Obesity is associated with reduced white matter integrity in otherwise healthy adults

Existing work demonstrates that obesity is independently associated with cognitive dysfunction and macrostructural brain changes; however, little is known about the association between obesity and white matter (WM) integrity. We explore this relationship in a large cohort of otherwise healthy subjects. The present study classified 103 adult participants from the Brain Resource International Database between 21 and 86 years of age without history of neurological, medical, or psychiatric illness according to BMI (normal weight, overweight, obese) and subjected them to diffusion tensor imaging (DTI). Resulting fractional anisotropy (FA) indexes for the corpus callosum and fornix were examined in relation to BMI and age in a multiple regression framework. Results indicated that increasing BMI was independently associated with lower FA in the genu, splenium, and fornix, and a BMI × age interaction emerged for FA in the splenium and body of the corpus callosum. When categorized, obese persons demonstrated lower FA than normal and overweight persons for all WM indexes, but no FA differences emerged between overweight and normal persons. Results indicate both a direct association between obesity and reduced WM tract integrity and an interaction between obesity and aging processes on certain WM tracts in otherwise healthy adults. While such findings suggest a possible role for adiposity in WM dysfunction and associated cognitive deficits, prospective studies are needed to clarify the nature of these relationships and elucidate underlying mechanisms.     

Characterization of the structural and functional changes in the myocardium following focal ischemia-reperfusion injury

High-resolution (11.7 T) cardiac magnetic resonance imaging (MRI) and histological approaches have been employed in tandem to characterize the secondary damage suffered by the murine myocardium following the initial insult caused by ischemia-reperfusion (I/R). I/R-induced changes in the myocardium were examined in five separate groups at the following time points after I/R: 1 h, day 1, day 3, day 7, and day 14. The infarct volume increased from 1 h to day 1 post-I/R. Over time, the loss of myocardial function was observed to be associated with increased infarct volume and worsened regional wall motion. In the infarct region, I/R caused a decrease in end-systolic thickness coupled with small changes in end-diastolic thickness, leading to massive wall thickening abnormalities. In addition, compromised wall thickening was also observed in left ventricular regions adjacent to the infarct region. A tight correlation (r2 = 0.85) between measured MRI and triphenyltetrazolium chloride (TTC) infarct volumes was noted. Our observation that until day 3 post-I/R the infarct size as measured by TTC staining and MRI was much larger than that of the myocyte-silent regions in trichrome- or hematoxylin-eosin-stained sections is consistent with the literature and leads to the conclusion that at such an early phase, the infarct site contains structurally intact myocytes that are functionally compromised. Over time, such affected myocytes were noted to structurally disappear, resulting in consistent infarct sizes obtained from MRI and TTC as well as trichrome and hematoxylin-eosin analyses on day 7 following I/R. Myocardial remodeling following I/R includes secondary myocyte death followed by the loss of cardiac function over time.     

Selective changes in white matter integrity in MCI and older adults with cognitive complaints

Background

White matter changes measured using diffusion tensor imaging have been reported in Alzheimer's disease and amnestic mild cognitive impairment, but changes in earlier pre-mild cognitive impairment stages have not been fully investigated.

Methods

In a cross-sectional analysis, older adults with mild cognitive impairment (n = 28), older adults with cognitive complaints but without psychometric impairment (n = 29) and healthy controls (n = 35) were compared. Measures included whole-brain diffusion tensor imaging, T1-weighted structural magnetic resonance imaging, and neuropsychological assessment. Diffusion images were analyzed using Tract-Based Spatial Statistics. Voxel-wise fractional anisotropy and mean, axial, and radial diffusivities were assessed and compared between groups. Significant tract clusters were extracted in order to perform further region of interest comparisons. Brain volume was estimated using FreeSurfer based on T1 structural images.

