Neighborhood Socioeconomic Disadvantage Across the Life Course and Premature Mortality.

Importance: There 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. Objective: To investigate the association of life course neighborhood SES and premature mortality. Design, Setting, and Participants: This 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. Exposure: Participants' 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 Measures: Premature 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. Results: Among 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 Relevance: In 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.

Psychosocial Health and the Association Between Cerebral Small Vessel Disease Markers With Dementia: The ARIC Study.

BACKGROUND: Associations between magnetic resonance imaging markers of cerebral small vessel disease (CSVD) and dementia risk in older adults have been established, but it remains unclear how lifestyle factors, including psychosocial health, may modify this association. METHODS: Social support and social isolation were assessed among participants of the community-based ARIC (Atherosclerosis Risk in Communities) Study, via self-reported questionnaires (1990-1992). Following categorization of both factors, participants were classified as having strong or poor mid-life social relationships. At visit 5 (2011-2013), participants underwent 3T brain magnetic resonance imaging quantifying CSVD measures: white matter hyperintensity volume, microbleeds (subcortical), infarcts (lacunar), and white matter integrity (diffusion tensor imaging). Incident dementia cases were identified from the time of imaging through December 31, 2020 with ongoing surveillance. Associations between CSVD magnetic resonance imaging markers and incident dementia were evaluated using Cox proportional-hazard regressions adjusted for demographic and additional risk factors (from visit 2). Effect modification by mid-life social relationships was evaluated. RESULTS: Of the 1977 participants with magnetic resonance imaging, 1617 participants (60.7% women; 26.5% Black participants; mean age at visit 2, 55.4 years) were examined. In this sample, mid-life social relationships significantly modified the association between white matter hyperintensity volume and dementia risk (P interaction=0.001). Greater white matter hyperintensity volume was significantly associated with risk of dementia in all participants, yet, more substantially in those with poor (hazard ratio, 1.84 [95% CI, 1.49-2.27]) versus strong (hazard ratio, 1.26 [95% CI, 1.08-1.47]) mid-life social relationships. Although not statistically significant, subcortical microbleeds in participants with poor mid-life social relationships were associated with a greater risk of dementia, relative to those with strong social relationships, in whom subcortical microbleeds were no longer associated with elevated dementia risk. CONCLUSIONS: The elevated risk of dementia associated with CSVD may be reduced in participants with strong mid-life social relationships. Future studies evaluating psychosocial health through the life course and the mechanisms by which they modify the relationship between CSVD and dementia are needed.

Effect of Hearing Intervention versus Health Education Control on Fatigue: A Secondary Analysis of the ACHIEVE study.

BACKGROUND: Fatigue is a common complaint among older adults with hearing loss. The impact of addressing hearing loss on fatigue symptoms has not been studied in a randomized controlled trial. In a secondary analysis of the ACHIEVE study, we investigated the effect of hearing intervention versus health education control on 3-year change in fatigue in community-dwelling older adults with hearing loss. METHODS: Participants aged 70-84 years old with untreated hearing loss recruited across 4 study sites in the United States (Forsyth County, NC; Jackson, MS; Minneapolis, MN; Washington County, MD) were randomized (1:1) to hearing intervention or health education control and followed for 3 years. Three-year change in fatigue symptoms was measured by 2 instruments (RAND-36 and PROMIS). We estimated the intervention effect as the difference in the 3-year change in fatigue between intervention and control groups using a linear mixed-effects model under the intention-to-treat principle. RESULTS: Participants (n=977) had a mean age (SD) of 76.8 (4.0) years, were 53.5% female and 87.8% White. Over 3 years, a beneficial effect of the hearing intervention versus health education control on fatigue was observed using the RAND-fatigue score (ß= -0.12 [95% CI -0.22, -0.02]). Estimates also suggested beneficial effect of hearing intervention on fatigue when measured by the PROMIS fatigue score (ß= -0.32 [95% CI -1.15, 0.51]). CONCLUSIONS: Our findings suggest that hearing intervention may reduce fatigue over 3 years among older adults with hearing loss.

Changes in Alzheimer Disease Blood Biomarkers and Associations With Incident All-Cause Dementia.

