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ImportanceThere are consistent data demonstrating that socioeconomic disadvantage is associated with risk of premature mortality, but research on the relationship between neighborhood socioeconomic factors and premature mortality is limited. Most studies evaluating the association between neighborhood socioeconomic status (SES) and mortality have used a single assessment of SES during middle to older adulthood, thereby not considering the contribution of early life neighborhood SES.ObjectiveTo investigate the association of life course neighborhood SES and premature mortality.Design, Setting, and ParticipantsThis cohort study included Black and White participants of the multicenter Atherosclerosis Risk in Communities Study, a multicenter study conducted in 4 US communities: Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and the northwestern suburbs of Minneapolis, Minnesota. Participants were followed up for a mean (SD) of 18.8 (5.7) years (1996-2020). Statistical analysis was performed from March 2023 through May 2024.ExposureParticipants’ residential addresses during childhood, young adulthood, and middle adulthood were linked with US Census–based socioeconomic indicators to create summary neighborhood SES scores for each of these life epochs. Neighborhood SES scores were categorized into distribution-based tertiles.Main Outcomes and MeasuresPremature death was defined as all-cause mortality occurring before age 75 years. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs.ResultsAmong 12 610 study participants, the mean (SD) age at baseline was 62.6 (5.6) years; 3181 (25.2%) were Black and 9429 (74.8%) were White; and 7222 (57.3%) were women. The lowest, compared with the highest tertile, of neighborhood SES score in middle adulthood was associated with higher risk of premature mortality (HR, 1.28; 95% CI, 1.07-1.54). Similar associations were observed for neighborhood SES in young adulthood among women (HR, 1.25; 95% CI, 1.00-1.56) and neighborhood SES in childhood among White participants (HR, 1.25; 95% CI, 1.01-1.56). Participants whose neighborhood SES remained low from young to middle adulthood had an increased premature mortality risk compared with those whose neighborhood SES remained high (HR, 1.25; 95% CI, 1.05-1.49).Conclusions and RelevanceIn this study, low neighborhood SES was associated with premature mortality. The risk of premature mortality was greatest among individuals experiencing persistently low neighborhood SES from young to middle adulthood. Place-based interventions that target neighborhood social determinants of health should be designed from a life course perspective that accounts for early-life socioeconomic inequality.

Importance Plasma biomarkers show promise for identifying Alzheimer disease (AD) neuropathology and neurodegeneration, but additional examination among diverse populations and throughout the life course is needed. Objective To assess temporal plasma biomarker changes and their association with all-cause dementia, overall and among subgroups of community-dwelling adults. Design, Setting, and Participants In 1525 participants from the US-based Atherosclerosis Risk in Communities (ARIC) study, plasma biomarkers were measured using stored specimens collected in midlife (1993-1995, mean age 58.3 years) and late life (2011-2013, mean age 76.0 years; followed up to 2016-2019, mean age 80.7 years). Midlife risk factors (hypertension, diabetes, lipids, coronary heart disease, cigarette use, and physical activity) were assessed for their associations with change in plasma biomarkers over time. The associations of biomarkers with incident all-cause dementia were evaluated in a subpopulation (n = 1339) who were dementia-free in 2011-2013 and had biomarker measurements in 1993-1995 and 2011-2013. Exposure Plasma biomarkers of amyloid-β 42 to amyloid-β 40 (Aβ42:Aβ40) ratio, phosphorylated tau at threonine 181 (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were measured using the Quanterix Simoa platform. Main Outcomes and Measures Incident all-cause dementia was ascertained from January 1, 2012, through December 31, 2019, from neuropsychological assessments, semiannual participant or informant contact, and medical record surveillance. Results Among 1525 participants (mean age, 58.3 [SD, 5.1] years), 914 participants (59.9%) were women, and 394 participants (25.8%) were Black. A total of 252 participants (16.5%) developed dementia. Decreasing Aβ42:Aβ40 ratio and increasing p-tau181, NfL, and GFAP were observed from midlife to late life, with more rapid biomarker changes among participants carrying the apolipoprotein E epsilon 4 ( APOE ε4) allele. Midlife hypertension was associated with a 0.15-SD faster NfL increase and a 0.08-SD faster GFAP increase per decade; estimates for midlife diabetes were a 0.11-SD faster for NfL and 0.15-SD faster for GFAP. Only AD-specific biomarkers in midlife demonstrated long-term associations with late-life dementia (hazard ratio per SD lower Aβ42:Aβ40 ratio, 1.11; 95% CI, 1.02-1.21; per SD higher p-tau181, 1.15; 95% CI, 1.06-1.25). All plasma biomarkers in late life had statistically significant associations with late-life dementia, with NfL demonstrating the largest association (1.92; 95% CI, 1.72-2.14). Conclusions and Relevance Plasma biomarkers of AD neuropathology, neuronal injury, and astrogliosis increase with age and are associated with known dementia risk factors. AD-specific biomarkers’ association with dementia starts in midlife whereas late-life measures of AD, neuronal injury, and astrogliosis biomarkers are all associated with dementia.

