Reduced Brain Volume Research Articles

The Longitudinal Association of Walking Efficiency With Brain Volumes in Community-Dwelling Older Adults

Walking efficiency (WE) predicts mobility decline and is linked with higher fatigability. Fatigability is associated with cognitive decline and reduced brain volumes (BV), but the link between WE and BV is undefined. We examined associations between WE and BV in 860 participants of the BLSA (mean age 66.4(14.4) years, 54.5% women). WE was assessed during 2.5-minutes of usual-paced walking using indirect calorimetry and standardized per meter (ml/kg/m). BV measures were derived using MRI scans and an automated multi-atlas region-of-interest approach. In linear mixed models adjusted for demographics, education, BMI, intracranial volume, and cognitive status, lower baseline WE was associated with lower total, white, and gray matter, primarily in the frontal and temporal lobes (all p<0.05). Longitudinally, declining WE was associated with increasing ventricular and decreasing hippocampal volumes over follow-up (all p<0.01). Findings suggest rising age-related inefficiencies may reflect underlying brain atrophy and serve as a novel indicator for future interventions.

Gut microbiota and brain alterations in a translational anorexia nervosa rat model

Anorexia nervosa (AN) is an eating disorder that leads to brain volume reduction and is difficult to treat since the underlying pathophysiology is poorly understood. The human gut microbiota is known to be involved in host metabolism, appetite- and bodyweight regulation, gut permeability, inflammation and gut-brain interactions. In this study, we used a translational activity-based anorexia (ABA) rat model including groups with food restriction, running-wheel access and a combination to disentangle the influences on the gut microbiota and associated changes in brain volume parameters. Our data demonstrated that chronic food restriction but not running-wheel activity had a major influence on the gut microbiota diversity and composition and reduced brain volume. Negative correlations were found between global brain weight and α-diversity, and astrocyte markers and relative abundances of the genera Odoribacter and Bifidobacterium. In contrast, the presence of lactobacilli was positively associated with white and grey brain matter volume. ABA and food-restricted rats are an interesting pre-clinical model to assess the causal influence of starvation on the gut microbiome and gut-brain interactions and can help to dissect the underlying pathophysiologic mechanisms relevant to AN.

RONC-02. MEASURING THE EFFECT OF CLINICALLY-RELEVANT RADIOTHERAPY PROTOCOLS ON THE JUVENILE MOUSE BRAIN

Treatment for medulloblastoma involves craniospinal irradiation which is associated with devastating late effects. Clinical trials that simply reduce radiotherapy dosage have resulted in inferior survival rates, whereas new chemo/radiotherapy combinations that improve survival have been identified using preclinical models. However, the potential late effects of novel treatments are currently understudied and the assessment of radiation-induced late effects in mice remains challenging. Here, we aimed to measure the effect of multifractionated radiotherapy on the juvenile mouse brain as a baseline measure for future studies. NOD/Rag1-/- mice received either 8Gy whole-brain radiotherapy (WBRT) using an X-RAD SmART preclinical platform, 18Gy fractionated WBRT (9x2Gy doses), single, or multiple sham treatments beginning at postnatal day (P)16. Mice were aged to adulthood (>P63), then high resolution anatomical brain scans were obtained on a Bruker 9.4T MRI to measure the effects of WBRT on whole brain and specific regional area volumes. A single 8Gy dose (n=10) markedly reduced brain volume by 8.5% compared to single-sham controls (n=11, p<0.0001), whereas fractionated 18Gy treatment (n=7) did not cause significant differences in brain volume compared to multi-sham controls (n=4, p>0.99). Current analyses are focused on measuring treatment effects on specific areas of the brain, as well as other anatomical differences using a range of MRI techniques. These results will serve as a valuable tool to measure potential treatment-associated effects caused by novel chemo/radiotherapy combinations on the developing brain. This will enable future studies to assess the potential safety of novel treatment to inform clinical decision making.

