GSK-3β in cerebrospinal fluid of schizophrenia patients

Summary. Cerebrospinal fluid contains proteins and metabolites of brain origin and was extensively studied in psychiatry in the 1970s with few definitive results. We have recently found 40% reduced protein levels of GSK-3 in schizophrenia in postmortem prefrontal cortex, but our attempt to develop a diagnostic marker using peripheral lymphocyte GSK-3 was not successful. In this study we aimed to find whether the reduction in brain GSK-3 is reflected in CSF of schizophrenia patients. We report a significant reduction in CSF GSK-3 protein levels in six schizophrenia patients compared to seventeen healthy subjects. Our results corroborate other studies in which CSF protein levels reflect the alteration found in these proteins in schizophrenia patients postmortem brain.     

Blood–cerebrospinal fluid barrier dysfunction in patients with bipolar disorder in relation to antipsychotic treatment

Blood–cerebrospinal barrier (BCB) dysfunction has previously been shown in subjects with schizophrenia and depressed patients with attempted suicide. Bipolar disorder (BPD) shares clinical features with both these disorders, but it is unknown if the integrity of the BCB is altered also in BPD. To assess if BCB function in BPD we surveyed 134 mood-stabilized BPD patients and 86 healthy controls. Serum and cerebrospinal fluid (CSF) samples were collected and analyzed for albumin concentration by immunonephelometry. CSF/serum albumin ratio, an established measure of BCB function, was significantly elevated in BPD patients as compared to controls. After stratifying patients according to diagnostic subtype, BPD I patients had the highest CSF/serum albumin ratios. Moreover, BPD patients on antipsychotic treatment had higher CSF/serum albumin ratio than BPD patients on other treatments. When excluding BPD patients on antipsychotic treatment the difference in CSF/serum albumin ratio between the BPD and control groups disappeared. In conclusion, antipsychotic treatment in BPD is associated with elevated CSF/serum albumin ratio, tentatively as a sign of impaired BCB function. Whether this elevation is caused by antipsychotic treatment or is associated with a certain subtype of BPD, requiring antipsychotic treatment, remains to be determined.     

Interleukin-1β and tumor necrosis factor-α in cerebrospinal fluid of children with bacterial meningitis

Certain cytokines may contribute to the sequence of events that lead to meningeal inflammation in bacterial meningitis. The purpose of this study was to determine the levels of cytokines in the cerebrospinal fluid (CSF) of children with bacterial meningitis and aseptic meningitis of different etiologies. We determined the concentrations of interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF-alpha) in the CSF of 171 specimens of 144 patients whose cases were classified as follow: bacterial meningitis (n=23), aseptic meningitis (n=26) and non-meningitis (n=95). The detectable IL-1beta concentration (> or =20 pg/ml) in the bacterial meningitis, aseptic meningitis and non-meningitis groups were observed with 78.3%, 3.8%, and 8.4%, respectively. Significantly higher serum IL-1beta concentrations were detected in those with bacterial meningitis than those with aseptic meningitis (538.93+/-605.32 pg/ml vs 2.52+/-11.57 pg/ml; P<0.001) or among non-meningitis subjects (2.90+/-11.91 pg/ml; P<0.001). The mean TNF-alpha concentration was 148.74+/-338.77 pg/ml. There was significantly more TNF-alpha than aseptic meningitis (6.85+/-17.93 pg/ml; P<0.001) or non-meningitis (7.67+/-16.07 pg/ml; P<0.001). With regard to diagnosis, measurement of IL-1beta and TNF-alpha levels showed sensitivities of 78% and 74%, respectively; specificities of 96% and 81%, respectively. It is suggested that the levels of these cytokines, especially IL-1beta and TNF-alpha, are useful markers for distinguishing bacterial meningitis from aseptic meningitis.     

