Diffusion imaging genomics provides novel insight into early mechanisms of cerebral small vessel disease.

Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia. Genetic risk loci for white matter hyperintensities (WMH), the most common MRI-marker of cSVD in older age, were recently shown to be significantly associated with white matter (WM) microstructure on diffusion tensor imaging (signal-based) in young adults. To provide new insights into these early changes in WM microstructure and their relation with cSVD, we sought to explore the genetic underpinnings of cutting-edge tissue-based diffusion imaging markers across the adult lifespan. We conducted a genome-wide association study of neurite orientation dispersion and density imaging (NODDI) markers in young adults (i-Share study: N = 1 758, (mean[range]) 22.1[18-35] years), with follow-up in young middle-aged (Rhineland Study: N = 714, 35.2[30-40] years) and late middle-aged to older individuals (UK Biobank: N = 33 224, 64.3[45-82] years). We identified 21 loci associated with NODDI markers across brain regions in young adults. The most robust association, replicated in both follow-up cohorts, was with Neurite Density Index (NDI) at chr5q14.3, a known WMH locus in VCAN. Two additional loci were replicated in UK Biobank, at chr17q21.2 with NDI, and chr19q13.12 with Orientation Dispersion Index (ODI). Transcriptome-wide association studies showed associations of STAT3 expression in arterial and adipose tissue (chr17q21.2) with NDI, and of several genes at chr19q13.12 with ODI. Genetic susceptibility to larger WMH volume, but not to vascular risk factors, was significantly associated with decreased NDI in young adults, especially in regions known to harbor WMH in older age. Individually, seven of 25 known WMH risk loci were associated with NDI in young adults. In conclusion, we identified multiple novel genetic risk loci associated with NODDI markers, particularly NDI, in early adulthood. These point to possible early-life mechanisms underlying cSVD and to processes involving remyelination, neurodevelopment and neurodegeneration, with a potential for novel approaches to prevention.

Brain-age prediction: Systematic evaluation of site effects, and sample age range and size.

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics.

Handedness and its genetic influences are associated with structural asymmetries of the cerebral cortex in 31,864 individuals.

Roughly 10% of the human population is left-handed, and this rate is increased in some brain-related disorders. The neuroanatomical correlates of hand preference have remained equivocal. We resampled structural brain image data from 28,802 right-handers and 3,062 left-handers (UK Biobank population dataset) to a symmetrical surface template, and mapped asymmetries for each of 8,681 vertices across the cerebral cortex in each individual. Left-handers compared to right-handers showed average differences of surface area asymmetry within the fusiform cortex, the anterior insula, the anterior middle cingulate cortex, and the precentral cortex. Meta-analyzed functional imaging data implicated these regions in executive functions and language. Polygenic disposition to left-handedness was associated with two of these regional asymmetries, and 18 loci previously linked with left-handedness by genome-wide screening showed associations with one or more of these asymmetries. Implicated genes included six encoding microtubule-related proteins: TUBB, TUBA1B, TUBB3, TUBB4A, MAP2, and NME7-mutations in the latter can cause left to right reversal of the visceral organs. There were also two cortical regions where average thickness asymmetry was altered in left-handedness: on the postcentral gyrus and the inferior occipital cortex, functionally annotated with hand sensorimotor and visual roles. These cortical thickness asymmetries were not heritable. Heritable surface area asymmetries of language-related regions may link the etiologies of hand preference and language, whereas nonheritable asymmetries of sensorimotor cortex may manifest as consequences of hand preference.

Brain artery diameters and risk of dementia and stroke.

INTRODUCTION: We tested the association of brain artery diameters with dementia and stroke risk in three distinct population-based studies using conventional T2-weighted brain magnetic resonance imaging (MRI) images. METHODS: We included 8420 adults > 40 years old from three longitudinal population-based studies with brain MRI scans. We estimated and meta-analyzed the hazard ratios (HRs) of the brain and carotids and basilar diameters associated with dementia and stroke. RESULT: Overall and carotid artery diameters > 95th percentile increased the risk for dementia by 1.74 (95% confidence interval [CI], 1.13-2.68) and 1.48 (95% CI, 1.12-1.96) fold, respectively. For stroke, meta-analyses yielded HRs of 1.59 (95% CI, 1.04-2.42) for overall arteries and 2.11 (95% CI, 1.45-3.08) for basilar artery diameters > 95th percentile. DISCUSSION: Individuals with dilated brain arteries are at higher risk for dementia and stroke, across distinct populations. Our findings underline the potential value of T2-weighted brain MRI-based brain diameter assessment in estimating the risk of dementia and stroke.

Association of retinal nerve layers thickness and brain imaging in healthy young subjects from the i-Share-Bordeaux study.

