Immune signature of multiple sclerosis-associated depression.

Multiple neurobiological pathways have been implicated in the pathobiology of major depressive disorder (MDD). The identification of reliable biological substrates across the entire MDD spectrum, however, is hampered by a vast heterogeneity in the clinical presentation, presumably as a consequence of heterogeneous pathobiology. One way to overcome this limitation could be to explore disease subtypes based on biological similarity such as "inflammatory depression". As such a subtype may be particularly enriched in depressed patients with an underlying inflammatory condition, multiple sclerosis (MS) could provide an informative disease context for this approach. Few studies have explored immune markers of MS-associated depression and replications are missing. To address this, we analyzed data from two independent case-control studies on immune signatures of MS-associated depression, conducted at two different academic MS centers (overall sample size of n = 132). Using a stepwise data-driven approach, we identified CD4+CCR7lowTCM cell frequencies as a robust correlate of depression in MS. This signature was associated with core symptoms of depression and depression severity (but not MS severity per se) and linked to neuroinflammation as determined by magnetic resonance imaging (MRI). Furthermore, exploratory analyses of T cell polarization revealed this was largely driven by cells with a TH1-like phenotype. Our findings suggest (neuro)immune pathways linked to affective symptoms of autoimmune disorders such as MS, with potential relevance for the understanding of "inflammatory" subtypes of depression.

Immunological substrates of depressive symptoms in patients with severe obesity: An exploratory study.

In this pilot study, we explored the immune phenotype of patients with severe obesity and comorbid depressive symptoms compared to non-depressed patients with obesity and normal-weight controls. Immune cell subsets were analysed by flow cytometry and depressive symptoms assessed using the Patient Health Questionnaire (PHQ-9). Cell frequencies were correlated with depressive symptom scores and waist-to-hip ratio (WHR). Patients with obesity and comorbid depression showed significantly lower numbers of circulating cytotoxic natural killer cells, dendritic cells and CD8+ effector memory T cells, compared to normal-weight controls. Regulatory T cells and CD4+ central memory T cells were increased compared to non-depressed patients with obesity and compared to normal-weight controls, respectively. Frequencies of cytotoxic natural killer cells and CD4+ central memory T cells significantly correlated with PHQ-9 scores, but not with WHR. Reduced numbers of dendritic cells were observed in both patient groups with obesity and correlated with PHQ-9 scores and WHR. These findings provide evidence for an altered immune composition in comorbid obesity and depression, supporting a pathobiological overlap between the two disorders.

Body mass, neuro-hormonal stress processing, and disease activity in lean to obese people with multiple sclerosis.

Overweight and obesity can worsen disease activity in multiple sclerosis (MS). Although psychobiological stress processing is increasingly recognized as important obesity factor that is tightly connected to proinflammatory metabolic hormones and cytokines, its role for MS obesity remains unexplored. Consequently, we investigated the interplay between body mass index (BMI), neural stress processing (functional connectivity, FC), and immuno-hormonal stress parameters (salivary cortisol and T cell glucocorticoid [GC] sensitivity) in 57 people with MS (six obese, 19 over-, 28 normal-, and four underweight; 37 females, 46.4 ± 10.6 years) using an Arterial-Spin-Labeling MRI task comprising a rest and stress stage, along with quantitative PCR. Our findings revealed significant positive connections between BMI and MS disease activity (i.e., higher BMI was accompanied by higher relapse rate). BMI was positively linked to right supramarginal gyrus and anterior insula FC during rest and negatively to right superior parietal lobule and cerebellum FC during stress. BMI showed associations with GC functioning, with higher BMI associated with lower CD8+ FKBP4 expression and higher CD8+ FKBP5 expression on T cells. Finally, the expression of CD8+ FKBP4 positively correlated with the FC of right supramarginal gyrus and left superior parietal lobule during rest. Overall, our study provides evidence that body mass is tied to neuro-hormonal stress processing in people with MS. The observed pattern of associations between BMI, neural networks, and GC functioning suggests partial overlap between neuro-hormonal and neural-body mass networks. Ultimately, the study underscores the clinical importance of understanding multi-system crosstalk in MS obesity.

A review on multiple sclerosis prognostic findings from imaging, inflammation, and mental health studies.