Effect of human cerebrospinal fluid sampling frequency on amyloid-β levels

Backgroundβ-amyloid peptide (Aβ) is associated with neurodegeneration in Alzheimer’s disease. Emerging evidence indicates that Aβ levels in cerebrospinal fluid (CSF) may serve as an early clinical biomarker for evaluating pharmacological activity of new drug candidates targeting Aβ production or Aβ clearance. Therefore, it is critical to understand whether intrasubject levels of CSF Aβ are consistent between sampling intervals to determine whether Aβ can be used as a pharmacodynamic biomarker for drug candidates. Previous studies have produced seemingly conflicting observations for the intrasubject stability of CSF Aβ levels; we attempt to reconcile these conflicting observations.MethodsThe current study examined the Aβ levels in CSF collected with various sampling frequencies from three clinical studies conducted in healthy young or elderly subjects at the same investigative site for the purpose of designing future studies.ResultsThe results suggest that CSF sampling frequency and/or sampling volume contributes to intrasubject variability in CSF Aβ levels, and that lowering the CSF sampling frequency may help minimize this effect.ConclusionThese results will help guide clinical trial design for Alzheimer’s disease therapy.     

Thought disorder in euthymic bipolar patients: a possible endophenotype of bipolar affective disorder?

The search for psychological markers or for psychological endophenotypes for bipolar affective disorder has been frustrating, and the study of neuropsychological and neurocognitive functioning may be useful in this search. This article presents the results of a study comparing Rorschach protocols from a sample of adult euthymic bipolar patients (N = 18) and matched healthy controls (N = 8). Bipolar patients showed a higher proportion of immature responses and more instances of thought disorder; patients also showed significantly more severe thought disorder. These findings are discussed in the context of 2 related previous studies. We suggest that our modest series of studies using the Rorschach Inkblot Test provides preliminary evidence that certain variables-especially the measures of thought disorder but possibly also the lack of emotional responses under cognitive "control" and the excessive proportion of immature content responses-may represent a possible endophenotype of bipolar disorder.     

Aminoterminally truncated and oxidized amyloid-β peptides in the cerebrospinal fluid of Alzheimer's disease patients

Carboxyterminally elongated and aminoterminally truncated amyloid-β (Aβ) peptides and their oxidized derivates are major constituents of human amyloid plaques. The objective of the present study was to clarify the diagnostic impact of the Aβ peptides 1-38ox, 2-40, and 2-42 peptides on the neurochemical cerebrospinal fluid (CSF) diagnosis of Alzheimer's disease (AD). For this purpose, 22 patients with AD and 20 non-demented disease controls (NDC) were comparatively analyzed for their cerebrospinal fluid pattern of Aβ1-38ox, Aβ2-40, and Aβ2-42 along with Aβ1-37, Aβ1-38, Aβ1-39, Aβ1-40, Aβ1-40ox, and Aβ1-42 using a novel sequential aminoterminally and carboxyterminally specific immunoprecipitation protocol and subsequent analysis in the Aβ-SDS-PAGE/immunoblot. The Aβ peptides 1-38ox, 2-40, and 2-42 could not be consistently detected in the investigated CSF samples, which applied to samples from AD and NDC patients alike. Otherwise, our approach revealed a striking decrease of Aβ1-42 and Aβ2-42, but not of Aβ1-38ox and Aβ2-40 in AD. Both Aβ1-42 and Aβ2-42 reached reasonable accuracies for diagnosing AD alone as well as in relation to Aβ1-40, Aβ1-38, or the sum of all measured Aβ peptides. Aβ1-38ox was negatively correlated to the Mini-Mental Status Examination score of AD patients, indicating that this peptide to linked to disease severity. We conclude that an exact analysis of CSF Aβ peptides regarding their carboxy- and aminoterminus as well as posttranslational modification may be a promising approach for diagnosing and tracking AD.     

Interleukin-1β is associated with depressive episode in major depression but not in bipolar disorder

Our work was sought to investigate possible changes in peripheral levels of interleukin-1β (IL-1β) according to the diagnosis of major depression (MD) and bipolar disorder (BD) and in different mood episodes. This is a cross-sectional nested in a population-based study comparing 240 young adults (80 controls, 80 MD and 80 BD), balanced for age and gender. Serum levels of IL-1β were significantly higher in MD when compared to control or BD subjects. In addition, when divided by current mood episode, MD subjects in current depression presented higher IL-1β levels than controls. No differences in IL-1β levels were found between different episodes of BD (euthymic, depressed, mania or mixed). Moreover, the use of psychiatric medication was very low in our sample and not associated with changes in IL-1β levels. In conclusion, increased peripheral IL-1β might be a useful marker associated with a depressive episode in the context of MD.     

