Daniel Lindqvist

Interleukin-6 Is Elevated in the Cerebrospinal Fluid of Suicide Attempters and Related to Symptom Severity

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-1beta, interleukin-6 (IL-6), interleukin-8, and tumor necrosis factor-alpha (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 MADRS scores and CSF IL-6 levels in all patients. IL-6 and TNF-alpha 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.

Connecting inflammation with glutamate agonism in suicidality

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 (P<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.

Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging.

Many psychiatric illnesses are associated with early mortality and with an increased risk of developing physical diseases that are more typically seen in the elderly. Moreover, certain psychiatric illnesses may be associated with accelerated cellular aging, evidenced by shortened leukocyte telomere length (LTL), which could underlie this association. Shortened LTL reflects a cells mitotic history and cumulative exposure to inflammation and oxidation as well as the availability of telomerase, a telomere-lengthening enzyme. Critically short telomeres can cause cells to undergo senescence, apoptosis or genomic instability, and shorter LTL correlates with poorer health and predicts mortality. Emerging data suggest that LTL may be reduced in certain psychiatric illnesses, perhaps in proportion to exposure to the psychiatric illnesses, although conflicting data exist. Telomerase has been less well characterized in psychiatric illnesses, but a role in depression and in antidepressant and neurotrophic effects has been suggested by preclinical and clinical studies. In this article, studies on LTL and telomerase activity in psychiatric illnesses are critically reviewed, potential mediators are discussed, and future directions are suggested. A deeper understanding of cellular aging in psychiatric illnesses could lead to re-conceptualizing them as systemic illnesses with manifestations inside and outside the brain and could identify new treatment targets.

Cerebrospinal fluid inflammatory markers in Parkinson’s disease – Associations with depression, fatigue, and cognitive impairment ☆

Neuroinflammation may be involved in the pathophysiology of Parkinsons 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.

Non-Motor Symptoms in Patients with Parkinson's Disease - Correlations with Inflammatory Cytokines in Serum

Background 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. Methods and Materials We measured C-reactive protein, interleukin (IL)-6, soluble IL-2 receptor (sIL-2R) and tumor necrosis factor-α (TNF-α) in blood samples from PD patients (n = 86) and healthy controls (n = 40). Symptoms of fatigue, depression, anxiety and sleeping difficulties were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT), the Hospital Anxiety and Depression Scale (HAD), and the Scales for Outcome in PD-Sleep Scale respectively. Results IL-6 was significantly higher in PD patients than in healthy controls. Compared to healthy controls, PD patients displayed significantly higher mean scores on HAD and lower scores on FACIT, thus indicating more severe symptoms as measured with these scales. Within the PD sample, high levels of both sIL-2R and TNF-α were significantly associated with more severe symptoms assessed by means of FACIT and HAD (depression and anxiety subscales). SIL-2-R levels were able to significantly predict FACIT and HAD scores after the effects of age, gender, anti-parkinsonian medications, and severity of motor symptoms were controlled for. Discussion We suggest that non-motor symptoms in PD patients, such as fatigue and depressive symptoms, might be generated via inflammatory mechanisms. This knowledge might contribute to the development of novel treatment options in PD, specifically targeting non-motor symptoms.

CSF biomarkers and clinical progression of Parkinson disease

Objective: To investigate whether certain CSF biomarkers at baseline can predict future progression of motor symptoms and cognitive decline in patients with Parkinson disease (PD). Methods: Patients and controls were recruited from hospitals in southern Sweden as part of the prospective and longitudinal Swedish BioFinder Study. In the present study, we included 42 patients with PD and 69 controls who had clinical assessment and lumbar puncture at baseline. Baseline CSF samples were analyzed for α-synuclein (αSyn), β-amyloid 1–42 (Aβ42), tau, phosphorylated tau, and neurofilament light. Associations between CSF markers at baseline and change in clinical characteristics after 2 years of follow-up were investigated using multivariate models adjusting for age, sex, disease duration, and levodopa-equivalent daily dose. Results: Higher levels of αSyn within the PD group were associated with progression of motor symptoms and cognitive decline over 2 years, indicated by significant relationships between αSyn and change in Hoehn and Yahr (β = 0.394, p = 0.043), Unified Parkinsons Disease Rating Scale, Part III (UPDRS-III) (β = 0.449, p = 0.013), Timed Up and Go (β = 0.406, p = 0.023), and A Quick Test of Cognitive Speed (β = 0.423, p = 0.018). Lower levels of Aβ42 were associated with worsening of performance on delayed memory recall (F = 5.834, p = 0.022). Finally, high levels of phosphorylated tau were associated with worsening in motor symptoms (UPDRS-III, β = 0.350, p = 0.045; Hoehn and Yahr, β = 0.366, p = 0.038). Conclusion: We found evidence of a link between higher levels of αSyn at baseline and worsening of motor symptoms and cognitive speed over 2 years in PD. Increased αSyn might be a marker of more intense synaptic degeneration in PD. The results indicate that cortical amyloid pathology (low CSF Aβ42) is associated with memory decline.

