ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials

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Abstract

Background

Development of new therapies for Alzheimer's disease (AD) is increasingly focused on more mildly affected populations, and requires new assessment and outcome strategies. Patients in early stages of AD have mild cognitive decline and no, or limited, functional impairment. To respond to these assessment challenges, we developed a measurement approach based on established scale items that exhibited change in previous amnestic Mild Cognitive Impairment (aMCI) trials.

Methods

Partial least squares regression with a longitudinal clinical decline model identified items from commonly used clinical scales with the highest combined sensitivity to change over time in aMCI and weighted these items according to their relative contribution to detecting clinical progression in patients’ early stages of AD. The resultant AD Composite Score (ADCOMS) was assessed for its ability to detect treatment effect in aMCI/prodromal AD (pAD) clinical trial populations.

Results

ADCOMS consists of 4 Alzheimer's Disease Assessment Scale–cognitive subscale items, 2 Mini-Mental State Examination items, and all 6 Clinical Dementia Rating—Sum of Boxes items. ADCOMS demonstrated improved sensitivity to clinical decline over individual scales in pAD, aMCI and in mild AD dementia. ADCOMS also detected treatment effects associated with the use of cholinesterase inhibitors in these populations. Improved sensitivity predicts smaller sample size requirements when ADCOMS is used in early AD trials.

Conclusions

ADCOMS is proposed as new standard outcome for pAD and mild AD dementia trials, and is progressing in a CAMD-sponsored qualification process for use in registration trials of pAD.

Related collections

Most cited references 15

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The diagnosis of mild cognitive impairment due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

Marilyn Albert, Steven Dekosky, Dennis D Dickson … (2011)

The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of developing criteria for the symptomatic predementia phase of Alzheimer's disease (AD), referred to in this article as mild cognitive impairment due to AD. The workgroup developed the following two sets of criteria: (1) core clinical criteria that could be used by healthcare providers without access to advanced imaging techniques or cerebrospinal fluid analysis, and (2) research criteria that could be used in clinical research settings, including clinical trials. The second set of criteria incorporate the use of biomarkers based on imaging and cerebrospinal fluid measures. The final set of criteria for mild cognitive impairment due to AD has four levels of certainty, depending on the presence and nature of the biomarker findings. Considerable work is needed to validate the criteria that use biomarkers and to standardize biomarker analysis for use in community settings. Copyright © 2011 The Alzheimer's Association. All rights reserved.

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Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.

Reisa Sperling, Paul S Aisen, Laurel A. Beckett … (2011)

The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious. Copyright © 2011. Published by Elsevier Inc.

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Vitamin E and donepezil for the treatment of mild cognitive impairment.

Ronald C. Petersen, Ronald G Thomas, Michael Grundman … (2005)

Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer's disease. In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer's disease; secondary outcomes were cognition and function. A total of 769 subjects were enrolled, and possible or probable Alzheimer's disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer's disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer's disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P=0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P=0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer's disease during the first 12 months of the study (P=0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E epsilon4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer's disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E epsilon4 carriers. Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer's disease during the first 12 months of treatment, the rate of progression to Alzheimer's disease after three years was not lower among patients treated with donepezil than among those given placebo. Copyright 2005 Massachusetts Medical Society.

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Author and article information

Journal

Journal ID (nlm-ta): J Neurol Neurosurg Psychiatry

Journal ID (iso-abbrev): J. Neurol. Neurosurg. Psychiatr

Journal ID (hwp): jnnp

Journal ID (publisher-id): jnnp

Title: Journal of Neurology, Neurosurgery, and Psychiatry

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 0022-3050

ISSN (Electronic): 1468-330X

Publication date (Print): September 2016

Publication date (Electronic): 23 March 2016

Volume: 87

Issue: 9

Pages: 993-999

Affiliations

[1 ]Department of Neuroscience and General Medicine, Eisai Inc. , Woodcliff Lake, New York, USA

[2 ]Pentara Corp. , Salt Lake City, Utah, USA

[3 ]Cleveland Clinic Lou Ruvo Center for Brain Health , Las Vegas, Nevada, USA

Author notes

[Correspondence to ] Dr Jeffrey Cummings, Cleveland Clinic Lou Ruvo Center for Brain Health, 888 W. Bonneville Avenue, Las Vegas, NV 89106, USA; cumminj@ 123456ccf.org

Article

Publisher ID: jnnp-2015-312383

DOI: 10.1136/jnnp-2015-312383

PMC ID: 5013117

PubMed ID: 27010616

SO-VID: facf4232-3acc-4d0d-9df4-1c157791a394

Copyright © Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

License:

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

History

Date received : 1 October 2015

Date revision received : 19 February 2016

Date accepted : 29 February 2016

Funding

Funded by: National Institutes of Health, http://dx.doi.org/10.13039/100000002;

Award ID: K01AG030514

Award ID: P30AG010129

Award ID: U01 AG024904

Funded by: U.S. Department of Defense, http://dx.doi.org/10.13039/100000005;

Award ID: W81XWH-12-2-0012

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