Magnetic resonance imaging (MRI) of the brain is commonly used to detect where chronic and active lesions are in multiple sclerosis (MS). MRI is also extensively used as a tool to calculate and extrapolate brain health by way of volumetric analysis or advanced imaging techniques. In MS patients, psychiatric symptoms are common comorbidities, with depression being the main one. Even though these symptoms are a major determinant of quality of life in MS, they are often overlooked and undertreated. There has been evidence of bidirectional interactions between the course of MS and comorbid psychiatric symptoms. In order to mitigate disability progression in MS, treating psychiatric comorbidities should be investigated and optimized. New research for the prediction of disease states or phenotypes of disability have advanced, primarily due to new technologies and a better understanding of the aging brain.

Associations between individual depressive symptoms and immunometabolic characteristics in major depression.

Inflammation and metabolic dysregulations are likely to underlie atypical, energy-related depressive symptoms such as appetite and sleep alterations. Indeed, increased appetite was previously identified as a core symptom of an immunometabolic subtype of depression. The aim of this study was 1) to replicate the associations between individual depressive symptoms and immunometabolic markers, 2) to extend previous findings with additional markers, and 3) to evaluate the relative contribution of these markers to depressive symptoms. We analyzed data from 266 persons with major depressive disorder (MDD) in the last 12 months from the German Health Interview and Examination Survey for Adults and its mental health module. Diagnosis of MDD and individual depressive symptoms were determined by the Composite International Diagnostic Interview. Associations were analyzed using multivariable regression models, adjusting for depression severity, sociodemographic/behavioral variables, and medication use. Increased appetite was associated with higher body mass index (BMI), waist circumference (WC), insulin, and lower high-density lipoprotein. In contrast, decreased appetite was associated with lower BMI, WC, and fewer metabolic syndrome (MetS) components. Insomnia was associated with higher BMI, WC, number of MetS components, triglycerides, insulin, and lower albumin, while hypersomnia was associated with higher insulin. Suicidal ideation was associated with higher number of MetS components, glucose, and insulin. None of the symptoms were associated with C-reactive protein after adjustment. Appetite alterations and insomnia were most important symptoms associated with metabolic markers. Longitudinal studies should investigate whether the candidate symptoms identified here are predicted by or predict the development of metabolic pathology in MDD.

Efficacy and Safety of Antidepressants in Patients With Comorbid Depression and Medical Diseases: An Umbrella Systematic Review and Meta-Analysis.

Importance: Every third to sixth patient with medical diseases receives antidepressants, but regulatory trials typically exclude comorbid medical diseases. Meta-analyses of antidepressants have shown small to medium effect sizes, but generalizability to clinical settings is unclear, where medical comorbidity is highly prevalent. Objective: To perform an umbrella systematic review of the meta-analytic evidence and meta-analysis of the efficacy and safety of antidepressant use in populations with medical diseases and comorbid depression. Data Sources: PubMed and EMBASE were searched from inception until March 31, 2023, for systematic reviews with or without meta-analyses of randomized clinical trials (RCTs) examining the efficacy and safety of antidepressants for treatment or prevention of comorbid depression in any medical disease. Study Selection: Meta-analyses of placebo- or active-controlled RCTs studying antidepressants for depression in individuals with medical diseases. Data Extraction and Synthesis: Data extraction and quality assessment using A Measurement Tool for the Assessment of Multiple Systematic Reviews (AMSTAR-2 and AMSTAR-Content) were performed by pairs of independent reviewers following PRISMA guidelines. When several meta-analyses studied the same medical disease, the largest meta-analysis was included. Random-effects meta-analyses pooled data on the primary outcome (efficacy), key secondary outcomes (acceptability and tolerability), and additional secondary outcomes (response and remission). Main Outcomes and Measures: Antidepressant efficacy presented as standardized mean differences (SMDs) and tolerability (discontinuation for adverse effects) and acceptability (all-cause discontinuation) presented as risk ratios (RRs). Results: Of 6587 references, 176 systematic reviews were identified in 43 medical diseases. Altogether, 52 meta-analyses in 27 medical diseases were included in the evidence synthesis (mean [SD] AMSTAR-2 quality score, 9.3 [3.1], with a maximum possible of 16; mean [SD] AMSTAR-Content score, 2.4 [1.9], with a maximum possible of 9). Across medical diseases (23 meta-analyses), antidepressants improved depression vs placebo (SMD, 0.42 [95% CI, 0.30-0.54]; I2 = 76.5%), with the largest SMDs for myocardial infarction (SMD, 1.38 [95% CI, 0.82-1.93]), functional chest pain (SMD, 0.87 [95% CI, 0.08-1.67]), and coronary artery disease (SMD, 0.83 [95% CI, 0.32-1.33]) and the smallest for low back pain (SMD, 0.06 [95% CI, 0.17-0.39]) and traumatic brain injury (SMD, 0.08 [95% CI, -0.28 to 0.45]). Antidepressants showed worse acceptability (24 meta-analyses; RR, 1.17 [95% CI, 1.02-1.32]) and tolerability (18 meta-analyses; RR, 1.39 [95% CI, 1.13-1.64]) compared with placebo. Antidepressants led to higher rates of response (8 meta-analyses; RR, 1.54 [95% CI, 1.14-1.94]) and remission (6 meta-analyses; RR, 1.43 [95% CI, 1.25-1.61]) than placebo. Antidepressants more likely prevented depression than placebo (7 meta-analyses; RR, 0.43 [95% CI, 0.33-0.53]). Conclusions and Relevance: The results of this umbrella systematic review of meta-analyses found that antidepressants are effective and safe in treating and preventing depression in patients with comorbid medical disease. However, few large, high-quality RCTs exist in most medical diseases.

