Supplementary Material for: Timing of cognitive test score decline prior to incident dementia diagnosis in Blacks and Whites: The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS)

Introduction: Commonly occurring dementias include those of Alzheimer’s, vascular, and mixtures of these and other pathologies. They are believed to evolve over many years, but that time interval has been difficult to establish. Our objective is to determine how many years in advance of a dementia diagnosis cognitive scores begin to change. Methods: 14,086 dementia-free ARIC participants underwent a cognitive exam at baseline visit 2 (1990-1992, mean age 57±5.72), and in 11,244 at visit 4 (1996-1998), 5,640 at visit 5 (2011-2013), and 3,574 at visit 6 (2016-2017) with surveillance for dementias of all causes combined. Within 5-year intervals after each visit, we compared performance on the Delayed Word Recall Test (DWRT), the Digit Symbol Substitution Test (DSST), the Word Fluency Test (WFT), and the combined mean of three cognitive tests at baseline in participants who were diagnosed with dementia within each interval versus those who survived the interval without a dementia diagnosis. Z-scores were adjusted for demographics and education in separate regression models for each visit. We plotted adjusted z-score means by time interval following each visit. Results: During follow-up 3,334, 2,821, 1,218, and 329 dementia cases were ascertained after visits 2, 4, 5, and 6 respectively. Adjusted DWRT z-scores were significantly lower 20-25 years before dementia than those who did not experience dementia within 25 years. DSST z-scores were significantly lower at 25-30 years and 3-test combination z-scores were significantly lower as early as 30-31 years before onset. The difference between dementia and non-dementia group in the visit 2 3-test combination z-score was -0.20 at 30-31 years prior to dementia diagnosis. As expected, differences between the dementia and non-dementia groups increased closer to the time of dementia occurrence, up to their widest point at 0-5 years prior to dementia diagnosis. The difference between dementia and non-dementia groups in the visit 2 3-test combination z-score was -0.90. WFT z-score differences were smaller than for the DSST or DWRT and began later. Patterns were similar in Black and White participants. Conclusion: DWRT, DSST and combined 3-test z-scores were significantly lower more than 20 years prior to diagnosis in the dementia group versus the non-dementia group. Findings contribute to our knowledge of the long prodromal period in Blacks and Whites

Supplementary Material for: Kidney Measures with Diabetes and Hypertension on Cardiovascular Disease: The Atherosclerosis Risk in Communities Study

<b><i>Background:</i></b> Whether the association of chronic kidney disease (CKD) with cardiovascular risk differs based on diabetes mellitus (DM) and hypertension (HTN) status remains unanswered. <b><i>Methods:</i></b> We investigated 11,050 participants from the Atherosclerosis Risk in Communities Study (fourth examination (1996-1998)) with follow-up for cardiovascular outcomes (coronary disease, heart failure and stroke) through 2009. Using the Cox regression models, we quantified cardiovascular risk associated with estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR) in individuals with and without DM and/or HTN and assessed their interactions. <b><i>Results:</i></b> Individuals with DM and HTN generally had higher cardiovascular risk relative to those without at all the levels of eGFR and ACR. Cardiovascular risk increased with lower eGFR and higher ACR regardless of DM and HTN status (e.g. adjusted hazards ratio (HR) for eGFR 30-44 vs. 90-104 ml/min/1.73 m², 2.32 (95% CI, 1.66-3.26) in non-diabetics vs. 1.83 (1.25-2.67) in diabetics and 2.45 (2.20-5.01) in non-hypertensives vs. 1.51 (1.27-1.81) in hypertensives and corresponding adjusted HR for ACR 30-299 vs. <10 mg/g, 1.70 (1.45-2.00) vs. 1.34 (1.10-1.64) and 1.42 (1.10-1.85) vs. 1.57 (1.36-1.81), respectively). Only the ACR-DM interaction reached significance, with a shallower relative risk gradient among diabetics than among non-diabetics (p = 0.02). Analysis of individual cardiovascular outcomes showed similar results. <b><i>Conclusion:</i></b> Although individuals with DM and HTN generally had higher cardiovascular risk relative to those without these complications, both low eGFR and high ACR were associated with cardiovascular diseases regardless of the presence or absence of DM and HTN. These findings reinforce the importance of CKD in cardiovascular outcomes

Supplementary Material for: Cognition and Incident Dementia Hospitalization: Results from the Atherosclerosis Risk in Communities Study

