Clinical, Health-Related Quality of Life, and Gait Differences Among Obesity Classes in Adults With Knee Osteoarthritis.

OBJECTIVE: The purpose of this study was to determine whether clinical, health-related quality of life (HRQL), and gait characteristics in adults with knee osteoarthritis (OA) differed by obesity category. METHODS: This cross-sectional analysis of 823 older adults (mean age 64.6 years, SD 7.8 years) with knee OA and overweight or obesity compared clinical, HRQL, and gait outcomes among obesity classifications (overweight or class I, body mass index [BMI] 27.0-34.9; class II, BMI 35.0-39.9; class III BMI ≥40.0). RESULTS: Patients with class III obesity had worse Western Ontario McMasters Universities Arthritis Index knee pain (0-20) than the overweight or class I (mean 8.6 vs 7.0; difference 1.5; 95% confidence interval [CI] 1.0-2.1; P < 0.0001) and class II (mean 8.6 vs 7.4; difference 1.1; 95% CI 0.6-1.7; P = 0.0002) obesity groups. The Short Form 36 physical HRQL measure was lower in the class III obesity group compared to the overweight or class I (mean 31.0 vs 37.3; difference -6.2; 95% CI -7.8 to -4.7; P < 0.0001) and class II (mean 31.0 vs 35.0; difference -3.9; 95% CI -5.6 to -2.2; P < 0.0001) obesity groups. The class III obesity group had a base of support (cm) during gait that was wider than that for the overweight or class I (mean 14.0 vs 11.6; difference 3.3; 95% CI 2.6-4.0; P < 0.0001) and class II (mean 14.0 vs 11.6; difference 2.4; 95% CI 1.6-3.2; P < 0.0001) obesity groups. CONCLUSION: Among adults with knee OA, those with class III obesity had significantly higher pain levels and worse physical HRQL and gait characteristics compared to adults with overweight or class I or class II obesity.

The osteoarthritis prevention study (TOPS) - A randomized controlled trial of diet and exercise to prevent Knee Osteoarthritis: Design and rationale.

Background: Osteoarthritis (OA), the leading cause of disability among adults, has no cure and is associated with significant comorbidities. The premise of this randomized clinical trial is that, in a population at risk, a 48-month program of dietary weight loss and exercise will result in less incident structural knee OA compared to control. Methods/design: The Osteoarthritis Prevention Study (TOPS) is a Phase III, assessor-blinded, 48-month, parallel 2 arm, multicenter randomized clinical trial designed to reduce the incidence of structural knee OA. The study objective is to assess the effects of a dietary weight loss, exercise, and weight-loss maintenance program in preventing the development of structural knee OA in females at risk for the disease. TOPS will recruit 1230 ambulatory, community dwelling females with obesity (Body Mass Index (BMI) â€‹≥ â€‹30 â€‹kg/m2) and aged ≥50 years with no radiographic (Kellgren-Lawrence grade ≤1) and no magnetic resonance imaging (MRI) evidence of OA in the eligible knee, with no or infrequent knee pain. Incident structural knee OA (defined as tibiofemoral and/or patellofemoral OA on MRI) assessed at 48-months from intervention initiation using the MRI Osteoarthritis Knee Score (MOAKS) is the primary outcome. Secondary outcomes include knee pain, 6-min walk distance, health-related quality of life, knee joint loading during gait, inflammatory biomarkers, and self-efficacy. Cost effectiveness and budgetary impact analyses will determine the value and affordability of this intervention. Discussion: This study will assess the efficacy and cost effectiveness of a dietary weight loss, exercise, and weight-loss maintenance program designed to reduce incident knee OA. Trial registration: ClinicalTrials.gov Identifier: NCT05946044.

Alzheimer's Related Neurodegeneration Mediates Air Pollution Effects on Medial Temporal Lobe Atrophy.

