| 1. |
- Beecham, Ashley H, et al.
(författare)
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Tidskriftsartikel (refereegranskat)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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| 2. |
- Bridel, Claire, et al.
(författare)
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Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology : A Systematic Review and Meta-analysis
- 2019
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:9, s. 1035-1048
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Forskningsöversikt (refereegranskat)abstract
- Importance Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.Objectives To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.Data Sources PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.Study Selection Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.Data Extraction and Synthesis Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.Main Outcome and Measure The cNfL levels adjusted for age and sex across diagnoses.Results Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.Conclusions and Relevance These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
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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. |
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| 5. |
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| 6. |
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| 7. |
- Ventorp, Filip, et al.
(författare)
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The CD44 ligand hyaluronic acid is elevated in the cerebrospinal fluid of suicide attempters and is associated with increased blood-brain barrier permeability.
- 2016
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Ingår i: Journal of Affective Disorders. - : Elsevier BV. - 1573-2517 .- 0165-0327. ; 193, s. 349-354
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Tidskriftsartikel (refereegranskat)abstract
- The glycosaminoglycan hyaluronic acid (HA) is an important component of the extracellular matrix (ECM) in the brain. CD44 is a cell adhesion molecule that binds to HA in the ECM and is present on astrocytes, microglia and certain neurons. Cell adhesion molecules have been reported to be involved in anxiety and mood disorders. CD44 levels are decreased in the cerebrospinal fluid (CSF) of depressed individuals, and the CD44 gene has been identified in brain GWAS studies as a possible risk gene for suicidal behavior.
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| 8. |
- Bay-Richter, Cecilie, et al.
(författare)
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A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality
- 2015
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Ingår i: Brain, behavior, and immunity. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0889-1591 .- 1090-2139. ; 43, s. 110-117
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with depression and suicidality suffer from low-grade neuroinflammation. Proinflammatory cytokines activate indoleamine 2,3-dioxygenase, an initial enzyme of the kynurenine pathway. This pathway produces neuroactive metabolites, including quinolinic- and kynurenic acid, binding to the glutamate N-methyl-D-aspartate-receptor, which is hypothesized to be part of the neural mechanisms underlying symptoms of depression. We therefore hypothesized that symptoms of depression and suicidality would fluctuate over time in patients prone to suicidal behavior, depending on the degree of inflammation and kynurenine metabolite levels in the cerebrospinal fluid (CSF). Methods: We measured cytokines and kynurenine metabolites in CSF, collected from suicide attempters at repeated occasions over 2 years (total patient samples n = 143, individuals n = 30) and healthy controls (n = 36). The association between the markers and psychiatric symptoms was assessed using the Montgomery Asberg Depression Rating Scale and the Suicide Assessment Scale. Results: Quinolinic acid was increased and kynurenic acid decreased over time in suicidal patients versus healthy controls. Furthermore, we found a significant association between low kynurenic acid and severe depressive symptoms, as well as between high interleukin-6 levels and more severe suicidal symptoms. Conclusions: We demonstrate a long-term dysregulation of the kynurenine pathway in the central nervous system of suicide attempters. An increased load of inflammatory cytokines was coupled to more severe symptoms. We therefore suggest that patients with a dysregulated kynurenine pathway are vulnerable to develop depressive symptoms upon inflammatory conditions, as a result the excess production of the NMDA-receptor agonist quinolinic acid. This study provides a neurobiological framework supporting the use of NMDA-receptor antagonists in the treatment of suicidality and depression. (C) 2014 Elsevier Inc. All rights reserved.
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| 9. |
- Boström, Gustaf, et al.
(författare)
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Different Inflammatory Signatures in Alzheimer's Disease and Frontotemporal Dementia Cerebrospinal Fluid
- 2021
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 81:2, s. 629-640
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases.Objective: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD.Methods: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing.Results: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95% confidence interval [CI] 1.14-1.53, q = 0.018; MCI/AD: FC = 1.53, 95% CI 1.20-1.94, q = 0.045; and FTD: FC = 1.42, 95% CI 1.10-1.83, q = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q < 0.05).Conclusion: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders.
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| 10. |
- Bronge, Mattias, et al.
(författare)
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Identification of four novel T cell autoantigens and personal autoreactive profiles in multiple sclerosis
- 2022
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 8:17
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), in which pathological T cells, likely autoimmune, play a key role. Despite its central importance, the autoantigen repertoire remains largely uncharacterized. Using a novel in vitro antigen delivery method combined with the Human Protein Atlas library, we screened for T cell autoreactivity against 63 CNS-expressed proteins. We identified four previously unreported autoantigens in MS: fatty acid-binding protein 7, prokineticin-2, reticulon-3, and synaptosomal-associated protein 91, which were verified to induce interferon-gamma responses in MS in two cohorts. Autoreactive profiles were heterogeneous, and reactivity to several autoantigens was MS-selective. Autoreactive T cells were predominantly CD4(+) and human leukocyte antigen-DR restricted. Mouse immunization induced antigen-specific responses and CNS leukocyte infiltration. This represents one of the largest systematic efforts to date in the search for MS autoantigens, demonstrates the heterogeneity of autoreactive profiles, and highlights promising targets for future diagnostic tools and immunomodulatory therapies in MS.
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| 11. |
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| 12. |
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| 13. |
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| 14. |
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| 15. |
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| 16. |
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| 17. |
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| 18. |
- Brundin, Martin, et al.
