A LONGITUDINAL MORPHOMETRIC STUDY OF FAMILIAL ALZHEIMER’S DISEASE: RESULTS FROM DIAN

Abstract

Background Cross-sectional MRI analyses have shown widespread decreases of gray matter in familial AD gene carriers compared with non-carriers. Within-subject longitudinal measures have potential advantages of greater sensitivity with fewer confounds; but to date these have largely focused on change within specific brain regions. In this study, we used participants from the Dominantly Inherited Alzheimer Network (DIAN) to perform a voxelwise whole brain analysis of within-subject changes from serial MRI. Methods Ninety-seven participants with serial T1 imaging were included in the analysis; five others were excluded due to poor image quality or probable non-AD pathologies. They were classified into four groups (see Table): 28 non-carriers, 17 presymptomatic mutation carriers (global CDR=0 at baseline or followup, CDR=0-0.5 at the other visit) with estimated onset > 5 years away and 19 with estimated onset ≤ 5 years away, and 33 symptomatic carriers (global CDR>0 at both visits). Longitudinal registration, tissue segmentation, and spatial normalization were performed using SPM12. Baseline and followup images were co-registered, producing midpoint images, which served as inputs for tissue segmentation, and Jacobian determinant maps, which represented annualized volume change within subject. Statistical analysis was performed on spatially normalized Jacobian determinant maps smoothed with a 6mm full width at half maximum kernel restricted to gray matter. The general linear model included a four-level factor for group, a three level factor for scanner model, with sex and age as covariates. Results Significant findings (p<0.05, Family Wise Error corrected) of volume contraction in symptomatic carriers were widespread, including the precuneus, fusiform gyrus, parahippocampal gyrus, middle frontal gyrus , posterior cingulate, hippocampus, and putamen (Figure 1). No findings in the far-from-onset presymptomatic carriers survived correction for multiple comparisons. While there were also no findings in the near-to-onset presymptomatic carriers, the visual pattern is similar to the symptomatic carriers (Figure 2), but observed changes were 4-8 times smaller in magnitude. Conclusions We have used longitudinal morphometry to determine brain-wide atrophy patterns in familial AD. These areas could identify sensitive biomarkers for clinical trial endpoints. There were no significant changes in presymptomatic carriers, which could reflect the heterogeneity of this group and a resulting lack of power.