Larger Total Brain Volume Research Articles

Cardiorespiratory Fitness And Aortic Hemodynamics Are Associated With Brain Volume In Healthy Older Adults

Cardiorespiratory fitness (CFR) is positively associated with greater brain volume in older adults; however, the mechanism is unknown. Improved structure and function of the large vessels supplying the brain due to habitual exercise may explain why CFR influences brain volume. PURPOSE: The purpose of this study was to determine if aortic hemodynamics modify the association between CFR and brain volume in both young and older adults. METHODS: Young (YA; n =27, age =25±5 y, women =15) and older (OA; n =23, age =64±5 y, women =11) healthy adults ranging from sedentary to exercise trained were studied. CFR was assessed using an incremental maximal exercise test on a cycle ergometer (VO2max). Total brain volume (gray matter + white matter) was determined using a T1 weighted scan on a 3T MRI scanner. Aortic hemodynamics were obtained from applanation tonometry (SphygmoCor) where the aortic pressure waveform was used to calculate aortic augmentation index (AIx). RESULTS: Young adults had a larger total brain volume (YA; 1.16±0.02 l vs. OA; 1.10±0.02 l, p<0.05), higher VO2 max (YA; 40±1 ml/kg/min vs. OA; 32±2 ml/kg/min, p<0.05), and lower AIx (YA; 2.9±2.5 % vs. OA; 19.2±2.4 %, p<0.05) compared with older adults. VO2max was not associated with AIx in young adults (p>0.05); however, VO2max was negatively associated with AIx in older adults (r =-0.61, p<0.05) such that older adults with higher CFR demonstrated lower aortic hemodynamics. There were no associations between VO2max, AIx, and total brain volume in young adults (p>0.05 for all). Conversely, both VO2max (r =0.51, p<0.05) and AIx (r =-0.64, p<0.05) were associated with total brain volume in older adults. When VO2max and AIx were entered into the model using multiple linear regression, VO2max was no longer a significant predictor of total brain volume in older adults (VO2max; p =0.41, AIx; p =0.03). CONCLUSIONS: High CFR and low aortic hemodynamics are associated with larger total brain volumes in older adults. Using multiple linear regression, aortic hemodynamics are a better predictor of total brain volume than CFR in older adults. Improved aortic hemodynamics may be a mechanism by which habitual exercise protects the brain from age-related volume decline. Supported by NIH grant HL118154.

Brain tissue volumes at term-equivalent age are associated with early motor behavior in very preterm infants.

Preterm birth is associated with a wide range of adverse developmental outcomes, including sensory, motor, cognitive and language impairments, and behavioral or attention problems. Subtle motor deficits that might emerge in premature infants with no evident or with mild brain injury encompass qualitative and quantitative aspects of motor behavior. This prospective cohort study provided an evaluation of the relationship between brain tissue volumes revealed by magnetic resonance imaging (MRI) at term-equivalent age and motor behavior in infancy in very preterm infants (total number=40; mean gestational age=28weeks+4days; mean birth weight=1190g) without evident or with mild brain injury. Infants were recruited at birth and assessed at 12months corrected age using the tool for qualitative and quantitative assessment of motor behavior, infant motor profile. The brain tissue was segmented first using advanced segmentation techniques and the volumes were measured by summing the volumes of all voxels belonging to a particular tissue class. The associations between volumetric brain MRI measures with motor behavior were explored using linear regression analyses. Results showed that larger total brain volumes were associated with higher motor score. Similar relationships were documented for parietal lobe, deep gray matter, and cerebellum volumes. Volumetric quantitative data of brain structures may serve as biomarkers for subtle motor deficits described in very preterm born infants without or with mild brain lesions apparent on MRI.

