Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis.

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan's unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = -0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = -0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = -0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = -0.02, p < 0.001) and frontal white matter Glx (z = -0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.

Possible association of elevated CSF IL-6 levels with anxiety and frustration in psychiatric disorders.

AIM: Neuroinflammation is an important causal factor for a variety of psychiatric disorders. We previously reported increased cerebrospinal fluid interleukin-6 levels in patients with schizophrenia and major depressive disorder. The present study aimed to examine the possible association of interleukin-6 levels with anxiety and frustration, negative valence symptoms shared in various psychiatric disorders. METHODS: We included 129 patients with psychiatric disorders and 70 controls. CSF and plasma interleukin-6 levels were measured by immunoassay kits, and psychological symptoms were assessed with the State-Trait Anxiety Inventory, and the Basic Psychological Need Satisfaction and Frustration Scale. To examine regional cerebral blood flow, patients underwent arterial spin labeling analysis using magnetic resonance imaging. RESULTS: Cerebrospinal fluid interleukin-6 levels were significantly correlated with State-Trait Anxiety Inventory-trait anxiety (r = 0.25, P = 0.046) and Basic Psychological Need Satisfaction and Frustration Scale-autonomy frustration scores (r = 0.29, P = 0.018). Patients with abnormally high cerebrospinal fluid interleukin-6 levels (defined >97.5 percentile of the controls) had higher scores for trait anxiety (P = 0.035) and autonomy frustration (P = 0.026), and significantly increased regional cerebral blood flow in the left superior temporal gyrus, bilateral nucleus accumbens, and cerebellum than the remaining patients. CONCLUSION: Patients with elevated cerebrospinal fluid interleukin-6 constitute a subpopulation of psychiatric disorders associated with anxiety and autonomy frustration, which may be related to altered functions in specific brain areas.

Correlation between the regional brain volume and glymphatic system activity in progressive supranuclear palsy.

INTRODUCTION: Tau protein accumulation in the brain is thought to be one of the causes of progressive supranuclear palsy (PSP). The glymphatic system was discovered a decade ago as a waste drainage system in the brain that promotes the elimination of amyloid-beta and tau protein. We here evaluated the relationships between glymphatic system activity and regional brain volumes in PSP patients. METHOD: Subjects were 24 patients with PSP and 42 healthy participants who underwent diffusion tensor imaging (DTI). We computed the diffusion tensor image analysis along the perivascular space (DTI­ALPS) index as a proxy of glymphatic system activity, and estimated the relationships between the DTI­ALPS index and regional brain volume in PSP patients by whole-brain and region-of-interest analyses, including analyses of the midbrain and third and lateral ventricles. RESULTS: The DTI­ALPS index was significantly lower in patients with PSP, compared with healthy subjects. Further, there were significant correlations between the DTI­ALPS index and the regional brain volumes in the midbrain tegmentum, pons, right frontal lobe, and lateral ventricles in patients with PSP. CONCLUSIONS: Our data suggest that the DTI­ALPS index is a good biomarker for PSP and might be effective to distinguish PSP from other neurocognitive disorders.

Association between behavioural and psychological symptoms of dementia and residence status in patients with Alzheimer's disease.

BACKGROUND: Examining the relationship between the behavioural and psychological symptoms of dementia (BPSD) and residence status is crucial to improving BPSD and reducing the burden on caregivers. However, studies on how BPSD differ between individuals living at home and those in institutional settings are lacking. We conducted a questionnaire survey among healthcare providers (HCPs) involved in dementia care and nursing to clarify the characteristics of BPSD by residence status in patients with Alzheimer's disease (AD) living at home or in facilities. METHODS: We sent questionnaires to HCPs and asked them to answer questions on up to five cases that needed treatment for BPSD and who received long-term care insurance services from 1 April 2016 to 31 March 2017. Responses were received for 371 cases, of which 130 diagnosed with AD were analyzed. The patients were divided into two groups: patients with AD living at home (home care group) and patients with AD living in facilities (facility care group). A Chi-square test was used to identify differences between the two groups. A binomial logistic regression analysis was also conducted to clarify the association between residence status and BPSD. RESULTS: Of the 130 patients, 72 lived at home (home care group) and 58 resided in facilities (facility care group). None of the background factors was significantly different between the two groups. The Chi-square test indicated that sleep disturbance was significantly more common in the facility care group (60.3% in the facility care group vs. 33.3% in the home care group, P = 0.003), while the logistic regression analysis indicated that sleep disturbance was significantly associated with residence status (odds ratio: 2.529, P = 0.038). CONCLUSIONS: Sleep disturbances were more frequently observed among patients with AD living in institutions than among those living in their homes.