Ibudilast

While the armamentarium to treat relapsing-remitting multiple sclerosis MS is ever-expanding, the choice of drugs to treat progressive forms of the disease remains limited. Although (ongoing) inflammation may play a role in neurodegeneration, other mechanisms are likely to contribute to it, and there is a need to identify drugs with a neuroprotective mode of action. Ibudilast is a drug that has previously been suggested to have a neuroprotective effect in relapsing-remitting MS1: ibudilast (60 mg) did not reduce the MRI activity or the relapse rate but reduced brain volume loss accumulation by 34%. The Safety, Tolerability and Activity Study of Ibudilast in Subjects With Progressive Multiple Sclerosis (SPRINT-MS) trial2 was a multicenter study sponsored by the NIH that included patients up to 65 years of age with primary and secondary progressive MS. The trial showed that ibudilast (100 mg) reduced brain volume loss by 48% over 2 years.

Using multimodal MRI to investigate alterations in brain structure and function in the BBZDR/Wor rat model of type 2 diabetes.

BackgroundThis is an exploratory study using multimodal magnetic resonance imaging (MRI) to interrogate the brain of rats with type 2 diabetes (T2DM) as compared to controls. It was hypothesized there would be changes in brain structure and function that reflected the human disorder, thus providing a model system by which to follow disease progression with noninvasive MRI.MethodsThe transgenic BBZDR/Wor rat, an animal model of T2MD, and age‐matched controls were studied for changes in brain structure using voxel‐based morphometry, alteration in white and gray matter microarchitecture using diffusion weighted imaging with indices of anisotropy, and functional coupling using resting‐state BOLD functional connectivity. Images from each modality were registered to, and analyzed, using a 3D MRI rat atlas providing site‐specific data on over 168 different brain areas.ResultsThere was an overall reduction in brain volume focused primarily on the somatosensory cortex, cerebellum, and white matter tracts. The putative changes in white and gray matter microarchitecture were pervasive affecting much of the brain and not localized to any region. There was a general increase in connectivity in T2DM rats as compared to controls. The cerebellum presented with strong functional coupling to pons and brainstem in T2DM rats but negative connectivity to hippocampus.ConclusionThe neuroradiological measures collected in BBBKZ/Wor rats using multimodal imaging methods did not reflect those reported for T2DB patients in the clinic. The data would suggest the BBBKZ/Wor rat is not an appropriate imaging model for T2DM.

Heart failure with preserved ejection fraction (HFpEF) is associated with cognitive impairment and reduced brain volume

AbstractBackgroundIncreasingly, vascular diseases are implicated in risk for Alzheimer’s disease and related dementias. Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF in the U.S and most commonly affects older women with overweight/obesity. Given known systemic microvascular effects of HFpEF, dementia risk may be a potential unrecognized downstream effect of the disease.MethodHarmonized cognitive testing and brain MRI protocols were employed in Wake Forest’s Alzheimer’s Disease Research Center’s Clinical Core and the SECRET‐2 clinical trial of HFpEF. Cognitive tests included components of NACC’s Uniform Data Set version 3. Brain imaging protocols included structural MRI and cerebral blood flow images. Statistical comparisons of cognitive and imaging data by cognitive/group status were done using multivariable general linear models adjusting for basic covariates including age, race, and sex in basic models and additional adjustments for intracranial volume (for MRI) and education (for cognitive test scores) in fully adjusted models using SAS 9.4.ResultThe analysis includes a comparison of 89 participants recruited into the Wake Forest ADRC (adjudicated as cognitively normal, n=43; MCI, n=22; and dementia, n=5) and SECTRET‐2 intervention trail in HFpEF (n=19) patients. Compared to cognitively normal participants, patients with HFpEF were significantly more likely to be Black (47% vs 2%, p&lt;0.01), have a higher body mass index (38.2 vs. 28.0, p&lt;0.01), and a diagnosis of hypertension (84% vs 26%). Patients with HFpEF had poorer global cognitive performance [MoCA score, beta(SE)=‐1.76(0.77), p=0.02)], but no differences in Craft Story delayed recall in models adjusted for age, gender, race and education. HFpEF was also significantly associated with smaller gray matter volume [beta(SE)=‐20.7(11.6), p=&lt;0.01)] at levels worse than MCI and dementia in models adjusted for age, gender, race and ICV. No initial differences were observed in resting cerebral blood flow or evoked cerebrovascular response due to hypercapnia.ConclusionHFpEF participants showed deficits in global cognitive function that were comparable to those with MCI, as well as global decreases in brain volume. Additional follow‐up of these participants with HFpEF will more deeply phenotype cognitive impairments by domain and adjudication criteria used for MCI and dementia.