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-ß 42 to amyloid-ß 40 (Aß42:Aß40) 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 Aß42:Aß40 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 (APOEε4) 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 Aß42:Aß40 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.

Lung Function and Brain MRI Outcomes in the Atherosclerosis Risk in Communities Neurocognitive Study.

Background: Brain imaging studies may provide etiologic insight into observed links between lung function and dementia and stroke. Objective: We evaluated associations of lung function measures with brain MRI markers of vascular and neurodegenerative disease in the ARIC Neurocognitive Study, as few studies have examined the associations. Methods: Lung function was measured at participants' midlife in 1990-1992 (mean age = 56±5 years) and later-life in 2011-2013 (mean age = 76±5 years), and brain MRI was performed in 2011-2013. Linear regression models were used to examine the associations of lung function with brain and white matter hyperintensity (WMH) volumes, and logistic regression models were used for cerebral infarcts and microbleeds, adjusting for potential confounders. Results: In cross-sectional analysis (i.e., examining later-life lung function and MRI markers, n = 1,223), higher forced-expiratory volume in one second (FEV1) and forced vital capacity (FVC) were associated with larger brain and lower WMH volumes [e.g., 8.62 (95% CI:2.54-14.71) cm3 greater total brain volume per one-liter higher FEV1]. No association was seen with microbleeds in the overall sample, but higher FVC was associated with lower odds of microbleeds in never-smokers and higher odds in ever-smokers. In the cross-temporal analysis (i.e., associations with midlife lung function, n = 1,787), higher FVC levels were significantly associated with lower later-life brain volumes. Conclusions: Our results support modest associations of better lung function with less neurodegenerative and cerebrovascular pathology, although findings for microbleeds were unexpected in ever-smokers.

Differences in [123I]Ioflupane Striatal Binding Between African American and White Patients.

Ethnic differences exist among patients with Parkinson disease (PD). PD is more common in the White than the African American population. This study aimed to explore whether differences exist in [123I]ioflupane binding, which reflects dopamine transporter binding, between African American and White individuals. Methods: Medical charts were reviewed for patients who underwent [123I]ioflupane SPECT imaging as part of routine practice in a single academic medical center. All images were visually graded as showing normal or abnormal presynaptic dopaminergic function (normal or abnormal scan status). Quantitative [123I]ioflupane uptake as measured by the specific binding ratios in the right and left striata and their subregions (caudate nucleus and anterior and posterior putamen) and by bilateral putamen-to-caudate ratios were compared between African American and White patients using multiple linear regression adjusted for age, sex, and abnormal scan status. Additional models included an ethnicity-by-abnormal-scan-status interaction term to determine whether abnormal scan status was modulated by ethnicity effect. Results: The percentage of patients with abnormal scan status was comparable between African American and White patients. Compared with White patients (n = 173), African American patients (n = 82) had statistically significantly higher uptake as measured by specific binding ratios in the right and left striata and some of their subregions (right and left caudate nuclei and right posterior putamen). Ethnicity-by-abnormal-scan-status interactions were not statistically supported for any models. Conclusion: We observed differences in [123I]ioflupane binding between African American and White patients independent of presynaptic dopaminergic dysfunction status. Future studies are needed to examine whether and how ethnicity affects dopamine transporter binding activities and its clinical relevance.

Effects of post-curing duration on the mechanical properties of complex 3D printed geometrical parts.

This study aims to assess the efficacy of post-curing guidance supplied by 3D printing resin manufacturers. Current guidance applies generically to all geometries with the caveat that post-curing should be extended for 'large' or 'complex' geometries but specific guidance is not provided. Two vat-polymerisation 3D printers (Form3B, Figure 4 Standalone) were used to print test models in 6 biocompatible resins (Pro Black, Med White, Med Amber, Biomed Black, Biomed White, Biomed Amber). The test model is of a complex geometry whilst also housing ISO 527 test specimens in concentric layers. Two separate intervals of curing were applied (100%, 500% stated guidance) creating different curing treatments of the specimens throughout the model. Post processed test models were disassembled and pull testing performed on each of the specimens to assess the mechanical properties. The analysis showed that extending the curing duration had significant effects on the mechanical properties of some materials but not all. The layers of the model had a significant effect except for elongation at break for the Med Amber material. This research demonstrates that generic post-curing guidance regarding UV exposures is not sufficient to achieve homogenous material strength properties for complex geometries. Large variations in mechanical properties throughout the models suggest some material was not fully-cured. This raises a query if such materials as originally marketed as biocompatible are fully cured and therefore safe to use for medical applications involving complex geometries.

