The relationships between the family impact and distress of the coronavirus disease-19 pandemic, parent insomnia, infant temperamental negative affectivity, and parent-reported infant sleep: a path analysis.

Study Objectives: The coronavirus disease 2019 (COVID-19) pandemic impact on infant sleep (IS) is understudied. The purpose of this study was to examine the relationships between family impact and distress from COVID-19 pandemic stressors, parental insomnia symptoms, infant temperamental negative affectivity, and parent-reported IS. Methods: Parents from the Phoenix metropolitan area with a full-term healthy infant (<1 year) were recruited from February 27, 2021, to August 7, 2021. A sample of 70 parents (baby age 5.5 ±â€…3.5 months; parental age: 31.7 ±â€…5.0 years) completed the COVID-19 Exposure and Family Impact Survey (CEFIS) Impact and Distress scales, the Insomnia Severity Index (ISI), the Infant Behavioral Questionnaire-Revised Negative Affectivity subscale (IBQ-R-NA), and the Brief Infant Sleep Questionnaire-Revised (BISQ-R). Based on the transactional model of IS, path analyses were conducted to identify the direct effect of CEFIS scores and the indirect effects of parental ISI and infant IBQ-R-NA scores on BISQ-R scores. Results: The parent sample was predominantly female (94.3%), white (72.9%), and married or in a domestic partnership (98.6%). Although COVID-19 pandemic impact and distress were not directly related to parent-reported IS, pandemic distress was negatively related to parent-reported IS indirectly through infant negative affectivity, including BISQ-R total score (ß = -0.14, 95% CI [-0.32, -0.01]) and IS subscale score (ß = -0.12, 95% CI [-0.27, -0.01]). Conclusions: Heightened COVID-19 pandemic family distress was related to poorer parent-reported IS through greater parent-reported infant negative affectivity, suggesting the importance of addressing family stress and emotional regulation during crises.

Clinical-transcriptional prioritization of the circulating proteome in human heart failure.

Given expanding studies in epidemiology and disease-oriented human studies offering hundreds of associations between the human "ome" and disease, prioritizing molecules relevant to disease mechanisms among this growing breadth is important. Here, we link the circulating proteome to human heart failure (HF) propensity (via echocardiographic phenotyping and clinical outcomes) across the lifespan, demonstrating key pathways of fibrosis, inflammation, metabolism, and hypertrophy. We observe a broad array of genes encoding proteins linked to HF phenotypes and outcomes in clinical populations dynamically expressed at a transcriptional level in human myocardium during HF and cardiac recovery (several in a cell-specific fashion). Many identified targets do not have wide precedent in large-scale genomic discovery or human studies, highlighting the complementary roles for proteomic and tissue transcriptomic discovery to focus epidemiological targets to those relevant in human myocardium for further interrogation.

Proteomic analyses reveal plasma EFEMP1 and CXCL12 as biomarkers and determinants of neurodegeneration.

INTRODUCTION: Plasma proteomic analyses of unique brain atrophy patterns may illuminate peripheral drivers of neurodegeneration and identify novel biomarkers for predicting clinically relevant outcomes. METHODS: We identified proteomic signatures associated with machine learning-derived aging- and Alzheimer's disease (AD) -related brain atrophy patterns in the Baltimore Longitudinal Study of Aging (n = 815). Using data from five cohorts, we examined whether candidate proteins were associated with AD endophenotypes and long-term dementia risk. RESULTS: Plasma proteins associated with distinct patterns of age- and AD-related atrophy were also associated with plasma/cerebrospinal fluid (CSF) AD biomarkers, cognition, AD risk, as well as mid-life (20-year) and late-life (8-year) dementia risk. EFEMP1 and CXCL12 showed the most consistent associations across cohorts and were mechanistically implicated as determinants of brain structure using genetic methods, including Mendelian randomization. DISCUSSION: Our findings reveal plasma proteomic signatures of unique aging- and AD-related brain atrophy patterns and implicate EFEMP1 and CXCL12 as important molecular drivers of neurodegeneration. HIGHLIGHTS: Plasma proteomic signatures are associated with unique patterns of brain atrophy. Brain atrophy-related proteins predict clinically relevant outcomes across cohorts. Genetic variation underlying plasma EFEMP1 and CXCL12 influences brain structure. EFEMP1 and CXCL12 may be important molecular drivers of neurodegeneration.

