Oliver Sander

Structural brain alterations associated with depression and anxiety are subtle, heterogeneous, and difficult to characterize. We applied autoencoder-based normative modeling to contrastively learned structural MRI representations from two large population-based cohorts (German National Cohort, N ≈ 29,000; UK Biobank, N ≈ 25,000) to quantify individual deviations from normative brain structure across symptom dimensions of depression, anxiety, and, for contextualization, alcohol use. Deviation magnitude increased with symptom severity for depressive and anxiety symptoms and was most pronounced in individuals with high alcohol use. Directional analyses revealed shared deviation patterns for depression and anxiety that were largely distinct from alcohol-related deviations, and these patterns generalized across cohorts. These affective-symptom-related patterns implicated distributed regional brain-structural variation. Individual deviation profiles improved classification of symptomatic status beyond demographic covariates, with gains concentrated at higher symptom severity. Together, these findings indicate that affective symptoms are associated with reproducible, dimensional patterns of regional brain-structural deviation that extend beyond normative population variability, supporting transdiagnostic models of internalizing psychopathology.

Background: The disease-specific patient-reported outcome for ANCA-associated vasculitis (AAV-PRO) was developed by the Outcome Measures in Rheumatology (OMERACT) group. Its interpretation in routine clinical practice remains challenging due to limited evidence regarding the association with established clinical outcome measures. Methodology: We conducted a prospective cohort study of 70 AAV-patients who completed the AAV-PRO and the following additional questionnaires: Short Form-36 (SF-36), assessing health-related quality of life; Fatigue Severity Scale (FSS) measuring fatigue severity; Index zur Messung von Einschränkungen der Teilhabe (IMET), assessing restrictions in participation in everyday life; Funktionsfragebogen-Hannover (FFbH), evaluating abilities and limitations in daily activities; Patient Health Questionnaire-9 (PHQ-9), screening for depressive symptoms; and Life Orientation Test–Revised (LOT-R), assessing optimism and expectations. Physicians assessed disease activity, related damage and glucocorticoid side-effects using the Birmingham Vasculitis Activity Score (BVAS), vasculitis damage index (VDI) and glucocorticoid toxicity index (GTI). Results: 70 patients with AAV participated in the study, including 45 patients with GPA; 64.3%, 16 with EGPA; 22.9%, and 9 with MPA; 12.8%. At study inclusion, the mean disease duration was 10.5 years (SD 7.9). Patients with active disease had higher AAV-PRO scores across all domains. We observed strong correlations between AAV-PRO subdomains and the following validated measures: “Systemic symptoms” with SF-36 physical function (r = –0.72, 95% CI -0.85 to -0.58) and FFbH (r = –0.88, 95% CI -0.56 to -0.97); “Social and emotional impact” with SF-36 social role functioning (r = –0.8, 95% CI -0.87 to -0.69), IMET (r = 0.7, 95% CI 0.55 to 0.81) and FFbH (r = -0.75, 95% CI -0.94 to -0.23); “Concerns about the future” with SF-36 social role functioning (r = –0.71, 95% CI -0.81 to -0.55) and FFbH (r = –0.77, 95% CI -0.94 to -0.27); “Physical function” with SF-36 physical function (r = –0.9, 95% CI -0.94 to -0.84) and IMET (r = 0.79, 95% CI 0.68 to 0.87). Conclusion: The German AAV-PRO captures patient-perceived disease burden, complementing traditional clinical outcome measures. Its multidimensional approach allows assessment of functional, psychosocial and symptom-related aspects of AAV, supporting its use in clinical practice.

Background: The Post-COVID syndrome is associated with the generation of autoantibodies to vasoregulative G-protein coupled receptors (GPCR). It remains elusive, however, whether these autoantibodies play a pathophysiological role in this disease. The present study investigates whether detection and concentration of GPCR autoantibodies are related to vascular function in patients with Post-COVID. Materials and methods: We performed a cross-sectional study, enrolling 80 patients with Post-COVID and 54 individuals with a history of SARS-CoV-2 infection without persisting symptoms (control group). ELISA measurement of GPCR autoantibodies encompassed autoantibodies to Angiotensin-II-Receptor-1 (AGTR2), Beta-1 Adrenergic Receptor (ADRB1), Beta-2 Adrenergic Receptor (ADRB2), Endothelin Receptor (EDNRA), Muscarinergic Choline Receptor 3 (CHRM3), and Muscarinergic Choline Receptor 4 (CHRM4). Endothelium-dependent vasodilation was assessed by flow mediated dilation (FMD). Measurement of central aortic blood pressure and capillary nailfold capillary microscopy were performed as additional assessments of vasoregulatory function. Lipoprotein-associated phospholipase A2 (Lp-PLA2) served as markers of vascular inflammation. Results: 52 (65%) patients with Post-COVID had positive autoantibody findings above previously established cut-off values, the incidence was lower in the non-Post-COVID group (n = 12, 22.2%, p = 0.0001). The median concentrations for AGTR2, ADRB1, CHRM3 and CHRM4 autoantibodies were significantly higher in the symptomatic cohort (p < 0.05 each). Spearman correlation analysis showed a strong and significant negative correlation of several GPCR autoantibodies with aortic systolic blood pressure (AGTR2 p = 0.026, ADRB1 p = 0.001, ADRB2 p = 0.012) and aortic diastolic blood pressure (ADRB1 p = 0.005, CHRM4 p = 0.046) in Post-COVID. High EDNRA autoantibodies titers were associated with FMD (p = 0.038). There was no significant association of any GPCR autoantibody concentration with FMD or Lp-PLA2 in the control group. Conclusion: GPCR autoantibodies were highly prevalent in this Post-COVID cohort. Several GPCR autoantibodies were associated with measures of vasorelaxation like lower systolic and diastolic aortic blood pressure and stronger endothelium-dependent vasodilation. However, given the absence of differences in microvascular and macrovascular function, the precise role of GPCR autoantibodies remains elusive.

Structural brain alterations associated with depression and anxiety are subtle, heterogeneous, and difficult to characterize. We applied autoencoder-based normative modeling to contrastively learned structural MRI representations from two large population-based cohorts (German National Cohort, N ≈ 29,000; UK Biobank, N ≈ 25,000) to quantify individual deviations from normative brain structure across symptom dimensions of depression, anxiety, and, for contextualization, alcohol use. Deviation magnitude increased with symptom severity for depressive and anxiety symptoms and was most pronounced in individuals with high alcohol use. Directional analyses revealed shared deviation patterns for depression and anxiety that were largely distinct from alcohol-related deviations, and these patterns generalized across cohorts. These affective-symptom-related patterns implicated distributed regional brain-structural variation. Individual deviation profiles improved classification of symptomatic status beyond demographic covariates, with gains concentrated at higher symptom severity. Together, these findings indicate that affective symptoms are associated with reproducible, dimensional patterns of regional brain-structural deviation that extend beyond normative population variability, supporting transdiagnostic models of internalizing psychopathology. Contact: emanuel.schwarz@zi-mannheim.de