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A Biomarker Combining Imaging and Neuropsychological Assessment for Tracking Early Alzheimer's Disease in Clinical Trials

[ Vol. 15 , Issue. 5 ]

Author(s):

Nishant Verma, S. Natasha Beretvas, Belen Pascual, Joseph C. Masdeu, Mia K. Markey* and The Alzheimer's Disease Neuroimaging Initiative   Pages 429 - 442 ( 14 )

Abstract:


Background: Combining optimized cognitive (Alzheimer's Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimer's disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimer's disease.

Method: Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimer's clinical trials that combines cognitive and atrophy markers.

Results: Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8±4.9% specificity at 80% sensitivity) that will evolve to Alzheimer's disease for clinical trials.

Conclusion: The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimer’s disease.

Keywords:

Latent variable modeling, Alzheimer's disease assessment scale, Alzheimer's clinical trial, cerebral atrophy, cognitive impairment, mild cognitive impairment.

Affiliation:

Department of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton Street Stop C0800, Austin, TX 78712, Department of Educational Psychology, The University of Texas at Austin, 1 University Station D5800, Austin, TX 78712, Nantz National Alzheimer Center, Houston Methodist Neurological Institute, 6560 Fannin Street, Houston, TX 77030, Nantz National Alzheimer Center, Houston Methodist Neurological Institute, 6560 Fannin Street, Houston, TX 77030, Department of Biomedical Engineering, The University of Texas at Austin, 107 W. Dean Keeton Street Stop C0800, Austin, TX 78712



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