Cerebrospinal fluid markers of neuroinflammation in delirium: A role for interleukin-1β in delirium after hip fracture

Objective

Exaggerated central nervous system (CNS) inflammatory responses to peripheral stressors may be implicated in delirium. This study hypothesised that the IL-1β family is involved in delirium, predicting increased levels of interleukin-1β (IL-1β) and decreased IL-1 receptor antagonist (IL-1ra) in the cerebrospinal fluid (CSF) of elderly patients with acute hip fracture. We also hypothesised that Glial Fibrillary Acidic Protein (GFAP) and interferon-γ (IFN-γ) would be increased, and insulin-like growth factor 1 (IGF-1) would be decreased.

Methods

Participants with acute hip fracture aged > 60 (N = 43) were assessed for delirium before and 3–4 days after surgery. CSF samples were taken at induction of spinal anaesthesia. Enzyme-linked immunosorbent assays (ELISA) were used for protein concentrations.

Results

Prevalent delirium was diagnosed in eight patients and incident delirium in 17 patients. CSF IL-1β was higher in patients with incident delirium compared to never delirium (incident delirium 1.74 pg/ml (1.02–1.74) vs. prevalent 0.84 pg/ml (0.49–1.57) vs. never 0.66 pg/ml (0–1.02), Kruskal–Wallis p = 0.03). CSF:serum IL-1β ratios were higher in delirious than non-delirious patients. CSF IL-1ra was higher in prevalent delirium compared to incident delirium (prevalent delirium 70.75 pg/ml (65.63–73.01) vs. incident 31.06 pg/ml (28.12–35.15) vs. never 33.98 pg/ml (28.71–43.28), Kruskal–Wallis p = 0.04). GFAP was not increased in delirium. IFN-γ and IGF-1 were below the detection limit in CSF.

Conclusion

This study provides novel evidence of CNS inflammation involving the IL-1β family in delirium and suggests a rise in CSF IL-1β early in delirium pathogenesis. Future larger CSF studies should examine the role of CNS inflammation in delirium and its sequelae.     

Peripheral levels of C-reactive protein,tumor necrosis factor-α, interleukin-6, and interleukin-1β across the mood spectrum in bipolar disorder: A meta-analysis of mean differences and variability

ImportanceIt is unclear whether differences exist in the magnitude and variability of pro-inflammatory mediators in the different phases of bipolar disorder (BD) and among subjects with BD, as compared to healthy controls.ObjectiveTo run a comparative meta-analysis of C-Reactive Protein (CRP), IL-1, IL-6, TNF-α in BD vs healthy controls, measuring mean and variability effects on all subjects. Sensitivity analyses include disease activity.Data sourcesSystematic review of observational studies in PubMed and PsycInfo up to February 2nd, 2020.Study selectionCase-control studies reporting inflammatory mediators' levels in BD and controls.Data extraction and synthesisSummary distribution measures of circulating CRP, IL-1β, IL-6, TNF-α in participants with BD and control groups were extracted. Random-effects multivariate meta-analyses were conducted based on individual study/mediator effect sizes (Hedge’s g).Main outcomes and measuresCo-primary outcomes were inflammatory mediators' levels (Hedge’s g) and variability (coefficient of variance ratio (CVR)) differences between participants with BD across the mood spectrum and controls.ResultsOut of the initial 729 papers, 72 were assessed and then excluded after full-text review, and ultimately 53 studies were included in the systematic review, while 49 were included in the meta-analysis. The mean age was 36.96 (SD: 9.29) years, and the mean female percentage was 56.31 (SD: 16.61). CRP (g = 0.70, 95% CI 0.31–1.09, k = 37, BD = 2,215 vs HC = 3,750), IL-6 (g = 0.81, 95% CI 0.46–1.16, k = 45, BD = 1,956 vs HC = 4,106), TNF-α (g = 0.49, 95% CI 0.19–0.78, k = 49, BD = 2,231 vs HC = 3,017) were elevated in subjects with BD vs HC, but not IL-1β (g = -0.28, 95% CI −0.68–0.12, k = 4, BD = 87 vs HC = 66). When considering euthymic, depressive, and manic episodes separately, CRP and TNF-α were elevated in both depressive and manic episodes, but not in euthymia, while IL-6 remained elevated regardless of the disease state. No difference in CVR emerged for CRP, IL-1β, and TNF-α, while a lower CVR was observed for IL-6. When considering disease phases, CVR was higher in BD than in HCs for CRP during depressive episodes, lower for IL-6 during euthymia, and higher during manic episodes for CRP, IL-6, and TNF-α. Sensitivity analyses after excluding outliers identified with funnel plot visual inspection, low-quality studies, and considering only studies matched per body mass index confirmed the main results. Meta-regression showed that age (IL-6, TNF-α), gender (CRP), duration of illness (CRP) moderated elevated individual inflammatory levels.Conclusions and relevancePeripheral pro-inflammatory marker elevations were confirmed in BD. CRP and TNF-α could represent state markers, as they were only elevated during mood episodes, while IL-6 appeared to be a trait marker for BD. Increased variability of specific inflammatory mediators in specific disease active states suggests that a subset of subjects with BD may exhibit elevated inflammation as part of a manic or depressive episode.     