Abstract MP26: Mediterranean Diet And Brain Magnetic Resonance Imaging Measures In Young And Older Adults

Introduction: Accumulative evidence has suggested that higher adherence to a healthy dietary pattern, such as Mediterranean diet (MeDi), is associated with preservation of brain structure and less cerebrovascular events. Little is known for these associations across lifespan. Hypothesis: We hypothesized that MeDi was associated with brain atrophy or small vessel pathology measured using magnetic resonance imaging (MRI) in a cohort of healthy adults aged 20-80. Methods: This cross-sectional study included 375 healthy, non-demented adults recruited from market mailing within a 50-mile radius of Columbia University Medical Center in New York City. The participants age ranged 20-80 years old (mean 55, SD=16); had on average 16 (SD=2.3) years of education; 210 (56%) were females; 67% were Whites, 20% African-Americans, and 13% others. MeDi score (range 0-9) was calculated based on food consumption information collected through food-frequency questionnaire. Total brain volume (TBV) and white matter hyperintensity (WMH) were derived from high-resolution structural MRI scans. We examined the association of MeDi with TBV (milliliter, adjusted for intracranial volume) and WMH (milliliter, log transformed) using regression models adjusted for age, gender, race, education, and total caloric intake. Stratified analyses were performed among young (20-45), mid-age (46-65), and older (65-80) adults. Results: In multivariable-adjusted linear regression models, one unit increase in MeDi score, indicating consumption of one more food meeting the desirable level, was associated with larger TBV (β=2.79, p=0.027) and of less WMH (β= -0.058, p=0.041), corresponding to roughly 1.8 years and 1.3 years of less aging (β=-1.54 for age on TBV and 0.044 for age on WMH), respectively. Furthermore, we found the association between MeDi and TBV was similar across age groups, while the association between MeDi and WMH was only significant in the young adults (b=-0.189, p=0.002). Conclusions: Higher MeDi adherence was associated with healthier brain, indicated by larger brain volumes and less white matter lesion burden. These findings suggest that following a healthy diet may help maintain brain health across life span. To our knowledge, this is the first study to examine the relation of MeDi adherence to brain measures in healthy adults of all ages. The novel findings, especially the finding of MeDi and WMH in young adults, are worth of further confirmation in larger and longitudinal studies.

Perinatal thalamic injury: MRI predictors of electrical status epilepticus in sleep and long-term neurodevelopment.

Perinatal thalamic injury is associated with epilepsy with electrical status epilepticus in sleep (ESES). The aim of this study was to prospectively quantify the risk of ESES and to assess neuroimaging predictors of neurodevelopment. We included patients with perinatal thalamic injury. MRI scans were obtained in the neonatal period, around three months of age and during childhood. Thalamic and total brain volumes were obtained from the three months MRI. Diffusion characteristics were assessed. Sleep EEGs distinguished patients into ESES (spike-wave index (SWI) >85%), ESES-spectrum (SWI 50-85%) or no ESES (SWI<50%). Serial Intelligence Quotient (IQ)/Developmental Quotient (DQ) scores were obtained during follow-up. Imaging and EEG findings were correlated to neurodevelopmental outcome. Thirty patients were included. Mean thalamic volume at three months was 8.11 (±1.67)ml and mean total brain volume 526.45 (±88.99)ml. In the prospective cohort (n=23) 19 patients (83%) developed ESES (-spectrum) abnormalities after a mean follow-up of 96 months. In the univariate analysis, larger thalamic volume, larger total brain volume and lower SWI correlated with higher mean IQ/DQ after 2 years (Pearson's r=0.74, p=0.001; Pearson's r=0.64, p=0.005; and Spearman's rho -0.44, p=0.03). In a multivariable mixed model analysis, thalamic volume was a significant predictor of IQ/DQ (coefficient 9.60 [p<0.001], i.e., corrected for total brain volume and SWI and accounting for repeated measures within patients, a 1ml higher thalamic volume was associated with a 9.6 points higher IQ). Diffusion characteristics during childhood correlated with IQ/DQ after 2 years. Perinatal thalamic injury is followed by electrical status epilepticus in sleep in the majority of patients. Thalamic volume and diffusion characteristics correlate to neurodevelopmental outcome.

