Over the past decade, there has been an abundance of research on the difference between age and age predicted using brain features, which is commonly referred to as the “brain age gap.” Researchers have identified that the brain age gap, as a linear transformation of an out‐of‐sample residual, is dependent on age. As such, any group differences on the brain age gap could simply be due to group differences on age. To mitigate the brain age gap's dependence on age, it has been proposed that age be regressed out of the brain age gap. If this modified brain age gap is treated as a corrected deviation from age, model accuracy statistics such as R² will be artificially inflated to the extent that it is highly improbable that an R² value below .85 will be obtained no matter the true model accuracy. Given the limitations of proposed brain age analyses, further theoretical work is warranted to determine the best way to quantify deviation from normality.

Comprehensive delineation of white matter (WM) microstructural maturation from birth to childhood is critical for understanding spatiotemporally differential circuit formation. Without a relatively large sample of datasets and coverage of critical developmental periods of both infancy and early childhood, differential maturational charts across WM tracts cannot be delineated. With diffusion tensor imaging (DTI) of 118 typically developing (TD) children aged 0–8 years and 31 children with autistic spectrum disorder (ASD) aged 2–7 years, the microstructure of every major WM tract and tract group was measured with DTI metrics to delineate differential WM maturation. The exponential model of microstructural maturation of all WM was identified. The WM developmental curves were separated into fast, intermediate, and slow phases in 0–8 years with distinctive time period of each phase across the tracts. Shorter periods of the fast and intermediate phases in certain tracts, such as the commissural tracts, indicated faster earlier development. With TD WM maturational curves as the reference, higher residual variance of WM microstructure was found in children with ASD. The presented comprehensive and differential charts of TD WM microstructural maturation of all major tracts and tract groups in 0–8 years provide reference standards for biomarker detection of neuropsychiatric disorders.

Progression of chronic kidney disease (CKD) portends myriad complications, including kidney failure. In this study, we analyze associations of 4638 plasma proteins among 3235 participants of the Chronic Renal Insufficiency Cohort Study with the primary outcome of 50% decline in estimated glomerular filtration rate or kidney failure over 10 years. We validate key findings in the Atherosclerosis Risk in the Communities study. We identify 100 circulating proteins that are associated with the primary outcome after multivariable adjustment, using a Bonferroni statistical threshold of significance. Individual protein associations and biological pathway analyses highlight the roles of bone morphogenetic proteins, ephrin signaling, and prothrombin activation. A 65-protein risk model for the primary outcome has excellent discrimination (C-statistic[95%CI] 0.862 [0.835, 0.889]), and 14/65 proteins are druggable targets. Potentially causal associations for five proteins, to our knowledge not previously reported, are supported by Mendelian randomization: EGFL9, LRP-11, MXRA7, IL-1 sRII and ILT-2. Modifiable protein risk markers can guide therapeutic drug development aimed at slowing CKD progression.

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.

BACKGROUND: Metabolomic profiling in individuals with chronic kidney disease (CKD) has the potential to identify novel biomarkers and provide insight into disease pathogenesis. METHODS: We examined the association between blood metabolites and CKD progression, defined as the subsequent development of end-stage renal disease (ESRD) or estimated glomerular filtrate rate (eGFR) halving, in 1,773 participants of the Chronic Renal Insufficiency Cohort (CRIC) study, 962 participants of the African-American Study of Kidney Disease and Hypertension (AASK), and 5,305 participants of the Atherosclerosis Risk in Communities (ARIC) study. RESULTS: In CRIC, more than half of the measured metabolites were associated with CKD progression in minimally adjusted Cox proportional hazards models, but the number and strength of associations were markedly attenuated by serial adjustment for covariates, particularly eGFR. Ten metabolites were significantly associated with CKD progression in fully adjusted models in CRIC; 3 of these metabolites were also significant in fully adjusted models in AASK and ARIC, highlighting potential markers of glomerular filtration (pseudouridine), histamine metabolism (methylimidazoleacetate), and azotemia (homocitrulline). Our findings also highlight N-acetylserine as a potential marker of kidney tubular function, with significant associations with CKD progression observed in CRIC and ARIC. CONCLUSION: Our findings demonstrate the application of metabolomics to identify potential biomarkers and causal pathways in CKD progression. FUNDING: This study was supported by the NIH (U01 DK106981, U01 DK106982, U01 DK085689, R01 DK108803, and R01 DK124399).