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J Alzheimers Dis. 2015;46(1):167-78. doi: 10.3233/JAD-150047.

Voxel Level Survival Analysis of Grey Matter Volume and Incident Mild Cognitive Impairment or Alzheimer's Disease.

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Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA.
Department of Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, PA, USA.
Department of Machine Learning, Carnegie Mellon University, Pittsburgh, PA, USA.
Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA.
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Radiology, University of California Los Angeles, Los Angeles, CA, USA.
Imaging Genetics Center, University of Southern California, Los Angeles, CA, USA.
Departments of Neurology, Psychiatry, Radiology, Pediatrics, Engineering, & Ophthalmology, Keck USC School of Medicine, Los Angeles, CA, USA.
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA.


The purpose of this study was to identify, at the voxel level, brain regions associated with the time to develop mild cognitive impairment (MCI) or Alzheimer's disease (AD) from normal cognition. We analyzed incident MCI (n = 58) or AD (n = 151) in 292 cognitively normal participants in the Cardiovascular Health Study-Cognition Study (mean age = 79.2 ± 3.6 years). We used segmented, modulated grey matter maps from 3D (spoiled gradient echo) MRI scans obtained in 1998/99 (with clinical follow-up through 2012) that were smoothed with a 3-D 4 mm Gaussian filter. We fit approximately 1.92 million voxel-level Cox proportional hazard models to examine the grey matter volume effect on time to event, adjusting for age, sex, and diabetes. We used the significance threshold of p <  0.005 with contiguity threshold of at least 68 voxels (false detection probability <2.5×10 -8). Areas within the mesial temporal lobe (MTL), anterior temporal lobe, hippocampus, and posterior cingulate gyrus were associated with time to MCI or AD. The presence of white matter lesions (a marker of small vessel disease in the brain) was associated with the volumes of the MTL and precuneus; MRI-identified infarcts also predicted MTL volume. These findings are important because we identified critical brain regions that predict a person's increased likelihood of developing MCI or AD over a decade prior to the onset of clinical symptoms; these critical brain regions were themselves affected by the presence of vascular disease.


Alzheimer’s disease; Cox survival model; MRI; incidence; mild cognitive impairment

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