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Abstract White matter hyperintensities index structural abnormalities in the cerebral white matter, including axonal damage. The latter may promote atrophy of the cerebral cortex, a key feature of dementia. Here, we report a study of 51,065 individuals from 10 cohorts demonstrating that higher white matter hyperintensity volume associates with lower cortical thickness. The meta-GWAS of white matter hyperintensities-associated cortical ‘atrophy’ identifies 20 genome-wide significant loci, and enrichment in genes specific to vascular cell types, astrocytes, and oligodendrocytes. White matter hyperintensities-associated cortical ‘atrophy’ showed positive genetic correlations with vascular-risk traits and plasma biomarkers of neurodegeneration, and negative genetic correlations with cognitive functioning. 15 of the 20 loci regulated the expression of 54 genes in the cerebral cortex that, together with their co-expressed genes, were enriched in biological processes of axonal cytoskeleton and intracellular transport. The white matter hyperintensities-cortical thickness associations were most pronounced in cortical regions with higher expression of genes specific to excitatory neurons with long-range axons traversing through the white matter. The meta-GWAS-based polygenic risk score predicts vascular and all-cause dementia in an independent sample of 500,348 individuals. Thus, the genetics of white matter hyperintensities-related cortical atrophy involves vascular and neuronal processes and increases dementia risk.

Abstract Background Glenoid version is an important factor in the evaluation of shoulder stability and shoulder pathologies. However, there are neither established reference values nor known factors that influence the glenoid version, even though valid reference values are needed for diagnostic and orthopaedic surgery like corrective osteotomy and total or reverse shoulder arthroplasty (TSA/RSA). The aim of our population-based study was to identify factors influencing the glenoid version and to establish reference values from a large-scale population cohort. Results Our study explored the glenoid versions in a large sample representing the general adult population. We investigated 3004 participants in the population-based Study of Health in Pomerania (SHIP). Glenoid version was measured for both shoulders via magnetic resonance imaging (MRI). Associations with the glenoid version were calculated for sex, age, body height, body weight and BMI. The reference values for glenoid version in the central European population range between −9° and 7.5°, while multiple factors are associated with the glenoid version. Conclusion To achieve a reliable interpretation prior to orthopaedic surgery, sex- and age-adjusted reference values are proposed.

Background and aim: As the spleen plays a significant role in immunity, the aim was to investigate the associations of different body composition markers derived from various sources with spleen volume in a general population sample. Materials and methods: Cross-sectional data of 1095 individuals (570 women; 52%) aged between 30 and 90 years were collected in the Study of Health in Pomerania (SHIP-START-2). We measured spleen volume by magnetic resonance imaging (MRI).Body composition markers were derived from classic anthropometry, bioelectrical impedance analysis, including absolute fat mass (FM) and fat-free mass (FFM), as well as from MRI, including visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and liver fat content. Sex-stratified-adjusted linear regression models were used to analyze the associations of body composition markers with spleen volumes. Results: We observed positive associations of body mass index, body weight, waist circumference, hip circumference, waist-to-height ratio, absolute FM, absolute FFM, and VAT and SAT with spleen volume in men and women. An 8.12 kg higher absolute FFM was associated with a 38.4 mL (95% confidence interval [CI]: 26.7–50.1) higher spleen volume in men and a 5.21 kg higher absolute FFM with a 42.6 mL (95% CI: 26.2–59.0) higher spleen volume in women. Conclusion: Our findings indicate that obesity-related body composition markers and FFM are associated with a higher spleen volume. Particularly, higher absolute FFM showed a strong association with a larger spleen volume in both men and women. Further studies are warranted to understand the clinical significance of body composition markers on large spleen volume.

Abstract Background To date, colchicine and prednisolone are two effective therapies for the treatment of acute gout but have never been compared directly in a randomized clinical trial. In addition, in previous trials of treating acute gout patients with concomitant comorbidities were often excluded due to contraindications to naproxen. Study design This pragmatic, prospective, double-blind, double-dummy, parallel-group, randomized, non-inferiority trial compares prednisolone with colchicine in terms of non-inferiority in patients with acute gout. Patients presenting to their general practitioner with acute gout can be included if the gout attack has occurred within the last 2 days. A total of 60 practices in the vicinity of three university medical centers (Greifswald, Göttingen, and Würzburg) participate in the study. The intervention group receives 30 mg prednisolone for 5 days, while the group of standard care receives low-dose colchicine (day 1: 1.5 mg; days 2–5: 1 mg). The first dose of treatment is provided at day 0 when patients present to the general practitioner due to an acute gout attack. From day 0 to day 6, patients will be asked to complete a study diary on daily basis regarding pain quantification. For safety reasons, potential side effects and the course of systolic blood pressure are also assessed. Statistical analysis plan N = 314 patients have to be recruited to compensate for 10% of dropout and to allow for showing non-inferiority of prednisolone compared to colchicine with a power of 90%. We use permuted block randomization with block sizes of 2, 4, and 6 to avoid imbalanced treatment arms in this multi-center study; patients are randomized in a 1:1 ratio. The absolute level of pain on day 3 (in the last 24 h) is the primary outcome and measured on a numerical rating scale (NRS: 0–10). Using a multiple linear regression model adjusted for age, sex, and pain at baseline, prednisolone is considered non-inferior if the effect estimate including the confidence intervals is lower than a margin of 1 unit on the NRS. Average response to treatment, joint swelling and tenderness, physical function of the joint, and patients’ global assessment of treatment success are secondary outcomes. Discussion The trial will provide evidence from a direct comparison of colchicine and prednisolone regarding their efficacy of pain reduction in acute gout patients of primary care and to indicate possible safety signals. Trial registration ClinicalTrials.gov Identifier: NCT05698680 first posted on January 26, 2023 (retrospectively registered).