(författare)
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Circulating microRNA-29-5p can add to the discrimination between dilated cardiomyopathy and ischaemic heart disease
- 2021
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Ingår i: ESC Heart Failure. - : John Wiley & Sons. - 2055-5822. ; 8:5, s. 3865-3874
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Heart failure describes a large and heterogeneous spectrum of underlying cardiac diseases. MicroRNAs (miRs) are small non-coding RNAs that in recent years have been shown to play an important role in the pathogenesis of heart failure. Cardiac magnetic resonance imaging is a powerful imaging modality for the evaluation of cardiac characteristics in heart failure. In this study, we sought to compare heart failure patients with a diagnosis of either idiopathic dilated cardiomyopathy (DCM) or ischaemic heart disease (IHD), in the context of serum levels of certain miRs and also magnetic resonance imaging parameters of cardiac structure and function.Methods and results: A total of 135 subjects were studied: 53 patients with DCM (age: 59 +/- 12 years, mean +/- SD), 34 patients with IHD (66 +/- 9 years), and 48 controls (64 +/- 5 years). The participants underwent baseline medical examination, blood sampling, and a cardiac magnetic resonance imaging examination at 3 Tesla (Philips Ingenia). The serum levels of seven different miRs were analysed and assessed: 16-5p, 21-5p, 29-5p, 133a-3p, 191-5p, 320a, and 423-5p, all of which have been demonstrated to play potential roles in the pathogenesis of heart failure. The patients in the DCM and IHD groups had left ventricles that had larger end-diastolic volume (P < 0.001), larger mass ( P < 0.001), and lower ejection fraction (P < 0.001) compared with controls. Serum levels of miR-29-5p were increased in DCM compared with IHD (P < 0.005) and serum levels of miR-320a were elevated in DCM compared with healthy controls ( P < 0.05). There was no significant association between miR levels and magnetic resonance imaging parameters of left ventricular structure and function.Conclusions: Circulating miR-320a can add to the discrimination between patients with DCM and healthy controls and circulating miR-29-5p can add to the discrimination between DCM and IHD.
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| 19. |
- de la Vega, Maria Pagnon, et al.
(författare)
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The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid beta fibril formation
- 2021
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 13:606
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Tidskriftsartikel (refereegranskat)abstract
- Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer's disease (AD) by increasing generation or altering conformation of amyloid beta (A beta). Here, we describe the Uppsala APP mutation (Delta 690-695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) A beta 42 and only slightly pathological amyloid-positron emission tomography signals. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing beta-secretase cleavage and affecting alpha-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated A beta, A beta Upp1-42(Delta 19-24), accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.
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| 20. |
- Djerf, Pauline, et al.
(författare)
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Validation of the paracetamol absorption test for measuring gastric tube emptying in esophagectomized patients versus gold standard scintigraphy
- 2015
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Ingår i: Scandinavian Journal of Gastroenterology. - : TAYLOR and FRANCIS LTD. - 0036-5521 .- 1502-7708. ; 50:11, s. 1339-1347
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Scintigraphy is the gold standard for objective measurement of delayed gastric tube emptying after esophagectomy. The aim of this pilot study is to validate, by reference to scintigraphy, the paracetamol absorption test for measuring gastric tube emptying in esophagectomized patients. Material and methods. The paracetamol absorption test and scintigraphy were performed simultaneously in 13 patients who had undergone an esophagectomy with gastric tube reconstruction. Emptying was calculated for both methods and compared. Post-esophagectomy symptoms and quality of life (QoL) were assessed by European Organization on Research and Treatment of Cancer questionnaires. Results. Mean time to 50% emptying was 17 min measured with the paracetamol absorption test and 23 min with scintigraphy. For time to 25% emptying, Bland-Altman calculation gave a bias of 1.6 min and 95% limits of agreement (LoA) of -6.3 to 9.5 min. For time to 50% emptying, there was one outlier resulting in a bias of -6.33 min and 95% LoA of -36.4 to 23.8 min. For time to 75% emptying, bias was -11.6 min and 95% LoA of -38.5 to 15.4 min. Post-esophagectomy symptoms were similar to those reported previously, and QoL was comparable to the general Swedish population. Conclusions. There was reasonably close correlation between the paracetamol absorption test and scintigraphy for time to 25% and 50% emptying, except for one outlier. For time to 75% emptying the methods were in less accordance. The results indicate that the paracetamol absorption test may be a useful screening tool for identifying delayed gastric tube emptying in this patient group.
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| 21. |
- Emami Khoonsari, Payam, et al.
(författare)
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Chitinase-3-like protein 1 (CH3L1) and Neurosecretory protein VGF (VGF) as two novel CSF biomarker candidates for improved diagnostics in Alzheimer’s disease
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by amyloid-β (Aβ) plaque deposition and accumulation of intracellular neurofibrillary tangles. This pathology is mirrored in the cerebrospinal fluid (CSF), where decreased Aβ42 together with increased total (t-tau) and phospho-tau (p-tau) today is used as a diagnostic marker. Although these biomarkers have a fairly good sensitivity and specificity, additional biomarkers are needed to further improve the accuracy for early disease detection and to monitor disease development. In this study, we used mass spectrometry-based shotgun proteomics to investigate the CSF proteome of patients with AD and mild cognitive impairment (MCI) as well as of non-demented controls. By combining the diagnostic markers (Aβ42, total t-tau, and p-tau) with a selection of proteomics biomarkers, the accuracy of predicting MCI to AD conversion increased from 83% to 92% with a specificity of 1.0 and sensitivity of 0.86. Among these markers, the levels of protein chitinase-3-like protein 1 (CH3L1) were significantly higher in AD and MCI converters compared to controls. In addition to Aβ42, t-tau, and p-tau the protein CH3L1 contributed mostly to the prediction accuracy. We also found statistically significant lower CSF levels of the neurosecretory protein VGF (VGF) in AD compared to controls. Taken together, our findings suggest that incorporating new CSF biomarkers can further enhance early diagnosis of AD.
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| 22. |
- Emami Khoonsari, Payam, et al.
(författare)
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Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers
- 2019
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Ingår i: Journal of Alzheimer's Disease. - : IOS PRESS. - 1387-2877 .- 1875-8908. ; 67:2, s. 639-651
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: A beta(42), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD. Objective: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects. Methods: We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4-9 years and 21 of these converted to AD, whereas 53 remained stable. Results: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCl/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively. Conclusions: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects.
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| 23. |
- Erhardt, Sophie, et al.
