Effects of Hippotherapy on Health-Related Quality of Life in Caregivers of Children with Cerebral Palsy: A Pilot Quasi-Experimental Study in Japan.

BACKGROUND: Despite accumulating data regarding the beneficial effects of hippotherapy on gait and balance skills in children with cerebral palsy (CP), its effects on caregivers' quality of life (QOL) are limited, presumably due to a lack of reliable and valid measurement tools. This study aims to evaluate the impact of hippotherapy on the health-related QOL of primary caregivers using the Japanese version of the Cerebral Palsy Quality of Life for Children (CP QOL) questionnaire. METHODS: A quasi-experimental design embedded within our existing cohort was utilized. A total of 29 children with CP (range 4-12 years) and their caregivers participated in either a weekly hippotherapy or recreation (usual care) program for 1 year. In addition to gait-related measurements (Gross Motor Function Measure [GMFM]-E) of children, CP QOL-evidenced determinants of the caregivers' health-related QOL and well-being were compared before and after the intervention. RESULTS: In addition to improvements in children's GMFM-E scores, hippotherapy improved CP QOL domains related to participation and physical health, children's emotional well-being, and parents' overall health (p < 0.05). Linear regression analysis showed a positive relationship between the children's GMFM-E scores and their caregivers' health domains in participants who received hippotherapy (r2 = 0.404; p = 0.011). CONCLUSIONS: Hippotherapy has a beneficial effect on the physical and mental well-being and satisfaction of Japanese parents caring for children with CP.

Efficacy of a mixture of Ginkgo biloba, sesame, and turmeric on cognitive function in healthy adults: Study protocol for a randomized, double-blind, placebo-controlled trial.

BACKGROUND AND PURPOSE: Ginkgo biloba extract (GBE) reportedly ameliorates cognitive function in patients with chronic cerebrovascular insufficiency. However, its efficacy in healthy adults is ambiguous. It was reported that concentrations of terpene lactones, active components of GBE that are present in very low concentrations in the brain, were significantly increased following administration of a mixture of GBE, sesame seed, and turmeric (GBE/MST) in mice. This study aims to investigate the effectiveness of GBE/MST on the cognitive function of healthy adults by comparing it with that of GBE alone. METHODS: Altogether, 159 participants providing informed consent will be recruited from a population of healthy adults aged 20-64 years. Normal cognitive function at baseline will be confirmed using the Japanese version of the Montreal Cognitive Assessment battery. Participants will be randomly assigned in a double-blind manner to the GBE/MST, GBE, and placebo groups in a 1:1:1 ratio. The Wechsler Memory Scale, Trail Making Test, and Stroop Color and Word Test will be used to assess the memory and executive functions at baseline and at the endpoint (24 weeks). For biological assessment, resting state functional magnetic resonance imaging (rs-fMRI) will be performed simultaneously with the neuropsychological tests. DISCUSSION: This study aims to obtain data that can help compare the profile changes in memory and executive functions among participants consuming GBE/MST, GBE alone, and placebo for 24 weeks. Alterations in the default mode network will be evaluated by comparing the rs-fMRI findings between baseline and 24 weeks in the aforementioned groups. Our results may clarify the impact of GBE on cognitive function and the functional mechanism behind altered cognitive function induced by GBE components. TRIAL REGISTRATION: This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; registration number: UMIN000043494). This information can be searched on the website of the International Clinical Trials Registry Platform Search Portal of the World Health Organization under the Japan Primary Registries Network.

Impact of medium-chain triglycerides on gait performance and brain metabolic network in healthy older adults: a double-blind, randomized controlled study.