Abstract Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects.

Abstract In magnetic resonance imaging (MRI), the perception of substandard image quality may prompt repetition of the respective image acquisition protocol. Subsequently selecting the preferred high-quality image data from a series of acquisitions can be challenging. An automated workflow may facilitate and improve this selection. We therefore aimed to investigate the applicability of an automated image quality assessment for the prediction of the subjectively preferred image acquisition. Our analysis included data from 11,347 participants with whole-body MRI examinations performed as part of the ongoing prospective multi-center German National Cohort (NAKO) study. Trained radiologic technologists repeated any of the twelve examination protocols due to induced setup errors and/or subjectively unsatisfactory image quality and chose a preferred acquisition from the resultant series. Up to 11 quantitative image quality parameters were automatically derived from all acquisitions. Regularized regression and standard estimates of diagnostic accuracy were calculated. Controlling for setup variations in 2342 series of two or more acquisitions, technologists preferred the repetition over the initial acquisition in 1116 of 1396 series in which the initial setup was retained (79.9%, range across protocols: 73–100%). Image quality parameters then commonly showed statistically significant differences between chosen and discarded acquisitions. In regularized regression across all protocols, ‘structured noise maximum’ was the strongest predictor for the technologists’ choice, followed by ‘N/2 ghosting average’. Combinations of the automatically derived parameters provided an area under the ROC curve between 0.51 and 0.74 for the prediction of the technologists’ choice. It is concluded that automated image quality assessment can, despite considerable performance differences between protocols and anatomical regions, contribute substantially to identifying the subjective preference in a series of MRI acquisitions and thus provide effective decision support to readers.

Abstract Background Gout is the most common form of rheumatic disease in which monosodium urate crystals are deposited in the joints followed by acute inflammatory reactions. There are various approved drugs that can be prescribed for pain relief during an acute gout attack. However, to date, no direct comparison of efficacy of colchicine and prednisolone for the treatment of acute gout attacks has been investigated. Furthermore, the majority of previous research studies were not only conducted in tertiary centres but also excluded patients with common comorbidities due to contraindications to naproxen. Methods This pragmatic, prospective, double-blind, double-dummy, parallel-group, randomized, non-inferiority trial investigates whether prednisolone (intervention) is non-inferior to treatment with colchicine (active control) in patients with acute gout. Adult patients presenting with acute gout to their general practitioners in 60 practices across 3 university sites (Greifswald, Göttingen, and Würzburg) are eligible to participate in the study. Participants in the intervention group receive 30 mg prednisolone for 5 days. Those in the control group receive low-dose colchicine (day 1: 1.5 mg; days 2–5: 1 mg). The primary outcome is the absolute level of the most severe pain on day 3 (in the last 24 h) measured with an 11-item numerical rating scale. Day 0 is the day patients take their study medication for the first time. They are then asked to fill out a study diary the same time each day for pain quantification. Pain scores are used for comparison between the two medications. Secondary outcomes are average response to treatment, swelling, tenderness and physical function of the joint, patients’ global assessment of treatment success, use of additional pain medication and non-pharmacological pain therapies. For safety reasons, potential side effects and course of systolic blood pressure are assessed. Discussion This trial will provide evidence on the effectiveness of pain reduction and side effects of colchicine and prednisolone in acute gout in primary care. Trial registration ClinicalTrials.gov Identifier: NCT05698680 first posted on January 26, 2023 (retrospectively registered). URL of trial registry record: https://clinicaltrials.gov/study/NCT05698680

Background: The aim of our study was to investigate associations of spleen volume with blood count markers and lipid profile in the general population. Materials & methods: Cross-sectional data from 1,106 individuals aged 30–90 years from the population-based Study of Health in Pomerania (SHIP-START-2) were analyzed. Blood count markers included red blood cell (RBC) counts, hemoglobin, platelet count, and white blood cell (WBC) counts. Lipid profile included total-cholesterol, high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) as well as triglycerides. Linear regression models adjusted for age, sex, body height, and weight were used to associate standardized spleen volume with blood counts and lipid profile markers. Results: Spleen volume was positively associated with RBC (β = 0.05; 95% confidence interval [CI] = 0.03 to 0.08) and hemoglobin (β = 0.05; 95% CI = 0.01 to 0.09) but inversely with platelet count (β = −16.3; 95% CI = –20.5 to −12.1) and WBC (β = −0.25; 95% CI = −0.37 to −0.14). Furthermore, spleen volume showed inverse associations with total cholesterol (β = −0.17; 95% CI = −0.24 to −0.09), HDL-C (β = −0.08; 95% CI = −0.10 to −0.05), and LDL-C (β = −0.12; 95% CI = −0.17 to −0.06). There was no significant association of spleen volume with triglycerides. Conclusion: Our study showed that the spleen volume is associated with markers of the blood count and lipid profile in the general population.