Given the anatomical and functional similarities between the retina and the brain, the retina could be a "window" for viewing brain structures. We investigated the association between retinal nerve fiber layers (peripapillary retinal nerve fiber layer, ppRNFL; macular ganglion cell-inner plexiform layer, GC-IPL; and macular ganglion cell complex, GCC), and brain magnetic resonance imaging (MRI) parameters in young health adults. We included 857 students (mean age: 23.3 years, 71.3% women) from the i-Share study. We used multivariate linear models to study the cross-sectional association of each retinal nerve layer thickness assessed by spectral-domain optical coherence tomography (SD-OCT) with structural (volumes and cortical thickness), and microstructural brain markers, assessed on MRI globally and regionally. Microstructural MRI parameters included diffusion tensor imaging (DTI) and Neurite Orientation Dispersion and Density Imaging (NODDI). On global brain analysis, thicker ppRNFL, GC-IPL and GCC were all significantly associated with patterns of diffusion metrics consistent with higher WM microstructural integrity. In regional analyses, after multiple testing corrections, our results suggested significant associations of some retinal nerve layers with brain regional gray matter occipital volumes and with diffusion MRI parameters in a region involved in the visual pathway and in regions containing associative tracts. No associations were found with global volumes or with global or regional cortical thicknesses. Results of this study suggest that some retinal nerve layers may reflect brain structures. Further studies are needed to confirm these results in young subjects.

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years.

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.

Greater male than female variability in regional brain structure across the lifespan.

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.

Large-Scale Phenomic and Genomic Analysis of Brain Asymmetrical Skew.

The human cerebral hemispheres show a left-right asymmetrical torque pattern, which has been claimed to be absent in chimpanzees. The functional significance and developmental mechanisms are unknown. Here, we carried out the largest-ever analysis of global brain shape asymmetry in magnetic resonance imaging data. Three population datasets were used, UK Biobank (N = 39 678), Human Connectome Project (N = 1113), and BIL&GIN (N = 453). At the population level, there was an anterior and dorsal skew of the right hemisphere, relative to the left. Both skews were associated independently with handedness, and various regional gray and white matter metrics oppositely in the two hemispheres, as well as other variables related to cognitive functions, sociodemographic factors, and physical and mental health. The two skews showed single nucleotide polymorphisms-based heritabilities of 4-13%, but also substantial polygenicity in causal mixture model analysis, and no individually significant loci were found in genome-wide association studies for either skew. There was evidence for a significant genetic correlation between horizontal brain skew and autism, which requires future replication. These results provide the first large-scale description of population-average brain skews and their inter-individual variations, their replicable associations with handedness, and insights into biological and other factors which associate with human brain asymmetry.

Novel characterization of the relationship between verbal list-learning outcomes and hippocampal subfields in healthy adults.

The relationship between hippocampal subfield volumetry and verbal list-learning test outcomes have mostly been studied in clinical and elderly populations, and remain controversial. For the first time, we characterized a relationship between verbal list-learning test outcomes and hippocampal subfield volumetry on two large separate datasets of 447 and 1,442 healthy young and middle-aged adults, and explored the processes that could explain this relationship. We observed a replicable positive linear correlation between verbal list-learning test free recall scores and CA1 volume, specific to verbal list learning as demonstrated by the hippocampal subfield volumetry independence from verbal intelligence. Learning meaningless items was also positively correlated with CA1 volume, pointing to the role of the test design rather than word meaning. Accordingly, we found that association-based mnemonics mediated the relationship between verbal list-learning test outcomes and CA1 volume. This mediation suggests that integrating items into associative representations during verbal list-learning tests explains CA1 volume variations: this new explanation is consistent with the associative functions of the human CA1.

Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes.

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade-albeit in a very limited manner-to behaviors as complex as the choice of one's occupation.

Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium.

Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here, the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium presents the largest-ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and intracranial volume. Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (n = 1,443 and 1,113, respectively), we found several asymmetries showing significant, replicable heritability. The structural asymmetries identified and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders.

Life-Course Socioeconomic Position and Hippocampal Atrophy in a Prospective Cohort of Older Adults.

