| 1. |
- Zetterberg, Henrik, 1973, et al.
(författare)
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Blood-cerebrospinal fluid barrier dysfunction in patients with bipolar disorder in relation to antipsychotic treatment
- 2014
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Ingår i: Psychiatry Research. - : Elsevier BV. - 0165-1781 .- 1872-7123. ; 217:3, s. 143-146
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Tidskriftsartikel (refereegranskat)abstract
- 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. (C) 2014 Elsevier Ireland 'Ltd. All rights reserved.
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| 2. |
- Abe, C., et al.
(författare)
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Genetic risk for bipolar disorder and schizophrenia predicts structure and function of the ventromedial prefrontal cortex
- 2021
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Ingår i: Journal of Psychiatry & Neuroscience. - : CMA Joule Inc.. - 1180-4882 .- 1488-2434. ; 46:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Bipolar disorder is highly heritable and polygenic. The polygenic risk for bipolar disorder overlaps with that of schizophrenia, and polygenic scores are normally distributed in the population. Bipolar disorder has been associated with structural brain abnormalities, but it is unknown how these are linked to genetic risk factors for psychotic disorders. Methods: We tested whether polygenic risk scores for bipolar disorder and schizophrenia predict structural brain alterations in 98 patients with bipolar disorder and 81 healthy controls. We derived brain cortical thickness, surface area and volume from structural MRI scans. In post-hoc analyses, we correlated polygenic risk with functional hub strength, derived from resting-state functional MRI and brain connectomics. Results: Higher polygenic risk scores for both bipolar disorder and schizophrenia were associated with a thinner ventromedial prefrontal cortex (vmPFC). We found these associations in the combined group, and separately in patients and drug-naive controls. Polygenic risk for bipolar disorder was correlated with the functional hub strength of the vmPFC within the default mode network. Limitations: Polygenic risk is a cumulative measure of genomic burden. Detailed genetic mechanisms underlying brain alterations and their cognitive consequences still need to be determined. Conclusion: Our multimodal neuroimaging study linked genomic burden and brain endophenotype by demonstrating an association between polygenic risk scores for bipolar disorder and schizophrenia and the structure and function of the vmPFC. Our findings suggest that genetic factors might confer risk for psychotic disorders by influencing the integrity of the vmPFC, a brain region involved in self-referential processes and emotional regulation. Our study may also provide an imaging-genetics vulnerability marker that can be used to help identify individuals at risk for developing bipolar disorder.
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| 3. |
- Brundin, L., et al.
(författare)
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An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation
- 2016
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an N-methyl-D-aspartate receptor agonist, are increased. The enzyme amino-beta-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Asberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (P<0.001) and blood (P=0.001 and P<0.01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.
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| 4. |
- Cremaschi, Laura, et al.
(författare)
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Prevalences of autoimmune diseases in schizophrenia, bipolar I and II disorder, and controls
- 2017
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Ingår i: Psychiatry Research. - : Elsevier BV. - 0165-1781 .- 1872-7123. ; 258, s. 9-14
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies on the relationship between autoimmune diseases, schizophrenia, and bipolar disorder are mainly based on hospital discharge registers with insufficient coverage of outpatient data. Furthermore, data is scant on the prevalence of autoimmune diseases in bipolar subgroups. Here we estimate the self-reported prevalences of autoimmune diseases in schizophrenia, bipolar disorder type I and II, and controls. Lifetime prevalence of autoimmune diseases was assessed through a structured interview in a sample of 9076 patients (schizophrenia N = 5278, bipolar disorder type I N = 1952, type II N = 1846) and 6485 controls. Comparative analyses were performed using logistic regressions. The prevalence of diabetes type 1 did not differ between groups. Hyperthyroidism, hypothyroidism regardless of lithium effects, rheumatoid arthritis, and polymyalgia rheumatica were most common in bipolar disorder. Systemic lupus erythematosus was less common in bipolar disorder than in the other groups. The rate of autoimmune diseases did not differ significantly between bipolar subgroups. We conclude that prevalences of autoimmune diseases show clear differences between schizophrenia and bipolar disorder, but not between the bipolar subgroups. © 2017 Elsevier B.V.
