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1.  Education mitigates age-related decline in N-Acetylaspartate levels 
Brain and Behavior  2015;5(3):e00311.
Greater educational attainment is associated with better neurocognitive health in older adults and is thought to reflect a measure of cognitive reserve. In vivo neuroimaging tools have begun to identify the brain systems and networks potentially responsible for reserve.
We examined the relationship between education, a commonly used proxy for cognitive reserve, and N-acetylaspartate (NAA) in neurologically healthy older adults (N = 135; mean age = 66 years). Using single voxel MR spectroscopy, we predicted that higher levels of education would moderate an age-related decline in NAA in the frontal cortex.
After controlling for the variance associated with cardiorespiratory fitness, sex, annual income, and creatine levels, there were no significant main effects of education (B = 0.016, P = 0.787) or age (B = −0.058, P = 0.204) on NAA levels. However, consistent with our predictions, there was a significant education X age interaction such that more years of education offset an age-related decline in NAA (B = 0.025, P = 0.031). When examining working memory via the backwards digit span task, longer span length was associated with greater education (P < 0.01) and showed a trend with greater NAA concentrations (P < 0.06); however, there was no age X education interaction on digit span performance nor a significant moderated mediation effect between age, education, and NAA on digit span performance.
Taken together, these results suggest that higher levels of education may attenuate an age-related reduction in neuronal viability in the frontal cortex.
PMCID: PMC4356844  PMID: 25798329
Aging; brain reserve; cognitive reserve; education; fitness
2.  Education mitigates age‐related decline in N‐Acetylaspartate levels 
Brain and Behavior  2015;e00311.
Greater educational attainment is associated with better neurocognitive health in older adults and is thought to reflect a measure of cognitive reserve. In vivo neuroimaging tools have begun to identify the brain systems and networks potentially responsible for reserve.
We examined the relationship between education, a commonly used proxy for cognitive reserve, and N‐acetylaspartate (NAA) in neurologically healthy older adults (N = 135; mean age = 66 years). Using single voxel MR spectroscopy, we predicted that higher levels of education would moderate an age‐related decline in NAA in the frontal cortex.
After controlling for the variance associated with cardiorespiratory fitness, sex, annual income, and creatine levels, there were no significant main effects of education (B = 0.016, P = 0.787) or age (B = −0.058, P = 0.204) on NAA levels. However, consistent with our predictions, there was a significant education X age interaction such that more years of education offset an age‐related decline in NAA (B = 0.025, P = 0.031). When examining working memory via the backwards digit span task, longer span length was associated with greater education (P < 0.01) and showed a trend with greater NAA concentrations (P < 0.06); however, there was no age X education interaction on digit span performance nor a significant moderated mediation effect between age, education, and NAA on digit span performance.
Taken together, these results suggest that higher levels of education may attenuate an age‐related reduction in neuronal viability in the frontal cortex.
PMCID: PMC4356844  PMID: 25798329
Aging; brain reserve; cognitive reserve; education; fitness
3.  The Brain-Derived Neurotrophic Factor Val66Met Polymorphism Moderates an Effect of Physical Activity on Working Memory Performance 
Psychological science  2013;24(9):1770-1779.
Physical activity enhances cognitive performance, yet individual variability in its effectiveness limits its widespread therapeutic application. Genetic differences might be one source of this variation. For example, carriers of the methionine-specifying (Met) allele of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have reduced secretion of BDNF and poorer memory, yet physical activity increases BDNF levels. To determine whether the BDNF polymorphism moderated an association of physical activity with cognitive functioning among 1,032 midlife volunteers (mean age = 44.59 years), we evaluated participants’ performance on a battery of tests assessing memory, learning, and executive processes, and evaluated their physical activity with the Paffenbarger Physical Activity Questionnaire. BDNF genotype interacted robustly with physical activity to affect working memory, but not other areas of cognitive functioning. In particular, greater levels of physical activity offset a deleterious effect of the Met allele on working memory performance. These findings suggest that physical activity can modulate domain-specific genetic (BDNF) effects on cognition.
PMCID: PMC3947596  PMID: 23907543
BDNF; physical activity; working memory; executive function; genetics; visual memory; episodic memory
4.  Physical Activity, Brain Plasticity, and Alzheimer’s Disease 
Archives of medical research  2012;43(8):615-621.