Abstract Large epidemiological studies such as the UK Biobank (UKBB) or German National Cohort (NAKO) provide unprecedented health-related data of the general population aiming to better understand determinants of health and disease. As part of these studies, Magnetic Resonance Imaging (MRI) is performed in a subset of participants allowing for phenotypical and functional characterization of different organ systems. Due to the large amount of imaging data, automated image analysis is required, which can be performed using deep learning methods, e. g. for automated organ segmentation. In this paper we describe a computational pipeline for automated segmentation of abdominal organs on MRI data from 20,000 participants of UKBB and NAKO and provide results of the quality control process. We found that approx. 90% of data sets showed no relevant segmentation errors while relevant errors occurred in a varying proportion of data sets depending on the organ of interest. Image-derived features based on automated organ segmentations showed relevant deviations of varying degree in the presence of segmentation errors. These results show that large-scale, deep learning-based abdominal organ segmentation on MRI data is feasible with overall high accuracy, but visual quality control remains an important step ensuring the validity of down-stream analyses in large epidemiological imaging studies.

Abstract Background In acute pancreatitis, secondary infection of pancreatic necrosis is a complication that mostly necessitates interventional therapy. A reliable prediction of infected necrotizing pancreatitis would enable an early identification of patients at risk, which however, is not possible yet. Methods This study aims to identify parameters that are useful for the prediction of infected necrosis and to develop a prediction model for early detection. We conducted a retrospective analysis from the hospital information and reimbursement data system and screened 705 patients hospitalized with diagnosis of acute pancreatitis who underwent contrast-enhanced computed tomography and additional diagnostic puncture or drainage of necrotic collections. Both clinical and laboratory parameters were analyzed for an association with a microbiologically confirmed infected pancreatic necrosis. A prediction model was developed using a logistic regression analysis with stepwise inclusion of significant variables. The model quality was tested by receiver operating characteristics analysis and compared to single parameters and APACHE II score. Results We identified a total of 89 patients with necrotizing pancreatitis, diagnosed by computed tomography, who additionally received biopsy or drainage. Out of these, 59 individuals had an infected necrosis. Eleven parameters showed a significant association with an infection including C-reactive protein, albumin, creatinine, and alcoholic etiology, which were independent variables in a predictive model. This model showed an area under the curve of 0.819, a sensitivity of 0.692 (95%-CI [0.547–0.809]), and a specificity of 0.840 (95%-CI [0.631–0.947]), outperforming single laboratory markers and APACHE II score. Even in cases of missing values predictability was reliable. Conclusion A model consisting of a few single blood parameters and etiology of pancreatitis might help for differentiation between infected and non-infected pancreatic necrosis and assist medical therapy in acute necrotizing pancreatitis.

Shoulder pain is a common issue often linked to conditions such as subacromial impingement or rotator cuff lesions. The role of the acromion in these symptoms remains a subject of debate. This study aims to establish standardized values for commonly used acromion dimensions based on whole-body MRI scans of a large and healthy population and to investigate potential correlations between acromion shape and influencing factors such as sex, age, BMI, dominant hand, and shoulder pain. The study used whole-body MRI scans from the Study of Health in Pomerania, a German population-based study. Acromion index, acromion tilt, and acromion slope were measured. Interrater variability was tested with two independent, trained viewers on 100 MRI sequences before actual measurements started. Descriptive statistics and logistic regression were used to evaluate the results. We could define reference values based on a shoulder-healthy population for each acromion parameter within the 2.5 to 97.5 percentile. No significant differences were found in acromion slope, tilt, and index between male and female participants. No significant correlations were observed between acromion morphology and anthropometric parameters such as height, weight, or BMI. No significant differences were observed in acromion parameters between dominant and non-dominant hands or stated pain intensity. This study provides valuable reference values for acromion-related parameters, offering insight into the anatomy of a healthy shoulder. The findings indicate no significant differences in acromion morphology based on sex, weight, BMI, or dominant hand. Further research is necessary to ascertain the clinical implications of these reference values. The establishment of standardized reference values opens new possibilities for enhancing clinical decision making regarding surgical interventions, such as acromioplasty.

White matter lesions (WML) emerge as a consequence of vascular injuries in the brain. While they are commonly observed in aging, associations have been established with neurodegenerative and neurological disorders such as dementia or stroke. Despite substantial research efforts, biological mechanisms are incomplete and biomarkers indicating WMLs are lacking. Utilizing data from the population-based Study of Health in Pomerania (SHIP), our objective was to identify plasma-circulating micro-RNAs (miRNAs) associated with WMLs, thus providing a foundation for a comprehensive biological model and further research. In linear regression models, direct association and moderating factors were analyzed. In 648 individuals, we identified hsa-miR-425-5p as directly associated with WMLs. In subsequent analyses, hsa-miR-425-5p was found to regulate various genes associated with WMLs with particular emphasis on the SH3PXD2A gene. Furthermore, miR-425-5p was found to be involved in immunological processes. In addition, noteworthy miRNAs associated with WMLs were identified, primarily moderated by the factors of sex or smoking status. All identified miRNAs exhibited a strong over-representation in neurodegenerative and neurological diseases. We introduced hsa-miR-425-5p as a promising candidate in WML research probably involved in immunological processes. Mir-425-5p holds the potential as a biomarker of WMLs, shedding light on potential mechanisms and pathways in vascular dementia.