AbstractINTRODUCTIONThe contribution of neuropsychological assessments to risk assessment for incident dementia is underappreciated.METHODSWe analyzed neuropsychological testing results in dementia‐free participants in the Atherosclerosis Risk in Communities (ARIC) study. We examined associations of index domain–specific neuropsychological test performance with incident dementia using cumulative incidence curves and Cox proportional hazards models.RESULTSAmong 5296 initially dementia‐free participants (mean [standard deviation] age of 75.8 [5.1] years; 60.1% women, 22.2% Black) over a median follow‐up of 7.9 years, the covariate‐adjusted hazard ratio varied substantially depending on the pattern of domain‐specific performance and age, in an orderly manner from single domain language abnormalities (lowest risk) to single domain executive or memory abnormalities, to multidomain abnormalities including memory (highest risk).DISCUSSIONBy identifying normatively defined cognitive abnormalities by domains based on neuropsychological test performance, there is a conceptually orderly and age‐sensitive spectrum of risk for incident dementia that provides valuable information about the likelihood of progression.Highlights Domain‐specific cognitive profiles carry enhanced prognostic value compared to mild cognitive impairment. Single‐domain non‐amnestic cognitive abnormalities have the most favorable prognosis. Multidomain amnestic abnormalities have the greatest risk for incident dementia. Patterns of domain‐specific risks are similar by sex and race.

Background: White matter hyperintensities (WMH) are associated with risk of dementia and stroke, so are an important therapeutic target for clinical trials. The cost of broad MRI screening to identify those individuals with significant WMH, however, limits the feasibility of designing clinical trials which target WMH presence and which test treatments that slow progression. Hypothesis: A low-cost retinal or clinical screening measure prior to an MRI screening stage reduces the cost of recruiting persons with significant WMH burden in a hypothetical clinical trial vs an MRI-only screening design. Method: Data were from participants in the Atherosclerosis Risk in Communities-Neurocognitive study with clinical, retinal and WMH measurements ( N = 1311) at ages 53-70 years. Significant WMH burden was defined as a Cardiovascular Health Study score >2. Three low-cost pre-screening measures were assessed: (1) retinal: a score incorporating multiple markers of abnormal retinal vasculature, (2) clinical: a score incorporating hypertension, diabetes, and age, (3) combined retinal-clinical: a score incorporating retinal and clinical factors. Given a prior published target sample for a WMH clinical trial (N= 646), we calculated a theoretical screening sample size based on the proportion of each pre-screening measure in the population multiplied by the proportion of significant WMH burden among those with a prevalent pre-screening feature. Total recruitment cost was calculated using standard retinal ($32.50) and MRI ($650) cost estimates. Results: Compared to the estimated cost of MRI-only screening (>$4.24M, requiring MRI screening 6,526 participants), pre-screening for a high clinical score reduced total cost to $2.47M, but increased the initial screening group to 52,778 participants, of whom 3,801 would be screened by MRI). A high retinal-clinical score cutoff reduced costs to $2.9M while only requiring 13,572 screened participants (of these only 3,801 would require MRI). Conclusion: A 2-stage recruitment design with a low-cost pre-screening retinal and clinical measure is a promising approach, resulting in a reduction of theoretical recruitment costs for recruiting persons with significant WMH burden compared to an MRI-only design.

