Cholinergic Pathways Hyperintensity Scale

White matter hyperintensities in cholinergic pathways were graded visually using the Cholinergic Pathways HyperIntensity Scale (CHIPS) by the first author on a single-rater basis. First reported by Bocti et al. (24 (link)), CHIPS is a visual rating scale developed based on published immunohistochemical tracings of the cholinergic pathways in humans (24 (link), 31 (link)), and was previously used by some studies for the relationship between WMH and cognition (12 (link), 13 (link)). According to Selden (31 (link)), the cholinergic pathways include the medial pathway and lateral pathway. The medial pathway is closely associated with the adjacent cingulate gyrus and rostrum of the corpus callosum; the lateral pathway courses through the external capsule and claustrum within the white matter (31 (link)). Accordingly, four axial planes of T2-FLAIR images were identified by major anatomical landmarks—low external capsule, high external capsule, corona radiata, and centrum semiovale (Figure 1). Medial pathway is included in two of the axial planes as anterior cingulate gyrus and posterior cingulate gyrus. A total of 10 regions are illustrated in Figures 1A–D. White matter hyperintensity of each region was determined visually on a 3-point scale for each region (0 = normal; 1 = minimal; 2 = confluent or moderate to severe). To account for the decreasing concentration of cholinergic fibers, each slice was weighted sequentially from 1 to 4 with one being the centrum semiovale and four being the lower external capsules (Table 1). The total CHIPS score (both hemispheres) ranged from 1 to 100. The lowest CHIPS score is 0, indicating no burden of WMH in cholinergic pathways, and the highest CHIPS score is 100 (24 (link)). The corresponding author independently rated CHIPS scores of random 65 participants to ascertain the inter-rater reliability of CHIPS. Controversial images were rated based on the consensus of the first author, the corresponding author, and a radiologist (Cheng-Feng Ho). The consensus CHIPS scores were used in our regression analyses. Intra-rater reliability was calculated by two independent ratings of the first author. The inter-rater reliability and intra-rater reliability were analyzed by inter-class correlation coefficient (ICC).