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.

Relationship of food allergy with quality of life and sleep in psychiatric patients.

AIM: Few studies have examined the relationship between food allergy (FA) and psychiatric disorders. We aimed to examine the possible relationship of FA with quality of life (QOL) and sleep in adult patients with psychiatric disorders. METHODS: Of the 812 participants (451 females, mean age: 42.7 ± 11.3 years), 430 had schizophrenia/schizoaffective disorder, 106 had depression, 124 had bipolar disorder, 40 had anxiety disorders, 38 had developmental disorders, and 11 had eating disorders; 63 were other cases. We documented FA and sleep disturbance via a questionnaire. QOL was assessed with the Medical Outcomes Study 8-Item Short-Form Health Survey (SF-8 Japanese version). RESULTS: There were 126 patients (15.5%) reporting FA. SF-8 physical component summary (PCS) and mental component summary (MCS) scores were both significantly lower among individuals with FA than those without. Moreover, PCS and MCS scores decreased as the number of allergens increased. Sleep disturbance was common among patients (76.0%). The proportions of individuals with sleep disturbance and nocturnal awakening were significantly higher in the group with FA, with the proportions increasing with higher number of allergens. CONCLUSION: We obtained the first evidence that FA is associated with impaired QOL and sleep in psychiatric patients, which can be improved by avoiding exposure to food allergens.

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.

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.

Increased apolipoprotein E and decreased TNF-α in the cerebrospinal fluid of nondemented APOE-ε4 carriers.

AIM: The ε4 allele of apolipoprotein E gene (APOE) is a well-known risk factor of late-onset Alzheimer's disease. However, little is known why this variant confers a risk for Alzheimer's disease. The aim of this study was to examine the influence of the APOE genotype on cerebrospinal fluid (CSF) protein levels. METHODS: The present study performed a secondary analysis on our previously generated database to compare the CSF levels of 1128 proteins between APOE-ε4 carriers (28 subjects) and noncarriers (104 subjects). All subjects were physically healthy Japanese individuals without dementia. RESULTS: CSF levels of apoE2, apoE3, and apoE4 were significantly higher (all nominal P < 10 × 10-5 , false discovery rate < 0.001) and those of tumor necrosis factor-α (TNF-α) were significantly lower (nominal P = 1.39 × 10-6 , false discovery rate < 0.001) in APOE-ε4 carriers than in noncarriers. No significant correlation was observed between the CSF levels of TNF-α and any of the apoE proteins. CONCLUSIONS: Our findings indicate the possible roles of apoE and TNF-α in the pathogenesis of APOE-ε4-associated Alzheimer's disease.

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.

Lower cerebrospinal fluid CRH concentration in chronic schizophrenia with negative symptoms.

Some patients with schizophrenia have impaired hypothalamic-pituitary-adrenal axis function. However, there is a dearth of studies focusing on corticotropin-releasing hormone (CRH) levels in the brains of schizophrenia patients, which motivated us to examine whether cerebrospinal fluid (CSF) CRH concentrations are altered in these patients. We also examined the possible correlation of CSF CRH level with clinical variables such as schizophrenia symptoms and antipsychotic medication. The study population comprised 20 patients with a diagnosis of schizophrenia according to DSM-5 criteria and 25 healthy controls, who underwent lumbar puncture. Most of the patients were treated with antipsychotic drugs and their doses were converted to chlorpromazine (CP) equivalent values. CSF CRH concentrations were measured by an enzyme immunoassay. Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS). There was a significantly lower CSF CRH concentration in the patients than in the controls (Mann-Whitney U test: p = 0.014). A significantly negative correlation of CSF CRH levels with PANSS negative scores was found in the patients (Spearman's: ρ = -0.58, p = 0.007). However, CSF CRH concentrations were not significantly correlated with the PANSS total (ρ = -0.035, p = 0.89), positive (ρ = 0.25, p = 0.30), or general psychopathology (ρ = 0.13, p = 0.59) scores. No significant correlation was found with CP equivalent values (ρ = 0.00, p = 1.00). In conclusion, we found that the patients with schizophrenia had lower CSF CRH concentrations compared to the controls and that the lower CSF CRH was associated with negative symptoms of the illness. Further studies in a larger sample and in drug-free patients are warranted.

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.

Cerebrospinal Fluid Inflammatory Cytokine Levels in Patients With Major Psychiatric Disorders: A Multiplex Immunoassay Study.

Aim: Accumulating evidence suggests that neural inflammation plays an important role in psychiatric disorders. We aimed to identify inflammatory cytokines involved in the pathophysiology of such disorders by quantifying them in cerebrospinal fluid (CSF) samples from a large sample of patients with major psychiatric disorders and healthy controls. Methods: The subjects included 94 patients with schizophrenia, 68 with bipolar disorder, 104 with major depressive disorder, and 118 healthy controls, matched for age, sex, and ethnicity (Japanese). Lumbar puncture was performed to collect these CSF samples. A multiplex immunoassay was then performed to measure CSF cytokine levels using magnetic on-bead antibody conjugation for 19 inflammatory cytokines. Results: CSF interferon-ß level was significantly higher in total psychiatric patients than in healthy controls (corrected p = 0.000029). In diagnostic group comparisons, CSF interferon-ß level was significantly higher in patients with schizophrenia, or bipolar disorder (corrected p = 0.000047 or 0.0034) than in healthy controls. Conclusion: We present novel evidence that CSF IFN-ß level showed prominent statistical differences between psychiatric groups and healthy controls. This suggests IFN-ß as the most important player among the 19 cytokines tested here in the inflammation-related pathophysiology of major psychiatric disorders.

Cerebrospinal fluid D-serine concentrations in major depressive disorder negatively correlate with depression severity.

