•Associations of vitamin D levels with brain age and brain volumes were tested in 1865 subjects.•Vitamin D deficiency was associated with increased brain aging.•Vitamin D levels were positively ...associated with total brain and gray matter volumes.•Hippocampal volumes showed no association with vitamin D levels.
Vitamin D deficiency has been associated with reduced neurocognitive functioning and the neurodegenerative processes. However, existing evidence on brain structural correlates of vitamin D deficiency is controversial. We sought to investigate associations of vitamin D levels with imaging patterns of brain aging. In addition, we investigated whether low vitamin D levels were associated with gray matter volumes, whole brain volumes and hippocampus volumes. Structural MRI data and vitamin D levels were obtained in 1,865 subjects from the general population. Linear regressions were applied to investigate the association of vitamin D levels and vitamin D deficiency with imaging derived brain age, total brain, gray matter and hippocampal volumes. Different sets of covariates were included. Vitamin D deficiency was significantly associated with increased brain age. Also, linear vitamin D levels were significantly associated with total brain and gray matter volumes, while no significant association with hippocampal volume was found. Further interaction analyses showed that this association was only significant for male subjects. Our results support previous findings suggesting that vitamin D-deficient individuals have an accelerated brain aging. In addition, associations between vitamin D levels and total brain/ gray matter volumes suggest neuroprotective effects of vitamin D on the brain.
One of the features that distinguishes modern humans from our extinct relatives and ancestors is a globular shape of the braincase 1–4. As the endocranium closely mirrors the outer shape of the ...brain, these differences might reflect altered neural architecture 4, 5. However, in the absence of fossil brain tissue, the underlying neuroanatomical changes as well as their genetic bases remain elusive. To better understand the biological foundations of modern human endocranial shape, we turn to our closest extinct relatives: the Neandertals. Interbreeding between modern humans and Neandertals has resulted in introgressed fragments of Neandertal DNA in the genomes of present-day non-Africans 6, 7. Based on shape analyses of fossil skull endocasts, we derive a measure of endocranial globularity from structural MRI scans of thousands of modern humans and study the effects of introgressed fragments of Neandertal DNA on this phenotype. We find that Neandertal alleles on chromosomes 1 and 18 are associated with reduced endocranial globularity. These alleles influence expression of two nearby genes, UBR4 and PHLPP1, which are involved in neurogenesis and myelination, respectively. Our findings show how integration of fossil skull data with archaic genomics and neuroimaging can suggest developmental mechanisms that may contribute to the unique modern human endocranial shape.
•We use fossil skull data to derive an index of endocranial shape in human MRI scans•In 4,468 Europeans, we screen introgressed Neandertal SNPs for association with the index•Lead SNPs consistently associate with reduced globularity in five separate subsamples•These SNPs affect neural expression of two genes linked to neurogenesis and myelination
Gunz, Tilot et al. combine paleoanthropology, archaic genomics, neuroimaging, and gene expression to study biological foundations of the characteristic modern human endocranial shape. They find introgressed Neandertal alleles that associate with reduced endocranial globularity and affect expression of genes linked to neurogenesis and myelination.
Childhood abuse was inconsistently related to whole-brain cortical thickness in former studies. However, both childhood abuse and cortical thickness have been associated with depressive symptoms. We ...hypothesised that childhood abuse moderates the association between depressive symptoms and cortical thickness. In 1551 individuals of the general population, associations between whole-brain cortical thickness and the interaction of childhood abuse (emotional, physical, and sexual) and depressive symptoms were analysed using an ANCOVA. Linear regression analyses were used to estimate the same effect on the cortical thickness of 34 separate regions (Desikan-Killiany-atlas). A significant interaction effect of childhood abuse and depressive symptoms was observed for whole-brain cortical thickness (
F
(2, 1534) = 5.28,
p
= 0.007). A thinner cortex was associated with depressive symptoms in abused (
t
value = 2.78,
p
= 0.025) but not in non-abused participants (
t
value = − 1.50,
p
= 0.224). Focussing on non-depressed participants, a thicker whole-brain cortex was found in abused compared to non-abused participants (
t
value = − 2.79,
p
= 0.025). Similar interaction effects were observed in 12 out of 34 cortical regions. Our results suggest that childhood abuse is associated with reduced cortical thickness in subjects with depressive symptoms. In abused subjects without depressive symptoms, larger cortical thickness might act compensatory and thus reflect resilience against depressive symptoms.
Background
In the medical imaging domain, deep learning‐based methods have yet to see widespread clinical adoption, in part due to limited generalization performance across different imaging devices ...and acquisition protocols. The deviation between estimated brain age and biological age is an established biomarker of brain health and such models may benefit from increased cross‐site generalizability.
Purpose
To develop and evaluate a deep learning‐based image harmonization method to improve cross‐site generalizability of deep learning age prediction.
Study Type
Retrospective.
Population
Eight thousand eight hundred and seventy‐six subjects from six sites. Harmonization models were trained using all subjects. Age prediction models were trained using 2739 subjects from a single site and tested using the remaining 6137 subjects from various other sites.
Field Strength/Sequence
Brain imaging with magnetization prepared rapid acquisition with gradient echo or spoiled gradient echo sequences at 1.5 T and 3 T.
Assessment
StarGAN v2, was used to perform a canonical mapping from diverse datasets to a reference domain to reduce site‐based variation while preserving semantic information. Generalization performance of deep learning age prediction was evaluated using harmonized, histogram matched, and unharmonized data.
Statistical Tests
Mean absolute error (MAE) and Pearson correlation between estimated age and biological age quantified the performance of the age prediction model.