Nutritional supplementation with medium-chain triglycerides (MCTs) has the potential to increase memory function in elderly patients with frailty and dementia. Our aim was to investigate the effects of MCT on cognitive and gait functions and their relationships with focal brain metabolism and functional connectivity even in healthy older adults. Participants were blindly randomized and allocated to two groups: 18 g/day of MCT oil and matching placebo formula (control) administered as a jelly stick (6 g/pack, ingested three times a day). Gait analysis during the 6-m walk test, cognition, brain focal glucose metabolism quantified by 18F-fluorodeocyglucose positron emission tomography, and magnetic resonance imaging-based functional connectivity were assessed before and after a 3-month intervention. Sixty-three healthy, normal adults (females and males) were included. Compared with the control group, the MCT group showed better balance ability, as represented by the lower Lissajous index (23.1 ± 14.4 vs. 31.3 ± 18.9; P < 0.01), although no time × group interaction was observed in cognitive and other gait parameters. Moreover, MCT led to suppressed glucose metabolism in the right sensorimotor cortex compared with the control (P < 0.001), which was related to improved balance (r = 0.37; P = 0.04) along with increased functional connectivity from the ipsilateral cerebellar hemisphere. In conclusion, a 3-month MCT supplementation improves walking balance by suppressing glucose metabolism, which suggests the involvement of the cerebro-cerebellar network. This may reflect, at least in part, the inverse reaction of the ketogenic switch as a beneficial effect of long-term MCT dietary treatment.

Alzheimer's Disease and Type 2 Diabetes Mellitus: The Use of MCT Oil and a Ketogenic Diet.

Recently, type 2 diabetes mellitus (T2DM) has been reported to be strongly associated with Alzheimer's disease (AD). This is partly due to insulin resistance in the brain. Insulin signaling and the number of insulin receptors may decline in the brain of T2DM patients, resulting in impaired synaptic formation, neuronal plasticity, and mitochondrial metabolism. In AD patients, hypometabolism of glucose in the brain is observed before the onset of symptoms. Amyloid-ß accumulation, a main pathology of AD, also relates to impaired insulin action and glucose metabolism, although ketone metabolism is not affected. Therefore, the shift from glucose metabolism to ketone metabolism may be a reasonable pathway for neuronal protection. To promote ketone metabolism, medium-chain triglyceride (MCT) oil and a ketogenic diet could be introduced as an alternative source of energy in the brain of AD patients.

Impact of Long-Term Hippotherapy on the Walking Ability of Children With Cerebral Palsy and Quality of Life of Their Caregivers.

Background: Cerebral palsy (CP) is a permanent motor disorder that occurs at birth or during early infancy. Despite advances in fetal and maternal medicine, the incidence of CP remains high. Hippotherapy has gradually been recognized as an excellent rehabilitation tool for children with CP. However, a scientific basis for how it achieves long-term functional improvements or provides additional benefits to patients' caregivers remains unknown. Objectives: We performed a prospective trial to determine how hippotherapy affects the gross motor and gait functions in children with CP and how it may also impact the quality of life (QOL) of patients' caregivers. Methods: In total, 24 children with CP (11 boys, 13 girls; age: 4-14 years; Gross Motor Function Classification System [GMFCS] II-III) underwent a program (30 min/day, once a week) of hippotherapy or day-care recreation (control) over a 1-year intervention and a 3-month follow-up period. Assessment measures used for the children were gait parameters for a 5-m walk test, Gross Motor Function Measure (GMFM)-66, and GMFM dimension-E (GMFM-E). The QOL of the caregivers was estimated using a brief version of the World Health Organization Quality Of Life (WHOQOL-BREF) self-assessment questionnaire. Results: In addition to better GMFM-66 and GMFM-E scores, hippotherapy was associated with increased cadence, step length, and mean acceleration; stabilized horizontal/vertical displacement of patients; and better relationship between the psychological status and QOL of the caregivers than those seen in the control group (p < 0.05). Additionally, the initially improved children's step length and their caregivers' psychological QOL domain (particularly in the "positive feeling" facet) tended to be preserved up to the 3-month follow-up. Conclusion: These data suggest that compared with common day-care recreational activities, a 1-year program of once-weekly hippotherapy can improve not only the walking ability of children with CP but also the psychological health and QOL of their caregivers. Clinical Trial Registration:: www.umin.ac.jp/ctr/, identifier: UMIN000022986.

rs1360780 of the FKBP5 gene modulates the association between maternal acceptance and regional gray matter volume in the thalamus in children and adolescents.

