| 1. |
- Bacelis, J., et al.
(author)
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Decreased Risk of Parkinson's Disease after Rheumatoid Arthritis Diagnosis: A Nested Case-Control Study with Matched Cases and Controls
- 2021
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In: Journal of Parkinson's Disease. - 1877-7171 .- 1877-718X. ; 11:2, s. 821-832
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Journal article (peer-reviewed)abstract
- Background: Rheumatoid arthritis (RA) and the genetic risk landscape of autoimmune disorders and Parkinson's disease (PD) overlap. Additionally, anti-inflammatory medications used to treat RA might influence PD risk. Objective: To use a population-based approach to determine if there is an association between pre-occurring rheumatoid arthritis (RA) and later-life risk of PD. Methods: The study population was 3.6 million residents of Sweden, who were alive during part or all of the follow-up period; 1997-2016. We obtained diagnoses from the national patient registry and identified 30,032 PD patients, 8,256 of whom each was matched to ten controls based on birth year, sex, birth location, and time of follow-up. We determined the risk reduction for PD in individuals previously diagnosed with RA. We also determined if the time (in relation to the index year) of the RA diagnosis influenced PD risk and repeated the analysis in a sex-stratified setting. Results: Individuals with a previous diagnosis of RA had a decreased risk of later developing PD by 30-50% compared to individuals without an RA diagnosis. This relationship was strongest in our conservative analysis, where the first PD diagnosis occurred close to the earliest PD symptoms (odds ratio 0.47 (CI 95% 0.28-0.75, p=0.0006); with the greatest risk reduction in females (odds ratio 0.40 (CI 95% 0,19-0.76, p=0.002). Discussion: Our findings provide evidence that individuals diagnosed with RA have a significantly lower risk of developing PD than the general population. Our data should be considered when developing or repurposing therapies aimed at modifying the course of PD. © 2021 - The authors. Published by IOS Press.
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| 2. |
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| 3. |
- Killinger, Bryan A., et al.
(author)
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The vermiform appendix impacts the risk of developing Parkinson’s disease
- 2018
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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 10:465
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Journal article (peer-reviewed)abstract
- The pathogenesis of Parkinson’s disease (PD) involves the accumulation of aggregated -synuclein, which has been suggested to begin in the gastrointestinal tract. Here, we determined the capacity of the appendix to modify PD risk and influence pathogenesis. In two independent epidemiological datasets, involving more than 1.6 million individuals and over 91 million person-years, we observed that removal of the appendix decades before PD onset was associated with a lower risk for PD, particularly for individuals living in rural areas, and delayed the age of PD onset. We also found that the healthy human appendix contained intraneuronal -synuclein aggregates and an abundance of PD pathology–associated -synuclein truncation products that are known to accumulate in Lewy bodies, the pathological hallmark of PD. Lysates of human appendix tissue induced the rapid cleavage and oligo-merization of full-length recombinant -synuclein. Together, we propose that the normal human appendix contains pathogenic forms of -synuclein that affect the risk of developing PD.
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| 4. |
- Santillo, Alexander, et al.
(author)
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Frontotemporal Dementia-amyotrophic Lateral Sclerosis Complex is Simulated by Neurodegeneration With Brain Iron Accumulation
- 2009
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In: Alzheimer Disease and Associated Disorders. - 0893-0341 .- 1546-4156. ; 23:3, s. 298-300
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Journal article (peer-reviewed)abstract
- We describe a case of late onset neurodegeneration with brain iron accumulation (NBIA) presenting as frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS). A male patient presented at age 66 with change of personality: disinhibition, emotional blunting, and socially inappropriate behavior, coupled with dysarthria, dystonia, and corticospinal tract involvement. Magnetic resonance imaging showed general cortical atrophy, iron deposits in the globus pallidus, and the "eye of the tiger" sign. Neuropsychologic performance was globally reduced, especially executive functions. Fluorodeoxyglucose positron emission tomography showed hypometabolism predominantly in frontal and temporal areas. Repeated neurophysiologic examinations showed signs of chronic denervation. The patient was diagnosed with NBIA but fulfilled consensus criteria for FTD and had a clinical picture of ALS, without neurophysiologic confirmation. Our finding introduces NBIA as a possible cause of FTD and as a differential diagnosis of the FTD-ALS complex.
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| 5. |
- Ventorp, Filip, et al.
(author)
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Exendin-4 Treatment Improves LPS-Induced Depressive-Like Behavior Without Affecting ProInflammatory Cytokines
- 2017
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In: Journal of Parkinson's Disease. - : IOS Press. - 1877-7171 .- 1877-718X. ; 7:2, s. 263-273
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Journal article (peer-reviewed)abstract
- Background: Exendin-4 is a peptide agonist of the glucagon-like peptide-1 (GLP-1) receptor, currently in clinical trials as a potential disease-modifying therapy for Parkinson's disease. In light of this, it is important to understand potential modes of action of exendin-4 in the brain. Exendin-4 is neuroprotective and has been proposed to be directly anti-inflammatory, and that this is one way it reduces neurodegeneration. However, prior studies have focused on animal models involving both neurodegeneration and inflammation, therefore, it is also possible that the observed decreased inflammation is secondary to reduced neurodegeneration. Objective: To investigate whether exendin-4 directly reduces inflammation in the brain following an insult that involves neuroinflammation but not neurodegeneration, namely systemic administration of lipopolysaccharide (LPS). Methods: Rats were administered LPS systemically and were treated with either 0.5 mu g/kg exendin-4 or saline vehicle injections over 5 days. Behavior was evaluated with forced swim test. We assayed TNF-alpha and IL-1 beta levels in cerebrospinal fluid and cytokine mRNA expression in striatal, hippocampal and cortical tissues using qPCR. We determined brain monoamines using high-performance liquid chromatography. Finally, we isolated primary brain microglia from rats and measured cytokine production after exendin-4 treatment and LPS stimulation. Results: Exendin-4 treatment did not affect cytokine mRNA expression in brain, cytokine levels in cerebrospinal fluid or cytokine production from cultured microglia, although there was a trend towards increased striatal dopamine. Importantly, exendin-4 significantly prevented depressive-like behavior at 24 hours after LPS injection, indicating that the drug engaged a target in the brain. Depressive-like behavior was associated with altered dopamine turnover in the striatum. Conclusion: We did not detect any anti-inflammatory effects of exendin-4. In previous studies exploring the effects of exendin-4 on brain insults involving neurodegeneration, observations of reduced inflammation might have been secondary to mitigation of neuronal death. Our results indicate that the effects of exendin-4 on behavior may be due to effects on dopamine synthesis or metabolism.