The API Generation program: Umibecestat treatment and discontinuation effects on hippocampal and whole brain volumes in the overall population and amyloid‐negative APOE4 homozygotes

AbstractBackgroundIn addition to early mild non‐progressive cognitive worsening, BACE inhibitors have been associated with early non‐progressive reductions in hippocampal and whole brain volume in trial participants with elevated amyloid (A+, Egan et al, 2019). We have begun to evaluate the effects of umibecestat treatment and discontinuation on cognitively unimpaired amyloid‐positive (A+) and A‐ APOE4 homozygotes and A+ heterozygotes, testing the hypotheses that BACE inhibitor‐related hippocampal and whole brain shrinkage is apparent soon after treatment initiation, non‐progressive, limited to A+ participants, and reversible following discontinuation.MethodThe API Generation Program had begun to evaluate umibecestat in 1,623 cognitively unimpaired 60‐75 year‐old participants including 921 A+ APOE4 heterozygotes and 702 homozygotes (A+ or A‐).Following randomization, volumetric brain MRIs were scheduled at month 6, month 12 and then annually. After discontinuation of study medication, participants continued to be assessed under double‐blind conditions, and MRIs were acquired within 3 months after the last dose. We investigated 6‐month hippocampal and whole brain volume changes and their relationship to RBANS immediate, delayed and total memory score changes; and we plan to investigate the persistence or reversibility of these changes within 3 months of discontinuation after study completion in Q2 2020.ResultUmibecestat was associated with significant 6‐month hippocampal and whole brain shrinkage in the aggregate APOE4 homozygote and A+ heterozygote group, but not in the A‐ homozygotes. While an early non‐progressive worsening in RBANS immediate, delayed, and total memory scores (Graf et al, AAIC 2020 submitted) was seen in the overall population as well as in A‐ HMs, we failed to demonstrate any significant association between brain shrinkage and cognitive worsening in the overall group (R2 coefficient &lt;0.1) in the active treatment group for any of the visits (on‐ and off‐ treatment).ConclusionBACE inhibitor‐related brain shrinkage appears to be early, non‐progressive, related to pre‐existing amyloid plaque burden, and unrelated to its cognitive worsening. Pending findings will help to clarify the extent to which it is also reversible. Together, our cognitive and MRI findings could help to assess potential benefits versus risks of BACE inhibitors in future prevention trials.

N-acetylcysteine prevents olanzapine-induced oxidative stress in mHypoA-59 hypothalamic neurons

Olanzapine is a second-generation antipsychotic (AP) drug commonly prescribed for the treatment of schizophrenia. Recently, olanzapine has been found to cause brain tissue volume loss in rodent and primate studies; however, the underlying mechanism remains unknown. Abnormal autophagy and oxidative stress have been implicated to have a role in AP-induced neurodegeneration, while N-acetylcysteine (NAC) is a potent antioxidant, shown to be beneficial in the treatment of schizophrenia. Here, we investigate the role of olanzapine and NAC on cell viability, oxidative stress, mitochondrial mass and mitophagy in hypothalamic cells. Firstly, cell viability was assessed in mHypoA-59 and mHypoA NPY/GFP cells using an MTS assay and flow cytometric analyses. Olanzapine treated mHypoA-59 cells were then assessed for mitophagy markers and oxidative stress; including quantification of lysosomes, autophagosomes, LC3B-II, p62, superoxide anion (O2–) and mitochondrial mass. NAC (10 mM) was used to reverse the effects of olanzapine (100 µM) on O2−, mitochondrial mass and LC3B-II. We found that olanzapine significantly impacted cell viability in mHypoA-59 hypothalamic cells in a dose and time-dependent manner. Olanzapine inhibited mitophagy, instigated oxidative stress and prompted mitochondrial abnormalities. NAC was able to mitigate olanzapine-induced effects. These findings suggest that high doses of olanzapine may cause neurotoxicity of hypothalamic neurons via increased production of reactive oxygen species (ROS), mitochondrial damage and mitophagy inhibition. This could in part explain data suggesting that APs may reduce brain volume.