Proteomics identifies potential immunological drivers of postinfection brain atrophy and cognitive decline.

Infections have been associated with the incidence of Alzheimer disease and related dementias, but the mechanisms responsible for these associations remain unclear. Using a multicohort approach, we found that influenza, viral, respiratory, and skin and subcutaneous infections were associated with increased long-term dementia risk. These infections were also associated with region-specific brain volume loss, most commonly in the temporal lobe. We identified 260 out of 942 immunologically relevant proteins in plasma that were differentially expressed in individuals with an infection history. Of the infection-related proteins, 35 predicted volumetric changes in brain regions vulnerable to infection-specific atrophy. Several of these proteins, including PIK3CG, PACSIN2, and PRKCB, were related to cognitive decline and plasma biomarkers of dementia (Aß42/40, GFAP, NfL, pTau-181). Genetic variants that influenced expression of immunologically relevant infection-related proteins, including ITGB6 and TLR5, predicted brain volume loss. Our findings support the role of infections in dementia risk and identify molecular mediators by which infections may contribute to neurodegeneration.

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.

Gastrointestinal and Neuropsychological Symptoms Are Associated With Distinct Vomiting Profiles in Patients Receiving Chemotherapy.

OBJECTIVES: To identify subgroups of patients with distinct chemotherapy-induced vomiting (CIV) profiles; determine how these subgroups differ on several demographic, clinical, and symptom characteristics; and evaluate factors associated with chemotherapy-induced nausea and CIV profiles. SAMPLE & SETTING: Adult patients (N = 1,338) receiving cancer chemotherapy. METHODS & VARIABLES: Data were collected on demographic, clinical, and symptom characteristics. Differences among subgroups of patients with distinct CIV profiles were evaluated using parametric and nonparametric tests. RESULTS: Three CIV profiles (None, Decreasing, and Increasing) were identified. Compared with the None class, Decreasing and Increasing classes were more likely to have lower household income and a higher comorbidity burden, as well as to report higher rates of dry mouth, nausea, diarrhea, depression, anxiety, sleep disturbance, morning fatigue, and pain interference. IMPLICATIONS FOR NURSING: Clinicians need to assess common and distinct risk factors for CIV and chemotherapy-induced nausea.

Dietary and water restriction leads to increased susceptibility to antimicrobial resistant pathogens.

Dehydration and malnutrition are common and often underdiagnosed in hospital settings. Multidrug-resistant bacterial infections result in more than 35,000 deaths a year in nosocomial patients. The effect of temporal dietary and water restriction (DWR) on susceptibility to multidrug-resistant pathogens is unknown. We report that DWR markedly increased susceptibility to systemic infection by ESKAPE pathogens. Using a murine bloodstream model of methicillin-resistant Staphylococcus aureus infection, we show that DWR leads to significantly increased mortality and morbidity. DWR causes increased bacterial burden, severe pathology, and increased numbers of phagocytes in the kidney. DWR appears to alter the functionality of these phagocytes and is therefore unable to control infection. Mechanistically, we show that DWR impairs the ability of macrophages to phagocytose multiple bacterial pathogens and efferocytose apoptotic neutrophils. Together, this work highlights the crucial impact that diet and hydration play in protecting against infection.

Relations Between Cardiorespiratory Fitness and Cognition in Older Adults With Amnestic Mild Cognitive Impairment From the Aerobic Exercise and Cognitive Training (ACT) Trial: Sex Differences.