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| 6. |
- Ventorp, Filip, et al.
(author)
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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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In: Journal of Affective Disorders. - : Elsevier BV. - 1573-2517 .- 0165-0327. ; 193, s. 349-354
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Journal article (peer-reviewed)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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| 7. |
- Bacos, Karl, et al.
(author)
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Islet beta-cell area and hormone expression are unaltered in Huntington's disease.
- 2008
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In: Histochemistry and Cell Biology. - : Springer Science and Business Media LLC. - 1432-119X .- 0948-6143. ; 129, s. 623-629
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Journal article (peer-reviewed)abstract
- Neurodegenerative disorders are often associated with metabolic alterations. This has received little attention, but might be clinically important because it can contribute to symptoms and influence the course of the disease. Patients with Huntington's disease (HD) exhibit increased incidence of diabetes mellitus (DM). This is replicated in mouse models of HD, e.g., the R6/2 mouse, in which DM is primarily caused by a deficiency of beta-cells with impaired insulin secretion. Pancreatic tissue from HD patients has previously not been studied and, thus, the pathogenesis of DM in HD is unclear. To address this issue, we examined pancreatic tissue sections from HD patients at different disease stages. We found that the pattern of insulin immunostaining, levels of insulin transcripts and islet beta-cell area were similar in HD patients and controls. Further, there was no sign of amyloid deposition in islets from HD patients. Thus, our data show that pancreatic islets in HD patients appear histologically normal. Functional studies of HD patients with respect to insulin secretion and islet function are required to elucidate the pathogenesis of DM in HD. This may lead to a better understanding of HD and provide novel therapeutic targets for symptomatic treatment in HD.
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| 8. |
- Bay-Richter, Cecilie, et al.
(author)
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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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In: Brain, behavior, and immunity. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0889-1591 .- 1090-2139. ; 43, s. 110-117
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Journal article (peer-reviewed)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. |
- Bay-Richter, Cecilie, et al.
(author)
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Aldosterone synergizes with peripheral inflammation to induce brain IL-1β expression and depressive-like effects.
- 2012
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In: Cytokine. - : Elsevier BV. - 1096-0023 .- 1043-4666. ; 60:3, s. 749-754
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Journal article (peer-reviewed)abstract
- Recent findings have shown that the physiological functions of the hormone aldosterone go far beyond its well-known role in blood-pressure regulation and salt/water homeostasis. Aldosterone is for example involved in the regulation of inflammation, and also binds directly to mineralocorticoid receptors in specific brain regions. Interestingly, depressive symptoms appear to correlate with alterations of the aldosterone system but the underlying mechanisms have not been elucidated. In this study aldosterone (2μg/100g body weight/day) was continuously administered via osmotic minipumps for 5days. Lipopolysaccharide (LPS) was administered once a day for 5days in a dose of 1mg/kg ip. The rats were tested for depressive-like behavior 24h after the last LPS injection. Protein levels of cytokines were measured in serum and cerebrospinal fluid (CSF). mRNA expression of interleukin (IL)-1β and IL-6 in the prefrontal cortex (PFC) was analyzed using reverse transcriptase qPCR. We found that aldosterone treatment increased LPS-induced IL-1β mRNA expression in the PFC and CSF. Moreover, there was a positive correlation between IL-1β in CSF and depressive-like behaviors. These findings suggest that IL-1β is affected by the renin-aldosterone-angiotensin system (RAAS) activity and connected to symptoms of depression.
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| 10. |
- Bay-Richter, Cecilie, et al.
(author)
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Behavioural and neurobiological consequences of macrophage migration inhibitory factor gene deletion in mice.
- 2015
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In: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 12:1
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Journal article (peer-reviewed)abstract
- Evidence from clinical studies and animal models show that inflammation can lead to the development of depression. Macrophage migration inhibitory factor (MIF) is an important multifunctional cytokine that is synthesized by several cell types in the brain. MIF can increase production of other cytokines, activates cyclooxygenase (COX)-2 and can counter-regulate anti-inflammatory effects of glucocorticoids. Increased plasma levels of MIF are associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and depressive symptoms in patients. In contrast, MIF knockout (KO) mice have been found to exhibit increased depressive-like behaviour. The exact role for MIF in depression is therefore still controversial. To further understand the role of MIF in depression, we studied depressive-like behaviour in congenic male and female MIF KO mice and wild-type (WT) littermates and the associated neurobiological mechanisms underlying the behavioural outcome.
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| 11. |
- Bay-Richter, Cecilie, et al.
(author)
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Changes in behaviour and cytokine expression upon a peripheral immune challenge
- 2011
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In: Behavioural Brain Research. - : Elsevier BV. - 0166-4328. ; 222:1, s. 193-199
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Journal article (peer-reviewed)abstract
- Depression is frequently associated with inflammation. Animal studies have shown that peripheral inflammation induces depressive-like behaviour, but the underlying mechanisms remain unclear. A distinction between sickness- and depressive-like behaviour has been proposed. We hypothesize that the behavioural distinction is due to changes in the central production of immune mediators. As a model of peripheral inflammation, we administered lipopolysaccharide (LPS) intraperitoneally daily for 4 days in rats. The effect of LPS on sickness- and depressive-like behaviour was assessed. We examined protein levels and mRNA expression of cytokines and cyclooxygenase (COX) enzymes in serum, cerebrospinal fluid (CSF) and specific brain regions. Two hours post-LPS, the rats displayed sickness behaviour and cytokine levels were elevated in both serum and CSF. This was paralleled by specific alterations of mRNA transcription of IL-1β, IL-6 and TNF-α in frontal cortex, hippocampus and striatum. Twenty-four hours post-LPS the rats showed depressive-like behaviour and peripheral cytokine levels were back close to baseline. In contrast, the central transcription of IL-1β mRNA had increased even further, as well as IL-1β CSF levels. IL-6 and TNF-α transcription was unaltered compared to controls. COX enzymes were downregulated in the hippocampus during sickness behaviour and unaltered during depressive-like behaviour. Our results show for the first time that a peripheral immune challenge induces a region specific transcription of cytokines and COX-enzymes in the brain, at time-points corresponding to behavioural sickness and depression. When the peripheral inflammation and sickness behaviour had ceased, a production of proinflammatory cytokines remained within the brain parenchyma.
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| 12. |
- Boström, Gustaf, et al.