Neuroimaging-based brain-age prediction in diverse forms of epilepsy: a signature of psychosis and beyond.

Epilepsy is a diverse brain disorder, and the pathophysiology of its various forms and comorbidities is largely unknown. A recent machine learning method enables us to estimate an individual's "brain-age" from MRI; this brain-age prediction is expected as a novel individual biomarker of neuropsychiatric disorders. The aims of this study were to estimate the brain-age for various categories of epilepsy and to evaluate clinical discrimination by brain-age for (1) the effect of psychosis on temporal lobe epilepsy (TLE), (2) psychogenic nonepileptic seizures (PNESs) from MRI-negative epilepsies, and (3) progressive myoclonic epilepsy (PME) from juvenile myoclonic epilepsy (JME). In total, 1196 T1-weighted MRI scans from healthy controls (HCs) were used to build a brain-age prediction model with support vector regression. Using the model, we calculated the brain-predicted age difference (brain-PAD: predicted age-chronological age) of the HCs and 318 patients with epilepsy. We compared the brain-PAD values based on the research questions. As a result, all categories of patients except for extra-temporal lobe focal epilepsy showed a significant increase in brain-PAD. TLE with hippocampal sclerosis presented a significantly higher brain-PAD than several other categories. The mean brain-PAD in TLE with inter-ictal psychosis was 10.9 years, which was significantly higher than TLE without psychosis (5.3 years). PNES showed a comparable mean brain-PAD (10.6 years) to that of epilepsy patients. PME had a higher brain-PAD than JME (22.0 vs. 9.3 years). In conclusion, neuroimaging-based brain-age prediction can provide novel insight into or clinical usefulness for the diverse symptoms of epilepsy.

Mental Health of Caregivers Working in Nursing Homes during the COVID-19 Pandemic.

INTRODUCTION: There have been numerous reports of cluster outbreaks of coronavirus disease 2019 (COVID-19) in hospitals and nursing homes. Healthcare workers fighting COVID-19 experience mental health issues. Caregivers in nursing homes experienced increased psychological distress and concern about deterioration of their mental health. We conducted a large-scale web-based survey exploring mental health among caregivers working in nursing homes during the COVID-19 pandemic with the aim of identifying their support needs. METHODS: Survey participants were caregivers working at 284 nursing homes in Ibaraki prefecture, Japan. The survey period was from September 2020 to March 2021. Participants responded to a questionnaire covering gender, age, occupation, infections at facilities, infection protection, changes in nursing home users, cooperation with other medical institutions, and prejudice/discrimination. The Hospital Anxiety and Depression Scale (HADS) was used to evaluate participants' depression and anxiety. RESULTS: In total, 676 participants completed the survey; 350 (52.5%) were with anxiety symptoms and 378 (56.7%) were with depressive symptoms (scores exceeding the HADS cut-off points). The risk for anxiety was associated with being care worker or social worker. The risk of anxiety or depression was high when family caregivers' mental state changed. DISCUSSION/CONCLUSION: This study found that caregivers working in nursing homes were exposed to high levels of stress during the COVID-19 pandemic and were at high risk for developing depression and anxiety.