Objective: To examine the associations of cardiorespiratory fitness with executive function, episodic memory, and global cognition and sex differences in these associations in community-dwelling older adults with amnestic mild cognitive impairment. Design: A cross-sectional study using baseline data from the aerobic exercise and cognitive training (ACT) trial. Setting: The ACT trial conducted exercise testing in an exercise laboratory and data collections in a research facility. Participants: ACT trial participants were recruited through referrals, registries, exhibits, flyers, media, and advertisements and screened for eligibility. To be eligible for this study, ACT enrollees needed complete data on all study variables. Among 146 ACT enrollees, 142 met eligibility for this study (N=142). Interventions: None. Main Outcome Measures: Cardiorespiratory fitness was measured as peak oxygen consumption (Vo2peak) with a peak cycle-ergometer test, executive function with the EXAMINER, episodic memory with the Brief Visuospatial Memory Test-Revised, and global cognition with Montreal Cognitive Assessment. Results: The average age of the sample was 73.8±5.8 years with 16.9±2.9 years of education, with 87.3% White, 51.4% men, and 69.7% married. After controlling for covariates, Vo2peak was significantly related to executive function (b=.037, standard error [SE]=0.015, P=.0154, semipartial [sr] correlation coefficient=.239) and episodic memory (b=.590, SE=0.226, P=.0102, sr=.216), but not global cognition (b=.074, SE=0.055, P=.1837, sr=.125). For men, Vo2peak was significantly associated with executive function (b=.063, SE=0.024, P=.0099, r=.430) and episodic memory (b=1.088, SE=0.312, P=.0009, r=.382). Conclusions: Our findings show that Vo2peak was associated with executive function and episodic memory in the overall sample and in men. Future studies can examine the longitudinal relations between cardiorespiratory fitness and cognition.

Plasma proteomic comparisons change as coverage expands for SomaLogic and Olink.

The number of assays on highly-multiplexed proteomic platforms has grown tenfold over the past 15 years from less than 1,000 to >11,000. The leading aptamer-based and antibody-based platforms have different strengths. For example, Eldjarn et al1 demonstrated that the aptamer-based SomaScan 5k (4,907 assays, assessed in the Icelandic 36K) and the antibody-based Olink Explore 3072 (2,931 assays, assessed in the UK BioBank) had a similar number of cis-pQTLs among all targets (2,120 vs. 2,101) but Olink had a greater number of cis-pQTLs among the overlapping targets (1,164 vs. 1,467). Analysis of split plasma measures showed the SomaScan assays to be more precise: median coefficient of variation (CV) of 9.9% vs. 16.5% for Olink.1 Precision of the newest versions of the platforms-SomaScan 11k (>11,000 assays, released in December 2023) and Olink Explore HT (>5,400 assays, released in July 2023)-has not yet been established. We assessed the reproducibility of the SomaScan 11k and Olink Explore HT using split plasma samples from 102 Atherosclerosis Risk in Communities (ARIC) Study participants. We found that the SomaScan 11k assays had a median CV of 6.8% (vs 6.6% for the subset of assays available on the SomaScan 5k) and the Olink Explore HT assays had a median CV of 35.7% (vs 19.8% for the subset of assays available on the Olink Explore 3072). Across Olink assays, the CVs were strongly negatively correlated with protein detectability, i.e., percent of samples above the limit of detection (LOD). For the 4,443 overlapping assays, the distribution of between-platform correlations was bimodal with a peak at r~0 and with another smaller peak at r~0.8. These findings on precision are consistent with the updated results by Eldjarn et al1 but indicate that precision of these two leading platforms in human plasma has diverged as the number of included proteins has increased.

Proteome-wide analysis identifies plasma immune regulators of amyloid-beta progression.

While immune function is known to play a mechanistic role in Alzheimer's disease (AD), whether immune proteins in peripheral circulation influence the rate of amyloid-ß (Aß) progression - a central feature of AD - remains unknown. In the Baltimore Longitudinal Study of Aging, we quantified 942 immunological proteins in plasma and identified 32 (including CAT [catalase], CD36 [CD36 antigen], and KRT19 [keratin 19]) associated with rates of cortical Aß accumulation measured with positron emission tomography (PET). Longitudinal changes in a subset of candidate proteins also predicted Aß progression, and the mid- to late-life (20-year) trajectory of one protein, CAT, was associated with late-life Aß-positive status in the Atherosclerosis Risk in Communities (ARIC) study. Genetic variation that influenced plasma levels of CAT, CD36 and KRT19 predicted rates of Aß accumulation, including causal relationships with Aß PET levels identified with two-sample Mendelian randomization. In addition to associations with tau PET and plasma AD biomarker changes, as well as expression patterns in human microglia subtypes and neurovascular cells in AD brain tissue, we showed that 31 % of candidate proteins were related to mid-life (20-year) or late-life (8-year) dementia risk in ARIC. Our findings reveal plasma proteins associated with longitudinal Aß accumulation, and identify specific peripheral immune mediators that may contribute to the progression of AD pathophysiology.

