The genetic architecture of multimodal human brain age.

The complex biological mechanisms underlying human brain aging remain incompletely understood. This study investigated the genetic architecture of three brain age gaps (BAG) derived from gray matter volume (GM-BAG), white matter microstructure (WM-BAG), and functional connectivity (FC-BAG). We identified sixteen genomic loci that reached genome-wide significance (P-value < 5×10-8). A gene-drug-disease network highlighted genes linked to GM-BAG for treating neurodegenerative and neuropsychiatric disorders and WM-BAG genes for cancer therapy. GM-BAG displayed the most pronounced heritability enrichment in genetic variants within conserved regions. Oligodendrocytes and astrocytes, but not neurons, exhibited notable heritability enrichment in WM and FC-BAG, respectively. Mendelian randomization identified potential causal effects of several chronic diseases on brain aging, such as type 2 diabetes on GM-BAG and AD on WM-BAG. Our results provide insights into the genetics of human brain aging, with clinical implications for potential lifestyle and therapeutic interventions. All results are publicly available at https://labs.loni.usc.edu/medicine .

Detection of Medication Taking Using a Wrist-Worn Commercially Available Wearable Device.

PURPOSE: Medication nonadherence is a persistent and costly problem across health care. Measures of medication adherence are ineffective. Methods such as self-report, prescription claims data, or smart pill bottles have been used to monitor medication adherence, but these are subject to recall bias, lack real-time feedback, and are often expensive. METHODS: We proposed a method for monitoring medication adherence using a commercially available wearable device. Passively collected motion data were analyzed on the basis of the Movelet algorithm, a dictionary learning framework that builds person-specific chapters of movements from short frames of elemental activities within the movements. We adapted and extended the Movelet method to construct a within-patient prediction model that identifies medication-taking behaviors. RESULTS: Using 15 activity features recorded from wrist-worn wearable devices of 10 patients with breast cancer on endocrine therapy, we demonstrated that medication-taking behavior can be predicted in a controlled clinical environment with a median accuracy of 85%. CONCLUSION: These results in a patient-specific population are exemplar of the potential to measure real-time medication adherence using a wrist-worn commercially available wearable device.

The Genetic Architecture of Multimodal Human Brain Age.

The complex biological mechanisms underlying human brain aging remain incompletely understood, involving multiple body organs and chronic diseases. In this study, we used multimodal magnetic resonance imaging and artificial intelligence to examine the genetic architecture of the brain age gap (BAG) derived from gray matter volume (GM-BAG, N=31,557 European ancestry), white matter microstructure (WM-BAG, N=31,674), and functional connectivity (FC-BAG, N=32,017). We identified sixteen genomic loci that reached genome-wide significance (P-value<5×10-8). A gene-drug-disease network highlighted genes linked to GM-BAG for treating neurodegenerative and neuropsychiatric disorders and WM-BAG genes for cancer therapy. GM-BAG showed the highest heritability enrichment for genetic variants in conserved regions, whereas WM-BAG exhibited the highest heritability enrichment in the 5' untranslated regions; oligodendrocytes and astrocytes, but not neurons, showed significant heritability enrichment in WM and FC-BAG, respectively. Mendelian randomization identified potential causal effects of several exposure variables on brain aging, such as type 2 diabetes on GM-BAG (odds ratio=1.05 [1.01, 1.09], P-value=1.96×10-2) and AD on WM-BAG (odds ratio=1.04 [1.02, 1.05], P-value=7.18×10-5). Overall, our results provide valuable insights into the genetics of human brain aging, with clinical implications for potential lifestyle and therapeutic interventions. All results are publicly available at the MEDICINE knowledge portal: https://labs.loni.usc.edu/medicine.

Analytical and Biological Variability of a Commercial Modified Aptamer Assay in Plasma Samples of Patients with Chronic Kidney Disease.