Structural Cerebral Network Differences in Prodromal Alzheimer's Disease and Prodromal Dementia with Lewy Bodies.

INTRODUCTION: Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) have long prodromal phases without dementia. However, the patterns of cerebral network alteration in this early stage of the disease remain to be clarified. METHOD: Participants were 48 patients with mild cognitive impairment (MCI) due to AD (MCI-AD), 18 patients with MCI with DLB (MCI with Lewy bodies: MCI-LB), and 23 healthy controls who underwent a 1.5-Tesla magnetic resonance imaging scan. Cerebral networks were extracted from individual T1-weighted images based on the intracortical similarity, and we estimated the differences of network metrics among the three diagnostic groups. RESULTS: Whole-brain analyses for degree, betweenness centrality, and clustering coefficient images were performed using SPM8 software. The patients with MCI-LB showed significant reduction of degree in right putamen, compared with healthy subjects. The MCI-AD patients showed significant lower degree in left insula and bilateral posterior cingulate cortices compared with healthy subjects. There were no significant differences in small-world properties and in regional gray matter volume among the three groups. CONCLUSIONS: We found the change of degree in the patients with MCI-AD and with MCI-LB, compared with healthy controls. These findings were consistent with the past single-photon emission computed tomography studies focusing on AD and DLB. The disease-related difference in the cerebral neural network might provide an adjunct biomarker for the early detection of AD and DLB.

The Multicomponent Day-Care Program Prevents Volume Reduction in a Memory-Related Brain Area in Patients with Mild Cognitive Impairment.

INTRODUCTION: Mild cognitive impairment (MCI) is considered an important period for interventions to prevent progression to dementia. Nonpharmacological interventions for MCI include exercise training, cognitive intervention, and music therapy. These play an important role in improving cognitive function, but their effects on brain plasticity in individuals with MCI are largely unknown. We investigated the effects of a multicomponent day-care program provided by the University of Tsukuba Hospital on the longitudinal brain volume changes in MCI patients. METHODS: MCI patients who participated in the multicomponent day-care program and underwent whole-brain magnetic resonance imaging (MRI) twice during their participation (n = 14), were included. We divided them into two groups according to their attendance rate and conducted a between-group analysis of longitudinal volume changes in the whole cerebral cortex. Regional brain volumes derived from the patients' MRI were calculated with Freesurfer 6.0.0. RESULTS: The neuroimaging analysis demonstrated that the left rostral anterior cingulate cortex volume was significantly preserved in the high-attendance group compared to that of the low-attendance group. CONCLUSION: Our results suggest that continuous participation in a multicomponent day-care program could help prevent a volume reduction in memory-related brain areas in patients with MCI.

Development of informant-reported or self-reported MCI-J questionnaire.

Several studies have reported a high prevalence of missed and delayed mild cognitive impairment (MCI) or mild dementia diagnosis, which could lead to delayed treatment and increased patient and caregiver burden. OBJECTIVES: This study aimed to develop a new questionnaire for nonprofessionals to help detect early signs of MCI and dementia. Respondents included patients, family caregivers, or health professionals. Scores are calculated based on the respondent type and age of subject. METHODS: This study consisted of four steps and included 461 respondents. Steps 1-3 were conducted by a working group, and step 4, by 67 specialist members of the Japanese Society of Geriatric Psychiatry. A scoring algorithm was created and predictive diagnostic probability was analyzed using misdiscrimination rate and cross-validation after item selection to establish a cut-off value for MCI or dementia symptoms. Alzheimer's disease, Lewy body dementia, and frontotemporal dementia were diagnosed. RESULTS: The prediction error rate for patient or informant respondents was confirmed from the evaluation results of 13 items. Sensitivity and specificity were 90.6% and 56.6%, respectively, with a cut-off score of 2. Overall, 82% (61 pairs) of respondents received a definitive diagnosis following a diagnosis from the questionnaire. CONCLUSIONS: This questionnaire could promote earlier presentation to clinical settings for treatment. The high sensitivity indicates the utility of this instrument, but it is not meant as a definitive diagnostic tool and should be followed with a professional assessment.