(author)
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Different Inflammatory Signatures in Alzheimer's Disease and Frontotemporal Dementia Cerebrospinal Fluid
- 2021
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 81:2, s. 629-640
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Journal article (peer-reviewed)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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| 13. |
- Brundin, Lena, et al.
(author)
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Cocaine and amphetamine regulated transcript (CART) in suicide attempters.
- 2008
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In: Psychiatry Research. - : Elsevier BV. - 1872-7123 .- 0165-1781. ; 158:2, s. 117-122
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Journal article (peer-reviewed)abstract
- Cocaine and amphetamine regulated transcript (CART) is a neuropeptide expressed in brain regions thought to regulate anxiety levels, depression, addiction and energy homeostasis. Individuals with a CART mutation display increased anxiety and depression. Severe anxiety is a core phenomenon of suicidality. We therefore studied levels of CART in the cerebrospinal fluid (CSF) of 98 patients with different psychiatric diagnoses, shortly after a suicide attempt. We also investigated the relationship between CSF-CART and relevant psychiatric symptoms. CART levels were determined using a radioimmunoassay and the psychiatric symptoms rated in structured interviews using the Comprehensive Psychopathological Rating Scale (CPRS) and the Karolinska Scales of Personality (KSP). No differences in CSF-CART were found between the diagnostic groups or controls. However, lower CART levels were associated with a higher degree of concentration difficulties. No significant association was found between CART levels and other psychiatric symptoms. CSF-CART correlated significantly with CSF-levels of orexin, but not with corticotrophin releasing factor (CRF). Further studies on the role of CART in psychiatric diseases where concentration difficulties are prominent, such as attention deficit disorder, are warranted.
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| 14. |
- Brundin, Lena, et al.
(author)
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Increased orexin levels in the cerebrospinal fluid the first year after a suicide attempt.
- 2009
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In: Journal of Affective Disorders. - : Elsevier BV. - 1573-2517 .- 0165-0327. ; Jun 2, s. 179-182
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Journal article (peer-reviewed)abstract
- BACKGROUND: The orexins (hypocretins) and cocaine and amphetamine regulated transcript (CART) are hypothalamic peptides involved in the regulation of sleep and appetite. We have previously shown that levels of both orexin-A and CART in the cerebrospinal fluid (CSF) are related to specific psychiatric symptoms. METHODS: Ten patients took part in lumbar punctures and psychiatric evaluations in conjunction to a suicide attempt and after 6 and 12 months. We measured CSF-orexin and CART using radioimmunoassays. RESULTS: Mean CSF-orexin was significantly higher at the first and second follow-up than at the suicide attempt. In contrast, mean CSF-CART did not differ over time. Total SUAS scores, as well as ratings of CPRS item 66 (global illness) were significantly lower at follow-up. At one year, there was a significant negative correlation between the change in CSF-orexin and the change in total SUAS score. LIMITATIONS: The number of patients who participated was relatively small. CONCLUSIONS: Our results support the hypothesis that orexin is involved in psychiatric symptomatology.
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| 15. |
- Brundin, Lena, et al.
(author)
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Orexin and psychiatric symptoms in suicide attempters.
- 2007
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In: Journal of Affective Disorders. - : Elsevier BV. - 1573-2517 .- 0165-0327. ; 100:1-3, s. 259-263
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Journal article (peer-reviewed)abstract
- BACKGROUND: The orexins (hypocretins) are recently discovered hypothalamic peptides that are involved in the regulation of sleep, appetite and state of arousal. In the present study, we investigated the relationship between cerebrospinal fluid (CSF) orexin and specific psychiatric symptoms in suicidal patients. METHODS: A total of 101 patients were enrolled in the study shortly after a suicide attempt. All patients underwent a lumbar puncture after a wash-out period during which they did not receive any antipsychotic or antidepressive medication. Structured interviews were performed using the Comprehensive Psychopathological Rating Scale (CPRS). CSF-orexin-A was measured and correlated with ratings of psychiatric symptoms. RESULTS: There were significant and negative correlations between CSF-orexin and the symptoms lassitude (difficulty to initiate activities) and slowness of movement, as well as the ratings of global illness (p<0.005 for all three items, Spearman's rho). LIMITATIONS: Correlation analysis is an indirect method of investigation and does not demonstrate causal relationships. CONCLUSION: Low CSF-orexin levels are related to pronounced symptoms of inertia and reduced motor activity in suicidal patients. Interestingly, the lower the orexin levels, the higher were ratings of overall illness, as observed by a specialist in psychiatry. Our results suggest that reduced orexin levels are involved in the etiology of specific psychiatric symptoms.
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| 16. |
- Brundin, Lena, et al.
(author)
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Reduced orexin levels in the cerebrospinal fluid of suicidal patients with major depressive disorder.
- 2007
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In: European Neuropsychopharmacology. - : Elsevier BV. - 1873-7862 .- 0924-977X. ; 17:Mar 6, s. 573-579
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Journal article (peer-reviewed)abstract
- Orexins are neuropeptides selectively expressed in a small number of neurons in the lateral–posterior hypothalamus. We measured orexin-A in the cerebrospinal fluid (CSF) of 66 patients with major depressive disorder (MDD), dysthymia and adjustment disorder after a suicide attempt. Blood samples confirmed that the patients were free from antidepressive and neuroleptic medication at the time of the lumbar punctures. CSF levels of orexin-A were significantly lower in patients with MDD than in patients with adjustment disorder and dysthymia. Orexin correlated significantly with CSF levels of somatostatin, delta sleep inducing peptide-like immunoreactivity (DSIP-LI) and corticotrophin releasing factor (CRF), but not with leptin or vasopressin. Plasma levels of thyroid-stimulating hormone (TSH) were not reduced in MDD patients, and did not correlate with CSF-orexin. Our results suggest that suicidal patients with MDD have distinct neurobiological features, involving compromised levels of hypothalamic peptides regulating the state of arousal.
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| 17. |
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| 18. |
- Brundin, S.G., et al.