A growth in bipolar disorder?

OBJECTIVE: This case report suggests that screening of patients with psychiatric symptoms using modern neuroimaging can help identify organic causes of mental illness. METHOD: A single case study was reported. RESULTS: We report the case of a 25-year-old woman with a recent diagnosis of bipolar II disorder having an magnetic resonance imaging (MRI) scan as part of a research project that reveals an intraventricular brain tumour. The latter is most likely the cause of her irritability and 'hypomanic' symptoms and is defined anatomically using diffusion tensor imaging and structural and functional imaging using MRI and positron emission tomography. CONCLUSION: The lesion in this individual case most probably produces mood symptoms by impinging upon the fornix, a component of the limbic system. However, more generally, the increase in diagnosis of bipolar disorder has to be tempered against alternate causes of similar symptoms and necessitates vigilance of potential organic mechanisms.     

Relation between TGF-β 1 levels in cerebrospinal fluid and ETV outcome in premature newborns with posthemorrhagic hydrocephalus

Object  

Therapy of posthaemorrhagic hydrocephalus (PHH) by using ventriculo-peritoneal drainage bears considerable rate of complications and remains a challenge in premature newborns. The role of endoscopic third ventriculostomy (ETV) in these patients is unclear, through obstruction is proven in some patients with PHH. Transforming growth factor beta 1 (TGF-β1) release into the cerebrospinal fluid (CSF) in time of primary bleeding is suggested as one of the possible pathophysiologic reasons of PHH formation. Relation between TGF-β1 levels and ETV success rate has not been reported yet. The aim of our study is to detect group of patients, according to the levels of TGF-β1, who have magnetic resonance imaging (MRI)-proven obstruction hydrocephalus without participation of hyporesorption—so that we can expect success of ETV.     

The impact of glycogen synthase kinase 3β gene on psychotic mania in bipolar disorder patients

Objective

The aim of this study was to examine the relationships between glycogen synthase 3β gene polymorphisms and bipolar I disorder, manic in a Korean sample.

Methods

Patients with bipolar disorder (n = 118) and a control group (n = 158) were assessed by genotyping for GSK3β single nucleotide polymorphisms (SNPs) − 1727A/T and − 50C/T. The patients were divided into two groups according to the presence of psychotic symptoms (psychotic mania, n = 92; non-psychotic mania, n = 26) and also divided based on gender and age of onset. The severity of symptoms was measured using the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS).

Results

There were no significant differences in the genotype distributions or allelic frequencies of GSK3β polymorphisms and gender between patients with bipolar disorder and a normal control group. According to haplotype analysis, there was no association between these two groups. However, analysis of the age of onset of bipolar disorder revealed significant differences in genotype and allele distributions among the patients. Patients who were homozygous for the wild-type variant (TT) had an older age of onset than carriers of the mutant allele (A/A: 27.4 ± 9.1; A/T: 30.1 ± 11.8; T/T: 42.3 ± 19.9; p = 0.034). We detected differences in allele frequencies of the GSK3β − 1727A/T polymorphism between the psychotic mania group and the non-psychotic mania group.

Conclusion

This study suggests that GSK3β polymorphisms are not associated with bipolar disorder. However, the GSK3β SNP − 1727A/T is associated with age of onset and presence of psychotic symptoms in bipolar disorder.     

Obsessive compulsive symptoms in bipolar disorder patients: a comorbid disorder or a subtype of bipolar disorder?