Clinical and neuroimaging findings in patients with lissencephaly/subcortical band heterotopia spectrum: a magnetic resonance conventional and diffusion tensor study.

PURPOSE: To clarify brain abnormalities on magnetic resonance imaging (MRI) and its clinical implications in lissencephaly/subcortical band heterotopia (LIS/SBH) spectrum patients. METHODS: The clinical severity and classification according to Di Donato were retrospectively reviewed in 23 LIS/SBH spectrum patients. The morphological and signal abnormalities of the brainstem, corpus callosum, and basal ganglia were also assessed. The brainstem distribution pattern of the corticospinal tract (CST) was analyzed by diffusion tensor imaging (DTI) and categorized into two types: normal pattern, in which the CST and medial lemniscus (ML) are separated by the dorsal portion of the transverse pontine fiber, and the abnormal pattern, in which the CST and ML are juxtaposed on the dorsal portion of a single transverse pontine fiber. Correlations between MR grading score and potential additional malformative findings of the brain and clinical symptoms were investigated. RESULTS: All patients with grade 3 (n = 5) showed brainstem deformities, signal abnormalities of pontine surface and had a tendency of basal ganglia deformity and callosal hypoplasia whereas those abnormalities were rarely seen in patients with grade 1 and 2 (n = 18). For DTI analysis, the patients with grade 3 LIS/SBH had typically abnormal CST, whereas the patients with grade 1 and 2 LIS/SBH had normal CST. The classification was well correlated with CST and brainstem abnormalities and clinical severity. CONCLUSION: MR assessment including DTI analysis may be useful in assessing the clinical severity in LIS/BH spectrum and may provide insight into its developmental pathology.

Relationships between the Fear of COVID-19 Scale and regional brain atrophy in mild cognitive impairment.

BACKGROUND: Several studies have reported that the pandemic of coronavirus disease 2019 (COVID-19) influenced cognitive function in the elderly. However, the effect of COVID-19-related fear on brain atrophy has not been evaluated. In this study, we evaluated the relation between brain atrophy and the effect of COVID-19-related fear by analysing changes in brain volume over time using magnetic resonance imaging (MRI). METHODS: Participants were 25 Japanese patients with mild cognitive impairment (MCI) or subjective cognitive decline (SCD), who underwent 1.5-tesla MRI scan twice, once before and once after the pandemic outbreak of COVID-19, and the Fear of Coronavirus Disease 2019 Scale (FCV-19S) assessment during that period. We computed regional brain atrophy per day between the 1st and 2nd scan, and evaluated the relation between the FCV-19S scores and regional shrinkage. RESULTS: There was significant positive correlation between the total FCV-19S score and volume reduction per day in the right posterior cingulate cortex. Regarding the subscales of FCV-19S, we found significant positive correlation between factor 2 of the FCV-19S and shrinkage of the right posterior cingulate cortex. CONCLUSIONS: There was positive correlation between the FCV-19S score and regional brain atrophy per day. Although it is already known that the psychological effects surrounding the COVID-19 pandemic cause cognitive function decline, our results further suggest that anxiety and fear related to COVID-19 cause regional brain atrophy.

Effects of a multicomponent day-care program on cerebral blood flow in patients with mild cognitive impairment.

BACKGROUND: Mild cognitive impairment (MCI) is a prodromal phase of dementia and is considered an important period for intervention to prevent conversion to dementia. It has been well established that multicomponent day-care programs including exercise training, cognitive intervention and music therapy have beneficial effects on cognition, but the effects on cerebral blood flow (CBF) in MCI remain unknown. This study examined whether a multicomponent day-care program would have beneficial effects on the longitudinal changes of CBF in MCI patients. METHODS: Participants were 24 patients with MCI attending a day-care program; they underwent two 99 mTc-ethyl cysteinate dimer single photon emission computed tomography scans during the study period. We evaluated the association between the changes of regional cerebral blood flow and the attendance rate. RESULTS: There was a significant negative correlation between the reduction of regional CBF in the right parietal region and the attendance rate. We found no significant relation between the baseline CBF images and the attendance rate. CONCLUSIONS: Our results suggest that continuous participation in a multicomponent day-care program might prevent reduction in brain activity in patients with MCI.