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

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

Comprehensive Approach to the Management of Patients with HLHS: Analysis of 100 Consecutive Neonates.

BACKGROUND: We report our comprehensive approach to patients with hypoplastic left heart syndrome (HLHS) and describe our outcomes in 100 consecutive neonates. METHODS: One-hundred consecutive neonates (2015-2023) were stratified into 3 pathways: Pathway(1): 77/100=77% were standard-risk and underwent initial Norwood (Stage 1). Pathway(2): 10/100=10% were high-risk with noncardiac risk factors and underwent initial Hybrid Stage 1. Pathway(3): 13/100=13% were high-risk with cardiac risk factors: 10 underwent initial Hybrid Stage 1 + ventricular assist device insertion (HYBRID+VAD), while 3 underwent primary transplantation. RESULTS: One-year mortality=9/100=9%. Pathway(1): Operative Mortality for initial Norwood (Stage 1)=2/77=2.6%. Of 75 survivors of Norwood (Stage 1): 72 underwent successful Glenn, 2 underwent successful biventricular repair, and 1 underwent successful cardiac transplantation. Pathway(2): Operative Mortality for initial Hybrid Stage 1 without VAD=1/10=10%. Of 9 survivors of Hybrid (Stage 1): 4 underwent successful cardiac transplantation, 2 died while awaiting cardiac transplantation, 3 underwent Comprehensive Stage 2 (with 1 death), and 1 underwent successful biventricular repair. Pathway(3): Of 10 HYBRID+VAD: 7/10=70% underwent successful cardiac transplantation and are alive today and 3/10=30% died on VAD while awaiting transplantation. Median VAD support time=134 days (range=56-226). (Two of three patients who were bridged-to-transplant with prostaglandin underwent successful transplantation and one died while awaiting transplantation.) CONCLUSIONS: A comprehensive approach to the management of patients with HLHS is associated with Operative Mortality after Norwood of 2/77=2.6% and an overall one-year mortality of 9/100=9%. 10/100 patients=10% were stabilized with HYBRID+VAD while awaiting transplantation. VAD facilitates survival on the waiting list during prolonged wait times.

A single-institutional experience with 36 children less than 5 kilograms supported with the Berlin Heart: Comparison of congenital versus acquired heart disease.

OBJECTIVES: We reviewed outcomes in all 36 consecutive children <5 kg supported with the Berlin Heart pulsatile ventricular assist device at the University of Florida, comparing those with acquired heart disease (n = 8) to those with congenital heart disease (CHD) (n = 28). METHODS: The primary outcome was mortality. The Kaplan-Meier method and log-rank tests were used to assess group differences in long-term survival after ventricular assist device insertion. T-tests using estimated survival proportions were used to compare groups at specific time points. RESULTS: Of 82 patients supported with the Berlin Heart at our institution, 49 (49/82 = 59.76%) weighed <10 kg and 36 (36/82 = 43.90%) weighed <5 kg. Of 36 patients <5 kg, 26 (26/36 = 72.22%) were successfully bridged to transplantation. (The duration of support with ventricular assist device for these 36 patients <5 kg was [days]: median = 109, range = 4-305.) Eight out of 36 patients <5 kg had acquired heart disease, and all eight [8/8 = 100%] were successfully bridged to transplantation. (The duration of support with ventricular assist device for these 8 patients <5 kg with acquired heart disease was [days]: median = 50, range = 9-130.) Twenty-eight of 36 patients <5 kg had congenital heart disease. Eighteen of these 28 [64.3%] were successfully bridged to transplantation. (The duration of support with ventricular assist device for these 28 patients <5 kg with congenital heart disease was [days]: median = 136, range = 4-305.) For all 36 patients who weighed <5 kg: 1-year survival estimate after ventricular assist device insertion = 62.7% (95% confidence interval = 48.5-81.2%) and 5-year survival estimate after ventricular assist device insertion = 58.5% (95% confidence interval = 43.8-78.3%). One-year survival after ventricular assist device insertion = 87.5% (95% confidence interval = 67.3-99.9%) in acquired heart disease and 55.6% (95% confidence interval = 39.5-78.2%) in CHD, P = 0.036. Five-year survival after ventricular assist device insertion = 87.5% (95% confidence interval = 67.3-99.9%) in acquired heart disease and 48.6% (95% confidence interval = 31.6-74.8%) in CHD, P = 0.014. CONCLUSION: Pulsatile ventricular assist device facilitates bridge to transplantation in neonates and infants weighing <5 kg; however, survival after ventricular assist device insertion in these small patients is less in those with CHD in comparison to those with acquired heart disease.