(författare)
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Connecting Inflammation with Glutamate Agonism in Suicidality
- 2013
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Ingår i: Neuropsychopharmacology. - : Nature Publishing Group: Open Access Hybrid Model Option A. - 0893-133X .- 1740-634X. ; 38:5, s. 743-752
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Tidskriftsartikel (refereegranskat)abstract
- The NMDA-receptor antagonist ketamine has proven efficient in reducing symptoms of suicidality, although the mechanisms explaining this effect have not been detailed in psychiatric patients. Recent evidence points towards a low-grade inflammation in brains of suicide victims. Inflammation leads to production of quinolinic acid (QUIN) and kynurenic acid (KYNA), an agonist and antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, respectively. We here measured QUIN and KYNA in the cerebrospinal fluid (CSF) of 64 medication-free suicide attempters and 36 controls, using gas chromatography mass spectrometry and high-performance liquid chromatography. We assessed the patients clinically using the Suicide Intent Scale and the Montgomery Asberg Depression Rating Scale (MADRS). We found that QUIN, but not KYNA, was significantly elevated in the CSF of suicide attempters (Pandlt;0.001). As predicted, the increase in QUIN was associated with higher levels of CSF interleukin-6. Moreover, QUIN levels correlated with the total scores on Suicide Intent Scale. There was a significant decrease of QUIN in patients who came for follow-up lumbar punctures within 6 months after the suicide attempt. In summary, we here present clinical evidence of increased QUIN in the CSF of suicide attempters. An increased QUIN/KYNA quotient speaks in favor of an overall NMDA-receptor stimulation. The correlation between QUIN and the Suicide Intent Scale indicates that changes in glutamatergic neurotransmission could be specifically linked to suicidality. Our findings have important implications for the detection and specific treatment of suicidal patients, and might explain the observed remedial effects of ketamine. Neuropsychopharmacology (2013) 38, 743-752; doi:10.1038/npp.2012.248; published online 9 January 2013
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| 24. |
- Giedraitis, Vilmantas, et al.
(författare)
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CALHM1 P86L polymorphism does not alter amyloid-beta or tau in cerebrospinal fluid
- 2010
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 469:2, s. 265-267
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Tidskriftsartikel (refereegranskat)abstract
- Recently, the P86L alteration in CALHM1 (calcium homeostasis modulator-1) was reported to be associated with Alzheimer's disease (AD). Moreover, the risk allele increased amyloid-beta (A beta) levels in conditioned media from cultured cells. Therefore, we hypothesized that CALHM1 P86L may modulate A beta or tau levels in cerebrospinal fluid (CSF). Nearly 200 individuals with AD or other cognitive disorders were included for CSF analysis and CALHM1 genotyping. No significant differences in CSF levels of A beta 42, tau or phospho-tau were found across the various CALHM1 genotypes. In conclusion, we found no evidence that CALHM1 P86L is associated with altered CSF levels of the investigated AD biomarkers.
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| 25. |
- Grabowski, Martin, et al.
(författare)
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Fetal neocortical grafts implanted in adult hypertensive rats with cortical infarcts following a middle cerebral artery occlusion: ingrowth of afferent fibers from the host brain
- 1992
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Ingår i: Experimental Neurology. - 0014-4886. ; 116:2, s. 105-121
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Tidskriftsartikel (refereegranskat)abstract
- This study is focused on the survival of fetal neocortical grafts placed in the infarcted adult host cortex of the spontaneously hypertensive rat and describes the ability of host axonal regeneration into the graft after a focal ischaemic lesion. Five to seven days following ligation of the right middle cerebral artery, dissociated neocortical primordium from fetuses of gestational age 12-18 days was implanted into the infarcted cortical area. Surviving transplants were seen in all rats, although grafts derived from gestational age 12-14 days displayed an irregular morphology rich in sinusoid-like cavities and containing fewer cells of apparently mature neuronal morphology. Grafts from older donors contained perikarya of neuronal appearance; however, they lacked normal cortical lamination. Ten days postgrafting, fibers stained by acetylcholinesterase histochemistry, dopamine-beta-hydroxylase, and 5-hydroxytryptamine immunohistochemistry were found in the grafts, and by 10-23 weeks after transplantation the fiber density had increased substantially. When the retrograde tracer Fluoro-Gold was injected into the grafted tissue, labeled cells were found in several subcortical nuclei of the host, including the nucleus basalis of Meynert, ventral pallidum, thalamus, dorsal raphe, locus coeruleus, as well as the ipsilateral and contralateral neocortex. This study shows that grafts of dissociated neocortical tissue exhibit good survival and growth potential when implanted into infarcted neocortex and that several nerve fiber systems of the adult host have a regenerative capacity sufficient to innervate the grafted tissue.
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| 26. |
- Grabowski, Martin, et al.
(författare)
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Fetal neocortical grafts placed in brain infarcts do not improve paw-reaching deficits in adult spontaneously hypertensive rats
- 1996
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Ingår i: Acta Neurochirurgica. Supplementum. - 0065-1419. ; 66, s. 68-72
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to study if neural grafts placed brain infarcts could improve functional recovery. The middle cerebral artery was occluded (MCAO) in 19 spontaneously hypertensive rats. Nine rats were sham operated. Twelve to 16 days after the ischemic insult, 9 of the MCAO rats received transplants of dissociated fetal neocortical tissue (MCAO-T) and 1, 3 and 6 months after transplantation surgery, the rats were behaviorally evaluated by a test for forelimb function. Infarct and transplant sizes were measured morphometrically. The remaining volume of the infarcted hemisphere was 66 +/- 7% (mean +/- SD) in the MCAO group and 71 +/- 9% in the MCAO-T group of the non-operated hemisphere. All grafted rats had surviving transplants. Contralateral to the lesion, paw-reaching was highly impaired in both infarcted groups compared with sham-operated controls with no significant difference between MCAO and MCAO-T. The lesion size correlated significantly with contralateral paw-reach performance at all test periods. We conclude that neocortical grafts did not alleviate the impaired forepaw function.
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| 27. |
- Grabowski, Martin, et al.
(författare)
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Functional integration of cortical grafts placed in brain infarcts of rats
- 1993
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Ingår i: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 34:3, s. 362-368
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Tidskriftsartikel (refereegranskat)abstract
- Five to 6 days after a right middle cerebral artery occlusion, a cell suspension of fetal neocortex was grafted into the infarcted area of adult spontaneously hypertensive rats. Three to 17 months later, functional integration of the grafts into the afferent somatosensory pathway was tested using the 2-[14C]deoxyglucose method for estimation of glucose utilization. Grafted rats (n = 8) and control rats (n = 5) with no arterial occlusion were stimulated in the left vibrissal region resulting in an increased glucose utilization in the left trigeminal sensory nucleus and the right ventroposterior nucleus of the thalamus, whereas the same regions in a group (n = 5) of nonstimulated grafted rats were not activated. Glucose uptake in the right somatosensory cortex of control rats was 96 +/- 5 (mean +/- SEM) mumol/100 gm/min. Neocortical grafts consumed less glucose than cortex in control rats but the vibrissae-stimulated group displayed a 110% higher value than the nonstimulated grafted group (32 +/- 5 vs 15 +/- 2, p < 0.05). We conclude that graft glucose metabolism is increased following stimulation of the host somatosensory pathway, which demonstrates that transplanted neurons can be functionally integrated with neural circuitries of the host after an ischemic insult.