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| 5. |
- Gracias, J., et al.
(författare)
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Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia risk has been associated with the complement component 4 (C4) genes. Here the authors show that C4A is elevated in individuals with schizophrenia. Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ: median 0.41 fmol/ul [CI = 0.34-0.45], FEP-non-SCZ: median 0.29 fmol/ul [CI = 0.22-0.35], healthy controls: median 0.28 [CI = 0.24-0.33]). We show that the CSF elevation of C4A in FEP-SCZ exceeds what can be expected from genetic risk variance in the C4 locus, and in patient-derived cellular models we identify a mechanism dependent on the disease-associated cytokines interleukin (IL)-1beta and IL-6 to selectively increase neuronal C4A mRNA expression. In patient-derived CSF, we confirm that IL-1beta correlates with C4A controlled for genetically predicted C4A RNA expression (r = 0.39; CI: 0.01-0.68). These results suggest a role of C4A in early schizophrenia pathophysiology.
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| 6. |
- Isgren, Anniella, et al.
(författare)
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Cerebrospinal fluid proteomic study of two bipolar disorder cohorts
- 2022
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 27:11, s. 4568-4574
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Tidskriftsartikel (refereegranskat)abstract
- The pathophysiology of bipolar disorder remains to be elucidated and there are no diagnostic or prognostic biomarkers for the condition. In this explorative proteomic study, we analyzed 201 proteins in cerebrospinal fluid (CSF) from mood stable bipolar disorder patients and control subjects sampled from two independent cohorts, amounting to a total of 204 patients and 144 controls. We used three Olink Multiplex panels, whereof one specifically targets immune biomarkers, to assess a broad set of CSF protein concentrations. After quality control and removal of proteins with a low detection rate, 105 proteins remained for analyses in relation to case-control status and clinical variables. Only case-control differences that replicated across cohorts were considered. Results adjusted for potential confounders showed that CSF concentrations of growth hormone were lower in bipolar disorder compared with controls in both cohorts. The effect size was larger when the analysis was restricted to bipolar disorder type 1 and controls. We found no indications of immune activation or other aberrations. Growth hormone exerts many effects in the central nervous system and our findings suggest that growth hormone might be implicated in the pathophysiology of bipolar disorder.
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| 7. |
- Lavebratt, C., et al.
(författare)
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The KMO allele encoding Arg(452) is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and reduced KMO expression
- 2014
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 19:3, s. 334-341
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Tidskriftsartikel (refereegranskat)abstract
- The kynurenine pathway metabolite kynurenic acid (KYNA), modulating glutamatergic and cholinergic neurotransmission, is increased in cerebrospinal fluid (CSF) of patients with schizophrenia or bipolar disorder type 1 with psychotic features. KYNA production is critically dependent on kynurenine 3-monooxygenase (KMO). KMO mRNA levels and activity in prefrontal cortex (PFC) are reduced in schizophrenia. We hypothesized that KMO expression in PFC would be reduced in bipolar disorder with psychotic features and that a functional genetic variant of KMO would associate with this disease, CSF KYNA level and KMO expression. KMO mRNA levels were reduced in PFC of bipolar disorder patients with lifetime psychotic features (P = 0.005, n = 19) or schizophrenia (P = 0.02, n = 36) compared with nonpsychotic patients and controls. KMO genetic association to psychotic features in bipolar disorder type 1 was studied in 493 patients and 1044 controls from Sweden. The KMO Arg(452) allele was associated with psychotic features during manic episodes (P = 0.003). KMO Arg(452) was studied for association to CSF KYNA levels in an independent sample of 55 Swedish patients, and to KMO expression in 717 lymphoblastoid cell lines and 138 hippocampal biopsies. KMO Arg(452) associated with increased levels of CSF KYNA (P = 0.03) and reduced lymphoblastoid and hippocampal KMO expression (P <= 0.05). Thus, findings from five independent cohorts suggest that genetic variation in KMO influences the risk for psychotic features in mania of bipolar disorder patients. This provides a possible mechanism for the previous findings of elevated CSF KYNA levels in those bipolar patients with lifetime psychotic features and positive association between KYNA levels and number of manic episodes.
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| 8. |
- Liberg, B., et al.
