Adults with type 2 diabetes are at an increased risk of developing certain brain or mental disorders, including stroke, dementia, and depression. Although these disorders are not usually considered ...classic microvascular complications of diabetes, evidence is growing that microvascular dysfunction is one of the key underlying mechanisms. Microvascular dysfunction is a widespread phenomenon in people with diabetes, including effects on the brain. Cerebral microvascular dysfunction is also apparent in adults with prediabetes, suggesting that cerebral microvascular disease processes start before the onset of diabetes. The microvasculature is involved in the regulation of many cerebral processes that when impaired predispose to lacunar and haemorrhagic stroke, cognitive dysfunction, and depression. Main drivers of diabetes-related cerebral microvascular dysfunction are hyperglycaemia, obesity and insulin resistance, and hypertension. Increasing amounts of data from observational studies suggest that diabetes-related microvascular dysfunction is associated with a higher risk of stroke, cognitive dysfunction, and depression. Cerebral outcomes in diabetes might be improved following treatments targeting the pathways through which diabetes damages the microcirculation. These treatments might include drugs that reduce dicarbonyl compounds, augment cerebral insulin signalling, or improve blood-brain barrier permeability and cerebral vasoreactivity.
Cardiovascular risk factors are closely linked with dementia risk, but whether heart disease predisposes to dementia is uncertain.
We systematically reviewed the literature and meta-analyzed risk ...estimates from longitudinal studies reporting the association of coronary heart disease (CHD) or heart failure (HF) with risk of dementia.
We identified 16 studies (1,309,483 individuals) regarding CHD, and seven studies (1,958,702 individuals) about HF. A history of CHD was associated with a 27% increased risk of dementia (pooled relative risk RR 95% confidence interval, CI: 1.27 1.07–1.50), albeit with considerable heterogeneity across studies (I2 = 80%). HF was associated with 60% increased dementia risk (pooled RR 1.60 1.19–2.13) with moderate heterogeneity (I2 = 59%). Among prospective population-based cohorts, pooled estimates were similar (for CHD, RR 1.26 1.06–1.49, nine studies; and HF, RR 1.80 1.41–2.31, four studies) and highly consistent (I2 = 0%).
CHD and HF are associated with an increased risk of dementia.
To determine whether classes of diabetes medications are associated with cognitive health and dementia risk, above and beyond their glycemic control properties.
Findings were pooled from 5 ...population-based cohorts: the Framingham Heart Study, the Rotterdam Study, the Atherosclerosis Risk in Communities (ARIC) Study, the Aging Gene-Environment Susceptibility-Reykjavik Study (AGES) and the Sacramento Area Latino Study on Aging (SALSA). Differences between users and non-users of insulin, metformin and sulfonylurea were assessed in each cohort for cognitive and brain MRI measures using linear regression models, and cognitive decline and dementia/AD risk using mixed effect models and Cox regression analyses, respectively. Findings were then pooled using meta-analytic techniques, including 3,590 individuals with diabetes for the prospective analysis.
After adjusting for potential confounders including indices of glycemic control, insulin use was associated with increased risk of new-onset dementia (pooled HR (95% CI) = 1.58 (1.18, 2.12);p = 0.002) and with a greater decline in global cognitive function (β = -0.014±0.007;p = 0.045). The associations with incident dementia remained similar after further adjustment for renal function and excluding persons with diabetes whose treatment was life-style change only. Insulin use was not related to cognitive function nor to brain MRI measures. No significant associations were found between metformin or sulfonylurea use and outcomes of brain function and structure. There was no evidence of significant between-study heterogeneity.
Despite its advantages in controlling glycemic dysregulation and preventing complications, insulin treatment may be associated with increased adverse cognitive outcomes possibly due to a greater risk of hypoglycemia.
To test the hypothesis that end-stage renal disease (ESRD) risk exposure during young adulthood is related to worse cognitive performance in midlife.
We included 2,604 participants from the ...population-based Coronary Artery Risk Development in Young Adults (CARDIA) Study (mean age 35 years, 54% women, 45% Black). Estimated glomerular filtration rate and albumin-to-creatinine ratio were measured every 5 years at year (Y) 10 through Y30. At each visit, moderate/high risk of ESRD according to the Kidney Disease: Improving Global Outcomes guidelines (estimated glomerular filtration rate <60 mL/min/1.73 m
or albumin-to-creatinine ratio >30 mg/g) was defined, totaled over examinations, and categorized into 0 episodes, 1 episode, and >1 episodes of ESRD risk. At Y30, participants underwent global and multidomain cognitive assessment. We used analysis of covariance to assess the association of ESRD risk categories with cognitive function, controlling for cardiovascular risk factors.
