Frauke Beyer

Predicting brain-age from multimodal imaging data captures cognitive impairment

Abstract The disparity between the chronological age of an individual and their brain‐age measured based on biological information has the potential to offer clinically relevant biomarkers of neurological syndromes that emerge late in the lifespan. While prior brain‐age prediction studies have relied exclusively on either structural or functional brain data, here we investigate how multimodal brain‐imaging data improves age prediction. Using cortical anatomy and whole‐brain functional connectivity on a large adult lifespan sample (N=2354, age 19–82), we found that multimodal data improves brain‐based age prediction, resulting in a mean absolute prediction error of 4.29 years. Furthermore, we found that the discrepancy between predicted age and chronological age captures cognitive impairment. Importantly, the brain‐age measure was robust to confounding effects: head motion did not drive brain‐based age prediction and our models generalized reasonably to an independent dataset acquired at a different site (N=475). Generalization performance was increased by training models on a larger and more heterogeneous dataset. The robustness of multimodal brain‐age prediction to confounds, generalizability across sites, and sensitivity to clinically‐relevant impairments, suggests promising future application to the early prediction of neurocognitive disorders. HighlightsBrain‐based age prediction is improved with multimodal neuroimaging data.Participants with cognitive impairment show increased brain aging.Age prediction models are robust to motion and generalize to independent datasets from other sites.

Higher body mass index is associated with reduced posterior default mode connectivity in older adults

Obesity is a complex neurobehavioral disorder that has been linked to changes in brain structure and function. However, the impact of obesity on functional connectivity and cognition in aging humans is largely unknown. Therefore, the association of body mass index (BMI), resting‐state network connectivity, and cognitive performance in 712 healthy, well‐characterized older adults of the Leipzig Research Center for Civilization Diseases (LIFE) cohort (60–80 years old, mean BMI 27.6 kg/m2 ± 4.2 SD, main sample: n = 521, replication sample: n = 191) was determined. Statistical analyses included a multivariate model selection approach followed by univariate analyses to adjust for possible confounders. Results showed that a higher BMI was significantly associated with lower default mode functional connectivity in the posterior cingulate cortex and precuneus. The effect remained stable after controlling for age, sex, head motion, registration quality, cardiovascular, and genetic factors as well as in replication analyses. Lower functional connectivity in BMI‐associated areas correlated with worse executive function. In addition, higher BMI correlated with stronger head motion. Using 3T neuroimaging in a large cohort of healthy older adults, independent negative associations of obesity and functional connectivity in the posterior default mode network were observed. In addition, a subtle link between lower resting‐state connectivity in BMI‐associated regions and cognitive function was found. The findings might indicate that obesity is associated with patterns of decreased default mode connectivity similar to those seen in populations at risk for Alzheimers disease. Hum Brain Mapp 38:3502–3515, 2017.

Effects of resveratrol on memory performance, hippocampus connectivity and microstructure in older adults: A randomized controlled trial

Introduction: The polyphenol resveratrol has been suggested to exert beneficial effects on memory and the aging hippocampus due to calorie‐restriction mimicking effects. However, the evidence based on human interventional studies is scarce. We therefore aimed to determine the effects of resveratrol on memory performance, and to identify potential underlying mechanisms using a broad array of blood‐based biomarkers as well as hippocampus connectivity and microstructure assessed with ultra‐high field magnetic resonance imaging (UHF‐MRI). Methods: In this double‐blind, randomized controlled trial, 60 elderly participants (60–79 years) with a wide body‐mass index (BMI) range of 21–37 kg/m2 were randomized to receive either resveratrol (200mg/day) or placebo for 26 weeks (registered at ClinicalTrials.gov: NCT02621554). Baseline and follow‐up assessments included the California Verbal Learning Task (CVLT, main outcome), the ModBent task, anthropometry, markers of glucose and lipid metabolism, inflammation and neurotrophins derived from fasting blood, multimodal neuroimaging at 3 and 7T, and questionnaires to assess confounding factors. Results: Multivariate repeated‐measures ANOVA did not detect significant time by group effects for CVLT performance. There was a trend for preserved pattern recognition memory after resveratrol, while performance decreased in the placebo group (n.s., p=0.07). Further exploratory analyses showed increases in both groups over time in body fat, cholesterol, fasting glucose, interleukin 6, high sensitive C‐reactive protein, tumor necrosis factor alpha and in mean diffusivity of the subiculum and presubiculum, as well as decreases in physical activity, brain‐derived neurotrophic factor and insulin‐like growth factor 1at follow‐up, which were partly more pronounced after resveratrol. Discussion: This interventional study failed to show significant improvements in verbal memory after 6 months of resveratrol in healthy elderly with a wide BMI range. A non‐significant trend emerged for positive effects on pattern recognition memory, while possible confounding effects of unfavorable changes in lifestyle behavior, neurotrophins and inflammatory markers occurred. Our findings also indicate the feasibility to detect (un)healthy aging‐related changes in measures of hippocampus microstructure after 6 months using 7T diffusion MRI. More studies incorporating a longer duration and larger sample size are needed to determine if resveratrol enhances memory performance in healthy older adults. HIGHLIGHTSIn this randomized clinical trial, 6 months resveratrol supplementation showed no significant effects on verbal memory compared to placebo.Unfavorable changes in lifestyle factors at follow‐up might have introduced confounding.Secondary analyses showed a trend towards preserved pattern recognition.We used multimodal ultra high field MRI to detect subtle changes in microstructure of hippocampus subfields.

