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Extracellular vesicles (EVs) are particles released from most cell types delimited by a lipid bilayer. Small EVs (sEVs) are nanosized (200 nm) and include exosomes. Brain-derived sEVs may provide a source for new biomarkers of brain status. CD9, CD63, and CD81 are major members of the tetraspanin family frequently used as sEV markers. However, according to a recent report, tetraspanins were not equally expressed in all sEVs, but rather show heterogeneity that reflects the expression levels in their secretory cells. We therefore investigated tetraspanin heterogeneity of sEVs in biofluids commonly used for clinical laboratory tests, and those in the brain. Expression levels and distributions of CD9, CD63 and CD81 on sEVs were determined in serum, plasma, and cerebrospinal fluid (CSF) samples collected from each healthy donor, and in post-mortem brain tissue samples. We found heterogeneous mixes of sEVs with various tetraspanin combinations among sEVs, and the predominant types and heterogeneous patterns of tetraspanins were specific to sample type. Hierarchical clustering revealed that brain sEVs were similar to those in the CSF, but different from those in peripheral blood. Our findings both provide basic information and contribute to the development of biomarkers for neurological and psychiatric disorders.

Background Lysophosphatidic acid (LPA) is involved in numerous biological processes, including neurodevelopment, chronic inflammation, and immunologic response in the central nervous system. Autotaxin (ATX) is a secreted enzyme that produces LPA from lysophosphatidylcholine (LPC). Previous studies have demonstrated decreased protein levels of ATX in cerebrospinal fluid (CSF) of patients with major depressive disorder (MDD). Based on those studies, the current study investigated the levels of lysophospholipids species including LPA and related metabolic enzymes, in CSF of patients with MDD and schizophrenia (SCZ). Methods The levels of lysophospholipids species and related metabolic enzymes were measured with either liquid chromatography-tandem mass spectrometry or enzyme-linked immunosorbent assay. Japanese patients were diagnosed with DSM-IV-TR. CSF was obtained from age- and sex-matched healthy controls (n = 27) and patients with MDD (n = 26) and SCZ (n = 27). Results Of all lysophospholipids species, the levels of LPA 22:6 (LPA - docosahexaenoic acid) were significantly lower in patients with MDD and SCZ than in healthy controls. These levels were negatively correlated with several clinical symptomatic scores of MDD, but not those of SCZ. In addition, the levels of LPA 22:6 were significantly correlated with the levels of LPC 22:6 among all 3 groups. On the other hand, the levels of LPA 22:6 were not correlated with ATX activity in patients with MDD and SCZ. Conclusion The lower levels of LPA 22:6 in patients with MDD and SCZ suggest an abnormality of LPA 22:6 metabolism. In addition, several depressive symptoms in patients with MDD were significantly associated with the lower levels of LPA 22:6, suggesting an involvement of LPA 22:6 in the pathophysiology of MDD.

Background Chronic inflammation of the brain has a pivotal role in the pathophysiology of major depressive disorder (MDD) and schizophrenia (SCZ). Matrix metalloproteinases (MMPs) are extracellular proteases involved in pro-inflammatory processes and interact with interleukin-6, which is increased in the cerebrospinal fluid (CSF) of patients with MDD and SCZ. However, MMPs in the CSF in patients with MDD and SCZ remain unclear. Therefore, we compared MMPs in the CSF of patients with MDD and SCZ with those of healthy controls (HC). Methods Japanese patients were diagnosed with DSM-IV-TR and clinical symptoms were assessed with the Hamilton Rating Scale for Depression for MDD and the Positive and Negative Syndrome Scale for SCZ. CSF was obtained from MDD (n = 90) and SCZ (n = 86) and from age- and sex-matched HC (n = 106). The levels of MMPs in CSF were measured with multiplex bead-based immunoassay. Results The levels of MMP-2 in CSF were higher in both MDD and SCZ than HC and were positively correlated with clinical symptomatic scores in MDD, but not in SCZ. Regardless of diagnosis, the levels of MMP-2, -7, and -10 were positively correlated with each other, and the levels of MMP-7 and -10 were higher in MDD, but not in SCZ, compared with HC. Conclusion Increased CSF levels of MMP-2 in MDD and SCZ may be associated with brain inflammation. State-dependent alteration of MMP-2 and activation of cascades involving MMP-2, -7, and -10 appeared to have a role in the pathophysiology of MDD.

Aim The efficacy of electroconvulsive therapy (ECT) has been established in psychiatric disorders but the high rate of relapse is a critical problem. The current study sought preventative factors associated with relapse after a response to ECT in a continuum of four major psychiatric disorders. Methods The records of 255 patients with four psychiatric disorders (83 unipolar depression, 60 bipolar depression, 91 schizophrenia, 21 schizoaffective disorder) were retrospectively reviewed. Results The relapse-free rate of all patients at 1 year was 56.3% in the four psychiatric disorders without a difference. As a result of univariate analysis, three items could be considered as preventative factors associated with relapse: a small number of psychiatric symptom episodes before an acute course of ECT, the use of mood stabilizers, and the use of maintenance ECT. Multivariate analysis was performed, keeping age, sex, and diagnosis constant in addition to the three items, and small number of psychiatric symptom episodes before an acute course of ECT (P = 0.003), the use of lithium (P = 0.025), the use of valproate (P = 0.027), and the use of maintenance ECT (P = 0.001) were found to be significant preventative measures against relapse. Conclusion The use of mood stabilizers, such as lithium and valproate, and maintenance ECT could be shared preventive factors associated with relapse after a response to ECT in four major psychiatric disorders.

Lysophosphatidic acid (LPA) is a bioactive phospholipid that acts as an extracellular signaling molecule through six G-protein-coupled receptors: LPA1-LPA6. Recent studies have demonstrated that LPA signaling via LPA1 receptor plays a crucial role in cognition and emotion. However, because of limited availability of reliable antibodies, it is currently difficult to identify the cell types expressing LPA1 receptor in the brain. The current study explored the cellular distribution pattern of LPA1 receptor in the brain using the LPA1 lacZ-knock-in reporter mice. In situ hybridization and immunohistochemistry revealed that LacZ gene expression in these mice reflected the expression of endogenous LPA1 receptor in the brain. Overall, some brain nuclei contained higher levels of LPA1 receptor than others. The majority of LPA1 receptor-expressing cells were Olig2+ oligodendrocytes. In addition, ALDH1l1+ astrocytes and CD31+ vascular endothelial cells also expressed LPA1 receptor. By contrast, NeuN+ neuron and Iba1+ microglia expressed little or no LPA1 receptor. The current neuroanatomical findings will aid in elucidating a role of brain LPA1 receptor, especially those involved in cognition and emotion.

Delayed neuropsychiatric sequelae (DNS) after acute carbon monoxide (CO) poisoning is a complication of CO intoxication. Hyperbaric oxygen (HBO) therapy is one of the only established treatments for CO poisoning, but as there is no specific treatment for DNS, the prognosis of DNS patients is generally poor. A 40-year-old male patient, following attempted suicide by CO poisoning, was referred to our department after having received HBO therapy at another hospital, but treatment had been subsequently discontinued due to patient agitation. The patient was diagnosed with DNS after acute CO poisoning, and we reinitiated HBO therapy. However, due to manifestation of symptoms of severe dementia, treatment was discontinued. After initiating thyrotropin-releasing hormone (TRH) therapy, psychiatric symptoms, such as difficulty in following instructions, improved, enabling the resumption of HBO therapy. Daily activities returned to premorbid levels following treatment. Thus, TRH therapy could be effective for patients with DNS due to acute CO poisoning who experience difficulty with HBO therapy.