In this review we summarize the epidemiological, cross-sectional, and interventional studies examining the association between physical activity and brain volume, function, and risk for Alzheimer’s disease. The epidemiological literature provides compelling evidence that greater amounts of physical activity are associated with a reduced risk of dementia in late life. In addition, randomized interventions using neuroimaging tools have reported that participation in physical activity increases the size of prefrontal and hippocampal brain areas, which may lead to a reduction in memory impairments. Consistent with these findings, longitudinal studies using neuroimaging tools also find that the volume of prefrontal and hippocampal brain areas are larger in individuals who engaged in more physical activity earlier in life. We conclude from this review that there is convincing evidence that physical activity has a consistent and robust association with brain regions implicated in age-related cognitive decline and Alzheimer’s disease. In addition to summarizing this literature we provide recommendations for future research on physical activity and brain health.
PMCID: PMC3567914  PMID: 23085449
5.  Physical Exercise and Brain Functions in Older Adults 
Journal of Aging Research  2013;2013:197326.
PMCID: PMC3791662  PMID: 24163767
6.  The Aging Hippocampus: Interactions between Exercise, Depression, and BDNF 
Late adulthood is associated with increased hippocampal atrophy and dysfunction. Although there are multiple paths by which hippocampal deterioration occurs in late life, the authors discuss the evidence that a single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene and age-related changes in BDNF protein or receptor expression contribute to hippocampal atrophy. The authors conclude that few studies have tested whether BDNF mediates age-related hippocampal atrophy and memory impairment. However, there is strong evidence that decreased BDNF is associated with age-related hippocampal dysfunction, memory impairment, and increased risk for depression, whereas increasing BDNF by aerobic exercise appears to ameliorate hippocampal atrophy, improve memory function, and reduce depression. Importantly, the most consistent associations between BDNF and hippocampal dysfunction have emerged from research on BDNF protein expression in rodents and serum and plasma concentrations of BDNF in humans. Current research suggests that the BDNF val66met polymorphism may be only weakly associated with hippocampal atrophy in late adulthood. These conclusions are interpreted in relation to age-related memory impairment and preventions for hippocampal atrophy.
PMCID: PMC3575139  PMID: 21531985
aging; BDNF; depression; exercise; hippocampus
7.  Caudate Nucleus Volume Mediates the Link between Cardiorespiratory Fitness and Cognitive Flexibility in Older Adults 
Journal of Aging Research  2012;2012:939285.
The basal ganglia play a central role in regulating the response selection abilities that are critical for mental flexibility. In neocortical areas, higher cardiorespiratory fitness levels are associated with increased gray matter volume, and these volumetric differences mediate enhanced cognitive performance in a variety of tasks. Here we examine whether cardiorespiratory fitness correlates with the volume of the subcortical nuclei that make up the basal ganglia and whether this relationship predicts cognitive flexibility in older adults. Structural MRI was used to determine the volume of the basal ganglia nuclei in a group of older, neurologically healthy individuals (mean age 66 years, N = 179). Measures of cardiorespiratory fitness (VO2max), cognitive flexibility (task switching), and attentional control (flanker task) were also collected. Higher fitness levels were correlated with higher accuracy rates in the Task Switching paradigm. In addition, the volume of the caudate nucleus, putamen, and globus pallidus positively correlated with Task Switching accuracy. Nested regression modeling revealed that caudate nucleus volume was a significant mediator of the relationship between cardiorespiratory fitness, and task switching performance. These findings indicate that higher cardiorespiratory fitness predicts better cognitive flexibility in older adults through greater grey matter volume in the dorsal striatum.
PMCID: PMC3415086  PMID: 22900181
8.  Beyond vascularization: aerobic fitness is associated with N-acetylaspartate and working memory 
Brain and Behavior  2012;2(1):32-41.
