2.3. Data analysis

Based on a previous study, axial sections from FLAIR images were used to rate the WMH lesion load in the cholinergic pathways using the CHIPS method [7]. To measure the CHIPS ratings, major anatomical landmarks on four index slices in the axial plane were selected (Fig. 1 and Table 1). The first slice (low external capsule level) had four regions: the bilateral anterior and posterior regions of the external capsule. The second slice (high external capsule level) had six regions: the bilateral anterior and posterior regions of the external capsule, and the bilateral cingulate. The third slice (corona radiate level) had six regions: the bilateral cingulate, and the bilateral anterior and posterior regions of the corona radiata. The fourth slice (centrum semiovale level) had four regions: the bilateral anterior and posterior regions of the centrum semiovale. The severity of WMH was visually rated on a three-point scale for each region: 0 = normal; 1 = mild [< 50% of region involved]; and 2 = moderate to severe [≥ 50% of region involved]. Each region was weighted to account for the concentration of cholinergic fibers. The further they spread out from the nucleus basalis to the neocortical regions, the closer they came to the basalis, the more concentrated the cholinergic fibers were. Therefore, as proposed by Bocti et al. [7], we weighted the data four times for each of the four regions of cholinergic fibers within the lateral pathway at the first basal slice and the cingulate region within the medial pathway at the second slice, three times for the two regions of cholinergic fibers within the lateral pathway at the second slice, and two times for the two regions of cholinergic fibers within the lateral pathway at the third slice. The CHIPS scoring system is summarized in Fig. 1 and Table 1. A high interrater reliability (intraclass correlation = 0.96 for the total CHIPS score, 95%CI: 0.91, 0.98) was obtained by two of the authors (YK and TM). Their average ratings were used in this analysis.

CHIPS scoring illustrated on a schema and FLAIR sequence MR images. To measure the CHIPS ratings, major anatomical landmarks on four index slices in the axial plane were selected: low external capsule (A, E), high external capsule (B, F), corona radiate (C, G), and centrum semiovale (D, H). The colored lines indicate the medial (blue) and lateral (red) cholinergic pathways. Each region was weighted to account for the decreasing concentration of cholinergic fibers as they spread out from the nucleus basalis to neocortical regions (maximum weight of 4 for the first slice; minimal weight of 1 for the fourth slice) (see Table 1). Examples of CHIPS scores are shown in E–H. (E) Low external capsule: anterior (right = 0, left = 0, factor = × 4, total = 0); posterior (right = 1, left = 1, factor = × 4, total = 8). (F) High external capsule: anterior (right = 1, left = 1, factor = × 3, total = 6); posterior (right = 0, left = 1, factor = × 3, total = 3); cingulate (right = 0, left = 0, factor = × 4, total = 0). (G) Corona radiata: anterior (right = 2, left = 2, factor = × 2, total = 8); posterior (right = 2, left = 2, factor = × 2, total = 8); cingulate (right = 0, left = 0, factor = × 1, total = 0). (H) Centrum semiovale: anterior (right = 1, left = 2, factor = × 1, total = 3); posterior (right = 1, left = 2, factor = × 1, total = 3). The total CHIPS score is 39. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

The Cholinergic Pathways Hyperintensities Scale.

LP = lateral pathway; MP = medial pathway.

Brain volumes were analyzed using FreeSurfer 5.1 automated software. Image processing included the removal of nonbrain tissue with a hybrid watershed/surface deformation procedure, automated Talairach transformation, and segmentation of cortical and subcortical WM and GM. In the present study, we used cortical volumes (e.g., middle temporal, inferior parietal, inferior temporal, rostral anterior cingulate, etc.) and subcortical volumes (e.g., hippocampus, amygdala, putamen, thalamus, corpus callosum (CC), etc.). To adjust for differences in head size, the volumes for each region were divided by the intracranial volume.

The total volume of the WMH lesion was calculated using the Lesion Segmentation Toolbox (LST version 1.2.3) [23] add-on in the Statistical Parametric Mapping (SPM8) imaging software; the total lesion volume of the WMH [mL], here named the “WMH volume,” was measured in each individual. The Lesion Segmentation Toolbox used T1-weighted and FLAIR images for lesion segmentation. GM, WM, and cerebrospinal fluid tissue classes were determined using the information from the T1-weighted scan.