Exposure to ambient air pollution, especially particulate matter with aerodynamic diameter <2.5 µm (PM2.5) and nitrogen dioxide (NO2), are environmental risk factors for Alzheimer's disease and related dementia. The medial temporal lobe (MTL) is an important brain region subserving episodic memory that atrophies with age, during the Alzheimer's disease continuum, and is vulnerable to the effects of cerebrovascular disease. Despite the importance of air pollution it is unclear whether exposure leads to atrophy of the MTL and by what pathways. Here we conducted a longitudinal study examining associations between ambient air pollution exposure and MTL atrophy and whether putative air pollution exposure effects resembled Alzheimer's disease-related neurodegeneration or cerebrovascular disease-related neurodegeneration. Participants included older women (n = 627; aged 71-87) who underwent two structural brain MRI scans (MRI-1: 2005-6; MRI-2: 2009-10) as part of the Women's Health Initiative Memory Study of Magnetic Resonance Imaging. Regionalized universal kriging was used to estimate annual concentrations of PM2.5 and NO2 at residential locations aggregated to 3-year averages prior to MRI-1. The outcome was 5-year standardized change in MTL volumes. Mediators included voxel-based MRI measures of the spatial pattern of neurodegeneration of Alzheimer's disease (Alzheimer's disease pattern similarity scores [AD-PS]) and whole-brain white matter small-vessel ischemic disease (WM-SVID) volume as a proxy of global cerebrovascular damage. Structural equation models were constructed to examine whether the associations between exposures with MTL atrophy were mediated by the initial level or concurrent change in AD-PS score or WM-SVID while adjusting for sociodemographic, lifestyle, clinical characteristics, and intracranial volume. Living in locations with higher PM2.5 (per interquartile range [IQR]=3.17µg/m3) or NO2 (per IQR=6.63ppb) was associated with greater MTL atrophy (ßPM2.5 = -0.29, 95% confidence interval [CI]=[-0.41,-0.18]; ßNO2 =-0.12, 95%CI=[-0.23,-0.02]). Greater PM2.5 was associated with larger increases in AD-PS (ßPM2.5 = 0.23, 95%CI=[0.12,0.33]) over time, which partially mediated associations with MTL atrophy (indirect effect= -0.10; 95%CI=[-0.15, -0.05]), explaining approximately 32% of the total effect. NO2 was positively associated with AD-PS at MRI-1 (ßNO2=0.13, 95%CI=[0.03,0.24]), which partially mediated the association with MTL atrophy (indirect effect= -0.01, 95% CI=[-0.03,-0.001]). Global WM-SVID at MRI-1 or concurrent change were not significant mediators between exposures and MTL atrophy. Findings support the mediating role of Alzheimer's disease-related neurodegeneration contributing to MTL atrophy associated with late-life exposures to air pollutants. Alzheimer's disease-related neurodegeneration only partially explained associations between exposure and MTL atrophy suggesting the role of multiple neuropathological processes underlying air pollution neurotoxicity on brain aging.

Association between late-life air pollution exposure and medial temporal lobe atrophy in older women.

Background: Ambient air pollution exposures increase risk for Alzheimer's disease (AD) and related dementias, possibly due to structural changes in the medial temporal lobe (MTL). However, existing MRI studies examining exposure effects on the MTL were cross-sectional and focused on the hippocampus, yielding mixed results. Method: To determine whether air pollution exposures were associated with MTL atrophy over time, we conducted a longitudinal study including 653 cognitively unimpaired community-dwelling older women from the Women's Health Initiative Memory Study with two MRI brain scans (MRI-1: 2005-6; MRI-2: 2009-10; Mage at MRI-1=77.3±3.5years). Using regionalized universal kriging models, exposures at residential locations were estimated as 3-year annual averages of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) prior to MRI-1. Bilateral gray matter volumes of the hippocampus, amygdala, parahippocampal gyrus (PHG), and entorhinal cortex (ERC) were summed to operationalize the MTL. We used linear regressions to estimate exposure effects on 5-year volume changes in the MTL and its subregions, adjusting for intracranial volume, sociodemographic, lifestyle, and clinical characteristics. Results: On average, MTL volume decreased by 0.53±1.00cm3 over 5 years. For each interquartile increase of PM2.5 (3.26µg/m3) and NO2 (6.77ppb), adjusted MTL volume had greater shrinkage by 0.32cm3 (95%CI=[-0.43, -0.21]) and 0.12cm3 (95%CI=[-0.22, -0.01]), respectively. The exposure effects did not differ by APOE ε4 genotype, sociodemographic, and cardiovascular risk factors, and remained among women with low-level PM2.5 exposure. Greater PHG atrophy was associated with higher PM2.5 (b=-0.24, 95%CI=[-0.29, -0.19]) and NO2 exposures (b=-0.09, 95%CI=[-0.14, -0.04]). Higher exposure to PM2.5 but not NO2 was also associated with greater ERC atrophy. Exposures were not associated with amygdala or hippocampal atrophy. Conclusion: In summary, higher late-life PM2.5 and NO2 exposures were associated with greater MTL atrophy over time in cognitively unimpaired older women. The PHG and ERC - the MTL cortical subregions where AD neuropathologies likely begin, may be preferentially vulnerable to air pollution neurotoxicity.

Application of the D3 -creatine muscle mass assessment tool to a geriatric weight loss trial: A pilot study.