Aerobic exercise is a promising form of prevention for cognitive decline; however, little is known about the molecular mechanisms by which exercise and fitness impacts the human brain. Several studies have postulated that increased regional brain volume and function are associated with aerobic fitness because of increased vascularization rather than increased neural tissue per se. We tested this position by examining the relationship between cardiorespiratory fitness and N-acetylaspartate (NAA) levels in the right frontal cortex using magnetic resonance spectroscopy. NAA is a nervous system specific metabolite found predominantly in cell bodies of neurons. We reasoned that if aerobic fitness was predominantly influencing the vasculature of the brain, then NAA levels should not vary as a function of aerobic fitness. However, if aerobic fitness influences the number or viability of neurons, then higher aerobic fitness levels might be associated with greater concentrations of NAA. We examined NAA levels, aerobic fitness, and cognitive performance in 137 older adults without cognitive impairment. Consistent with the latter hypothesis, we found that higher aerobic fitness levels offset an age-related decline in NAA. Furthermore, NAA mediated an association between fitness and backward digit span performance, suggesting that neuronal viability as measured by NAA is important in understanding fitness-related cognitive enhancement. Since NAA is found exclusively in neural tissue, our results indicate that the effect of fitness on the human brain extends beyond vascularization; aerobic fitness is associated with neuronal viability in the frontal cortex of older adults.
PMCID: PMC3343297  PMID: 22574272
Aging; brain; exercise; fitness; human; N-acetylaspartate; working memory
9.  Striatal Volume Predicts Level of Video Game Skill Acquisition 
Cerebral Cortex (New York, NY)  2010;20(11):2522-2530.
Video game skills transfer to other tasks, but individual differences in performance and in learning and transfer rates make it difficult to identify the source of transfer benefits. We asked whether variability in initial acquisition and of improvement in performance on a demanding video game, the Space Fortress game, could be predicted by variations in the pretraining volume of either of 2 key brain regions implicated in learning and memory: the striatum, implicated in procedural learning and cognitive flexibility, and the hippocampus, implicated in declarative memory. We found that hippocampal volumes did not predict learning improvement but that striatal volumes did. Moreover, for the striatum, the volumes of the dorsal striatum predicted improvement in performance but the volumes of the ventral striatum did not. Both ventral and dorsal striatal volumes predicted early acquisition rates. Furthermore, this early-stage correlation between striatal volumes and learning held regardless of the cognitive flexibility demands of the game versions, whereas the predictive power of the dorsal striatal volumes held selectively for performance improvements in a game version emphasizing cognitive flexibility. These findings suggest a neuroanatomical basis for the superiority of training strategies that promote cognitive flexibility and transfer to untrained tasks.
PMCID: PMC3841463  PMID: 20089946
basal ganglia; caudate nucleus; cognitive flexibility; nucleus accumbens; procedural learning
10.  Aerobic Fitness is Associated With Hippocampal Volume in Elderly Humans 
Hippocampus  2009;19(10):1030-1039.
Deterioration of the hippocampus occurs in elderly individuals with and without dementia, yet individual variation exists in the degree and rate of hippocampal decay. Determining the factors that influence individual variation in the magnitude and rate of hippocampal decay may help promote lifestyle changes that prevent such deterioration from taking place. Aerobic fitness and exercise are effective at preventing cortical decay and cognitive impairment in older adults and epidemiological studies suggest that physical activity can reduce the risk for developing dementia. However, the relationship between aerobic fitness and hippocampal volume in elderly humans is unknown. In this study, we investigated whether individuals with higher levels of aerobic fitness displayed greater volume of the hippocampus and better spatial memory performance than individuals with lower fitness levels. Furthermore, in exploratory analyses, we assessed whether hippocampal volume mediated the relationship between fitness and spatial memory. Using a region-of-interest analysis on magnetic resonance images in 165 nondemented older adults, we found a triple association such that higher fitness levels were associated with larger left and right hippocampi after controlling for age, sex, and years of education, and larger hippocampi and higher fitness levels were correlated with better spatial memory performance. Furthermore, we demonstrated that hippocampal volume partially mediated the relationship between higher fitness levels and enhanced spatial memory. Our results clearly indicate that higher levels of aerobic fitness are associated with increased hippocampal volume in older humans, which translates to better memory function.
