👤 Karishma Choksi

Evidence linking modifiable risk factors to age-related brain diseases, such as dementia, stroke, and depression (DSD), is robust, yet limited regarding long-term change in modifiable risk factors in association with these conditions, particularly in real-world settings. This study aimed to assess whether longitudinal changes in modifiable brain health risk factors were associated with reduced risk of DSD. We analyzed UK Biobank data (2006-2019) from 155,469 participants with general practitioner-linked data. The Brain Care Score (BCS) assesses 12 modifiable risk factors across lifestyle, physical, and social-emotional domains. Longitudinal BCS measurements were derived from repeated general practitioner (GP)-recorded measurements. Changes in the BCS were modeled using linear mixed-effects models, and associations with DSD were evaluated using multivariable Cox models, adjusting for baseline BCS and genetic risk (polygenic risk scores for stroke and depression, and APOE genotype for dementia). Among 155,469 participants (median age = 51 years, 54.3% women), the median annual BCS change was 0.14 (Q1-Q3 = 0.008-0.30) points over a median follow-up of 12.3 years (Q1-Q3 = 11.5-13.1 years). Over time, 82.1% improved their BCS, 12.9% remained stable, and 5.0% worsened over time. Each 1-point annual increase in the BCS was associated with 4% lower risk of incident age-related brain diseases (hazard ratio [HR] = 0.96, 95% confidence interval [CI] = 0.95-0.97). In this large real-world cohort, improvements in modifiable risk factor profiles were associated with lower incidence of DSD, regardless of genetic risk or baseline BCS. Our results provide important information for communicating with patients about the brain health benefits of improving risk factor profiles. ANN NEUROL 2026;99:1113-1123. Show less

Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus. Vision loss in DR principally occurs due to breakdown of the blood-retinal barrier (BRB), leading to macular edema, retinal detachment and inner retinal and vitreous hemorrhage. Several growth factors have been shown to play crucial role in the development of these vascular changes; however, the cellular and molecular mechanisms of DR are not yet fully revealed. In the current study we investigated the role of bone morphogenetic protein-2 (BMP2) in DR. We examined the changes in the protein levels of BMP2 in human vitreous and retina in addition to the mouse retina of streptozotocin-induced diabetes. To detect the source of BMP2 during diabetes, human retinal endothelial cells (hRECs) were subjected to high glucose (HG) for 5 days and levels of BMP2 protein were analyzed in conditioned media of these cells relative to control. We also evaluated the effect of BMP2 on the levels of VEGF in cultured rat Müller cells (rMC1). In addition, we tested the pro-inflammatory effects of BMP2 by examining its effect on leukocyte adhesion to cultured hRECs, and levels of adhesion molecules and cytokines production. Finally, the effect of different concentrations of BMP2 on permeability of confluent monolayer of hRECs was evaluated using FITC-Dextran flux permeability assay and by measuring Transcellular Electrical Resistance (TER) using Electric Cell-substrate Impedance Sensing (ECIS). Our results show, for the first time, the up-regulation of BMP2 in diabetic human and mouse retinas in addition to its detection in vitreous of patients with proliferative DR (72 ± 7 pg/ml). In vitro, hRECs showed upregulation of BMP2 in HG conditions suggesting that these cells are a potential source of BMP2 in diabetic conditions. Furthermore, BMP2 induced VEGF secretion by Müller cells in-vitro; and showed a dose response in increasing permeability of cultured hRECs. Meanwhile, BMP2 pro-inflammatory effects were recognized by its ability to induce leukocyte adhesion to the hRECs, intercellular adhesion molecule-1 (ICAM-1) and upregulation of interleukin-6 and 8 (IL-6 and IL-8). These results show that BMP2 could be a contributing growth factor to the development of microvascular dysfunction during DR via enhancing both pro-angiogenic and inflammatory pathways. Our findings suggest BMP2 as a potential therapeutic target to prevent/treat DR. Show less