Salivary cortisol and suicidal behavior-A follow-up study.

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.

The Association Between Psychiatric Disorders and Telomere Length: A Meta-Analysis Involving 14,827 Persons.

Objective This study examined the relationship between leukocyte telomere length (LTL), a marker of cell aging, and psychiatric disorders in adults compared with controls using meta-analytic methods. Methods Data were abstracted from studies examining the relationship between LTL and adult psychiatric disorders. In addition to an overall estimate of effect size, subgroup analyses and meta-regression were performed to examine whether covariates (including psychiatric diagnoses) moderated the estimate. Results A significant overall effect size showing LTL shortening was found across all psychiatric disorders (Hedge g = −0.50, p < .001). Subgroup analyses did not demonstrate significant differences in effect size based on individual covariates (psychiatric disorder, sex, age, or assay method). The meta-regression indicated that although type of disorder and, likely, age moderate the overall effect size, the heterogeneity between studies could not be explained by a model that included these variables as well as sex and assay method. Although not significantly different, posttraumatic stress disorder, anxiety disorders, and depressive disorders had comparatively larger effect sizes (−1.27, −0.53, and −0.55), and psychotic and bipolar disorders had comparatively smaller ones (−0.23 and −0.26). Conclusions We observed a robust effect size of LTL shortening for psychiatric disorders as a whole compared with controls. The results were less straightforward regarding relative differences in the strength of this association by specific disorder. Future studies should focus on mechanisms explaining accelerated cell aging with psychiatric illness, defining directions (if any) of causality and elucidating possible differences in this association between disorders.

CSF biomarkers in suicide attempters – a principal component analysis

Lindqvist D, Janelidze S, Erhardt S, Träskman‐Bendz L, Engström G, Brundin L. CSF biomarkers in suicide attempters – a principal component analysis.

Increased CSF biomarkers of angiogenesis in Parkinson disease.

Objective: To study biomarkers of angiogenesis in Parkinson disease (PD), and how these are associated with clinical characteristics, blood–brain barrier (BBB) permeability, and cerebrovascular disease. Methods: In this cross-sectional analysis, 38 elderly controls and 100 patients with PD (82 without dementia and 18 with dementia) were included from the prospective Swedish BioFinder study. CSF samples were analyzed for the angiogenesis biomarkers vascular endothelial growth factor (VEGF); its receptors, VEGFR-1 and VEGFR-2; placental growth factor (PlGF); angiopoietin 2 (Ang2); and interleukin-8. BBB permeability, white matter lesions (WMLs), and cerebral microbleeds (CMB) were assessed. CSF angiogenesis biomarkers were also measured in 2 validation cohorts: (1) 64 controls and 87 patients with PD with dementia; and (2) 35 controls and 93 patients with neuropathologically confirmed diagnosis of PD with and without dementia. Results: Patients with PD without dementia displayed higher CSF levels of VEGF, PlGF, and sVEGFR-2, and lower levels of Ang2, compared to controls. Similar alterations in VEGF, PlGF, and Ang2 levels were observed in patients with PD with dementia. Angiogenesis markers were associated with gait difficulties and orthostatic hypotension as well as with more pronounced BBB permeability, WMLs, and CMB. Moreover, higher levels of VEGF and PlGF levels were associated with increased CSF levels of neurofilament light (a marker of neurodegeneration) and monocyte chemotactic protein–1 (a marker of glial activation). The main results were validated in the 2 additional cohorts. Conclusions: CSF biomarkers of angiogenesis are increased in PD, and they are associated with gait difficulties, BBB dysfunction, WMLs, and CMB. Abnormal angiogenesis may be important in PD pathogenesis and contribute to dopa-resistant symptoms.