Investigating the effects of gene-environment interactions (G × E) with regard to brain structure may help to elucidate the putative mechanisms associated with psychiatric risk. rs1360780 (C/T) is a functional single-nucleotide polymorphism (SNP) in the gene encoding FK506-binding protein 5 (FKBP5), which is involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis stress responses. The minor (T) allele of FKBP5 is considered a risk allele for stress-related disorders, due to the overproduction of FKBP5, which results in impaired communication of stress signals with the HPA axis. Previous studies have reported that interactions between childhood maltreatment and the rs1360780 genotype affect structures in subcortical areas of the brain. However, it is unclear how this SNP modulates the association between non-adverse environments and brain structure. In this study, we examined the interactive effect of the rs1360780 genotype and maternal acceptance on the regional gray matter volume (rGMV) in 202 Japanese children. Maternal acceptance was assessed using a Japanese psychological questionnaire for mothers. Whole-brain multiple regression analysis using voxel-based morphometry showed a significant positive association between maternal acceptance and rGMV in the left thalamus of T-allele carriers, while a significant negative association was found in C/C homozygotes. Post-hoc analysis revealed that at or below the 70th percentiles of maternal acceptance, the T-allele carriers had a reduced thalamic rGMV compared with that of C/C homozygotes. Thus, our investigation indicated that the effect of the maternal acceptance level on brain development was different, depending on the rs1360780 genotype. Importantly, we found that the differences in brain structure between the T-allele carriers and C/C homozygotes at low to moderate levels of maternal acceptance, which is not equivalent to maltreatment. The present study contributes to the G × E research by highlighting the necessity to investigate the role of non-adverse environmental factors.

Effect of hippotherapy on gait symmetry in children with cerebral palsy: A pilot study.

We aimed to investigate the effect of hippotherapy on gait symmetry in children with cerebral palsy (CP). Twelve children with Gross Motor Function Classification System (GMFCS) levels II-IV received weekly hippotherapy lesson for 1 year. Gait analyses were performed during a 5-m walking test, using a portable, tri-axial accelerometer-based motion recorder. The baseline symmetry index derived from the Lissajous index (LI) figure before hippotherapy was greater than the LI in age-matched normal subjects (P < 0.01). Hippotherapy was associated with a decreased LI (-10.4 ± 4.9%, P = 0.018) and an improved GMFCS score (-0.6 ± 0.7, P = 0.02). These data suggest that hippotherapy has a beneficial effect on symmetry of the trunk movement in children with CP.

Association of copper levels in the hair with gray matter volume, mean diffusivity, and cognitive functions.

Although copper plays a critical role in normal brain functions and development, it is known that excess copper causes toxicity. Here we investigated the associations of copper levels in the hair with regional gray matter volume (rGMV), mean diffusivity (MD), and cognitive differences in a study cohort of 924 healthy young adults. Our findings showed that high copper levels were associated mostly with low cognitive abilities (low scores on the intelligence test consisting of complex speed tasks, involving reasoning task, a complex arithmetic task, and a reading comprehension task) as well as lower reverse Stroop interference, high rGMV over widespread areas of the brain [mainly including the bilateral lateral and medial parietal cortices, medial temporal structures (amygdala, hippocampus, and parahippocampal gyrus), middle cingulate cortex, orbitofrontal cortex, insula, perisylvian areas, inferior temporal lobe, temporal pole, occipital lobes, and supplementary motor area], as well as high MD of the right substantia nigra and bilateral hippocampus, which are indicative of low density in brain tissues. These results suggest that copper levels are associated with mostly aberrant cognitive functions, greater rGMV in extensive areas, greater MD (which are indicative of low density in brain tissues) in subcortical structures in the healthy young adults, possibly reflecting copper's complex roles in neural mechanisms.

A Common CACNA1C Gene Risk Variant has Sex-Dependent Effects on Behavioral Traits and Brain Functional Activity.

Genome-wide association studies have suggested that allelic variations in the CACNA1C gene confer susceptibility to schizophrenia and bipolar disorder only in women. Here we investigated the sex-specific effects of the CACNA1C variant rs1024582 on psychiatry-related traits, brain activity during tasks and rest, and brain volume in 1207 normal male and female subjects. After correcting for multiple comparisons, there were significant interaction effects between sex and the minor allele of this polymorphism on the hostile behavior subscale scores of the Coronary-Prone Type Scale mediated by higher scores in female carriers of the minor allele. Imaging analyses revealed significant interaction effects between sex and the minor allele on fractional amplitude of low-frequency fluctuations in the right dorsolateral prefrontal cortex and on brain activity during the 2-back task in areas of the right posterior cingulate cortex, right thalamus, and right hippocampus, which were all mediated by reduced activity in female carriers of the minor allele. Our results demonstrated that the rs1024582 risk variant of CACNA1C is associated with reduced activity in the frontolimbic regions at rest and during a working memory task as well as with greater hostility in females in the healthy population.