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| 28. |
- Grabowski, Martin, et al.
(författare)
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Neocortical grafts placed in the infarcted brain of adult rats: few or no efferent fibers grow from transplant to host
- 1995
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 134:2, s. 273-276
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Tidskriftsartikel (refereegranskat)abstract
- The present study examines the capacity of fetal neocortical grafts placed in a brain infarct to exchange axonal projections with the host brain. Five to 7 days after a middle cerebral artery occlusion in adult spontaneously hypertensive rats, dissociated neocortical primordium from fetuses of gestational age 15-16 days was implanted into the infarcted area. Four to 11 months later, the neural tracers Phaseolus vulgaris-leucoagglutinin and Fluoro-Gold were injected in the grafts and host neocortex. An extensive axonal network was present in the transplants but only one of eight rats with appropriate placed injections displayed efferent connections from transplant to host. The sparse axonal outgrowth indicates major limitations for fetal rat cortical grafts to form connections with host neural circuitries after an ischemic insult.
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| 29. |
- Grabowski, Martin, et al.
(författare)
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Paw-reaching, sensorimotor, and rotational behavior after brain infarction in rats
- 1993
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 24:6, s. 889-895
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Functional tests that are stable and consistent over time are an advantage for long-term evaluation of treatment in experimental stroke research. Because little information on this subject is available in rodents with focal cerebral ischemia, we investigated the outcome of three behavioral tests for a period of 3 months after the insult. METHODS: Spontaneously hypertensive rats were sham-operated (n = 27) or underwent an occlusion (n = 36) of the right middle cerebral artery. Before surgery all rats were tested for amphetamine-induced rotational behavior, and half of the rats were trained in a paw-reaching task. One, 2, and 3 months after surgery the tests were repeated, together with a test for sensorimotor function. Infarct size was measured morphometrically. RESULTS: In the lesion group, total hemisphere area was reduced by 22%, caudate putamen by 47%, and the thalamus by 24%. Contralateral to the lesion, paw-reaching was highly impaired, regardless of whether or not the rats had been pretrained, and lesion size correlated significantly to paw-reach performance. Ipsilateral rotation increased and sensorimotor function recovered with time in infarcted rats. CONCLUSIONS: In contrast to amphetamine-induced rotation and sensorimotor behavior, the paw-reaching test provides a stable behavioral parameter after a middle cerebral artery occlusion. Moreover, the lesion-induced deficit in paw-reaching is highly correlated to the extent of the infarct, suggesting that this test is useful in evaluating treatment effects for a longer period of time.
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| 30. |
- Grabowski, Martin, et al.
(författare)
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Survival of fetal neocortical grafts implanted in brain infarcts of adult rats: the influence of postlesion time and age of donor tissue
- 1994
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 127:1, s. 126-136
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Tidskriftsartikel (refereegranskat)abstract
- We have previously found that fetal cortex taken from 16- to 18-day-old donors survives grafting to the infarcted cortex 5-7 days after middle cerebral artery occlusion. The present study was undertaken to examine the effect on graft survival of varying the age of the fetal donor tissue and the time between vessel occlusion and graft implantation. First, a cell suspension of neocortical tissue was grafted from fetuses aged 15, 17, or 20 gestational days to the infarcted cortex of hypertensive rats which had undergone arterial occlusion 5-7 days earlier. There were no significant differences in the mean size or general morphology assessed in Nissl- and acetylcholinesterase-stained sections between the groups. Second, neocortical tissue was grafted from fetuses aged 15 gestational days to the infarcted cortex at different times following arterial occlusion. When surgery was delayed until 5-7 days, 3 weeks, or 8 weeks postocclusion, graft survival was significantly better than when implanted 1 day postocclusion. Implantation after 3 weeks yielded grafts that also were significantly larger than those in rats grafted 5-7 days after cortical infarction. The results indicate that there is no crucial upper donor age limit for dissociated fetal neocortical grafts in terms of graft survival and volume. Furthermore, a delay between lesion and transplantation is desirable in this stroke model. The host brain environment seems to be most hospitable around 3 weeks after arterial occlusion.
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| 31. |
- Grabowski, Martin, et al.
(författare)
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Vascularization of fetal neocortical grafts implanted in brain infarcts in spontaneously hypertensive rats
- 1992
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Ingår i: Neuroscience. - 1873-7544. ; 51:3, s. 673-682
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Tidskriftsartikel (refereegranskat)abstract
- The vascularization of neural grafts in ischemic brain was studied in spontaneously hypertensive rats grafted with a suspension of fetal neocortical tissue into the infarcted area five to six days after ligation of the middle cerebral artery. The brain vasculature was examined by scanning electron microscopy of corrosion vascular casts and the cortical microvasculature was stereologically quantified in light microscopy three months after the occlusion. Patent anastomoses were present between the middle cerebral artery distal to occlusion and the proximal part, as well as to the anterior and posterior cerebral arteries, in both grafted and non-grafted rats. A vascular plexus covering the infarct cavities and the grafts contained leptomeningeal vessels intermingled with a thin capillary network which is not normally found on the brain surface. The graft vessels were derived from this vascular plexus. The regular pattern of arterioles and venules penetrating from the cortical surface in normal neocortex was absent in the grafts but the capillary morphology was similar in both types of tissue. The grafts had a lower capillary density than normal tissue and lacked the laminar distribution of capillaries characteristic of normal neocortex. The results demonstrate the plasticity of the vascular system where remodeling of the vascular tree after an ischemic insult provides suitable conditions for the vascularization of neocortical grafts.
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| 32. |
- Hansen, Christian, et al.
(författare)
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A novel α-synuclein-GFP mouse model displays progressive motor impairment, olfactory dysfunction and accumulation of α-synuclein-GFP.