Abstract MP39: Association of MIND Diet Adherence With Brain Volume, Silent Brain Infarcts and Brain Atrophy in the Framingham Heart Study

Objective: Adherence to the Mediterranean- DASH for Neurodegenerative Delay (MIND) diet has previously been associated with cognitive decline and dementia. To our knowledge, no prior study has investigated the association between the MIND diet and measures of brain volume, silent brain infarcts (SBIs) or brain atrophy. Methods: We aimed to evaluate, cross-sectionally and longitudinally, whether consumption of a diet consist with the MIND diet was associated with larger brain volumes, fewer SBIs and fewer atrophy in the community-based Framinham Heart Study. We included 1,904 participants (mean age 69 (SD, 9)) who completed a brain MRI and a validated food frequency questionnaire (FFQ). The MIND diet consists of 10 healthy and five unhealthy components (range: 0-15). A cumulative MIND diet score was calculated by averaging across three FFQs (exams 5 (1991-1995), 6 (1995-1998), and 7 (1998-2001)). From the total study population, 86 % completed all three FFQs. Brain MRI was performed proximal to exam 7 and again after a mean of 7 years (SD, 1.1) (n=1,317). Total brain volume (TBV), hippocampal volume (HPV), white matter hyperintensity volume (WMHV), expressed as a percentage of total cranial volume, and presence of SBIs were assessed from MRI scans. We used multivariable linear (TBV, HPV and WMHV) and logistic (SBIs) regressions for the cross-sectional analyses, and we analyzed the annualized change of TBV and HPV as atrophy measures using multivariable linear regression. Results: In cross-sectional analyses, higher MIND diet scores were significantly associated with larger TBV (β±SE, +0.09±0.04; p=0.03) after adjustment for basic demographic factors, total daily energy intake, and APOE e4 allele status, but was not associated with HPV (+0.001±0.001; p=0.09), WMHV (-0.01±0.01; p=0.27), SBIs (OR (95%CI), +1.01, 0.92:1.10; p=0.61) or atrophy (TBV, -0.001±0.01; p=0.88; HPV, -0.0003±0.001; p=0.62). After additional adjustments for cardiovascular risk factors the association with TBV was attenuated (+0.05±0.04; p=0.17). Significant interactions were observed for HPV by APOE ε4 status and BMI in the basic model. After stratification by APOE ε4 status, higher MIND diet scores were significantly associated with higher HPV among APOE ε4 non-carriers (+0.002±0.001; p=0.01) but not carriers (n=412). After stratification by BMI, higher adherence to the MIND diet was associated with larger HPV among participants with a BMI above 25 (+0.002±0.001; p=0.01), but not among participants with a BMI below 25. Conclusions: Higher adherence to the MIND diet was not independently associated with brain volume measures, SBIs or brain atrophy in our community cohort as the associations appeared to be mediated by cardiovascular risk factors. In addition, we observed that adherence to the diet was associated with larger brain volume measures in sub groups. Replication is needed to confirm our findings.

Longitudinal evaluation of ventricular volume changes associated with mild traumatic brain injury in military service members

ABSTRACTPrimary objective: To investigate differences in longitudinal trajectories of ventricle-brain ratio (VBR), a general measure of brain atrophy, between Veterans with and without history of mild traumatic brain injury (mTBI).Research design: Structural magnetic resonance imaging (MRI) was used to calculate VBR in 70 Veterans with a history of mTBI and 34 Veterans without such history at two time points approximately 3 and 8 years after a combat deployment.Main outcomes and results: Both groups demonstrated a quadratic relationship between VBR and age that is consistent with normal developmental trajectories. Veterans with history of mTBI had larger total brain volume, but no interaction between mTBI and age was observed for brain volume, ventricular volume, or VBR.Conclusions: In our longitudinal sample of deployed Veterans, mTBI was not associated with gross brain atrophy as reflected by abnormally high VBR or abnormal increases in VBR over time.