(author)
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Comparisons of Manure Handling Systems Under Swedish Conditions
- 1994
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In: Journal of Agricultural Engineering Research. - : Elsevier BV. - 0021-8634 .- 1095-9246. ; 58:2-3, s. 181-190
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Journal article (peer-reviewed)abstract
- Interest in manure handling has been rekindled in Sweden because of increasing awareness of environmental problems and high fertilizer prices. This study deals with the problem of optimizing the design of manure systems on Swedish farms. A mathematical model has been used which describes slurry systems for farms with growing fattening pigs and dairy cows and also solid manure systems for farms with dairy cows. The model deals with manure handling from animal to field crop, with an emphasis on application. Storage capacity and the quantity spread in different seasons were optimized using mixed integer linear programming. Various manure systems were compared when used in an economically optimal way. Key factors were uniformity of application, nitrogen losses through leaching and ammonia volutilization, timeliness and soil compaction. These factors place contradictory demands on the technical design of the equipment and on the timing of applications. Solid manure systems appear to be more profitable than slurry systems for small dairy farms with about 20 cows. For larger farms, slurry systems are better. Slurry systems will generally give a higher utilization of plant nutrients than solid manure systems. The utilization of nitrogen when using liquid manure is about 50% compared with about 30% for solid manure. A slurry tanker with conventional application equipment, i.e. a splash plate is the most profitable slurry spreader for small farms with 20 cows or 250 pig places. A low spreading boom is better on a larger scale, with about 2000 pigs or 160 dairy cows. A pendular nozzle is preferred on a scale in between. Irrigation systems for liquid manure may be profitable in even larger-scale systems. Some promising areas for technical development are identified, such as improved urine separation in solid manure systems and application with irrigation equipment in large-scale slurry systems.
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| 19. |
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| 20. |
- de la Vega, Maria Pagnon, et al.
(author)
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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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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 13:606
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Journal article (peer-reviewed)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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| 21. |
- Emami Khoonsari, Payam, et al.
(author)
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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
-
Other publication (other academic/artistic)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.
(author)
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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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In: Journal of Alzheimer's Disease. - : IOS PRESS. - 1387-2877 .- 1875-8908. ; 67:2, s. 639-651
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Journal article (peer-reviewed)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. |
- Englund, Hillevi, 1980-, et al.
(author)
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Oligomerization partially explains the lowering of Aβ42 in Alzheimer's disease cerebrospinal fluid
- 2009
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In: Neuro-degenerative diseases. - : S. Karger AG. - 1660-2862 .- 1660-2854. ; 6:4, s. 139-147
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Journal article (peer-reviewed)abstract
- Background/aim: The lowering of natively analyzed Aβ42 in cerebrospinal fluid (CSF) is used as a diagnostic tool in Alzheimer’s disease (AD). Presence of Aβ oligomers can interfere with such analyses causing underestimation of Aβ levels due to epitope masking. The aim was to investigate if the lowering of CSF Aβ42 seen is caused by oligomerization. Methods: Aβ42 was analyzed under both denaturing and non-denaturing conditions. An Aβ42 oligomer ratio was calculated from these quantifications. Presence of oligomers leads to Aβ42 epitope masking during non-denaturing assays, resulting in a higher ratio. Results: The Aβ42 oligomer ratio was used for assessment of oligomerized Aβ in human CSF, after being evaluated in transgenic mouse brain homogenates. AD and mild cognitive impairment (MCI) samples displayed the expected decrease in natively measured Aβ42 compared to healthy controls and frontotemporal dementia, but not when analyzing under denaturing conditions. Accordingly, AD and MCI CSF had a higher Aβ42 oligomer ratio in CSF. Conclusion: Combining denaturing and non-denaturing quantifications of Aβ42 into an oligomer ratio enables assessment of Aβ oligomers in biological samples. The increased Aβ42 oligomer ratio for AD and MCI indicates presence of oligomers in CSF and that the lowering of natively measured Aβ42 is caused by oligomerization.
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| 24. |
- Erhardt, Sophie, et al.
(author)
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Connecting Inflammation with Glutamate Agonism in Suicidality
- 2013
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In: Neuropsychopharmacology. - : Nature Publishing Group: Open Access Hybrid Model Option A. - 0893-133X .- 1740-634X. ; 38:5, s. 743-752
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Journal article (peer-reviewed)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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| 25. |
- Fernström, Johan, et al.
(author)
-
Six autoantibodies associated with autoimmune encephalitis are not detectable in the cerebrospinal fluid of suicide attempters
- 2017
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:4
-
Journal article (peer-reviewed)abstract
- Previous findings suggest a link between neuroinflammatory processes and suicidality. Despite several lines of evidence supporting this link, including increased pro-inflammatory markers in blood-, cerebrospinal fluid (CSF)- and in post-mortem brain samples from suicidal individuals, the underlying mechanisms remain poorly understood. In this pilot study, we explored the possibility that autoimmune encephalopathies might be found among suicide attempters. We analysed the presence of six different autoantibodies (N-methyl-D-aspartate receptor, the α-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid receptor, the γ-amino-butyric acid B-receptor, the leucine-rich, glioma-inactivated 1, the contactin-associated protein-like 2, and the dipeptidyl-peptidase-like protein-6), all previously associated with psychopathology, in CSF samples from 29 unmedicated suicide attempters. Five of these subjects had high CSF/serum albumin ratio, indicative of increased blood-brain-barrier permeability. We were not able to detect any of these autoantibodies in the CSF samples. These pilot data do not support a role for autoimmune encephalopathies in suicidal behaviour, although the presence of lower levels of these autoantibodies cannot be ruled out in these patients.
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| 26. |
- Giedraitis, Vilmantas, et al.
(author)
-
CALHM1 P86L polymorphism does not alter amyloid-beta or tau in cerebrospinal fluid
- 2010
-
In: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 469:2, s. 265-267
-
Journal article (peer-reviewed)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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| 27. |
- Giedraitis, Vilmantas, et al.
(author)
-
New Alzheimer's disease locus on chromosome 8
- 2006
-
In: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 43:12, s. 931-935
-
Journal article (peer-reviewed)abstract
- Background: Family history is one of the most consistent risk factors for dementia. Therefore, analysis of families with a distinct inheritance pattern of disease can be a powerful approach for the identification of previously unknown disease genes. Objective: To map susceptibility regions for Alzheimer's disease. Methods: A complete genome scan with 369 microsatellite markers was carried out in 12 extended families collected in Sweden. Age at disease onset ranged from 53 to 78 years, but in 10 of the families there was at least one member with age at onset of <= 65 years. Mutations in known early-onset Alzheimer's disease susceptibility genes have been excluded. All people were genotyped for APOE, but no clear linkage with the epsilon 4 allele was observed. Results: Although no common disease locus could be found in all families, in two families an extended haplotype was identified on chromosome 8q shared by all affected members. In one of the families, a non-parametric multi-marker logarithm of the odds (LOD) score of 4.2 (p = 0.004) was obtained and analysis based on a dominant model showed a parametric LOD score of 2.4 for this region. All six affected members of this family shared a haplotype of 10 markers spanning about 40 cM. Three affected members in another family also shared a haplotype in the same region. Conclusion: On the basis of our data, we propose the existence of a dominantly acting Alzheimer's disease susceptibility locus on chromosome 8.