Performance on the Wechsler Adult Intelligence Scale (WAIS) in Japanese patients with bipolar and major depressive disorders in euthymic and depressed states.

AIM: This study aimed to examine the cognitive performance of patients with bipolar disorder (BD) stratified by illness phase compared to that of patients with major depressive disorder (MDD) and healthy controls. METHODS: Participants were 139 patients with BD (55 euthymic and 84 depressed), 311 patients with MDD (88 euthymic and 223 depressed), and 386 healthy controls who underwent the Wechsler Adult Intelligence Scale-Revised or the Third Edition. They were non-elderly Japanese individuals with normal estimated premorbid intelligence quotient (IQ; >90), group-matched for age, sex, and premorbid IQ. RESULTS: The depressed BD group showed significantly lower scores on verbal IQ, performance IQ, full-scale IQ, and three group indexes of perceptual organization, working memory, and processing speed when compared with healthy controls (all P < 0.001). All IQs and working memory index were also significantly lower than those of the depressed MDD group. The depressed MDD group scored significantly lower than controls in performance IQ (P < 0.001), full-scale IQ, and only in the index of processing speed (P < 0.001). The euthymic BD group scored significantly lower than controls in performance IQ (P = 0.004), whereas the euthymic MDD group scored significantly lower than controls only in processing speed (P = 0.030). CONCLUSION: Patients with BD appear to have global and more intense cognitive impairments in depressed states compared with those with MDD whose impairments seem to be apparent only in processing speed in the Wechsler Adult Intelligence Scale. Attenuated impairments appear to exist in euthymic states of both patients.

Structural brain network differences in bipolar disorder using with similarity-based approach.

Objective: Previous studies have shown differences in the regional brain structure and function between patients with bipolar disorder (BD) and healthy subjects, but little is known about the structural connectivity between BD patients and healthy subjects. In this study, we evaluated the disease-related changes in regional structural connectivity derived from gray matter magnetic resonance imaging (MRI) scans. Methods: The subjects were 73 patients with BD and 80 healthy volunteers who underwent 3-Tesla MRI. Network metrics, such as the small world properties, were computed. We also performed rendering of the network metric images such as the degree, betweenness centrality, and clustering coefficient, on individual brain image. Then, we estimated the differences between them, and evaluate the relationships between the clinical symptoms and the network metrics in the patients with BD. Results: BD patients showed a lower clustering coefficient in the right parietal region and left occipital region, compared with healthy subjects. A weak negative correlation between Young mania rating scale and clustering coefficient was found in left anterior cingulate cortex. Conclusions: We found differences in gray matter structural connectivity between BD patients and healthy subjects by a similarity-based approach. These points may provide objective biological information as an adjunct to the clinical diagnosis of BD.

Structural Brain Network Correlated with Reading Impairment in Alzheimer's Disease.

AIM: Alzheimer's disease (AD) is the most common age-related neurodegenerative disease and leads to dementia. AD is characterized by progressive declines in memory and, as the disease progresses, language dysfunction. Although it has been reported that AD patients show progressive aphasia, no study has examined the relationship between language functions estimated by the Standard Language Test for Aphasia (SLTA) and brain network connectivity in Japanese AD patients. If present, such a relationship would be of particular interest because Japanese speakers are accustomed to mingling ideography and phonography. METHODS: 22 Japanese patients with AD who underwent 1.5-tesla MRI scan and SLTA, the scale for speech and reading impairment, participated in this study. We computed brain network connectivity metrics such as degree, betweenness centrality, and clustering coefficient, and estimated their relationships with the subscores of SLTA. RESULTS: There was a significant negative correlation between the score for "reading aloud Kanji words" and the clustering coefficient in the left inferior temporal region, bilateral hippocampal regions, and right parietotemporal region. We also found a significant negative correlation between the score for "auditory comprehension of words" and the clustering coefficient in the left prefrontal region. No significant relationship was found between the other SLTA scores and the network metrics. CONCLUSIONS: Our data suggest relationships between reading impairments and regional brain network connectivity in Japanese patients with AD. The brain connectome may provide adjunct biological information that could improve our understanding of reading impairment.