Negative Associations of Stress and Anxiety Levels With Cytotoxic and Regulatory Natural Killer Cell Frequency in Chronic Tinnitus.

Background: Depression and anxiety are known to be associated with stress-induced changes in the immune system. Bothersome tinnitus can be related to stress and often co-occurs with depression and anxiety. This study investigates associations of psychological and audiological tinnitus-related factors with inflammatory parameters and immune cell subsets in chronic tinnitus patients as well as treatment-related effects. Methods: This longitudinal study of inpatients treated with compact multimodal tinnitus-specific cognitive behavioral therapy included four repeated measurement sessions: baseline (N = 41), treatment end, 7.8-week (N = 35), and 13.8-week follow-up (N = 34). Data collection included audiometric testing, blood sampling, and psychometric questionnaires: Tinnitus Handicap Inventory (THI), Perceived Stress Questionnaire (PSQ-20), and Hospital Anxiety Depression Scale (HADS). Flow cytometry was used to analyze immune cell subsets. Statistical analyses comprised correlation and network analysis (cross-sectional), and linear mixed effect models (longitudinal). Results: Bootstrapped network analysis showed negative averaged cross-sectional associations of cytotoxic natural killer (NKc) cell frequency (CD56 + CD16+) and PSQ-20 (-0.21 [-0.48, 0]) and of regulatory natural killer (NKreg) cell frequency (CD56 + CD16dim/-) and HADS anxiety (-0.14 [-0.38, 0]). No significant treatment effects were found. A negative predictive effect of baseline PSQ-20 scores (ß = -6.22 [-12.18, -0.26], p = 0.041) and a positive predictive effect of baseline ferritin levels (ß = 8.90 [2.76, 15.03], p = 0.004) on NKc cell frequency across the repeated measurement sessions were observed. Conclusion: We observed negative relationships between perceived stress levels and NKc cell frequency and between anxiety levels and NKreg cell frequency in chronic tinnitus patients. These exploratory results suggest stress-/anxiety-related immune alterations in bothersome tinnitus but need to be tested in further confirmatory studies with larger sample sizes. The potential of NK cells as biomarkers of emotional distress in chronic tinnitus should be further investigated.

Prefrontal-amygdala emotion regulation and depression in multiple sclerosis.

Depression is among the most common comorbidities in multiple sclerosis and has severe psychosocial consequences. Alterations in neural emotion regulation in amygdala and prefrontal cortex have been recognized as key mechanism of depression but never been investigated in multiple sclerosis depression. In this cross-sectional observational study, we employed a functional MRI task investigating neural emotion regulation by contrasting regulated versus unregulated negative stimulus perception in 16 persons with multiple sclerosis and depression (47.9 ± 11.8 years; 14 female) and 26 persons with multiple sclerosis but without depression (47.3 ± 11.7 years; 14 female). We tested the impact of depression and its interaction with lesions in amygdala-prefrontal fibre tracts on brain activity reflecting emotion regulation. A potential impact of sex, age, information processing speed, disease duration, overall lesion load, grey matter fraction, and treatment was taken into account in these analyses. Patients with depression were less able (i) to downregulate negative emotions than those without (t = -2.25, P = 0.012, ß = -0.33) on a behavioural level according to self-report data and (ii) to downregulate activity in a left amygdala coordinate (t = 3.03, P Family-wise error [FWE]-corrected = 0.017, ß = 0.39). Moreover, (iii) an interdependent effect of depression and lesions in amygdala-prefrontal tracts on activity was found in two left amygdala coordinates (t = 3.53, pFWE = 0.007, ß = 0.48; t = 3.21, pFWE = 0.0158, ß = 0.49) and one right amygdala coordinate (t = 3.41, pFWE = 0.009, ß = 0.51). Compatible with key elements of the cognitive depression theory formulated for idiopathic depression, our study demonstrates that depression in multiple sclerosis is characterized by impaired neurobehavioural emotion regulation. Complementing these findings, it shows that the relation between neural emotion regulation and depression is affected by lesion load, a key pathological feature of multiple sclerosis, located in amygdala-prefrontal tracts.