Over the course of 20 years, 427 participants (16% of the study population) had ≥1 episodes of ESRD risk exposure. Individuals with more risk episodes had lower composite cognitive function (
< 0.001), psychomotor speed (
< 0.001), and executive function (
= 0.007). All these associations were independent of sociodemographic status and cardiovascular risk factors.
In this population-based longitudinal study, we show that episodes of decline in kidney function over the young-adulthood course are associated with worse cognitive performance at midlife. Preserving kidney function in young age needs to be investigated as a potential strategy to preserve cognitive function in midlife.
Underlying genetic determinants contribute to developing type 2 diabetes (T2D) future diseases. The present study aimed to identify which genetic variants are associated with the incident of the ...major T2D co-morbid disease. First, we conducted a discovery study by investigating the genetic associations of comorbid diseases within the framework of the Utrecht Cardiovascular Pharmacogenetic studies by turning information of > 25 years follow-up data of 1237 subjects whom were genotyped and included in the discovery study. We performed Cox proportional-hazards regression to examine associations between genetic variants and comorbid diseases including cardiovascular diseases (CVD), chronic eye disease, cancer, neurologic diseases and chronic kidney disease. Secondly, we replicated our findings in two independent cohorts consisting of 1041 subjects. Finally, we performed a meta-analysis by combining the discovery and two replication cohorts. We ascertained 390 (39.7%) incident cases of CVD, 182 (16.2%) of chronic eye disease, 155 (13.8%) of cancer, 31 (2.7%) of neurologic disease and 13 (1.1%) of chronic kidney disease during a median follow-up of 10.2 years. In the discovery study, we identified a total of 39 Single Nucleotide Polymorphisms (SNPs) associated with comorbid diseases. The replication study, confirmed that rs1870849 and rs8051326 may play a role in the incidence of chronic eye disease in T2D patients. Half of patients developed at least one comorbid disease, with CVD occurring most often and earliest followed by chronic eye disease. Further research is needed to confirm the associations of two associated SNPs with chronic eye disease in T2D.
Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale ...whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10
) and SLC2A9 (p = 4.5 × 10
). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10
). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.
Intracranial atherosclerosis disease (ICAD) alters cerebrovascular hemodynamics and brain structural integrity. Multiple studies have evaluated the link between ICAD and cognitive impairment, with ...mixed results. This study aims to systematically review and summarize the current evidence on this link.
PubMed, EMBASE, PsycInfo, and Web of Science were searched from 2000 to 2023 without language restriction. Cross-sectional and prospective cohort studies as well as postmortem studies were included. Studies containing data on the link between ICAD, defined as at least 50% stenosis in 1 intracranial vessel, and cognitive impairment and dementia were screened by 2 independent reviewers. A total of 22 (17 observational and 5 postmortem) unique studies, comprising 11 184 individuals (average age range, 59.8-87.6 years; 45.7% women; 36.5% Asian race), were included in the systematic review. Seven of 10 cross-sectional studies and 5 of 7 prospective studies showed a significant association between ICAD and cognitive impairment. In the pooled analysis, ICAD was associated with greater cognitive impairment (measure of association, 1.87 95% CI, 1.49-2.35). Meta-regression analyses did not show a significant impact of age, sex, and race. All postmortem studies showed that patients with Alzheimer disease and vascular dementia had a higher burden of ICAD compared with controls.
This study shows that ICAD is associated with cognitive impairment and dementia across age, sex, and race groups. Our findings may underscore the need to develop individualized dementia preventive care plans in patients with ICAD.
There are inconsistent findings on the role of hyperuricemia as an independent risk factor for chronic kidney disease (CKD). Hypertension has been implicated as a factor influencing the association ...between serum uric acid and CKD. In this population-based study we investigated the association between serum uric acid and decline in renal function and tested whether hypertension moderates this association.
We included 2601 subjects aged 55 years and over from the Rotterdam Study. Serum uric acid and estimated glomerular filtration rate (eGFR) were assessed at baseline. After average 6.5 years of follow-up, second eGFR was assessed. CKD was defined as eGFR<60 ml/min/1.73 m(2). All associations were corrected for socio-demographic and cardiovascular factors.