Results
Our results indicated a substantial improvement in age prediction in out‐of‐sample data, with the overall MAE improving from 15.81 (±0.21) years to 11.86 (±0.11) with histogram matching to 7.21 (±0.22) years with generative adversarial network (GAN)‐based harmonization. In the multisite case, across the 5 out‐of‐sample sites, MAE improved from 9.78 (±6.69) years to 7.74 (±3.03) years with histogram normalization to 5.32 (±4.07) years with GAN‐based harmonization.
Data Conclusion
While further research is needed, GAN‐based medical image harmonization appears to be a promising tool for improving cross‐site deep learning generalization.
Level of Evidence
4
Technical Efficacy
Stage 1
Perivascular spaces (PVS) are emerging markers of cerebral small vessel disease (CSVD), but research on their determinants has been hampered by conflicting results from small single studies using ...heterogeneous rating methods. In this study, we therefore aimed to identify determinants of PVS burden in a pooled analysis of multiple cohort studies using 1 harmonized PVS rating method.
Individuals from 10 population-based cohort studies with adult participants from the Uniform Neuro-Imaging of Virchow-Robin Spaces Enlargement consortium and the UK Biobank were included. On MRI scans, we counted PVS in 4 brain regions (mesencephalon, hippocampus, basal ganglia, and centrum semiovale) according to a uniform and validated rating protocol, both manually and automated using a deep learning algorithm. As potential determinants, we considered demographics, cardiovascular risk factors,
genotypes, and other imaging markers of CSVD. Negative binomial regression models were used to examine the association between these determinants and PVS counts.
In total, 39,976 individuals were included (age range 20-96 years). The average count of PVS in the 4 regions increased from the age 20 years (0-1 PVS) to 90 years (2-7 PVS). Men had more mesencephalic PVS (OR 95% CI = 1.13 1.08-1.18 compared with women), but less hippocampal PVS (0.82 0.81-0.83). Higher blood pressure, particularly diastolic pressure, was associated with more PVS in all regions (ORs between 1.04-1.05). Hippocampal PVS showed higher counts with higher high-density lipoprotein cholesterol levels (1.02 1.01-1.02), glucose levels (1.02 1.01-1.03), and
ε4-alleles (1.02 1.01-1.04). Furthermore, white matter hyperintensity volume and presence of lacunes were associated with PVS in multiple regions, but most strongly with the basal ganglia (1.13 1.12-1.14 and 1.10 1.09-1.12, respectively).
Various factors are associated with the burden of PVS, in part regionally specific, which points toward a multifactorial origin beyond what can be expected from PVS-related risk factor profiles. This study highlights the power of collaborative efforts in population neuroimaging research.
Using oral contraceptives has been implicated in the aetiology of stress-related disorders like depression. Here, we followed the hypothesis that oral contraceptives deregulate the HPA-axis by ...elevating circulating cortisol levels. We report for a sample of 233 pre-menopausal women increased circulating cortisol levels in those using oral contraceptives. For women taking oral contraceptives, we observed alterations in circulating phospholipid levels and elevated triglycerides and found evidence for increased glucocorticoid signalling as the transcript levels of the glucocorticoid-regulated genes DDIT4 and FKBP5 were increased in whole blood. The effects were statistically mediated by cortisol. The associations of oral contraceptives with higher FKBP5 mRNA and altered phospholipid levels were modified by rs1360780, a genetic variance implicated in psychiatric diseases. Accordingly, the methylation pattern of FKBP5 intron 7 was altered in women taking oral contraceptives depending on the rs1360780 genotype. Moreover, oral contraceptives modified the association of circulating cortisol with depressive symptoms, potentially explaining conflicting results in the literature. Finally, women taking oral contraceptives displayed smaller hippocampal volumes than non-using women. In conclusion, the integrative analyses of different types of physiological data provided converging evidence indicating that oral contraceptives may cause effects analogous to chronic psychological stressors regarding the regulation of the HPA axis.
Previous studies provided evidence for the importance of cardiac structure abnormalities, in particular greater left ventricular (LV) mass, for brain aging, but longitudinal studies are lacking to ...date. We included 926 individuals (median age 48 years; 53% women) from the TREND cohort of the Study of Health in Pomerania (SHIP) without reduced ejection fraction or a history of myocardial infarction. LV mass index (LVMI) was determined by echocardiography at baseline. Brain morphometric measurements were derived from magnetic resonance images at baseline and 7‐year follow‐up. Direct effects of baseline LVMI on brain morphometry at follow‐up were estimated using linear regression models with adjustment for baseline brain morphometry. At baseline, median LVMI was 40 g/m2.7 and 241 individuals (26%) met the criterion of LV hypertrophy. After correction for multiple testing, baseline LVMI was directly associated with reduced global cortical thickness and increased cortical brain age at follow‐up independent from hypertension and blood pressure. Exposure‐outcome relations were nonlinear and significantly stronger in the upper half of the exposure distribution. Specifically, an increase in baseline LVMI from the 50% quantile to the 95% quantile was associated additional 2.7 years (95% confidence interval = 1.5 years, 3.8 years) of cortical brain age at follow‐up. Additional regional analyses yielded bilateral effects on multiple frontal cortical regions. Our findings highlight the role of cardiac structure in brain aging. LVMI constitutes an easily measurable marker that might help to identify persons at risk for cognitive impairment and dementia.
We investigated if a larger heart predicts faster brain aging. We found that in the general population, a greater heart (beyond clinical cut‐off points) is related to advanced brain aging 7 years later. This highlights the importance of future interventional studies to normalize heart size and improve neuroprotective effects.
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