Impact of serial gait analyses on long-term outcome of hippotherapy in children and adolescents with cerebral palsy.

The aim of this study was to obtain data of gait parameters on predicting long-term outcome of hippotherapy. In 20 participants (4-19 years; GMFCS levels I to III) with cerebral palsy (CP), gait and balance abilities were examined after 10-m walking test using a portable motion recorder. Hippotherapy was associated with increased Gross Motor Function Measure (GMFM)-66 at 1 year from the baseline (P < 0.001). Hippotherapy increased stride length, walking speed, and mean acceleration and decreased horizontal/vertical displacement ratio over time (P < 0.05). Stride length and mean acceleration at 6 weeks predicted the elevation of GMFM-66 score. These data suggest that 1-year outcome of hippotherapy on motor and balance functions can be assessed from the early phase by serial monitoring of the gait parameters.

Mean diffusivity of basal ganglia and thalamus specifically associated with motivational states among mood states.

Previously, we proposed that the mean diffusivity (MD), a measure of diffusion tensor imaging (DTI) in areas of the dopaminergic system (MDDS), is associated with motivation. In this study, we tested if and how the motivational state is associated with MD in comparison with other mood states. We also tested the associations of these mood states with multiple cognitive functions. We examined these issues in 766 right-handed healthy young adults. We employed analyses of MD and a psychological measure of the profile of mood states (POMS) as well as multiple cognitive functions. We detected associations between the higher Vigor subscale of POMS and lower MD in the right globus pallidum, right putamen to right posterior insula, right caudate body, and right thalamus, and these associations were highly specific to the Vigor subscale. Similarly, the association of the motivational state with creativity measured by divergent thinking (CMDT) was rather specific and prominent compared with that of the other mood states and cognitive functions. In conclusion, when affective states are finely divided, only the motivational state is associated with MD in the areas related to the dopaminergic system, and psychological mechanisms that had been associated with dopaminergic system (CMDT). These results suggest that these mechanisms specifically contribute to the motivational state and not to the other states, such as depression and anxiety.

Application of a tri-axial accelerometry-based portable motion recorder for the quantitative assessment of hippotherapy in children and adolescents with cerebral palsy.

[Purpose] This case series aims to evaluate the effects of hippotherapy on gait and balance ability of children and adolescents with cerebral palsy using quantitative parameters for physical activity. [Subjects and Methods] Three patients with gait disability as a sequela of cerebral palsy (one female and two males; age 5, 12, and 25 years old) were recruited. Participants received hippotherapy for 30 min once a week for 2 years. Gait parameters (step rate, step length, gait speed, mean acceleration, and horizontal/vertical displacement ratio) were measured using a portable motion recorder equipped with a tri-axial accelerometer attached to the waist before and after a 10-m walking test. [Results] There was a significant increase in step length between before and after a single hippotherapy session. Over the course of 2 year intervention, there was a significant increase in step rate, gait speed, step length, and mean acceleration and a significant improvement in horizontal/vertical displacement ratio. [Conclusion] The data suggest that quantitative parameters derived from a portable motion recorder can track both immediate and long-term changes in the walking ability of children and adolescents with cerebral palsy undergoing hippotherapy.

Postoperative hormonal therapy prevents recovery of neurological damage after surgery in patients with breast cancer.

Cancer survivors are exposed to several risk factors for cognitive dysfunction, such as general anesthesia, surgical trauma, and adjuvant therapies. In our recent study we showed that thalamic volume reduction and attentional dysfunction occurred shortly after surgery. Here, we examined the 6-month prognosis of the 20 patients with breast cancer who underwent surgery. Seven patients did not receive any adjuvant therapy after the surgery and 13 patients received a hormonal therapy after the surgery. We assessed their attentional functions, and thalamic volumes shortly after and 6 months after surgery. We found a significant group x time interaction in the attentional functions (p = 0.033) and the right thalamus (p < 0.05, small volume correction), suggesting the thalamic volume reduction and attentional dysfunction recovered in patients without adjuvant therapy. Our findings provide a better understanding of the potential role of hormonal therapy in relation to the cognitive dysfunction of cancer survivors.