PMCID: PMC3072565  PMID: 19123237
aging; MRI; spatial memory; cognition; brain
11.  BDNF is Associated With Age-Related Decline in Hippocampal Volume 
Hippocampal volume shrinks in late adulthood, but the neuromolecular factors that trigger hippocampal decay in aging humans remains a matter of speculation. In rodents, brain derived neurotrophic factor (BDNF) promotes the growth and proliferation of cells in the hippocampus and is important in long-term potentiation and memory formation. In humans, circulating levels of BDNF decline with advancing age and a genetic polymorphism for BDNF has been related to gray matter volume loss in old age. In this study, we tested whether age-related reductions in serum levels of BDNF would be related to shrinkage of the hippocampus and memory deficits in older adults. Hippocampal volume was acquired by automated segmentation of magnetic resonance images in 142 older adults without dementia. The caudate nucleus was also segmented and examined in relation to levels of serum BDNF. Spatial memory was tested using a paradigm in which memory load was parametrically increased. We found that increasing age was associated with smaller hippocampal volumes, reduced levels of serum BDNF, and poorer memory performance. Lower levels of BDNF were associated with smaller hippocampi and poorer memory, even when controlling for the variation related to age. In an exploratory mediation analysis, hippocampal volume mediated the age-related decline in spatial memory and BDNF mediated the age-related decline in hippocampal volume. Caudate nucleus volume was unrelated to BDNF levels or spatial memory performance. Our results identify serum BDNF as a significant factor related to hippocampal shrinkage and memory decline in late adulthood.
PMCID: PMC3069644  PMID: 20392958
brain-derived neurotrophic factor; hippocampus; human; brain; caudate nucleus; aging
12.  A cross-sectional study of hormone treatment and hippocampal volume in postmenopausal women: Evidence for a limited window of opportunity 
Neuropsychology  2010;24(1):68-76.
The influence of hormone treatment on brain and cognition in postmenopausal women has been a controversial topic. Contradictory patterns of results have prompted speculation that a critical period, or a limited window of opportunity, exists for hormone treatment to protect against cognitive and neural decline in older women. Consistent with this hypothesis, studies in both humans and rodents indicate that the latency between the time of menopause and the initiation of hormone treatment is an important factor in determining whether hormone treatment will prevent or exacerbate cognitive impairment. In this cross-sectional study of 102 postmenopausal women, we examined whether hippocampal, amygdala, or caudate nucleus volumes and spatial memory performance were related to the interval between menopause and the initiation of hormone treatment. Consistent with a critical period hypothesis, we found that shorter intervals between menopause and the initiation of hormone treatment, as determined by self-report, were associated with larger hippocampal volumes compared with longer intervals between menopause and treatment initiation. Initiation of hormone treatment at the time of menopause was also associated with larger hippocampal volumes when compared to peers who had never used hormone treatment. Furthermore, these effects were independent from potentially confounding factors such as age, years of education, the duration of hormone treatment, current or past use of hormone therapy, the type of therapy, and the age at menopause. Larger hippocampal volumes in women who initiated hormone treatment at the time of menopause failed to translate to improved spatial memory performance. There was no relationship between the timing of hormone initiation, spatial memory performance, and amygdala or caudate nucleus volume. Our results provide support for the idea that there is a limited window of opportunity at the time of menopause for hormone treatment to influence hippocampal volume, yet the degree to which these effects translate to improved memory performance is uncertain.
PMCID: PMC2843433  PMID: 20063947
13.  Omega-3 Fatty Acids Moderate Effects of Physical Activity on Cognitive Function 
Neuropsychologia  2014;59:103-111.
Greater amounts of physical activity (PA) and omega-3 fatty acids have both been independently associated with better cognitive performance. Because of the overlapping biological effects of omega-3 fatty acids and PA, fatty acid intake may modify the effects of PA on neurocognitive function. The present study tested this hypothesis by examining whether the ratio of serum omega-6 to omega-3 fatty acid levels would moderate the association between PA and executive and memory functions in 344 participants (Mean age = 44.42 years, SD = 6.72). The Paffenbarger Physical Activity Questionnaire (PPAQ), serum fatty acid levels, and performance on a standard neuropsychological battery were acquired on all subjects. A principal component analysis reduced the number of cognitive outcomes to three factors: n-back working memory, Trail Making test, and Logical Memory. We found a significant interaction between PA and the ratio of omega-6 to omega-3 fatty acid serum levels on Trail Making performance and n-back performance, such that higher amounts of omega-3 levels offset the deleterious effects of lower amounts of PA. These effects remained significant in a subsample (n=299) controlling for overall dietary fat consumption. There were no significant additive or multiplicative benefits of higher amounts of both omega-3 and PA on cognitive performance. Our results demonstrate that a diet high in omega-3 fatty acids might mitigate the effect of lower levels of PA on cognitive performance. This study illuminates the importance of understanding dietary and PA factors in tandem when exploring their effects on neurocognitive health.
