Mediating and moderating effects of plasma proteomic biomarkers on the association between poor oral health problems and brain white matter microstructural integrity: the UK Biobank study.

The plasma proteome can mediate associations between periodontal disease (Pd) and brain white matter integrity (WMI). We screened 5089 UK Biobank participants aged 40-70 years for poor oral health problems (POHP). We examined the association between POHP and WMI (fractional anisotropy (FA), mean diffusivity (MD), Intracellular Volume Fraction (ICVF), Isotropic Volume Fraction (ISOVF) and Orientation Diffusion (OD)), decomposing the total effect through the plasma proteome of 1463 proteins into pure mediation, pure interaction, neither, while adjusting for socio-demographic and cardiovascular health factors. Similarly, structural equations modeling (SEM) was conducted. POHP was more prevalent among men (12.3% vs. 9.6%), and was associated with lower WMI on most metrics, in a sex-specific manner. Of 15 proteins strongly associated with POHP, growth differentiation factor 15 (GDF15) and WAP four-disulfide core domain 2 (WFDC2; also known as human epididymis protein 4; HE4) were consistent mediators. Both proteins mediated 7-8% of total POHP effect on FAmean. SEM yielded significant total effects for FAmean, MDmean and ISOVFmean in full models, with %mediated by common latent factor (GDF15 and WFDC2) ranging between 13% (FAmean) and 19% (ISOVFmean). For FA, mediation by this common factor was found for 16 of 49 tract-specific and global mean metrics. Protein metabolism, immune system, and signal transduction were the most common pathways for mediational effects. POHP was associated with poorer WMI, which was partially mediated by GDF15 and WFDC2.

Infection burden, periodontal pathogens, and their interactive association with incident all-cause and Alzheimer's disease dementia in a large national survey.

INTRODUCTION: Relationships and interplay of an infection burden (IB) and periodontal pathogens or periodontal disease (Pd) markers with Alzheimer's disease (AD) and all-cause dementia among US adults were examined. METHODS: Less than or equal to 2997 participants from the National Health and Nutrition Survey III were linked to CMS-Medicare [≥45 years (1988-1994); ≤30 years follow-up]. RESULTS: Hepatitis C (hazard ratio = 3.33, p = 0.004) and herpes simplex virus 2 were strongly associated with greater all-cause dementia risk. Porphyromonas gingivalis and Streptococcus oralis were associated with greater AD risk at higher IB. The red-green periodontal pathogen cluster coupled with higher IB count increased the risk of all-cause dementia among minority racial groups. Pocket probing depth associated with dementia risk at lower IB in the overall sample. DISCUSSION: Select viruses and bacteria were associated with all-cause and AD dementia, while the IB interacted with Pd markers in relation to these outcomes. HIGHLIGHTS: Interplay of infection burden (IB) and periodontal disease with dementia was tested. ≤2997 participants from NHANES III were linked to Medicare. Hepatitis C and herpes simplex virus 2 strongly associated with dementia risk. Tetanus sero-positivity increased Alzheimer's disease (AD) risk. Porphyromonas gingivalis and Streptococcus oralis associated with AD at higher IB. Red-green periodontal cluster at high IB, increased dementia in racial minorities. Pocket probing depth associated with dementia risk at lower IB.

GDF15 and its association with cognitive performance over time in a longitudinal study of middle-aged urban adults.

