Structural MRI changes detectable up to ten years before clinical Alzheimer's disease  Manuela Tondelli, Gordon K. Wilcock, Paolo Nichelli, Celeste A. De Jager, Mark Jenkinson, Giovanna Zamboni  Neurobiology of Aging  Volume 33, Issue 4, Pages 825.e25-825.e36 (April 2012) DOI: 10.1016/j.neurobiolaging.2011.05.018 Copyright © 2012 Elsevier Inc. Terms and Conditions

Fig. 1 Schematic plot of the natural history for the 3 groups included in the study. Subjects clinically diagnosed as having Alzheimer's disease (AD) anytime between years 5 and 10 of follow-up—with or without having been through a diagnosis of mild cognitive impairment (MCI)—were included in the preclinical AD group (n = 8). Subjects clinically diagnosed as MCI anytime between years 5 and 10 of follow-up and who did not convert to AD in the same time window were included in the preclinical MCI group (n = 32). Age-, gender-, and education-matched subjects who remained cognitively healthy for the full 10-year follow-up were included in the healthy control group (n = 40). Numbers in the x axes indicate when neuropsychological and clinical assessments were performed. The magnetic resonance imaging scans (MRIs) used in the study were performed at time 0. Colors indicate different cognitive status over the 10-year follow-up. Neurobiology of Aging 2012 33, 825.e25-825.e36DOI: (10.1016/j.neurobiolaging.2011.05.018) Copyright © 2012 Elsevier Inc. Terms and Conditions

Fig. 2 Results of the voxel-based morphometry (VBM) group comparison analyses. Images are selected to highlight changes in (A) medial-temporal lobe and (B) medial-posterior cortex. First row: regions of volume loss in subjects who would develop Alzheimer's disease (AD) anytime between years 5 and 10 of follow-up compared with healthy control subjects (HC). Second row: regions of volume loss in subjects who would develop AD anytime between years 5 and 10 of follow-up compared with future mild cognitive impairment (MCI). Third row: regions of volume loss in subjects who would develop AD any time between years 7 and 10 of follow-up compared with HC. Results are displayed at p < 0.05, threshold-free cluster enhancement (TFCE)-corrected. In red are results of group comparisons with no additional covariates, in yellow the same comparisons performed by adding age, apolipoprotein E (ApoE) status, and gender as confounder variables. Images are shown in radiological convention. Coordinates according to Montreal Neurological Institute (MNI). Neurobiology of Aging 2012 33, 825.e25-825.e36DOI: (10.1016/j.neurobiolaging.2011.05.018) Copyright © 2012 Elsevier Inc. Terms and Conditions

Fig. 3 Plot representing gray matter density peak value of the right medial temporal lobe cluster resulting from the voxel-based morphometry (VBM) comparison between preclinical Alzheimer's disease (AD) and healthy control (HC) subjects (Montreal Neurological Institute [MNI] coordinates: 20, −12, −24), organized by “time to diagnosis” and future diagnosis. In line with the idea that our groups represent different phases of a continuum progressing from normal cognition to AD, preclinical mild cognitive impairment (MCI) subjects converting later in time are “closer” to HC subjects, whereas preclinical MCI converting sooner are “closer” to preclinical AD subjects. Neurobiology of Aging 2012 33, 825.e25-825.e36DOI: (10.1016/j.neurobiolaging.2011.05.018) Copyright © 2012 Elsevier Inc. Terms and Conditions

Fig. 4 Results of the voxel-based morphometry (VBM) correlation analysis. Regions of significant correlation between gray matter (GM) density at baseline and Mini Mental State Examination (MMSE) scores at the tenth (in yellow-red, p < 0.05, threshold-free cluster enhancement [TFCE]-corrected) and fifth year (in blue, p < 0.001, uncorrected) of follow-up. Images are shown in radiological convention. Coordinates according to MNI. Neurobiology of Aging 2012 33, 825.e25-825.e36DOI: (10.1016/j.neurobiolaging.2011.05.018) Copyright © 2012 Elsevier Inc. Terms and Conditions

Fig. 5 Results of the shape and discriminant analysis for the right hippocampus. Thresholded F statistic (top) and prediction accuracy (bottom) for each vertex in the right hippocampus (preclinical Alzheimer's disease [AD] compared with healthy control [HC] subjects). Surface color reflects the F statistic surviving false discovery rate (FDR) correction (with 3 and 12 degrees of freedom, on top) or prediction accuracy (bottom) (see color bar). Vectors inward direction represents relative atrophy (preclinical AD subjects compared with HC subjects). Neurobiology of Aging 2012 33, 825.e25-825.e36DOI: (10.1016/j.neurobiolaging.2011.05.018) Copyright © 2012 Elsevier Inc. Terms and Conditions

Supplementary Fig. 1 Medial view of the right hippocampus, showing thresholded p statistic of the discriminant analysis (same as that in Fig. 4, but from a different perspective). Neurobiology of Aging 2012 33, 825.e25-825.e36DOI: (10.1016/j.neurobiolaging.2011.05.018) Copyright © 2012 Elsevier Inc. Terms and Conditions