BACKGROUND: We carried out a study of the aptamer proteomic assay, SomaScan V4, to evaluate the analytical and biological variability of the assay in plasma samples of patients with moderate to severe chronic kidney disease (CKD). METHODS: Plasma samples were selected from 2 sources: (a) 24 participants from the Chronic Renal Insufficiency Cohort (CRIC) and (b) 49 patients from the Brigham and Women's Hospital-Kidney/Renal Clinic. We calculated intra-assay variability from both sources and examined short-term biological variability in samples from the Brigham clinic. We also measured correlations of aptamer measurements with traditional biomarker assays. RESULTS: A total of 4656 unique proteins (4849 total aptamer measures) were analyzed in all samples. Median (interquartile range [IQR] intra-assay CV) was 3.7% (2.8-5.3) in CRIC and 5.0% (3.8-7.0) in Brigham samples. Median (IQR) biological CV among Brigham samples drawn from one individual on 2 occasions separated by median (IQR) 7 (4-14) days was 8.7% (6.2-14). CVs were independent of CKD stage, diabetes, or albuminuria but were higher in patients with systemic lupus erythematosus. Rho correlations between aptamer and traditional assays for biomarkers of interest were cystatin C = 0.942, kidney injury model-1 = 0.905, fibroblast growth factor-23 = 0.541, tumor necrosis factor receptors 1 = 0.781 and 2 = 0.843, P < 10-100 for all. CONCLUSIONS: Intra-assay and within-subject variability for SomaScan in the CKD setting was low and similar to assay variability reported from individuals without CKD. Intra-assay precision was excellent whether samples were collected in an optimal research protocol, as were CRIC samples, or in the clinical setting, as were the Brigham samples.

Quality of Life and Physical Activity in 629 Individuals With Sarcoidosis: Prospective, Cross-sectional Study Using Smartphones (Sarcoidosis App).

BACKGROUND: Large gaps exist in understanding the symptomatic and functional impact of sarcoidosis, a rare multisystem granulomatous disease affecting fewer than 200,000 individuals in the United States. Smartphones could be used for prospective research, especially for rare diseases where organizing large cohorts can be challenging, given their near ubiquitous ownership and ability to track objective and subjective data with increasingly sophisticated technology. OBJECTIVE: We aimed to investigate whether smartphones could assess the quality of life (QoL) and physical activity of a large cohort of individuals with sarcoidosis. METHODS: We developed a mobile app (Sarcoidosis App) for a prospective, cross-sectional study on individuals with sarcoidosis. The Sarcoidosis App was made available on both Apple and Android smartphones. Individuals with sarcoidosis were recruited, consented, and enrolled entirely within the app. Surveys on sarcoidosis history, medical history, and medications were administered. Patients completed modules from the Sarcoidosis Assessment Tool, a validated patient-reported outcomes assessment of physical activity, fatigue, pain, skin symptoms, sleep, and lungs symptoms. Physical activity measured by smartphones was tracked as available. RESULTS: From April 2018 to May 2020, the App was downloaded 2558 times, and 629 individuals enrolled (404, 64.2% female; mean age 51 years; 513, 81.6% White; 86, 13.7% Black). Two-thirds of participants had a college or graduate degree, and more than half of them reported an income greater than US $60,000. Both QoL related to physical activity (P<.001, ρ=0.250) and fatigue (P<.01, ρ=-0.203) correlated with actual smartphone-tracked physical activity. Overall, 19.0% (98/517) of participants missed at least 1 week of school or work in an observed month owing to sarcoidosis, and 44.4% (279/629) reported that finances "greatly" or "severely" affected by sarcoidosis. Furthermore, 71.2% (437/614) of participants reported taking medications for sarcoidosis, with the most common being prednisone, methotrexate, hydroxychloroquine, and infliximab. Moreover, 46.4% (244/526) reported medication side effects, most commonly due to prednisone. CONCLUSIONS: We demonstrate that smartphones can prospectively recruit, consent, and study physical activity, QoL, and medication usage in a large sarcoidosis cohort, using both passively collected objective data and qualitative surveys that did not require any in-person encounters. Our study's limitations include the study population being weighted toward more educated and wealthier individuals, suggesting that recruitment was not representative of the full spectrum of patients with sarcoidosis in the United States. Our study provides a model for future smartphone-enabled clinical research for rare diseases and highlights key technical challenges that future research teams interested in smartphone-based research for rare diseases should anticipate.