Central stress processing, T-cell responsivity to stress hormones and disease severity in multiple sclerosis.

Epidemiological, clinical and neuroscientific studies support a link between psychobiological stress and multiple sclerosis. Neuroimaging suggests that blunted central stress processing goes along with higher multiple sclerosis severity, neuroendocrine studies suggest that blunted immune system sensitivity to stress hormones is linked to stronger neuroinflammation. Until now, however, no effort has been made to elucidate whether central stress processing and immune system sensitivity to stress hormones are related in a disease-specific fashion, and if so, whether this relation is clinically meaningful. Consequently, we conducted two functional MRI analyses based on a total of 39 persons with multiple sclerosis and 25 healthy persons. Motivated by findings of an altered interplay between neuroendocrine stress processing and T-cell glucocorticoid sensitivity in multiple sclerosis, we searched for neural networks whose stress task-evoked activity is differentially linked to peripheral T-cell glucocorticoid signalling in patients versus healthy persons as a potential indicator of disease-specific CNS-immune crosstalk. Subsequently, we tested whether this activity is simultaneously related to disease severity. We found that activity of a network comprising right anterior insula, right fusiform gyrus, left midcingulate and lingual gyrus was differentially coupled to T-cell glucocorticoid signalling across groups. This network's activity was simultaneously linked to patients' lesion volume, clinical disability and information-processing speed. Complementary analyses revealed that T-cell glucocorticoid signalling was not directly linked to disease severity. Our findings show that alterations in the coupling between central stress processing and T-cell stress hormone sensitivity are related to key severity measures of multiple sclerosis.

Reduced mitochondrial respiration in T cells of patients with major depressive disorder.

Converging evidence indicates that major depressive disorder (MDD) and metabolic disorders might be mediated by shared (patho)biological pathways. However, the converging cellular and molecular signatures remain unknown. Here, we investigated metabolic dysfunction on a systemic, cellular, and molecular level in unmedicated patients with MDD compared with matched healthy controls (HC). Despite comparable BMI scores and absence of cardiometabolic disease, patients with MDD presented with significant dyslipidemia. On a cellular level, T cells obtained from patients with MDD exhibited reduced respiratory and glycolytic capacity. Gene expression analysis revealed increased carnitine palmitoyltransferase IA (CPT1a) levels in T cells, the rate-limiting enzyme for mitochondrial long-chain fatty acid oxidation. Together, our results indicate metabolic dysfunction in unmedicated, non-overweight patients with MDD on a systemic, cellular, and molecular level. This evidence for reduced mitochondrial respiration in T cells of patients with MDD provides translation of previous animal studies regarding a putative role of altered immunometabolism in depression pathobiology.

Neural mechanisms of perceptual decision-making and their link to neuropsychiatric symptoms in multiple sclerosis.

BACKGROUND: Decision-making (DM) capabilities are impaired in multiple sclerosis (MS). A variety of researchers hypothesized that this impairment is associated with reduced quality of life (QoL) and neuropsychiatric symptoms. Studies explicitly testing this hypothesis, however, are rare, provided inconclusive results, or evaluated only a limited selection of DM domains. Consequently, we conducted the first MS study on perceptual DM (e.g. deciding whether a car will fit into a parking lot based on a visual percept) to test this assumption. METHODS: Specifically, we used an fMRI task that measured brain activity in 30 MS patients and 19 healthy controls (HCs) while the participants repeatedly decided whether objects referenced indirectly via their written object names would fit into a shoebox to investigate neural mechanisms of perceptual DM. The objects varied in size and thus decision difficulty. From these data, we determined voxel-wise brain activity parameters reflecting (i) decision difficulty and (ii) decision speed and related them to behavioral DM performance, QoL, mild to moderate depressive symptoms, and fatigue. RESULTS: Patients showed reduced DM performance. Activity reflecting decision difficulty in the middle temporal gyrus was negatively related to DM performance across MS patients and HCs; activity reflecting decision speed in MS patients was associated with depressive symptoms and fatigue in areas of the dorsal visual stream. CONCLUSION: The study shows that the perceptual DM capacity is reduced in MS. Moreover, the link between neural mechanisms of perceptual DM and neuropsychiatric symptoms suggests that an impairment in this domain is clinically relevant.