Serum GDF15 levels are correlated with multiple neurodegenerative diseases. Few studies have tested this marker's association with middle-aged cognitive performance over time, and whether race affects this association is unknown. We examined associations of initial serum GDF15 concentrations with longitudinal cognitive performance, spanning domains of global mental status, visual and verbal memory, attention, fluency, and executive function in a sub-sample of adults participating in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study (n = 776, Agev1:30-66y, 45.6 % male, 57.0 % African American, 43.0 % below poverty). This analysis consisted of mixed-effects regression models applied to the total selected sample, while also stratifying the analyses by race in the main analyses and further stratifying by sex, age group and poverty status in an exploratory analysis. Our main findings, which passed multiple testing and covariate-adjustment, indicated that GDF15 was associated with poorer baseline performance on several cognitive tests, including animal fluency [overall sample: (Model 1: γ0 ± SE: -0.664 ± 0.208, P < 0.001; Model 2, γ0 ± SE: -0.498 ± 0.217, P < 0.05)]. Among White adults, GDF15 was linked to poorer performance on a brief test of attention (Model 1: γ0 ± SE: -0.426 ± 0.126, P < 0.001; Model 2, γ0 ± SE: -0.281 ± 0.139, P < 0.05); and Trailmaking test, part B (Model 1: γ0 ± SE: +0.129 ± 0.040, P < 0.001; Model 2, γ0 ± SE: +0.089 ± 0.041, P < 0.05), the latter being also linked to higher GDF15 among individuals living below poverty. Among women, GDF15 was associated with poor global mental status (Normalized MMSE: Model 1: γ0 ± SE: -2.617 ± 0.746, P < 0.001; Model 2: γ0 ± SE: -1.729 ± 0.709, P < 0.05). GDF15 was not associated with decline on any of the 11 cognitive test scores considered in âˆ¼ 4 years of follow-up. In sum, we detected cross-sectional associations between GDF15 and cognition, although GDF15 did not predict rate of change in cognitive performance over time among a sample of middle-aged adults. More longitudinal studies are needed to address the clinical utility of this biomarker for early cognitive defects.

Cardiovascular health, infection burden and their interactive association with brain volumetric and white matter integrity outcomes in the UK Biobank.

BACKGROUND: Cardiovascular health is associated with brain magnetic resonance imaging (MRI) markers of pathology and infections may modulate this association. METHODS: Using data from 38,803 adults (aged 40-70 years) and followed-up for 5-15 years, we tested associations of prevalent total (47.5%) and hospital-treated infection burden (9.7%) with brain structural and diffusion-weighted MRI (i.e., sMRI and dMRI, respectively) common in dementia phenome. Poor white matter tissue integrity was operationalized with lower global and tract-specific fractional anisotropy (FA) and higher mean diffusivity (MD). Volumetric sMRI outcomes included total, gray matter (GM), white matter (WM), frontal bilateral GM, white matter hyperintensity (WMH), and selected based on previous associations with dementia. Cardiovascular health was measured with Life's Essential 8 score (LE8) converted to tertiles. Multiple linear regression models were used, adjusting for intracranial volumes (ICV) for subcortical structures, and for demographic, socio-economic, and the Alzheimer's Disease polygenic risk score for all outcomes, among potential confounders. RESULTS: In fully adjusted models, hospital-treated infections were inversely related to GM (ß ± SE: -1042 ± 379, p = 0.006) and directly related to WMH as percent of ICV (Loge transformed) (ß ± SE:+0.026 ± 0.007, p < 0.001). Both total and hospital-treated infections were associated with poor WMI, while the latter was inversely related to FA within the lowest LE8 tertile (ß ± SE:-0.0011 ± 0.0003, p < 0.001, PLE8×IB < 0.05), a pattern detected for GM, Right Frontal GM, left accumbens and left hippocampus volumes. Within the uppermost LE8 tertile, total infection burden was linked to smaller right amygdala while being associated with larger left frontal GM and right putamen volumes, in the overall sample. Within that uppermost tertile of LE8, caudate volumes were also positively associated with hospital-treated infections. CONCLUSIONS: Hospital-treated infections had more consistent deleterious effects on volumetric and white matter integrity brain neuroimaging outcomes compared with total infectious burden, particularly in poorer cardiovascular health groups. Further studies are needed in comparable populations, including longitudinal studies with multiple repeats on neuroimaging markers.

Retirement age and disability status as pathways to later-life cognitive impairment: Evidence from the Norwegian HUNT Study linked with Norwegian population registers.

