Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes.

BACKGROUND: Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease. METHODS: In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m2 of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed. RESULTS: A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m2 in the allopurinol group and 67.3 ml per minute per 1.73 m2 in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m2 (95% confidence interval [CI], -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m2 per year with allopurinol and -2.5 ml per minute per 1.73 m2 per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m2 per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups. CONCLUSIONS: We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).

Patient Cognitive Status and Physician Recommendations for Cardiovascular Disease Treatment: Results of Two Nationwide, Randomized Survey Studies.

BACKGROUND: Clinical guidelines recommend that older patients (65+) with mild cognitive impairment (MCI) and early-stage dementia receive similar guideline-concordant care after cardiovascular disease (CVD) events as those with normal cognition (NC). However, older patients with MCI and dementia receive less care for CVD and other conditions than those with NC. Whether physician recommendations for guideline-concordant treatments after two common CVD events, acute myocardial infarction (AMI) and acute ischemic stroke (stroke), differ between older patients with NC, MCI, and early-stage dementia is unknown. OBJECTIVE: To test the influence of patient cognitive status (NC, MCI, early-stage dementia) on physicians' recommendations for guideline-concordant treatments for AMI and stroke. DESIGN: We conducted two parallel, randomized survey studies for AMI and stroke in the US using clinical vignettes where the hypothetical patient's cognitive status was randomized between physicians. PARTICIPANTS: The study included cardiologists, neurologists, and generalists who care for most patients hospitalized for AMI and stroke. MAIN MEASURES: The primary outcome was a composite quality score representing the number of five guideline-concordant treatments physicians recommended for a hypothetical patient after AMI or stroke. KEY RESULTS: 1,031 physicians completed the study (58.5% response rate). Of 1,031 respondents, 980 physicians had complete information. After adjusting for physician factors, physicians recommended similar treatments after AMI and stroke in hypothetical patients with pre-existing MCI (adjusted ratio of expected composite quality score, 0.98 [95% CI, 0.94, 1.02]; P = 0.36) as hypothetical patients with NC. Physicians recommended fewer treatments to hypothetical patients with pre-existing early-stage dementia than to hypothetical patients with NC (adjusted ratio of expected composite quality score, 0.90 [0.86, 0.94]; P < 0.001). CONCLUSION: In these randomized survey studies, physicians recommended fewer guideline-concordant AMI and stroke treatments to hypothetical patients with early-stage dementia than those with NC. We did not find evidence that physicians recommend fewer treatments to hypothetical patients with MCI than those with NC.

Results of untargeted analysis using the SOMAscan proteomics platform indicates novel associations of circulating proteins with risk of progression to kidney failure in diabetes.

This study applies a large proteomics panel to search for new circulating biomarkers associated with progression to kidney failure in individuals with diabetic kidney disease. Four independent cohorts encompassing 754 individuals with type 1 and type 2 diabetes and early and late diabetic kidney disease were followed to ascertain progression to kidney failure. During ten years of follow-up, 227 of 754 individuals progressed to kidney failure. Using the SOMAscan proteomics platform, we measured baseline concentration of 1129 circulating proteins. In our previous publications, we analyzed 334 of these proteins that were members of specific candidate pathways involved in diabetic kidney disease and found 35 proteins strongly associated with risk of progression to kidney failure. Here, we examined the remaining 795 proteins using an untargeted approach. Of these remaining proteins, 11 were significantly associated with progression to kidney failure. Biological processes previously reported for these proteins were related to neuron development (DLL1, MATN2, NRX1B, KLK8, RTN4R and ROR1) and were implicated in the development of kidney fibrosis (LAYN, DLL1, MAPK11, MATN2, endostatin, and ROR1) in cellular and animal studies. Specific mechanisms that underlie involvement of these proteins in progression of diabetic kidney disease must be further investigated to assess their value as targets for kidney-protective therapies. Using multivariable LASSO regression analysis, five proteins (LAYN, ESAM, DLL1, MAPK11 and endostatin) were found independently associated with risk of progression to kidney failure. Thus, our study identified proteins that may be considered as new candidate prognostic biomarkers to predict risk of progression to kidney failure in diabetic kidney disease. Furthermore, three of these proteins (DLL1, ESAM, and MAPK11) were selected as candidate biomarkers when all SOMAscan results were evaluated.