Each unit (mg/dL) increase in serum uric acid was associated with 0.19 ml/min per 1.73 m(2) faster annual decline in eGFR. While the association between serum uric acid and incidence of CKD was not significant in our study population (Hazard Ratio: 1.12, 95% confidence interval CI: 0.98-1.28), incorporating our results in a meta-analysis with eleven published studies revealed a significant association (Relative Risk: 1.18, 95%CI: 1.15-1.22). In the stratified analyses, we observed that the associations of serum uric acid with eGFR decline and incident CKD were stronger in hypertensive subjects (P for interaction = 0.046 and 0.024, respectively).
Our findings suggest that hyperuricemia is independently associated with a decline in renal function. Stronger association in hypertensive individuals may indicate that hypertension mediates the association between serum uric acid and CKD.
Background
Anatomic and hemodynamic similarities between renal and cerebral vessels suggest a tight link between kidney disease and brain disease. Although several distinct markers are used to ...identify subclinical kidney and brain disease, a comprehensive assessment of how these markers link damage at both end organs is lacking.
Aim
To investigate whether measures of kidney function were associated with cerebral small vessel disease on MRI.
Methods
In 2526 participants of the population-based Rotterdam Study, we measured urinary albumin-to-creatinine ratio, and estimated glomerular filtration rate based on serum creatinine and cystatin C. All participants underwent brain magnetic resonance imaging. We assessed presence of cerebral small vessel disease by calculating white matter lesion volumes and rating the presence of lacunes and cerebral microbleeds. We used multivariable linear and logistic regression to investigate the association between kidney function and cerebral small vessel disease.
Results
Worse kidney function was consistently associated with a larger white matter lesion volume (mean difference per standard deviation increase in albumin-to-creatinine ratio: 0·09, 95% confidence interval 0·05; 0·12; per standard deviation decrease in creatinine-based estimated glomerular filtration rate: −0·04, 95% confidence interval −0·08;−0·01, and per standard deviation decrease in cystatin C-based estimated glomerular filtration rate: −0·09, 95% confidence interval −0·13;−0·05). Persons with higher albumin-to-creatinine ratio or lower cystatin C-based estimated glomerular filtration rate levels had a higher prevalence of lacunes (odds ratio per standard deviation increase in albumin-to-creatinine ratio: 1·24, 95% confidence interval 1·07; 1·43). Only participants in the highest quartile of albumin-to-creatinine ratio had a higher frequency of microbleeds compared to the lowest quartile.
Conclusions
Worse kidney function is associated with cerebral small vessel disease. Of all measures of kidney function, in particular albumin-to-creatinine ratio is related to cerebral small vessel disease.
To investigate the association of kidney function with white matter microstructural integrity.
We included 2,726 participants with a mean age of 56.6 years (45% men) from the population-based ...Rotterdam Study. Albumin-to-creatinine ratio, and estimated glomerular filtration rate (eGFR), using serum cystatin C (eGFRcys) and creatinine (eGFRcr), were measured to evaluate kidney function. Diffusion-MRI was used to assess microstructural integrity of the normal-appearing white matter. Multiple linear regression models, adjusted for macrostructural MRI markers and cardiovascular risk factors, were used to model the association of kidney function with white matter microstructure.
Participants had average eGFRcr of 86.1 mL/min/1.73 m(2), average eGFRcys of 86.2 mL/min/1.73 m(2), and median albumin-to-creatinine ratio of 3.4 mg/g. Lower eGFRcys was associated with worse global white matter microstructural integrity, reflected as lower fractional anisotropy (standardized difference per SD: -0.053, 95% confidence interval CI: -0.092, -0.014) and higher mean diffusivity (0.036, 95% CI: 0.001, 0.070). Similarly, higher albumin-to-creatinine ratio was associated with lower fractional anisotropy (-0.044, 95% CI: -0.078, -0.011). There was no linear association between eGFRcr and white matter integrity. Subgroup analyses showed attenuation of the associations after excluding subjects with hypertension. The associations with global diffusion tensor imaging measures did not seem to be driven by particular tracts, but rather spread across multiple tracts in various brain regions.
Reduced kidney function is associated with worse white matter microstructural integrity. Our findings highlight the importance for clinicians to consider concomitant macro- and microstructural changes of the brain in patients with impaired kidney function.
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