The Entire Brain Is Susceptible To Radiation-Induced Volume Loss After Radiotherapy: Results From A Deformation-Based Morphometry Analysis

Morphometric changes in the brain after radiotherapy (RT) have seen increased interest in the last decade, in an effort to explain the cognitive symptoms seen after tumor treatment. Studies have largely restricted themselves to predefined structures, specifically grey matter, white matter and subcortical areas. However, changes in the brain may not necessarily conform to the boundaries of these structures, and may either be more diffuse or more localized. Therefore, it is of interest to analyze post-RT changes in the entire brain without first specifying which areas or regions to test. Deformation based morphometry (DBM) is a technique which allows this. A cohort of 28 grade II-IV glioma patients treated with RT was selected from patient records. High-quality T1 MRIs before and 1 year after RT were collected, along with basic clinical data. Scans were non-linearly warped to a standard brain. Transformations applied to each voxel in this step were collected for each scan, resulting in 3D deformation fields for every brain. The voxelwise Jacobian-determinant of the 3D deformation field shows the local, net volume changes. Morphological changes after RT were then determined in each patient by comparing the deformations of the two scans, and were related to the applied dose. For ease of interpretation, results are presented per brain region according to the Neuromorphometrics brain atlas. Significant reductions in brain volume were seen in 104 out of the 142 regions, with changes observed in both white and grey matter. The regions most affected are shown in the table. Conversely, a significant increase in volume was seen in the ventricles, with rates of 43.0 and 61.1 %/30 Gy for the left and right ventricle, respectively. The brain is susceptible to radiation induced volume loss. A decrease was seen in white and grey matter, with three-quarter of brain areas affected. This loss of brain tissue was accompanied by an increase in volume of the ventricles. Current cranial radiotherapy protocols have only identified several organs at risk (OARs) which have to be spared in order to prevent radiation damage to critical structures. Our results need to be correlated to neurocognitive outcomes in future studies; together with our current data, this may lead to the conclusion that the entire brain is an OAR, and should subsequently receive as little dose as possible. This means that the focus has to shift towards more precise sparing strategies, such as proton therapy or image-guided RT.Abstract 3732; TableRegion nameAffected voxels within area (%)Relative volume change (%/30 Gy)p-valueLeft Frontal Operculum67.715.0<0.001Left Anterior Insula51.610.50.001Left Superior Temporal51.45.30.002Left Middle Occipital46.710.80.001Left Inferior Frontal Angular45.115.3<0.001Left Cerebrum and Motor44.59.30.001Left Middle Temporal43.98.40.001 Open table in a new tab

Reversal of Age-Related Neuronal Atrophy by α5-GABAA Receptor Positive Allosteric Modulation.

Aging is associated with reduced brain volume, altered neural activity, and neuronal atrophy in cortical-like structures, comprising the frontal cortex and hippocampus, together contributing to cognitive impairments. Therapeutic efforts aimed at reversing these deficits have focused on excitatory or neurotrophic mechanisms, although recent findings show that reduced dendritic inhibition mediated by α5-subunit containing GABA-A receptors (α5-GABAA-Rs) occurs during aging and contributes to cognitive impairment. Here, we aimed to confirm the beneficial effect on working memory of augmenting α5-GABAA-R activity in old mice and tested its potential at reversing age-related neuronal atrophy. We show that GL-II-73, a novel ligand with positive allosteric modulatory activity at α5-GABAA-R (α5-PAM), increases dendritic branching complexity and spine numbers of cortical neurons in vitro. Using old mice, we confirm that α5-PAM reverses age-related working memory deficits and show that chronic treatment (3months) significantly reverses age-related dendritic shrinkage and spine loss in frontal cortex and hippocampus. A subsequent 1-week treatment cessation (separate cohort) resulted in loss of efficacy on working memory but maintained morphological neurotrophic effects. Together, the results demonstrate the beneficial effect on working memory and neurotrophic efficacy of augmenting α5-GABAA-R function in old mice, suggesting symptomatic and disease-modifying potential in age-related brain disorders.

