Subcortical vascular cognitive impairment (SVCI) is a heterogeneous cognitive impairment caused by small vessel disease. Diagnosis of SVCI remains challenging when neuropsychological assessment is impractical. This study proposes a diffusion tensor imaging (DTI)-based DenseNet to identify SVCI from subcortical ischemic vascular disease (SIVD) and to profile multidomain cognitive risks. We collected neuropsychological scales and DTI from 134 SVCI and 171 SIVD patients in our internal dataset for model development. An external target-domain dataset of 90 SVCI and 103 SIVD patients was used for unsupervised domain adaptation (UDA). Within this dataset, 45 SVCI and 53 SIVD patients were used for unlabeled UDA fitting; the remaining 45 SVCI and 50 SIVD patients were held out as a target-domain test set. Model-generated salient maps identified white matter (WM) regions associated with SVCI. Mutual information (MI) maps between DTI and 6 neuropsychological scales were computed to identify structural correlates of cognitive domains for cognitive profiling. We computed structural similarity index measure (SSIM) between individual-level salient maps derived from DenseNet and the MI maps for unsupervised clustering to stratify domain-specific cognitive impairment risk in SVCI. The DenseNet achieves high accuracy (0.902 internal, 0.926 target-domain) with AUCs of 0.951 and 0.942, respectively. SVCI probabilities reflect cognitive severity, and salient maps are associated with neuropsychological performance. Regarding cognitive profiling, each cognitive domain is divided into low, moderate, and high subgroups, with significantly different SSIM. Our DTI-based study demonstrates accurate SVCI identification and individualized multi-domain cognitive profiling. This offers a complementary framework to support diagnosis and personalized intervention.

As a pathological hallmark of type 2 diabetes mellitus (T2DM), islet amyloid is formed by the aggregation of islet amyloid polypeptide (IAPP). Endoplasmic reticulum (ER) stress interacts with IAPP aggregates and has been implicated in the pathogenesis of T2DM. To examine the role of ER stress in T2DM, we cloned the hIAPP promoter and analyzed its promoter activity in human β-cells. We found that ER stress significantly enhanced hIAPP promoter activity and expression in human β-cells via triggering X-box binding protein 1 (XBP1) splicing. We identified a binding site of XBP1 in the hIAPP promoter. Disruption of this binding site by substitution or deletion mutagenesis significantly diminished the effects of ER stress on hIAPP promoter activity. Blockade of XBP splicing by MKC3946 treatment inhibited ER stress-induced hIAPP up-regulation and improved human β-cell survival and function. Our study uncovers a link between ER stress and IAPP at the transcriptional level and may provide novel insights into the role of ER stress in IAPP cytotoxicity and the pathogenesis of T2DM.