概述

在过去十年中，人们越来越关注同时符合两种或两种以上精神障碍诊断标准的患者。上述共病情况之一就是双相障碍合并强迫症，这在以双相障碍为主要诊断的患者中比较常见。但是，关于这种共病的诊断和治疗的研究很少，在中国尤为如此。现有的研究主要集中在小样本的横断面研究，因此它们在对理解这种共病情况的病因和病程作用有限。对有限的文献进行回顾发现这是双相障碍中一种相对严重的、难治性的亚型，只有少数情况可以被认为是一种共病障碍。要阐明这种共病的病因、预后以及合适的治疗方法，则需要大样本的前瞻性研究。

中文全文

本文全文中文版从2015年10月26日起在http://dx.doi.org/10.11919/j.issn.1002-0829.215091可供免费阅览下载 The Forum by Peng and Jiang[1] highlights the lack of literature about comorbid bipolar disorder and obsessive compulsive (OCD) disorder. To provide a preliminary summary of the available English-language literature, a search of PubMed using three relevant keywords (‘bipolar disorder’, ‘obsessive compulsive disorder’, and ‘comorbidity’) was conducted in July 2015. Only a few of the 176 papers retrieved by this search were directly related to the topic of interest: most of the relevant papers described the incidence and clinical features of comorbid bipolar disorder and OCD in relatively small samples of patients; some discussed the etiology and treatment of the comorbid condition; and a few reported on prospective, multi-center studies with relatively large samples. Bipolar-OCD comorbidity was first reported in a 1995 study from Germany[2] which found that more than half of all patients with bipolar disorder had experienced other mental disorders, including OCD, during the course of the bipolar disorder. The study reported that the prevalence of comorbid OCD was higher in patients with unipolar depression than among patients with bipolar disorder. A subsequent systematic review[3] of 64 relevant articles in 2014 reported that from 11 to 21% of persons with bipolar disorder experience comorbid OCD at some time during the course of their bipolar disorder. Most reports indicate that comorbid OCD exacerbates the symptoms of bipolar disorder and makes the diagnosis and treatment of bipolar disorder more difficult. Compared to OCD patients and bipolar disorder patients without other comorbid conditions, bipolar patients with comorbid OCD have: a) higher rates of obsessive ideas about sex and religion and lower rates of ritual checking;[4] b) higher rates of substance abuse (including use of alcohol, sedatives, caffeine, etc.);[5,6] more episodes of depression, higher rates of suicide, and more frequent admissions to hospitals;[7] and d) more chronic episodes and residual symptoms.[8,9] There were no differences between bipolar patients with and without comorbid OCD in age, gender, education, marital status, age of onset of bipolar disorder, personality, prevalence of psychotic symptoms or rapid cycling, history of suicide attempts, the type of initial bipolar episode (i.e., depressed or manic), and the type of episode that was most prevalent throughout the course of bipolar disorder.[9] The systematic review by Amerio and colleagues[3] found that compared to bipolar patients without comorbid OCD, patients with bipolar disorder with comorbid OCD were more likely to experience OCD symptoms during an affective disorder episode (75% v. 3%), had a higher mean (sd) number of depressive episodes (8.9 [4.2] v. 4.1 [2.7] episodes), and were more likely to experience an antidepressant-induced manic episode (39% v. 9%). They also found that among patients with comorbid bipolar disorder and OCD, OCD symptoms were more like to occur during depressive episodes than manic episodes (78% v. 64%). Based on their findings, these authors argue that the obsessive-compulsive symptoms observed in these patients were secondary to bipolar disorder, not a co-occurring independent disorder.[3] Following this logic, I recommend that the occurrence of obsessivecompulsive symptoms during the depressive (or manic) episodes of a bipolar disorder should not be sufficient to merit a diagnosis of comorbid bipolar disorder and OCD; this comorbid diagnosis should be restricted to situations in which a patient with bipolar disorder also meets the full OCD symptomatic and duration criteria when the patient is not experiencing a depressive or manic episode. There are only a few articles about the possible etiology of bipolar-OCD comorbidity. A long-term family study based on a multi-generational dataset[10] (cases registered from January 1969 to 2009 included 19, 814 with OCD, 58, 336 with schizophrenia, 48, 180 with bipolar disorders, and 14, 904 with schizoaffective disorder) found familial associations among individuals with bipolar disorder, OCD, and schizophrenia spectrum disorders. There are also few reports about the long-term prognosis of comorbid bipolar disorder and OCD. One study[11] that followed 20 patients with bipolar disorder without comorbid disorders and 20 patients with comorbid bipolar disorder and OCD for 4 years found no significant differences in the long-term outcomes between the two groups. The treatment of bipolar-OCD comorbidity is difficult because the use of antidepressants to treat obsessive compulsive disorder may induce manic episodes. The existing literature about the treatment is primarily composed of case reports, retrospective cross-sectional studies, and a few treatment studies with small samples. A recent systematic review that combined the results of four treatment studies[12] found that 42% of patients with comorbid bipolar disorder and OCD were simultaneously treated with multiple mood stabilizers and another 10% needed combined treatment with mood stabilizers and anti-psychotic medications. One of the four studies reported that the combined use of antidepressants and mood stabilizers was effective and another study reported that some patients benefitted from the combined use of mood stabilizers and psychological therapy.[11] Based on currently available information, I recommend that patients with comorbid bipolar disorder and OCD be initially treated with mood stabilizers; if mono-therapy with mood stabilizers is ineffective, adjunctive treatment with selective serotonin reuptake inhibitor antidepressants (which are less likely to induce mania) should be considered. In my opinion, the basic treatment for bipolar-OCD is mood stabilizers and could be combined with antidepressants if the patients do not respond to the single treatment (ineffective). Despite ongoing debates about the etiology, diagnosis, and treatment of comorbid bipolar disorder and OCD, the clinicians who regularly treat bipolar patients need more high-quality, evidence-based information to improve their identification and management of this relatively severe and refractory subgroup of bipolar patients. Well-designed prospective studies with relatively large samples that are specifically focused on this important subgroup of bipolar disorder patients are needed.     