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.

Proteomic analysis of cardiorespiratory fitness for prediction of mortality and multisystem disease risks.

Despite the wide effects of cardiorespiratory fitness (CRF) on metabolic, cardiovascular, pulmonary and neurological health, challenges in the feasibility and reproducibility of CRF measurements have impeded its use for clinical decision-making. Here we link proteomic profiles to CRF in 14,145 individuals across four international cohorts with diverse CRF ascertainment methods to establish, validate and characterize a proteomic CRF score. In a cohort of around 22,000 individuals in the UK Biobank, a proteomic CRF score was associated with a reduced risk of all-cause mortality (unadjusted hazard ratio 0.50 (95% confidence interval 0.48-0.52) per 1 s.d. increase). The proteomic CRF score was also associated with multisystem disease risk and provided risk reclassification and discrimination beyond clinical risk factors, as well as modulating high polygenic risk of certain diseases. Finally, we observed dynamicity of the proteomic CRF score in individuals who undertook a 20-week exercise training program and an association of the score with the degree of the effect of training on CRF, suggesting potential use of the score for personalization of exercise recommendations. These results indicate that population-based proteomics provides biologically relevant molecular readouts of CRF that are additive to genetic risk, potentially modifiable and clinically translatable.

Proteomic analysis of Alzheimer's disease cerebrospinal fluid reveals alterations associated with APOE ε4 and atomoxetine treatment.

Alzheimer's disease (AD) is currently defined by the aggregation of amyloid-ß (Aß) and tau proteins in the brain. Although biofluid biomarkers are available to measure Aß and tau pathology, few markers are available to measure the complex pathophysiology that is associated with these two cardinal neuropathologies. Here, we characterized the proteomic landscape of cerebrospinal fluid (CSF) changes associated with Aß and tau pathology in 300 individuals using two different proteomic technologies-tandem mass tag mass spectrometry and SomaScan. Integration of both data types allowed for generation of a robust protein coexpression network consisting of 34 modules derived from 5242 protein measurements, including disease-relevant modules associated with autophagy, ubiquitination, endocytosis, and glycolysis. Three modules strongly associated with the apolipoprotein E ε4 (APOE ε4) AD risk genotype mapped to oxidant detoxification, mitogen-associated protein kinase signaling, neddylation, and mitochondrial biology and overlapped with a previously described lipoprotein module in serum. Alterations of all three modules in blood were associated with dementia more than 20 years before diagnosis. Analysis of CSF samples from an AD phase 2 clinical trial of atomoxetine (ATX) demonstrated that abnormal elevations in the glycolysis CSF module-the network module most strongly correlated to cognitive function-were reduced by ATX treatment. Clustering of individuals based on their CSF proteomic profiles revealed heterogeneity of pathological changes not fully reflected by Aß and tau.

Patterns of cognitive domain abnormalities enhance discrimination of dementia risk prediction: The ARIC study.

INTRODUCTION: The contribution of neuropsychological assessments to risk assessment for incident dementia is underappreciated. METHODS: We 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. RESULTS: Among 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). DISCUSSION: By 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.

Mid-life plasma proteins associated with late-life prefrailty and frailty: a proteomic analysis.