The Association Between Mild Cognitive Impairment Diagnosis and Patient Treatment Preferences: a Survey of Older Adults.

BACKGROUND: Older patients (65+) with mild cognitive impairment (MCI) receive less guideline-concordant care for cardiovascular disease (CVD) and other conditions than patients with normal cognition (NC). One potential explanation is that patients with MCI want less treatment than patients with NC; however, the treatment preferences of patients with MCI have not been studied. OBJECTIVE: To determine whether patients with MCI have different treatment preferences than patients with NC. DESIGN: Cross-sectional survey conducted at two academic medical centers from February to December 2019 PARTICIPANTS: Dyads of older outpatients with MCI and NC and patient-designated surrogates. MAIN MEASURES: The modified Life-Support Preferences-Predictions Questionnaire score measured patients' preferences for life-sustaining treatment decisions in six health scenarios including stroke and acute myocardial infarction (range, 0-24 treatments rejected with greater scores indicating lower desire for treatment). KEY RESULTS: The survey response rate was 73.4%. Of 136 recruited dyads, 127 (93.4%) completed the survey (66 MCI and 61 NC). The median number of life-sustaining treatments rejected across health scenarios did not differ significantly between patients with MCI and patients with NC (4.5 vs 6.0; P=0.55). Most patients with MCI (80%) and NC (80%) desired life-sustaining treatments in their current health (P=0.99). After adjusting for patient and surrogate factors, the difference in mean counts of rejected treatments between patients with MCI and patients with NC was not statistically significant (adjusted ratio, 1.08, 95% CI, 0.80-1.44; P=0.63). CONCLUSION: We did not find evidence that patients with MCI want less treatment than patients with NC. These findings suggest that other provider and system factors might contribute to patients with MCI getting less guideline-concordant care.

Preexisting Mild Cognitive Impairment, Dementia, and Receipt of Treatments for Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Differences in acute ischemic stroke (AIS) treatment by cognitive status are unclear, but some studies have found patients with preexisting dementia get less treatment. We compared AIS care by preexisting cognitive status. METHODS: Cross-sectional analysis of prospectively obtained data on 836 adults ≥45 with AIS from the population-based Brain Attack Surveillance in Corpus Christi project from 2008 to 2013. We compared receipt of a composite quality measure representing the percentage of 7 treatments/procedures received (ordinal scale; values, <0.75, 0.75-0.99, and 1.0), a binary defect-free quality score, and individual treatments after AIS between patients with preexisting dementia (Informant Questionnaire on Cognitive Decline in the Elderly score ≥3.44), mild cognitive impairment (MCI, score 3.1-3.43), and normal cognition (score ≤3). RESULTS: Among patients with AIS, 42% had normal cognition (47% women; median age [interquartile range], 65 [56-76]), 32% had MCI (54% women; median age, 70 [60-78]), 26% had dementia (56% women; median age, 78 [64-85]). After AIS, 44% of patients with preexisting dementia and 55% of patients with preexisting MCI or normal cognition received defect-free care. Compared with cognitively normal patients, patients with preexisting MCI had similar cumulative odds (unadjusted cumulative odds ratio =0.99, P=0.92), and patients with preexisting dementia had 36% lower cumulative odds of receiving the composite quality measure (unadjusted cumulative odds ratio [OR]=0.64, P=0.005). However, the dementia-quality association became nonsignificant after adjusting for patient factors, namely sex, comorbidity, and body mass index (adjusted cumulative OR [acOR]=0.79, P=0.19). Independent of patient factors, preexisting MCI was negatively associated with receipt of IV tPA (intravenous tissue-type plasminogen activator; acOR=0.36, P=0.04), rehabilitation assessment (acOR=0.28, P=0.016), and echocardiogram (acOR=0.48, P<0.001). Preexisting dementia was negatively associated with receipt of antithrombotic by day 2 (acOR=0.39, P=0.04) and echocardiogram (acOR=0.42, P<0.001). CONCLUSIONS: Patients with preexisting MCI and dementia, compared with cognitively normal patients, may receive less frequently some treatments and procedures, but not the composite quality measure, after AIS.