BACKGROUND: Traditionally, weight loss (WL) trials utilize dual energy X-ray absorptiometry (DXA) to measure lean mass. This method assumes lean mass, as the sum of all non-bone and non-fat tissue, is a reasonable proxy for muscle mass. In contrast, the D3 -creatine (D3 Cr) dilution method directly measures whole body skeletal muscle mass, although this method has yet to be applied in the context of a geriatric WL trial. The purpose of this project was to (1) describe estimates of change and variability in D3 Cr muscle mass in older adults participating in an intentional WL intervention and (2) relate its change to other measures of body composition as well as muscle function and strength. METHODS: The INVEST in Bone Health trial (NCT04076618), used as a scaffold for this ancillary pilot project, is a three-armed, 12-month randomized, controlled trial designed to determine the effects of resistance training or weighted vest use during intentional WL on a battery of musculoskeletal health outcomes among 150 older adults living with obesity. A convenience sample of 24 participants (n = 8/arm) are included in this analysis. At baseline and 6 months, participants were weighed, ingested a 30 mg D3 Cr tracer dose, provided a fasted urine sample 3-6 days post-dosage, underwent DXA (total body fat and lean masses, appendicular lean mass) and computed tomography (mid-thigh and trunk muscle/intermuscular fat areas) scans, and performed 400-m walk, stair climb, knee extensor strength, and grip strength tests. RESULTS: Participants were older (68.0 ± 4.4 years), mostly White (75.0%), predominantly female (66.7%), and living with obesity (body mass index: 33.8 ± 2.7 kg/m2 ). Six month total body WL was -10.3 (95% confidence interval, CI: -12.7, -7.9) kg. All DXA and computed tomography-derived body composition measures were significantly decreased from baseline, yet D3 Cr muscle mass did not change [+0.5 (95% CI: -2.0, 3.0) kg]. Of muscle function and strength measures, only grip strength significantly changed [+2.5 (95% CI: 1.0, 4.0) kg] from baseline. CONCLUSIONS: Among 24 older adults, significant WL with or without weighted vest use or resistance training over a 6-month period was associated with significant declines in all bioimaging metrics, while D3 Cr muscle mass and muscle function and strength were preserved. Treatment assignment for the trial remains blinded; therefore, full interpretation of these findings is limited. Future work in this area will assess change in D3 Cr muscle mass by parent trial treatment group assignment in all study participants.

Ambient Air Quality and Fatal Asthma Exacerbations among Children in North Carolina.

BACKGROUND: Little is known about the role of air quality in fatal asthma exacerbations among children. METHODS: We collected information about 80 deaths that occurred in North Carolina from 2001 through 2016, among children aged 5-17 years, with asthma identified as the primary cause of death. We linked information about each death with county-level estimates of particulate matter ≤2.5 µm (PM2.5) and ozone (O3). Using the linked data, we conducted a case-crossover analysis of associations between PM2.5 and O3 lagged by 3-5 days with the odds of fatal asthma exacerbations. RESULTS: In the highest tertile of PM2.5 lag(3-5), the odds of a fatal exacerbation of asthma were more than twice the odds in the lowest tertile (odds ratio = 2.2; 95% confidence interval = 1.1, 4.6). CONCLUSION: These findings from North Carolina provide evidence to support the hypothesis that ambient air pollution increases the risk of fatal exacerbations of asthma among children.

Strategies to reduce the onset of sleeve gastrectomy associated bone loss (STRONG BONES): Trial design and methods.

Background: Despite recognized improvements in obesity-related comorbidities, mounting evidence implicates surgical weight loss in the onset of skeletal fragility. Sleeve gastrectomy (SG) is the most commonly performed bariatric procedure and is associated with 3-7% axial bone loss in the year following surgery. Bisphosphonates are FDA-approved medications for the prevention and treatment of age-related bone loss and may represent a strategy to reduce bone loss following SG surgery. Methods: The Strategies to Reduce the Onset of Sleeve Gastrectomy Associated Bone Loss (STRONG BONES) trial (NCT04922333) is designed to definitively test whether monthly administration of the bisphosphonate, risedronate, for six months can effectively counter SG-associated bone loss. Approximately 120 middle-aged and older (≥40 years) SG patients will be randomized to six months of risedronate or placebo treatment, with skeletal outcomes assessed at baseline, six, and 12-months post-surgery. The primary outcome of the trial is 12-month change in total hip areal bone mineral density (aBMD), measured by dual energy x-ray absorptiometry (DXA). This will be complemented by DXA-acquired aBMD assessment at other skeletal sites and quantitative computed tomography (QCT) derived changes in bone quality. Change in muscle mass and function will also be assessed, as well as biomarkers of bone health, turnover, and crosstalk, providing mechanistic insight into intervention-related changes to the bone-muscle unit. Discussion: Results from the STRONG BONES trial have the potential to influence current clinical practice by determining the ability of bisphosphonate use to mitigate bone loss and concomitant fracture risk in middle-aged and older SG patients.

Risedronate use may blunt appendicular lean mass loss secondary to sleeve gastrectomy: Results from a pilot randomized controlled trial.

