Neuronal autoantibodies in the cerebrospinal fluid of 148 patients with schizophrenia and 151 healthy controls.

Schizophrenia is a syndrome with multiple etiologies, one of which is the potential for an autoimmune disease of the brain such as N-methyl-d-aspartate receptor (NMDAR) encephalitis, which can induce psychosis resembling schizophrenia. Here, we examined anti-neuronal autoantibodies related to psychosis using both cell- (CBA) and tissue-based assays (TBA) in the cerebrospinal fluid (CSF) of patients with chronic schizophrenia and control participants. First, we screened for the antibodies against leucine-rich glioma-inactivated 1 (LGI1), γ-aminobutyric acid B receptor (GABABR), dipeptidyl aminopeptidase-like protein 6 (DPPX), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR1/R2), and contactin-associated protein-like 2 (CASPR2) in 148 patients with schizophrenia. No antibodies were detected. Next, we performed CBA for NMDAR antibodies in 148 patients with schizophrenia and 151 age- and sex-matched controls. Although we detected relatively weak immunoreactivity for NMDAR in the CSFs of two patients with schizophrenia and three controls, no samples were positive when strict criteria were applied. For TBA in the rat hippocampus and cerebellum, we detected positive signals in the CSFs of 13 patients with schizophrenia and eight controls. Positive samples were analyzed for paraneoplastic syndrome and antinuclear antibodies using immunoblotting. The CSFs of nine patients and six controls were positive for dense fine speckle 70 (DFS70) antibodies. Additionally, antibodies against centromere protein (CENP)-A and CENP-B were detected in patients with schizophrenia. Our results suggest that autoantibodies against NMDAR, LG1, GABABR, DPPX, AMPAR1/R2, and CASPR2 are not associated with the pathogenesis of chronic schizophrenia. Moreover, we emphasize the importance of considering the effect of anti-DFS70 antibodies when analyzing autoantibodies in CSF samples. Conclusively, we obtained no evidence suggesting that the most frequent neuronal autoantibodies in the CSF play a role in the pathogenesis of schizophrenia, even in our sample.

Association of sugary drinks, carbonated beverages, vegetable and fruit juices, sweetened and black coffee, and green tea with subsequent depression: A five-year cohort study.

BACKGROUND & AIMS: Evidence on the impact of beverage consumption on depression is limited in the Asian population. Specifically, there is little information available on vegetable and fruit juices, while whole vegetables and fruits are reportedly protective against depression. Furthermore, evidence is scarce in differentiating the impacts of sweetened and black coffee. We aimed to examine the association of the consumption of total sugary drinks, carbonated beverages, vegetable and fruit juices, sweetened and black coffee, and green tea with subsequent depression in a general population sample. METHODS: We studied individuals without a history of cancer, myocardial infarction, stroke, diabetes, or depression at baseline in 2011-2016, with a five-year follow-up. We used Poisson regression models and the g-formula, thereby calculating the risk difference (RD) for depression. Multiple sensitivity analyses were conducted. Missing data were handled using random forest imputation. We also examined effect heterogeneity based on sex, age, and body mass index by analyzing the relative excess risk due to interaction and the ratio of risk ratios. RESULTS: In total, 94,873 individuals were evaluated, and 80,497 completed the five-year follow-up survey for depression. Of these, 18,172 showed depression. When comparing the high consumption group with the no consumption group, the fully adjusted RD (95% CI) was 3.6% (2.8% to 4.3%) for total sugary drinks, 3.5% (2.1% to 4.7%) for carbonated beverages, 2.3% (1.3% to 3.4%) for vegetable juice, 2.4% (1.1% to 3.6%) for 100% fruit juice, and 2.6% (1.9% to 3.5%) for sweetened coffee. In contrast, the fully adjusted RD (95% CI) was -1.7% (-2.6% to -0.7%) for black coffee. The fully adjusted RD for green tea did not reach statistical significance. The results were robust in multiple sensitivity analyses. We did not find substantial effect heterogeneity based on sex, age, and body mass index. CONCLUSIONS: Total sugary drinks, carbonated beverages, vegetable and fruit juices, and sweetened coffee may increase the risk of depression, whereas black coffee may decrease it.

Search for cerebrospinal fluid biomarkers in patients with major psychiatric disorders: Multiplex immunoassay findings and proximity extension assay prospects.