Sexually dimorphic subcortical brain volumes in emerging psychosis

BackgroundIn schizophrenic psychoses, the normal sexual dimorphism of the brain has been shown to be disrupted or even reversed. Little is known, however, at what time point in emerging psychosis this occurs. We have therefore examined, if these alterations are already present in the at-risk mental state (ARMS) for psychosis and in first episode psychosis (FEP) patients. MethodsData from 65 ARMS (48 (73.8%) male; age=25.1±6.32) and 50 FEP (37 (74%) male; age=27±6.56) patients were compared to those of 70 healthy controls (HC; 27 (38.6%) male; age=26±4.97). Structural T1-weighted images were acquired using a 3 Tesla magnetic resonance imaging (MRI) scanner. Linear mixed effects models were used to investigate whether subcortical brain volumes are dependent on sex. ResultsWe found men to have larger total brain volumes (p<0.001), and smaller bilateral caudate (p=0.008) and hippocampus volume (p<0.001) than women across all three groups. Older subjects had more GM and WM volume than younger subjects. No significant sex×group interaction was found. ConclusionsIn emerging psychosis there still seem to exist patterns of normal sexual dimorphism in total brain and caudate volume. The only structure affected by reversed sexual dimorphism was the hippocampus, with women showing larger volumes than men even in HC. Thus, we conclude that subcortical volumes may not be primarily affected by disrupted sexual dimorphism in emerging psychosis.

Investigation of brain structure in the 1-month infant.

The developing brain undergoes systematic changes that occur at successive stages of maturation. Deviations from the typical neurodevelopmental trajectory are hypothesized to underlie many early childhood disorders; thus, characterizing the earliest patterns of normative brain development is essential. Recent neuroimaging research provides insight into brain structure during late childhood and adolescence; however, few studies have examined the infant brain, particularly in infants under 3 months of age. Using high-resolution structural MRI, we measured subcortical gray and white matter brain volumes in a cohort (N = 143) of 1-month infants and examined characteristics of these volumetric measures throughout this early period of neurodevelopment. We show that brain volumes undergo age-related changes during the first month of life, with the corresponding patterns of regional asymmetry and sexual dimorphism. Specifically, males have larger total brain volume and volumes differ by sex in regionally specific brain regions, after correcting for total brain volume. Consistent with findings from studies of later childhood and adolescence, subcortical regions appear more rightward asymmetric. Neither sex differences nor regional asymmetries changed with gestation-corrected age. Our results complement a growing body of work investigating the earliest neurobiological changes associated with development and suggest that asymmetry and sexual dimorphism are present at birth.

Fronto-Parietal gray matter and white matter efficiency differentially predict intelligence in males and females.

While there are minimal sex differences in overall intelligence, males, on average, have larger total brain volume and corresponding regional brain volumes compared to females, measures that are consistently related to intelligence. Limited research has examined which other brain characteristics may differentially contribute to intelligence in females to facilitate equal performance on intelligence measures. Recent reports of sex differences in the neural characteristics of the brain further highlight the need to differentiate how the structural neural characteristics relate to intellectual ability in males and females. The current study utilized a graph network approach in conjunction with structural equation modeling to examine potential sex differences in the relationship between white matter efficiency, fronto-parietal gray matter volume, and general cognitive ability (GCA). Participants were healthy adults (n = 244) who completed a battery of cognitive testing and underwent structural neuroimaging. Results indicated that in males, a latent factor of fronto-parietal gray matter was significantly related to GCA when controlling for total gray matter volume. In females, white matter efficiency and total gray matter volume were significantly related to GCA, with no specificity of the fronto-parietal gray matter factor over and above total gray matter volume. This work highlights that different neural characteristics across males and females may contribute to performance on intelligence measures. Hum Brain Mapp 37:4006-4016, 2016. © 2016 Wiley Periodicals, Inc.

Mediterranean diet and brain structure in a multiethnic elderly cohort.