White matter microstructural variability mediates the relation between obesity and cognition in healthy adults

&NA; Obesity has been linked with structural and functional brain changes. However, the impact of obesity on brain and cognition in aging remains debatable, especially for white matter. We therefore aimed to determine the effects of obesity on white matter microstructure and potential implications for cognition in a well‐characterized large cohort of healthy adults. In total, 1255 participants (50% females, 19–80 years, BMI 16.8–50.2 kg/m2) with diffusion‐weighted magnetic resonance imaging at 3T were analysed. Tract‐based spatial statistics (TBSS) probed whether body mass index (BMI) and waist‐to‐hip ratio (WHR) were related to fractional anisotropy (FA). We conducted partial correlations and mediation analyses to explore whether obesity or regional FA were related to cognitive performance. Analyses were adjusted for demographic, genetic, and obesity‐associated confounders. Results showed that higher BMI and higher WHR were associated with lower FA in multiple white matter tracts (p < 0.05, FWE‐corrected). Mediation analyses provided evidence for indirect negative effects of higher BMI and higher WHR on executive functions and processing speed through lower FA in fiber tracts connecting (pre)frontal, visual, and associative areas (indirect paths, |ß| ≥ 0.01; 99% |CI| > 0). This large cross‐sectional study showed that obesity is correlated with lower FA in multiple white matter tracts in otherwise healthy adults, independent of confounders. Moreover, although effect sizes were small, mediation results indicated that visceral obesity was linked to poorer executive functions and lower processing speed through lower FA in callosal and associative fiber tracts. Longitudinal studies are needed to support this hypothesis. HighlightsWe examined effects of obesity on white matter microstructure in DTI.Obesity was associated with reduced FA in multiple white matter tracts.Obesity related to poorer cognitive performance via lower FA.

Planar cell polarity pathway and development of the human visual cortex

The radial unit hypothesis provides a framework for global (proliferation) and regional (distribution) expansion of the primate cerebral cortex1. Using principal component analysis (PCA), we have identified cortical regions with shared variance in their surface area and cortical thickness, respectively, segmented from magnetic resonance images obtained in 19,171 participants. We then carried out meta-analyses of genome-wide association studies of the first two principal components for each phenotype. For surface area (but not cortical thickness), we have detected strong associations between each of the components and single nucleotide polymorphisms in a number of gene loci. The first (“global”) component was associated mainly with loci on chromosome 17 (8.8×10 -26 ≤ p ≤ 2.3×10-14), including those detected previously as linked with intracranial volume2,3. The second (regional) component captured shared variation in the surface area of the primary and adjacent secondary visual cortices and showed a robust association with polymorphisms in a locus on chromosome 14 containing Disheveled Associated Activator of Morphogenesis 1 (DAAM1; p=3.0×10-32). DAAM1 is a key component in the planar-cell-polarity signaling pathway4,5. In follow-up studies, we have focused on the latter finding and established that: (1) DAAM1 is highly expressed between 12th and 22nd post-conception weeks in the human cerebral cortex; (2) genes co-expressed with DAAM1 in the primary visual cortex are enriched in mitochondria-related pathways; and (3) volume of the lateral geniculate nucleus, which projects to regions of the visual cortex staining for cytochrome oxidase (a mitochondrial enzyme), correlates with the surface area of the visual cortex in major-allele homozygotes but not in carriers of the minor allele. Altogether, we speculate that - in concert with thalamocortical input to cortical subplate - DAAM1 enables migration of neurons to cytochrome-oxidase rich regions of the visual cortex, and, in turn, facilitates regional expansion of this set of cortical regions during development.