Multiplex immunoassays have been developed to detect multiple proteins simultaneously and are used to search for biomarkers, including those present in major psychiatric disorders. This study aimed to review multiplex immunoassay studies on cerebrospinal fluid (CSF) biomarkers in patients with schizophrenia, bipolar disorder (BD), and major depressive disorder (MDD) and examine future research directions using improved proteomic techniques. According to the results of previous multiplex immunoassay studies, increased CSF IFN-ß, IL-8, MCP-2, MMP-2, PAI-1, sICAM-1, and sVCAM-1 and decreased CSF ACE, APP, fibrinogen, and GDNF were observed in patients with schizophrenia, while CSF HGF and S100B were positively correlated with psychotic symptom and CSF IL-11, IL-29/IFN-λ1, and TSLP were negatively correlated. Increased CSF IFN-ß and IL-1ß and decreased CSF Aß42, APP, IL-6, and NCAM-1 were observed, while CSF S100B was positively correlated with manic symptom in patients with BD. Increased CSF IL-4, MCP-1, MIP-1ß, and MMP-2 were observed in patients with MDD, while CSF HGF and MMP-2 were positively correlated with depressive symptom and CSF IL-15 and MCP-1 were negatively correlated. However, signal cross-talk and cross-reactivity problems have been observed in previous studies using multiplex immunoassay. The proximity extension assay can be used to overcome cross-reactivity and enable ultrasensitive multiplexed detection and quantification of more than 1000 target proteins. However, proteomic studies using proximity extension assay technology in patients with schizophrenia, BD, or MDD are still scarce. Therefore, future high-quality proteomic studies are required to identify CSF biomarkers for larger sets of target proteins in patients with major psychiatric disorders.

Reduced homovanillic acid, SDF-1α and SCGF-ß levels in cerebrospinal fluid are related to depressive states in systemic lupus erythematosus.

OBJECTIVE: This study aimed to seek a new method of evaluation and surrogate markers for diffuse neuropsychiatric SLE (NPSLE). METHODS: We enrolled 44 patients with SLE between 2017 and 2020 who fulfilled at least one of three specific inclusion criteria: high disease activity, abnormal findings (cerebrospinal fluid [CSF] examination, brain MRI, or electroencephalography), or history of neuropsychiatric illness. Psychiatric symptom rating scales (PSYRATS) were evaluated retrospectively. The primary end point was the PSYRATS positivity rate in SLE patients who had not been diagnosed with diffuse NPSLE. RESULTS: Based on the 1999 ACR classifications, 7 out of the 44 patients evaluated using PSYRATS had been diagnosed with diffuse NPSLE. PSYRATS positivity was seen in 13 out of 37 SLE patients (35.1%) who had not been diagnosed with diffuse NPSLE, and all these patients were positive for Montgomery-Åsberg Depression Rating Scale (MADRS), an indicator of depression state in PSYRATS. Additionally, in the 20 SLE patients exhibiting depression symptoms who were MADRS-positive, CSF concentrations of the neuroinflammatory markers homovanillic acid (HVA; P = 0.0400), stromal cell-derived factor-1α (SDF-1α; P = 0.0431) and stem cell growth factor-ß (SCGF-1ß; P = 0.0061) were significantly reduced compared with the 24 MADRS-negative SLE patients, and the levels of HVA, SDF-1α and SCGF-1ß correlated with one another (P < 0.05). CONCLUSION: Many patients with active SLE have subclinical depression, and MADRS evaluation of neuropsychiatric symptoms is useful for detecting them. Additionally, the decrease in CSF levels of HVA, SDF-1 α and SCGF-1ß reflects the same pathology, and these may serve as surrogate markers.

Plasma neuropeptide levels in patients with schizophrenia, bipolar disorder, or major depressive disorder and healthy controls: A multiplex immunoassay study.

AIM: We aimed to compare neuropeptide levels between patients with major psychiatric disorders and healthy controls and examine their association with symptoms and cognitive function. METHODS: The participants were 149 patients with schizophrenia, 115 patients with bipolar disorder (BD), 186 unremitted patients with major depressive disorder (MDD), and 350 healthy controls. Psychiatric (schizophrenic, manic, and depressive) symptoms, sleep state, and cognitive (premorbid intelligence quotient, general cognitive, and memory) functions were evaluated. A multiplex immunoassay kit was used to measure cerebrospinal fluid (CSF) and plasma α-melanocyte-stimulating hormone (MSH), ß-endorphin, neurotensin, oxytocin, and substance P levels. RESULTS: The verification assay revealed that CSF α-MSH, ß-endorphin, neurotensin, oxytocin, and substance P levels were too low to be reliably measured, while plasma α-MSH, ß-endorphin, neurotensin, oxytocin, and substance P levels could be successfully measured. Plasma α-MSH, ß-endorphin, neurotensin, oxytocin, and substance P levels were not significantly different between patients with schizophrenia, BD, or MDD and healthy controls. Plasma α-MSH, ß-endorphin, neurotensin, oxytocin, and substance P levels were not significantly correlated with psychiatric symptom scores in patients with schizophrenia, BD, or MDD and cognitive function scores in patients or healthy controls. CONCLUSION: Our data suggest that plasma neuropeptide levels do not elucidate the involvement of neuropeptides in the pathology of schizophrenia, BD, or MDD.

