Multimodal analysis in normal aging, mild cognitive impairment, and Alzheimer's disease: Group differentiation, baseline cognition, and predicition of future cognitive decline

Alzheimer's disease (AD) is a progressive neurodegenerative disease with an insidious onset that makes it difficult to distinguish from normal aging. It begins with an impairment of memory that develops into amnestic mild cognitive impairment (aMCI) and later to dementia as deficits become apparent in other cognitive domains. Effective biomarkers that differentiate normal aging, MCI, and AD and predict future cognitive decline are needed. Potential biomarkers have been studied in isolation, but their impact when combined is not understood. The goal of this project is to determine the optimal combination of CSF biomarkers, MRI morphometry, FDG PET metabolism, and neuropsychological test scores to differentiate between normal aging subjects and those with MCI and AD. This study addresses: 1) the optimal normalization region and partial volume correction method to quantify FDG PET analysis, 2) the effects of adjusting MRI-based cortical thickness measures for differences in gray/white matter tissue contrast in normal aging and disease, 3) whether multimodal multivariate stepwise logistic regression models can predict group membership, and 4) whether multimodal multivariate stepwise linear regression models can determine which imaging and CSF biomarker variables best predict future cognitive decline. The results indicate that normalizing FDG PET to the cerebellum along with using a gray matter mask for partial volume correction provides optimal prediction. In contrast, age-associated changes in gray/white matter intensity ratio did not differentiate between the groups and only slightly improved the efficacy of cortical thickness as a biomarker. MRI morphometry of the gray matter and neuropsychological test scores were better able to discriminate between the groups than FDG PET or CSF biomarker concentrations. Combining all modalities significantly improved the index of discrimination, especially at the earliest stages of the disease. MRI gray matter morphometry variables were more highly associated with baseline cognitive function and best predicted future cognitive decline compared to other variables. Overall these findings demonstrate that a multimodal approach using MRI morphometry, FDG PET metabolism, neuropsychological test scores, and CSF biomarkers provides significantly better discrimination than any modality alone. Hence, the variables important for discriminating between the groups may be candidates for biomarkers in human clinical interventional trials.