Physical frailty is a syndrome that typically manifests in later life, although the pathogenic process causing physical frailty likely begins decades earlier. To date, few studies have examined the biological signatures in mid-life associated with physical frailty later in life. Among 4,189 middle-aged participants (57.8 ± 5.0 years, 55.8% women) from the Atherosclerosis Risk in Community (ARIC) study, we evaluated the associations of 4,955 plasma proteins (log 2-transformed and standardized) measured using the SomaScan platform with their frailty status approximately 20 years later. Using multinomial logistic regression models adjusting for demographics, health behaviors, kidney function, total cholesterol, and comorbidities, 12 and 221 proteins were associated with prefrailty and frailty in later life, respectively (FDR p < 0.05). Top frailty-associated proteins included neurocan core protein (NCAN, OR = 0.66), fatty acid-binding protein heart (FABP3, OR = 1.62) and adipocyte (FABP4, OR = 1.65), as well proteins involved in the contactin-1 (CNTN1), toll-like receptor 5 (TLR5), and neurogenic locus notch homolog protein 1 (NOTCH1) signaling pathway relevant to skeletal muscle regeneration, myelination, and inflammation. Pathway analyses suggest midlife dysregulation of inflammation, metabolism, extracellular matrix, angiogenesis, and lysosomal autophagy among those at risk for late-life frailty. After further adjusting for midlife body mass index (BMI) - an established frailty risk factor - only CNTN1 (OR = 0.75) remained significantly associated with frailty. Post-hoc analyses demonstrated that the top 41 midlife frailty-associated proteins mediate 32% of the association between mid-life BMI and late-life frailty. Our findings provide new insights into frailty etiology earlier in the life course, enhancing the potential for prevention.

Associations of mid-to-late-life inflammation with late-life mobility and the influences of chronic comorbidities, race, and social determinants of health: The Atherosclerosis Risk in Communities Study.

BACKGROUND: Relationships of midlife inflammation with late-life mobility and influences of chronic health conditions, race, and social determinants of health (SDoH) on these relationships are poorly understood. METHODS: Among 4758 community-dwelling participants (41% men, 20% Black), high-sensitivity C-reactive protein (hsCRP) was measured over 20+ years: in midlife at study visit 2 (V2: 1990-1992, 47-68 years); at V4 (1996-1998, 53-74 years); and with concurrent late-life 4-m gait speed at V5 (2011-2013, 67-88 years, mean 75 years). SDoH measures included race, the national-rank area deprivation index, education, and income. We examined associations of late-life gait speed with midlife hsCRP (V2 continuous and clinically high ≥3 mg/L), with 20-year hsCRP history from midlife (V2-V5 average continuous hsCRP and clinically high ≥3 mg/L) and with inflammation accumulation (visits and years with high hsCRP). Regression models adjusted for demographic, cardiovascular, and SDoH measures; effect modification by the presence of other common chronic conditions (obesity, diabetes, hypertension) and race were examined, with and without accounting for SDoH. RESULTS: High midlife hsCRP was associated with slower late-life gait speed, even among those without chronic conditions in midlife: -4.6 cm/s (95% CI: -6.4, -2.8). Importantly, sustained high hsCRP was associated with a 20-year slowing of -10.0 cm/s (-14.9, -5.1) among those who never experienced obesity, diabetes, or hypertension over the 20-year period. Associations were similar between Black participants, -3.8 cm/s (-6.9, -0.7) and White participants -3.3 (-4.5, -2.2) per interquartile range of midlife hsCRP; effect modifications by chronic conditions and race were unsupported throughout. Results were robust to accounting for SDoH or otherwise; however, worse SDoH was associated with higher inflammation and slower gait speed in both Black and White participants. CONCLUSIONS: Inflammation in midlife may contribute to clinically meaningful late-life slowing of gait speed, even among otherwise healthy-appearing adults and regardless of race and socioeconomic disadvantage. Regular monitoring and interventions for inflammation may be warranted from midlife.

Signatures and Discriminative Abilities of Multi-Omics between States of Cognitive Decline.

Dementia poses a substantial global health challenge, warranting an exploration of its intricate pathophysiological mechanisms and potential intervention targets. Leveraging multi-omic technology, this study utilizes data from 2251 participants to construct classification models using lipidomic, gut metabolomic, and cerebrospinal fluid (CSF) proteomic markers to distinguish between the states of cognitive decline, namely, the cognitively unimpaired state, mild cognitive impairment, and dementia. The analysis identifies three CSF proteins (apolipoprotein E, neuronal pentraxin-2, and fatty-acid-binding protein), four lipids (DEDE.18.2, DEDE.20.4, LPC.O.20.1, and LPC.P.18.1), and five serum gut metabolites (Hyodeoxycholic acid, Glycohyodeoxycholic acid, Hippuric acid, Glyceric acid, and Glycodeoxycholic acid) capable of predicting dementia prevalence from cognitively unimpaired participants, achieving Area Under the Curve (AUC) values of 0.879 (95% CI: 0.802-0.956), 0.766 (95% CI: 0.700-0.835), and 0.717 (95% CI: 0.657-0.777), respectively. Furthermore, exclusively three CSF proteins exhibit the potential to predict mild cognitive impairment prevalence from cognitively unimpaired subjects, with an AUC of 0.760 (95% CI: 0.691-0.828). In conclusion, we present novel combinations of lipids, gut metabolites, and CSF proteins that showed discriminative abilities between the states of cognitive decline and underscore the potential of these molecules in elucidating the mechanisms of cognitive decline.