Background: Despite robust weight loss and cardiometabolic benefit, lean mass loss following sleeve gastrectomy (SG) confers health risk. Bisphosphonates are a potential therapeutic agent for lean mass maintenance. Thus, our objective was to explore the effect of six months of risedronate (vs placebo) on change in dual energy x-ray absorptiometry (DXA) and computed tomography (CT) derived lean mass metrics in the year following SG. Methods: 24 SG patients were randomized to six months of 150 mg oral risedronate or placebo capsules (NCT03411902). Body composition was assessed at baseline and six months with optional 12-month follow-up using whole-body DXA and CT at the lumbar spine and mid-thigh. Group treatment effects and 95% CIs were generated from a mixed model using contrast statements at six and 12 months, adjusted for baseline values. Results: Of 24 participants enrolled [55.7±6.7 years (mean±SD), 79% Caucasian, 83% women, body mass index (BMI) 44.7±6.3kg/m2], 21 returned for six-month testing, and 14 returned for 12-month testing. Six-month weight loss was -16.3 kg (-20.0, -12.5) and -20.9 kg (-23.7, -18.1) in the risedronate and placebo groups, respectively (p=.057). Primary analysis at six-months revealed a non-significant sparing of appendicular lean mass in the risedronate group compared to placebo [-1.2 kg (-2.3, -0.1) vs -2.1 kg (-3.0, -1.2)]; p=.20. By 12-months, the risedronate group displayed no change in appendicular lean mass from baseline [-0.5 kg (-1.5, 0.6)]; however, the placebo group experienced significantly augmented loss [-2.9 kg (-3.6, -2.1)]. Conclusion: Pilot data indicate risedronate treatment may mitigate appendicular lean mass loss following SG. Further study is warranted.

Association of antenatal corticosteroids with kidney function in adolescents born preterm with very low birth weight.

OBJECTIVE: Investigate if antenatal corticosteroids (ANCS) are associated with worse kidney function in adolescence and if greater adiposity magnifies this association. STUDY DESIGN: Prospective cohort of 162 14-year-olds born preterm with very low birth weight (<1500 g). Outcomes were estimated glomerular filtration rate (eGFR) and first-morning urine albumin-to-creatinine ratio (UACR). We used adjusted generalized linear models, stratified by waist-to-height ratio (WHR) ≥ 0.5. RESULTS: Fifty-five percent had ANCS exposure and 31.3% had WHR ≥ 0.5. In adjusted analyses of the entire cohort, ANCS was not significantly associated with eGFR or UACR. However, the ANCS-eGFR association was greater in those with WHR ≥ 0.5 (ß -16.8 ml/min/1.73 m2, 95% CL -31.5 to -2.1) vs. WHR < 0.5: (ß 13.9 ml/min/1.73 m2, 95% CL -0.4 to 28.1), interaction term p = 0.02. CONCLUSION: ANCS exposure was not associated with worse kidney function in adolescence, though ANCS may be associated with lower eGFR if children develop obesity by adolescence.

Impact on Cardiovascular Health of Using Phentermine/Topiramate in Combination With Laparoscopic Sleeve Gastrectomy in Super Obesity.

INTRODUCTION: Management of patients with BMI≥50 kg/m2 is challenging. In previous work, pre and postoperative pharmacotherapy with phentermine/topiramate plus laparoscopic sleeve gastrectomy (PT + SG) promoted greater weight loss than sleeve gastrectomy (SG) alone at 24 mo postoperatively. This current secondary analysis studied the impact of PT + SG on blood pressure (BP), heart rate, and antihypertensive usage. METHODS: Patients with BMI≥50 kg/m2 planning to have SG (n = 13) were recruited from 2014 to 2016, at an academic medical center in Winston-Salem, North Carolina, for this open-label trial. Participants took phentermine/topiramate (PT; 7.5/46-15/92 mg/d) for ≥3 mo preoperatively and 24 mo postoperatively. The control group (n = 40) underwent SG during the same time frame. We used mixed models for BP and heart rate to compare PT + SG versus SG alone over time, adjusted for age, sex, and initial BP. RESULTS: By 24 mo postoperatively the model adjusted changes in systolic blood pressure/diastolic blood pressure (SBP/DBP) (mm Hg) were -24.44 (-34.46,-14.43)/-28.60 (-40.74,-16.46) in the PT + SG group versus -11.81 (-17.58,-6.05)/-13.89 (-21.32,-6.46) in the control group (SBP P = 0.02; DBP P = 0.03). At baseline 8 (61.5%) participants in the PT + SG arm and 22 (55.0%) in the control group used antihypertensives. Excluding patients lost to follow-up (n = 3), by 24 mo postoperatively, none of the PT + SG participants were on antihypertensives compared to 14 (41.2%) in the control group (P = 0.01). CONCLUSIONS: Patients with BMI≥50 kg/m2 treated with PT + SG had greater improvement in BP with no use of antihypertensive medication at 24 mo postoperatively versus SG alone, where 41% continued medication use. Larger trials are required to evaluate this.