Aortic distensibility is a risk factor for multiple cardiovascular events, but the genetic etiology is not well understood. Here, the authors identify genetic variants linked to aortic distensibility, highlighting mechanistic pathways and causal relationships between distensibility and both aortic aneurysms and brain small vessel disease.

Abstract Evidence from previous studies suggests that elevated body mass index (BMI) and genetic risk for obesity is associated with reduced brain volume, particularly in areas of reward-related cognition, e.g. the medial prefrontal cortex (AC-MPFC), the orbitofrontal cortex (OFC), the striatum and the thalamus. However, only few studies examined the interplay between these factors in a joint approach. Moreover, previous findings are based on cross-sectional data. We investigated the longitudinal relationship between increased BMI, brain structural magnetic resonance imaging (MRI) parameters and genetic risk scores in a cohort of n = 502 community-dwelling participants from the Study of Health in Pomerania (SHIP) with a mean follow-up-time of 4.9 years. We found that (1) increased BMI values at baseline were associated with decreased brain parameters at follow-up. These effects were particularly pronounced for the OFC and AC-MPFC. (2) The genetic predisposition for BMI had no effect on brain parameters at baseline or follow-up. (3) The interaction between the genetic score for BMI and brain parameters had no effect on BMI at baseline. Finding a significant impact of overweight, but not genetic predisposition for obesity on altered brain structure suggests that metabolic mechanisms may underlie the relationship between obesity and altered brain structure.

Abstract The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5–90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

Abstract Background Cancer is often associated with a hypercoagulable state and new thrombosis is often the first clinical manifestation of cancer. Surgical treatment of the primary tumor is crucial since it provides the only curative approach in most cases, but management of patients is highly complex, especially in the presence of new antiplatelet drugs and/or anticoagulants. Paraneoplastic syndromes (PNS) represent a frequent complication of renal cell carcinomas (RCC) and include different hematological symptoms in patients, whilst occlusion of arterial blood vessels displays a rare form of PNS accompanying renal tumors. Case presentation We report the case of a 62-year old man who was initially hospitalized due to acute coronary syndrome. He subsequently underwent coronary angioplasty treatment including multiple stenting and treatment with ticagrelor and aspirin. Post-interventional, acute arterial thrombotic emboli of several limb arteries required thrombectomy. By computer tomography we identified a renal lesion suspicious for an RCC and suspected a PNS as underlying cause of the thrombotic complications. Triple anticoagulant therapy was maintained with therapeutic dose low molecular weight heparin (LMWH), aspirin, and clopidogrel, by which we replaced ticagrelor. Surgery was postponed for 4 weeks. We paused LMWH, aspirin and clopidogrel only at the day of surgery and perioperatively restored hemostasis by transfusion of two platelet concentrates. Laparoscopic nephrectomy was uneventful. Pathology confirmed a clear cell RCC. The patient fully recovered whilst slowly reducing anticoagulation dose. Conclusions A multidisciplinary team approach of experts in urology, cardiology and hemostasis was key in managing this patient since a personalized thrombosis consult was needed to minimize the risk of reinfarction due to in-stent thrombosis. We report a therapeutic protocol that may be helpful for the management of similar cases. Furthermore, the finding of thrombotic arterial occlusions in larger blood vessels represents a novel complication of PNS in RCC and adds to the varied possible manifestations of this clinical chameleon.

Abstract The aim of our study was to investigate the association of hepatic steatosis derived from quantitative ultrasound and magnetic resonance imaging (MRI) with prediabetes in a large population-based study conducted in Northeast Germany. Hepatic steatosis was assessed through transabdominal ultrasound and quantitative MRI. For analysis we included 1622 subjects with MRI who participated in an oral glucose tolerance test and reported no known type 2 diabetes mellitus (T2DM). We classified participants as proposed by the American Diabetes Association: isolated impaired fasting glucose (i-IFG), isolated impaired glucose tolerance (i-IGT), combined IFG and IGT (IFG + IGT), and undiagnosed T2DM. Regression models were adjusted for age, sex body mass index and alcohol consumption. We observed positive associations of hepatic steatosis with glycated hemoglobin, fasting glucose and insulin, 2-h glucose and insulin, as well as homeostasis model assessment-insulin resistance index. Similarly, individuals having hepatic steatosis as defined by MRI had a higher relative risk ratio (RR) to be in the prediabetes groups i-IFG (RR = 1.6; 95% confidence interval (CI) 1.2; 2.2), i-IGT (RR = 3.3, 95% CI 2.0; 5.6) and IFG + IGT (RR = 2.5, 95% CI 1.6; 3.9) or to have undiagnosed T2DM (RR = 4.8, 95% CI 2.6; 9.0). All associations were attenuated when defining hepatic steatosis by ultrasound. Hepatic steatosis is associated with prediabetes and undiagnosed T2DM in the general population. Quantitative liver MRI revealed stronger associations with prediabetes and undiagnosed T2DM compared to ultrasound, which indicates the higher sensitivity and specificity of MRI to determine hepatic steatosis.