Biomarkers of Neurodegeneration and Alzheimer's Disease Neuropathology in Adolescents and Young Adults with Youth-Onset Type 1 or Type 2 Diabetes: A Proof-of-Concept Study.

Adult-onset diabetes increases one's risk of neurodegenerative disease including Alzheimer's disease (AD); however, the risk associated with youth-onset diabetes (Y-DM) remains underexplored. We quantified plasma biomarkers of neurodegeneration and AD in participants with Y-DM from the SEARCH cohort at adolescence and young adulthood (Type 1, n = 25; Type 2, n = 25; 59% female; adolescence, age = 15 y/o [2.6]; adulthood, age = 27.4 y/o [2.2]), comparing them with controls (adolescence, n = 25, age = 14.8 y/o [2.7]; adulthood, n = 21, age = 24.9 y/o [2.8]). Plasma biomarkers, including glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), phosphorylated tau-181 (pTau181), and amyloid beta (Aß40, Aß42), were measured via Simoa. A subset of participants (n = 7; age = 27.5 y/o [5.7]) and six controls (age = 25.1 y/o [4.5]) underwent PET scans to quantify brain amyloid and tau densities in AD sensitive brain regions. Y-DM adolescents exhibited lower plasma levels of Aß40, Aß42, and GFAP, and higher pTau181 compared to controls (p < 0.05), a pattern persisting into adulthood (p < 0.001). All biomarkers showed significant increases from adolescence to adulthood in Y-DM (p < 0.01), though no significant differences in brain amyloid or tau were noted between Y-DM and controls in adulthood. Preliminary evidence suggests that preclinical AD neuropathology is present in young people with Y-DM, indicating a potential increased risk of neurodegenerative diseases.

Association between retinal microvascular abnormalities and late-life brain amyloid-ß deposition: the ARIC-PET study.

BACKGROUND: Retinal microvascular signs are accessible measures of early alterations in microvascular dysregulation and have been associated with dementia; it is unclear if they are associated with AD (Alzheimer's disease) pathogenesis as a potential mechanistic link. This study aimed to test the association of retinal microvascular abnormalities in mid and late life and late life cerebral amyloid. METHODS: Participants from the ARIC-PET (Atherosclerosis Risk in Communities-Positron Emission Tomography) study with a valid retinal measure (N = 285) were included. The associations of mid- and late-life retinal signs with late-life amyloid-ß (Aß) by florbetapir PET were tested. Two different measures of Aß burden were included: (1) elevated amyloid (SUVR > 1.2) and (2) continuous amyloid SUVR. The retinal measures' association with Aß burden was assessed using logistic and robust linear regression models. A newly created retinal score, incorporating multiple markers of retinal abnormalities, was also evaluated in association with greater Aß burden. RESULTS: Retinopathy in midlife (OR (95% CI) = 0.36 (0.08, 1.40)) was not significantly associated with elevated amyloid burden. In late life, retinopathy was associated with increased continuous amyloid standardized value uptake ratio (SUVR) (ß (95%CI) = 0.16 (0.02, 0.32)) but not elevated amyloid burden (OR (95%CI) = 2.37 (0.66, 9.88)) when accounting for demographic, genetic and clinical risk factors. A high retinal score in late life, indicating a higher burden of retinal abnormalities, was also significantly associated with increased continuous amyloid SUVR (ß (95% CI) = 0.16 (0.04, 0.32)) independent of vascular risk factors. CONCLUSIONS: Retinopathy in late life may be an easily obtainable marker to help evaluate the mechanistic vascular pathway between retinal measures and dementia, perhaps acting via AD pathogenesis. Well-powered future studies with a greater number of retinal features and other microvascular signs are needed to test these findings.