Developmental Alterations in Cortical Organization and Socialization in Adolescents Who Sustained a Traumatic Brain Injury in Early Childhood.

This study investigated patterns of cortical organization in adolescents who had sustained a traumatic brain injury (TBI) during early childhood to determine ways in which early head injury may alter typical brain development. Increased gyrification in other patient populations is associated with polymicrogyria and aberrant development, but this has not been investigated in TBI. Seventeen adolescents (mean age = 14.1 ± 2.4) who sustained a TBI between 1-8 years of age, and 17 demographically-matched typically developing children (TDC) underwent a high-resolution, T1-weighted 3-Tesla magnetic resonance imaging (MRI) at 6-15 years post-injury. Cortical white matter volume and organization was measured using FreeSurfer's Local Gyrification Index (LGI). Despite a lack of significant difference in white matter volume, participants with TBI demonstrated significantly increased LGI in several cortical regions that are among those latest to mature in normal development, including left parietal association areas, bilateral dorsolateral and medial frontal areas, and the right posterior temporal gyrus, relative to the TDC group. Additionally, there was no evidence of increased surface area in the regions that demonstrated increased LGI. Higher Vineland-II Socialization scores were associated with decreased LGI in right frontal and temporal regions. The present results suggest an altered pattern of expected development in cortical gyrification in the TBI group, with changes in late-developing frontal and parietal association areas. Such changes in brain structure may underlie cognitive and behavioral deficits associated with pediatric TBI. Alternatively, increased gyrification following TBI may represent a compensatory mechanism that allows for typical development of cortical surface area, despite reduced brain volume.

Hippocampus and Parahippocampus Volume Reduction Associated With Impaired Olfactory Abilities in Subjects Without Evidence of Cognitive Decline.

The aim of this study was to investigate the relationship between olfactory recognition and morphological changes in olfactory brain regions including the amygdala, hippocampus, rectus, parahippocampus, orbitofrontal cortex, and medial frontal cortex in 27 elderly subjects and 27 younger healthy controls. The specific aim of the study was to determine which brain areas are associated with the initial decline of olfaction in elderly subjects, which occurs before the onset of dementia. All subjects underwent magnetic resonance imaging to measure anatomical brain volume and cortical thickness, and subjects were assessed using tests of olfactory acuity and cognitive function measured with the Montreal Cognitive Assessment. Overall brain volume reductions were observed in elderly subjects compared with young healthy controls, but only reduction in the volume of the left hippocampus was associated with decreased olfactory ability. The parahippocampus of elderly subjects was not different from that of controls; the extent of the reduction of parahippocampus volume varied among individuals, and reduction in this region was associated with olfactory decline. Similarly, parahippocampus thinning was associated with decreased olfactory function. The path analysis showed direct and indirect effects of hippocampus and parahippocampus volume on olfactory ability and that volume reductions in these areas were not associated with cognitive function. Parahippocampus volume reduction and thinning exhibited individual variation; this may be the first appearance of pathological changes and may lead to dysfunction in the connection of olfactory memory to the neocortex. Parahippocampus change may reflect the first sign of olfactory impairment prior to pathological changes in the hippocampus, amygdala and orbitofrontal cortex.

Differences in Advanced Magnetic Resonance Imaging in MOG-IgG and AQP4-IgG Seropositive Neuromyelitis Optica Spectrum Disorders: A Comparative Study.