Abstract Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Abstract A retrospective meta-analysis of magnetic resonance imaging voxel-based morphometry studies proposed that reduced gray matter volumes in the dorsal anterior cingulate and the left and right anterior insular cortex—areas that constitute hub nodes of the salience network—represent a common substrate for major psychiatric disorders. Here, we investigated the hypothesis that the common substrate serves as an intermediate phenotype to detect genetic risk variants relevant for psychiatric disease. To this end, after a data reduction step, we conducted genome-wide association studies of a combined common substrate measure in four population-based cohorts (n = 2271), followed by meta-analysis and replication in a fifth cohort (n = 865). After correction for covariates, the heritability of the common substrate was estimated at 0.50 (standard error 0.18). The top single-nucleotide polymorphism (SNP) rs17076061 was associated with the common substrate at genome-wide significance and replicated, explaining 1.2% of the common substrate variance. This SNP mapped to a locus on chromosome 5q35.2 harboring genes involved in neuronal development and regeneration. In follow-up analyses, rs17076061 was not robustly associated with psychiatric disease, and no overlap was found between the broader genetic architecture of the common substrate and genetic risk for major depressive disorder, bipolar disorder, or schizophrenia. In conclusion, our study identified that common genetic variation indeed influences the common substrate, but that these variants do not directly translate to increased disease risk. Future studies should investigate gene-by-environment interactions and employ functional imaging to understand how salience network structure translates to psychiatric disorder risk.

White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

Cortex morphology varies with age, cognitive function, and in neurological and psychiatric diseases. Here the authors report 160 genome-wide significant associations with thickness, surface area and volume of the total cortex and 34 cortical regions from a GWAS meta-analysis in 22,824 adults.

The aim of this study was to disentangle the effects of various genetic factors on hippocampal subfield volumes using three different approaches: a biologically driven candidate gene approach, a hypothesis-free GWAS approach, and a polygenic approach, where AD risk alleles are combined with a polygenic risk score (PRS). The impact of these genetic factors was investigated in a large dementia-free general population cohort from the Study of Health in Pomerania (SHIP, n = 1806). Analyses were performed using linear regression models adjusted for biological and environmental risk factors. Hippocampus subfield volume alterations were found for APOE ε4, BDNF Val, and 5-HTTLPR L allele carriers. In addition, we were able to replicate GWAS findings, especially for rs17178139 (MSRB3), rs1861979 (DPP4), rs7873551 (ASTN2), and rs572246240 (MAST4). Interaction analyses between the significant SNPs as well as the PRS for AD revealed no significant results. Our results confirm that hippocampal volume reductions are influenced by genetic variation, and that different variants reveal different association patterns that can be linked to biological processes in neurodegeneration. Thus, this study underlines the importance of specific genetic analyses in the quest for acquiring deeper insights into the biology of hippocampal volume loss, memory impairment, depression, and neurodegenerative diseases.

Background: Basal cortisol concentrations vary between men and women. Likewise, previous findings suggest stress-related cortical thickness alterations. Thus, we aimed at elucidating sex differences in the association between serum cortisol concentrations and cortical thickness. Methods: Data of 2594 participants (55.55% male; mean age = 53.55 years ± 13.17 years) of the general population were used to investigate sex differences in basal serum cortisol concentrations and associations of serum cortisol concentrations with global and regional cortical thickness. The validity of the results was tested by including sex hormone concentrations as a biological and childhood maltreatment and depressive symptoms as a psychological confounder. Results: Basal serum cortisol concentrations were higher in men than in women (β = −0.158, t(2575) = -6.852, p = 9.056e-12). Sex differences in serum cortisol concentrations were diminished by including serum concentrations of testosterone, estrone, or estradiol in the models. In men but not in women, serum cortisol concentrations were inversely associated with the global cortical thickness (men: β = −0.064, t(1412) = -3.010, p = .003; women: β = −0.016, t(1131) = -0.607, p = .544). Additionally, these effects were observed in eleven cortical regions after adjusting for multiple testing. The associations were independent of childhood maltreatment and depressive symptoms. Conclusion: Sex differences in serum cortisol concentrations and the association between serum cortisol concentrations and cortical thickness suggest important sex-specific effects of stress on the brain. Future studies should integrate the interaction between the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamic-pituitary-gonadal (HPG) axis in sex-stratified analyses.

Background Lower cardiorespiratory fitness (CRF) is associated with an increased risk for cardiovascular disease. However, very little information is available about the association between lower CRF and right ventricular (RV) remodeling. We investigated the relationship between CRF and RV structure and function in a large, aging, and largely sedentary adult population–based cohort. Methods and Results We used cross‐sectional data of 2844 subjects (1486 women; median age, 51 years; interquartile range, 40–62 years) from the population‐based cohort SHIP (Study of Health in Pomerania) with echocardiography, of which 941 also had cardiac magnetic resonance imaging. We analyzed the associations of peak oxygen uptake with RV parameters determined by both imaging techniques using multivariable‐adjusted linear regression models. In echocardiography, a 1 L/min lower peak oxygen uptake was associated with a 1.18 mm (95% CI, 0.66–1.71; P