Association of Blood Pressure and Cognition after Stroke.

BACKGROUND AND AIM: It is unclear whether blood pressure (BP) is associated with cognition after stroke. We examined associations between systolic and diastolic BP (SBP, DBP), pulse pressure (PP), mean arterial pressure (MAP), and cognition, each measured 90 days after stroke. METHODS: Cross-sectional analysis of prospectively obtained data of 432 dementia-free subjects greater than or equal to 45 (median age, 66; 45% female) with stroke (92% ischemic; median NIH stroke score, 3 [IQR, 2-6]) from the population-based Brain Attack Surveillance in Corpus Christi (BASIC) project in 2011-2013. PRIMARY OUTCOME: Modified Mini-Mental Status Examination (3MSE; range, 0-100). SECONDARY OUTCOMES: Animal Fluency Test (AFT; range, 0-10) and Trail Making Tests A and B (number of correct items [range, 0-25]/completion time [Trails A: 0-180 seconds; Trails B: 0-300 second]). Linear or tobit regression adjusted associations for age, education, and race/ethnicity as well as variables significantly associated with BP and cognition. RESULTS: Higher SBP, lower DBP, higher PP, and lower MAP each were associated with worse cognitive performance for all 4 tests (all P < .001). After adjusting for patient factors, no BP measures were associated with any of the 4 tests (all P > .05). Lower cognitive performance was associated with older age, less education, Mexican American ethnicity, diabetes, higher stroke severity, more depressive symptoms, and lower BMI. Among survivors with hypertension, anti-hypertensive medication use 90 days after stroke was significantly associated with higher AFT scores (P = .02) but not other tests (P > .15). CONCLUSIONS: Stroke survivors' BP levels were not associated with cognitive performance at 90 days independent of sociodemographic and clinical factors.

Risk Factors for Poststroke Cognitive Decline: The REGARDS Study (Reasons for Geographic and Racial Differences in Stroke).

BACKGROUND AND PURPOSE: Poststroke cognitive decline causes disability. Risk factors for poststroke cognitive decline independent of survivors' prestroke cognitive trajectories are uncertain. METHODS: Among 22 875 participants aged ≥45 years without baseline cognitive impairment from the REGARDS cohort (Reasons for Geographic and Racial Differences in Stroke), enrolled from 2003 to 2007 and followed through September 2015, we measured the effect of incident stroke (n=694) on changes in cognitive functions and cognitive impairment (Six-Item Screener score <5) and tested whether patient factors modified the effect. Median follow-up was 8.2 years. RESULTS: Incident stroke was associated with acute declines in global cognition, new learning, verbal memory, and executive function. Acute declines in global cognition after stroke were greater in survivors who were black (P=0.04), men (P=0.04), and had cardioembolic (P=0.001) or large artery stroke (P=0.001). Acute declines in executive function after stroke were greater in survivors who had

Markers of early progressive renal decline in type 2 diabetes suggest different implications for etiological studies and prognostic tests development.

To identify determinants of early progressive renal decline in type 2 diabetes a range of markers was studied in 1032 patients enrolled into the 2nd Joslin Kidney Study. eGFR slopes estimated from serial measurements of serum creatinine during 5-12 years of follow-up were used to define early renal decline. At enrollment, all patients had normal eGFR, 58% had normoalbuminuria and 42% had albuminuria. Early renal decline developed in 6% and in 18% patients, respectively. As determinants, we examined baseline values of clinical characteristics, circulating markers: TNFR1, KIM-1, and FGF23, and urinary markers: albumin, KIM-1, NGAL, MCP-1, EGF (all normalized to urinary creatinine) and the ratio of EGF to MCP-1. In univariate analysis, all plasma and urinary markers were significantly associated with risk of early renal decline. When analyzed together, systolic blood pressure, TNFR1, KIM-1, the albumin to creatinine ratio, and the EGF/MCP-1 ratio remained significant with the latter having the strongest effect. Integration of these markers into a multi-marker prognostic test resulted in a significant improvement of discriminatory performance of risk prediction of early renal decline, compared with the albumin to creatinine ratio and systolic blood pressure alone. However, the positive predictive value was only 50% in albuminuric patients. Thus, markers in plasma and urine indicate that the early progressive renal decline in Type 2 diabetes has multiple determinants with strong evidence for involvement of tubular damage. However, new, more informative markers are needed to develop a better prognostic test for such decline that can be used in a clinical setting.