Mid-Life Vascular Risk and Rate of Physical Function Decline Among Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Physical function and its decline in older age may be connected to treatable vascular risk factors in mid-life. This study aimed to evaluate whether these factors affect the underlying rate of decline. METHODS: This prospective cohort included 5 481 older adults aged 67-91 in the Atherosclerosis Risk in Communities Study (mean [standard deviation {SD}] age = 75.8 [5.0], 58% women, 21% Black race) without a history of stroke. The main outcome was the rate of Short Physical Performance Battery (SPPB) decline over a median late-life follow-up of 4.8 years. Primary mid-life (aged 45-64) exposures were Visit 1 hypertension (>140/90 mm Hg or treatment), diabetes (>126 mg/dL or treatment), high cholesterol (>240 mg/dL or treatment), and smoking, and number of decades of vascular risk exposure across Visits 1-4. RESULTS: The average adjusted rate of SPPB decline (points per 5 years) for older adults was -0.79 (confidence interval [CI]: -0.87, 0.71) and was accelerated by mid-life hypertension (+57% decline vs normotension: additional decline of -0.47, 95% CI: -0.64, -0.30), diabetes (+73% decline vs no diabetes: additional decline of -0.67, 95% CI: -1.09, -0.24), elevated systolic blood pressure (+17% decline per SD: -0.16, 95% CI: -0.23, -0.10), and elevated fasting blood glucose (+16% decline per SD: -0.015, 95% CI: -0.24, -0.06). Each decade greater mid-life exposure to hypertension (+32% decline: -0.93, 95% CI: -1.25, -0.61) and diabetes (+35% decline: -1.03, 95% CI: -1.68, -0.38) was associated with faster SPPB decline. CONCLUSIONS: Mid-life control of blood pressure and diabetes may offset aging-related functional decline.

Timing of Cognitive Test Score Decline Prior to Incident Dementia Diagnosis in Blacks and Whites: The Atherosclerosis Risk in Communities Neurocognitive Study.

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

Orthostatic Blood Pressure Change, Dizziness, and Risk of Dementia in the ARIC Study.

BACKGROUND: Abnormal orthostatic blood pressure (BP) regulation may result in cerebral hypoperfusion and brain ischemia and contribute to dementia. It may also manifest as early symptoms of the neurodegenerative process associated with dementia. The relationship between the magnitude and timing of orthostatic BP responses and dementia risk is not fully understood. METHODS: We conducted a prospective cohort analysis of the associations of orthostatic BP changes and self-reported orthostatic dizziness with the risk of dementia in the Atherosclerosis Risk in Communities study (ARIC). We calculated changes in BP from the supine to the standing position at 5 measurements taken within 2 minutes after standing during the baseline visit (1987-1989). The primary outcome was adjudicated dementia ascertained through 2019. RESULTS: Among 11 644 participants (mean [SD] age, 54.5 [5.7] years; 54.1% women; 25.9% Black), 2303 dementia cases were identified during a median follow-up of 25.9 years. Large decreases in systolic BP from the supine to standing position measured at the first 2 measurements ≈30 and 50 seconds after standing, but not afterward, were associated with orthostatic dizziness and a higher risk of dementia. Comparing a decrease in systolic BP of ≤-20 or >-20 to -10 mm Hg to stable systolic BP (>-10 to 10 mm Hg) at the first measurement, the adjusted hazard ratios were 1.22 (95% CI, 1.01-1.47) and 1.10 (95% CI, 0.97-1.25), respectively. CONCLUSIONS: Abnormal orthostatic BP regulation, especially abrupt drops in BP within the first minute, might be early risk markers for the development of dementia. Transient early orthostatic hypotension warrants more attention in clinical settings.