PMCID: PMC4104997  PMID: 24813150
omega-3; physical activity; working memory; task-switching; logical memory; DHA
14.  Exercise is Medicine, For the Body and the Brain 
British journal of sports medicine  2014;48(12):943-944.
Dementia is one of the most pressing health care issues of the 21st century. Exercise is a modifiable lifestyle factor that has been identified as positively impacting cognitive functioning across the lifespan. Despite surmounting evidence linking exercise and cognitive functions in older adults, there is reluctance to adopt exercise as a prevention strategy; this view has been partially fueled by published reviews that have failed to include all the relevant literature. Therefore, in this commentary, we provide an update on the recent converging neuroimaging, behavioural, and biomarker evidence linking exercise with cognitive and brain health. We highlight that endorsing exercise as an effective strategy for improving health and well-being among older adults may potentially have a high impact for mitigating multiple health concerns, and should therefore be considered as a leading treatment strategy for dementia prevention.
PMCID: PMC4330095  PMID: 24659507 CAMSID: cams4566
Exercise; Physical activity; Cognition; Brain health; Aging
15.  Greater intake of vitamins B6 and B12 spares gray matter in healthy elderly: a voxel-based morphometry study 
Brain research  2008;1199:20-26.
Previous studies have reported that high concentrations of homocysteine and lower concentrations of vitamin B6, B12, and folate increase the risk for cognitive decline and pathology in aging populations. In this cross-sectional study, high-resolution magnetic resonance imaging (MRI) scans and a 3-day food diary were collected on 32 community-dwelling adults between the ages of 59 and 79. We examined the relation between vitamin B6, B12, and folate intake on cortical volume using an optimized voxel-based morphometry (VBM) method and global gray and white matter volume after correcting for age, sex, body mass index, calorie intake, and education. All participants met or surpassed the recommended daily intake for these vitamins. In the VBM analysis, we found that adults with greater vitamin B6 intake had greater gray matter volume along the medial wall, anterior cingulate cortex, medial parietal cortex, middle temporal gyrus, and superior frontal gyrus, whereas people with greater B12 intake had greater volume in the left and right superior parietal sulcus. These effects were driven by vitamin supplementation and were negated when only examining vitamin intake from diet. Folate had no effect on brain volume. Furthermore, there was no relationship between vitamin B6, B12, or folate intake on global brain volume measures, indicating that VBM methods are more sensitive for detecting localized differences in gray matter volume than global measures. These results are discussed in relation to a growing literature on vitamin intake on age-related neurocognitive deterioration.
PMCID: PMC2323025  PMID: 18281020
homocysteine; VBM; aging; brain; MRI; vitamin B6; vitamin B12
16.  An investigation of fMRI time series stationarity during motor sequence learning foot tapping tasks 
Understanding complex brain networks using functional magnetic resonance imaging (fMRI) is of great interest to clinical and scientific communities. To utilize advanced analysis methods such as graph theory for these investigations, the stationarity of fMRI time series needs to be understood as it has important implications on the choice of appropriate approaches for the analysis of complex brain networks.
New Method:
In this paper, we investigated the stationarity of fMRI time series acquired from twelve healthy participants while they performed a motor (foot tapping sequence) learning task. Since prior studies have documented that learning is associated with systematic changes in brain activation, a sequence learning task is an optimal paradigm to assess the degree of non-stationarity in fMRI time-series in clinically relevant brain areas. We predicted that brain regions involved in a “learning network” would demonstrate non-stationarity and may violate assumptions associated with some advanced analysis approaches. Six blocks of learning, and six control blocks of a foot tapping sequence were performed in a fixed order. The reverse arrangement test was utilized to investigate the time series stationarity.
Our analysis showed some non-stationary signals with a time varying first moment as a major source of non-stationarity. We also demonstrated a decreased number of non-stationarities in the third block as a result of priming and repetition.
