04157nas a2200409 4500008004100000022001400041245009900055210006900154260001600223520291000239100002303149700002003172700002303192700002103215700002403236700002703260700002303287700002303310700002303333700002003356700002603376700002303402700002103425700002003446700002603466700002203492700001903514700002303533700002003556700002003576700002003596700002303616700002403639700002403663700002403687856003603711 2020 eng d a2168-615700aAssociation Between Blood Pressure and Later-Life Cognition Among Black and White Individuals.0 aAssociation Between Blood Pressure and LaterLife Cognition Among c2020 Apr 133 a

Importance: Black individuals are more likely than white individuals to develop dementia. Whether higher blood pressure (BP) levels in black individuals explain differences between black and white individuals in dementia risk is uncertain.

Objective: To determine whether cumulative BP levels explain racial differences in cognitive decline.

Design, Setting, and Participants: Individual participant data from 5 cohorts (January 1971 to December 2017) were pooled from the Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represented a 0.1-SD difference in cognition. The median (interquartile range) follow-up was 12.4 (5.9-21.0) years. Analysis began September 2018.

Main Outcomes and Measures: The primary outcome was change in global cognition, and secondary outcomes were change in memory and executive function.

Exposures: Race (black vs white).

Results: Among 34 349 participants, 19 378 individuals who were free of stroke and dementia and had longitudinal BP, cognitive, and covariate data were included in the analysis. The mean (SD) age at first cognitive assessment was 59.8 (10.4) years and ranged from 5 to 95 years. Of 19 378 individuals, 10 724 (55.3%) were female and 15 526 (80.1%) were white. Compared with white individuals, black individuals had significantly faster declines in global cognition (-0.03 points per year faster [95% CI, -0.05 to -0.01]; P = .004) and memory (-0.08 points per year faster [95% CI, -0.11 to -0.06]; P < .001) but significantly slower declines in executive function (0.09 points per year slower [95% CI, 0.08-0.10]; P < .001). Time-dependent cumulative mean systolic BP level was associated with significantly faster declines in global cognition (-0.018 points per year faster per each 10-mm Hg increase [95% CI, -0.023 to -0.014]; P < .001), memory (-0.028 points per year faster per each 10-mm Hg increase [95% CI, -0.035 to -0.021]; P < .001), and executive function (-0.01 points per year faster per each 10-mm Hg increase [95% CI, -0.014 to -0.007]; P < .001). After adjusting for cumulative mean systolic BP, differences between black and white individuals in cognitive slopes were attenuated for global cognition (-0.01 points per year [95% CI, -0.03 to 0.01]; P = .56) and memory (-0.06 points per year [95% CI, -0.08 to -0.03]; P < .001) but not executive function (0.10 points per year [95% CI, 0.09-0.11]; P < .001).

Conclusions and Relevance: These results suggest that black individuals' higher cumulative BP levels may contribute to racial differences in later-life cognitive decline.

1 aLevine, Deborah, A1 aGross, Alden, L1 aBriceño, Emily, M1 aTilton, Nicholas1 aKabeto, Mohammed, U1 aHingtgen, Stephanie, M1 aGiordani, Bruno, J1 aSussman, Jeremy, B1 aHayward, Rodney, A1 aBurke, James, F1 aElkind, Mitchell, S V1 aManly, Jennifer, J1 aMoran, Andrew, E1 aKulick, Erin, R1 aGottesman, Rebecca, F1 aWalker, Keenan, A1 aYano, Yuichiro1 aGaskin, Darrell, J1 aSidney, Stephen1 aYaffe, Kristine1 aSacco, Ralph, L1 aWright, Clinton, B1 aRoger, Veronique, L1 aAllen, Norrina, Bai1 aGalecki, Andrzej, T uhttps://chs-nhlbi.org/node/839802821nas a2200289 4500008004100000022001400041245010000055210006900155260001600224520195600240100001602196700002202212700002502234700001802259700002002277700002302297700001802320700002302338700001702361700002002378700002102398700001802419700001802437700001802455700002202473856003602495 2023 eng d a1474-972600aLate-life plasma proteins associated with prevalent and incident frailty: A proteomic analysis.0 aLatelife plasma proteins associated with prevalent and incident  c2023 Sep 113 a