Aims: To explore differences in advanced brain magnetic resonance imaging (MRI) characteristics between myelin oligodendrocyte (MOG) immunoglobulin (IgG) and aquaporin-4 (AQP4) IgG seropositive (+) neuromyelitis optica spectrum disorders (NMOSD).Methods: 33 AQP4-IgG and 18 MOG-IgG seropositive NMOSD patients and 61 healthy control (HC) subjects were included. All 112 participants were scanned with the same standardized MRI-protocol on a 3-Tesla MRI-scanner. Brain volume and diffusion tensor imaging (DTI) parameters were assessed.Results: MOG-IgG+ patients showed reduced parallel diffusivity within white matter tracts compared to HC whereas AQP4-IgG+ showed no significant brain parenchymal damage in DTI analysis. AQP4-IgG+ patients showed reduced whole brain volumes and reduced volumes of several deep gray matter structures compared to HC whereas MOG-IgG+ patients did not show reduced brain or deep gray matter volumes compared to HC.Conclusions: Microstructural brain parenchymal damage in MOG-IgG+ patients was more pronounced than in AQP4-IgG+ patients, compared with HC, whereas normalized brain volume reduction was more severe in AQP4-IgG+ patients. Longitudinal imaging studies are warranted to further investigate this trend in NMOSD. Our results suggest that MOG-IgG+ and AQP4-IgG+ NMOSD patients differ in cerebral MRI characteristics. Advanced MRI analysis did not help to differentiate between MOG-IgG+ and AQP4-IgG+ patients in our study.

Subcutaneous anti-CD20 antibody treatment delays gray matter atrophy in human myelin oligodendrocyte glycoprotein-induced EAE mice

BackgroundThe human myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (huMOG-EAE) model, generates B-cell driven demyelination in mice, making it a suitable multiple sclerosis model to study B cell depletion. ObjectivesWe investigated the effect of subcutaneous anti-CD20 antibody treatment on huMOG-EAE gray matter (GM) pathology. MethodsC57Bl/6, 8-week old mice were immunized with 200 huMOG1-125 and treated with 50 μg/mouse of anti-CD20 antibody (n = 16) or isotype control (n = 16). Serial brain volumetric 9.4 T MRI scans was performed at baseline, 1 and 5 wkPI. Disease severity was measured by clinical disability score (CDS) and performance on rotarod test. ResultsAnti-CD20 antibody significantly reduced brain volume loss compared with the isotype control across all timepoints longitudinally in the basal ganglia (p = 0.01), isocortex (p = 0.025) and thalamus (p = 0.023). The CDS was reduced significantly with anti-CD20 antibody vs. the isotype control at 3 (p = 0.003) and 4 (p = 0.03) wkPI, while a trend was observed at 5 (p = 0.057) and 6 (p = 0.086) wkPI. Performance on rotarod was also improved significantly at 3 (p = 0.007) and 5 (p = 0.01) wkPI compared with the isotype control. At cellular level, anti-CD20 therapy suppressed the percentage of proliferative nuclear antigen positive microglia in huMOG-EAE isocortex (p = 0.016). Flow cytometry confirmed that anti-CD20 antibody strongly depleted the CD19-expressing B cell fraction in peripheral blood mononuclear cells, reducing it from 39.7% measured in isotype control to 1.59% in anti-CD20 treated mice (p < 0.001). ConclusionsAnti-CD20 antibody treatment delayed brain tissue neurodegeneration in GM, and showed clinical benefit on measures of disease severity in huMOG-EAE mice.

Estrogen, brain structure, and cognition in postmenopausal women.

Declining estrogen levels before, during, and after menopause can affect memory and risk for Alzheimer's disease. Undesirable side effects of hormone variations emphasize a role for hormone therapy (HT) where possible benefits include a delay in the onset of dementia—yet findings are inconsistent. Effects of HT may be mediated by estrogen receptors found throughout the brain. Effects may also depend on lifestyle factors, timing of use, and genetic risk. We studied the impact of self‐reported HT use on brain volume in 562 elderly women (71–94 years) with mixed cognitive status while adjusting for aforementioned factors. Covariate‐adjusted voxelwise linear regression analyses using a model with 16 predictors showed HT use as positively associated with regional brain volumes, regardless of cognitive status. Examinations of other factors related to menopause, oophorectomy and hysterectomy status independently yielded positive effects on brain volume when added to our model. One interaction term, HTxBMI, out of several examined, revealed significant negative association with overall brain volume, suggesting a greater reduction in brain volume than BMI alone. Our main findings relating HT to regional brain volume were as hypothesized, but some exploratory analyses were not in line with existing hypotheses. Studies suggest lower levels of estrogen resulting from oophorectomy and hysterectomy affect brain volume negatively, and the addition of HT modifies the relation between BMI and brain volume positively. Effects of HT may depend on the age range assessed, motivating studies with a wider age range as well as a randomized design.