BACKGROUND: D-serine is an endogenous co-agonist of N-methyl-D-aspartate receptor (NMDAR) and plays an important role in glutamate neurotransmission. Several studies suggested the possible involvement of D-serine related in the pathophysiology of psychiatric disorders including major depression disorders (MDD). We tried to examine whether cerebrospinal fluid (CSF) or plasma D-serine concentrations are altered in MDD and whether D-serine concentrations correlated with disease severity. METHODS: 26 MDD patients and 27 healthy controls matched for age, sex and ethnicity were enrolled. We measured amino acids in these samples using by high-performance liquid chromatography with fluorometric detection. RESULTS: D-serine and L-serine, precursor of D-serine, levels in CSF or plasma were not significantly different in patients of MDD compared to controls. Furthermore, a significant correlation between D-serine levels in CSF and Hamilton Depression Rating Scale (HAMD)-17 score was observed (r = -0.65, p = 0.006). Furthermore, we found a positive correlation between CSF D-serine and HVA concentrations in MDD patients (r = 0.54, p = 0.007). CSF D-serine concentrations were correlated with those of plasma in MDD (r = 0.61, p = 0.01) but not in controls. In CSF, we also confirmed a significant correlation between D-serine and L-serine levels in MDD (r = 0.72, p < 0.0001) and controls (r = 0.70, p < 0.0001). CONCLUSIONS: The study has some limitations; sample size was relatively small and most patients were medicated. We revealed that CSF D-serine concentrations were correlated with depression severity and HVA concentrations and further investigation were required to reveal the effect of medication and disease heterogeneity.

Plasma and cerebrospinal fluid G72 protein levels in schizophrenia and major depressive disorder.

G72 is a modulator of D-amino acid oxidase, the enzyme that degrades D-serine, an amino acid that plays a critical role in glutamate neurotransmission, and has been implicated in psychiatric disorders. The aim of this study was to examine whether plasma or cerebrospinal fluid (CSF) G72 protein levels were altered in either schizophrenia or major depressive disorder (MDD) and whether any correlation between G72 levels and disease severity existed. Initially, 27 schizophrenic patients, 26 MDD patients, and 27 healthy controls matched for age, sex, and ethnicity were enrolled. Compared to those of controls, plasma or CSF G72 levels were not significantly different in patients with schizophrenia or MDD. Although we found a significant positive correlation between plasma G72 levels and a positive symptoms score on the positive and negative syndrome scale (PANSS), this was not replicated in the second study (40 schizophrenic patients). CSF G72 levels showed no significant correlation with PANSS scores. In MDD, neither plasma nor CSF G72 levels correlated significantly with depression severity. Since severity of our patients were relatively mild, further investigations in a large number of subjects including drug-free patients, younger patients, and more severely affected patients are warranted.

Cerebrospinal fluid neural cell adhesion molecule levels and their correlation with clinical variables in patients with schizophrenia, bipolar disorder, and major depressive disorder.

PURPOSE: Neural cell adhesion molecule (NCAM) plays an important role in neural plasticity, and its altered function has been implicated in psychiatric disorders. However, previous studies have yielded inconsistent results on cerebrospinal fluid (CSF) NCAM levels in psychiatric disorders. The aim of our study was to examine CSF NCAM levels in patients with schizophrenia, bipolar disorder (BD), and major depressive disorder (MDD), and their possible relationship with clinical variables. METHODS: The participants comprised 85 patients with schizophrenia, 57 patients with BD, 83 patients with MDD and 111 healthy controls, all matched for age, sex, and Japanese ethnicity. The CSF samples were drawn using a lumbar puncture and NCAM levels were quantified by an enzyme-linked immunosorbent assay. RESULTS: Analysis of covariance controlling for age and sex revealed that CSF NCAM levels were lower in all patients (p=0.033), and in those with BD (p=0.039), than in the controls. NCAM levels positively correlated with age in patients with BD (p<0.01), MDD (p<0.01), and the controls (p<0.01). NCAM levels negatively correlated with depressive symptom scores in patients with BD (p=0.040). In patients with schizophrenia, NCAM levels correlated negatively with negative symptom scores (p=0.029), and correlated positively with scores for cognitive functions such as category fluency (p=0.011) and letter fluency (p=0.023) scores. CONCLUSION: We showed that CSF NCAM levels were lower in psychiatric patients, particularly bipolar patients than in the controls. Furthermore, we found correlations of NCAM levels with clinical symptoms in patients with BD and in those with schizophrenia, suggesting the involvement of central NCAM in the symptom formation of severe psychiatric disorders.

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.

Increased cerebrospinal fluid fibrinogen in major depressive disorder.

Major depressive disorder (MDD) presumably includes heterogeneous subgroups with differing pathologies. To obtain a marker reflecting such a subgroup, we analyzed the cerebrospinal fluid (CSF) levels of fibrinogen, which has been reported to be elevated in the plasma of patients with MDD. Three fibrinogen-related proteins were measured using aptamer-based analyses and CSF samples of 30 patients with MDD and 30 controls. The numbers of patients with an excessively high level (>99 percentile of the controls) was significantly increased (17 to 23%). Measurement reproducibility of these results was confirmed by an ELISA for fibrinogen (Pearson's r = 0.77). In an independent sample set from 36 patients and 30 controls, using the ELISA, results were similar (22%). When these two sample sets were combined, the number of patients with a high fibrinogen level was significantly increased (15/66; odds ratio 8.53; 95% confidence interval 1.9-39.1, p = 0.0011). By using diffusion tensor imaging, we found white matter tracts abnormalities in patients with a high fibrinogen level but not those patients with a normal fibrinogen level, compared with controls. Plasma fibrinogen levels were similar among the diagnostic groups. Our results point to a subgroup of MDD represented by increased CSF fibrinogen and white matter tract abnormalities.