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| 28. |
- Grudet, Cécile, et al.
(author)
-
Suicidal patients are deficient in vitamin D, associated with a pro-inflammatory status in the blood.
- 2014
-
In: Psychoneuroendocrinology. - : Elsevier BV. - 1873-3360 .- 0306-4530. ; 50, s. 210-219
-
Journal article (peer-reviewed)abstract
- Low levels of vitamin D may play a role in psychiatric disorders, as cross-sectional studies show an association between vitamin D deficiency and depression, schizophrenia and psychotic symptoms. The underlying mechanisms are not well understood, although vitamin D is known to influence the immune system to promote a T helper (Th)-2 phenotype. At the same time, increased inflammation might be of importance in the pathophysiology of depression and suicide. We therefore hypothesized that suicidal patients would be deficient in vitamin D, which could be responsible for the inflammatory changes observed in these patients.
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| 29. |
- Grudet, Cécile, et al.
(author)
-
Vitamin D and inflammation in major depressive disorder
- 2020
-
In: Journal of Affective Disorders. - : Elsevier BV. - 0165-0327. ; 267, s. 33-41
-
Journal article (peer-reviewed)abstract
- Background: Increased inflammation is reported in Major Depressive Disorder (MDD), which may be more pronounced in suicidal subjects. Vitamin D deficiency may drive this pro-inflammatory state due to vitamin D's anti-inflammatory effects. Methods: We quantified plasma 25-hydroxyvitamin D (25(OH)D) and inflammatory markers interleukin (IL)-6 and tumor necrosis factor (TNF)-α, and other inflammatory indices, neutrophil-to-lymphocyte ratio (NLR) and white blood cell count (WBC) in 48 un-medicated MDD subjects (n = 17 with mild-to-moderate suicidal ideation [SI]) and 54 controls. IL-6 and TNF-α were combined into a composite inflammation score. Results: There were no significant differences in 25(OH)D levels between MDD and controls (p = 0.24) or between MDD with and without SI (p = 0.61). However, 25(OH)D was negatively correlated with all measured inflammatory markers; these correlations were stronger in MDD subjects, and particularly in those with SI. MDD status significantly moderated the relationships between 25(OH)D and NLR (p = 0.03), and 25(OH)D and WBC (p < 0.05), and SI significantly moderated the relationship between 25(OH)D and NLR (p = 0.03). Limitations: The study was cross-sectional, thereby limiting causal inference, and had a small sample size. Only seventeen of the MDD subjects had SI. Conclusion: While 25(OH)D levels did not significantly differ in MDD vs. controls, or in MDD with or without SI, lower 25(OH)D was associated with indices of immune activation in MDD, especially in cases with SI. Although our findings do not address causality, they are consistent with findings that relatively low 25(OH)D levels in MDD are associated with a pro-inflammatory state.
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| 30. |
- Hagell, Peter, et al.
(author)
-
Towards an understanding of fatigue in Parkinson's disease.
- 2009
-
In: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 80:5, s. 489-492
-
Journal article (peer-reviewed)abstract
- OBJECTIVES: To gain an improved understanding of fatigue in Parkinson's disease (PD) by exploring possible predictors among a wide range of motor and non-motor aspects of PD. METHODS: 118 consecutive PD patients (54% men; mean age, 64 years) were assessed regarding fatigue, demographics and a range of non-motor and motor symptoms. Variables significantly associated with fatigue scores in bivariate analyses were used in multiple regression analyses with fatigue as the dependent variable. RESULTS: Fatigue was associated with increasing Hoehn & Yahr stages, specifically transition from stages I-II to stages III-V. Regression analysis identified five significant independent variables explaining 48% of the variance in fatigue scores: anxiety, depression, lack of motivation, Unified PD Rating Scale (UPDRS) motor score and pain. Gender, age, body mass index, PD duration, motor fluctuations, dyskinesias, symptomatic orthostatism, thought disorder, cognition, drug treatment, sleep quality and daytime sleepiness were not significantly associated with fatigue scores. When considering individual motor symptom clusters instead of the UPDRS motor score, only axial/postural/gait impairment was associated with fatigue. CONCLUSIONS: We found fatigue to be primarily associated with symptoms of depression and anxiety, and with compromised motivation, parkinsonism (particularly axial/postural/gait impairment) and pain. These results are in agreement with findings in other disorders and imply that fatigue should be considered a separate PD entity differing from, e.g., excessive daytime sleepiness. Fatigue may have a distinguished neurobiological background, possibly related to neuroinflammatory mechanisms. This implies that novel treatment options, including anti-inflammatory therapies, could be effective.
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| 31. |
- Hallberg, Ludvig, et al.
(author)
-
Decreased aldosterone in the plasma of suicide attempters with major depressive disorder.
- 2011
-
In: Psychiatry Research. - : Elsevier BV. - 1872-7123 .- 0165-1781. ; 187, s. 135-139
-
Journal article (peer-reviewed)abstract
- Hormones and neurobiological factors may be regulated differently in suicidal versus non-suicidal depressive patients. There is currently limited knowledge about the relation of substances in the Renin-Angiotensin-Aldosterone system to depression and suicidality. We therefore investigated whether plasma levels of renin and aldosterone differ between suicide attempters, non-suicidal depressive patients and healthy controls. Furthermore, we analyzed the relation of renin and aldosterone to psychiatric symptoms in the patients. Suicidal patients with MDD, adjustment disorder and dysthymia, as well as two control groups consisting of non-suicidal MDD patients and healthy subjects, were rated using the Comprehensive Psychopathological Rating Scale (CPRS), including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Scale for Anxiety (BSA). Plasma samples were frozen immediately after collection and stored at -80 degrees C for 5-18years. Aldosterone and renin levels were analyzed using radioactive- and chemiluminescent immunoassays. We found that suicide attempters with MDD had significantly lower plasma levels of aldosterone than the other patient groups, as well as than the healthy controls. Moreover, increasing severity of psychiatric symptoms was associated with lower aldosterone levels in the suicide attempters with MDD. Non-suicidal patients with MDD did not differ significantly compared to healthy controls with respect to aldosterone and renin levels. These findings may indicate that low aldosterone levels could be a marker of suicidality in patients with MDD.
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| 32. |
- Hallberg, Ludvig, et al.
(author)
-
Exercise-induced release of cytokines in patients with major depressive disorder.