- 2013
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 56C:April,30, s. 145-155
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Tidskriftsartikel (refereegranskat)abstract
- Compelling evidence suggests that accumulation and aggregation of alpha-synuclein (α-syn) contribute to the pathogenesis of Parkinson's disease (PD). Here, we describe a novel Bacterial Artificial Chromosome (BAC) transgenic model, in which we have expressed wild-type human α-syn fused to green fluorescent protein (GFP), under control of the mouse α-syn promoter. We observed a widespread and high expression of α-syn-GFP in multiple brain regions, including the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and the ventral tegmental area, the olfactory bulb as well as in neocortical neurons. With increasing age, transgenic mice exhibited reductions in amphetamine-induced locomotor activity in the open field, impaired rotarod performance and a reduced striatal dopamine release, as measured by amperometry. In addition, they progressively developed deficits in an odor discrimination test. Western blot analysis revealed that α-syn-GFP and phospho-α-syn levels increased in multiple brain regions, as the mice grew older. Further, we observed, by immunohistochemical staining for phospho-α-syn and in vivo by two-photon microscopy, the formation of α-syn aggregates as the mice aged. The latter illustrates that the model can be used to track α-syn aggregation in vivo. In summary, this novel BAC α-syn-GFP model mimics a unique set of aspects of PD progression combined with the possibility of tracking α-syn aggregation in neocortex of living mice. Therefore, this α-syn-GFP-mouse model can provide a powerful tool that will facilitate the study of α-syn biology and its involvement in PD pathogenesis.
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| 33. |
- Henningsson, Markus, et al.
(författare)
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Quantification of epicardial fat using 3D cine Dixon MRI
- 2020
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Ingår i: BMC Medical Imaging. - : BMC. - 1471-2342. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background There is an increased interest in quantifying and characterizing epicardial fat which has been linked to various cardiovascular diseases such as coronary artery disease and atrial fibrillation. Recently, three-dimensional single-phase Dixon techniques have been used to depict the heart and to quantify the surrounding fat. The purpose of this study was to investigate the merits of a new high-resolution cine 3D Dixon technique for quantification of epicardial adipose tissue and compare it to single-phase 3D Dixon in patients with cardiovascular disease. Methods Fifteen patients referred for clinical CMR examination of known or suspected heart disease were scanned on a 1.5 T scanner using single-phase Dixon and cine Dixon. Epicardial fat was segmented by three readers and intra- and inter-observer variability was calculated per slice. Cine Dixon segmentation was performed in the same cardiac phase as single-phase Dixon. Subjective image quality assessment of water and fat images were performed by three readers using a 4-point Likert scale (1 = severe; 2 = significant; 3 = mild; 4 = no blurring of cardiac structures). Results Intra-observer variability was excellent for cine Dixon images (ICC = 0.96), and higher than single-phase Dixon (ICC = 0.92). Inter-observer variability was good for cine Dixon (ICC = 0.76) and moderate for single-phase Dixon (ICC = 0.63). The intra-observer measurement error (mean +/- standard deviation) per slice for cine was - 0.02 +/- 0.51 ml (- 0.08 +/- 0.4%), and for single-phase 0.39 +/- 0.72 ml (0.18 +/- 0.41%). Inter-observer measurement error for cine was 0.46 +/- 0.98 ml (0.11 +/- 0.46%) and for single-phase 0.42 +/- 1.53 ml (0.17 +/- 0.47%). Visual scoring of the water image yielded median of 2 (interquartile range = [Q3-Q1] 2-2) for cine and median of 3 (interquartile range = 3-2) for single-phase (P < 0.05) while no significant difference was found for the fat images, both techniques yielding a median of 3 and interquartile range of 3-2. Conclusion Cine Dixon can be used to quantify epicardial fat with lower intra- and inter-observer variability compared to standard single-phase Dixon. The time-resolved information provided by the cine acquisition appears to support the delineation of the epicardial adipose tissue depot.
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| 34. |
- Janelidze, Shorena, et al.
(författare)
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Altered chemokine levels in the cerebrospinal fluid and plasma of suicide attempters
- 2013
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Ingår i: Psychoneuroendocrinology. - : Elsevier. - 0306-4530 .- 1873-3360. ; 38:6, s. 853-862
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Tidskriftsartikel (refereegranskat)abstract
- Chemokines constitute a class of small inflammatory proteins that control the chemotaxis of leukocytes. They are also present in the central nervous system (CNS) and contribute to diverse physiological functions, such as the regulation of cell migration, axonal growth and neuronal survival. It is to date not known whether chemokines in the CNS are affected in psychiatric disorders. In this study, chemokine levels were measured in the cerebrospinal fluid (CSF) of 137 psychiatric patients in conjunction to a suicide attempt, and 43 healthy controls. A subgroup of patients (n = 42) was followed up with blood samples 12 years after the initial CSF collection, when they did not show suicidal behavior. The follow-up chemokine levels were compared to those of psychiatric patients (n = 17) who had never attempted suicide. Ultrasensitive chemokine multiplex immunoassay was used to quantify eotaxin-1 (CCL11), interferon gamma-induced protein-10 (IP-10, CXCL10), macrophage inflammatory protein-1 beta (MIP-1 beta, CCL4), monocyte chemotactic protein-1 (MCP-1, CCL2), MCP-4 (CCL13) and thymus and activation regulated chemokine (TARC, CCL17). Patients were diagnosed using DSM-III-R/DSM-IV, and assessed using the Comprehensive Psychopathological Rating Scale (CPRS), including subscales, and the Suicidal Intent Scale (SIS). CSF eotaxin-1, MIP-1 beta, MCP-1, MCP-4 and TARC were significantly lower in suicide attempters than in healthy controls. Low chemokine levels were specifically associated with psychotic symptoms and pain. In the samples collected at follow-up, TARC was significantly lower in suicide attempters compared to psychiatric patients who had never attempted suicide. We also found a positive correlation between blood TARC and brain-derived neurotrophic factor (BDNF) levels. Our study thus provides evidence of reduced chemokine levels in suicide attempters, both in the acute suicidal setting, and at long-term, compared to non-attempters. These results warrant future studies on the detailed neurobiological functions of chemokines in psychiatric patients. (C) 2012 Elsevier Ltd. All rights reserved.
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| 35. |
- Janelidze, Shorena, et al.
