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 27 been shown by Hobart et al 64,65 that the r esponse categories for these subjective ADAS-Cog subtests could be made dichotomous without loss of information. It also possible that a version of the ADAS- Cog that includes only those items that are w ell-targeted to a population with mild cognitive changes (i.e., excluding items aimed at more severe illness) would provide a clearer signal of the cognitive impact of an intervention in early AD. Regardless of the statistical approach used to improve sensitivity of outcome measures, consideration should be given to an evaluation of how well the assessment tool measures the latent trait under study. In the case of cognitive, functional, or clinical decline in AD, the measurement tool chosen should be capable of measuring the range of performance that will likely be exhibited by the people entering the specific study and the expected changes that will follow intervention. The gradation of measurement for each item should be sufficient to show any clinically meaningful change for every patient and, as such, should not be sparse. DISCUSSION AND FUTURE DIRECTIONS The design of prevention trials poses an enormous challenge and risk for sponsors. As clinical trials focus more on prevention of AD or intervention in very early disease stages, the assessment tools used to detect change will need to be matched to the status of the participants in the study. Furthermore, the psychometric properties of these assessment tools will need to be optimized for the study population. Newer statistical methods and novel cognitive and functional measures, as discussed by Harvey et al, 43 hold great promise in this regard as we move forward. While the majority of risk in any trial lies in whether the drug under study has the desired effect, failure to use appropriate tools for assessing cognitive and functional change adds the risk of missing interventions that work. The use of unmodified outcome measures designed for more severe stages of illness in trials holds as great a risk as imprudent drug selection. Careful conceptualization of treatment targets and state-of-the-art understanding of the characteristics of the very early stages of A D are required to make progress. Regulatory guidance is being updated in concert with new developments in understanding treatment targets and populations of interest. While novel ways o f using existing instruments hold some promise for detection of change in populations with very early AD, this effort will have to be paired with developing new assessment strategies. ACKNOWLEDGMENT This paper is a product of the "Cognitive Assessment of Early Alzheimer's Disease in Clinical Trials" working group of the 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. Brookmeyer R, Johnson E, Ziegler- Graham K, Arrighi HM. 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Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev. 2006;(1):CD005593. 12. Knapp MJ, Knopman DS, Solomon PR, et al. A 30-week, randomized, controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group. JAMA. 1994;271:985–991. 13. McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev. 2006;(2):CD003154. 14. Coric V, Salloway S, van Dyck CH, et al. Targeting prodromal Alzheimer disease with avagacestat: a randomized clinical trial. JAMA Neurol. 2015;72:1324–1333. 15. Cummings JL, Morstorf T, Zhong K. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;6:37. 16. Doody RS, Farlow M, Aisen PS, Alzheimer's disease cooperative study

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