Background Hypertrophy of the left ventricle (LV) has recently been associated with adverse changes of brain structure in older adults, notably increased burden of white matter hyperintensities (WMHs). Whether greater LV size or mass is also related to WMH burden in middle‐aged adults is currently unclear. In addition, its relation with alterations in cortical thickness (CT) has not been studied to date. Methods and Results Data from 1602 participants of the population‐based SHIP (Study of Health in Pomerania) with LV ejection fraction >40% and no history of myocardial infarction were included (aged 21–82 years; median age, 49 years; 53% women). Participants underwent both echocardiography and magnetic resonance imaging of the head. Imaging markers of brain aging (ie, CT and WMH volume) were determined from magnetic resonance imaging scans. LV mass and diameter were associated with lower global CT and greater WMH volume, while adjusting for age, sex, body height, fat‐free body mass, and intracranial volume. Moreover, thicknesses of the interventricular septum and posterior wall were also associated with lower global CT. These associations could not be explained by cardiovascular risk factors (including hypertension), inflammatory markers, or sociodemographic factors. Regional analyses showed distinct spatial patterns of lower CT in association with LV diameter and posterior wall thickness. Conclusions LV diameter and mass are associated with lower global and regional CT as well as greater WMH burden in the general population. These findings highlight the brain structural underpinnings of the associations of LV hypertrophy with cognitive decline and dementia.

Representative epidemiologic data on the average volume of the parotid gland in a large population-based MRI survey is non-existent. Within the Study of Health in Pomerania (SHIP), we examined the parotid gland in 1725 non-contrast MRI-scans in T1 weighted sequence of axial layers. Thus, a reliable standard operating procedure (Intraclass Correlation Coefficient > 0.8) could be established. In this study, we found an average, single sided parotid gland volume of 27.82 cm3 (95% confidence interval (CI) 27.15 to 28.50) in male and 21.60 cm3 (95% CI 21.16 to 22.05) in female subjects. We observed positive associations for age, body mass index (BMI), as well as male sex with parotid gland size in a multivariate model. The prevalence of incidental tumors within the parotid gland regardless of dignity was 3.94% in the Northeast German population, slightly higher than assumed. Further epidemiologic investigations regarding primary salivary gland diseases are necessary.

Although the common pathology of Alzheimer’s disease (AD) and white matter hyperintensities (WMH) is disputed, the gene TREML2 has been implicated in both conditions: its whole-blood gene expression was associated with WMH volume and its missense variant rs3747742 with AD risk. We re-examined those associations within one comprehensive dataset of the general population, additionally searched for cross-relations and illuminated the role of the apolipoprotein E (APOE) ε4 status in the associations. For our linear regression and linear mixed effect models, we used 1949 participants from the Study of Health in Pomerania (Germany). AD was assessed using a continuous pre-symptomatic MRI-based score evaluating a participant’s AD-related brain atrophy. In our study, increased whole-blood TREML2 gene expression was significantly associated with reduced WMH volume but not with the AD score. Conversely, rs3747742-C was significantly associated with a reduced AD score but not with WMH volume. The APOE status did not influence the associations. In sum, TREML2 robustly associated with WMH volume and AD-related brain atrophy on different molecular levels. Our results thus underpin TREML2’s role in neurodegeneration, might point to its involvement in AD and WMH via different biological mechanisms, and highlight TREML2 as a worthwhile target for disentangling the two pathologies.

The German Consortium Hereditary Breast and Ovarian Cancer (GC-HBOC) consists of 23 academic centers striving to provide high-quality regional care for affected individuals and healthy at-risk family members. According to the standard operating procedures defined by the GC-HBOC, a Familial Breast and Ovarian Cancer Center was implemented at the University Medicine Greifswald over a four-year period from 2018 to 2021, despite the COVID-19 pandemic. Genetic analyses were performed in a total of 658 individuals, including 41 males, which paved the way to local annual risk-adapted breast cancer surveillance for 91 women and prophylactic surgery for 34 women in 2021. Our experience in the North Eastern part of Germany demonstrates that it is possible to establish a high-risk breast and ovarian cancer service even in a sparsely populated region. Major facilitators are the interdisciplinary collaboration of dedicated local experts, the support of the GC-HBOC, fruitful clinical and scientific cooperations and the use of technical improvements. As a blueprint, our project report may help to further expand the network of specialized and knowledge-generating care for HBOC families.

Abstract Background Mortality attributable to heart failure remains high. The prevalence of heart failure in patients with diabetes mellitus ranges from 19 to 26%. It is estimated that up to 21.1 million adults in the United States have diagnosed diabetes mellitus and around 80.8 million have impaired fasting glucose. We investigated the associations of fasting glucose (FG) and fasting insulin (FI), the homeostasis model assessment-insulin resistance index (HOMA-IR) and 2-h postload glucose (2HG) and insulin (2HI) with parameters of left ventricular geometry and function and arterial stiffness determined by magnetic resonance imaging in individuals without diagnosed type 2 diabetes. Methods Cross-sectional analyses of 1001 individuals (453 women, 45.3%), aged 21 to 80 years, from two independent population-based studies, the Study of Health in Pomerania (SHIP-TREND-0) and KORA FF4 Study. FG, FI, HOMA-IR, 2HG and 2HI, as well as glucose tolerance categories, were analyzed for associations with heart and arterial parameters using multivariable-adjusted linear regression models. Results In total, 390 individuals (39%) had prediabetes (isolated impaired fasting glucose, isolated glucose tolerance or both), and 49 (4.9%) were found to have unknown type 2 diabetes. In the multivariable-adjusted analysis, positive linear associations of FG, FI, HOMA-IR, 2HG and 2HI with arterial stiffness index and left ventricular wall-thickness and concentricity and inverse linear associations with left ventricular end-diastolic volume were observed. A 1 mmol/l higher FG was associated with a 1.18 ml/m2.7 (1.80 to 0.57; p