Improved clinical trial enrollment criterion to identify patients with diabetes at risk of end-stage renal disease.

Design of Phase III trials for diabetic nephropathy currently requires patients at a high risk of progression defined as within three years of a hard end point (end-stage renal disease, 40% loss of estimated glomerular filtration rate, or death). To improve the design of these trials, we used natural history data from the Joslin Kidney Studies of chronic kidney disease in patients with diabetes to develop an improved criterion to identify such patients. This included a training cohort of 279 patients with type 1 diabetes and 134 end points within three years, and a validation cohort of 221 patients with type 2 diabetes and 88 end points. Previous trials selected patients using clinical criteria for baseline urinary albumin-to-creatinine ratio and estimated glomerular filtration rate. Application of these criteria to our cohort data yielded sensitivities (detection of patients at risk) of 70-80% and prognostic values of only 52-63%. We applied classification and regression trees analysis to select from among all clinical characteristics and markers the optimal prognostic criterion that divided patients with type 1 diabetes according to risk. The optimal criterion was a serum tumor necrosis factor receptor 1 level over 4.3 ng/ml alone or 2.9-4.3 ng/ml with an albumin-to-creatinine ratio over 1900 mg/g. Remarkably, this criterion produced similar results in both type 1 and type 2 diabetic patients. Overall, sensitivity and prognostic value were high (72% and 81%, respectively). Thus, application of this criterion to enrollment in future clinical trials could reduce the sample size required to achieve adequate statistical power for detection of treatment benefits.

Does Stroke Contribute to Racial Differences in Cognitive Decline?

BACKGROUND AND PURPOSE: It is unknown whether blacks' elevated risk of dementia is because of racial differences in acute stroke, the impact of stroke on cognitive health, or other factors. We investigated whether racial differences in cognitive decline are explained by differences in the frequency or impact of incident stroke between blacks and whites, controlling for baseline cognition. METHODS: Among 4908 black and white participants aged ≥65 years free of stroke and cognitive impairment in the nationally representative Health and Retirement Study with linked Medicare data (1998-2010), we examined longitudinal changes in global cognition (modified version of the Telephone Interview for Cognitive Status) by race, before and after adjusting for time-dependent incident stroke followed by a race-by-incident stroke interaction term, using linear mixed-effects models that included fixed effects of participant demographics, clinical factors, and cognition, and random effects for intercept and slope for time. RESULTS: We identified 34 of 453 (7.5%) blacks and 300 of 4455 (6.7%) whites with incident stroke over a mean (SD) of 4.1 (1.9) years of follow-up (P=0.53). Blacks had greater cognitive decline than whites (adjusted difference in modified version of the Telephone Interview for Cognitive Status score, 1.47 points; 95% confidence interval, 1.21 to 1.73 points). With further adjustment for cumulative incidence of stroke, the black-white difference in cognitive decline persisted. Incident stroke was associated with a decrease in global cognition (1.21 points; P<0.001) corresponding to ≈7.9 years of cognitive aging. The effect of incident stroke on cognition did not statistically differ by race (P=0.52). CONCLUSIONS: In this population-based cohort of older adults, incident stroke did not explain black-white differences in cognitive decline or impact cognition differently by race.

Clostridium difficile ribotype 027: relationship to age, detectability of toxins A or B in stool with rapid testing, severe infection, and mortality.