BACKGROUND: Research shows that retirement age is associated with later-life cognition but has not sufficiently distinguished between retirement pathways. We examined how retirement age was associated with later-life dementia and mild cognitive impairment (MCI) for people who retired via the disability pathway (received a disability pension prior to old-age pension eligibility) and those who retired via the standard pathway. METHODS: The study sample comprised 7210 participants from the Norwegian Trøndelag Health Study (HUNT4 70+, 2017-2019) who had worked for at least one year in 1967-2019, worked until age 55+, and retired before HUNT4. Dementia and MCI were clinically assessed in HUNT4 70+ when participants were aged 69-85 years. Historical data on participants' retirement age and pathway were retrieved from population registers. We used multinomial regression to assess the dementia/MCI risk for women and men retiring via the disability pathway, or early (<67 years), on-time (age 67, old-age pension eligibility) or late (age 68+) via the standard pathway. RESULTS: In our study sample, 9.5% had dementia, 35.3% had MCI, and 28.1% retired via the disability pathway. The disability retirement group had an elevated risk of dementia compared to the on-time standard retirement group (relative risk ratio [RRR]: 1.64, 95% CI 1.14-2.37 for women, 1.70, 95% CI 1.17-2.48 for men). MCI risk was lower among men who retired late versus on-time (RRR, 0.76, 95% CI 0.61-0.95). CONCLUSION: Disability retirees should be monitored more closely, and preventive policies should be considered to minimize the dementia risk observed among this group of retirees.

Predicting mortality from 57 economic, behavioral, social, and psychological factors.

Behavioral and social scientists have identified many nonbiological predictors of mortality. An important limitation of much of this research, however, is that risk factors are not studied in comparison with one another or from across different fields of research. It therefore remains unclear which factors should be prioritized for interventions and policy to reduce mortality risk. In the current investigation, we compare 57 factors within a multidisciplinary framework. These include (i) adverse socioeconomic and psychosocial experiences during childhood and (ii) socioeconomic conditions, (iii) health behaviors, (iv) social connections, (v) psychological characteristics, and (vi) adverse experiences during adulthood. The current prospective cohort investigation with 13,611 adults from 52 to 104 y of age (mean age 69.3 y) from the nationally representative Health and Retirement Study used weighted traditional (i.e., multivariate Cox regressions) and machine-learning (i.e., lasso, random forest analysis) statistical approaches to identify the leading predictors of mortality over 6 y of follow-up time. We demonstrate that, in addition to the well-established behavioral risk factors of smoking, alcohol abuse, and lack of physical activity, economic (e.g., recent financial difficulties, unemployment history), social (e.g., childhood adversity, divorce history), and psychological (e.g., negative affectivity) factors were also among the strongest predictors of mortality among older American adults. The strength of these predictors should be used to guide future transdisciplinary investigations and intervention studies across the fields of epidemiology, psychology, sociology, economics, and medicine to understand how changes in these factors alter individual mortality risk.

Pathways explaining racial/ethnic disparities in incident all-cause dementia among middle-aged US adults.

INTRODUCTION: Racial disparities in dementia incidence exist, but less is known about their presence and drivers among middle-aged adults. METHODS: We used time-to-event analysis among a sample of 4378 respondents (age 40-59 years at baseline) drawn from the third National Health and Nutrition Examination Surveys (NHANES III) with administrative linkage-spanning the years 1988-2014-to evaluate potential mediating pathways through socioeconomic status (SES), lifestyle, and health-related characteristics. RESULTS: Compared with Non-Hispanic White (NHW) adults, Non-White adults had a higher incidence of AD-specific (hazard ratio [HR] = 2.05, 95% confidence interval [CI]: 1.21, 3.49) and all-cause dementia (HR = 2.01, 95% CI: 1.36, 2.98). Diet, smoking, and physical activity were among characteristics on the pathway between race/ethnicity, SES, and dementia, with health-mediating effects of smoking and physical activity on dementia risk. DISCUSSION: We identified several pathways that may generate racial disparities in incident all-cause dementia among middle-aged adults. No direct effect of race was observed. More studies are needed to corroborate our findings in comparable populations.

Cardiovascular health, infection burden, and incident dementia in the UK Biobank.