Distinctive Neuroanatomical Substrates for Depression in Bipolar Disorder versus Major Depressive Disorder.

No neuroanatomical substrates for distinguishing between depression of bipolar disorder (dBD) and major depressive disorder (dMDD) are currently known. The aim of the current multicenter study was to identify neuroanatomical patterns distinct to depressed patients with the two disorders. Further analysis was conducted on an independent sample to enable generalization of results. We directly compared MR images of these subjects using voxel-based morphometry (VBM) and a support vector machine (SVM) algorithm using 1531 participants. The VBM analysis showed significantly reduced gray matter volumes in the bilateral dorsolateral prefrontal (DLPFC) and anterior cingulate cortices (ACC) in patients with dBD compared with those with dMDD. Patients with the two disorders shared small gray matter volumes for the right ACC and left inferior frontal gyrus when compared with healthy subjects. Voxel signals in these regions during SVM analysis contributed to an accurate classification of the two diagnoses. The VBM and SVM results in the second cohort also supported these results. The current findings provide new evidence that gray matter volumes in the DLPFC and ACC are core regions in displaying shared and distinct neuroanatomical substrates and can shed light on elucidation of neural mechanism for depression within the bipolar/major depressive disorder continuum.

Altered ethanolamine plasmalogen and phosphatidylethanolamine levels in blood plasma of patients with bipolar disorder.

AIM: Ethanolamine-containing phospholipids are synthesized in endoplasmic reticulum (ER) and mitochondria. ER stress and mitochondrial dysfunction have been implicated in bipolar disorder (BP). In this study, we aimed to examine the relationship of ethanolamine plasmalogen (PLE) and phosphatidylethanolamine (PTE) levels in blood plasma with BP. METHODS: Plasma PLE and PTE levels were compared between 34 patients with BP (DSM-IV) and 38 healthy control participants matched for age, sex, and ethnicity (Japanese). Furthermore, the relationships of plasma PLE and PTE levels with clinical variables were explored. RESULTS: Plasma PLE levels were significantly lower in patients with BP than in healthy controls (P = 0.0033). In subgroup analyses, plasma PLE levels were significantly lower in patients with BP type I (BP I) than in healthy controls (P = 0.0047); furthermore, plasma PTE levels were significantly lower in patients with BP I than in controls (P = 0.016) and patients with BP type II (BP II) (P = 0.010). Receiver-operating characteristic curve analysis revealed that the discriminatory power of plasma PTE levels for distinguishing between BP I and II was fair (area under the curve = 0.78; P = 0.0095). There were no significant correlations of plasma PLE or PTE levels with depression or manic symptoms in patients. CONCLUSIONS: Plasma PLE and PTE levels were associated with BP I, but not with BP II. Moreover, plasma PTE levels differed between patients with BP I and II. Our findings highlight the importance of ethanolamine phospholipids in the pathophysiology of BP, especially BP I.

Genome-wide quantitative trait loci mapping of the human cerebrospinal fluid proteome.