BACKGROUND: Clostridium difficile infection (CDI) can cause severe disease and death, especially in older adults. A better understanding of risk factors for adverse outcomes is needed. This study tests the hypotheses that infection with specific ribotypes and presence of stool toxins independently associate with severity and constructs predictive models of adverse outcomes. METHODS: Cases of non-recurrent CDI were prospectively included after positive stool tests for toxins A and/or B by enzyme immunoassay (EIA) or tcdB by polymerase chain reaction. Outcomes included severe CDI (intensive care unit admission, colectomy, or death attributable to CDI within 30 days of diagnosis) and 30-day all-cause mortality. Adjusted models were developed to test hypotheses and predict outcomes. RESULTS: In total, 1144 cases were included. The toxin EIA was positive in 37.2% and 35.6% of patients were of age >65 years. One of the 137 unique ribotypes was ribotype 027 (16.2%). Detectable stool toxin did not associate with outcomes. Adjusting for covariates, including age, Ribotype 027 was a significant predictor of severe CDI (90 cases; odds ratio [OR], 1.73; 95% confidence interval [CI], 1.03-2.89; P = .037) and mortality (89 cases; OR, 2.02; 95% CI, 1.19-3.43; P = .009). Concurrent antibiotic use associated with both outcomes. Both multivariable predictive models had excellent performance (area under the curve >0.8). CONCLUSIONS: Detection of stool toxin A and/or B by EIA does not predict severe CDI or mortality. Infection with ribotype 027 independently predicts severe CDI and mortality. Use of concurrent antibiotics is a potentially modifiable risk factor for severe CDI.

Dissection of complex adult traits in a mouse synthetic population.

Finding the causative genetic variations that underlie complex adult traits is a significant experimental challenge. The unbiased search strategy of genome-wide association (GWAS) has been used extensively in recent human population studies. These efforts, however, typically find only a minor fraction of the genetic loci that are predicted to affect variation. As an experimental model for the analysis of adult polygenic traits, we measured a mouse population for multiple phenotypes and conducted a genome-wide search for effector loci. Complex adult phenotypes, related to body size and bone structure, were measured as component phenotypes, and each subphenotype was associated with a genomic spectrum of candidate effector loci. The strategy successfully detected several loci for the phenotypes, at genome-wide significance, using a single, modest-sized population (N = 505). The effector loci each explain 2%-10% of the measured trait variation and, taken together, the loci can account for over 25% of a trait's total population variation. A replicate population (N = 378) was used to confirm initially observed loci for one trait (femur length), and, when the two groups were merged, the combined population demonstrated increased power to detect loci. In contrast to human population studies, our mouse genome-wide searches find loci that individually explain a larger fraction of the observed variation. Also, the additive effects of our detected mouse loci more closely match the predicted genetic component of variation. The genetic loci discovered are logical candidates for components of the genetic networks having evolutionary conservation with human biology.

Trajectory of Cognitive Decline After Incident Stroke.

IMPORTANCE: Cognitive decline is a major cause of disability in stroke survivors. The magnitude of survivors' cognitive changes after stroke is uncertain. OBJECTIVE: To measure changes in cognitive function among survivors of incident stroke, controlling for their prestroke cognitive trajectories. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 23,572 participants 45 years or older without baseline cognitive impairment from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, residing in the continental United States, enrolled 2003-2007 and followed up through March 31, 2013. Over a median follow-up of 6.1 years (interquartile range, 5.0-7.1 years), 515 participants survived expert-adjudicated incident stroke and 23,057 remained stroke free. EXPOSURE: Time-dependent incident stroke. MAIN OUTCOMES AND MEASURES: The primary outcome was change in global cognition (Six-Item Screener [SIS], range, 0-6). Secondary outcomes were change in new learning (Consortium to Establish a Registry for Alzheimer Disease Word-List Learning; range, 0-30), verbal memory (Word-List Delayed Recall; range, 0-10), and executive function (Animal Fluency Test; range, ≥0), and cognitive impairment (SIS score <5 [impaired] vs ≥5 [unimpaired]). For all tests, higher scores indicate better performance. RESULTS: Stroke was associated with acute decline in global cognition (0.10 points [95% CI, 0.04 to 0.17]), new learning (1.80 points [95% CI, 0.73 to 2.86]), and verbal memory (0.60 points [95% CI, 0.13 to 1.07]). Participants with stroke, compared with those without stroke, demonstrated faster declines in global cognition (0.06 points per year faster [95% CI, 0.03 to 0.08]) and executive function (0.63 points per year faster [95% CI, 0.12 to 1.15]), but not in new learning and verbal memory, compared with prestroke slopes. Among survivors, the difference in risk of cognitive impairment acutely after stroke, compared with immediately before stroke, was not statistically significant (odds ratio, 1.32 [95% CI, 0.95 to 1.83]; P = .10); however, there was a significantly faster poststroke rate of incident cognitive impairment compared with the prestroke rate (odds ratio, 1.23 per year [95% CI, 1.10 to 1.38]; P < .001). For a 70-year-old black woman with average values for all covariates at baseline, stroke at year 3 was associated with greater incident cognitive impairment: absolute difference of 4.0% (95% CI, -1.2% to 9.2%) at year 3 and 12.4% (95% CI, 7.7% to 17.1%) at year 6. CONCLUSIONS AND RELEVANCE: Incident stroke was associated with an acute decline in cognitive function and also accelerated and persistent cognitive decline over 6 years.