OBJECTIVE: Low socioeconomic position (SEP) has been linked to an increased risk of dementia and cognitive decline. However, little is known about the association between SEP and morphologic brain changes in older age. This study examines the relationships between indicators of life-course SEP with both hippocampal volume (HcV) and HcV loss in a population-based cohort of 1328 older adults aged 65 to 80 years. METHODS: Multivariable linear regression models were used to estimate the associations of SEP with baseline HcV and the annual rate of HcV atrophy according to three life-course conceptual models: the sensitive/critical periods model (which explored SEP in specific periods: in childhood [using parental education], early adulthood [based on participants' education], and midlife [based on participants' socioprofessional group]); the accumulation-of-risk model (life-course cumulative SEP), and the social mobility model (life-course SEP trajectories). RESULTS: Participants with lower midlife SEP had smaller HcV (-0.08 cm; 95% confidence interval, -0.15 to -0.01) and 0.17% (95% confidence interval, 0.04%-0.30%) faster hippocampal atrophy than participants with higher midlife SEP. Childhood and early adulthood SEPs were not related to hippocampal measures. The accumulation-of-risk and the social mobility models revealed that the accumulation of socioeconomic disadvantage and declining socioeconomic trajectories were related to faster hippocampal atrophy. CONCLUSIONS: In this cohort of older adults, lower socioprofessional attainment in midlife and disadvantageous life-course socioeconomic position were associated with faster hippocampal atrophy, a cerebral change linked to cognitive disorders. Results support the hypothesized links between socioenvironmental exposures related to stress and/or cognitive enrichment and brain/cognitive reserve capacities.

Strong rightward lateralization of the dorsal attentional network in left-handers with right sighting-eye: an evolutionary advantage.

Hemispheric lateralization for spatial attention and its relationships with manual preference strength and eye preference were studied in a sample of 293 healthy individuals balanced for manual preference. Functional magnetic resonance imaging was used to map this large sample while performing visually guided saccadic eye movements. This activated a bilateral distributed cortico-subcortical network in which dorsal and ventral attentional/saccadic pathways elicited rightward asymmetrical activation depending on manual preference strength and sighting eye. While the ventral pathway showed a strong rightward asymmetry irrespective of both manual preference strength and eye preference, the dorsal frontoparietal network showed a robust rightward asymmetry in strongly left-handers, even more pronounced in left-handed subjects with a right sighting-eye. Our findings brings support to the hypothesis that the origin of the rightward hemispheric dominance for spatial attention may have a manipulo-spatial origin neither perceptual nor motor per se but rather reflecting a mechanism by which a spatial context is mapped onto the perceptual and motor activities, including the exploration of the spatial environment with eyes and hands. Within this context, strongly left-handers with a right sighting-eye may benefit from the advantage of having the same right hemispheric control of their dominant hand and visuospatial attention processing. We suggest that this phenomenon explains why left-handed right sighting-eye athletes can outperform their competitors in sporting duels and that the prehistoric and historical constancy of the left-handers ratio over the general population may relate in part on the hemispheric specialization of spatial attention.

Hippocampal atrophy and subsequent depressive symptoms in older men and women: results from a 10-year prospective cohort.

Several studies have reported smaller hippocampal volume in patients with depression. However, the temporality of the association is undetermined. One hypothesis is that hippocampal atrophy might be a susceptibility factor for depression. In the present study, we assessed whether hippocampal atrophy was associated with subsequent depressive symptoms in a cohort of older French adults (n = 1,309) who were 65-80 years of age and enrolled into the study in 1999-2001 in Dijon, France. Subjects were followed for more than 10 years. Participants underwent 2 cerebral magnetic resonance imaging scans, one at baseline and one at the 4-year follow-up. We used linear mixed models to estimate the associations of hippocampal atrophy with 1) the average depressive symptom scores over follow-up (using the Center for Epidemiologic Studies-Depression scale) measured biennially over the subsequent 6 years and 2) changes in symptom scores over follow-up. In women, a 2-standard-deviation increase in annual hippocampal atrophy was associated with a 1.67-point (95% confidence interval: 0.59, 2.77) increase in the average depressive symptom score over follow-up and with a 1.97-point (95% confidence interval: 0.68, 3.24) increase in scores over the 2 subsequent years but not with later changes in symptoms. No association was detected in men. Accounting for potential selective attrition (using inverse probability weights) did not alter results. Hippocampal atrophy was associated with more subsequent depressive symptoms and with shorter-term worsening of symptoms in women.

Normative modelling of brain morphometry across the lifespan with CentileBrain: algorithm benchmarking and model optimisation.

The value of normative models in research and clinical practice relies on their robustness and a systematic comparison of different modelling algorithms and parameters; however, this has not been done to date. We aimed to identify the optimal approach for normative modelling of brain morphometric data through systematic empirical benchmarking, by quantifying the accuracy of different algorithms and identifying parameters that optimised model performance. We developed this framework with regional morphometric data from 37 407 healthy individuals (53% female and 47% male; aged 3-90 years) from 87 datasets from Europe, Australia, the USA, South Africa, and east Asia following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The multivariate fractional polynomial regression (MFPR) emerged as the preferred algorithm, optimised with non-linear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3000 study participants. This model can inform about the biological and behavioural implications of deviations from typical age-related neuroanatomical changes and support future study designs. The model and scripts described here are freely available through CentileBrain.