Association of Olfaction and Microstructural Integrity of Brain Tissue in Community-Dwelling Adults: Atherosclerosis Risk in Communities Neurocognitive Study.

BACKGROUND AND OBJECTIVES: Research on olfaction and brain neuropathology may help understand brain regions associated with normal olfaction and dementia pathophysiology. To identify early regional brain structures affected in poor olfaction, we examined cross-sectional associations of microstructural integrity of the brain with olfaction in the Atherosclerosis Risk in Communities Neurocognitive Study. METHODS: Participants were selected from a prospective cohort study of community-dwelling adults; selection criteria included the following: evidence of cognitive impairment, participation in a previous MRI study, and a random sample of cognitively normal participants. Microstructural integrity was measured by 2 diffusion tensor imaging (DTI) measures, fractional anisotropy (FA) and mean diffusivity (MD), and olfaction by a 12-item odor identification test at the same visit. Higher FA and MD values indicate better and worse microstructural integrity, respectively, and higher odor identification scores indicate better olfaction. We used brain region-specific linear regression models to examine associations between DTI measures and olfaction, adjusting for potential confounders. RESULTS: Among 1,418 participants (mean age 76 ± 5 years, 41% male, 21% Black race, 59% with normal cognition), the mean olfaction score was 9 ± 2.3. Relevant to olfaction, higher MD in the medial temporal lobe (MTL) regions, namely the hippocampus (ß -0.79 [95% CI -0.94 to -0.65] units lower olfaction score per 1 SD higher MD), amygdala, entorhinal area, and some white matter (WM) tracts connecting to these regions, was associated with olfaction. We also observed associations with MD and WM FA in multiple atlas regions that were not previously implicated in olfaction. The associations between MD and olfaction were particularly stronger in the MTL regions among individuals with mild cognitive impairment (MCI) compared with those with normal cognition (e.g., ßhippocampus -0.75 [95% CI -1.02 to -0.49] and -0.44 [95% CI -0.63 to -0.26] for MCI and normal cognition, respectively, p interaction = 0.004). DISCUSSION: Neuronal microstructural integrity in multiple brain regions, particularly the MTL (the regions known to be affected in early Alzheimer disease), is associated with odor identification ability. Differential associations in the MTL regions among cognitively normal individuals compared with those with MCI may reflect the earlier vs later effects of the dementia pathogenesis. It is likely that some of the associated regions may not have any functional relevance to olfaction.

Association of Plasma Aß42/Aß40 Ratio and Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study.

BACKGROUND AND OBJECTIVES: The objective of this study was to determine the relationship between plasma ß-amyloid (Aß), specifically the ratio of 2 Aß peptides (the Aß42/Aß40 ratio, which correlates with increased accumulation of Aß in the CNS), and late-onset epilepsy (LOE). METHODS: We used Medicare fee-for-service claims codes from 1991 to 2018 to identify cases of LOE among 1,424 Black and White men and women enrolled in the Atherosclerosis Risk in Communities (ARIC) study cohort. The Aß42/Aß40 ratio was calculated from plasma samples collected from ARIC participants in 1993-1995 (age 50-71 years) and 2011-2013 (age 67-90 years). We used survival analysis accounting for the competing risk of death to determine the relationship between late-life plasma Aß42/Aß40, and its change from midlife to late life, and the subsequent development of epilepsy. We adjusted for demographics, the apolipoprotein e4 genotype, and comorbidities, including stroke, dementia, and head injury. A low plasma ratio of 2 Aß peptides, the Aß42/Aß40 ratio, correlates with low CSF Aß42/Aß40 and with increased accumulation of Aß in the CNS. RESULTS: Decrease in plasma Aß42/Aß40 ratio from midlife to late life, but not an isolated measurement of Aß42/Aß40, was associated with development of epilepsy in later life. For every 50% reduction in Aß42/Aß40, there was a 2-fold increase in risk of epilepsy (adjusted subhazard ratio 2.30, 95% CI 1.27-4.17). DISCUSSION: A reduction in plasma Aß42/Aß40 is associated with an increased risk of subsequent epilepsy. Our observations provide a further validation of the link between Aß, hyperexcitable states, and LOE.