Introduction: It has been shown that Alzheimer’s disease (AD) is accompanied by marked structural brain changes that can be detected several years before clinical diagnosis via structural magnetic resonance (MR) imaging. In this study, we developed a structural MR-based biomarker for in vivo detection of AD using a supervised machine learning approach. Based on an individual’s pattern of brain atrophy a continuous AD score is assigned which measures the similarity with brain atrophy patterns seen in clinical cases of AD.Methods: The underlying statistical model was trained with MR scans of patients and healthy controls from the Alzheimer’s Disease Neuroimaging Initiative (ADNI-1 screening). Validation was performed within ADNI-1 and in an independent patient sample from the Open Access Series of Imaging Studies (OASIS-1). In addition, our analyses included data from a large general population sample of the Study of Health in Pomerania (SHIP-Trend).Results: Based on the proposed AD score we were able to differentiate patients from healthy controls in ADNI-1 and OASIS-1 with an accuracy of 89% (AUC = 95%) and 87% (AUC = 93%), respectively. Moreover, we found the AD score to be significantly associated with cognitive functioning as assessed by the Mini-Mental State Examination in the OASIS-1 sample after correcting for diagnosis, age, sex, age·sex, and total intracranial volume (Cohen’s f2 = 0.13). Additional analyses showed that the prediction accuracy of AD status based on both the AD score and the MMSE score is significantly higher than when using just one of them. In SHIP-Trend we found the AD score to be weakly but significantly associated with a test of verbal memory consisting of an immediate and a delayed word list recall (again after correcting for age, sex, age·sex, and total intracranial volume, Cohen’s f2 = 0.009). This association was mainly driven by the immediate recall performance.Discussion: In summary, our proposed biomarker well differentiated between patients and healthy controls in an independent test sample. It was associated with measures of cognitive functioning both in a patient sample and a general population sample. Our approach might be useful for defining robust MR-based biomarkers for other neurodegenerative diseases, too.

An increase in the volume of the brain lateral ventricles is a sign of normal aging, but can also be associated with neurological and psychiatric disorders. Here, Vojinovic et al. identify seven genetic loci in a GWA study for ventricular volume in 23,500 individuals and find correlation with thalamus volume.

The Study of Health in Pomerania (SHIP), a population-based study from a rural state in northeastern Germany with a relatively poor life expectancy, supplemented its comprehensive examination program in 2008 with whole-body MR imaging at 1.5 T (SHIP-MR). We reviewed more than 100 publications that used the SHIP-MR data and analyzed which sequences already produced fruitful scientific outputs and which manuscripts have been referenced frequently. Upon reviewing the publications about imaging sequences, those that used T1-weighted structured imaging of the brain and a gradient-echo sequence for R2* mapping obtained the highest scientific output; regarding specific body parts examined, most scientific publications focused on MR sequences involving the brain and the (upper) abdomen. We conclude that population-based MR imaging in cohort studies should define more precise goals when allocating imaging time. In addition, quality control measures might include recording the number and impact of published work, preferably on a bi-annual basis and starting 2 years after initiation of the study. Structured teaching courses may enhance the desired output in areas that appear underrepresented.

BACKGROUND:Benign osseous lesions of the spine are common but precise population prevalence estimates are lacking. Our study aimed to provide the first population-based prevalence estimates and examine association with back and neck pain. MATERIALS AND METHODS:We used data from the population-based Study of Health in Pomerania (SHIP). Whole-body MRI examinations (1.5 Tesla: T1, T2, and TIRM weightings) were available from 3,259 participants. Readings of the spinal MRI images were conducted according to a standardized protocol by a single reader (JS). The intra-rater reliability was greater than Kappa values of 0.98. Pain measures included the seven-day prevalence of spine pain and neck pain, and average spine pain intensity due to spine pain during the past three months. RESULTS:We found 1,200 (36.8%) participants with at least one osseous lesion (2,080 lesions in total). Osseous lesions were less common in men than in women (35.5% vs 38.9%; P = .06). The prevalence of osseous lesions was highest at L2 in both sexes. The prevalence of osseous lesions increased with age. Up to eight osseous lesions were observed in a single subject. Hemangioma (28%), and lipoma (13%) occurred most often. Sclerosis (1.7%), aneurysmal bone cysts (0.7%), and blastoma (0.3%) were rare. Different osseous lesions occurred more often in combination with each other. The association with back or neck pain was mostly negligible. CONCLUSION:Osseous lesions are common in the general population but of no clinical relevance for spinal pain. The prevalence of osseous lesions varied strongly across different regions of the spine and was also associated with age and gender. Our population-based data offer new insights and assist in judging the relevance of osseous lesions observed on MRIs of patients.

PURPOSE:To provide population-based reference values for cervical spinal canal parameters and vertebral body (VB) width and to study their associations with sex, age, body height, body weight and body mass index (BMI) using MRI. METHODS:Cross-sectional analyses included data from 2,453 participants, aged 21-89 years, of the population-based Study of Health in Pomerania (SHIP) who underwent whole-body MRI at 1.5 Tesla between July 2008 and March 2011. A standardised reading was performed for the C2-C7 cervical spine levels at sagittal T2 TSE weighted sequences. RESULTS:Reference intervals for spinal canal parameters were similar in males and females, while VB width was on average 2.1-2.2 mm larger in males. Age effects were only substantial regarding VB width with a 0.5 mm per ten-year age increase. Body height effects were only substantial regarding the osseous spinal canal and VB width. Body weight and BMI effects are mostly not substantial. CONCLUSIONS:Our study provides MRI-based reference values for the cervical spinal canal parameters in an adult Caucasian population. Except for VB width, associations with sex, age and somatometric measures are mostly small and thus have only limited clinical implications. Some available cut-off values may need a revision because they likely overestimate risks.

