P4‐320: DURA MATTERS: FAILURE TO ACCOUNT FOR THE DURA MATER CONFOUNDS MEASURES OF ATROPHY IN CORTICAL REGIONS LINKED TO THE EARLIEST NEUROFIBRILLARY TANGLE PATHOLOGY (2018)

Medial temporal lobe (MTL) substructures (perirhinal cortex, entorhinal cortex, hippocampus) are the earliest regions affected by neurofibrillary tangle pathology – and thus are promising biomarkers for preclinical Alzheimer's disease (AD). However, in T1-weighted MRI, the MTL cortex is challenging to separate from dura, which has similar intensity to gray matter (GM) on T1-contrast but can be easily separated on T2-contrast (Figure 1), leading to overestimation of cortical measurements. Importantly, we hypothesize that the degree of overestimation may be linked to disease severity (Figure 2), which would introduce differential errors in the quantification and could potentially confound imaging studies of the MTL cortex. The dura has similar intensity with gray matter in T1-weighted MRI (A) but can be easily separated in T2-weighted MRI (B). Conventional method commonly mislabels the dura as gray matter (red arrows in C), which potentially confounds findings of research studies. ASHS-T1 is able to separate dura from gray matter (D) and generate reliable segmentation of the medial temporal lobe substructures. Abbreviations: ERC = entorhinal cortex; BA35/36 = Brodmann areas 35/36. We hypothesize that the degree of overestimation may be linked to disease severity. It is possible that as the cortex atrophy due to Alzheimer's disease, it moves further away from the dura, resulting the cerebrospinal fluid between them can be better resolved in the T1-weighted MRI (left column). This may cause differential segmentation accuracy in controls (middle column in A, including dura in gray matter segmentation) and patients (middle column in B, excluding dura in gray matter segmentation) generated by conventional methods. ASHS-T1 (right column) is able to reliably segment the dura in both cases. Abbreviations: ERC = entorhinal cortex; BA35/36 = Brodmann areas 35/36. We developed a multi-atlas segmentation pipeline (ASHS-T1) for MTL substructures that explicitly labels dura and a thin layer of CSF separating dura from the cortex. It was trained using datasets that have both T1 and T2-weighted MRI scans. We applied ASHS-T1 and FreeSurfer 6.0 to a dataset of 626 subjects from ADNI (Table 2); amyloid negative (A-) controls, A+ controls, A+ early MCI (EMCI), A+ late MCI (LMCI) and A+ AD. In addition to extracting volume, we computed the proportion of dura that are labeled as GM by FreeSurfer. Bilateral measurements were averaged and compared between A- controls and all other groups. ASHS-T1 is able to reliably segment MTL substructures (Table 1). Table 3 shows that FreeSurfer mislabels 70-80% of the dura as GM and significant lower proportions of mislabeling in A+ EMCI, LMCI and AD, introducing measurement error and potentially a bias of overestimation of GM volume in controls but less so in patients. ASHS-T1, but not FreeSurfer, generates MTL cortex measurements that are sensitive to changes in A+ EMCI stage (Table 4), which could be due to accounting for the confound of dura. We showed that failure to explicitly correct for dura in FreeSurfer results in most of the dura labeled as GM, with the degree of GM overestimation decreasing with disease severity. In contrast, ASHS-T1 trained with an explicit dura label is able separate GM from dura more accurately. Our findings suggest that analyses on MTL atrophy should take into account the confound of dura.