Association between the Pittsburgh sleep quality index and white matter integrity in healthy adults: a whole-brain magnetic resonance imaging study.

To disclose possible associations between poorer sleep quality and structural brain alterations in a non-psychiatric healthy population, this study investigated the association between the Pittsburgh sleep quality index (PSQI) and brain correlates, using a whole-brain approach. This study included 371 right-handed healthy adults (138 males, mean age: 46.4 ± 14.0 years [range: 18-75]) who were right-handed. Subjective sleep quality was assessed using the Japanese version of the PSQI (PSQI-J), and the cutoff score for poor subjective sleep quality was set at ≥ 6. Voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) were performed to examine whether a higher score of the PSQI-J indicates, poorer sleep quality is associated with gray matter volume and white matter microstructure alternations, respectively. Among the participants, 38.8% had a PSQI-J cutoff score of ≥ 6. VBM did not reveal any correlation between PSQI-J scores and gray matter volume. However, DTI revealed that PSQI-J global scores were significantly and negatively correlated with diffuse white matter fractional anisotropy (FA) values (p < 0.05, corrected). Moreover, the PSQI-J sleep disturbance and use of sleep medication component scores were significantly and negatively correlated with right anterior thalamic radiation and diffuse white matter FA values, respectively (p < 0.05, corrected). There were no significant differences in gray matter volume and white matter metrics (FA, axial, radial, and mean diffusivities) between the groups with PSQI-J scores above or below the cutoff. Our findings suggest that lower sleep quality, especially the use of sleep medication, is associated with impaired white matter integrity in healthy adults. Limitations of this study are relatively small number of participants and cross-sectional design. Fine sleep quality, possibly preventing the use of sleep medication, may contribute to preserve white matter integrity in the brain of healthy adults. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-022-00442-0.

Association of body mass index and its classifications with gray matter volume in individuals with a wide range of body mass index group: A whole-brain magnetic resonance imaging study.

Aim: To examine the association of body mass index (BMI) [kg/m2] and its classifications (underweight [BMI < 18.5], normal [18.5 ≤ BMI < 25], overweight [25 ≤ BMI < 30], and obese [BMI ≥ 30]) with brain structure in individuals with a wide range of BMI group. Materials and methods: The participants included 382 right-handed individuals (mean age: 46.9 ± 14.3 years, 142 men and 240 women). The intelligence quotient was assessed using the Japanese Adult Reading Test. Voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) were performed to analyze the association of BMI and its classifications with gray and white matter structures, respectively. Results: According to VBM, BMI was significantly and negatively correlated with the bilateral cerebellum exterior volumes. In group comparisons, the right cerebellum exterior volume was significantly lower in the overweight or obese group than in the underweight or normal group, while the bilateral cuneus and calcarine cortex, left cuneus, and left precuneus volume was significantly lower in the underweight group than in the non-underweight group. Sex-related stratification analyses for VBM revealed that BMI was significantly and negatively correlated with the bilateral cerebellum exterior volumes only in women. In group comparisons, the left cerebellum exterior volume was significantly lower in obese women than in non-obese women. The left thalamus proper and the right cerebellum exterior volumes were significantly lower in overweight or obese group than in underweight or normal group in men and women, respectively. The bilateral cuneus and calcarine cortex, left cuneus and carcarine cortex, and bilateral cuneus volume was significantly lower in underweight men than in non-underweight men. In contrast, there were no notable findings on DTI. Conclusion: Our results suggest association of continuous BMI, being overweight or obese, and being underweight with decreased gray matter volume in individuals with a wide range of BMI group. Furthermore, sex-related differences are seen in the association of BMI and its classifications with regional gray matter volume reductions. Abnormally high or low BMIs may have a negative influence on regional gray matter volumes.

Association between vascular endothelial growth factor-mediated blood-brain barrier dysfunction and stress-induced depression.