- 2010
-
In: Journal of Affective Disorders. - : Elsevier BV. - 1573-2517 .- 0165-0327. ; Apr 8, s. 262-267
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Patients with major depressive disorder (MDD) may display elevated plasma levels of pro-inflammatory substances. Although the underlying mechanisms are unknown, inflammation has been proposed to play a direct role in the generation of depressive symptoms. Skeletal muscle is a potent producer of cytokines, and physical exercise has been suggested to alleviate symptoms of depression. In this study we therefore addressed the question of whether MDD patients display altered levels of pro-, anti-inflammatory and regulatory factors in the blood in response to acute exercise. METHODS: Eighteen MDD patients and 18 healthy controls performed a maximal-workload exercise challenge. Blood samples were taken before the test, at sub-maximal and maximal workload, as well as 30 and 60min after testing. The plasma levels of SAA, TNF-alpha, S-VCAM, S-ICAM, CRP, IFN-gamma, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 and IL-13 were assayed using multiplex sandwich ELISA. RESULTS: Exercise-induced significant changes in the plasma levels of inflammatory substances in both MDD patients and controls. IL-8, IL-6 and TNF-alpha increased, and IL-4 decreased during the challenge in both groups. In addition, IFN-gamma decreased in the controls. There was a significant difference in IL-6 reactivity between the groups at the sub-max timepoint. LIMITATIONS: Group sizes are comparably limited. CONCLUSION: Exercise induces changes in the blood levels of cytokines in unmedicated MDD patients. Whether these changes affect symptoms of depression should be evaluated in long-term studies of the anti-depressive effects of exercise.
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| 33. |
- Janelidze, Shorena, et al.
(author)
-
Altered chemokine levels in the cerebrospinal fluid and plasma of suicide attempters
- 2013
-
In: Psychoneuroendocrinology. - : Elsevier. - 0306-4530 .- 1873-3360. ; 38:6, s. 853-862
-
Journal article (peer-reviewed)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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| 34. |
- Janelidze, Shorena, et al.
(author)
-
Cytokine levels in the blood may distinguish suicide attempters from depressed patients.
- 2011
-
In: Brain, Behavior, and Immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 25, s. 335-339
-
Journal article (peer-reviewed)abstract
- Elevated plasma cytokines is a common finding in Major Depressive Disorder (MDD), although not consistent. It is currently not known whether the inflammatory changes are confined to any specific subgroup of depressive patients. We here analyzed three inflammatory markers in suicidal and non-suicidal depressive patients, as well as healthy controls. Plasma interleukin (IL)-2, IL-6 and tumor necrosis factor (TNF)-α were measured in 47 suicide attempters, 17 non-suicidal depressed patients and 16 healthy controls. Study participants were evaluated using the Comprehensive Psychopathological Rating Scale (CPRS) with subscales for anxiety and degree of depression, as well as the Suicide Assessment Scale (SUAS). We found increased levels of IL-6 and TNF-α as well as decreased IL-2 concentrations in suicide attempters compared to non-suicidal depressed patients and healthy controls. The results were adjusted for potential confounders of cytokine expression, such as age, sex, body mass index (BMI), degree of depression, anxiety, personality disturbance, abuse and type of medication. These results demonstrate for the first time that suicidal patients display a distinct peripheral blood cytokine profile compared to non-suicidal depressed patients. Thus, our study provides further support for a role of inflammation in the pathophysiology of suicidality.
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| 35. |
- Janelidze, Shorena, et al.
(author)
-
IL-8 is associated with anxiety in suicidal patients: genotypes and biological measures in cerebrospinal fluid and plasma
- 2015
-
In: Acta Psychiatrica Scandinavica. - : Wiley. - 0001-690X .- 1600-0447. ; 131:4, s. 269-278
-
Journal article (peer-reviewed)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.
(author)
-
Low IL-8 is associated with anxiety in suicidal patients: genetic variation and decreased protein levels
- 2015
-
In: Acta Psychiatrica Scandinavica. - : Wiley: 12 months. - 0001-690X .- 1600-0447. ; 131:4, s. 269-278
-
Journal article (peer-reviewed)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. |
- Johnson, Philip L., et al.
(author)
-
A key role for orexin in panic anxiety
- 2010
-
In: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 16:1, s. 111-149
-
Journal article (peer-reviewed)abstract
- Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In individuals with panic disorder there is evidence of decreased central gamma-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratory responses after intravenous infusions of hypertonic sodium lactate(1-3). In a rat model of panic disorder, chronic inhibition of GABA synthesis in the dorsomedial-perifornical hypothalamus of rats produces anxiety-like states and a similar vulnerability to sodium lactate-induced cardioexcitatory responses(4-9). The dorsomedial-perifornical hypothalamus is enriched in neurons containing orexin (ORX, also known as hypocretin)(10), which have a crucial role in arousal(10,11), vigilance(10) and central autonomic mobilization(12), all of which are key components of panic. Here we show that activation of ORX-synthesizing neurons is necessary for developing a panic-prone state in the rat panic model, and either silencing of the hypothalamic gene encoding ORX (Hcrt) with RNAi or systemic ORX-1 receptor antagonists blocks the panic responses. Moreover, we show that human subjects with panic anxiety have elevated levels of ORX in the cerebrospinal fluid compared to subjects without panic anxiety. Taken together, our results suggest that the ORX system may be involved in the pathophysiology of panic anxiety and that ORX antagonists constitute a potential new treatment strategy for panic disorder. (C) 2010 Nature America, Inc. All rights reserved.
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| 38. |
- Keaton, Sarah A., et al.
(author)
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Altered Tryptophan Catabolism in Placentas From Women With Pre-eclampsia
- 2019
-
In: International Journal of Tryptophan Research. - : SAGE Publications. - 1178-6469. ; 12
-
Journal article (peer-reviewed)abstract
- Background: The kynurenine pathway enzymes, breaking down tryptophan, are abundant in placental tissue. These metabolites are involved in immunoregulatory mechanisms, although the role of this pathway in pre-eclampsia (PE) has only begun to be characterized. Here, we determined tryptophan and metabolite levels together with the expression of kynurenine pathway enzymes and inflammatory factors in placental tissue from women with and without PE. Methods: Thirty-six placentas (18 PE and 18 controls) were analyzed for expression of kynurenine pathway enzymes indoleamine-2,3-dioxygenase (IDO1 and 2), tryptophan-2,3-dioxygenase (TDO), kynurenine-3-mono-oxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) as well as interleukin (IL)-1β, IL-6, and serum amyloid A (SAA). Tryptophan and kynurenine content were measured using high-pressure liquid chromatography and quinolinic acid was measured using gas chromatography-mass spectrometry. Conclusions: Tryptophan content was reduced in placentas from women with PE. There was an increased kynurenine/tryptophan ratio in placentas from women with PE but no significant change in downstream metabolites. We confirmed a reduction in IDO1 expression and found a compensatory increase in TDO expression in placentas from women with PE. SAA was reduced in PE placentas compared with controls. Our data show that tryptophan content and the inflammatory mediator SAA are both compromised in placentas from women with PE. Further studies on the role of tryptophan catabolism and mediators of inflammation in sustaining healthy immunobiological pathways in the placenta are warranted.