(författare)
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Vertex-based morphometry in euthymic bipolar disorder implicates striatal regions involved in psychomotor function
- 2014
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Ingår i: Psychiatry Research-Neuroimaging. - : Elsevier BV. - 0925-4927 .- 1872-7123. ; 221:3, s. 173-178
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Tidskriftsartikel (refereegranskat)abstract
- We hypothesized that psychomotor disturbances in patients with bipolar disorder are associated with morphometric changes in functionally specific regions of the basal ganglia and thalamus. We used structural magnetic resonance imaging and vertex-based morphometry to investigate whether psychomotor performance is associated with changes in volume and shape in euthymic subjects with bipolar disorder (n=27) compared with matched healthy controls (n=27). We saw no significant differences between age- and sex-matched groups in motor performance. We found a statistically significant group difference in the shape of the right putamen in the absence of psychomotor disturbances. There was an association between shape and motor performance in controls that was lacking in patients. We conclude that euthymic subjects with bipolar disorder without psychomotor disturbances show shape changes in regions of the right putamen that contribute to executive functions and motor function. It may be that other brain regions sustain the psychomotor functions that produce nearly identical motor performance in both groups. (C) 2014 Elsevier Ireland Ltd. All rights reserved
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| 9. |
- Pålsson, Erik, 1975, et al.
(författare)
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Markers of glutamate signaling in cerebrospinal fluid and serum from patients with bipolar disorder and healthy controls
- 2015
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Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X. ; 25:1, s. 133-140
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Tidskriftsartikel (refereegranskat)abstract
- Glutamate is the major excitatory neurotransmitter in the brain. Aberrations in glutamate signaling have been linked to the pathophysiology of mood disorders. Increased plasma levels of glutamate as well as higher glutamine+glutamate levels in the brain have been demonstrated in patients with bipolar disorder as compared to healthy controls. In this study, we explored the glutamate hypothesis of bipolar disorder by examining peripheral and central levels of amino acids related to glutamate signaling. A total of 215 patients with bipolar disorder and 112 healthy controls from the Swedish St. Goran bipolar project were included in this study. Glutamate, glutamine, glycine, L-serine and D-serine levels were determined in serum and in cerebrospinal fluid using high performance liquid chromatography with fluorescence detection. Serum levels of glutamine, glycine and D-serine were significantly higher whereas L-serine levels were lower in patients with bipolar disorder as compared to controls. No differences between the patient and control group in amino acid levels were observed in cerebrospinal fluid. The observed differences in serum amino acid levels may be interpreted as a systemic aberration in amino acid metabolism that affects several amino acids related to glutamate signaling. (C) 2014 Elsevier B.V. and ECNP. All rights reserved.
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| 10. |
- Rolstad, Sindre, 1976, et al.
(författare)
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Cognitive Performance and Cerebrospinal Fluid Biomarkers of Neurodegeneration: A Study of Patients with Bipolar Disorder and Healthy Controls
- 2015
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the present study was to investigate if cerebrospinal fluid (CSF) biomarkers of neurodegeneration are associated with cognition in bipolar disorder and healthy controls, respectively. CSF concentrations of total and phosphorylated tau, amyloid beta (A beta) 1-42, ratios of A beta 42/40 and A beta 42/38, soluble amyloid precursor protein alpha and beta, and neurofilament light chain protein were analyzed in relation to neuropsychological performance in 82 euthymic bipolar disorder patients and 71 healthy controls. Linear regression models were applied to account for performance in five cognitive domains using the CSF biomarkers. In patients, the CSF biomarkers explained a significant proportion of the variance (15-36%, p =. 002 -<. 0005) in all cognitive domains independently of age, medication, disease status, and bipolar subtype I or II. However, the CSF biomarkers specifically mirroring Alzheimer-type brain changes, i.e., P-tau and A beta 1-42, did not contribute significantly. In healthy controls, CSF biomarkers did not explain the variance in cognitive performance. Selected CSF biomarkers of neurodegenerative processes accounted for cognitive performance in persons with bipolar disorder, but not for healthy controls. Specifically, the ratios of A beta 42/40 and A beta 42/38 were consistently associated with altered cognitive performance.
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