Factors Associated with Poor Olfaction and Olfactory Decline in Older Adults in the ARIC Neurocognitive Study.

Olfactory function has significant implications for human health, but few risk factors for olfactory decline have been identified. We examined the factors associated with olfactory status and decline over five years in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study. A 12-item odor identification test was used to assess olfaction in 6053 participants in 2011-2013 (ARIC visit 5, mean age: 75.6, 41% male, 23% Black race) and in 3235 participants in 2016-2017 (visit 6). We used Poisson regression models to examine cross-sectional associations of a range of potential factors with the total odor identification errors (mean errors: 2.8 ± 2.4) in visit 5 participants. We used mixed-effect Poisson regression to examine associations with olfactory decline between visits 5 and 6. We also examined associations with visit 5 anosmia prevalence (847 cases, 14%) and incident anosmia between the two visits (510 cases, 16%) using Poisson models. Older age, male sex, lower education, Black race, APOE ε4 alleles, and diabetes were associated with higher odor identification errors and higher anosmia prevalence, and greater physical activity and hypertension with better olfaction. Age, male sex, lower education, Black race, APOE ε4 allele, and vitamin B12 levels were associated with incident anosmia over 5 years. Older age was associated with faster olfactory decline. Future studies with longer follow-ups are warranted.

Outcomes of Children Supported With Pulsatile Paracorporeal Ventricular Assist Device: Congenital Versus Acquired Heart Disease.

BACKGROUND: We reviewed the outcomes of 82 consecutive pediatric patients (less than 18 years of age) supported with the Berlin Heart ventricular assist device (VAD), comparing those with congenital heart disease (CHD; n = 44) with those with acquired heart disease (AHD; n = 37). METHODS: The primary outcome was mortality after VAD insertion. Kaplan-Meier methods and log-rank tests were used to assess group differences in long-term survival. RESULTS: Forty-four CHD patients were supported (age: median = 65 days, range = 4 days-13.3 years; weight [kg]: median = 4, range = 2.4-42.3). Ten biventricular CHD patients were supported with eight biventricular assist devices (BiVADs), one left ventricular assist device (LVAD) only, and one LVAD converted to BiVAD, while 34 univentricular CHD patients were supported with single ventricle-ventricular assist devices (sVADs). In CHD patients, duration of VAD support was [days]: median = 134, range = 4-554. Of 44 CHD patients, 28 underwent heart transplantation, 15 died on VAD, and one was still on VAD. Thirty-seven AHD patients were supported (age: median = 1.9 years, range = 27 days-17.7 years; weight [kg]: median = 11, range = 3.1-112), including 34 BiVAD and 3 LVAD. In AHD patients, duration of VAD support was [days]: median = 97, range = 4-315. Of 37 AHD patients, 28 underwent transplantation, three died on VAD, five weaned off VAD (one of whom underwent heart transplantation 334 days after weaning), and one was still on VAD. One-year survival after VAD insertion was 59.9% (95% CI = 46.7%-76.7%) in CHD and 88.6% (95% CI = 78.8%-99.8%) in AHD, P = .0004. Five-year survival after VAD insertion was 55.4% (95% CI = 40.8%-75.2%) in CHD and 85.3% (95% CI = 74.0%-98.2%) in AHD, P = .002. CONCLUSIONS: Pulsatile VAD facilitates bridge-to-transplantation in neonates, infants, and children with CHD; however, survival after VAD insertion is worse in patients with CHD than in patients with AHD.

Association of Lung Function With Cognitive Decline and Incident Dementia in the Atherosclerosis Risk in Communities Study.