To determine whether higher adherence to a Mediterranean-type diet (MeDi) is related with larger MRI-measured brain volume or cortical thickness. In this cross-sectional study, high-resolution structural MRI was collected on 674 elderly (mean age 80.1 years) adults without dementia who participated in a community-based, multiethnic cohort. Dietary information was collected via a food frequency questionnaire. Total brain volume (TBV), total gray matter volume (TGMV), total white matter volume (TWMV), mean cortical thickness (mCT), and regional volume or CT were derived from MRI scans using FreeSurfer program. We examined the association of MeDi (scored as 0-9) and individual food groups with brain volume and thickness using regression models adjusted for age, sex, ethnicity, education, body mass index, diabetes, and cognition. Compared to lower MeDi adherence (0-4), higher adherence (5-9) was associated with 13.11 (p = 0.007), 5.00 (p = 0.05), and 6.41 (p = 0.05) milliliter larger TBV, TGMV, and TWMV, respectively. Higher fish (b = 7.06, p = 0.006) and lower meat (b = 8.42, p = 0.002) intakes were associated with larger TGMV. Lower meat intake was also associated with larger TBV (b = 12.20, p = 0.02). Higher fish intake was associated with 0.019 mm (p = 0.03) larger mCT. Volumes of cingulate cortex, parietal lobe, temporal lobe, and hippocampus and CT of the superior-frontal region were associated with the dietary factors. Among older adults, MeDi adherence was associated with less brain atrophy, with an effect similar to 5 years of aging. Higher fish and lower meat intake might be the 2 key food elements that contribute to the benefits of MeDi on brain structure.

Normal Variation in Early Parental Sensitivity Predicts Child Structural Brain Development

Early caregiving can have an impact on brain structure and function in children. The influence of extreme caregiving experiences has been demonstrated, but studies on the influence of normal variation in parenting quality are scarce. Moreover, no studies to date have included the role of both maternal and paternal sensitivity in child brain maturation. This study examined the prospective relation between mothers' and fathers' sensitive caregiving in early childhood and brain structure later in childhood. Participants were enrolled in a population-based prenatal cohort. For 191 families, maternal and paternal sensitivity was repeatedly observed when the child was between 1 year and 4 years of age. Head circumference was assessed at 6 weeks, and brain structure was assessed using magnetic resonance imaging (MRI) measurements at 8 years of age. Higher levels of parental sensitivity in early childhood were associated with larger total brain volume (adjusted β= 0.15, p= .01) and gray matter volume (adjusted β= 0.16, p= .01) at 8 years, controlling for infant head size. Higher levels of maternal sensitivity in early childhood were associated with a larger gray matter volume (adjusted β= 0.13, p= .04) at 8 years, independent of infant head circumference. Associations with maternal versus paternal sensitivity were not significantly different. Normal variation in caregiving quality is related to markers of more optimal brain development in children. The results illustrate the important role of both mothers and fathers in child brain development.

Aggressive behavior, brain size and domestication in clonal rainbow trout lines.

Domestication causes behavior and brain size changes in many species. We addressed three questions using clonal rainbow trout lines: What are the mirror-elicited aggressive tendencies in lines with varying degrees of domestication? How does brain size relate to genotype and domestication level? Finally, is there a relationship between aggressive behavior and brain size? Clonal lines, although sampling a limited subset of the species variation, provide us with a reproducible experimental system with which we can develop hypotheses for further research. We performed principal component analyses on 12 continuous behavior and brain/body size variables and one discrete behavioral variable ("yawn") and detected several aggression syndromes. Two behaviors, "freeze" and "escape", associated with high domestication; "display" and "yawn" behavior associated with wild lines and "swim against the mirror" behavior associated with semi-wild and domestic lines. Two brain size traits, total brain and olfactory volume, were significantly related to domestication level when taking total body size into account, with domesticated lines having larger total brain volume and olfactory regions. The aggression syndromes identified indicate that future QTL mapping studies on domestication-related traits would likely be fruitful.