INTRODUCTION: Among older adults, total and hospitalized infection may be associated with incidence of all-cause and Alzheimer's disease (AD) dementias, with variation by cardiovascular health (CVH). METHODS: We used Cox proportional hazards (PH) models to examine the relationships between International Classification of Diseases-10th revision (ICD-10)-specific viral and bacterial infectious agents and incident all-cause and AD dementia among 355,046 UK Biobank participants ≥50 years at baseline. Life's Essential 8 (LE8) index reflected CVH. RESULTS: In both sexes, total infection burden (yes vs. no) was associated with all-cause dementia, with significant interactions by LE8 tertiles, whereby this relationship was significant only in the lowest LE8 tertile. Hospital-treated infection burden (yes vs no) was significantly related to all-cause and AD dementia, with no significant interaction with LE8 tertile. Age group patterns were detected. DISCUSSION: AD and all-cause dementia were related to hospital-treated infections, while CVH modified the relationship of total infection burden with all-cause dementia. Highlights Secondary analysis on >355,000 UK Biobank participants ≥50 years at baseline. Alzheimer's disease and all-cause dementia are both related to hospital-treated infection. Cardiovascular health modifies association of infection burden with all-cause dementia.

Apolipoprotein E (APOE) genotype, dementia, and memory performance among Caribbean Hispanic versus US populations.

INTRODUCTION: Apolipoprotein E (APOE) is considered the major susceptibility gene for developing Alzheimer's disease. However, the strength of this risk factor is not well established across diverse Hispanic populations. METHODS: We investigated the associations among APOE genotype, dementia prevalence, and memory performance (immediate and delayed recall scores) in Caribbean Hispanics (CH), African Americans (AA), Hispanic Americans (HA) and non-Hispanic White Americans (NHW). Multivariable logistic regressions and negative binomial regressions were used to examine these associations by subsample. RESULTS: Our final dataset included 13,516 participants (5198 men, 8318 women) across all subsamples, with a mean age of 74.8 years. Prevalence of APOE ε4 allele was similar in CHs, HAs, and NHWs (21.8%-25.4%), but was substantially higher in AAs (33.6%; P < 0.001). APOE ε4 carriers had higher dementia prevalence across all groups. DISCUSSION: APOE ε4 was similarly associated with increased relative risk of dementia and lower memory performance in all subsamples.

Plasma neurofilament light and its association with all-cause mortality risk among urban middle-aged men and women.

BACKGROUND: Neurofilament light chain (NfL) is released into the blood during neuronal damage. NfL is linked to mortality in neurological disorders, remaining unexplored in population studies. We investigated whether initial (v1) and annualized change (δ) in plasma NfL can predict all-cause mortality in middle-aged dementia-free urban adults. METHODS: Longitudinal data were from 694 participants in the Healthy Aging in Neighborhoods of Diversity Across the Life Span study (HANDLS, mean agev1: 47.8 years, 42% male, 55.8% African American). Plasma NfL was measured prospectively at three visits. Analyses included Cox proportional hazards models for all-cause mortality risk and 4-way decomposition testing for interaction and mediation. RESULTS: Unlike men, women exhibited a direct association between δNfL (above vs. below median) and all-cause mortality risk in both the minimally (HR = 3.91, 95% CI 1.10-13.9, p = 0.036) and fully adjusted models (HR = 4.92, 95% CI 1.26-19.2, p = 0.022), and for δNfL (per unit increase) in the full model (HR = 1.65, 95% CI 1.04-2.61, p = 0.034). In both models, and among women, 1 standard deviation of NfLv1 was associated with an increased all-cause mortality risk (reduced model: HR = 2.01, 95% CI 1.24-3.25, p = 0.005; full model: HR = 1.75, 95% CI 1.02-2.98, p = 0.041). Only few interactions were detected for cardio-metabolic risk factors. Notably, NfLv1 was shown to be a better prognostic indicator at normal hsCRP values among women, while HbA1c and δNfL interacted synergistically to determine mortality risk, overall. CONCLUSIONS: These findings indicate that plasma NfL levels at baseline and over time can predict all-cause mortality in women and interacts with hsCRP and HbA1c to predict that risk.

BMI and Allostatic Load Are Directly Associated with Longitudinal Increase in Plasma Neurofilament Light among Urban Middle-Aged Adults.