Association of Multiple Plasma Biomarker Concentrations with Progression of Prevalent Diabetic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals. METHODS: In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of <60 ml/min per 1.73 m2 at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change. RESULTS: Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline. CONCLUSIONS: Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.

Early Cardiac Effects of Contemporary Radiation Therapy in Patients With Breast Cancer.

PURPOSE: To characterize the early changes in echocardiographically derived measures of cardiac function with contemporary radiation therapy (RT) in breast cancer and to determine the associations with radiation dose-volume metrics, including mean heart dose (MHD). METHODS AND MATERIALS: In a prospective longitudinal cohort study of 86 patients with breast cancer treated with photon or proton thoracic RT, clinical and echocardiographic data were assessed at 3 time points: within 4 weeks before RT initiation (T0), within 3 days before 6 weeks after the end of RT (T1), and 5 to 9 months after RT completion (T2). Associations between MHD and echocardiographically derived measures of cardiac function were assessed using generalized estimating equations to define the acute (T0 to T1) and subacute (T0 to T2) changes in cardiac function. RESULTS: The median estimates of MHD were 139 cGy (interquartile range, 99-249 cGy). In evaluating the acute changes in left ventricular ejection fraction (LVEF) from T0 to T1, and accounting for the time from RT, age, race, preexisting cardiovascular disease, and an interaction term with anthracycline or trastuzumab exposure and MHD, there was a modest decrease in LVEF of borderline significance (0.22%; 95% confidence interval [CI], -0.44% to 0.01%; P = .06) per 30-day interval for every 100 cGy increase of MHD. Similarly, there was a modest worsening in longitudinal strain (0.19%; 95% CI, -0.01% to 0.39%; P = .06) per 30-day interval for each 100 cGy increase in MHD. We did not find significant associations between MHD and changes in circumferential strain or diastolic function. CONCLUSIONS: With modern radiation planning techniques, there are modest subclinical changes in measures of cardiac function in the short-term. Longer-term follow-up studies are needed to determine whether these early changes are associated with the development of overt cardiac disease.

Iron imaging in myocardial infarction reperfusion injury.

Restoration of coronary blood flow after a heart attack can cause reperfusion injury potentially leading to impaired cardiac function, adverse tissue remodeling and heart failure. Iron is an essential biometal that may have a pathologic role in this process. There is a clinical need for a precise noninvasive method to detect iron for risk stratification of patients and therapy evaluation. Here, we report that magnetic susceptibility imaging in a large animal model shows an infarct paramagnetic shift associated with duration of coronary artery occlusion and the presence of iron. Iron validation techniques used include histology, immunohistochemistry, spectrometry and spectroscopy. Further mRNA analysis shows upregulation of ferritin and heme oxygenase. While conventional imaging corroborates the findings of iron deposition, magnetic susceptibility imaging has improved sensitivity to iron and mitigates confounding factors such as edema and fibrosis. Myocardial infarction patients receiving reperfusion therapy show magnetic susceptibility changes associated with hypokinetic myocardial wall motion and microvascular obstruction, demonstrating potential for clinical translation.

Spatial Distribution of Intracranial Vessel Wall Enhancement in Hypertension and Primary Angiitis of the CNS.

