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Composite cognitive and functional measures for early stage Alzheimer's disease trials.

ABSTRACT: Introduction:Composite scales have been advanced as primary outcomes in early stage Alzheimer's disease trials, and endorsed by the U.S. Food and Drug Administration (FDA) for pivotal trials. They are generally composed of several neurocognitive subscales and may include clinical and functional activity scales. Methods:We summarized the development of 12 composite scales intended as outcomes for clinical trials and assessed their characteristics. Results:Composite scales have been constructed from past observational and clinical trial databases by selecting components of individual neuropsychological tests previously used in clinical trials. The atheoretical approaches to combining scales into a composite scale that have often been used risk omitting clinically important measures and so may include redundant, irrelevant, or noncontributory tests. The deliberate combining of neurocognitive scales with functional activity scales provides arbitrary weightings that also may be clinically irrelevant or obscure change in a particular domain. Basic psychometric information is lacking for most of the composites. Discussion:Although composite scales are desirable for pivotal clinical trials because they, in principle, provide for a single, primary outcome combining neurocognitive and/or functional domains, they have substantial limitations, including their common derivations, inattention to basic psychometric principles, redundancy, absence of alternate forms, and, arguably, the inclusion of functional measures in some. In effect, any currently used composite is undergoing validation through its use in a trial. The assumption that a composite, by its construction alone, is more likely than an individual measure to detect an effect from any particular drug and that the effect is more clinically relevant or valid has not been demonstrated.

SUBMITTER: Schneider LS

PROVIDER: S-EPMC7233425 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Composite cognitive and functional measures for early stage Alzheimer's disease trials.

Schneider Lon S LS Goldberg Terry E TE

Alzheimer's & dementia (Amsterdam, Netherlands) 20200515 1

<h4>Introduction</h4>Composite scales have been advanced as primary outcomes in early stage Alzheimer's disease trials, and endorsed by the U.S. Food and Drug Administration (FDA) for pivotal trials. They are generally composed of several neurocognitive subscales and may include clinical and functional activity scales.<h4>Methods</h4>We summarized the development of 12 composite scales intended as outcomes for clinical trials and assessed their characteristics.<h4>Results</h4>Composite scales ha ...[more]

PMID: 32432155

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Project description:BackgroundBoth subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) have a high risk of progression to Alzheimer's disease (AD). While most of the available evidence described changes in functional connectivity (FC) in SCD and aMCI, there was no confirmation of changes in functional connectivity density (FCD) that have not been confirmed. Therefore, the purpose of this study was to investigate the specific alterations in resting-state FCD in SCD and aMCI and further assess the extent to which these changes can distinguish the preclinical and early-stage AD.MethodsA total of 57 patients with SCD, 59 patients with aMCI, and 78 healthy controls (HC) were included. The global FCD, local FCD, and long-range FCD were calculated for each voxel to identify brain regions with significant FCD alterations. The brain regions with abnormal FCD were then used as regions of interest for FC analysis. In addition, we calculated correlations between neuroimaging alterations and cognitive function and performed receiver-operating characteristic analyses to assess the diagnostic effect of the FCD and FC alterations on SCD and aMCI.ResultsFCD mapping revealed significantly increased global FCD in the left parahippocampal gyrus (PHG.L) and increased long-range FCD in the left hippocampus for patients with SCD when compared to HCs. However, when compared to SCD, patients with aMCI showed significantly decreased global FCD and long-range FCD in the PHG.L. The follow-up FC analysis further revealed significant variations between the PHG.L and the occipital lobe in patients with SCD and aMCI. In addition, patients with SCD also presented significant changes in FC between the left hippocampus, the left cerebellum anterior lobe, and the inferior temporal gyrus. Moreover, changes in abnormal indicators in the SCD and aMCI groups were significantly associated with cognitive function. Finally, combining FCD and FC abnormalities allowed for a more precise differentiation of the clinical stages.ConclusionTo our knowledge, this study is the first to investigate specific alterations in FCD and FC for both patients with SCD and aMCI and confirms differential abnormalities that can serve as potential imaging markers for preclinical and early-stage Alzheimer's disease (AD). Also, it adds a new dimension of understanding to the diagnosis of SCD and aMCI as well as the evaluation of disease progression.

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Composite cognitive and functional measures for early stage Alzheimer's disease trials.

Publications

Composite cognitive and functional measures for early stage Alzheimer's disease trials.

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