Results

The mild cognitive impairment group showed lower fractional anisotropy and higher radial diffusivity than controls in bilateral parahippocampal white matter. When comparing extracted diffusivity measurements from bilateral parahippocampal white matter clusters, the cognitive complaint group had values that were intermediate to the mild cognitive impairment and healthy control groups. Group difference in diffusion tensor imaging measures remained significant after controlling for hippocampal atrophy. Across the entire sample, diffusion tensor imaging indices in parahippocampal white matter were correlated with memory function.

Conclusions

These findings are consistent with previous results showing changes in parahippocampal white matter in Alzheimer's disease and mild cognitive impairment compared to controls. The intermediate pattern found in the cognitive complaint group suggests the potential of diffusion tensor imaging to contribute to earlier detection of neurodegenerative changes during prodromal stages. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Clock genes associate with white matter integrity in depressed bipolar patients

Human genetic studies have implicated specific genes that constitute the molecular clock in the manifestation of bipolar disorder (BD). Among the clock genes involved in the control system of circadian rhythms, CLOCK 3111 T/C and Period3 (PER3) influence core psychopathological features of mood disorders, such as patterns of sleep, rest, and activity, diurnal preference, cognitive performances after sleep loss, age at the onset of the illness, and response to antidepressant treatment. Furthermore, several studies pointed out that bipolar symptomatology is associated with dysfunctions in white matter (WM) integrity, suggesting these structural alterations as a possible biomarker of the disorder. We hypothesise that CLOCK and PER3 polymorphisms could be potential factors affecting WM microstructure integrity in bipolar patients. The relationship between these clock genes and DTI measures of WM integrity in a sample of 140 (53 M; 87 F) patients affected by BD type I was studied. Tract-based spatial statistics analyses on DTI measures of WM integrity were performed for each clock gene polymorphism, between the genetic groups. We accounted for the effect of nuisance covariates known to influence WM microstructure: age, sex, lithium treatment, age at the onset of the illness, and the number of illness episodes. We found that compared to T homozygotes, CLOCK C carriers showed a widespread increase of the mean diffusivity in several WM tracts. Compared with PER3^5/5 homozygotes, PER3^4/4 homozygotes showed significantly increased radial diffusivity and reduced fractional anisotropy in several brain WM tracts. No significant difference was observed between heterozygotes and the other subgroups. Altogether, this pattern of results suggests WM disruption in CLOCK C carrier and in PER3⁴ homozygotes. Sleep promotes myelination and oligodendrocyte precursor cell proliferation and associates with higher expression of genes coding for phospholipid synthesis and myelination in oligodendrocytes. These clock genes play a pivotal role in maintaining circadian rhythms and the sleep-wake cycle. Thus, it may be suggested that CLOCK rs1801260*C and PER3^4/4 influence myelination processes by regulating sleep quality and quantity.     

Diffusion tensor imaging of cerebral white matter integrity in cognitive aging

In this article we review recent research on diffusion tensor imaging (DTI) of white matter (WM) integrity and the implications for age-related differences in cognition. Neurobiological mechanisms defined from DTI analyses suggest that a primary dimension of age-related decline in WM is a decline in the structural integrity of myelin, particularly in brain regions that myelinate later developmentally. Research integrating behavioral measures with DTI indicates that WM integrity supports the communication among cortical networks, particularly those involving executive function, perceptual speed, and memory (i.e., fluid cognition). In the absence of significant disease, age shares a substantial portion of the variance associated with the relation between WM integrity and fluid cognition. Current data are consistent with one model in which age-related decline in WM integrity contributes to a decreased efficiency of communication among networks for fluid cognitive abilities. Neurocognitive disorders for which older adults are at risk, such as depression, further modulate the relation between WM and cognition, in ways that are not as yet entirely clear. Developments in DTI technology are providing a new insight into both the neurobiological mechanisms of aging WM and the potential contribution of DTI to understanding functional measures of brain activity. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Abnormal white matter integrity in adolescents with internet addiction disorder: a tract-based spatial statistics study

Background

Internet addiction disorder (IAD) is currently becoming a serious mental health issue around the globe. Previous studies regarding IAD were mainly focused on associated psychological examinations. However, there are few studies on brain structure and function about IAD. In this study, we used diffusion tensor imaging (DTI) to investigate white matter integrity in adolescents with IAD.