We hypothesized a difference in the spatial distribution of intracranial vessel wall enhancement between CNS vasculitis and risk factors for intracranial atherosclerotic disease (ICAD). Fifty-five vessel wall MR imaging (VWI) exams were included in this retrospective observational study. Intracranial arteries were evaluated for vessel wall enhancement by branching pattern (e.g., primary, secondary, and tertiary segments). Demographic and laboratory data as well as ICAD risk factors, including a diagnosis of hypertension, were collected. A diagnosis of primary angiitis of the CNS (PACNS) was confirmed by biopsy or clinical assessment by a stroke neurologist. Univariate and multivariate Poisson regression models were fit for the outcomes. In multivariate analyses, hypertension showed significant associations with primary (ß = 1.31, 95% CI 0.78-1.88, p < 0.0001) and secondary (ß = 1.15, 95% CI 0.29-2.18, p = 0.05) segments, contrasting with PACNS which showed a distal spatial distribution with significant associations with secondary (ß = 0.77, 95% CI 0.14-1.39, p = 0.05) and tertiary (ß = 1.34, 95% CI 0.68-2.01, p < 0.0001) segments. Our results suggest the spatial distribution of vessel wall enhancement is an important consideration when interpreting VWI exams, particularly in patients with a comorbid diagnosis of hypertension. Given the global prevalence of hypertension, these results are impactful and may improve image interpretation of VWI in stroke patients.

Non-GFR Determinants of Low-Molecular-Weight Serum Protein Filtration Markers in CKD.

BACKGROUND: Unlike the case with creatinine, conditions affecting the non-glomerular filtration rate (GFR) determinants of low-molecular-weight serum proteins, ß-trace protein (BTP), ß2-microglobulin (B2M), and cystatin C, are not well characterized. STUDY DESIGN: Pooled cross-sectional analysis of 3 studies. SETTING & PARTICIPANTS: 3,156 persons with chronic kidney disease from the MDRD (Modification of Diet in Renal Disease) Study, AASK (African American Study of Kidney Disease and Hypertension), and CRIC (Chronic Renal Insufficiency Cohort) Study. PREDICTORS: Demographic and clinical factors hypothesized to be associated with non-GFR determinants of the filtration markers, selected from literature review and physiologic and clinical considerations. OUTCOMES: Serum creatinine, BTP, B2M, and cystatin C levels. RESULTS: In multivariable-adjusted errors-in-variables regression models that included adjustment for measured GFR (mGFR) and mGFR measurement error, creatinine level had stronger associations with male sex, black race, and higher urine creatinine excretion than the other filtration markers. BTP was associated less strongly with age, similar in direction with sex, and opposite in direction with race than creatinine level. Like cystatin C, B2M level was associated less strongly with age, sex, and race than creatinine level. BTP, B2M, and cystatin C levels were associated more strongly than creatinine level with other factors, including urine protein excretion and weight for BTP, smoking and urine protein excretion for B2M, and smoking for cystatin C. LIMITATIONS: Findings may not be generalizable to populations without chronic kidney disease, and residual confounding with GFR due to incomplete adjustment for GFR measurement error. CONCLUSIONS: Like creatinine, serum levels of low-molecular-weight proteins are affected by conditions other than GFR. Knowledge of these conditions can aid the interpretation of GFR estimates and risk using these markers and guide the use of these filtration markers in developing GFR estimating equations.

[Cholesterol concentrations in cord blood of newborn infants].

OBJECTIVE: Familial hypercholesterolemia (FH) is an autosomal dominant disease with an estimated worldwide prevalence of 0.2%. It is caused by a multitude of low density lipoprotein receptor gene mutations. It is characterized with high levels of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and a high incidence of coronary artery disease in young adults. Cord blood cholesterol concentration is used for mass screening of FH. The purpose of this study was to detect the lipid levels of cord blood in newborn infants from China and to determine the cut-off point after 1 to 2 years follow-up. METHODS: TC, triglycerides (TG), LDL-C and high density lipoprotein cholesterol (HDL-C) were determined in 242 healthy full-term newborn infants. RESULTS: The mean values of TC, TG, LDL-C and HDL-C in cord blood were (1.69 +/- 0.40) mmol/L, (0.23 +/- 0.12) mmol/L, (0.81 +/- 0.21) mmol/L and (0.58 +/- 0.16) mmol/L (mean +/- standard deviation), respectively. The HDL-C concentration in male neonates was lower than that in female neonates (P < 0.05). CONCLUSION: After the follow-up of 1 to 2 years for FH, the recommended screening cut-off points were TC > or = 2.47 mmol/L and LDL-C > or = 0.89 mmol/L.