Understanding heterogeneity of responses to, and optimizing clinical efficacy of, exercise training in older adults: NIH NIA Workshop summary.

Exercise is a cornerstone of preventive medicine and a promising strategy to intervene on the biology of aging. Variation in the response to exercise is a widely accepted concept that dates back to the 1980s with classic genetic studies identifying sequence variations as modifiers of the VO2max response to training. Since that time, the literature of exercise response variance has been populated with retrospective analyses of existing datasets that are limited by a lack of statistical power from technical error of the measurements and small sample sizes, as well as diffuse outcomes, very few of which have included older adults. Prospective studies that are appropriately designed to interrogate exercise response variation in key outcomes identified a priori and inclusive of individuals over the age of 70 are long overdue. Understanding the underlying intrinsic (e.g., genetics and epigenetics) and extrinsic (e.g., medication use, diet, chronic disease) factors that determine robust versus poor responses to various exercise factors will be used to improve exercise prescription to target the pillars of aging and optimize the clinical efficacy of exercise training in older adults. This review summarizes the proceedings of the NIA-sponsored workshop entitled, "Understanding Heterogeneity of Responses to, and Optimizing Clinical Efficacy of, Exercise Training in Older Adults" and highlights the importance and current state of exercise response variation research, particularly in older adults, prevailing challenges, and future directions.

Effect of Diet and Exercise on Knee Pain in Patients With Osteoarthritis and Overweight or Obesity: A Randomized Clinical Trial.

Importance: Some weight loss and exercise programs that have been successful in academic center-based trials have not been evaluated in community settings. Objective: To determine whether adaptation of a diet and exercise intervention to community settings resulted in a statistically significant reduction in pain, compared with an attention control group, at 18-month follow-up. Design, Setting, and Participants: Assessor-blinded randomized clinical trial conducted in community settings in urban and rural counties in North Carolina. Patients were men and women aged 50 years or older with knee osteoarthritis and overweight or obesity (body mass index ≥27). Enrollment (N = 823) occurred between May 2016 and August 2019, with follow-up ending in April 2021. Interventions: Patients were randomly assigned to either a diet and exercise intervention (n = 414) or an attention control (n = 409) group for 18 months. Main Outcomes and Measures: The primary outcome was the between-group difference in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) knee pain score (range, 0 [none] to 20 [severe]; minimum clinically important difference, 1.6) over 18 months, tested using a repeated-measures mixed linear model with adjustments for covariates. There were 7 secondary outcomes including body weight. Results: Among the 823 randomized patients (mean age, 64.6 years; 637 [77%] women), 658 (80%) completed the trial. At 18-month follow-up, the adjusted mean WOMAC pain score was 5.0 in the diet and exercise group (n = 329) compared with 5.5 in the attention control group (n = 316) (adjusted difference, -0.6; 95% CI, -1.0 to -0.1; P = .02). Of 7 secondary outcomes, 5 were significantly better in the intervention group compared with control. The mean change in unadjusted 18-month body weight for patients with available data was -7.7 kg (8%) in the diet and exercise group (n = 289) and -1.7 kg (2%) in the attention control group (n = 273) (mean difference, -6.0 kg; 95% CI, -7.3 kg to -4.7 kg). There were 169 serious adverse events; none were definitely related to the study. There were 729 adverse events; 32 (4%) were definitely related to the study, including 10 body injuries (9 in diet and exercise; 1 in attention control), 7 muscle strains (6 in diet and exercise; 1 in attention control), and 6 trip/fall events (all 6 in diet and exercise). Conclusions and Relevance: Among patients with knee osteoarthritis and overweight or obesity, diet and exercise compared with an attention control led to a statistically significant but small difference in knee pain over 18 months. The magnitude of the difference in pain between groups is of uncertain clinical importance. Trial Registration: ClinicalTrials.gov Identifier: NCT02577549.

Estimating heterogeneity of physical function treatment response to caloric restriction among older adults with obesity.

