👤 Nirupama Yechoor

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

This study was aimed at the elucidation of the pathogenesis of glucotoxicity, i.e. the mechanism whereby hyperglycaemia damages pancreatic beta cells. The identification of pathways in the process may help identify targets for beta cell-protective therapy. Carbohydrate response element-binding protein (ChREBP), a transcription factor that regulates the expression of multiple hyperglycaemia-induced genes, is produced in abundance in pancreatic beta cells. We hypothesise that ChREBP plays a pivotal role in mediating beta cell glucotoxicity. We assessed the role of ChREBP in glucotoxicity in 832/13 beta cells, isolated mouse islets and human pancreas tissue sections using multiple complementary approaches under control and high-glucose-challenge conditions as well as in adeno-associated virus-induced beta cell-specific overexpression of Chrebp (also known as Mlxipl) in mice. Under both in vitro and in vivo conditions, ChREBP activates downstream target genes, including fatty acid synthase and thioredoxin-interacting protein, leading to lipid accumulation, increased oxidative stress, reduced insulin gene transcription/secretion and enhanced caspase activity and apoptosis, processes that collectively define glucotoxicity. Immunoreactive ChREBP is enriched in the nucleuses of beta cells in pancreatic tissue sections from diabetic individuals compared with non-diabetic individuals. Finally, we demonstrate that induced beta cell-specific Chrebp overexpression is sufficient to phenocopy the glucotoxicity manifestations of hyperglycaemia in mice in vivo. These data indicate that ChREBP is a key transcription factor that mediates many of the hyperglycaemia-induced activations in a gene expression programme that underlies beta cell glucotoxicity at the molecular, cellular and whole animal levels. Show less