BACKGROUND: Plasma neurofilament light chain (NfL) is a novel biomarker for age-related neurodegenerative disease. We tested whether NfL may be linked to cardiometabolic risk factors, including BMI, the allostatic load (AL) total score (ALtotal), and related AL continuous components (ALcomp). We also tested whether these relations may differ by sex or by race. METHODS: We used data from the HANDLS (Healthy Aging in Neighborhoods of Diversity across the Life Span) study [n = 608, age at visit 1 (v1: 2004-2009): 30-66 y, 42% male, 58% African American] to investigate associations of initial cardiometabolic risk factors and time-dependent plasma NfL concentrations over 3 visits (2004-2017; mean ± SD follow-up time: 7.72 ± 1.28 y), with outcomes being NfLv1 and annualized change in NfL (δNfL). We used mixed-effects linear regression and structural equations modeling (SM). RESULTS: BMI was associated with lower initial (γ01 = -0.014 ± 0.002, P < 0.001) but faster increase in plasma NfL over time (γ11 = +0.0012 ± 0.0003, P < 0.001), a pattern replicated for ALtotal. High-sensitivity C-reactive protein (hsCRP), serum total cholesterol, and resting heart rate at v1 were linked with faster plasma NfL increase over time, overall, while being uncorrelated with NfLv1 (e.g., hsCRP × Time, full model: γ11 = +0.004 ± 0.002, P = 0.015). In SM analyses, BMI's association with δNfL was significantly mediated through ALtotal among women [total effect (TE) = +0.0014 ± 0.00038, P < 0.001; indirect effect = +0.00042 ± 0.00019, P = 0.025; mediation proportion = 30%], with only a direct effect (DE) detected among African American adults (TE = +0.0011 ± 0.0004, P = 0.015; DE = +0.0010 ± 0.00048, P = 0.034). The positive associations between ALtotal/BMI and δNfL were mediated through increased glycated hemoglobin (HbA1c) concentrations, overall. CONCLUSIONS: Cardiometabolic risk factors, particularly elevated HbA1c, should be screened and targeted for neurodegenerative disease, pending comparable longitudinal studies. Other studies examining the clinical utility of plasma NfL as a neurodegeneration marker should account for confounding effects of BMI and AL.

Helicobacter pylori, periodontal pathogens, and their interactive association with incident all-cause and Alzheimer's disease dementia in a large national survey.

Co-infection between Helicobacter pylori (Hp) and groups of periodontal pathogens may alter the onset of Alzheimer's disease (AD) and all-cause dementia. We examined the interactive associations among Hp sero-positivity, periodontal disease (Pd), and infections with incident AD and all-cause dementia, among older adults (≥65 years at baseline). Up to 1431 participants from phase 1 of the National Health and Nutrition Survey III (1988-1991) had complete data till January 1st, 2014 on Hp sero-positivity with a mean follow-up of 10-11 years for AD and all-cause dementia incidence. Exposures consisted of 19 periodontal pathogens, constructed factors and clusters, and two Pd markers- probing depth and clinical attachment loss (CAL). Cox proportional hazards models were performed. Around 55% of the selected sample was Hp+. We found that Prevotella intermedia, Campylobacter Rectus, Factor 2 (Pi/Prevotella nigrescens/Prevotella melaninogenica), and the Orange-Red cluster interacted synergistically with Hp sero-positivity, particularly with respect to AD incidence. The presence of higher levels of Actinomyces Naeslundii (An) enhanced the effect of being Hp+ on both AD and all-cause dementia incidence. In contrast, Fusobacterim nucleatum (Fn), and Factor 1 (which included Fn), exhibited an antagonistic interaction with Hp in relation to all-cause dementia. Both probing depth and CAL had direct associations with all-cause dementia among Hp+ individuals, despite nonsignificant interaction. Selected periodontal pathogen titers, factors, and clusters interacted mostly synergistically, with Hp sero-positivity, to alter the risk of AD and all-cause dementia. Ultimately, a randomized controlled trial is needed, examining effects of co-eradication of Hp and select periodontal pathogens on neurodegenerative disease.

Participation in Collision Sports and Cognitive Aging Among Swedish Twins.