Clinical trials conventionally test aggregate mean differences and assume homogeneous variances across treatment groups. However, significant response heterogeneity may exist. The purpose of this study was to model treatment response variability using gait speed change among older adults participating in caloric restriction (CR) trials. Eight randomized controlled trials (RCTs) with five- or six-month assessments were pooled, including 749 participants randomized to CR and 594 participants randomized to non-CR (NoCR). Statistical models compared means and variances by CR assignment and exercise assignment or select subgroups, testing for treatment differences and interactions for mean changes and standard deviations. Continuous equivalents of dichotomized variables were also fit. Models used a Bayesian framework, and posterior estimates were presented as means and 95% Bayesian credible intervals (BCI). At baseline, participants were 67.7 (SD = 5.4) years, 69.8% female, and 79.2% white, with a BMI of 33.9 (4.4) kg/m2. CR participants reduced body mass [CR: -7.7 (5.8) kg vs. NoCR: -0.9 (3.5) kg] and increased gait speed [CR: +0.10 (0.16) m/s vs. NoCR: +0.07 (0.15) m/s] more than NoCR participants. There were no treatment differences in gait speed change standard deviations [CR-NoCR: -0.002 m/s (95% BCI: -0.013, 0.009)]. Significant mean interactions between CR and exercise assignment [0.037 m/s (95% BCI: 0.004, 0.070)], BMI [0.034 m/s (95% BCI: 0.003, 0.066)], and IL-6 [0.041 m/s (95% BCI: 0.009, 0.073)] were observed, while variance interactions were observed between CR and exercise assignment [-0.458 m/s (95% BCI: -0.783, -0.138)], age [-0.557 m/s (95% BCI: -0.900, -0.221)], and gait speed [-0.530 m/s (95% BCI: -1.018, -0.062)] subgroups. Caloric restriction plus exercise yielded the greatest gait speed benefit among older adults with obesity. High BMI and IL-6 subgroups also improved gait speed in response to CR. Results provide a novel statistical framework for identifying treatment heterogeneity in RCTs.

Air quality improvement and cognitive decline in community-dwelling older women in the United States: A longitudinal cohort study.

BACKGROUND: Late-life exposure to ambient air pollution is a modifiable risk factor for dementia, but epidemiological studies have shown inconsistent evidence for cognitive decline. Air quality (AQ) improvement has been associated with improved cardiopulmonary health and decreased mortality, but to the best of our knowledge, no studies have examined the association with cognitive function. We examined whether AQ improvement was associated with slower rate of cognitive decline in older women aged 74 to 92 years. METHODS AND FINDINGS: We studied a cohort of 2,232 women residing in the 48 contiguous US states that were recruited from more than 40 study sites located in 24 states and Washington, DC from the Women's Health Initiative (WHI) Memory Study (WHIMS)-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO) study. They were predominantly non-Hispanic White women and were dementia free at baseline in 2008 to 2012. Measures of annual (2008 to 2018) cognitive function included the modified Telephone Interview for Cognitive Status (TICSm) and the telephone-based California Verbal Learning Test (CVLT). We used regionalized universal kriging models to estimate annual concentrations (1996 to 2012) of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) at residential locations. Estimates were aggregated to the 3-year average immediately preceding (recent exposure) and 10 years prior to (remote exposure) WHIMS-ECHO enrollment. Individual-level improved AQ was calculated as the reduction from remote to recent exposures. Linear mixed effect models were used to examine the associations between improved AQ and the rates of cognitive declines in TICSm and CVLT trajectories, adjusting for sociodemographic (age; geographic region; race/ethnicity; education; income; and employment), lifestyle (physical activity; smoking; and alcohol), and clinical characteristics (prior hormone use; hormone therapy assignment; depression; cardiovascular disease (CVD); hypercholesterolemia; hypertension; diabetes; and body mass index [BMI]). For both PM2.5 and NO2, AQ improved significantly over the 10 years before WHIMS-ECHO enrollment. During a median of 6.2 (interquartile range [IQR] = 5.0) years of follow-up, declines in both general cognitive status (ß = -0.42/year, 95% CI: -0.44, -0.40) and episodic memory (ß = -0.59/year, 95% CI: -0.64, -0.54) were observed. Greater AQ improvement was associated with slower decline in TICSm (ßPM2.5improvement = 0.026 per year for improved PM2.5 by each IQR = 1.79 µg/m3 reduction, 95% CI: 0.001, 0.05; ßNO2improvement = 0.034 per year for improved NO2 by each IQR = 3.92 parts per billion [ppb] reduction, 95% CI: 0.01, 0.06) and CVLT (ßPM2.5 improvement = 0.070 per year for improved PM2.5 by each IQR = 1.79 µg/m3 reduction, 95% CI: 0.02, 0.12; ßNO2improvement = 0.060 per year for improved NO2 by each IQR = 3.97 ppb reduction, 95% CI: 0.005, 0.12) after adjusting for covariates. The respective associations with TICSm and CVLT were equivalent to the slower decline rate found with 0.9 to 1.2 and1.4 to 1.6 years of younger age and did not significantly differ by age, region, education, Apolipoprotein E (ApoE) e4 genotypes, or cardiovascular risk factors. The main limitations of this study include measurement error in exposure estimates, potential unmeasured confounding, and limited generalizability. CONCLUSIONS: In this study, we found that greater improvement in long-term AQ in late life was associated with slower cognitive declines in older women. This novel observation strengthens the epidemiologic evidence of an association between air pollution and cognitive aging.