Proteomic approaches have unique advantages in the identification of biological pathways that influence physical frailty, a multifactorial geriatric syndrome predictive of adverse health outcomes in older adults. To date, proteomic studies of frailty are scarce, and few evaluated prefrailty as a separate state or examined predictors of incident frailty. Using plasma proteins measured by 4955 SOMAmers in the Atherosclerosis Risk in Community study, we identified 134 and 179 proteins cross-sectionally associated with prefrailty and frailty, respectively, after Bonferroni correction (p < 1 × 10 ) among 3838 older adults aged ≥65 years, adjusting for demographic and physiologic factors and chronic diseases. Among them, 23 (17%) and 82 (46%) were replicated in the Cardiovascular Health Study using the same models (FDR p < 0.05). Notably, higher odds of prefrailty and frailty were observed with higher levels of growth differentiation factor 15 (GDF15; p  = 1 × 10 , p  = 2 × 10 ), transgelin (TAGLN; p  = 2 × 10 , p  = 6 × 10 ), and insulin-like growth factor-binding protein 2 (IGFBP2; p  = 5 × 10 , p  = 1 × 10 ) and with a lower level of growth hormone receptor (GHR, p  = 3 × 10 , p  = 2 × 10 ). Longitudinally, we identified 4 proteins associated with incident frailty (p < 1 × 10 ). Higher levels of triggering receptor expressed on myeloid cells 1 (TREM1), TAGLN, and heart and adipocyte fatty-acid binding proteins predicted incident frailty. Differentially regulated proteins were enriched in pathways and upstream regulators related to lipid metabolism, angiogenesis, inflammation, and cell senescence. Our findings provide a set of plasma proteins and biological mechanisms that were dysregulated in both the prodromal and the clinical stage of frailty, offering new insights into frailty etiology and targets for intervention.

1 aLiu, Fangyu1 aAustin, Thomas, R1 aSchrack, Jennifer, A1 aChen, Jingsha1 aWalston, Jeremy1 aMathias, Rasika, A1 aGrams, Morgan1 aOdden, Michelle, C1 aNewman, Anne1 aPsaty, Bruce, M1 aRamonfaur, Diego1 aShah, Amil, M1 aWindham, Gwen1 aCoresh, Josef1 aWalker, Keenan, A uhttps://chs-nhlbi.org/node/948304295nas a2200529 4500008004100000022001400041245009000055210006900145260001600214300001200230490000600242520289400248653000903142653001503151653001103166653001203177653001803189653001103207653001403218653000903232653001603241653001503257653001703272100002103289700002003310700002103330700001603351700002303367700002303390700002203413700001903435700002303454700002003477700003103497700001903528700002003547700002003567700002003587700002203607700001603629700001803645700001703663700001803680700001303698700001803711856003603729 2024 eng d a2380-659100aHigh Throughput Plasma Proteomics and Risk of Heart Failure and Frailty in Late Life.0 aHigh Throughput Plasma Proteomics and Risk of Heart Failure and  c2024 Jul 01 a649-6580 v93 a

IMPORTANCE: Heart failure (HF) and frailty frequently coexist and may share a common pathobiology, although the underlying mechanisms remain unclear. Understanding these mechanisms may provide guidance for preventing and treating both conditions.

OBJECTIVE: To identify shared pathways between incident HF and frailty in late life using large-scale proteomics.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, 4877 aptamers (Somascan v4) were measured among participants in the community-based longitudinal Atherosclerosis Risk In Communities (ARIC) cohort study at visit 3 (V3; 1993-1995; n = 10 638) and at visit 5 (V5; 2011-2013; n = 3908). Analyses were externally replicated among 3189 participants in the Cardiovascular Health Study (CHS). Data analysis was conducted from February 2022 to June 2023.

EXPOSURES: Protein aptamers, measured at study V3 and V5.

MAIN OUTCOMES AND MEASURES: Outcomes assessed included incident HF hospitalization after V3 and after V5, prevalent frailty at V5, and incident frailty between V5 and visit 6 (V6; 2016-2017; n = 4131). Frailty was assessed using the Fried criteria. Analyses were adjusted for age, gender, race, field center, hypertension, diabetes, smoking status, body mass index, estimated glomerular filtration rate, prevalent coronary heart disease, prevalent atrial fibrillation, and history of myocardial infarction. Mendelian randomization (MR) analysis was performed to assess potential causal effects of candidate proteins on HF and frailty.

RESULTS: A total of 4877 protein aptamers were measured among 10 638 participants at V3 (mean [SD] age, 60 [6] years; 4886 [46%] men). Overall, 286 proteins were associated with incident HF after V3 (822 events; P < 1.0 × 10-5), 83 of which were also associated with incident after V5 (336 events; P < 1.7 × 10-4). Among HF-free participants at V5 (n = 3908; mean [SD] age, 75 [5] years; 1861 [42%] men), 48 of 83 HF-associated proteins were associated with prevalent frailty (223 cases; P < 6.0 × 10-4), 18 of which were also associated with incident frailty at V6 (152 cases; P < 1.0 × 10-3). These proteins enriched fibrosis and inflammation pathways and demonstrated stronger associations with incident HF with preserved ejection fraction (HFpEF) than HF with reduced ejection fraction. All 18 proteins were associated with both prevalent frailty and incident HF in CHS. MR identified potential causal effects of several proteins on frailty and HF.