Abstract We hypothesized that poorer cerebral perfusion could impair mobility, particularly at lower systolic blood pressure (SBP). Cerebral perfusion was measured via arterial spin-labelled (ASL)-MRI in community-dwelling adults of the Mayo Clinic Study of Aging. Usual-pace gait speed was assessed over 5.6 meters on an electronic mat. Linear regression models estimated cross-sectional gait speed associations with ASL and modifying effects of age and SBP, adjusting for sex and body mass index. Results report differences in gait speed (meter/second) per standard deviation (SD) lower ASL or SBP (mean=139.1 mmHg, SD=19.7 mmHg). Among 479 participants (aged 31-94 years; mean age 67.6 years; 44% women; mean gait speed 1.17m/s), relationships of ASL with gait speed varied by age and SBP (ASL-x-age interaction: p<.007; ASL-x-SBP interaction: p<.007). At age 65, 75 or 85 years and a SBP of 120mmHg, each SD lower ASL was associated with a 0.04 m/s (0.01,0.07), 0.07 m/s (0.04,0.10), and 0.09 m/s (0.05,0.13) slower gait speed at respective ages. At age 65, 75 or 85 years with low ASL (1 SD below the mean), each SD lower SBP was associated with 0.06 (0.02,0.09) m/s, 0.03 (0.01,0.06) m/s or .01 (-0.02,0.04) m/s slower gait speed, respectively. With high ASL (mean ASL+1SD), lower SBP trended towards faster gait at older age, e.g. estimated gait speed was 0.04 m/s (0.00,0.09) faster for each SD lower SBP at age 85years. Poorer cerebral perfusion may contribute to slower gait, particularly with lower SBP. The interrelations of cerebral perfusion, SBP, and age with mobility merit further study.

At visit 3 (1993–1995) of the ARIC Study, 1.5T brain MRI was completed in 1,881 stroke-free participants (Mean age = 62.9±4.9, 50% Black). Cox regression examined associations between infarct group [infarct-free (referent; n = 1,611), smaller only (<3 mm; n = 50), larger only (≥3 mm but <20 mm; n = 185), both (n = 35)] and up to 25-year incident dementia (n = 539). Participants with both infarcts were over 2.5 times more likely to develop dementia [HR = 2.61; 95% CI = 1.44, 4.72]. Smaller only (HR = 1.22; 95% CI = 0.70, 2.13) and larger only (HR = 1.27; 95% CI = 0.92, 1.74) groups showed associations with wide confidence intervals, unsupported statistically. A late midlife infarct profile including smaller and larger infarcts may represent particular vulnerability to dementia risk.