Effect of Population-Level Blood Pressure Treatment Strategies on Cardiovascular and Cognitive Outcomes.

BACKGROUND: The large and increasing number of adults living with dementia is a pressing societal priority, which may be partially mitigated through improved population-level blood pressure (BP) control. We explored how tighter population-level BP control affects the incidence of atherosclerotic cardiovascular disease (ASCVD) events and dementia. METHODS: Using an open-source ASCVD and dementia simulation analysis platform, the Michigan Chronic Disease Simulation Model, we evaluated how optimal implementation of 2 BP treatments based on the Eighth Joint National Committee recommendations and SPRINT (Systolic Blood Pressure Intervention Trial) protocol would influence population-level ASCVD events, global cognitive performance, and all-cause dementia. We simulated 3 populations (usual care, Eighth Joint National Committee based, SPRINT based) using nationally representative data to annually update risk factors and assign ASCVD events, global cognitive performance scores, and dementia, applying different BP treatments in each population. We tabulated total ASCVD events, global cognitive performance, all-cause dementia, optimal brain health, and years lived in each state per population. RESULTS: Optimal implementation of SPRINT-based BP treatment strategy, compared with usual care, reduced ASCVD events in the United States by ≈77 000 per year and produced 0.4 more years of stroke- or myocardial infarction-free survival when averaged across all Americans. Population-level gains in years lived free of ASCVD events were greater for SPRINT-based than Eighth Joint National Committee-based treatment. Survival and years spent with optimal brain health improved with optimal SPRINT-based BP treatment implementation versus usual care: the average patient with hypertension lived 0.19 additional years and 0.3 additional years in optimal brain health. SPRINT-based BP treatment increased the number of years lived without dementia (by an average of 0.13 years/person with hypertension), but increased the total number of individuals with dementia, mainly through more adults surviving to advanced ages. CONCLUSIONS: Tighter BP control likely benefits most individuals but is unlikely to reduce dementia prevalence and might even increase the number of older adults living with dementia.

Cumulative Systolic Blood Pressure and Incident Stroke Type Variation by Race and Ethnicity.

Importance: Stroke risk varies by systolic blood pressure (SBP), race, and ethnicity. The association between cumulative mean SBP and incident stroke type is unclear, and whether this association differs by race and ethnicity remains unknown. Objective: To examine the association between cumulative mean SBP and first incident stroke among 3 major stroke types-ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH)-and explore how these associations vary by race and ethnicity. Design, Setting, and Participants: Individual participant data from 6 US longitudinal cohorts (January 1, 1971, to December 31, 2019) were pooled. The analysis was performed from January 1, 2022, to January 2, 2024. The median follow-up was 21.6 (IQR, 13.6-31.8) years. Exposure: Time-dependent cumulative mean SBP. Main Outcomes and Measures: The primary outcome was time from baseline visit to first incident stroke. Secondary outcomes consisted of time to first incident IS, ICH, and SAH. Results: Among 40 016 participants, 38 167 who were 18 years or older at baseline with no history of stroke and at least 1 SBP measurement before the first incident stroke were included in the analysis. Of these, 54.0% were women; 25.0% were Black, 8.9% were Hispanic of any race, and 66.2% were White. The mean (SD) age at baseline was 53.4 (17.0) years and the mean (SD) SBP at baseline was 136.9 (20.4) mm Hg. A 10-mm Hg higher cumulative mean SBP was associated with a higher risk of overall stroke (hazard ratio [HR], 1.20 [95% CI, 1.18-1.23]), IS (HR, 1.20 [95% CI, 1.17-1.22]), and ICH (HR, 1.31 [95% CI, 1.25-1.38]) but not SAH (HR, 1.13 [95% CI, 0.99-1.29]; P = .06). Compared with White participants, Black participants had a higher risk of IS (HR, 1.20 [95% CI, 1.09-1.33]) and ICH (HR, 1.67 [95% CI, 1.30-2.13]) and Hispanic participants of any race had a higher risk of SAH (HR, 3.81 [95% CI, 1.29-11.22]). There was no consistent evidence that race and ethnicity modified the association of cumulative mean SBP with first incident stroke and stroke type. Conclusions and Relevance: The findings of this cohort study suggest that cumulative mean SBP was associated with incident stroke type, but the associations did not differ by race and ethnicity. Culturally informed stroke prevention programs should address modifiable risk factors such as SBP along with social determinants of health and structural inequities in society.