CONCLUSIONS AND RELEVANCE: In this study, the proteins associated with risk of HF and frailty enrich for pathways related to inflammation and fibrosis as well as risk of HFpEF. Several of these proteins could potentially contribute to the shared pathophysiology of frailty and HF.

10aAged10aBiomarkers10aFemale10aFrailty10aHeart Failure10aHumans10aIncidence10aMale10aMiddle Aged10aProteomics10aRisk Factors1 aRamonfaur, Diego1 aBuckley, Leo, F1 aArthur, Victoria1 aYang, Yimin1 aClaggett, Brian, L1 aNdumele, Chiadi, E1 aWalker, Keenan, A1 aAustin, Thomas1 aOdden, Michelle, C1 aFloyd, James, S1 avan Wijk, Sandra, Sanders-1 aNjoroge, Joyce1 aKizer, Jorge, R1 aKitzman, Dalane1 aKonety, Suma, H1 aSchrack, Jennifer1 aLiu, Fangyu1 aWindham, Gwen1 aPalta, Priya1 aCoresh, Josef1 aYu, Bing1 aShah, Amil, M uhttps://chs-nhlbi.org/node/970503300nas a2200397 4500008004100000245011700041210006900158260001600227520210200243100002302345700001302368700002202381700001802403700001602421700002002437700002302457700002102480700002002501700001802521700002202539700002002561700001902581700002102600700002002621700002902641700002102670700002602691700002202717700002202739700002302761700001902784700002302803700001802826700002202844856003602866 2024 eng d00aPlasma proteome-wide analysis of cerebral small vessel disease identifies novel biomarkers and disease pathways.0 aPlasma proteomewide analysis of cerebral small vessel disease id c2024 Oct 083 a

Cerebral small vessel disease (SVD), as defined by neuroimaging characteristics such as white matter hyperintensities (WMHs), cerebral microhemorrhages (CMHs), and lacunar infarcts, is highly prevalent and has been associated with dementia risk and other clinical sequelae. Although conditions such as hypertension are known to contribute to SVD, little is known about the diverse set of subclinical biological processes and molecular mediators that may also influence the development and progression of SVD. To better understand the mechanisms underlying SVD and to identify novel SVD biomarkers, we used a large-scale proteomic platform to relate 4,877 plasma proteins to MRI-defined SVD characteristics within 1,508 participants of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Our proteome-wide analysis of older adults (mean age: 76) identified 13 WMH-associated plasma proteins involved in synaptic function, endothelial integrity, and angiogenesis, two of which remained associated with late-life WMH volume when measured nearly 20 years earlier, during midlife. We replicated the relationship between 9 candidate proteins and WMH volume in one or more external cohorts; we found that 11 of the 13 proteins were associated with risk for future dementia; and we leveraged publicly available proteomic data from brain tissue to demonstrate that a subset of WMH-associated proteins was differentially expressed in the context of cerebral atherosclerosis, pathologically-defined Alzheimer's disease, and cognitive decline. Bidirectional two-sample Mendelian randomization analyses examined the causal relationships between candidate proteins and WMH volume, while pathway and network analyses identified discrete biological processes (lipid/cholesterol metabolism, NF-kB signaling, hemostasis) associated with distinct forms of SVD. Finally, we synthesized these findings to identify two plasma proteins, oligodendrocyte myelin glycoprotein (OMG) and neuronal pentraxin receptor (NPTXR), as top candidate biomarkers for elevated WMH volume and its clinical manifestations.

1 aGomez, Gabriela, T1 aShi, Liu1 aFohner, Alison, E1 aChen, Jingsha1 aYang, Yunju1 aFornage, Myriam1 aDuggan, Michael, R1 aPeng, Zhongsheng1 aDaya, Gulzar, N1 aTin, Adrienne1 aSchlosser, Pascal1 aLongstreth, W T1 aKalani, Rizwan1 aSharma, Malveeka1 aPsaty, Bruce, M1 aNevado-Holgado, Alejo, J1 aBuckley, Noel, J1 aGottesman, Rebecca, F1 aLutsey, Pamela, L1 aJack, Clifford, R1 aSullivan, Kevin, J1 aMosley, Thomas1 aHughes, Timothy, M1 aCoresh, Josef1 aWalker, Keenan, A uhttps://chs-nhlbi.org/node/9781