ObjectivesIt is still not clear why impaction of third molars occurs. Craniofacial morphology and facial parameters have been discussed to be strong predictors for third molar impaction. Thus, this study aimed to investigate the effect of craniofacial morphology on erupted or impacted third molars in a German population sample.Materials and methodsErupted and impacted third molars in 2,484 participants from the Study of Health in Pomerania were assessed by whole-body magnetic resonance imaging. Markers of facial morphology were determined in 619 individuals of those participants in whose 421 participants (16.7%) had at least one impacted third molar. Craniofacial morphology was estimated as linear measurements and was associated in a cross-sectional study design with impacted and erupted third molars by multinomial logistic regression models. Erupted third molars were used as reference outcome category and regression models were adjusted for age and sex.ResultsMaximum Cranial Width (Eurion-Eurion distance) was significantly associated with impacted third molars (RR: 1.079; 95% confidence interval 1.028-1.132). This association was even more pronounced in the mandible. Individuals with a lower total anterior facial height (Nasion-Menton distance) and a lower facial index also have an increased risk for impacted third molars in the mandible (RR 0.953; 95% confidence interval 0.913-0.996 and RR: 0.943; 95% confidence interval 0.894-0.995). No significant associations of third molar status with facial width (Zygion-Zygion distance), and sagittal cranial dimension (Nasion-Sella distance; Sella-Basion distance) were observed.ConclusionIndividuals with an increased maximal cranial width have a higher risk for impaction of third molars in the mandible and in the maxilla. Individuals with a lower anterior total anterior facial height and lower facial index also have an increased risk for third molars impaction in the mandible. These findings could help orthodontic dentists, oral surgeons and oral and maxillofacial surgeons in decision-making for third molars removal in their treatment. These findings highlight the necessity of an additional analysis of the maximal cranial width by the Eurion- Eurion distance.

The aim of this study was to evaluate the association of sex hormones with anthropometry in a large population-based cohort, with liquid chromatography-mass spectrometry (LCMS)-based sex hormone measurements and imaging markers.Cross-sectional data from 957 men and women from the population-based Study of Health in Pomerania (SHIP) were used. Associations of a comprehensive panel of LCMS-measured sex hormones with anthropometric parameters, laboratory, and imaging markers were analyzed in multivariable regression models for the full sample and stratified by sex. Sex hormone measures included total testosterone (TT), free testosterone (fT), estrone and estradiol, androstenedione (ASD), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG). Domains of anthropometry included physical measures (body-mass-index (BMI), waist circumference, waist-to-height-ratio, waist-to-hip-ratio, and hip circumference), laboratory measures of adipokines (leptin and vaspin), and magnet resonance imaging-based measures (visceral and subcutaneous adipose tissue).In men, inverse associations between all considered anthropometric parameters with TT were found: BMI (β-coefficient, standard error (SE): -0.159, 0.037), waist-circumference (β-coefficient, SE: -0.892, 0.292), subcutaneous adipose tissue (β-coefficient, SE: -0.156, 0.023), and leptin (β-coefficient, SE: -0.046, 0.009). In women TT (β-coefficient, SE: 1.356, 0.615) and estrone (β-coefficient, SE: 0.014, 0.005) were positively associated with BMI. In analyses of variance, BMI and leptin were inversely associated with TT, ASD, and DHEAS in men, but positively associated with estrone. In women, BMI and leptin were positively associated with all sex hormones.The present population-based study confirmed and extended previously reported sex-specific associations between sex hormones and various anthropometric markers of overweight and obesity.

Using 3D anatomical landmarks from adult human head MRIs, we assessed the magnitude of inter-operator differences in Procrustes-based geometric morphometric analyses. An in depth analysis of both absolute and relative error was performed in a subsample of individuals with replicated digitization by three different operators. The effect of inter-operator differences was also explored in a large sample of more than 900 individuals. Although absolute error was not unusual for MRI measurements, including bone landmarks, shape was particularly affected by differences among operators, with up to more than 30% of sample variation accounted for by this type of error. The magnitude of the bias was such that it dominated the main pattern of bone and total (all landmarks included) shape variation, largely surpassing the effect of sex differences between hundreds of men and women. In contrast, however, we found higher reproducibility in soft-tissue nasal landmarks, despite relatively larger errors in estimates of nasal size. Our study exemplifies the assessment of measurement error using geometric morphometrics on landmarks from MRIs and stresses the importance of relating it to total sample variance within the specific methodological framework being used. In summary, precise landmarks may not necessarily imply negligible errors, especially in shape data; indeed, size and shape may be differentially impacted by measurement error and different types of landmarks may have relatively larger or smaller errors. Importantly, and consistently with other recent studies using geometric morphometrics on digital images (which, however, were not specific to MRI data), this study showed that inter-operator biases can be a major source of error in the analysis of large samples, as those that are becoming increasingly common in the 'era of big data'.