Methodology/Principal Findings

Seventeen IAD subjects and sixteen healthy controls without IAD participated in this study. Whole brain voxel-wise analysis of fractional anisotropy (FA) was performed by tract-based spatial statistics (TBSS) to localize abnormal white matter regions between groups. TBSS demonstrated that IAD had significantly lower FA than controls throughout the brain, including the orbito-frontal white matter, corpus callosum, cingulum, inferior fronto-occipital fasciculus, and corona radiation, internal and external capsules, while exhibiting no areas of higher FA. Volume-of-interest (VOI) analysis was used to detect changes of diffusivity indices in the regions showing FA abnormalities. In most VOIs, FA reductions were caused by an increase in radial diffusivity while no changes in axial diffusivity. Correlation analysis was performed to assess the relationship between FA and behavioral measures within the IAD group. Significantly negative correlations were found between FA values in the left genu of the corpus callosum and the Screen for Child Anxiety Related Emotional Disorders, and between FA values in the left external capsule and the Young''s Internet addiction scale.

Conclusions

Our findings suggest that IAD demonstrated widespread reductions of FA in major white matter pathways and such abnormal white matter structure may be linked to some behavioral impairments. In addition, white matter integrity may serve as a potential new treatment target and FA may be as a qualified biomarker to understand the underlying neural mechanisms of injury or to assess the effectiveness of specific early interventions in IAD.     

A neural network model for kindling of focal epilepsy: basic mechanism

A simple neural network model is proposed for kindling — the phenomenon of generating epilepsy by means of repeated electrical stimulation. The model satisfies Dale's hypothesis, incorporates a Hebb-like learning rule and has low periodic activity in absence of shocks. Many of the experimental observations are reproduced and some new experiments are suggested. It is proposed that the main reason for kindling is the formation of a large number of excitatory synaptic connections due to learning.     

The ACTH and cortisol content of the blood in experimental focal epilepsy

In experiments on 87 freely behaving rats and 7 cats treated with d-tubocurarine and anesthetized with nembutal it was established that the generation of focus of epileptic activity (EA) in cerebral cortex by surface application of sodium benzylpenicillin is accompanied by an increase in the plasma level of ACTH (2-fold in rats and 2.5-fold in cats) with consequent rise in the plasma cortisol level (1.5-fold both in rats and cats). In cats a "delayed" rise in plasma ACTH was observed after the cessation of cortical EA. The described changes in plasma ACTH are a result of the pathological hyperactivity of neurons rather then a stressor component under the EA.     

Regional grey and white matter changes in heavy male smokers

Cigarette smoking is highly prevalent in the general population but the effects of chronic smoking on brain structures are still unclear. Previous studies have found mixed results regarding regional grey matter abnormalities in smokers. To characterize both grey and white matter changes in heavy male smokers, we investigated 16 heavy smokers and 16 matched healthy controls, using both univariate voxel-based morphometry (VBM) and multivariate pattern classification analysis. Compared with controls, heavy smokers exhibited smaller grey matter volume in cerebellum, as well as larger white matter volume in putamen, anterior and middle cingulate cortex. Further, the spatial patterns of grey matter or white matter both discriminated smokers from controls in these regions as well as in other brain regions. Our findings demonstrated volume abnormalities not only in the grey matter but also in the white matter in heavy male smokers. The multivariate analysis suggests that chronic smoking may be associated with volume alternations in broader brain regions than those identified in VBM analysis. These results may better our understanding of the neurobiological consequence of smoking and inform smoking treatment.     

