Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth.

Arterial spin labeling (ASL) is a promising non-invasive magnetic resonance imaging (MRI) technique for measuring regional cerebral blood flow (rCBF) or perfusion in vivo. To evaluate the feasibility of ASL as a biomarker for clinical trials, it is important to examine test-retest reproducibility. We investigated both inter-and intra-session reproducibility of perfusion MRI using a pulsed ASL (PASL) sequence PICORE Q2TIPS with an echo-planar imaging (EPI) readout. Structural MRI regions of interest (ROIs) were extracted individually by automated parcellation and segmentation methods using FreeSurfer. These cortical and subcortical ROIs were used to assess regional perfusion stability. Our results indicated regional variability in grey matter rCBF. Although rCBF measurements were characterized by intersubject variation, our results also indicated relatively less within-subject variability estimated as within-subject standard deviation (SD W ) (intersession SD W : 2.0 to 8.8; intrasession SD W : 2.8 to 9.6) and acceptable reliabilities as measured using intraclass correlation coefficient (ICC) (intersession ICC: 0.68 to 0.94; intrasession ICC: 0.66 to 0.95) for regional MRI perfusion measurements using the PICORE Q2TIPS technique. Overall, our findings suggest that PASL is a technique with good within and between session reproducibility. Further reproducibility studies in target populations relevant for specific clinical trials of neurovascular related agents will be important and the present results provide a framework for such assessments.

Background: Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease impacting an estimated 44 million adults worldwide. The causal pathology of AD (accumulation of amyloid-beta and tau), precedes hallmark symptoms of dementia by more than a decade, necessitating development of early diagnostic markers of disease onset, particularly for new drugs that aim to modify disease processes. To evaluate differentially methylated positions (DMPs) as novel blood-based biomarkers of AD, we used a subset of 653 individuals with peripheral blood (PB) samples in the Alzheimer's disease Neuroimaging Initiative (ADNI) consortium. The selected cohort of AD, mild cognitive impairment (MCI), and age-matched healthy controls (CN) all had imaging, genetics, transcriptomics, cerebrospinal protein markers, and comprehensive clinical records, providing a rich resource of concurrent multiomics and phenotypic information on a well-phenotyped subset of ADNI participants.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.