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| 39. |
- Koskinen Holm, Cecilia, et al.
(author)
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Successful rehabilitation after multiple severe complications following orthognathic surgery : a case report
- 2023
-
In: BMC Oral Health. - : BioMed Central (BMC). - 1472-6831. ; 23:1
-
Journal article (peer-reviewed)abstract
- Background. Complications of orthognathic surgery are quite rare, but they cause suffering in affected individuals.The range of complications is broad and includes both hard and soft tissue.Case presentation: We here present a case of a fully healthy woman without signs of impaired healing capacity. Thepatient underwent bimaxillary orthognathic surgery and experienced multiple complications both peri- and postoperatively.During the post operative period, the patient also suffered from soft tissue complications after an orthopaedicinjury. Therefore, we referred the patient to her general practitioner for further medical investigation. Wealso present the result after restorative surgery and endodontic and prosthodontic treatment resulting in a successfulrehabilitation.Conclusion: This case report clearly shows the need for a good collaboration between different odontologicaland medical fields to achieve a good and predictable result. In situations where normal healing processesdo not occur, in-depth analysis must be carried out.Highlights: Orthognathic surgery affects soft and hard tissue which can result in adverse healing and complications.It is of great importance to follow up performed surgery to see late complications. Be restrictive with earlyre-operations when there are signs of necrosis. Always use a multidisciplinary approach when handling complicationsafter surgery.
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| 40. |
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| 41. |
- Lindqvist, Daniel, et al.
(author)
-
Cerebrospinal fluid inflammatory markers in Parkinson's disease - Associations with depression, fatigue, and cognitive impairment.
- 2013
-
In: Brain Behavior and Immunity. - : Elsevier BV. - 1090-2139 .- 0889-1591. ; 33:Jul.,31, s. 183-189
-
Journal article (peer-reviewed)abstract
- Neuroinflammation may be involved in the pathophysiology of Parkinson's disease (PD) and specifically in non-motor symptoms such as depression, fatigue and cognitive impairment. The aim of this study was to measure inflammatory markers in cerebrospinal fluid (CSF) samples from PD patients and a reference group, and to investigate correlations between non-motor symptoms and inflammation. We quantified C-reactive protein (CRP), interleukin-6, tumor necrosis factor-alpha, eotaxin, interferon gamma-induced protein-10, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein 1-β in CSF samples from PD patients (N=87) and the reference group (N=33). Sixteen of the PD patients had a dementia diagnosis (PDD). We assessed symptoms of fatigue, depression, anxiety and cognitive function using the Functional Assessment of Chronic Illness Therapy-Fatigue, the Hospital Anxiety and Depression Scale, and the Mini Mental State Examination, respectively. There were no significant differences in mean levels of inflammatory markers between PD patients and the reference group. After controlling for age, gender and somatic illness, patients with PDD had significantly higher levels of CRP compared to non-demented PD patients (p=0.032) and the reference group (p=0.026). Increased levels of inflammatory markers in CSF were significantly associated with more severe symptoms of depression, anxiety, fatigue, and cognition in the entire PD group. After controlling for PD duration, age, gender, somatic illness and dementia diagnosis, high CRP levels were significantly associated with more severe symptoms of depression (p=0.010) and fatigue (p=0.008), and high MCP-1 levels were significantly associated with more severe symptoms of depression (p=0.032). Our results indicate that non-motor features of PD such as depression, fatigue, and cognitive impairment are associated with higher CSF levels of inflammatory markers.
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| 42. |
- Lindqvist, Daniel, et al.
(author)
-
CSF biomarkers in suicide attempters - a principal component analysis.
- 2011
-
In: Acta Psychiatrica Scandinavica. - : Wiley. - 1600-0447 .- 0001-690X. ; 124, s. 52-61
-
Journal article (peer-reviewed)abstract
- Lindqvist D, Janelidze S, Erhardt S, Träskman-Bendz L, Engström G, Brundin L. CSF biomarkers in suicide attempters - a principal component analysis. Objective: The objective of the present study was to identify biological patterns (factors) among 20 cerebrospinal fluid (CSF) biomarkers in suicide attempters and subsequently analyse their association with suicidal behaviour. Method: We measured kynurenic acid, orexin, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol, chemokines, matrix metalloproteases and cytokines in the CSF of 124 drug-free suicide attempters. Patients were evaluated for suicidality and psychiatric symptoms using well-defined psychiatric rating scales and followed-up regarding future suicide. We used principal component analysis to identify factors among the biological substances. Results: Four factors were extracted from the 20 biomarkers, explaining 52.4% of the total variance. Factors 1 and 2 were characterized by high loadings of chemokines and cytokines respectively. They were both associated with severe depressive symptoms. Factor 2 was also associated with a high suicidal intent. Factor 4 was characterized by strong loadings of the monoamine metabolites 5-HIAA and HVA, as well as orexin and interleukin-6. High scores on this factor were found in patients who performed a violent suicide attempt and in patients who subsequently completed suicide. Conclusion: Our results suggest that specific combinations of CSF biomarkers may discriminate between types of suicidal behaviour and indicate increased risk for future suicide.
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| 43. |
- Lindqvist, Daniel, et al.
(author)
-
Interleukin-6 Is Elevated in the Cerebrospinal Fluid of Suicide Attempters and Related to Symptom Severity
- 2009
-
In: BIOLOGICAL PSYCHIATRY. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 66:3, s. 287-292
-
Journal article (peer-reviewed)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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| 44. |
- Lindqvist, Daniel, et al.
(author)
-
Non-motor symptoms in patients with Parkinson's disease - correlations with inflammatory cytokines in serum.