How Traumatic Brain Injury History Relates to Brain Health MRI Markers and Dementia Risk: Findings from the 3C Dijon Cohort.

BACKGROUND: The long-term effects of traumatic brain injury (TBI) with loss of consciousness (LOC) on magnetic resonance imaging (MRI) markers of brain health and on dementia risk are still debated. OBJECTIVE: To investigate the associations of history of TBI with LOC with incident dementia and neuroimaging markers of brain structure and small vessel disease lesions. METHODS: The analytical sample consisted in 4,144 participants aged 65 and older who were dementia-free at baseline from the Three City -Dijon study. History of TBI with LOC was self-reported at baseline. Clinical Dementia was assessed every two to three years, up to 12 years of follow-up. A subsample of 1,675 participants <80 years old underwent a brain MRI at baseline. We investigated the associations between history of TBI with LOC and 1) incident all cause and Alzheimer's disease (AD) dementia using illness-death models, and 2) neuroimaging markers at baseline. RESULTS: At baseline, 8.3% of the participants reported a history of TBI with LOC. In fully-adjusted models, participants with a history of TBI with LOC had no statistically significant differences in dementia risk (HR = 0.90, 95% CI = 0.60-1.36) or AD risk (HR = 1.03, 95% CI = 0.69-1.52), compared to participants without TBI history. History of TBI with LOC was associated with lower white matter volume (ß= -4.58, p = 0.048), but not with other brain volumes, white matter hyperintensities volume, nor covert brain infarct. CONCLUSION: This study did not find evidence of an association between history of TBI with LOC and dementia or AD dementia risks over 12-year follow-up, brain atrophy, or markers of small vessel disease.

Normative Modeling of Brain Morphometry Across the Lifespan Using CentileBrain: Algorithm Benchmarking and Model Optimization.

We present an empirically benchmarked framework for sex-specific normative modeling of brain morphometry that can inform about the biological and behavioral significance of deviations from typical age-related neuroanatomical changes and support future study designs. This framework was developed using regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The Multivariate Factorial Polynomial Regression (MFPR) emerged as the preferred algorithm optimized using nonlinear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins, and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3,000 study participants. The model and scripts described here are freely available through CentileBrain (https://centilebrain.org/).

Patterns of hemodynamic low-frequency oscillations in the brain are modulated by the nature of free thought during rest.

During conscious rest, the mind switches into a state of wandering. Although this rich inner experience occupies a large portion of the time spent awake, how it relates to brain activity has not been well explored. Here, we report the results of a behavioral and functional magnetic resonance imaging (fMRI) study of the continuous resting state in 307 healthy participants. The analysis focused on the relationship between the nature of inner experience and the temporal correlations computed between the low-frequency blood oxygen level-dependent (BOLD) fluctuations (0.01-0.1 Hz) of five large-scale modules. The subjects' self-reported time spontaneously spent on visual mental imagery and/or inner language was used as the behavioral variable. Decreased temporal correlations between modules were revealed when subjects reported more time spent thinking in mental images and inner language. These changes segregated the three modules supporting inner-oriented activities from those associated with sensory-related and externally guided activities. Among the brain areas associated with inner-oriented processing, the module including the lateral parietal and frontal regions (commonly described as being engaged in the manipulation and maintenance of internal information) was implicated in the majority of these effects. The preponderance of segregation appears to be the signature of the spontaneous sequence of thoughts during rest that are not constrained by logic, causality, or even a rigorous temporal organization. In other words, though goal-directed tasks have been demonstrated to rely on specific regional integration, mind wandering can be characterized by widespread modular segregation. Overall, the present study provides evidence that modulation of spontaneous low-frequency fluctuations in the brain is at least partially explained by spontaneous conscious cognition while at rest.

MRI atrophy of the caudate nucleus and slower walking speed in the elderly.

Cerebral white matter lesions are associated with poorer motor performances in the elderly, but the role of gray matter atrophy remains largely unknown. We investigated the cross-sectional relation between brain regional gray matter volumes and walking speed over 6m in the 3C-Dijon study, a large population-based study of community-dwelling persons aged 65 years and over (N=1623). Regional gray matter volumes were obtained using an automated anatomical labeling parcellation method. Multivariable analyses were performed using a semi-Bayes approach. After adjustment for potential confounders, persons who walked slower had a smaller volume of basal ganglia (regression coefficient [ß]=0.054, standard error [SE]=0.028, p=0.05). In more detailed analyses, the volume of the caudate nucleus had a preponderant role on this association (ß=0.049, SE=0.019, p=0.009), and walking speed decreased progressively with the volume of the caudate nucleus (p for linear trend<0.001). These results underline the role of gray matter subcortical structures, in particular of the caudate nucleus, in the age-related decline of motor performances among community-dwelling elderly subjects.