Central inhibition of interleukin-1β ameliorates sickness behavior in aged mice

In elderly individuals high levels of interleukin-1β (IL-1β) in the brain have been implicated in infection-related behavioral pathologies but this has not been directly tested. Therefore, the current study investigated if sickness behavior in aged animals elicited by peripheral injection of lipopolysaccharide (LPS) is mediated through central IL-1β. Adult and aged mice were injected intracerebroventricularly with either saline or IL-1ra (4 μg) immediately prior to intraperitoneal administration of saline or LPS (10 μg) and locomotor and social behaviors were assessed. As anticipated, LPS depressed locomotor activity and social behavior in both adult and aged mice but the behavioral deficits were markedly greater in the aged at 24 h. Pretreatment with IL-1ra did not affect LPS-induced sickness behavior in adults; however, in aged mice IL-1ra attenuated LPS-induced sickness behavior, restoring it to the level exhibited by young adults. Twenty-four hours post-injection hippocampal and hypothalamic tissues were collected to determine IL-1β mRNA expression. Neither LPS nor IL-1ra affected IL-1β mRNA levels in adults, presumably because any effect of LPS had dissipated by 24 h. In contrast, IL-1β mRNA was markedly higher in aged mice 24 h after LPS, and prior treatment with IL-1ra either blocked or attenuated this effect in the hippocampus and hypothalamus, respectively. Taken together these data provide the first direct evidence that central IL-1β is responsible for the severe sickness behavior observed in aged animals after LPS treatment. Thus, inhibiting the central actions of IL-1β may be useful for minimizing behavioral complications in older individuals with an infection.     

Study of cerebrospinal fluid flow dynamics in TGF-β1 induced chronic hydrocephalic mice

Abstract

In a previous study, we found that the CSF level of transforming growth factor/11 (TGF-fll) is elevated following subarachnoid hemorrhage (SAH) in patients who later develop communicating hydrocephalus, while in mice, an intrathecal injection of TGF-fll can induce communicating hydrocephalus. Recently, histopathological changes in the leptomeninges were studied using the above TGF-fll induced mice model of hydrocephalus. In the present study, in order to further clarify the ventricular dilatation mechanism, we examined cerebrospinal fluid (CSF) flow dynamics in TGF-fll induced hydrocephalic mice. To assess CSF flow, Indian ink was injected into the passage pathway and the time taken for the ink to pass from the parietal intrameningeal CSF space to cervical lymph nodes was determined. The ink study revealed a significant lengthening of the ink passage time due to altered CSF flow dynamics, while a histological examination showed ink stasis in the altered leptomeningeaI CSF space compared to PBS injected control mice. TGF-fl 1 induced increased cellularity in the leptomeninx and fibrosis, and a subsequent narrowing of the intrameningeal CSF space. This narrowing causes a disturbance in CSF flow, thus generating a mild pressure gradient, which ultimately leads to the development of slowly progressive ventricular dilatation. After SAH, elevated TGF-fll in the CSF may play a similar role, in concert with other factors, in the development of communicating hydrocephalus in human. [Neurol Res 2000; 22: 215-222]     