Comparison with Existing Methods:
Most of the current literature does not examine stationarity prior to processing.
The implication of our findings is that future investigations analyzing complex brain networks should utilize approaches robust to non-stationarities, as graph-theoretical approaches can be sensitive to non-stationarities present in data.
PMCID: PMC3987746  PMID: 24530436
functional magnetic resonance imaging; time series; stationarity; reverse arrangement test; foot tapping
17.  Genetic Contributions to Age-Related Decline in Executive Function: A 10-Year Longitudinal Study of COMT and BDNF Polymorphisms 
Genetic variability in the dopaminergic and neurotrophic systems could contribute to age-related impairments in executive control and memory function. In this study we examined whether genetic polymorphisms for catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) were related to the trajectory of cognitive decline occurring over a 10-year period in older adults. A single nucleotide polymorphism in the COMT (Val158/108Met) gene affects the concentration of dopamine in the prefrontal cortex. In addition, a Val/Met substitution in the pro-domain for BDNF (Val66Met) affects the regulated secretion and trafficking of BDNF with Met carriers showing reduced secretion and poorer cognitive function. We found that impairments over the 10-year span on a task-switching paradigm did not vary as a function of the COMT polymorphism. However, for the BDNF polymorphism the Met carriers performed worse than Val homozygotes at the first testing session but only the Val homozygotes demonstrated a significant reduction in performance over the 10-year span. Our results argue that the COMT polymorphism does not affect the trajectory of age-related executive control decline, whereas the Val/Val polymorphism for BDNF may promote faster rates of cognitive decay in old age. These results are discussed in relation to the role of BDNF in senescence and the transforming impact of the Met allele on cognitive function in old age.
PMCID: PMC2572207  PMID: 18958211
BDNF; COMT; aging; task-switching; cognition; executive control; longitudinal
18.  Functional MR imaging of a simulated balance task 
Brain research  2014;1555:20-27.
Human postural control, which relies on information from vestibular, visual, and proprioceptive inputs, degrades with aging, and falls are the leading cause of injury in older adults. In the last decade, functional neuroimaging studies have been performed in order to gain a greater understanding of the supraspinal control of balance and walking. It is known that active balancing involves cortical and subcortical structures in the brain, but neuroimaging of the brain during these tasks has been limited. The study of the effect of aging on the functional neuroimaging of posture and gait has only recently been undertaken. In this study, an MRI-compatible force platform was developed to simulate active balance control. Eleven healthy participants (mean age 75 ± 5 yr) performed an active balance simulation task by using visual feedback to control anterior–posterior center of pressure movements generated by ankle dorsiflexor (DF) and plantarflexor (PF) movements, in a pattern consistent with upright stance control. An additional ankle DF/PF exertion task was performed. During both the active balance simulation and the ankle DF/PF tasks, the bilateral fusiform gyrus and middle temporal gyrus, right inferior, middle, and superior frontal gyrii were activated. No areas were found to be more active during the ankle DF/PF task when compared with the active balance simulation task. When compared to the ankle DF/PF task, the active balance simulation task elicited greater activation in the middle and superior temporal gyrii, insula, and a large cluster that covered the corpus callosum, superior and medial frontal gyrii, as well as the anterior cingulate and caudate nucleus. This study demonstrates the utility in using a force platform to simulate active balance control during MR imaging that elicits activity in cortical regions consistent with studies of active balance and mental imagery of balance.
PMCID: PMC4001860  PMID: 24480476
Balance; fMRI; Brain activation
19.  The role of sleep continuity and total sleep time in executive function across the adult lifespan 
Psychology and aging  2014;29(3):658-665.
The importance of sleep for cognition in young adults is well established, but the role of habitual sleep behavior in cognition across the adult lifespan remains unknown. We examined the relationship between sleep continuity and total sleep time assessed with a sleep detection device and cognitive performance using a battery of tasks in young (n = 59, mean age = 23.05) and older (n = 53, mean age = 62.68) adults. Across age groups, higher sleep continuity was associated with better cognitive performance. In the younger group, higher sleep continuity was associated with better working memory and inhibitory control. In the older group, higher sleep continuity was associated with better inhibitory control, memory recall, and verbal fluency. Very short and very long total sleep time was associated with poorer working memory and verbal fluency, specifically in the younger group. Total sleep time was not associated with cognitive performance in any domains for the older group. These findings reveal that sleep continuity is important for executive function in both young and older adults, but total sleep time may be more important for cognition in young adults.