Physical activity, structural brain changes and cognitive decline. The SMART-MR study

ObjectiveWe aimed to examine the cross-sectional and prospective relationship between leisure time physical activity, brain MRI abnormalities and cognitive performance in patients with vascular disease. MethodsWithin the SMART-MR study, 1.5 T MRI of the brain and neuropsychological examinations were performed at baseline (n = 1232) and after 3.9 ± 0.4 years follow-up (n = 663). Automatic brain segmentation was used to quantify intracranial (ICV), total brain, ventricular, and white matter lesion (WML) volumes. Brain infarcts were rated visually. Level of physical activity was expressed in metabolic equivalents (MET) hours p/week. With linear regression analysis we examined associations of level of physical activity with brain MRI measures and with cognitive performance, adjusted for potential confounders. For the association with brain infarcts relative risks (RR) were calculated with Poisson regression. ResultsAt baseline, an increase in physical activity of one SD (39.7 METh/w) was significantly associated with larger total brain volume (B = 0.20% of ICV; 95% CI 0.06; 0.33%). A trend was found for the association of physical activity with smaller ventricular volume (B = −0.04% of ICV; 95% CI −0.09; 0.02%) and with a decreased risk for brain infarcts (RR = 0.91, 95% CI: 0.82–1.02). No association was found with smaller WML volume (B = −0.02% of ICV; 95% CI −0.07; 0.04%). No associations with change in brain structures over time were observed. Also, no associations between physical activity and cognitive performance or cognitive decline were found. ConclusionThese data suggest that leisure time physical activity does not have a significant contribution in preventing or slowing down brain abnormalities and cognitive decline in this cohort of middle-aged individuals already burdened with vascular disease.

Alcohol intake and brain structure in a multiethnic elderly cohort

Evidence suggests that consuming light-to-moderate amounts of alcohol reduces the risk of dementia and is associated better cognitive function and less cardiovascular disease, relative to those consuming no or heavy alcohol. There are only minimal data on the association between alcohol and brain magnetic resonance imaging (MRI) markers. This study aimed to examine the association between alcohol and brain structure measured with MRI. In this cross-sectional study, high-resolution structural MRI was collected on 589 multi-ethnic community residents of New York aged ≥65 with available alcohol intake assessments via a food frequency questionnaire. Total brain volume (TBV), white matter hyperintensity volume (WMHV), and presence of infarcts were derived from MRI scans with established methods. We examined the association of alcohol intake with these imaging markers using regression models adjusted for demographic, clinical, and vascular risk factors. Compared to non-drinking, light-to-moderate total alcohol (b = 0.007, p = 0.04) or wine (b = 0.008, p = 0.05) intake, but not beer or liquor intake, was associated with larger TBV. Further analysis showed a dose-response association between alcohol (p-trend = 0.03) or wine (p-trend = 0.006) and TBV. Overall, alcohol intake was not associated with WMHV or brain infarcts. Our study suggests that among older adults in the community, light-to-moderate alcohol intake, in particular wine, is associated with larger TBV. These findings suggest that light to moderate alcohol consumption is potentially beneficial for brain aging, but replication is needed.

Is dementia incidence declining?