Therapeutic Potential of Natural Product-Based Oral Nanomedicines for Stroke Prevention.

Cerebral stroke is the leading cause of death and permanent disability in elderly persons. The impaired glucose and oxygen transport to the brain during ischemia causes bioenergetic failure, leading to oxidative stress, inflammation, blood-brain barrier dysfunction, and eventually cell death. However, the development of effective therapies against stroke has been hampered by insufficient oral absorption of pharmaceuticals and subsequent delivery to the brain. Nanotechnology has emerged as a new method of treating cerebral diseases, with the potential to fundamentally change currently available therapeutic approaches using compounds with low bioavailability. This perspective review provides an overview of the therapeutic potential of oral nanomedicines for stroke, focusing on novel natural product-loaded delivery system with potent antioxidant and anti-inflammatory effects.

Postoperative Structural Brain Changes and Cognitive Dysfunction in Patients with Breast Cancer.

OBJECTIVE: The primary purpose of this study was to clarify the influence of the early response to surgery on brain structure and cognitive function in patients with breast cancer. It was hypothesized that the structure of the thalamus would change during the early response after surgery due to the effects of anesthesia and would represent one aspect of an intermediate phenotype of postoperative cognitive dysfunction (POCD). METHODS: We examined 32 postmenopausal females with breast cancer and 20 age-matched controls. We assessed their cognitive function (attention, memory, and executive function), and performed brain structural MRI 1.5 ± 0.5 days before and 5.6 ± 1.2 days after surgery. RESULTS: We found a significant interaction between regional grey matter volume (rGMV) in the thalamus (P < 0.05, familywise error (FWE), small volume correction (SVC)) and one attention domain subtest (P = 0.001, Bonferroni correction) after surgery in the patient group compared with the control group. Furthermore, the changes in attention were significantly associated with sevoflurane anesthetic dose (r2 = 0.247, ß = ‒0.471, P = 0.032) and marginally associated with rGMV changes in the thalamus (P = 0.07, FWE, SVC) in the Pt group. CONCLUSION: Our findings suggest that alterations in brain structure, particularly in the thalamus, may occur shortly after surgery and may be associated with attentional dysfunction. This early postoperative response to anesthesia may represent an intermediate phenotype of POCD. It was assumed that patients experiencing other risk factors of POCD, such as the severity of surgery, the occurrence of complications, and pre-existing cognitive impairments, would develop clinical POCD with broad and multiple types of cognitive dysfunction.

Assessment of myocardial metabolic disorder associated with mediastinal radiotherapy for esophageal cancer -a pilot study.

BACKGROUND: To evaluate the dose-effect relations for myocardial metabolic disorders after mediastinal radiotherapy (RT) by performing iodine-123 ß-methyl-iodophenyl pentadecanoic acid (I-123 BMIPP) scintigraphy. METHODS: Between 2011 and 2012, we performed I-123 BMIPP scintigraphy for patients with esophageal cancer before and six months after curative mediastinal RT. Single photon emission computed tomography (SPECT) images of pre-RT and post-RT were registered into RT dose distributions. The myocardium was contoured, and the regional RT dose was calculated. Normalization is required to compare pre- and post-RT SPECT images because the uptake pattern is changed due to the breathing level. Normalization was applied on the mean of SPECT counts in regions of the myocardium receiving less than 5 Gy. Relative values in each dose region (interval of 5 Gy) were calculated on the basis of this normalization for each patient. The reduction in the percent of relative values was calculated. RESULTS: Five patients were enrolled in this study. None of the patients had a past history of cardiac disease. The left ventricle was partially involved in RT fields in all patients. The patients received RT with median total doses of 60-66 Gy for the primary tumor and metastatic lymph nodes. Concomitant chemotherapy consisting of cisplatin or nedaplatin and 5-fluorouracil with RT was performed in 4 patients. All patients had reduced uptake corresponding to RT fields. Dose-effect relations for reduced uptake tended to be observed at 6 months after RT with mean decreases of 8.96% in regions at 10-15 Gy, 12.6% in regions at 20-25 Gy, 15.6% in regions at 30-35 Gy, 19.0% in regions at 40-45 Gy and 16.0% in regions at 50-55 Gy. CONCLUSIONS: Dose-effect relations for myocardial metabolic disorders tended to be observed. We may need to make an effort to reduce high-dose mediastinal RT to the myocardium in RT planning.