We examined the association between early-life participation in collision sports and later-life cognitive health over a 28-year period in a population-based sample drawn from the longitudinal Swedish Adoption/Twin Study of Aging (1987-2014). Cognitive measures included the Mini-Mental State Examination and performance across multiple cognitive domains (e.g., global cognition, verbal ability, spatial ability, memory, processing speed). Among a sample of 660 adults (mean age at baseline, 62.8 years (range: 50-88); 58.2% female), who contributed 10,944 person-years of follow-up, there were 450 cases of cognitive impairment (crude rate = 41.1/1,000 person-years). Early-life participation in collision sports was not significantly associated with cognitive impairment at baseline or with its onset over a 28-year period in a time-to-event analysis, which accounted for the semi-competing risk of death. Furthermore, growth curve models revealed no association between early-life participation in collision sports and the level of or change in trajectories of cognition across multiple domains overall or in sex-stratified models. We discuss the long-term implications of adolescent participation in collision sports on cognitive health.

Systemic inflammation is associated with depressive symptoms differentially by sex and race: a longitudinal study of urban adults.

Systemic inflammation may influence trajectories of depressive symptoms over time, perhaps differentially by sex and race. Inflammatory markers and the Center for Epidemiologic Studies-Depression scale [total score: CES-Dtotal and four distinctive domains: somatic complaints, depressed affect, positive affect and interpersonal problems] were examined among African-American (AA) and White urban adults participating in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study [2004-2013, Agebase:30-64 y, mean ± SD follow-up time: 4.64 ± 0.93 y, N = 150 (with cytokine data) to N = 1,767 (with other inflammatory markers)]. Findings suggest that serum concentrations of high-sensitivity C-reactive protein (hsCRP), z-inflammation composite score [ICS, combining elevated hsCRP and ESR with low serum albumin and iron], and serum interleukin (IL) 1ß were positively associated with ΔCES-Dtotal (Δ: annual rate of increase) among Whites only. IL-12 was directly related to ΔCES-Dtotal among men and AA. The race-specific associations of hsCRP, ICS, IL-1ß and the sex-specific association of IL-12 with ΔCES-Dtotal were replicated for the "depressed affect" domain. Similarly, among men, lower serum albumin and higher ICS were linked with higher baseline "somatic complaints". IL-10 among AA and IL-12 among men were inversely related to Δ"positive affect", while "interpersonal problems" were cross-sectionally associated with IL-6 among AA and IL-10 among Whites. Finally, baseline ICS was positively associated with incident "elevated depressive symptoms" (EDS: CES-Dtotal ≥ 16) among AA (HR = 1.28, 95% CI: 1.04-1.56, P = 0.017). Overall, systemic inflammation was directly linked to increased depressive symptoms over time and at baseline, differentially across sex and race groups. More longitudinal research is needed to replicate our findings.

The Effects of Aerobic Exercise on Psychological Functioning in Family Caregivers: Secondary Analyses of a Randomized Controlled Trial.

BACKGROUND: The responsibility and stress of being a family caregiver are associated with reduced physical and mental health. PURPOSE: To examine whether a 24-week aerobic exercise program improves multiple aspects of psychological functioning in family caregivers. METHODS: Family caregivers of patients with Alzheimer's disease and other dementias (n = 68) were recruited and randomized into either an aerobic exercise group (n = 34) or a waitlist control group (n = 34). The exercise group was assigned a 24-week aerobic training program that incrementally increased the intensity, duration, and frequency of the exercise program until 150 min of moderate to vigorous activity were completed per week by the ninth week. Twelve measures of psychological functioning were administered at baseline and compared with responses completed following the intervention. RESULTS: Multilevel modeling revealed significant decreases in caregiver burden (ß = -4.60, 95% confidence interval [CI] = [-8.82, -0.38], RLMM2 = 0.11) and depression (ß = -2.59, 95% CI = [-4.79, -0.38], RLMM2 = 0.13), as well as increases in mastery (ß = 1.78, 95% CI = [0.09, 3.46], RLMM2 = .04) in the exercise intervention group compared to the control group. CONCLUSION: Family caregivers report high levels of depression and caregiver burden. Engagement in a 24-week exercise intervention can ameliorate the perceived burden of caregiving, symptoms of depression, and their sense of mastery.