PMCID: PMC4369772  PMID: 25244484
20.  Cardiovascular risks and brain function: a functional magnetic resonance imaging study of executive function in older adults 
Neurobiology of aging  2013;35(6):1396-1403.
Cardiovascular (CV) risk factors, such as hypertension, diabetes, and hyperlipidemia are associated with cognitive impairment and risk of dementia in older adults. However, the mechanisms linking them are not clear. This study aims to investigate the association between aggregate CV risk, assessed by the Framingham general cardiovascular risk profile, and functional brain activation in a group of community-dwelling older adults. Sixty participants (mean age: 64.6 years) from the Brain Health Study, a nested study of the Baltimore Experience Corps Trial, underwent functional magnetic resonance imaging using the Flanker task. We found that participants with higher CV risk had greater task-related activation in the left inferior parietal region, and this increased activation was associated with poorer task performance. Our results provide insights into the neural systems underlying the relationship between CV risk and executive function. Increased activation of the inferior parietal region may offer a pathway through which CV risk increases risk for cognitive impairment.
PMCID: PMC4282177  PMID: 24439485
Cardiovascular risk; Framingham risk score; fMRI; Brain function; Executive function; Older adults
21.  The influence of aerobic fitness on cerebral white matter integrity and cognitive function in older adults: Results of a one-year exercise intervention 
Human brain mapping  2012;34(11):2972-2985.
Cerebral white matter degeneration occurs with increasing age and is associated with declining cognitive function. Research has shown that cardiorespiratory fitness and exercise are effective as protective, even restorative, agents against cognitive and neurobiological impairments in older adults. In this study, we investigated whether the beneficial impact of aerobic fitness would extend to white matter integrity in the context of a one-year exercise intervention. Further, we examined the pattern of diffusivity changes to better understand the underlying biological mechanisms. Finally, we assessed whether training-induced changes in white matter integrity would be associated with improvements in cognitive performance independent of aerobic fitness gains. Results showed that aerobic fitness training did not affect group-level change in white matter integrity, executive function, or short-term memory, but that greater aerobic fitness derived from the walking program was associated with greater change in white matter integrity in the frontal and temporal lobes, and greater improvement in short-term memory. Increases in white matter integrity, however, were not associated with short-term memory improvement, independent of fitness improvements. Therefore, while not all findings are consistent with previous research, we provide novel evidence for correlated change in training-induced aerobic fitness, white matter integrity, and cognition among healthy older adults.
PMCID: PMC4096122  PMID: 22674729
Diffusion tensor imaging; Anisotropy; Cerebrum; Cognition; Physical fitness; Aging
22.  Competing physiological pathways link individual differences in weight and abdominal adiposity to white matter microstructure 
NeuroImage  2013;79:129-137.
Being overweight or obese is associated with reduced white matter integrity throughout the brain. It is not yet clear which physiological systems mediate the association between inter-individual variation in adiposity and white matter. We tested whether composite indicators of cardiovascular, lipid, glucose, and inflammatory factors would mediate the adiposity-related variation in white matter microstructure, measured with diffusion tensor imaging on a group of neurologically healthy adults (N=155). A composite factor representing adiposity (comprised of body mass index and waist circumference) was negatively associated fractional anisotropy, and increased radial diffusivity, throughout the brain, a pattern linked to myelin structure changes in non-human animal models. A similar global negative association was found for factors representing inflammation and, to a lesser extent, glucose regulation. In contrast, factors for blood pressure and dyslipidemia had positive associations with white matter in isolated brain regions. Taken together, these competing influences on the diffusion signal were significant mediators linking adiposity to white matter and explained up to fifty-percent of the adiposity-white matter variance. These results provide the first evidence for contrasting physiological pathways, a globally distributed immunity-linked negative component and a more localized vascular-linked positive component, that associate adiposity to individual differences in the microstructure of white matter tracts in otherwise healthy adults.
PMCID: PMC3752776  PMID: 23639257
adiposity; inflammation; obesity; metabolic syndrome; white matter
23.  Inflammatory Pathways Link Socioeconomic Inequalities to White Matter Architecture 
Cerebral Cortex (New York, NY)  2012;23(9):2058-2071.
