Small vessel strokes (SVS) and intracerebral haemorrhages (ICH) are acute outcomes of cerebral small vessel disease (SVD). Genetic studies combining both phenotypes have identified three loci associated with both traits. However, the genetic cis-regulation at the protein level associated with SVD has not been studied before. We performed a proteome-wide association study (PWAS) using FUSION to integrate a genome-wide association study (GWAS) and brain proteomic data to discover the common mechanisms regulating both SVS and ICH. Dorsolateral prefrontal cortex (dPFC) brain proteomes from the ROS/MAP study (N = 376 subjects and 1443 proteins) and the summary statistics for the SVS GWAS from the MEGASTROKE study (N = 237,511) and multi-trait analysis of GWAS (MTAG)-ICH–SVS from Chung et al. (N = 240,269) were selected. We performed PWAS and then a co-localization analysis with COLOC. The significant and nominal results were validated using a replication dPFC proteome (N = 152). The replicated results (q-value < 0.05) were further investigated for the causality relationship using summary data-based Mendelian randomization (SMR). One protein (ICA1L) was significantly associated with SVS (z-score = −4.42 and p-value = 9.6 × 10⁻⁶) and non-lobar ICH (z-score = −4.8 and p-value = 1.58 × 10⁻⁶) in the discovery PWAS, with a high co-localization posterior probability of 4. In the validation PWAS, ICA1L remained significantly associated with both traits. The SMR results for ICA1L indicated a causal association of protein expression levels in the brain with SVS (p-value = 3.66 × 10⁻⁵) and non-lobar ICH (p-value = 1.81 × 10⁻⁵). Our results show that the association of ICA1L with SVS and non-lobar ICH is conditioned by the cis-regulation of its protein levels in the brain.

Background/Objectives: Obesity is associated with cognitive decline, and metabolic bariatric surgery (MBS) can improve both physical and cognitive outcomes. However, cognitive improvements post-surgery are variable. This study explores the role of skeletal muscle health, specifically muscle strength and mass, in cognitive performance after MBS, aiming to identify factors that influence cognitive recovery. Methods: In this prospective study, 55 patients scheduled for MBS were assessed 1 month before and 12 months after surgery. Body composition, including appendicular lean mass (ALM) and fat mass, was measured using dual-energy X-ray absorptiometry (DXA). Handgrip strength (HGS) was assessed via dynamometry, and neurocognitive performance was evaluated using a standardized test battery. Results: Significant improvements in cognitive performance were observed at 12 months post-surgery in attention, memory, language, executive functions and overall cognitive performance. Regarding body composition, significant reductions were observed in fat mass and body mass index (BMI). A decrease in ALM and no changes in HGS were observed; however, when adjusted for body size, both showed an increase. Regression analysis identified baseline HGS, but not muscle mass, as a significant predictor of cognitive performance at 12 months post-surgery. Conclusions: MBS leads to significant improvements in cognitive function. Our results suggest that baseline HGS may play a role in predicting cognitive outcomes post-surgery, highlighting the need for comprehensive assessments of both physical and cognitive health in patients undergoing MBS. Further longitudinal studies are needed to explore causal relationships and the potential reversibility of cognitive deficits post-surgery.