Red Cell Distribution Width Is Directly Associated with Poor Cognitive Performance among Nonanemic, Middle-Aged, Urban Adults.

BACKGROUND: Epidemiological evidence suggests that both anemia and elevated red cell distribution width (RDW) are associated with cognitive impairment. However, the interplay between these 2 predictors has been understudied. OBJECTIVES: We examined sex- and anemia-specific associations between RDW and cognitive performance among urban adults in the United States. METHODS: Data from the Healthy Aging in Neighborhoods of Diversity Across the Life Span Study (Baltimore, MD; participants aged 30-65 y at baseline, ∼59% African-American, 45% men) were used. Participants were selected based on the completion of 11 cognitive tasks at baseline (2004-2009) and follow-up (2009-2013) visits (mean time between visits: 4.64 ± 0.93 y) and availability of exposure and covariate data, yielding a sample of between 1526 and 1646 adults out of the initial 3720 adults recruited at baseline. Multiple linear mixed-effects regression models were conducted with RDW as the main exposure of interest and anemia/sex as the key effect modifiers. RESULTS: Overall, high RDWs were linked to poorer baseline performance on the California Verbal Learning Test (CVLT) List A (per 1 unit increase in RDW %, main effect: γ01 = -0.369 ± 0.114; P = 0.001) and to slower rates of decline on the CVLT Delayed Free Recall (per 1 unit increase in RDW %, RDW × time: γ11 = +0.036 ± 0.013; P = 0.007). Among nonanemic participants, RDWs were consistently associated with poorer baseline performance on the Trailmaking Test, Part A (γ01 = +3.11 ± 0.89; P < 0.001) and on the CVLT List A (γ01 = -0.560 ± 0.158; P < 0.001). Moreover, RDWs were associated with poorer baseline performance on the Brief Test of Attention in the total population (γ01 = -0.123 ± 0.039; P = 0.001) and among men (γ01 = -0.221 ± 0.068; P = 0.001). We did not detect an association between hemoglobin (Hb) and baseline cognitive performance or changes over time. CONCLUSIONS: Elevated RDW had a consistent cross-sectional association with poor cognitive performance in the domains of verbal memory and attention among the nonanemic group in a sample of middle-aged, urban adults. Anemia and Hb concentrations were not associated with cognition. More longitudinal studies are needed to replicate our findings.

Longitudinal associations between dietary quality and Alzheimer's disease genetic risk on cognitive performance among African American adults.

Poor diet quality (DQ) is associated with poor cognition and increased neurodegeneration, including Alzheimer's disease (AD). We are interested in the role of DQ on cognitive functioning (by sex and increasing genetic risk for AD), in a sample of African American (AA) middle-aged adults. We analysed a sub-group of participants (about 55 % women; mean follow-up time of about 4·7 years) from the Healthy Aging in Neighborhoods of Diversity across the Life Span study with a genetic risk score for AD (hAlzScore). The Healthy Eating Index-2010, Dietary Approaches to Stop Hypertension and the mean adequacy ratio computed at baseline (2004-2009) and follow-up visits (2009-2013) were used to assess initial DQ and change over time. Linear mixed-effects regression models were utilised, adjusting for select covariates, selection bias and multiple testing. DQ change (ΔDQ) was associated with California Verbal Learning Test-List A - overall (0·15 (se 0·06), P = 0·008) and in women (0·21 (se 0·08), P = 0·006), at highest AD risk, indicating protective effects over time. Greater AD risk was longitudinally associated with poorer Clock Command Test scores in men. Poor DQ was positively and cross-sectionally associated with Trails B scores, but in women only. Better-quality diet was associated with a slower decline in verbal memory among AA women, with greater AD risk. Insufficient clinical evidence and/or mixed findings dictate that more studies are needed to investigate brain morphology and volume changes in relation to DQ in an at-risk population for AD, over time.

Cytokines are associated with longitudinal changes in cognitive performance among urban adults.