Amyloid-β oligomers in cerebrospinal fluid are associated with cognitive decline in patients with Alzheimer's disease

Oligomers of the amyloid-β peptide (Aβ) are thought to be the most toxic form of Aβ and are linked to the development of Alzheimer's disease (AD). Here, we used a flow cytometric approach for the detection and assessment of oligomers in cerebrospinal fluid (CSF) from AD patients and other neurological disorders. 30 CSF samples from patients suffering from AD (n = 14), non-demented controls (n = 12), and other neurological disorders (dementia with Lewy bodies, n = 2; vascular dementia, n = 1; primary progressive aphasia, n = 1) were analyzed for the presence of Aβ-oligomers by flow cytometry. The CSF levels of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ)42 were determined using ELISA. CSF Aβ-oligomer levels in AD patients were elevated in comparison to the non-AD group (p = 0.073). The ratio Aβ-oligomers/Aβ42 was significantly elevated in AD subjects compared to non-AD subjects (p = 0.001). Most important, there was a negative correlation between the amount of Aβ-oligomers and the Mini-Mental Status Exam score (r = -0.65; p = 0.013) in AD patients. The detection of Aβ-oligomers using flow cytometry analysis seems to be useful in assessing the stage of AD. This is a novel and important finding as none of the currently used CSF biomarkers are clearly associated with dementia severity.     

Association of N-acetylaspartate and cerebrospinal fluid Aβ42 in dementia

The interplay of amyloid and mitochondrial function is considered crucial in the pathophysiology of Alzheimer's disease (AD). We tested the association of the putative marker of mitochondrial function N-acetylaspartate (NAA) as measured by proton magnetic resonance spectroscopy within the medial temporal lobe and cerebrospinal fluid amyoid-β42 (Aβ42), total Tau and pTau181. 109 patients were recruited in a multicenter study (40 mild AD patients, 14 non-AD dementia patients, 29 mild cognitive impairment (MCI) AD-type patients, 26 MCI of non-AD type patients). NAA correlated with Aβ42 within the AD group. Since the NAA concentration is coupled to neuronal mitochondrial function, the correlation between NAA and Aβ42 may reflect the interaction between disrupted mitochondrial pathways and amyloid production.     

Gender differences in bipolar–II disorder

Gender differences in bipolar–II disorder (BP–II) are understudied. Study aim was to test if there were gender differences in the clinical and family history features of BP–II. Methods Consecutive 374 BP–II private practice outpatients were interviewed by a senior psychiatrist using the Structured Clinical Interview for DSM–IV, modified to improve the detection of BP–II (by Benazzi and Akiskal 2003, J Affect Disord 73:33–38), the Montgomery Asberg Depression Rating Scale (MADRS), the Hypomania Interview Guide, and the Family History Screen. Logistic regression was used to study associations and control for confounding. Alpha level was set at 0.05; P was two–tailed. Results Females represented 67.3% of the group. The female to male ratio was independent of age. Females were more common in younger onset BP–II. Females, versus males, had significantly lower age at onset, more axis I comorbidity, atypical depressions, intra–depression hypomanic symptoms (i. e., mixed depression), and family history of suicidal behavior. On the MADRS, females had more sadness, loss of energy, loss of interest, and suicidal ideas. The symptom structure of hypomanic episodes was similar between females and males. Limitations Single interviewer, outpatient sample, private practice study setting. Discussion Clinical differences were found between BP–II females and males. Differences were found only on the depressive pole of the disorder.However, the magnitude of the differences had not a strong clinical significance, suggesting that at present, on the basis of the variables and the population studied, there is little ground to support a female BP–II depression.