Early microstructural white matter changes in patients with HIV: a diffusion tensor imaging study

ABSTRACT: Previous studies have reported white matter (WM) brain alterations in asymptomatic patients with human immunodeficiency virus (HIV). We compared diffusion tensor imaging (DTI) derived WM fractional anisotropy (FA) between HIV-patients with and without mild macroscopic brain lesions determined using standard magnetic resonance imaging (MRI). We furthermore investigated whether WM alterations co-occurred with neurocognitive deficits and depression. We performed structural MRI and DTI for 19 patients and 19 age-matched healthy controls. Regionally-specific WM integrity was investigated using voxel-based statistics of whole-brain FA maps and region-of-interest analysis. Each patient underwent laboratory and neuropsychological tests. Structural MRI revealed no lesions in twelve (HIV-MRN) and unspecific mild macrostructural lesions in seven patients (HIV-MRL). Both analyses revealed widespread FA-alterations in all patients. Patients with HIV-MRL had FA-alterations primarily adjacent to the observed lesions and, whilst reduced in extent, patients with HIV-MRN also exhibited FA-alterations in similar regions. Patients with evidence of depression showed FA-increase in the ventral tegmental area, pallidum and nucleus accumbens in both hemispheres, and patients with evidence of HIV-associated neurocognitive disorder showed widespread FA-reduction. These results show that patients with HIV-MRN have evidence of FA-alterations in similar regions that are lesioned in HIV-MRL patients, suggesting common neuropathological processes. Furthermore, they suggest a biological rather a reactive origin of depression in HIV-patients.     

Impaired small-world network efficiency and dynamic functional distribution in patients with cirrhosis

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome and a major complication of liver cirrhosis. Dysmetabolism of the brain, related to elevated ammonia levels, interferes with intercortical connectivity and cognitive function. For evaluation of network efficiency, a 'small-world' network model can quantify the effectiveness of information transfer within brain networks. This study aimed to use small-world topology to investigate abnormalities of neuronal connectivity among widely distributed brain regions in patients with liver cirrhosis using resting-state functional magnetic resonance imaging (rs-fMRI). Seventeen cirrhotic patients without HE, 9 with minimal HE, 9 with overt HE, and 35 healthy controls were compared. The interregional correlation matrix was obtained by averaging the rs-fMRI time series over all voxels in each of the 90 regions using the automated anatomical labeling model. Cost and correlation threshold values were then applied to construct the functional brain network. The absolute and relative network efficiencies were calculated; quantifying distinct aspects of the local and global topological network organization. Correlations between network topology parameters, ammonia levels, and the severity of HE were determined using linear regression and ANOVA. The local and global topological efficiencies of the functional connectivity network were significantly disrupted in HE patients; showing abnormal small-world properties. Alterations in regional characteristics, including nodal efficiency and nodal strength, occurred predominantly in the association, primary, and limbic/paralimbic regions. The degree of network organization disruption depended on the severity of HE. Ammonia levels were also significantly associated with the alterations in local network properties. Results indicated that alterations in the rs-fMRI network topology of the brain were associated with HE grade; and that focal or diffuse lesions disturbed the functional network to further alter the global topology and efficiency of the whole brain network. These findings provide insights into the functional changes in the human brain in HE.     

Assessing ecological integrity: A multi-scale structural and functional approach using Structural Equation Modeling

Facing increasing levels of ecosystem degradation, scientists and practitioners aim to preserve ecological integrity — to maintain structures and functions expected of ecosystems in a region. This requires an understanding of the relationship between structural components and functional integrity. In this paper we focused on the study forests of the Credit River Watershed (Southern Ontario, Canada). For this ecosystem we consider one of the major contributors to functional integrity: habitat functions which are defined as the capacity of the ecosystem to provide refuge and reproduction habitat to wild species of plants and animals. We define these ‘habitat functions’ as a latent variable in Structural Equation Modeling, which allows us to examine its relationship with a number of candidate indicators. We first determined two community-level structural indicators to represent the latent variable: native plant cover and forest bird abundance. We then found underlying causal relationships between multi-scale structural components of the ecosystem and the provision of habitat functions. Three variables at the local scale explain native plant cover — soil nitrogen, soil organic matter, and soil pH. A significant landscape-level variable, patch area, explained native plant cover. Percent natural land cover in a 500 m radius explained forest bird abundance. From a theoretical point of view, this modeling technique allows us to explore complex and simultaneous interactions between structures and functions of ecosystems. As for its practical applications, it can be used to improve ecological integrity monitoring programs by contributing to the selection of meaningful indicators.     