Ambient air pollution exposure and increasing depressive symptoms in older women: The mediating role of the prefrontal cortex and insula.

Exposures to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) have been associated with the emergence of depressive symptoms in older adulthood, although most studies used cross-sectional outcome measures. Elucidating the brain structures mediating the adverse effects can strengthen the causal role between air pollution and increasing depressive symptoms. We evaluated whether smaller volumes of brain structures implicated in late-life depression mediate associations between ambient air pollution exposure and changes in depressive symptoms. This prospective study included 764 community-dwelling older women (aged 81.6 ± 3.6 in 2008-2010) from the Women's Health Initiative Memory Study (WHIMS) Magnetic Resonance Imaging study (WHIMS-MRI; 2005-06) and WHIMS-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO; 2008-16). Three-year average annual mean concentrations (scaled by interquartile range [IQR]) of ambient PM2.5 (in µg/m3; IQR = 3.14 µg/m3) and NO2 (in ppb; IQR = 7.80 ppb) before WHIMS-MRI were estimated at participants' addresses via spatiotemporal models. Mediators included structural brain MRI-derived grey matter volumes of the prefrontal cortex and structures of the limbic-cortical-striatal-pallidal-thalamic circuit. Depressive symptoms were assessed annually by the 15-item Geriatric Depression Scale. Structural equation models were constructed to estimate associations between exposure, structural brain volumes, and depressive symptoms. Increased exposures (by each IQR) were associated with greater annual increases in depressive symptoms (ßPM2.5 = 0.022; 95% Confidence Interval (CI) = 0.003, 0.042; ßNO2 = 0.019; 95% CI = 0.001, 0.037). The smaller volume of prefrontal cortex associated with exposures partially mediated the associations of increased depressive symptoms with NO2 (8%) and PM2.5 (13%), and smaller insula volume associated with NO2 contributed modestly (13%) to the subsequent increase in depressive symptoms. We demonstrate the first evidence that the smaller volumes of the prefrontal cortex and insula may mediate the subsequent increases in depressive symptoms associated with late-life exposures to NO2 and PM2.5.

Association of improved air quality with lower dementia risk in older women.

Late-life ambient air pollution is a risk factor for brain aging, but it remains unknown if improved air quality (AQ) lowers dementia risk. We studied a geographically diverse cohort of older women dementia free at baseline in 2008 to 2012 (n = 2,239, aged 74 to 92). Incident dementia was centrally adjudicated annually. Yearly mean concentrations of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) were estimated using regionalized national universal kriging models and averaged over the 3-y period before baseline (recent exposure) and 10 y earlier (remote exposure). Reduction from remote to recent exposures was used as the indicator of improved AQ. Cox proportional hazard ratios (HRs) for dementia risk associated with AQ measures were estimated, adjusting for sociodemographic, lifestyle, and clinical characteristics. We identified 398 dementia cases during follow up (median = 6.1 y). PM2.5 and NO2 reduced significantly over the 10 y before baseline. Larger AQ improvement was associated with reduced dementia risks (HRPM2.5 0.80 per 1.78 µg/m3, 95% CI 0.71-0.91; HRNO2 0.80 per 3.91 parts per billion, 95% CI 0.71-0.90), equivalent to the lower risk observed in women 2.4 y younger at baseline. Higher PM2.5 at baseline was associated with higher dementia risk (HRPM2.5 1.16 per 2.90 µg/m3, 95% CI 0.98-1.38), but the lower dementia risk associated with improved AQ remained after further adjusting for recent exposure. The observed associations did not substantially differ by age, education, geographic region, Apolipoprotein E e4 genotypes, or cardiovascular risk factors. Long-term AQ improvement in late life was associated with lower dementia risk in older women.

Changes in Body Weight and Knee Pain in Adults With Knee Osteoarthritis Three-and-a-Half Years After Completing Diet and Exercise Interventions: Follow-Up Study for a Single-Blind, Single-Center, Randomized Controlled Trial.

OBJECTIVE: To determine whether long-term diet (D) and exercise (E) interventions, alone or in combination (D+E), have beneficial effects for older adults with knee osteoarthritis (OA) 3.5 years after the interventions end. METHODS: This is a secondary analysis of a subset (n = 94) of the first 184 participants who had successfully completed the Intensive Diet and Exercise in Arthritis (IDEA) trial (n = 399) and who consented to follow-up testing. Participants were older (age ≥55 years), overweight, and obese adults with radiographic and symptomatic knee OA in at least 1 knee who completed 1.5-year D+E (n = 27), D (n = 35), or E (n = 32) interventions and returned for 5-year follow-up testing an average of 3.5 years later. RESULTS: During the 3.5-years following the interventions, weight regain in D+E and D was 5.9 kg (7%) and 3.1 kg (4%), respectively, with a 1-kg (1%) weight loss in E. Compared to baseline, weight (D+E -3.7 kg [P = 0.0007], D -5.8 kg [P < 0.0001], E -2.9 kg [P = 0.003]) and Western Ontario and McMaster Universities Osteoarthritis Index pain subscale scores (D+E -1.2 [P = 0.03], D -1.5 [P = 0.001], E -1.6 [P = 0.0008]) were lower in each group at the 5-year follow-up. The effect of group assignment at the 5-year follow-up was significant for body weight, with D being less than E (-3.5 kg; P = 0.04). CONCLUSION: Older adults with knee OA who completed 1.5-year D or D+E interventions experienced partial weight regain 3.5 years later; yet, relative to baseline, they preserved statistically significant changes in weight loss and reductions in knee pain.