Neuroanatomy of Patients with Deficit Schizophrenia: An Exploratory Quantitative Meta-Analysis of Structural Neuroimaging Studies.

Little is known regarding the neuroanatomical correlates of patients with deficit schizophrenia or persistent negative symptoms. In this meta-analysis, we aimed to determine whether patients with deficit schizophrenia have characteristic brain abnormalities. We searched PubMed, CINAHL and Ovid to identify studies that examined the various regions of interest amongst patients with deficit schizophrenia, patients with non-deficit schizophrenia and healthy controls. A total of 24 studies met our inclusion criteria. A random-effects model was used to calculate a combination of outcome measures, and heterogeneity was assessed by the I2 statistic and Cochran’s Q statistic. Our findings suggested that there was statistically significant reduction in grey matter volume (−0.433, 95% confidence interval (CI): −0.853 to −0.014, p = 0.043) and white matter volume (−0.319, 95% CI: −0.619 to −0.018, p = 0.038) in patients with deficit schizophrenia compared to healthy controls. There is also statistically significant reduction in total brain volume (−0.212, 95% CI: −0.384 to −0.041, p = 0.015) and white matter volume (−0.283, 95% CI: −0.546 to −0.021, p = 0.034) in patients with non-deficit schizophrenia compared to healthy controls. Between patients with deficit and non-deficit schizophrenia, there were no statistically significant differences in volumetric findings across the various regions of interest.

Soccer heading and concussion are not associated with reduced brain volumeor cortical thickness.

Soccer is the most popular sport in the world and, since it is a contact sport, players are at risk for head injury, including concussion. Here, we proposed to investigate the association of heading and concussion with macroscopic brain structure among adult amateur soccer players. For this study, 375 amateur soccer players (median age 23 years) completed HeadCount-12m to estimate heading over the 12 months prior to MRI and lifetime concussion. T1-weighted 3D magnetization prepared rapid acquisition gradient echo (MP-RAGE) MRI was performed at 3 Tesla. Parcellation was performed using Freesurfer to extract regional gray and white matter volumes as well as regional cortical thickness and total intracranial volume. Regional cortical brain volumes were normalized by total intracranial volume. We categorized heading into quartiles and concussion as 0, 1 or 2 or more. Generalized linear regressions were used to test the association of heading or concussion with each brain morphometry metric, including age and sex, as covariates. Neither heading nor concussion were associated with reduced brain volume or cortical thickness. We observed that greater heading was associated with greater gray matter volume in the left inferior parietal area, which may reflect effects related to training.

Interplay of TRIM2 E3 Ubiquitin Ligase and ALIX/ESCRT Complex: Control of Developmental Plasticity During Early Neurogenesis.

Tripartite motif 2 (TRIM2) drives neurite outgrowth and polarization, is involved in axon specification, and confers neuroprotective functions during rapid ischemia. The mechanisms controlling neuronal cell fate determination and differentiation are fundamental for neural development. Here, we show that in Xenopus, trim2 knockdown affects primary neurogenesis and neural progenitor cell survival. Embryos also suffer from severe craniofacial malformation, a reduction in brain volume, and the loss of motor sensory function. Using a high-throughput LC-MS/MS approach with GST-Trim2 as bait, we pulled down ALG-2 interacting protein X (Alix) from Xenopus embryonic lysates. We demonstrate that the expression of trim2/TRIM2 and alix/ALIX overlap during larval development and on a cellular level in cell culture. Interestingly, trim2 morphants showed a clustering and apoptosis of neural progenitors, which are phenotypic hallmarks that are also observed in Alix KO mice. Therefore, we propose that the interaction of Alix and Trim2 plays a key role in the determination and differentiation of neural progenitors via the modulation of cell proliferation/apoptosis during neurogenesis.

