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 37 biomarkers. The task of measuring decline i n prevention trials is challenging, in that subtle declines need to be differentiated from clinical stability induced by treatment. This task will require tools with minimal retesting effects and measures that can be r epeated over lengthy periods of time. The task of functional assessment is no less challenging, but it is potentially even more important because of its direct relevance to disease and disability; only subtle deficits are likely present and the psychometric challenges in prevention trials are similar to those for cognitive deficits. Innovative observational and simulation strategies are being explored, but these will require regulatory endorsement for use in trials. As discussed by Posner et al, 1 functional co- primary measures may not be required in very early phase AD studies, but a focus on development of sensitive functional measures could also lead to their use as a single outcome measure as well. Tests of metacognition, social cognition, and prospective memory are also newer approaches to tapping into different aspects of cognition than standard tests of episodic memory. Strategies such as controlled learning (when subjects are used as their own control) and optimizing initial encoding to enhance the potential for detection of very subtle forgetting processes appear to be promising avenues for future research. It should be noted that the various cognitive- and performance-based tasks discussed above are not without limitation. Many of the cognitive tasks we describe target highly specific abilities, by definition missing the other components of complex cognitive constructs that may be important to assess. Moreover, challenging cognitive tasks demand some level of general cognitive abilities in order for the participant to engage in the task in a valid manner, which may make them difficult to apply at later stages of the disease process. Finally, the utility of assessing certain abilities such as social cognition and metacognition, for example, as early markers of impairment may be limited by the fact that as opposed to memory, which is quite uniformly impaired in early AD, significant heterogeneity exists in these abilities across individuals. Nonetheless, measurement of these areas would fill a current gap in assessment practice and h old promise for predicting important patient outcomes over the disease course. ACKNOWLEDGMENT This paper is a product of the " Cognitive Assessment of Early Alzheimer's Disease in Clinical Trials" working group of the International Society for Clinical Trials and Methods (ISCTM). The executive committee of the society has endorsed this paper. The authors of the paper consist of individuals who presented at meetings, wrote and edited the manuscript, and approved its final content. Other individuals who attended these meetings contributed to the concepts and content of this paper. This paper does not reflect the opinions or endorsement of the employers of the authors or funding agencies that supported the research reviewed in this paper. Order of authorship, other than the workshop co- chairs, is presented in alphabetical order. REFERENCES 1. Posner H, Curiel R, Edgar C, et al. Outcomes assessment in clinical trials of Alzheimer's disease and its precursors: readying for short-term and long-term clinical trial needs. Innov Clin Neurosci. 2017;14(1–2):xx–xx 2. Duara R, Loewenstein DA, Greig, et al. PreMCI and MCI: neuropsychological, and imaging features and progression rates. Am J Ger Psychiat. 2011;9:951– 960. 3. Espinosa A, Alegret M, Valero S, et al. A longitudinal follow-up of 550 mild cognitive impairment patients: evidence for large conversion to dementia rates and detection of major risk factors involved. J Alzheimers Dis. 2013;34:769–780. 4. Petersen RC, Wiste HJ, Weigand SD, et al. Association of elevated amyloid levels with cognition and biomarkers in cognitively normal people from the community. JAMA Neurol. 2016;73:85– 92. 5. Katsumata Y, Mathews M, Abner EL, et al. Assessing the discriminant ability, reliability, and comparability of multiple short forms of the Boston Naming Test in an Alzheimer's disease center cohort. Dement Geriatr Cogn Disord. 2015;39:215–227. 6. Goldberg TE, Keefe RS, Goldman RS, et al. Circumstances under which practice does not make perfect: a review of the practice effect literature in schizophrenia and its relevance to clinical treatment studies. Neuropsychopharmacology. 2010;35:1053–1062. 7. Goldberg TE, Harvey PD, Wesnes KA, et al. Practice effects due to serial cognitive assessment: Implications for preclinical Alzheimer's disease randomized controlled trials. Alz Dem Diag, Assess, Dis Monitor. 2015;1:103–111. 8. Welsh KA, Butters N, Hughes J, et al. Detection and staging of dementia in Alzheimer s disease: use of the neuropsychological measures developed for the Consortium to Establish a Registry for Alzheimer's disease (CERAD). Arch Neurol. 1992;49:448– 452. 9. Welsh KA, Butters N, Hughes J, et al. Detection of abnormal memory decline in mild cases of Alzheimer's disease using CERAD neuropsychological measures. Arch Neurol. 1991;48:278– 281. 10. Rolstad S, Nordlund A, Eckerström C, et al. High education may offer protection against tauopathy in patients with mild cognitive impairment. J Alzheimers Dis. 2010;21:221–228. 11. O'Bryant SE, Lacritz LH, Hall, et al. Validation of the new interpretive guidelines for the clinical dementia rating scale sum of boxes score in the national Alzheimer's coordinating center database. Arch Neurol. 2010;67:746– 749. 12. Harvey PD, Heaton RK, Palmer BA, et al. Stability of cognitive impairment in elderly schizophrenic patients receiving conventional antipsychotic treatment. Am J Psychiat. 2005;162:110–117. 13. Loewenstein DA, Greig-Custo MT, Schinka JA, et al. An Investigation of PreMCI: Subtypes and Longitudinal Outcomes. Alzheim Dement. 2012;8:172–179. 14. Loewenstien DA, Acevedo A, Agron J, Duara R. Vulnerability to proactive semantic interference and progression to dementia in older adults with mild cognitive impairment (MCI). Dement Geriatr Cogn Disord. 2007;24:363–368. 15. Loewenstein DA, Acevedo A, Luis C, et al. Semantic interference deficits and the

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