(författare)
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IL-8 is associated with anxiety in suicidal patients: genotypes and biological measures in cerebrospinal fluid and plasma
- 2015
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Ingår i: Acta Psychiatrica Scandinavica. - : Wiley. - 0001-690X .- 1600-0447. ; 131:4, s. 269-278
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Tidskriftsartikel (refereegranskat)abstract
- Objective Recent studies indicate that inflammation may play a role in the pathophysiology of suicidality. Interleukin-8 (IL-8) is a chemokine that in addition to its function in the immune system also exert neuroprotective properties. The involvement of this chemokine in neuropsychiatric conditions is incompletely known. Method We measured plasma and cerebrospinal fluid (CSF) IL-8, as well as the genotype frequency of a single nucleotide polymorphism (-251A/T, rs4073) in the promoter region of the IL8 gene, in suicide attempters (n = 206) and healthy controls (n = 578). Results Plasma and CSF levels of IL-8 were significantly lower in suicide attempters with anxiety than in healthy controls. IL-8 in both plasma and CSF correlated negatively with symptoms of anxiety. Compared with the population-based cohort, the IL-8-251T allele was more prevalent among female suicide attempters. Furthermore, suicide attempters carrying this allele showed more severe anxiety. This correlative study warrants further mechanistic studies on the effects of IL-8 in the central nervous system. Conclusion We suggest that IL-8 might be involved in the biological mechanisms mediating resilience to anxiety. Thus, our findings highlight the chemokine IL-8 as a potential target for future development of anti-anxiety treatments and suicide prevention.
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| 36. |
- Janelidze, Shorena, et al.
(författare)
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Low IL-8 is associated with anxiety in suicidal patients: genetic variation and decreased protein levels
- 2015
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Ingår i: Acta Psychiatrica Scandinavica. - : Wiley: 12 months. - 0001-690X .- 1600-0447. ; 131:4, s. 269-278
-
Tidskriftsartikel (refereegranskat)abstract
- ObjectiveRecent studies indicate that inflammation may play a role in the pathophysiology of suicidality. Interleukin-8 (IL-8) is a chemokine that in addition to its function in the immune system also exert neuroprotective properties. The involvement of this chemokine in neuropsychiatric conditions is incompletely known. MethodWe measured plasma and cerebrospinal fluid (CSF) IL-8, as well as the genotype frequency of a single nucleotide polymorphism (-251A/T, rs4073) in the promoter region of the IL8 gene, in suicide attempters (n=206) and healthy controls (n=578). ResultsPlasma and CSF levels of IL-8 were significantly lower in suicide attempters with anxiety than in healthy controls. IL-8 in both plasma and CSF correlated negatively with symptoms of anxiety. Compared with the population-based cohort, the IL-8-251T allele was more prevalent among female suicide attempters. Furthermore, suicide attempters carrying this allele showed more severe anxiety. This correlative study warrants further mechanistic studies on the effects of IL-8 in the central nervous system. ConclusionWe suggest that IL-8 might be involved in the biological mechanisms mediating resilience to anxiety. Thus, our findings highlight the chemokine IL-8 as a potential target for future development of anti-anxiety treatments and suicide prevention.
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| 37. |
- Kalimo, H., et al.
(författare)
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Details of neuropathology in Arctic Alzheimer's disease
- 2010
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Ingår i: Abstracts of the XVIIth International Congress of Neuropathology (ICN 2010), Salzburg, Austria, 11-15 September 2010. - : Wiley. ; , s. 22-23
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 38. |
- Kalimo, Hannu, et al.
(författare)
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The Arctic AβPP mutation leads to Alzheimer's disease pathology with highly variable topographic deposition of differentially truncated Aβ
- 2013
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Ingår i: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 1:1, s. 60-
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Arctic mutation (p.E693G/p.E22G)fs within the β-amyloid (Aβ) region of the β-amyloid precursor protein gene causes an autosomal dominant disease with clinical picture of typical Alzheimer's disease. Here we report the special character of Arctic AD neuropathology in four deceased patients.RESULTS: Aβ deposition in the brains was wide-spread (Thal phase 5) and profuse. Virtually all parenchymal deposits were composed of non-fibrillar, Congo red negative Aβ aggregates. Congo red only stained angiopathic vessels. Mass spectrometric analyses showed that Aβ deposits contained variably truncated and modified wild type and mutated Aβ species. In three of four Arctic AD brains, most cerebral cortical plaques appeared targetoid with centres containing C-terminally (beyond aa 40) and variably N-terminally truncated Aβ surrounded by coronas immunopositive for Aβx-42. In the fourth patient plaque centres contained almost no Aβ making the plaques ring-shaped. The architectural pattern of plaques also varied between different anatomic regions. Tau pathology corresponded to Braak stage VI, and appeared mainly as delicate neuropil threads (NT) enriched within Aβ plaques. Dystrophic neurites were scarce, while neurofibrillary tangles were relatively common. Neuronal perikarya within the Aβ plaques appeared relatively intact.CONCLUSIONS: In Arctic AD brain differentially truncated abundant Aβ is deposited in plaques of variable numbers and shapes in different regions of the brain (including exceptional targetoid plaques in neocortex). The extracellular non-fibrillar Aβ does not seem to cause overt damage to adjacent neurons or to induce formation of neurofibrillary tangles, supporting the view that intracellular Aβ oligomers are more neurotoxic than extracellular Aβ deposits. However, the enrichment of NTs within plaques suggests some degree of intra-plaque axonal damage including accumulation of hp-tau, which may impair axoplasmic transport, and thereby contribute to synaptic loss. Finally, similarly as the cotton wool plaques in AD resulting from exon 9 deletion in the presenilin-1 gene, the Arctic plaques induced only modest glial and inflammatory tissue reaction.
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| 39. |
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| 40. |
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| 41. |
- Kurowska, Zuzanna, et al.
(författare)
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Intracellular Nogo-A facilitates initiation of neurite formation in mouse midbrain neurons in vitro.