We examined the associations between lung function and incident dementia and cognitive decline in 12,688 participants in the ARIC Study who provided lung function measurements in 1990-1992. Cognitive tests were administered up to 7 times, and dementia was ascertained through 2019. We used shared parameter models to jointly fit proportional hazard models and linear mixed-effect models to estimate lung-function-associated dementia rate and cognitive change, respectively. Higher forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were associated with reduced dementia (n = 2,452 persons developed dementia); hazard ratios per 1-L increase in FEV1 and FVC were 0.79 (95% confidence interval (CI): 0.71, 0.89) and 0.81 (95% CI: 0.74, 0.89), respectively. Each 1-L increase in FEV1 and FVC was associated with a 0.08-standard deviation (SD) (95% CI: 0.05, 0.12) and a 0.05-SD (95% CI: 0.02, 0.07) attenuation of 30-year cognitive decline, respectively. A 1% increase in FEV1/FVC ratio was associated with 0.008-SD (95% CI: 0.004, 0.012) less cognitive decline. We observed statistical interaction between FEV1 and FVC, suggesting that cognitive declines depended on values of specific FEV1 and FVC (as compared with FEV1, FVC, or FEV1/FVC ratio models that suggested linear incremental associations). Our findings may have important implications for reducing the burden of cognitive decline that is attributable to environmental exposures and associated lung function impairment.

Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life.

A diverse set of biological processes have been implicated in the pathophysiology of Alzheimer's disease (AD) and related dementias. However, there is limited understanding of the peripheral biological mechanisms relevant in the earliest phases of the disease. Here, we used a large-scale proteomics platform to examine the association of 4877 plasma proteins with 25-year dementia risk in 10,981 middle-aged adults. We found 32 dementia-associated plasma proteins that were involved in proteostasis, immunity, synaptic function, and extracellular matrix organization. We then replicated the association between 15 of these proteins and clinically relevant neurocognitive outcomes in two independent cohorts. We demonstrated that 12 of these 32 dementia-associated proteins were associated with cerebrospinal fluid (CSF) biomarkers of AD, neurodegeneration, or neuroinflammation. We found that eight of these candidate protein markers were abnormally expressed in human postmortem brain tissue from patients with AD, although some of the proteins that were most strongly associated with dementia risk, such as GDF15, were not detected in these brain tissue samples. Using network analyses, we found a protein signature for dementia risk that was characterized by dysregulation of specific immune and proteostasis/autophagy pathways in adults in midlife ~20 years before dementia onset, as well as abnormal coagulation and complement signaling ~10 years before dementia onset. Bidirectional two-sample Mendelian randomization genetically validated nine of our candidate proteins as markers of AD in midlife and inferred causality of SERPINA3 in AD pathogenesis. Last, we prioritized a set of candidate markers for AD and dementia risk prediction in midlife.

Proteomic Analysis Identifies Circulating Proteins Associated With Plasma Amyloid-ß and Incident Dementia.

Background: Plasma amyloid-ß (Aß) (Aß42, Aß40, and Aß42/Aß40), biomarkers of the Alzheimer's form of dementia, are under consideration for clinical use. The associations of these peptides with circulating proteins may identify novel plasma biomarkers of dementia and inform peripheral factors influencing the levels of these peptides. Methods: We analyzed the association of these 3 plasma Aß measures with 4638 circulating proteins among a subset of the participants of the Atherosclerosis Risk in Communities (ARIC) study (midlife: n = 1955; late life: n = 2082), related the Aß-associated proteins with incident dementia in the overall ARIC cohort (midlife: n = 11,069, late life: n = 4110) with external replication in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study (n = 4973), estimated the proportion of Aß variance explained, and conducted enrichment analyses to characterize the proteins associated with the plasma Aß peptides. Results: At midlife, of the 296 Aß-associated proteins, 8 were associated with incident dementia from midlife and late life in the ARIC study, and NPPB, IBSP, and THBS2 were replicated in the AGES-Reykjavik Study. At late life, of the 34 Aß-associated proteins, none were associated with incident dementia at midlife, and kidney function explained 10%, 12%, and 0.2% of the variance of Aß42, Aß40, and Aß42/Aß40, respectively. Aß42-associated proteins at midlife were found to be enriched in the liver, and those at late life were found to be enriched in the spleen. Conclusions: This study identifies circulating proteins associated with plasma Aß levels and incident dementia and informs peripheral factors associated with plasma Aß levels.