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Brain, blood, cerebrospinal fluid, and serum biomarkers in schizophrenia.

Over the last decade, finding a reliable biomarker for the early detection of schizophrenia (Scz) has been a topic of interest. The main goal of the current review is to provide a comprehensive view of the brain, blood, cerebrospinal fluid (CSF), and serum biomarkers of Scz disease. Imaging studies have demonstrated that the volumes of the corpus callosum, thalamus, hippocampal formation, subiculum, parahippocampal gyrus, superior temporal gyrus, prefrontal and orbitofrontal cortices, and amygdala-hippocampal complex were reduced in patients diagnosed with Scz. It has been revealed that the levels of interleukin 1β (IL-1β), IL-6, IL-8, and TNF-α were increased in patients with Scz. Decreased mRNA levels of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), neurotrophin-3 (NT-3), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) genes have also been reported in Scz patients. Genes with known strong relationships with this disease include BDNF, catechol-O-methyltransferase (COMT), regulator of G-protein signaling 4 (RGS4), dystrobrevin-binding protein 1 (DTNBP1), neuregulin 1 (NRG1), Reelin (RELN), Selenium-binding protein 1 (SELENBP1), glutamic acid decarboxylase 67 (GAD 67), and disrupted in schizophrenia 1 (DISC1). The levels of dopamine, tyrosine hydroxylase (TH), serotonin or 5-hydroxytryptamine (5-HT) receptor 1A and B (5-HTR1A and 5-HTR1B), and 5-HT1B were significantly increased in Scz patients, while the levels of gamma-aminobutyric acid (GABA), 5-HT transporter (5-HTT), and 5-HT receptor 2A (5-HTR2A) were decreased. The increased levels of SELENBP1 and Glycogen synthase kinase 3 subunit α (GSK3α) genes in contrast with reduced levels of B-cell translocation gene 1 (BTG1), human leukocyte antigen DRB1 (HLA-DRB1), heterogeneous nuclear ribonucleoprotein A3 (HNRPA3), and serine/arginine-rich splicing factor 1 (SFRS1) genes have also been reported. This review covers various dysregulation of neurotransmitters and also highlights the strengths and weaknesses of studies attempting to identify candidate biomarkers.

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GABA Receptor Availability Changes Underlie Symptoms in Isolated Cervical Dystonia.

GABA receptor availability changes within sensorimotor regions have been reported in some isolated forms of dystonia. Whether similar abnormalities underlie symptoms in cervical dystonia is not known. In the present study, a total of 15 cervical dystonia patients and 15 age- and sex-matched controls underwent C-flumazenil PET/CT scanning. The density of available GABA receptors was estimated using a Simplified Reference Tissue Model 2. Group differences were evaluated using a two-sample -test, and correlations with dystonia severity, as measured by the Toronto Western Spasmodic Torticollis Rating Scale, and disease duration were evaluated using a regression analysis. Voxel-based analyses revealed increased GABA availability within the right precentral gyrus in brain motor regions previously associated with head turning and the left parahippocampal gyrus. GABA availability within the bilateral cerebellum was negatively correlated with dystonia severity, and GABA availability within the right thalamus and a variety of cerebellar and cortical regions were negatively correlated with disease duration. While GABA availability changes within primary motor areas could represent a partial compensatory response to loss of inhibition within sensorimotor network, GABAergic signaling impairment within the cerebellum may be a key contributor to dystonia severity.

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Widespread associations between trait conscientiousness and thickness of brain cortical regions.

The neural correlates of human personality have been of longstanding interest; however, most studies in the field have relied on modest sample sizes and few replicable results have been reported to date. We investigated relationships between personality and brain gray matter in a sample of generally healthy, older (mean age 73 years) adults from Scotland drawn from the Lothian Birth Cohort 1936. Participants (N = 578) completed a brain MRI scan and self-reported Big Five personality trait measures. Conscientiousness trait scores were positively related to brain cortical thickness in a range of regions, including bilateral parahippocampal gyrus, bilateral fusiform gyrus, left cingulate gyrus, right medial orbitofrontal cortex, and left dorsomedial prefrontal cortex. These associations - most notably in frontal regions - were modestly-to-moderately attenuated by the inclusion of biomarker variables assessing allostatic load and smoking status. None of the other personality traits showed robust associations with brain cortical thickness, nor did we observe any personality trait associations with cortical surface area and gray matter volume. These findings indicate that brain cortical thickness is associated with conscientiousness, perhaps partly accounted for by allostatic load and smoking status.

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Investigation of microstructural abnormalities in white and gray matter around hippocampus with diffusion tensor imaging (DTI) in temporal lobe epilepsy (TLE).

The objective of this study was to apply diffusion tensor imaging (DTI) to investigate microstructural abnormalities in temporal lobe epilepsy (TLE) with and without hippocampal sclerosis (HS).

