02821nas 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<p>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.</p>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/948303300nas 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<p>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.</p>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