Several lines of evidence suggest that stress induces the neurovascular dysfunction associated with increased blood-brain barrier (BBB) permeability, which could be an important pathology linking stress and psychiatric disorders, including major depressive disorder (MDD). However, the detailed mechanism resulting in BBB dysfunction associated in the pathophysiology of MDD still remains unclear. Herein, we demonstrate the role of vascular endothelial growth factor (VEGF), a key mediator of vascular angiogenesis and BBB permeability, in stress-induced BBB dysfunction and depressive-like behavior development. We implemented an animal model of depression, chronic restraint stress (RS) in BALB/c mice, and found that the BBB permeability was significantly increased in chronically stressed mice. Immunohistochemical and electron microscopic observations revealed that increased BBB permeability was associated with both paracellular and transcellular barrier alterations in the brain endothelial cells. Pharmacological inhibition of VEGF receptor 2 (VEGFR2) using a specific monoclonal antibody (DC101) prevented chronic RS-induced BBB permeability and anhedonic behavior. Considered together, these results indicate that VEGF/VEGFR2 plays a crucial role in the pathogenesis of depression by increasing the BBB permeability, and suggest that VEGFR2 inhibition could be a potential therapeutic strategy for the MDD subtype associated with BBB dysfunction.

Gut permeability and its clinical relevance in schizophrenia.

AIM: We aimed to examine the gut permeability in patients with schizophrenia and its relevance to schizophrenia symptoms, medication, cognitive functions, and blood immune markers. METHODS: We selected 22 patients with schizophrenia (mean age: 37.9 ± 10.5 years) comprising 9 men and 13 women. Furthermore, we included 86 healthy controls (mean age: 43.5 ± 11.0 years) comprising 41 men and 45 women. All participants were biologically unrelated and of Japanese descent. We used the Positive and Negative Syndrome Scale (PANSS) and Brief Assessment of Cognition in Schizophrenia (BACS) to measure the severity of schizophrenia symptoms and cognitive functions, respectively. The lactulose-mannitol loading test was used to measure the permeability of the small intestine. Furthermore, we used the lactulose to mannitol ratio (LMR) as an index of gut permeability. We measured the C-reactive protein and natural killer (NK) cell activity in the blood as highly sensitive immune markers. RESULTS: The patients had a significantly higher rate of "leaky gut" (defined as LMR ≥ 0.1) compared to the control group (22.7% vs. 5.8%, odds ratio: 4.8 [95% confidence interval, 1.2-18.3], Fisher's exact test, P = 0.03). There was no significant correlation between the LMR and PANSS scores or in the daily antipsychotic dose. In addition, the LMR was negatively correlated with the total Z-score of the BACS and NK cell activity in the patients. CONCLUSIONS: Our results suggest a higher rate of abnormally increased gut permeability in patients with schizophrenia than in controls. Moreover, gut permeability may be related to the cognitive and cellular immunity function of patients with schizophrenia.

Relationship between Interpersonal Sensitivity Measure score and clinical symptoms in patients with major psychiatric disorders and healthy individuals.

Aim: We compared the Interpersonal Sensitivity Measure (IPSM) scores between diagnostic groups and examined the relationship between IPSM scores and clinical variables. Methods: This study included 166 patients with schizophrenia, 47 patients with bipolar disorder (BD) Ⅰ, 110 patients with BD Ⅱ, 380 patients with major depressive disorder (MDD), and 558 healthy individuals. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale, 21-item Hamilton Depression Rating Scale (HAMD-21), and Pittsburgh Sleep Quality Index (PSQI). Results: The IPSM interpersonal awareness, separation anxiety, timidity, fragile inner self, and total scores were significantly higher in all the patient groups compared with healthy individuals (corrected p < 0.05). The IPSM need for approval score was significantly higher in patients with BD Ⅰ and those with BD Ⅱ than in those with schizophrenia or MDD (corrected p < 0.05). The PSQI total score and PANSS general psychopathology score, HAMD-21 delusion subscale score, HAMD-21 total score, and HAMD-21 core subscale score and PSQI sleep disturbance subscale score were significantly and positively correlated with the IPSM total score in patients with schizophrenia, those with BD Ⅰ, those with BD Ⅱ, and those with MDD, respectively, while the PSQI total score and daytime dysfunction subscale score were significantly and positively correlated with the IPSM total score in healthy individuals (corrected p < 0.05). Conclusion: Our data suggest that higher interpersonal sensitivity may play a role in the development of major psychiatric disorders and may be involved in some clinical symptom formations.