- 2012
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:10
-
Journal article (peer-reviewed)abstract
- Parkinson's Disease (PD) is the second most common neurodegenerative disorder of the central nervous system. Motor symptoms are the focus of pharmacotherapy, yet non-motor features of the disease (e.g. fatigue, mood disturbances, sleep disturbances and symptoms of anxiety) are both common and disabling for the patient. The pathophysiological mechanisms behind the non-motor symptoms in PD are yet to be untangled. The main objective of this study was to investigate associations between pro-inflammatory substances and non-motor symptoms in patients with PD.
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| 45. |
- Lindqvist, Daniel, et al.
(author)
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Salivary cortisol and suicidal behavior-A follow-up study.
- 2008
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In: Psychoneuroendocrinology. - : Elsevier BV. - 1873-3360 .- 0306-4530. ; 33:8, s. 1061-1068
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Hyperactivity of the hypothalamic-pituitary-adrenal (HPA)-axis is a common finding in major depressive disorder. Similar studies on suicide attempters are less abundant, and the results are divergent. The main aim of the present study was to investigate HPA-axis parameters by the time of a suicide attempt and at follow-up in search for associations between HPA-axis function and suicidal behavior. METHODS: Thirty-five suicide attempters and 16 non-suicidal controls were admitted to a psychiatric ward between the years of 1986 and 1992. Corticotrophin-releasing hormone (CRH) in cerebrospinal fluid and urinary cortisol were obtained for the suicide attempters. The patients were followed up approximately 12 years after the index admission. Cortisol was measured in saliva, and additional suicide attempts and current psychiatric symptoms were registered. RESULTS: At follow-up, evening salivary cortisol was lower in suicide attempters compared to controls. Low cortisol levels at follow-up were associated with severe psychiatric symptoms. Among women, repeated suicide attempts were associated with low morning and lunch salivary cortisol, and in this subgroup we also found significant correlations between salivary cortisol at follow-up, and CRH as well as urinary cortisol at index. CONCLUSION: We found evidence for an association between low HPA-axis activity and suicidal behavior. This could be due to long-lasting and severe psychiatric morbidity, which in turn has exhausted the HPA-axis of these patients. The potential role of hypocortisolism should be given more attention in studies on suicidal patients.
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| 46. |
- Pagnon de la Vega, María, 1994-, et al.
(author)
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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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In: BMC Genomics. - : Springer Nature. - 1471-2164. ; 23
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Journal article (peer-reviewed)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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| 47. |
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| 48. |
- Schwieler, Lilly, et al.
(author)
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A novel, robust method for quantification of multiple kynurenine pathway metabolites in the cerebrospinal fluid
- 2020
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In: Bioanalysis. - : Future Science Ltd. - 1757-6180 .- 1757-6199. ; 12:6, s. 379-392
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Journal article (peer-reviewed)abstract
- Aim: Kynurenine metabolites are potential modulators of psychiatric disease. We aimed to develop a highly sensitive biochemical analysis of cerebrospinal fluid (CSF) tryptophan (TRP) metabolites, to investigate the stability of metabolites and to confirm our previous findings of aberrant CSF quinolinic acid (QUIN) and picolinic acid (PIC) in suicide attempters using this method. Methodology & results: Ten CSF TRP metabolites were analyzed with ultraperformance LC-MS/MS. The method showed small intra- and interassay variation. Metabolites were stable following freeze-thaw cycles. A decreased CSF PIC/QUIN ratio was found in suicide attempters. Conclusion: The feasibility of reliably determining CSF TRP metabolites were demonstrated, including separation of the two isomers PIC and nicotinic acid (NA) and the finding of a reduced PIC/QUIN ratio replicated in suicide attempters.
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| 49. |
- Serafini, Gianluca, et al.
(author)
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Abnormalities in kynurenine pathway metabolism in treatment-resistant depression and suicidality : a systematic review
- 2017
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In: CNS and Neurological Disorders - Drug Targets. - : Bentham Science Publishers Ltd.. - 1871-5273. ; 16:4, s. 440-453
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Research review (peer-reviewed)abstract
- Treatment resistant depression (TRD) and suicidal behavior are among the most important public health problems and are commonly associated with significant disability and psychosocial impairment. Although there have been recent advances in identifying neurobiological correlates of these complex conditions, their pathophysiology still remains unclear. Although the recent advances concerning the neurobiological determinants underlying these complex conditions, their pathophysiology still remains unclear. Compared to non-suicidal subjects, higher mean concentrations of inflammatory mediators have been found in both the periphery and brain of individuals at risk for suicide. Several lines of evidence suggest that neuroinflammation is accompanied by a dysregulation of the kynurenine pathway (KP) in both TRD and suicidal individuals, resulting in an imbalance of neuroactive metabolites. In particular, neuroinflammation may trigger an increased production of the N-Methyl-D-aspartate (NMDA) receptor agonist quinolinic acid and a concomitant reduction of neuroprotective metabolites, potentially causing downstream effects in glutamatergic systems resulting in depressive symptoms and suicidal behavior. This systematic review of the current literature is mainly aimed at summarizing the most important evidence pertaining to KP metabolism abnormalities in TRD and suicidal behavior. Targeting the KP enzymes may provide innovative approaches in the management of both TRD and suicidality.
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| 50. |
- Serafini, Gianluca, et al.
(author)
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Neuropeptides : Active neuromodulators involved in the pathophysiology of suicidal behavior and major affective disorders
- 2015
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In: Bioactive Natural Products: Chemistry and Biology. - Weinheim, Germany : Wiley-VCH Verlag GmbH & Co. KGaA. - 9783527337941 - 9783527684403 ; , s. 409-442
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Book chapter (peer-reviewed)abstract
- Neuropeptides, protein-like molecules used for direct communication between neurons, may play a critical role in the pathophysiology of mood disorders and suicidal behavior. This chapter aims to critically review the current literature on associations between neuropeptides, major affective disorders, and suicidal behavior. Most studies included in this overview reported an association between suicidality and corticotropin-releasing factor (CRF), VGF nerve growth factor inducible (VGF), cholecystokinin (CCK), orexin, substance P, and neuropeptide Y (NPY). It has been suggested that these molecules play a key role in many biological functions and act as important neuromodulators of emotional processing. The majority of the studies reviewed in this chapter found that suicidal subjects display higher mean concentrations of various neuropeptides compared to control subjects although depressed patients and suicide completers may also display lower NPY levels throughout the brain compared to healthy controls or individuals deceased from causes other than suicide. In addition, some studies have reported that orexin and corticotropin-releasing hormone (CRH) levels are lower in suicidal patients. In spite of these cross-sectional reports, a causal link between neuropeptide dysregulation and suicidality cannot be determined. The main implications of the studies that are included in the present chapter are critically analyzed and discussed.
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