- 2014
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Ingår i: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 256, s. 456-466
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Tidskriftsartikel (refereegranskat)abstract
- Nogo-A is a transmembrane protein originally discovered in myelin, produced by postnatal central nervous system (CNS) oligodendrocytes. Nogo-A induces growth cone collapse and inhibition of axonal growth in the injured adult CNS. In the intact CNS, Nogo-A functions as a negative regulator of growth and plasticity. Nogo-A is also expressed by certain neurons. Neuronal Nogo-A depresses long-term potentiation in hippocampus and modulates neurite adhesion and fasciculation during development in mice. Here we show that Nogo-A is present in neurons derived from human midbrain (LUHMES cell line), as well as in embryonic and postnatal mouse midbrain (dopaminergic) neurons. In LUHMES cells, Nogo-A was upregulated 3-fold upon differentiation and neurite extension. Nogo-A was localized intracellularly in differentiated LUHMES cells. Cultured midbrain (dopaminergic) neurons from Nogo-A knock-out mice exhibited decreased numbers of neurites and branches when compared with neurons from wild type mice. However, this phenotype was not observed when the cultures from wild type mice were treated with an antibody neutralizing plasma membrane Nogo-A. In vivo, neither the regeneration of nigrostriatal tyrosine hydroxylase fibers, nor the survival of nigral dopaminergic neurons after partial 6-hydroxydopamine lesions were affected by Nogo-A deletion. These results indicate that during maturation of cultured midbrain (dopaminergic) neurons, intracellular Nogo-A supports neurite growth initiation and branch formation. Abbreaviations: 6-OHDA, (6-hydroxydopamine); CNS, (central nervous system); DAB, (3,3'-Diaminobenzidine); DAPI, (4',6-diamidino-2-phenylindole); KO, (knock-out); LTP, (long term potentiation); LUHMES cells (Lund University Human Mesencephalon cells); PFA, (paraformaldehyde); SDS-PAGE, (sodium dodecyl sulfate polyacrylamide gel electrophoresis); TH, (tyrosine hydroxylase); WT, (wild type).
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| 42. |
- Lindqvist, Daniel, et al.
(författare)
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Interleukin-6 Is Elevated in the Cerebrospinal Fluid of Suicide Attempters and Related to Symptom Severity
- 2009
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Ingår i: BIOLOGICAL PSYCHIATRY. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 66:3, s. 287-292
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Tidskriftsartikel (refereegranskat)abstract
- Background: Depressive disorders are associated with immune system alterations that can be detected in the blood. Cytokine concentrations in cerebrospinal fluid (CSF) and their relationship to aspects of suicidality have previously not been investigated. Methods: We measured interleukin-1 beta interleukin-6 (IL-6), interleukin-8, and tumor necrosis factor-a (TNF-alpha) in CSF and plasma of suicide attempters (n = 63) and healthy control subjects (n = 47). Patients were classified according to diagnosis and violent or nonviolent suicide attempt. We evaluated suicidal ideation and depressive symptoms using the Suicide Assessment Scale and the Montgomery-Asberg Depression Rating Scale (MADRS). We also analyzed the relation between cytokines and monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) in CSF, as well as the integrity of the blood-brain barrier as reflected by the CSF:serum albumin ratio. Results: IL-6 in CSF was significantly higher in suicide attempters than in healthy control subjects. Patients who performed violent suicide attempts displayed the highest IL-6. Furthermore, there was a significant positive correlation between MANS scores and CSF IL-6 levels in all patients. IL-6 and TNF-a correlated significantly with 5-HIAA and HVA in CSF, but not with MHPG. Cytokine levels in plasma and CSF were not associated, and patients with increased blood-brain barrier permeability did not exhibit elevated cytokine levels. Conclusions: We propose a role for CSF IL-6 in the symptomatology of suicidal behavior, possibly through mechanisms involving alterations of dopamine and serotonin metabolism.
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| 43. |
- Netz, Joakim, et al.
(författare)
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Adaptive strategizing: The role of affective expressions for effective crisis management.
- 2015
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Ingår i: Academy of Management Proceedings.
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Konferensbidrag (refereegranskat)abstract
- This study sets out to investigate the role of affectivity in crisis management groups and its connection to effective crisis management. We studied the affective reactions in 23 crisis management groups in a major global corporation that participated in a global training program of crisis management. Our results elucidate a condition of asymmetrical affectivity, where positive expressions are associated with negative outcomes and negative expressions are associated with positive outcomes when groups commit to making sense of a crisis. These patterns were moderated by prior crisis experience at the organizational level as well as managerial behavior at the individual level. To explain this multi-level and dynamic complexity of crisis management effectiveness, we theorize a model of adaptive strategizing building on the strategy-as-practice perspective. The model contributes to the strategic management literature on organizational crisis, and especially the stream that focuses on social-emotional aspects of crisis management, by explaining why some organizations’ crisis management groups strategize more effectively than others.
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| 44. |
- Netz, Joakim, et al.
(författare)
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Business disruptions and affective reactions : A strategy-as-practice perspective on fast strategic decision making
- 2020
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Ingår i: Long range planning. - : Elsevier. - 0024-6301 .- 1873-1872. ; 53:5
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Tidskriftsartikel (refereegranskat)abstract
- This study examines management teams' work in making fast strategic decisions under extreme time pressure. Focusing on affective reactions as behavioural responses to business disruptions due to unforeseen events, we elaborate the strategy-as-practice perspective by drawing upon qualitative and quantitative datasets collected from 39 sites in a corporate setting over three consecutive phases during a four-year period. The data show two types of patterns: intensity-focused and type-focused affective reactions in management teams' use of management tools as part of mental shortcuts when making fast decisions. These patterns are contingent on whether the teams functioned in contexts that had previous experience of management of similar unforeseen events. Affective reactions in the use of tool-based mental shortcuts unveil a mechanism of practices that explains middle management teams’ strategic actions during business disruption due to unforeseen events. While research predominantly suggests that affect is “bad” for management teams in crisis-related contexts, we find that this view is misleading. Affective reactions not only hinder but also aid crucial information exchanges between middle management teams and corporate levels while making strategic decisions under extreme time pressure. Therefore, we propose a reconceptualized view of managing fast strategic decision making and discuss the implications for theory and practice.
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| 45. |
- Netz, Joakim, et al.