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Sedentary behavior associated with reduced medial temporal lobe thickness in middle-aged and older adults.

Atrophy of the medial temporal lobe (MTL) occurs with aging, resulting in impaired episodic memory. Aerobic fitness is positively correlated with total hippocampal volume, a heavily studied memory-critical region within the MTL. However, research on associations between sedentary behavior and MTL subregion integrity is limited. Here we explore associations between thickness of the MTL and its subregions (namely CA1, CA23DG, fusiform gyrus, subiculum, parahippocampal, perirhinal and entorhinal cortex,), physical activity, and sedentary behavior. We assessed 35 non-demented middle-aged and older adults (25 women, 10 men; 45-75 years) using the International Physical Activity Questionnaire for older adults, which quantifies physical activity levels in MET-equivalent units and asks about the average number of hours spent sitting per day. All participants had high resolution MRI scans performed on a Siemens Allegra 3T MRI scanner, which allows for detailed investigation of the MTL. Controlling for age, total MTL thickness correlated inversely with hours of sitting/day (r = -0.37, p = 0.03). In MTL subregion analysis, parahippocampal (r = -0.45, p = 0.007), entorhinal (r = -0.33, p = 0.05) cortical and subiculum (r = -0.36, p = .04) thicknesses correlated inversely with hours of sitting/day. No significant correlations were observed between physical activity levels and MTL thickness. Though preliminary, our results suggest that more sedentary non-demented individuals have less MTL thickness. Future studies should include longitudinal analyses and explore mechanisms, as well as the efficacy of decreasing sedentary behaviors to reverse this association.

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Severe TBI patients without focal lesion but with behavioral disorders: shrinkage of gray matter nuclei and thalamus revealed in a pilot voxel based MRI study.

After a traumatic brain injury (TBI), behavioral disorders can occur without major focal brain lesion and in this case, their pathophysiology remains unclear. The aim of this study is to examine whether TBI patients with behavioral disorders but without any focal damage, as observed from an initial clinical CT scan, present subtle volumetric alterations that could be measured voxel-by-voxel in the whole brain with magnetic resonance imaging (MRI). Eight severe TBI male adults with behavioral sequela but without major focal cerebral lesion and 17 age-matched controls underwent a volumetric T1-weighted 1.5T MRI. A two-step analysis was performed. First, gray and white matter (GM and WM) volumes were compared between groups using Voxel-Based Morphometry. Second, we examined brain regions systematically damaged using the sum of the individual binary maps obtained from z-maps thresholded at -1.75 for significant GM and WM atrophy. TBI patients had lower GM volume than controls (p<0.001, uncorrected) in the right parahippocampal gyrus, the left and right superior, middle and inferior temporal gyri, left superior frontal gyrus, right middle frontal gyrus, thalami, mammillary bodies, caudate nuclei, insulae, cerebellar cortex and vermis. WM volume was lower (p<0.001, uncorrected) in the TBI group compared with controls in the periventricular area and around the basal nuclei. We found shrinkage in the dorsomedial thalami in each of the TBI patients, and in the posterior part of the right putamen and caudate nuclei in 7 TBI patients. Shrinkage in the dorsomedial thalami and in the posterior part of the right putamen and caudate nuclei may be the common effect of the disseminated microscopic lesions and be associated with behavioral issues in severe TBI patients without major focal lesions.

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Gray/White Matter Contrast in Parkinson's Disease.

Gray/white matter contrast (GWC) decreases with aging and has been found to be a useful MRI biomarker in Alzheimer's disease (AD), but its utility in Parkinson's disease (PD) patients has not been investigated. The aims of the study were to test whether GWC is sensitive to aging changes in PD patients, if PD patients differ from healthy controls (HCs) in GWC, and whether the use of GWC data would improve the sensitivity of cortical thickness analyses to differentiate PD patients from controls. Using T1-weighted structural images, we obtained individual cortical thickness and GWC values from a sample of 90 PD patients and 27 controls. Images were processed with the automated FreeSurfer stream. GWC was computed by dividing the white matter (WM) by the gray matter (GM) values and projecting the ratios onto a common surface. The sample characteristics were: 52 patients and 14 controls were males; mean age of 64.4 ± 10.6 years in PD and 64.7 ± 8.6 years in controls; 8.0 ± 5.6 years of disease evolution; 15.6 ± 9.8 UPDRS; and a range of 1.5-3 in Hoehn and Yahr (H&Y) stage. In both PD and controls we observed significant correlations between GWC and age involving almost the entire cortex. When applying a stringent cluster-forming threshold of < 0.0001, the correlation between GWC and age also involved the entire cortex in the PD group; in the control group, the correlation was found in the parahippocampal gyrus and widespread frontal and parietal areas. The GWC of PD patients did not differ from controls', whereas cortical thickness analyses showed thinning in temporal and parietal cortices in the PD group. Cortical thinning remained unchanged after adjusting for GWC. GWC is a very sensitive measure for detecting aging effects, but did not provide additional information over other parameters of atrophy in PD.