To investigate whether dementia incidence has changed over the last 2 decades. We compared dementia incidence in 2 independent subcohorts of persons aged 60-90 years from the Rotterdam Study, a population-based cohort study. The first subcohort started in 1990 (n = 5,727), the second in 2000 (n = 1,769). Participants were dementia-free at baseline and followed for at maximum 5 years. We calculated age-adjusted dementia incidence rates for the 2 subcohorts in total, in 10-year age strata, and for men and women separately. We also compared mortality rates, differences in prevalence of vascular risk factors, and medication use. Finally, we compared brain volumes and the extent of cerebral small vessel disease in participants who underwent brain imaging 5 years after the baseline examinations. In the 1990 subcohort (25,696 person-years), 286 persons developed dementia, and in the 2000 subcohort (8,384 person-years), 49 persons. Age-adjusted dementia incidence rates were consistently, yet nonsignificantly, lower in the 2000 subcohort in all strata, reaching borderline significance in the overall analysis (incidence rate ratio 0.75, 95% confidence interval [CI] 0.56-1.02). Mortality rates were also lower in the 2000 subcohort (rate ratio 0.63, 95% CI 0.52-0.77). The prevalence of hypertension and obesity significantly increased between 1990 and 2000. This was paralleled by a strong increase in use of antithrombotics and lipid-lowering drugs. Participants in 2005-2006 had larger total brain volumes (p < 0.001) and less cerebral small vessel disease (although nonsignificant in men) than participants in 1995-1996. Although the differences in dementia incidence were nonsignificant, our study suggests that dementia incidence has decreased between 1990 and 2005.

The effect of midlife physical activity on structural brain changes in the elderly

Physical activity has been associated with decreased dementia risk in recent studies, but the effects for structural brain changes (i.e. white matter lesions (WML) and/or brain atrophy) have remained unclear. The CAIDE participants were a random population-based sample studied in midlife and re-examined on average 21 years later (n=2000). A subpopulation (n=75; 31 control, 23 MCI, 21 dementia) was MRI scanned at the re-examination. T1-weighted images were used to investigate grey matter (GM) density, and FLAIR-images for WML rating. Persons who actively participated in physical activity at midlife tended to have larger total brain volume (β 0.12; 95% CI 0.17-1.16, p=0.10) in late-life than sedentary persons even after adjustments. GM volume was larger among the active (β 0.19; 95% CI 0.07-1.48, p=0.03), whereas the association between midlife physical activity and larger WM volume became non-significant (β 0.03; 95% CI -0.64 to 0.86, p=0.77) after full adjustments. The differences in the GM density localized mainly in frontal lobes. There was no significant association between midlife physical activity and severe WML later in life after full adjustments (OR 4.20, 95% CI 0.26-69.13, p=0.32).

P4-127: The effect of midlife physical activity on subsequent structural brain changes

Background: Physical activity has been associated with decreased risk of dementia in recent studies. Simultaneously, several dementia risk factors have been associated with WML and/or brain atrophy in magnetic resonance images (MRI), but the role of physical activity is unclear. In this study, we aimed at clarifying the associations between midlife physical activity and subsequent structural brain changes using MRI. Methods: The CAIDE subjects were randomly selected from population based samples first studied in 1972-1987, and re-examined in 1998 (average follow-up time 21 years). For this study, a subpopulation of 91 persons was scanned at the re-examination with Siemens Magnetom 1.5T MR scanner, and T1-weighted images were used to investigate grey matter (GM) density using voxel-based morphometry. WML were assessed on FLAIR-images using a semi-quantitative visual rating scale. Additionally, all participants were investigated for their health status/habits at midlife and re-examination. Results: Persons who participated in leisure time physical activity at midlife tended to have larger total brain volume ( 0.12; 95% CI -0.171.16, p 0.10) later in life than the more sedentary persons even after adjustments for socio-demographic and vascular factors, apoE 4 genotype, smoking, diagnosis of dementia or mild cognitive impairment and cerebrospinal fluid/white matter/grey matter volumes. Interestingly, GM volume was significantly larger among the active ( 0.19; 95% CI 0.071.48, p 0.03), whereas the association between midlife physical activity and larger WM volume became non-significant after full adjustments. Further, the differences in the GM density between the active and sedentary groups localized mainly in frontal lobes. Finally, there was no significant association between midlife physical activity and severe WML later in life after full adjustments. Conclusions: Midlife physical activity might have an effect on total brain and GM volumes later in life, while there might not be an association between midlife physical activity and either WM volume or WML later in life. However, more studies with different methods are warranted for further understanding about the association between physical activity and structural brain changes.