We characterized the MCI (n
= 175) and AD (n
= 84) cohorts relative to the normal controls (n
= 139) using methods based on volumetric segmentation [30
] and cortical surface reconstruction and parcellation [15
] techniques for each individual’s brain, combining region of interest (ROI) and cortical surface vertex-wide approaches that allow greater exploitation of information obtained from all brain areas [29
]. The results demonstrated robust performance of the methods and evidenced measurements sufficiently sensitive to reveal the subtle morphometric characterization of SMCI and MMCI in this cross-sectional sample of individuals who may be in a prodromal AD state (). While significant mesial temporal atrophy characterized all groups, including SMCI, MMCI, and AD, smaller volumes and thinner cortex were widespread and evident across the cortex even within the SMCI group.
Fig. 1 Group differences in average thickness (mm) for left hemisphere. Top row: SMCI vs. NC; Bottom row: MMCI vs. NC. LEFT mesial views, RIGHT lateral views. The scale ranges from <−0.3 (yellow) to > + 0.3 (cyan) mm thickness. Areas (more ...)
The regions that were most sensitive to early changes were within temporal, rostral posterior cingulate, inferior parietal, precuneus, and caudal midfrontal cortices (). Areas critical for distinguishing SMCI from NC were in the mesial temporal regions as expected, including bilateral hippocampus, bilateral entorhinal cortex, and left amygdala, similar to recent findings [42
], supporting these regions as the most sensitive to early AD-related changes. Given previous work suggesting that mesial temporal asymmetries also may be modified by disease state, we also examined left/right asymmetries as potential measures indicative of risk or disease progression. Building on findings in AD (e.g. [4
]), several investigators [75
] have suggested that left hemisphere regions may be more affected than the right, changing the natural asymmetries, in individuals at increased risk for AD, although reports are conflicting [56
]. Our findings supported natural right dominant asymmetries in the hippocampus and entorhinal cortex of normal controls, as suggested in some previous work (e.g. [28
]), however, these asymmetries did not interact with diagnostic group providing no support for structural asymmetries as an indication of disease state ().
Estimated marginal mean volume (mm3) for Hippocampus and Entorhinal Cortex thickness (mm) by group accounting for sex and age effects. Error bars = std error of the mean. Solid bar = Left Hemisphere; outlined open bar = Right Hemisphere.
Importantly, in the SMCI cohort, characterized with impairment in the memory domain only, significant atrophy extended beyond the mesial temporal regions into posterior cingulate, parietal, and frontal regions indicating that widespread damage occurs before standard clinical measures can detect AD. The pattern of thinning in SMCI overlapped to some extent with recent findings by Seo and colleagues [75
], although our larger sample demonstrated greater thinning in medial parietal, lateral middle temporal, and anterior cingulate regions and powered significant differences from NC in numerous ROIs. These broad changes even within individuals impaired only in the memory domain suggest that standard neuropsychological measures may not be sufficiently sensitive, although novel approaches may be more informative (see Jacobson et al., this issue). The pattern of results also broadly supported the view that MMCI may be a later stage of prodromal AD than SMCI, although some of the structural changes observed confirmed the potential heterogeneity of the sample. Relative to SMCI, the presumably later stage of MMCI showed greater atrophy in the inferior and lateral temporal lobe, and significantly thinner temporo-parietal association cortices, retrosplenial, anterior cingulate, and other frontal regions; these significant findings were more widespread relative to previous work [75
], perhaps due to a larger MMCI sample. The AD and MMCI groups were relatively similar, with greater differences in some parietal, retrosplenial and frontal regions. These profiles may prove useful in defining a pattern of degeneration that will enable discrimination of early stage AD from other disorders that also impact mesial temporal regions.