Neuroanatomical correlates of food addiction and obesity in the general population

The food addiction model suggests neurobiological similarities between substance-related and addictive disorders and obesity. While structural brain differences have been consistently reported in these conditions, little is known about the neuroanatomical correlates of food addiction. We therefore assessed whether food addiction, assessed with the Yale Food Addiction Scale (YFAS), related to obesity, personality and brain structure in a large population-based sample (n=625; 20-59 years old, 45% women). A higher YFAS symptom score correlated with obesity and disinhibited eating. In a whole-brain analysis, YFAS symptom score was not associated with cortical thickness nor subcortical gray matter volumes. Higher body mass index (BMI) correlated with reduced thickness of (pre)frontal, temporal and occipital cortex. Bayes factor analysis suggested that BMI and - to a smaller extent - YFAS symptom score contributed independently to right lateral orbitofrontal cortex thickness. Our study shows that food addiction is not associated with neuroanatomical differences in a large population-based sample, and does not account for the major part of obesity-associated gray matter alterations. Yet, food addiction might explain additional variance in orbitofrontal cortex, a hub area of the reward network. Longitudinal studies implementing both anatomical and functional MRI could further disentangle the neural mechanisms of addictive eating behaviors.

Genetic Determinants of Cortical Structure (Thickness, Surface Area and Volumes) among Disease Free Adults in the CHARGE Consortium

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,822 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 161 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

The age-dependent relationship between resting heart rate variability and functional brain connectivity

&NA; Resting heart rate variability (HRV), an index of parasympathetic cardioregulation and an individual trait marker related to mental and physical health, decreases with age. Previous studies have associated resting HRV with structural and functional properties of the brain – mainly in cortical midline and limbic structures. We hypothesized that aging affects the relationship between resting HRV and brain structure and function. In 388 healthy subjects of three age groups (140 younger: 26.0 ± 4.2 years, 119 middle‐aged: 46.3 ± 6.2 years, 129 older: 66.9 ± 4.7 years), gray matter volume (GMV, voxel‐based morphometry) and resting state functional connectivity (eigenvector centrality mapping and exploratory seed‐based functional connectivity) were related to resting HRV, measured as the root mean square of successive differences (RMSSD). Confirming previous findings, resting HRV decreased with age. For HRV‐related GMV, there were no statistically significant differences between the age groups, nor similarities across all age groups. In whole‐brain functional connectivity analyses, we found an age‐dependent association between resting HRV and eigenvector centrality in the bilateral ventromedial prefrontal cortex (vmPFC), driven by the younger adults. Across all age groups, HRV was positively correlated with network centrality in the bilateral posterior cingulate cortex. Seed‐based functional connectivity analysis using the vmPFC cluster revealed an HRV‐related cortico‐cerebellar network in younger but not in middle‐aged or older adults. Our results indicate that the decrease of HRV with age is accompanied by changes in functional connectivity along the cortical midline. This extends our knowledge of brain‐body interactions and their changes over the lifespan.

Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρgenetic = −0.59, p-value = 3.14 × 10−6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.An increase in the volume of the brain lateral ventricles is a sign of normal aging, but can also be associated with neurological and psychiatric disorders. Here, Vojinovic et al. identify seven genetic loci in a GWA study for ventricular volume in 23,500 individuals and find correlation with thalamus volume.

EFFECTS OF LEPTIN ON HIPPOCAMPUS VOLUME AND COGNITIVE PERFORMANCE

VENs were the same in AD compared to controls. Interestingly, while the ratio of GABRQ-expressing neurons was significantly lower in bvFTD (p1⁄40.03) compared to controls, this ratio was significantly increased in AD compared to controls (p1⁄40.05). Conclusions:We show that GABRQ-expressing neurons are selectively vulnerable in bvFTD. Our data indicates that in AD cases this group of neurons is spared in the ACC, and suggests that other Layer 5 neurons are targeted by neurodegeneration in AD. The selective vulnerability of VENs in bvFTD is shared with the surrounding GABRQ-expressing neurons, implicating that a larger neuronal group specific to ACC and FI is linked to social-emotional behavior.