Socioeconomic disadvantage confers risk for aspects of ill health that may be mediated by systemic inflammatory influences on the integrity of distributed brain networks. Following this hypothesis, we tested whether socioeconomic disadvantage related to the structural integrity of white matter tracts connecting brain regions of distributed networks, and whether such a relationship would be mediated by anthropometric, behavioral, and molecular risk factors associated with systemic inflammation. Otherwise healthy adults (N= 155, aged 30–50 years, 78 men) completed protocols assessing multilevel indicators of socioeconomic position (SEP), anthropometric and behavioral measures of adiposity and cigarette smoking, circulating levels of C-reactive protein (CRP), and white matter integrity by diffusion tensor imaging. Mediation modeling was used to test associations between SEP indicators and measures of white matter tract integrity, as well as indirect mediating paths. Measures of tract integrity followed a socioeconomic gradient: individuals completing more schooling, earning higher incomes, and residing in advantaged neighborhoods exhibited increases in white matter fractional anisotropy and decreases in radial diffusivity, relative to disadvantaged individuals. Moreover, analysis of indirect paths showed that adiposity, cigarette smoking, and CRP partially mediated these effects. Socioeconomic inequalities may relate to diverse health disparities via inflammatory pathways impacting the structural integrity of brain networks.
PMCID: PMC3729196  PMID: 22772650
diffusion tensor imaging; inflammation; social health disparities; socioeconomic inequality; stress; white matter fractional anisotropy
24.  White matter microstructure is associated with cognitive control in children 
Biological psychology  2013;94(1):109-115.
Cognitive control, which involves the ability to pay attention and suppress interference, is important for learning and achievement during childhood. The white matter tracts related to control during childhood are not well known. We examined the relationship between white matter microstructure and cognitive control in 61 children aged 7 to 9 years using diffusion tensor imaging (DTI). This technique enables an in vivo characterization of microstructural properties of white matter based on properties of diffusion. Such properties include fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity, measures thought to reflect specific biological properties of white matter integrity. Our results suggest that children with higher estimates of white matter integrity in the corona radiata, superior longitudinal fasciculus, posterior thalamic radiation, and cerebral peduncle, were more accurate during incongruent (>><>>, <<><<) and neutral (-->--, --<--) trials of a task of cognitive control. Importantly, less interference during the task (i.e., incongruent and neutral difference scores) was associated with greater white matter microstructure in the posterior thalamic radiation and cerebral peduncle. Fiber tracts in a frontal-parietal-striatal-motor circuit seem to play a role in cognitive control in children.
PMCID: PMC3742734  PMID: 23714226
child; cognition; diffusion tensor imaging; flanker; MRI
25.  Basal ganglia morphology links the metabolic syndrome and depressive symptoms 
Physiology & behavior  2013;123:214-222.
The metabolic syndrome (MetS) is a clustering of cardiovascular and cerebrovascular risk factors that are often comorbid with depressive symptoms. Individual components of the MetS also covary with the morphology of basal ganglia regions that are altered by depression. However, it remains unknown whether the covariation between the MetS and depressive symptomatology can be accounted for in part by morphological changes in the basal ganglia. Accordingly, we tested the hypothesis that increased depressive symptoms among individuals with the MetS might be statistically mediated by reduced grey matter volume in basal ganglia regions. The presence of the MetS was determined in 147 middle-aged adults using the criteria of the National Cholesterol Education Program, Adult Treatment Panel III. Basal ganglia volumes were determined on an a priori basis by automated segmentation of high-resolution magnetic resonance images. Depressive symptoms were assessed using the Patient Health Questionnaire. Even after controlling for demographic and other confounding factors, having the MetS and meeting more MetS criteria covaried with reduced globus pallidus volume. Meeting more MetS criteria and reduced pallidal volume were also related to depressive symptoms. Moreover, the MetS-depression association was statistically mediated by pallidal volume. In summary, reduced globus pallidus volume is a neural correlate of the MetS that may partly account for its association with depressive symptoms.
PMCID: PMC4118460  PMID: 24096008
basal ganglia; cardiovascular disease; depression; metabolic syndrome

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