Development and validation of the Michigan Chronic Disease Simulation Model (MICROSIM).

Strategies to prevent or delay Alzheimer's disease and related dementias (AD/ADRD) are urgently needed, and blood pressure (BP) management is a promising strategy. Yet the effects of different BP control strategies across the life course on AD/ADRD are unknown. Randomized trials may be infeasible due to prolonged follow-up and large sample sizes. Simulation analysis is a practical approach to estimating these effects using the best available existing data. However, existing simulation frameworks cannot estimate the effects of BP control on both dementia and cardiovascular disease. This manuscript describes the design principles, implementation details, and population-level validation of a novel population-health microsimulation framework, the MIchigan ChROnic Disease SIMulation (MICROSIM), for The Effect of Lower Blood Pressure over the Life Course on Late-life Cognition in Blacks, Hispanics, and Whites (BP-COG) study of the effect of BP levels over the life course on dementia and cardiovascular disease. MICROSIM is an agent-based Monte Carlo simulation designed using computer programming best practices. MICROSIM estimates annual vascular risk factor levels and transition probabilities in all-cause dementia, stroke, myocardial infarction, and mortality in a nationally representative sample of US adults 18+ using the National Health and Nutrition Examination Survey (NHANES). MICROSIM models changes in risk factors over time, cognition and dementia using changes from a pooled dataset of individual participant data from 6 US prospective cardiovascular cohort studies. Cardiovascular risks were estimated using a widely used risk model and BP treatment effects were derived from meta-analyses of randomized trials. MICROSIM is an extensible, open-source framework designed to estimate the population-level impact of different BP management strategies and reproduces US population-level estimates of BP and other vascular risk factors levels, their change over time, and incident all-cause dementia, stroke, myocardial infarction, and mortality.

Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study.

Diabetic kidney disease causes significant morbidity and mortality among people with type 1 diabetes (T1D). Intensive glucose and blood pressure control have thus far failed to adequately curb this problem and therefore a major need for novel treatment approaches exists. Multiple observations link serum uric acid levels to kidney disease development and progression in diabetes and strongly argue that uric acid lowering should be tested as one such novel intervention. A pilot of such a trial, using allopurinol, is currently being conducted by the Preventing Early Renal Function Loss (PERL) Consortium. Although the PERL trial targets T1D individuals at highest risk of kidney function decline, the use of allopurinol as a renoprotective agent may also be relevant to a larger segment of the population with diabetes. As allopurinol is inexpensive and safe, it could be cost-effective even for relatively low-risk patients, pending the completion of appropriate trials at earlier stages.

Association of Obesity With Cognitive Decline in Black and White Americans.