<b><i>Background/Aims:</i></b> Cognitive decline is a defining feature of dementia. We sought to determine if a single baseline cognitive test score or change in test score over time is more strongly associated with risk of dementia hospitalization. We also sought to compare short- and long-term dementia risk. <b><i>Methods:</i></b> Prospective cohort study of 9,399 individuals from the Atherosclerosis Risk in Communities Study (median 10 years of follow-up). Cognition was assessed at two time points (6 years apart) using three tests: Delayed Word Recall Test (DWRT), Digit Symbol Substitution Test (DSST), and Word Fluency Test. Dementia hospitalizations were determined using ICD-9 codes. <b><i>Results:</i></b> Baseline cognitive test scores were associated with both short-term and long-term risk of dementia. The association of 6-year change in cognitive test score with dementia risk was stronger than that of individual test scores at a single visit [change from highest to lowest tertile, DWRT: hazard ratio = 6.45 (95% confidence interval = 1.80–23.08); DSST: hazard ratio = 10.94 (95% confidence interval = 3.07–38.97)]. <b><i>Conclusions:</i></b> In this community-based population, 6-year changes in cognitive scores were more strongly associated with risk of incident dementia hospitalization than baseline scores, although single DWRT and DSST scores were predictive. Our findings support the contention that cognitive changes may precede clinical dementia by a decade or more

Supplementary Material for: One-Year Change in Kidney Function Is Associated with an Increased Mortality Risk

<b><i>Background:</i></b> Serum creatinine is routinely measured to estimate glomerular filtration rate (GFR). Long-term cohort studies report that death is a likelier outcome than progression to kidney failure. However, it is unclear how short-term changes in estimated GFR (eGFR) over a 1-year period relate to subsequent mortality risk. <b><i>Methods:</i></b> Using a provincial laboratory registry from Alberta, Canada, we identified 598,397 adults who had ≥2 outpatient eGFR measurements at least 6 months apart during a 1-year accrual period. Change in kidney function was categorized by both changes in eGFR category and percent change ≥25% into 5 groups: certain drop, uncertain drop, stable (no change in CKD category), uncertain rise, and certain rise. Cox proportional hazards models, adjusting for baseline covariates, kidney function, and proteinuria were used to estimate the risk of all-cause mortality associated with each group change in kidney function in reference to stable kidney function. <b><i>Results:</i></b> Among the study participants, 447,570 (74.8%) had stable kidney function, 19,591 (3.3%) had a certain drop, and 22,171 (3.7%) had a certain rise in kidney function. Participants with change in kidney function (both drop and rise) were older, more likely to be female, and had a higher prevalence of comorbidities in comparison to those with stable kidney function. There were 51,473 (8.6%) deaths during a median follow-up of 3.5 years. Compared to participants with stable kidney function, those with a certain drop had an almost twofold increased mortality risk (hazard ratio 1.89, 95% CI 1.83–1.95) adjusted for baseline eGFR, proteinuria, and covariates. Participants with a certain rise (3.7%) in kidney function also experienced an increased mortality risk (hazard ratio 1.51, 95% CI 1.46–1.56) compared to those with stable kidney function. Risk of death was similarly increased with adjustment for eGFR at the last visit. <b><i>Conclusion:</i></b> Change in kidney function of ≥25% in any direction over a 1-year period is associated with a substantially increased risk of mortality

Supplementary Material for: Race, Mineral Homeostasis and Mortality in Patients with End-Stage Renal Disease on Dialysis

<b><i>Background:</i></b> Abnormalities in mineral homeostasis are ubiquitous in patients on dialysis, and influenced by race. In this study, we determine the race-specific relationship between mineral parameters and mortality in patients initiating hemodialysis. <b><i>Methods:</i></b> We measured the levels of fibroblast growth factor 23 (FGF23) and 25-hydroxyvitamin D (25 D) in 184 African American and 327 non-African American hemodialysis patients who enrolled between 1995 and 1998 in the Choices for Healthy Outcomes in Caring for ESRD Study. Serum calcium, phosphorus, parathyroid hormone (PTH) and total alkaline phosphatase levels were averaged from clinical measurements during the first 4.5 months of dialysis. We evaluated the associated prospective risk of mortality using multivariable Cox proportional hazards models stratified by race. <b><i>Results:</i></b> PTH and total alkaline phosphatase levels were higher, whereas calcium, phosphorus, FGF23 and 25 D levels were lower in African Americans compared to those of non-African Americans. Higher serum phosphorus and FGF23 levels were associated with greater mortality risk overall; however, phosphorus was only associated with risk among African Americans (HR 5.38, 95% CI 2.14-13.55 for quartile 4 vs. 1), but not among non-African Americans (p-interaction = 0.04). FGF23 was associated with mortality in both groups, but more strongly in African Americans (HR 3.91, 95% CI 1.74-8.82 for quartiles 4 vs. 1; p-interaction = 0.09). Serum calcium, PTH, and 25 D levels were not consistently associated with mortality. The lowest and highest quartiles of total alkaline phosphatase were associated with higher mortality risk, but this did not differ by race (p-interaction = 0.97). <b><i>Conclusions:</i></b> Aberrant phosphorus homeostasis, reflected by higher phosphorus and FGF23, may be a risk factor for mortality in patients initiating hemodialysis, particularly among African Americans