白质消融性白质脑病致病基因EIF2B的突变功能研究

白质消融性白质脑病(leukoencephalopathy with vanishing white matter,VWM)是儿童最常见的遗传性白质脑病之一,是目前人类遗传性疾病中首个被确定由于mRNA翻译启动异常所致疾病,是由编码真核细胞翻译启动因子2B(eukaryotic translation initiation factor 2B,eIF2B)的五个亚单位(eIF2Bα、β、γ、δ、ε)的基因(EIF2B1-5)任一突变所致。eIF2B是一种鸟嘌呤核苷酸交换因子,调控全部mRNA的翻译起始过程。eIF2B突变功能研究尚处于起步阶段。EIF2B突变可能通过不同的途径影响eIF2B的功能。例如,通过影响eIF2B复合体的形成或其与底物的结合从而破坏eIF2B的鸟苷酸转移因子(GEF)活性或引起细胞应激反应异常。EIF2B突变是否影响胶质前体细胞的分化是VWM发病机制的另一个关键问题。     

Relationship between structural modeling and hyperelastic material behavior: application to CNS white matter

 Recent measurements of the material properties of brain tissue allow an examination of the underlying microstructural basis in both physiological and pathophysiological conditions. The purpose of this study is to develop a mathematical relationship between microstructurally based models of the central nervous system (CNS) white matter and equivalent hyperelastic material models. For simplicity, time dependent material behavior is not included in this formulation. The microstructural representation is used to formulate structural property relationships for highly oriented white matter, and is mathematically compared to one isotropic and two anisotropic hyperelastic formulations. For the anisotropic characterizations, the population of axons in the white matter is assumed to align along one preferred direction of the material, yielding a transversely isotropic formulation. Relatively simple strain–energy functions incorporating material anisotropy provide sufficient flexibility to model the nonlinear behavior predicted from structurally based models, although the tangential stiffness of the hyperelastic approaches does not follow completely the behavior of the structurally based formulations. This analysis is an initial step towards linking microstructural aspects of the tissue to material models commonly used for large deformations, and may be an important step in relating predicted tissue deformation to the deformation and stress of cellular and subcellular structures. Received: 15 October 2001 / Accepted: 30 September 2002 Funds for this work were provided by CDC grant R49/CCR312712 and NIH grants P50 NS08803, NICHD RO1 41699, and NINDS RO1 35712.     

Age-related structural and functional changes of brain mitochondria

Normal ageing is associated with a gradual decline in the capacity of various cell types, including neurones, to respond to metabolic stress and return to the resting state. An important factor in the decrease of this 'homeostatic reserve' is the gradual, age-dependent impairment of mitochondrial function. In this article we review some of the major structural and functional changes in mitochondria associated with ageing. Apart from the increased mutations in mitochondrial DNA and the evidence for increased oxidative stress with ageing, we also discuss, in some detail, the importance of the mitochondrial membrane structure and composition (in particular lipid composition) for mitochondrial function in general and during ageing. Although some of the neurodegenerative diseases are also associated with some degree of mitochondrial dysfunction, it is not yet clear if these changes are due to the underlining process of normal, physiological ageing or due to the specific pathophysiologic agents responsible for the neurodegenerative processes. Furthermore, we are proposing that there are important differences between normal ageing and neurodegeneration.     

Transient protein-protein interactions: structural, functional, and network properties

Transient interactions, which involve protein interactions that are formed and broken easily, are important in many aspects of cellular function. Here we describe structural and functional properties of transient interactions between globular domains and between globular domains, short peptides, and disordered regions. The importance of posttranslational modifications in transient interactions is also considered. We review techniques used in the detection of the different types of transient protein-protein interactions. We also look at the role of transient interactions within protein-protein interaction networks and consider their contribution to different aspects of these networks.