BACKGROUND: Chronic systemic inflammation has been positively associated with structural and functional brain changes representing early markers of Alzheimer's Disease (AD) and cognitive decline. The current study examined associations between systemic inflammation and cognitive performance among African-Americans and Whites urban adults. METHODS: Participants were selected from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study (2004-2013, baseline age: 30-64 y, mean ±â€¯SD follow-up time of 4.64 ±â€¯0.93 y, N = 189-222, k = 1.5-1.7 observations/participant). Cytokines known to be positively linked to AD incidence among others were tested against cross-sectional and longitudinal cognitive function, stratifying by age group (≤50 y vs. >50 y), sex and race. A series of mixed-effects regression models were conducted, adjusting for key confounders. RESULTS: Among key findings, IL1ß was positively associated with a faster rate of decline on a test of executive functioning, among older adults (age >50 y, γ11 = +2.49 ±â€¯0.89, p = 0.005), while in the total population, IL-6 was linked to a faster decline on a test of verbal memory (γ11 = -0.011 ±â€¯0.004, p = 0.009). Among younger participants, IL-18 was linked to a poorer performance on a test of attention at baseline (age ≤50 y, γ01 = -0.007 ±â€¯0.0025, p = 0.004) though a slower rate of decline with higher IL-18 was detected for a test of psychomotor speed in older adults (age >50 y, γ11 = +0.0010 ±â€¯0.0004, p = 0.008). Finally, among Whites, unlike among African-Americans, IL-6 was associated with a better baseline performance on two tests of verbal and working memory. CONCLUSIONS: Cytokines were shown to be associated with age-related cognitive decline among middle-aged and older urban adults in an age group and race-specific manner. Further longitudinal studies are needed to replicate our findings and mediation through relevant biological and psychosocial factors need to be studied as well.

Association of genetic and behavioral characteristics with the onset of diabetes.

BACKGROUND: Prior work has established sociodemographic, lifestyle, and behavioral risk factors for diabetes but the contribution of these factors to the onset of diabetes remains unclear when accounting for genetic propensity for diabetes. We examined the contribution of a diabetes polygenic score (PGS) to the onset of diabetes in the context of modifiable known risk factors for diabetes. METHODS: Our sample consisted of 15,190 respondents in the United States-based Health and Retirement Study, a longitudinal study with up to 22 years of follow-up. We performed multivariate Cox regression models stratified by race (non-Hispanic white and non-Hispanic black) with time-varying covariates. RESULTS: We observed 4217 (27.76%) cases of incident diabetes over the survey period. The diabetes PGS was statistically significantly associated with diabetes onset for both non-Hispanic whites (hazard ratio [HR] = 1.38, 95% confidence interval [CI] = 1.30, 1.46) and non-Hispanic blacks (HR = 1.22, 95% CI = 1.06, 1.40) after adjusting for a range of known risk factors for diabetes, highlighting the critical role genetic endowment might play. Nevertheless, genetics do not downplay the role that modifiable characteristics could still play in diabetes management; even with the inclusion of the diabetes PGS, several behavioral and lifestyle characteristics remained significant for both race groups. CONCLUSIONS: The effects of genetic and lifestyle characteristics should be taken into consideration for both future studies and diabetes management.

Blind Deconvolution for Distributed Parameter Systems with Unbounded Input and Output and Determining Blood Alcohol Concentration from Transdermal Biosensor Data.

We develop a blind deconvolution scheme for input-output systems described by distributed parameter systems with boundary input and output. An abstract functional analytic theory based on results for the linear quadratic control of infinite dimensional systems with unbounded input and output operators is presented. The blind deconvolution problem is then reformulated as a series of constrained linear and nonlinear optimization problems involving infinite dimensional dynamical systems. A finite dimensional approximation and convergence theory is developed. The theory is applied to the problem of estimating blood or breath alcohol concentration (respectively, BAC or BrAC) from biosensor-measured transdermal alcohol concentration (TAC) in the field. A distributed parameter model with boundary input and output is proposed for the transdermal transport of ethanol from the blood through the skin to the sensor. The problem of estimating BAC or BrAC from the TAC data is formulated as a blind deconvolution problem. A scheme to identify distinct drinking episodes in TAC data based on a Hodrick Prescott filter is discussed. Numerical results involving actual patient data are presented.