BACKGROUND AND OBJECTIVES: There are disparities in the prevalence of obesity by race, and the relationship between obesity and cognitive decline is unclear. The objective of this study was to determine whether obesity is independently associated with cognitive decline and whether the association between obesity and cognitive decline differs in Black and White adults. We hypothesized that obesity is associated with greater cognitive decline compared with normal weight and that the effect of obesity on cognitive decline is more pronounced in Black adults compared with their White counterparts. METHODS: We pooled data from 28,867 participants free of stroke and dementia (mean, SD: age 61 [10.7] years at the first cognitive assessment, 55% female, 24% Black, and 29% obese) from 6 cohorts. The primary outcome was the annual change in global cognition. We performed linear mixed-effects models with and without time-varying cumulative mean systolic blood pressure (SBP) and fasting plasma glucose (FPG). Global cognition was set to a t-score metric (mean 50, SD 10) at a participant's first cognitive assessment; a 1-point difference represents a 0.1 SD difference in global cognition across the 6 cohorts. The median follow-up was 6.5 years (25th percentile, 75th percentile: 5.03, 20.15). RESULTS: Obese participants had lower baseline global cognition than normal-weight participants (difference in intercepts, -0.36 [95% CI, -0.46 to -0.17]; p < 0.001). This difference in baseline global cognition was attenuated but was borderline significant after accounting for SBP and FPG (adjusted differences in intercepts, -0.19 [95% CI, -0.39 to 0.002]; p = 0.05). There was no difference in the rate of decline in global cognition between obese and normal-weight participants (difference in slope, 0.009 points/year [95% CI, -0.009 to 0.03]; p = 0.32). After accounting for SBP and FPG, obese participants had a slower decline in global cognition (adjusted difference in slope, 0.03 points/year slower [95% CI, 0.01 to 0.05]; p < 0.001). There was no evidence that race modified the association between body mass index and global cognitive decline (p = 0.34). DISCUSSION: These results suggest that obesity is associated with lower initial cognitive scores and may potentially attenuate declines in cognition after accounting for BP and FPG.

Associations Between Vascular Risk Factor Levels and Cognitive Decline Among Stroke Survivors.

Importance: Incident stroke is associated with accelerated cognitive decline. Whether poststroke vascular risk factor levels are associated with faster cognitive decline is uncertain. Objective: To evaluate associations of poststroke systolic blood pressure (SBP), glucose, and low-density lipoprotein (LDL) cholesterol levels with cognitive decline. Design, Setting, and Participants: Individual participant data meta-analysis of 4 US cohort studies (conducted 1971-2019). Linear mixed-effects models estimated changes in cognition after incident stroke. Median (IQR) follow-up was 4.7 (2.6-7.9) years. Analysis began August 2021 and was completed March 2023. Exposures: Time-dependent cumulative mean poststroke SBP, glucose, and LDL cholesterol levels. Main Outcomes and Measures: The primary outcome was change in global cognition. Secondary outcomes were change in executive function and memory. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Results: A total of 1120 eligible dementia-free individuals with incident stroke were identified; 982 (87.7%) had available covariate data and 138 (12.3%) were excluded for missing covariate data. Of the 982, 480 (48.9%) were female individuals, and 289 (29.4%) were Black individuals. The median age at incident stroke was 74.6 (IQR, 69.1-79.8; range, 44.1-96.4) years. Cumulative mean poststroke SBP and LDL cholesterol levels were not associated with any cognitive outcome. However, after accounting for cumulative mean poststroke SBP and LDL cholesterol levels, higher cumulative mean poststroke glucose level was associated with faster decline in global cognition (-0.04 points/y faster per each 10-mg/dL increase [95% CI, -0.08 to -0.001 points/y]; P = .046) but not executive function or memory. After restricting to 798 participants with apolipoprotein E4 (APOE4) data and controlling for APOE4 and APOE4 × time, higher cumulative mean poststroke glucose level was associated with a faster decline in global cognition in models without and with adjustment for cumulative mean poststroke SBP and LDL cholesterol levels (-0.05 points/y faster per 10-mg/dL increase [95% CI, -0.09 to -0.01 points/y]; P = .01; -0.07 points/y faster per 10-mg/dL increase [95% CI, -0.11 to -0.03 points/y]; P = .002) but not executive function or memory declines. Conclusions and Relevance: In this cohort study, higher poststroke glucose levels were associated with faster global cognitive decline. We found no evidence that poststroke LDL cholesterol and SBP levels were associated with cognitive decline.