Abstract Objectives Peritoneal metastasis (PM) from appendiceal cancer or colorectal cancer (CRC) has significant morbidity and limited survival. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a minimally invasive approach to treat PM. We aim to conduct a dose-escalation trial of mitomycin C (MMC)-PIPAC combined with systemic chemotherapy (FOLFIRI) in patients with PM from appendiceal cancer or CRC. Methods This is a multicenter Phase I study of MMC-PIPAC (NCT04329494). Inclusion criteria include treatment with at least 4 months of first- or second-line systemic chemotherapy with ineligibility for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Exclusion criteria are: progression on chemotherapy; extraperitoneal metastases; systemic chemotherapy intolerance; bowel obstruction; or poor performance status (ECOG>2). Escalating MMC-PIPAC doses (7–25 mg/m 2 ) will be administered in combination with standard dose systemic FOLFIRI. Safety evaluation will be performed on 15 patients (dose escalation) and six expansion patients: 21 evaluable patients total. Results The primary endpoints are recommended MMC dose and safety of MMC-PIPAC with FOLFIRI. Secondary endpoints are assessment of response (by peritoneal regression grade score; Response Evaluation Criteria in Solid Tumors [RECIST 1.1], and peritoneal carcinomatosis index), progression free survival, overall survival, technical failure rate, surgical complications, conversion to curative-intent CRS-HIPEC, patient-reported outcomes, and functional status. Longitudinal blood and tissue specimens will be collected for translational correlatives including pharmacokinetics, circulating biomarkers, immune profiling, and single-cell transcriptomics. Conclusions This Phase I trial will establish the recommended dose of MMC-PIPAC in combination with FOLFIRI. Additionally, we expect to detect an early efficacy signal for further development of this therapeutic combination.

Abstract Background This study aimed to examine if the association of cerebral perfusion with gait speed differs across systolic blood pressure (SBP) and age. Methods Cerebral perfusion was measured via arterial spin labeled (ASL)-MRI among community-dwelling adults aged 31–94 years in the population-based Mayo Clinic Study of Aging. Usual gait speed was assessed over 5.6 meters on an electronic mat. Sex- and body mass index (BMI)-adjusted linear regression models estimated cross-sectional gait speed associations with ASL and modifying effects of age and SBP using 3-way and 2-way interaction terms between continuous age, SBP, and ASL. Results report estimated differences in gait speed per standard deviation (SD) lower ASL for exemplar SBPs and ages. Results Among 479 participants (mean age 67.6 years; 44% women; mean gait speed 1.17 m/s), ASL relations to gait speed varied by age (ASL-x–age interaction: p = .001) and SBP (ASL-x–SBP interaction: p = .009). At an SBP of 120 mmHg, each SD lower ASL was associated with a 0.04 m/s (95% confidence interval [CI]: 0.01, 0.07) slower gait speed at 65 years, 0.07 m/s (0.04, 0.10) at 75 years, and 0.09 m/s (0.05, 0.13) at 85 years. At an SBP of 140 mmHg, ASL associations with gait speed were attenuated to 0.01 (−0.01, 0.04), 0.04 (0.02, 0.06), and 0.06 (0.04, 0.09) m/s slower gait speed at ages 65, 75, and 85, respectively. Conclusion Poorer cerebral perfusion is associated with clinically meaningful slower gait speeds, particularly with older age, while higher perfusion markedly attenuates age differences in gait speed.

AbstractBackgroundPhysical frailty is associated with increased risk for dementia and other neurologic sequelae. However, the neurobiological changes underlying frailty and frailty risk remain unknown. We examined the association of cerebral white matter structure with current and future frailty.MethodsAtherosclerosis Risk in Communities Study Neurocognitive Study participants who underwent 3T brain MRI were included. Frailty status was classified according to the Fried criteria. Cerebral white matter integrity was defined using white matter hyperintensity (WMH) volume and microstructure, measured using diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD). Multivariable linear regression was used to relate baseline frailty to white matter structure; multivariable logistic regression was used to relate baseline white matter to frailty risk among participants nonfrail at baseline.ResultsIn the cross-sectional analysis (N = 1 754; mean age: 76 years), frailty was associated with greater WMH volume, lower FA, and greater MD. These associations remained consistent after excluding participants with a history of stroke or dementia. Among participants nonfrail at baseline who completed follow-up frailty assessment (N = 1 379; 6.6-year follow-up period), each standard deviation increase in WMH volume was associated with 1.46 higher odds of frailty at follow-up. Composite FA and MD measures were not associated with future frailty; however, secondary analyses found several significant white matter tract-specific associations with frailty risk.ConclusionThe current study demonstrates a robust association of WMH volume with current and future frailty. Although measures of white matter microstructure were altered in frail individuals, these measures were not generally associated with progression from nonfrail to frail status.