Effect of Lacticaseibacillus paracasei Strain Shirota on Improvement in Depressive Symptoms, and Its Association with Abundance of Actinobacteria in Gut Microbiota.

We previously reported lower counts of lactobacilli and Bifidobacterium in the gut microbiota of patients with major depressive disorder (MDD), compared with healthy controls. This prompted us to investigate the possible efficacy of a probiotic strain, Lacticaseibacillus paracasei strain Shirota (LcS; basonym, Lactobacillus casei strain Shirota; daily intake of 8.0 × 1010 colony-forming units), in alleviating depressive symptoms. A single-arm trial was conducted on 18 eligible patients with MDD or bipolar disorder (BD) (14 females and 4 males; 15 MDD and 3 BD), assessing changes in psychiatric symptoms, the gut microbiota, and biological markers for intestinal permeability and inflammation, over a 12-week intervention period. Depression severity, evaluated by the Hamilton Depression Rating Scale, was significantly alleviated after LcS treatment. The intervention-associated reduction of depressive symptoms was associated with the gut microbiota, and more pronounced when Bifidobacterium and the Atopobium clusters of the Actinobacteria phylum were maintained at higher counts. No significant changes were observed in the intestinal permeability or inflammation markers. Although it was difficult to estimate the extent of the effect of LcS treatment alone, the results indicated that it was beneficial to alleviate depressive symptoms, partly through its association with abundance of Actinobacteria in the gut microbiota.

Profiling of Cerebrospinal Fluid Lipids and Their Relationship with Plasma Lipids in Healthy Humans.

Lipidomics provides an overview of lipid profiles in biological systems. Although blood is commonly used for lipid profiling, cerebrospinal fluid (CSF) is more suitable for exploring lipid homeostasis in brain diseases. However, whether an individual's background affects the CSF lipid profile remains unclear, and the association between CSF and plasma lipid profiles in heathy individuals has not yet been defined. Herein, lipidomics approaches were employed to analyze CSF and plasma samples obtained from 114 healthy Japanese subjects. Results showed that the global lipid profiles differed significantly between CSF and plasma, with only 13 of 114 lipids found to be significantly correlated between the two matrices. Additionally, the CSF total protein content was the primary factor associated with CSF lipids. In the CSF, the levels of major lipids, namely, phosphatidylcholines, sphingomyelins, and cholesterolesters, correlated with CSF total protein levels. These findings indicate that CSF lipidomics can be applied to explore changes in lipid homeostasis in patients with brain diseases.

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.

Association between obesity and white matter microstructure impairments in patients with schizophrenia: A whole-brain magnetic resonance imaging study.

AIM: We aimed to examine the possible association of obesity (body mass index [BMI] ≥ 30) with symptoms, psychotropic medication, and whole-brain structure in patients with schizophrenia. METHODS: Participants were 65 patients diagnosed with schizophrenia (mean age: 37.2 ± 11.3 years, 32 females). All participants were Japanese and right-handed. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and Pittsburgh Sleep Quality Index (PSQI). Voxel based morphometry (VBM) and diffusion tensor imaging (DTI) were performed to analyze the association of obesity with gray and white matter structures, respectively. RESULTS: There was no significant difference in PANSS scores between obese and non-obese patients, while the PSQI score was significantly higher in the former than in the latter (p < 0.05). The daily dose of typical antipsychotics was significantly higher in obese patients than in non-obese patients (p < 0.001). In VBM, there was no significant difference in gray matter volume between obese and non-obese patients. In DTI, fractional anisotropy values in the corpus callosum, corona radiata, corticospinal tract, superior longitudinal fasciculus, and posterior thalamic radiations were significantly lower in obese patients than in non-obese patients (corrected p < 0.05). Axial diffusivity was significantly lower while radial and mean diffusivities values were significantly higher in obese patients than in non-obese patients (corrected p < 0.05) in similar but more restricted brain regions. CONCLUSION: Our results suggest that obesity is related to sleep disturbances, daily dose of typical antipsychotics, and regional white matter microstructure impairments in patients with schizophrenia.

Corrigendum: Correlation Between the Wechsler Adult Intelligence Scale- 3 rd Edition Metrics and Brain Structure in Healthy Individuals: A Whole-Brain Magnetic Resonance Imaging Study.

[This corrects the article DOI: 10.3389/fnhum.2020.00211.].

Correlation Between the Wechsler Adult Intelligence Scale- 3 rd Edition Metrics and Brain Structure in Healthy Individuals: A Whole-Brain Magnetic Resonance Imaging Study.