(författare)
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Strategizing affective reactions in organizational crisis : A practices-in-use perspective
- 2017
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Konferensbidrag (refereegranskat)abstract
- Prior research underscore the importance of strategic capabilities as well as managing affective reactions for better coordination of organizational responses during crisis. Surprisingly, studies on the role affective reactions play in constructing strategic capabilities for organizational crisis are largely absent. We collected observational data from a firms’ global training program of crisis management. By logistical regressions and temporal analysis, we model how groups are practicing organizational crisis management through affective reactions but differently: they map the direction of organizational responses by sorting information upon either types of expressed affective reaction or the intensity. Our model informs how strategic capabilities for crisis management are rooted in the present use of affective reactions, pointing to a more strategic skill than what has been previously suggested.
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| 46. |
- Nordström, Ulrika, et al.
(författare)
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Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease.
- 2015
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 73, s. 70-82
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Tidskriftsartikel (refereegranskat)abstract
- Current research on Parkinson's disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests that En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1(+/-) mice with a focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1(+/-) mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of the En1(+/-) mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of the En1(+/-) mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely deficient in dopamine release and reuptake. Our findings support a progressive retrograde degeneration of En1(+/-) nigrostriatal neurons, akin to what is suggested to occur in PD. We suggest that using the En1(+/-) mice as a model will provide further key insights into PD pathogenesis, and propose that axon terminal integrity and function can be utilized to estimate dopaminergic neuron health and efficacy of experimental PD therapies.
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| 47. |
- Pagnon de la Vega, María, 1994-, et al.
(författare)
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Mutation analysis of disease causing genes in patients with early onset or familial forms of Alzheimer’s disease and frontotemporal dementia
- 2022
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Ingår i: BMC Genomics. - : Springer Nature. - 1471-2164. ; 23
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Tidskriftsartikel (refereegranskat)abstract
- Background: Most dementia disorders have a clear genetic background and a number of disease genes have beenidentified. Mutations in the tau gene (MAPT) lead to frontotemporal dementia (FTD), whereas mutations in the genesfor the amyloid-β precursor protein (APP) and the presenilins (PSEN1, PSEN2) cause early-onset, dominantly inheritedforms of Alzheimer’s disease (AD).Even if mutations causing Mendelian forms of these diseases are uncommon, elucidation of the pathogenic effects ofsuch mutations have proven important for understanding the pathogenic processes. Here, we performed a screen toidentify novel pathogenic mutations in known disease genes among patients undergoing dementia investigation.Results: Using targeted exome sequencing we have screened all coding exons in eleven known dementia genes(PSEN1, PSEN2, APP, MAPT, APOE, GRN, TARDBP, CHMP2B, TREM2, VCP and FUS) in 102 patients with AD, FTD, otherdementia diagnoses or mild cognitive impairment.We found three AD patients with two previously identified pathogenic mutations in PSEN1 (Pro264Leu and Met-146Val). In this screen, we also identified the recently reported APP mutation in two siblings with AD. This mutation,named the Uppsala mutation, consists of a six amino acid intra-amyloid β deletion.In addition, we found several potentially pathogenic mutations in PSEN2, FUS, MAPT, GRN and APOE. Finally, APOE ε4was prevalent in this patient group with an allele frequency of 54%Conclusions: Among the 102 screened patients, we found two disease causing mutations in PSEN1 and one in APP,as well as several potentially pathogenic mutations in other genes related to neurodegenerative disorders. Apart fromgiving important information to the clinical investigation, the identification of disease mutations can contribute to anincreased understanding of disease mechanisms.
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| 48. |
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| 49. |
- Sehlin, Dag, et al.
(författare)
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Interference from Heterophilic Antibodies in Amyloid-beta Oligomer ELISAs
- 2010
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Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 21:4, s. 1295-1301
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta (Abeta) oligomers of different sizes and forms have recently been the focus for many Alzheimer's disease (AD) researchers. Various immunoassays have been used to detect low concentrations of these elusive Abeta species in different forms of human samples using little or no sample dilutions. However, the possibility that positive results may be caused by interference from heterophilic antibodies (HA) is often overlooked. HA, which recognize immunoglobulins from other species, are present in human plasma and cerebrospinal fluid (CSF) and may cause interference in sandwich immunoassays like enzyme-linked immunosorbent assays (ELISAs) by cross-binding the capture and detection antibodies of the assay. They thus may generate a false positive signal. Here we show that when assessing the Abeta oligomer content in plasma samples from 44 individuals with a sandwich ELISA, none of the 21 positive signals remained when the assay was repeated in the presence of factors blocking HA. Similarly, in CSF samples from 104 individuals, the signals from the 22 positive samples were strongly reduced when analyzed after anti-HA treatment. Taken together, HA interference is a problem that needs to be addressed when measuring low levels of an antigen in human plasma and CSF samples.
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| 50. |
- Skoglund, Lena, et al.
(författare)
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Frontotemporal dementia in a large Swedish family is caused by a progranulin null mutation
- 2009
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Ingår i: Neurogenetics. - : Springer Science and Business Media LLC. - 1364-6745 .- 1364-6753. ; 10:1, s. 27-34
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the progranulin (PGRN) gene have recently been identified in families with frontotemporal lobar degeneration and ubiquitin-positive brain inclusions linked to chromosome 17q21. We have previously described a Swedish family displaying frontotemporal dementia with rapid progression and linkage to chromosome 17q21. In this study, we performed an extended clinical and neuropathological investigation of affected members of the family and a genetic analysis of the PGRN gene. There was a large variation of the initial presenting symptoms in this family, but common clinical features were non-fluent aphasia and loss of spontaneous speech as well as personality and behavioural changes. Mean age at onset was 54 years with disease duration of close to 4 years. Neuropathological examination revealed frontotemporal neurodegeneration with ubiquitin and TAR DNA binding protein-43 immunoreactive intraneuronal inclusions. Mutation screening of the PGRN gene identified a 1 bp deletion in exon 1 causing a frameshift of the coding sequence and introducing a premature termination codon in exon 2 (Gly35GlufsX19). Analysis of PGRN messenger RNA (mRNA) levels revealed a considerable decrease in lymphoblasts from mutation carriers and fragment size separation, and sequence analysis confirmed that the mutated mRNA allele was almost absent in these samples. In conclusion, the PGRN Gly35fs mutation causes frontotemporal dementia with variable clinical presentation in a large Swedish family, most likely through nonsense-mediated decay of mutant PGRN mRNA and resulting haploinsufficiency.
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