelong level of functioning on the cognitive endpoints, as expected in contemporary prevention trials, then d etection of impairment is not important. Rather, the utility of the assessment measures employed will be indexed in terms of longitudinal sensitivity to decline on the part of u ntreated (i.e., placebo) participants and separation of this subtle decline from stabilized performance induced by successful preventative treatment. This is an extremely high bar to meet. In contrast to studies in patients with mild-to-moderate AD, cognitive and functional impairments in preclinical and pre-MCI individuals will be minimal to absent. Thus, there is less need for concern about tasks being too challenging and leading to floor effects. There will also be fewer challenges associated with participants not understanding instructions or having gross linguistic, perceptual, or praxic deficits, leading to findings of nonspecific impairment. However, the relatively unimpaired status of the participants at entry to the clinical treatment trial produces several challenges. The challenges are reduced in inverse proportion to the level of impairment seen at entry into the study. A clear challenge for assessment in prevention trials will be balancing minimal practice effects and the sensitivity of measures. Alternate forms of neuropsychological tests are often challenged by form-to-form variance that is greater than differences associated with practice effects. 12 Potential assessment instruments to identify effective prevention interventions will need to meet several criteria, such as the following: 1. Minimal and quantifiable improvements in performance associated with retesting alone (i.e., practice effects) 2. Sensitivity to the subtle declines seen in placebo-treated patients 3. Ability to be repeated multiple times throughout a lengthy trial. Further, assessment of functioning, including performance-based tasks, could also be included as outcomes pending regulatory decisions and development of sufficiently sensitive measures. ADVANCES IN ASSESSMENT OF EARLY COGNITIVE IMPAIRMENT Cognitive deficits in MCI and in AD have been widely studied. For treatment studies of AD, the ADAS-Cog is a widely used outcome measure. The ADAS-Cog, a lthough used in some studies of MCI, is not as suited to this population because many of the cognitive impairments examined in the ADAS-Cog are not yet present in MCI, thus making most of the items uninformative. Loewenstein et al 13 have found that older adults with pre- MCI have a 6-fold to 8-fold risk of progressing to MCI or dementia relative to elderly cognitively normal individuals over a two to three year period. 2,13 Thus, the question arises: When one is attempting to identify important deficits in pre-MCI or preclinical individuals, is a more challenging version of the tasks used to assess deficits in MCI required or are the deficits different, requiring different tests? The general focus in assessment of the earliest signs of AD has been on the detection of episodic memory impairments, both in terms of impairments in learning/encoding and rate of forgetting. Increasing difficulty in standard tasks can be accomplished by adding more stimuli to the assessment (e.g., a longer story), modifying the encoding potential of the stimuli, changing the presentation rate, and altering the recall/recognition instructions. However, increasing the difficulty of tests has some risks. These include questions as to whether more difficult tests measure the same construct as the easier tests and whether there are possible reductions in the test's psychometric properties such as floor and ceiling effects or test-retest reliability induced by increasing difficulty. More difficult cognitive tests may be more highly related to global intelligence and therefore associated with reduced performance in healthy, but less educated adults. The closer the score is to the floor of the test, the greater the risk for reductions in test- retest reliability due to regression to the mean and general instability of scores at the extremes of distributions. Shortcomings of existing measures and targets for modification in

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