BACKGROUND: The Wechsler Adult Intelligence Scale, 3rd edition (WAIS-III) is widely used to evaluate the intelligence quotient (IQ). We aimed to investigate the correlation between the WAIS-III metrics and whole-brain structures using magnetic resonance imaging. METHODS: The participants were 266 healthy, right-handed individuals (age: 45.6 ± 12.9 years, 98 males and 168 females). IQs were evaluated using the WAIS-III and Japanese Adult Reading Test (JART). Voxel-based morphometry and diffusion tensor imaging were performed to analyze the correlation of the WAIS-III metrics and JART score with the gray matter volume and white matter integrity, respectively. RESULTS: The verbal IQ significantly and positively correlated with the left gyrus rectus and anterior cingulate gyrus, left posterior insula and planum polare, and left superior and middle frontal gyri volumes (p < 0.05, corrected). The verbal comprehension group index significantly and positively correlated with the left superior and middle frontal gyri, left gyrus rectus and anterior cingulate gyrus, and left middle frontal gyrus volumes, while the processing speed group index significantly and positively correlated with the bilateral various regional white matter fractional anisotropy values (p < 0.05, corrected). In contrast, the JART score showed no correlation with any brain structure. CONCLUSION: These results suggested the neurostructural bases of the WAIS-III IQs and group indices in the brain of healthy individuals.

Characterization of Postprandial Effects on CSF Metabolomics: A Pilot Study with Parallel Comparison to Plasma.

Cerebrospinal fluid (CSF) metabolites reflect biochemical diffusion/export from the brain and possibly serve as biomarkers related to brain disease severity, pathophysiology, and therapeutic efficacy/toxicity. Metabolomic studies using blood matrices have demonstrated interindividual and preanalytical variation of blood metabolites, whereas those of CSF metabolites remain unclear. In this study, we aimed to delineate the postprandial effects on CSF metabolites because fasting of patients with brain-related disorders is challenging. We collected pre- and postprandial (1.5, 3, and 6 h) plasma and CSF from nine healthy subjects. Using a mass-spectrometry-based global metabolomics approach, 150 and 130 hydrophilic metabolites and 263 and 340 lipids were detected in CSF and plasma, respectively. Principal component analysis of CSF hydrophilic metabolites and lipids primarily classified individual subjects at any time point, suggesting that the postprandial effects had a lower impact than interindividual variations on CSF metabolites. Individually, less than 10% of the CSF metabolites were putatively altered by postprandial effects (with either significant differences or over 2-fold changes, but not both) at any time point. Thus, global CSF metabolite levels are not directly associated with food intake, and except for several putatively altered CSF metabolites, postprandial effects are not a major concern when applying CSF metabolomics to screen biomarkers.

Cerebrospinal fluid neuroplasticity-associated protein levels in patients with psychiatric disorders: a multiplex immunoassay study.

To examine the role of neuroplasticity in the pathology of psychiatric disorders, we measured cerebrospinal fluid (CSF) neuroplasticity-associated protein levels. Participants were 94 patients with schizophrenia, 68 with bipolar disorder (BD), 104 with major depressive disorder (MDD), and 118 healthy controls, matched for age, sex, and ethnicity (Japanese). A multiplex immunoassay (22-plex assay) was performed to measure CSF neuroplasticity-associated protein levels. Among 22 proteins, 11 were successfully measured in the assay. CSF amyloid precursor protein (APP) and glial cell-derived neurotrophic factor (GDNF) levels were significantly lower in patients with schizophrenia, and CSF APP and neural cell adhesion molecule (NCAM)-1 levels were significantly lower in patients with BD, than in healthy controls (all p < 0.05). Positive and Negative Syndrome Scale total, positive, and general scores were significantly and positively correlated with CSF hepatocyte growth factor (HGF) (p < 0.01) and S100 calcium-binding protein B (S100B) (p < 0.05) levels in patients with schizophrenia. Young mania-rating scale score was significantly and positively correlated with CSF S100B level in patients with BD (p < 0.05). Hamilton Depression Rating Scale, core, sleep, activity, somatic anxiety, and delusion subscale scores were significantly and positively correlated with CSF HGF level, while sleep subscale score was positively correlated with CSF S100B and VEGF receptor 2 levels in patients with MDD (p < 0.05). Our results suggest that CSF APP, GDNF, and NCAM-1 levels are associated with psychiatric disorders, and that CSF HGF, S100B, and VEGF receptor 2 levels are related to psychiatric symptoms.