The impact of television viewing on brain structures: cross-sectional and longitudinal analyses.

Television (TV) viewing is known to affect children's verbal abilities and other physical, cognitive, and emotional development in psychological studies. However, the brain structural development associated with TV viewing has never been investigated. Here we examined cross-sectional correlations between the duration of TV viewing and regional gray/white matter volume (rGMV/rWMV) among 133 boys and 143 girls as well as correlations between the duration of TV viewing and longitudinal changes that occurred a few years later among 111 boys and 105 girls. After correcting for confounding factors, we found positive effects of TV viewing on rGMV of the frontopolar and medial prefrontal areas in cross-sectional and longitudinal analyses, positive effects of TV viewing on rGMV/rWMV of areas of the visual cortex in cross-sectional analyses, and positive effects of TV viewing on rGMV of the hypothalamus/septum and sensorimotor areas in longitudinal analyses. We also confirmed negative effects of TV viewing on verbal intelligence quotient (IQ) in cross-sectional and longitudinal analyses. These anatomical correlates may be linked to previously known effects of TV viewing on verbal competence, aggression, and physical activity. In particular, the present results showed effects of TV viewing on the frontopolar area of the brain, which has been associated with intellectual abilities.

Biofeedback-based training for stress management in daily hassles: an intervention study.

BACKGROUND: The day-to-day causes of stress are called daily hassles. Daily hassles are correlated with ill health. Biofeedback (BF) is one of the tools used for acquiring stress-coping skills. However, the anatomical correlates of the effects of BF with long training periods remain unclear. In this study, we aimed to investigate this. METHODS: PARTICIPANTS WERE ASSIGNED RANDOMLY TO TWO GROUPS: the intervention group and the control group. Participants in the intervention group performed a biofeedback training (BFT) task (a combination task for heart rate and cerebral blood flow control) every day, for about 5 min once a day. The study outcomes included MRI, psychological tests (e.g., Positive and Negative Affect Schedule, Center for Epidemiologic Studies Depression Scale, and Brief Job Stress Questionnaire), and a stress marker (salivary cortisol levels) before (day 0) and after (day 28) the intervention. RESULTS: We observed significant improvements in the psychological test scores and salivary cortisol levels in the intervention group compared to the control group. Furthermore, voxel-based morphometric analysis revealed that compared to the control group, the intervention group had significantly increased regional gray matter (GM) volume in the right lateral orbitofrontal cortex, which is an anatomical cluster that includes mainly the left hippocampus, and the left subgenual anterior cingulate cortex. The GM regions are associated with the stress response, and, in general, these regions seem to be the most sensitive to the detrimental effects of stress. CONCLUSIONS: Our findings suggest that our BFT is effective against the GM structures vulnerable to stress.

Relationship between body mass index and gray matter volume in 1,428 healthy individuals.

OBJECTIVE: To investigate any correlation between BMI and brain gray matter volume, we analyzed 1,428 healthy Japanese subjects by applying volumetric analysis and voxel-based morphometry (VBM) using brain magnetic resonance (MR) imaging, which enables a global analysis of brain structure without a priori identification of a region of interest. METHODS AND PROCEDURES: We collected brain MR images from 690 men and 738 women, and their height, weight, and other clinical information. The collected images were automatically normalized into a common standard space for an objective assessment of neuroanatomical correlations in volumetric analysis and VBM with BMI. RESULTS: Volumetric analysis revealed a significant negative correlation in men (P < 0.001, adjusting for age, lifetime alcohol intake, history of hypertension, and diabetes mellitus), although not in women, between BMI and the gray matter ratio, which represents the percentage of gray matter volume in the intracranial volume. VBM revealed that, in men, the regional gray matter volume of the bilateral medial temporal lobes, anterior lobe of the cerebellum, occipital lobe, frontal lobe, precuneus, and midbrain showed significant negative correlations with BMI, while those of the bilateral inferior frontal gyri, posterior lobe of the cerebellum, frontal lobes, temporal lobes, thalami, and caudate heads showed significant positive correlations with BMI. DISCUSSION: Global loss and regional alterations in gray matter volume occur in obese male subjects, suggesting that male subjects with a high BMI are at greater risk for future declines in cognition or other brain functions.