Neurobiology of emotional trauma.

An emotional trauma may induce a cascade of neurobiological events that have long-lasting consequences even altered gene expression. Early abuse and neglect can deregulate the child's developing neurobiological system by reducing its resistance to stressful events, leading to later problems of emotional regulation. Children who have been subjected to physical or emotional abuse tend to pay more attention to signs that contain anger and are hypersensitive to threat. Scar hypothesis and the theories of behavioural sensitization or electrophysiological kindling suggest that emotional traumas may leave traces that persist even after remission of depression, and render individuals vulnerable to the onset of new episodes, even under the influence of only moderate psychosocial stress. Unfavorable early social experiences, such as emotional abuse or institutionalization can affect the structure and function of the prefrontal cortex. Exposure to repeated emotional stressors, even in the absence of post-traumatic stress disorder (PTSD) diagnoses, has been shown to produce increased synapse formation and dendritic growth in basolateral amygdala, dendritic retraction in the hippocampus, and anxiety-like behavior against specific triggers, such as phobia of open spaces. During the narration of an emotionally traumatic event, there is activation of the limbic system, the right amygdale, the orbitofrontal cortex and the anterior cingulate gyrus. In addition, there is an activation of the anterior insula, which records the physical impact of negative emotions, and the anterior and medial temporal cortex, which are involved in negative emotions. Neuroimaging studies in PTSD patients have found hypoactivity in the frontal lobe, anterior cingulate and thalamic areas, indicating the effects of PTSD on executive function, attention and cognitive, memorial, and affective and somatosensory integration. One of the most replicated findings in studies involving PTSD patients is the decreased activation of the dorsolateral prefrontal cortex. Studies have also found a negative correlation between the dorsolateral prefrontal cortex and amygdala activation. A recent meta-analysis revealed structural brain abnormalities associated with PTSD and emotional trauma and suggested that global brain volume reductions can distinguish PTSD from major depression. Neuroimaging studies of successful eye movement desensitization and reprocessing (EMDR) treatment have consistently shown that patients exhibited increased frontal lobe activation. Moving beyond diagnostic boundaries, focusing on the causal interplay between specific traumatic processes and using standardized measures, are useful directions for future research in memory, emotion and emotional trauma.

Altered brain fluid management in a rat model of arterial hypertension

BackgroundProper neuronal function is directly dependent on the composition, turnover, and amount of interstitial fluid that bathes the cells. Most of the interstitial fluid is likely to be derived from ion and water transport across the brain capillary endothelium, a process that may be altered in hypertension due to vascular pathologies as endothelial dysfunction and arterial remodelling. In the current study, we investigated the effects of hypertension on the brain for differences in the water homeostasis.MethodsMagnetic resonance imaging (MRI) was performed on a 7T small animal MRI system on male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) of 10 months of age. The MRI protocol consisted of T2-weighted scans followed by quantitative apparent diffusion coefficient (ADC) mapping to measure volumes of different anatomical structures and water diffusion respectively. After MRI, we assessed the spatial distribution of aquaporin 4 expression around blood vessels.ResultsMRI analysis revealed a significant reduction in overall brain volume and remarkably higher cerebroventricular volume in SHR compared to WKY. Whole brain ADC, as well as ADC values of a number of specific anatomical structures, were significantly lower in hypertensive animals. Additionally, SHR exhibited higher brain parenchymal water content. Immunohistochemical analysis showed a profound expression of aquaporin 4 around blood vessels in both groups, with a significantly larger area of influence around arterioles. Evaluation of specific brain regions revealed a decrease in aquaporin 4 expression around capillaries in the corpus callosum of SHR.ConclusionThese results indicate a shift in the brain water homeostasis of adult hypertensive rats.