Predictors of Clinically Meaningful Gait Speed Response to Caloric Restriction Among Older Adults Participating in Weight Loss Interventions.

BACKGROUND: The purpose of this study was to examine whether select baseline characteristics influenced the likelihood of an overweight/obese, older adult experiencing a clinically meaningful gait speed response (±0.05 m/s) to caloric restriction (CR). METHODS: Individual level data from 1 188 older adults participating in 8, 5/6-month, weight loss interventions were pooled, with treatment arms collapsed into CR (n = 667) or no CR (NoCR; n = 521) categories. Exercise assignment was equally distributed across groups (CR: 65.3% vs NoCR: 65.4%) and did not interact with CR (p = .88). Poisson risk ratios (95% confidence interval [CI]) were used to examine whether CR assignment interacted with select baseline characteristic subgroups: age (≥65 years), sex (female/male), race (Black/White), body mass index (BMI; ≥35 kg/m2), comorbidity (diabetes, hypertension, cardiovascular disease) status (yes/no), gait speed (<1.0 m/s), or inflammatory burden (C-reactive protein ≥3 mg/L, interleukin-6 ≥2.5 pg/mL) to influence achievement of ±0.05 m/s fast-paced gait speed change. Main effects were also examined. RESULTS: The study sample (69.5% female, 80.1% White) was 67.6 ± 5.3 years old with a BMI of 33.8 ± 4.4 kg/m2. Average weight loss achieved in the CR versus NoCR group was -8.3 ± 5.9% versus -1.1 ± 3.8%; p < .01. No main effect of CR was observed on the likelihood of achieving a clinically meaningful gait speed improvement (risk ratio [RR]: 1.09 [95% CI: 0.93, 1.27]) or gait speed decrement (RR: 0.77 [95% CI: 0.57, 1.04]). Interaction effects were nonsignificant across all subgroups. CONCLUSION: The proportion of individuals experiencing a clinically meaningful gait speed change was similar for CR and NoCR conditions. This finding is consistent across several baseline subgroupings.

Associations Between Air Pollution Exposure and Empirically Derived Profiles of Cognitive Performance in Older Women.

BACKGROUND: Elucidating associations between exposures to ambient air pollutants and profiles of cognitive performance may provide insight into neurotoxic effects on the aging brain. OBJECTIVE: We examined associations between empirically derived profiles of cognitive performance and residential concentrations of particulate matter of aerodynamic diameter < 2.5 (PM2.5) and nitrogen dioxide (NO2) in older women. METHOD: Women (N = 2,142) from the Women's Health Initiative Study of Cognitive Aging completed a neuropsychological assessment measuring attention, visuospatial, language, and episodic memory abilities. Average yearly concentrations of PM2.5 and NO2 were estimated at the participant's addresses for the 3 years prior to the assessment. Latent profile structural equation models identified subgroups of women exhibiting similar profiles across tests. Multinomial regressions examined associations between exposures and latent profile classification, controlling for covariates. RESULT: Five latent profiles were identified: low performance across multiple domains (poor multi-domain; n = 282;13%), relatively poor verbal episodic memory (poor memory; n = 216; 10%), average performance across all domains (average multi-domain; n = 974; 45%), superior memory (n = 381; 18%), and superior attention (n = 332; 15%). Using women with average cognitive ability as the referent, higher PM2.5 (per interquartile range [IQR] = 3.64µg/m3) was associated with greater odds of being classified in the poor memory (OR = 1.29; 95% Confidence Interval [CI] = 1.10-1.52) or superior attention (OR = 1.30; 95% CI = 1.10-1.53) profiles. NO2 (per IQR = 9.86 ppb) was associated with higher odds of being classified in the poor memory (OR = 1.38; 95% CI = 1.17-1.63) and lower odds of being classified with superior memory (OR = 0.81; 95% CI = 0.67-0.97). CONCLUSION: Exposure to PM2.5 and NO2 are associated with patterns of cognitive performance characterized by worse verbal episodic memory relative to performance in other domains.