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Altered whole-brain gray matter volume in high myopia patients: a voxel-based morphometry study.

High myopia (HM) was associated with impaired long-distance vision. Previous neuroimaging studies showed that abnormal visual experience leads to dysfunction in brain activity in HM even corrected. However, whether alterations in brain structure occur in HM remains unknown. In this study, we analyzed the difference in the whole-brain gray matter volume (GMV) and white matter volume between HM patients and healthy controls (HCs) using a voxel-based morphology method. A total of 82 HM patients (52 men and 30 women) and 58 HCs (28 men and 30 women), matched closely in terms of age and education, were enrolled in this study. All participants underwent MRI scans. The MRI data were processed using the SPM8 software. The relationship between the mean GMV values of the brain regions and clinical features, including refractive diopter and the mean retinal nerve fiber layer thickness, in the HM group were analyzed using Pearson's correlation. Compared with HCs, HM patients showed significantly decreased GMV values in the right cuneus/lingual gyrus and the right thalamus. In contrast, HM groups showed higher GMV values in the brain stem, right parahippocampal gyrus/thalamus, left parahippocampal gyrus/thalamus, as well as the right and the left putamen. No significantly different white matter volume values were found between the two groups. Moreover, in the HM group, the mean retinal nerve fiber layer of the left eye showed a negative correlation with the mean GMV values of the brain stem (r=-0.218; P=0.049), right parahippocampal gyrus/thalamus (r=-0.262; P=0.017), left parahippocampal gyrus/thalamus (r=-0.249; P=0.024), and left putamen (r=-0.232; P=0.036). We found that HM patients showed an altered brain structure in the visual pathway regions and the limbic system, which may provide useful information to explore the neural mechanisms of impaired long-distance vision in HM.

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Decreased Event-Related Beta Synchronization During Memory Maintenance Marks Early Cognitive Decline in Mild Cognitive Impairment.

Mild cognitive impairment (MCI) refers to a measurable deficit in cognition in the absence of dementia or impairment in activities of daily living. Working memory impairment is among the earliest signs of MCI. Oscillatory analysis of working memory might be a potential tool for identifying patients at increased risk of developing dementia. Our study aimed to assess the temporospatial pattern of spectral differences during working memory maintenance between MCI patients and healthy controls and to compare the sources of oscillatory activity between the two groups. Event-related spectral perturbation of 17 MCI patients and 21 healthy control participants was studied with 128-channel EEG during the Sternberg working memory task. Source localization was performed by using the eLORETA software. Among the participants, 13 MCI and 15 control participants underwent a structural brain MRI examination. Event-related synchronization (ERS) in the alpha and beta frequency band was significantly lower in MCI patients compared to healthy control participants during retention. Both study groups showed significant memory load-related enhancement in both frequency band. In the MCI group, source localization revealed significantly attenuated beta oscillatory activity in the inferior and middle temporal gyrus, in the fusiform gyrus, and in the cuneus. Beta ERS correlated significantly with the size of the hippocampus, entorhinal cortex, and parahippocampal gyrus. During the retention period, MCI is characterized by decreased alpha and beta ERS compared to controls indicating early impairment in neural networks serving working memory maintenance. The assessment of electrophysiological changes in the beta frequency range may provide a useful diagnostic tool for the early detection of cognitive impairment.

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Decreased functional connectivity and structural deficit in alertness network with right-sided temporal lobe epilepsy.

Patients with temporal lobe epilepsy (TLE) often suffer from alertness alterations. However, specific regions connected with alertness remain controversial, and whether these regions have structural impairment is also elusive. This study aimed to investigate the characteristics and neural mechanisms underlying the functions and structures of alertness network in patients with right-sided temporal lobe epilepsy (rTLE) by performing the attentional network test (ANT), resting-state functional magnetic resonance imaging (R-SfMRI), and diffusion tensor imaging (DTI).A total of 47 patients with rTLE and 34 healthy controls underwent ANT, R-SfMRI, and DTI scan. The seed-based functional connectivity (FC) method and deterministic tractography were used to analyze the data.Patients with rTLE had longer reaction times in the no-cue and double-cue conditions. However, no differences were noted in the alertness effect between the 2 groups. The patient group had lower FC compared with the control group in the right inferior parietal lobe (IPL), amygdala, and insula. Structural deficits were found in the right parahippocampal gyrus, superior temporal pole, insula, and amygdala in the patient group compared with the control group. Also significantly negative correlations were observed between abnormal fractional anisotropy (between the right insula and the superior temporal pole) and illness duration in the patients with rTLE.The findings of this study suggested abnormal intrinsic and phasic alertness, decreased FC, and structural deficits within the alerting network in the rTLE. This study provided new insights into the mechanisms of alertness alterations in rTLE.

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