Cerebrospinal fluid (CSF) is virtually the only one accessible source of proteins derived from the central nervous system (CNS) of living humans and possibly reflects the pathophysiology of a variety of neuropsychiatric diseases. However, little is known regarding the genetic basis of variation in protein levels of human CSF. We examined CSF levels of 1,126 proteins in 133 subjects and performed a genome-wide association analysis of 514,227 single nucleotide polymorphisms (SNPs) to detect protein quantitative trait loci (pQTLs). To be conservative, Spearman's correlation was used to identify an association between genotypes of SNPs and protein levels. A total of 421 cis and 25 trans SNP-protein pairs were significantly correlated at a false discovery rate (FDR) of less than 0.01 (nominal P < 7.66 × 10-9). Cis-only analysis revealed additional 580 SNP-protein pairs with FDR < 0.01 (nominal P < 2.13 × 10-5). pQTL SNPs were more likely, compared to non-pQTL SNPs, to be a disease/trait-associated variants identified by previous genome-wide association studies. The present findings suggest that genetic variations play an important role in the regulation of protein expression in the CNS. The obtained database may serve as a valuable resource to understand the genetic bases for CNS protein expression pattern in humans.

Brain abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome: Evaluation by diffusional kurtosis imaging and neurite orientation dispersion and density imaging.

BACKGROUND: Diffusional kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI) metrics provide more specific information regarding pathological changes than diffusion tensor imaging (DTI). PURPOSE: To detect microstructural abnormalities in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS) patients by using DKI and NODDI metrics. STUDY TYPE: Prospective. POPULATION: Twenty ME/CFS patients and 23 healthy controls were recruited. FIELD STRENGTH/SEQUENCE: Three-b value DWI (b-values = 0, 1000, and 2000 sec/mm2 ) and 3D T1 -weighted images were at 3.0T. ASSESSMENT: Mean kurtosis (MK), neurite density index (NDI), orientation dispersion index (ODI), fractional anisotropy (FA), and mean diffusivity (MD) were calculated. STATISTICAL TESTING: The two-sample t-test analysis in SPM12 software was used to compare the differences between ME/CFS and control groups. RESULTS: In the ME/CFS patients, we observed significant FA decreases in the genu of the corpus callosum and the anterior limb of the right internal capsule (P < 0.05), but no significant difference in MD (P = 0.164); there were also significant MK decreases in the right frontal area, anterior cingulate gyrus, superior longitudinal fasciculus (SLF), and left parietal area (P < 0.05). Significant NDI decreases were observed in the right posterior cingulate gyrus, SLF, and left frontal area of the ME/CFS patients (P < 0.05). Significant ODI decreases were seen in the bilateral occipital areas, right superior temporal gyrus, the anterior limb of internal capsule, and the posterior cingulate gyrus (P < 0.05), and significant ODI increases were revealed in the bilateral occipital and right temporal areas (P < 0.05). DATA CONCLUSION: Right SLF abnormalities may be a diagnostic marker for ME/CFS. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:818-824.

The relationship between the Wechsler Memory Scale-Revised scores and whole-brain structure in patients with schizophrenia and healthy individuals.

INTRODUCTION: The Wechsler Memory Scale (WMS) is a standardised battery for assessing memory functions. We aimed to investigate the relationship between all WMS scores, including subtests, and whole-brain structure in a relatively large sample. METHODS: Participants were 93 patients with schizophrenia and 117 healthy individuals, all right-handed and of Japanese ethnicity, and matched for age and sex. Their memory functions were assessed using the WMS-Revised (WMS-R). Their grey and white matter structure was analyzed using voxel-based morphometry and diffusion tensor imaging. RESULTS: Verbal memory score correlated positively with volumes of the left parahippocampal gyrus and hippocampus, while general memory score correlated positively with volumes of the left parahippocampal and fusiform gyri and hippocampus (p < 0.05, corrected), while there was no correlation with white matter fractional anisotropy values in healthy individuals. No correlation was observed between any WMS-R score and grey or white matter structure in patients. CONCLUSIONS: Using whole-brain structural magnetic resonance imaging, we found several significant correlations between WMS-R scores and grey matter volume in the brains of healthy individuals, while no correlation was found in those of patients with schizophrenia.