Childhood and adolescence factors and multiple sclerosis: results from the German National Cohort (NAKO).

BACKGROUND: Multiple Sclerosis (MS) represents the most common inflammatory neurological disease causing disability in early adulthood. Childhood and adolescence factors might be of relevance in the development of MS. We aimed to investigate the association between various factors (e.g., prematurity, breastfeeding, daycare attendance, weight history) and MS risk. METHODS: Data from the baseline assessment of the German National Cohort (NAKO) were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association between childhood and adolescence factors and risk of MS. Analyses stratified by sex were conducted. RESULTS: Among a total of 204,273 participants, 858 reported an MS diagnosis. Male sex was associated with a decreased MS risk (HR 0.48; 95% CI 0.41-0.56), while overweight (HR 2.03; 95% CI 1.41-2.94) and obesity (HR 1.89; 95% CI 1.02-3.48) at 18 years of age compared to normal weight were associated with increased MS risk. Having been breastfed for ≤ 4 months was associated with a decreased MS risk in men (HR 0.59; 95% CI 0.40-0.86) compared to no breastfeeding. No association with MS risk was observed for the remaining factors. CONCLUSIONS: Apart from overweight and obesity at the age of 18 years, we did not observe considerable associations with MS risk. The proportion of cases that can be explained by childhood and adolescence factors examined in this study was low. Further investigations of the association between the onset of overweight and obesity in childhood and adolescence and its interaction with physical activity and MS risk seem worthwhile.

A genome-wide association study meta-analysis in a European sample of stage III/IV grade C periodontitis patients ≤35 years of age identifies new risk loci.

AIM: Few genome-wide association studies (GWAS) have been conducted for severe forms of periodontitis (stage III/IV grade C), and the number of known risk genes is scarce. To identify further genetic risk variants to improve the understanding of the disease aetiology, a GWAS meta-analysis in cases with a diagnosis at ≤35 years of age was performed. MATERIALS AND METHODS: Genotypes from German, Dutch and Spanish GWAS studies of III/IV-C periodontitis diagnosed at age ≤35 years were imputed using TopMed. After quality control, a meta-analysis was conducted on 8,666,460 variants in 1306 cases and 7817 controls with METAL. Variants were prioritized using FUMA for gene-based tests, functional annotation and a transcriptome-wide association study integrating eQTL data. RESULTS: The study identified a novel genome-wide significant association in the FCER1G gene (p = 1.0 × 10-9 ), which was previously suggestively associated with III/IV-C periodontitis. Six additional genes showed suggestive association with p < 10-5 , including the known risk gene SIGLEC5. HMCN2 showed the second strongest association in this study (p = 6.1 × 10-8 ). CONCLUSIONS: This study expands the set of known genetic loci for severe periodontitis with an age of onset ≤35 years. The putative functions ascribed to the associated genes highlight the significance of oral barrier tissue stability, wound healing and tissue regeneration in the aetiology of these periodontitis forms and suggest the importance of tissue regeneration in maintaining oral health.

Impaired B Cell Expression of the Inhibitory Fcγ Receptor IIB in Myasthenia Gravis.

Myasthenia gravis (MG) is an autoimmune disease in which pathogenic immunoglobulin G antibodies bind to acetylcholine receptors (or to functionally related molecules at the neuromuscular junction). B cell expression of the inhibitory immunoglobulin G receptor, Fc-gamma receptor (FcγR) IIB, maintains peripheral immune tolerance, and its absence renders B cells hyperresponsive to autoantigen. Here, we report that FcγRIIB expression levels are substantially reduced in B lineage cells derived from immunotherapy-naïve patients with acetylcholine receptor antibody-positive early-onset MG. In contrast, genetic variants associated with impaired FcγRIIB expression are not enriched in MG, indicating post-transcriptional dysregulation. FcγR-targeted therapies could have therapeutic benefits in MG. ANN NEUROL 2022;92:1046-1051.

Genome-wide interaction study with major depression identifies novel variants associated with cognitive function.

Major Depressive Disorder (MDD) often is associated with significant cognitive dysfunction. We conducted a meta-analysis of genome-wide interaction of MDD and cognitive function using data from four large European cohorts in a total of 3510 MDD cases and 6057 controls. In addition, we conducted analyses using polygenic risk scores (PRS) based on data from the Psychiatric Genomics Consortium (PGC) on the traits of MDD, Bipolar disorder (BD), Schizophrenia (SCZ), and mood instability (MIN). Functional exploration contained gene expression analyses and Ingenuity Pathway Analysis (IPA®). We identified a set of significantly interacting single nucleotide polymorphisms (SNPs) between MDD and the genome-wide association study (GWAS) of cognitive domains of executive function, processing speed, and global cognition. Several of these SNPs are located in genes expressed in brain, with important roles such as neuronal development (REST), oligodendrocyte maturation (TNFRSF21), and myelination (ARFGEF1). IPA® identified a set of core genes from our dataset that mapped to a wide range of canonical pathways and biological functions (MPO, FOXO1, PDE3A, TSLP, NLRP9, ADAMTS5, ROBO1, REST). Furthermore, IPA® identified upstream regulator molecules and causal networks impacting on the expression of dataset genes, providing a genetic basis for further clinical exploration (vitamin D receptor, beta-estradiol, tadalafil). PRS of MIN and meta-PRS of MDD, MIN and SCZ were significantly associated with all cognitive domains. Our results suggest several genes involved in physiological processes for the development and maintenance of cognition in MDD, as well as potential novel therapeutic agents that could be explored in patients with MDD associated cognitive dysfunction.

Major depressive disorders increase the susceptibility to self-reported infections in two German cohort studies.

INTRODUCTION: In several claims-based studies, major depressive disorder (MDD) has been associated with increased risk of hospitalization due to acute infections. It remains unclear if this is a causal effect, and if it generalizes to an increased susceptibility to infections. METHODS: We used data of the BiDirect (n = 925) and the HaBIDS (n = 1007) cohort studies to estimate the effect of MDD on self-reported infections, which were assessed with identical infection susceptibility questionnaires in both studies. We used the Center for Epidemiologic Studies Depression Scale (CES-D) to examine if there was a dose-response relationship between depressive symptom severity and self-reported infections. RESULTS: BiDirect participants with MDD diagnosis (48%) had a higher risk of lower respiratory tract infections (incidence rate ratio 1.32, 95% confidence interval [1.00-1.75]), gastrointestinal infections (1.68 [1.30-2.16]) and fever (1.48 [1.11-1.98]) after adjusting for confounders identified by a directed acyclic graph approach. There was a dose-response relationship, i.e. individuals with higher CES-D scores reported more infections. Effect sizes were similar in HaBIDS (4% individuals with MDD). CONCLUSION: We found increased risks of mild infections in patients with MDD diagnosis and a dose-response relationship between depressive symptom severity and infection frequency. While causal immunological pathways remain unclear, the results of our study might contribute to a change in prevention strategies, e.g. by recommending vaccination against influenza and S. pneumoniae to MDD patients because observed effect sizes in our study are similar to those of patients with cardiovascular and metabolic diseases for which the respective vaccinations are recommended.

[Specialization of Acute Stroke Care in Germany: Structural Changes During 2006-2017]. / Spezialisierung der Schlaganfallversorgung in Deutschland: Strukturveränderungen im Zeitraum von 2006­2017.

HINTERGRUND: Um die Schlaganfallversorgung zu optimieren, wurden in Deutschland in den letzten Jahren verschiedene qualitätsfördernde Maßnahmen (qfM) in regional unterschiedlichem Maß eingeführt. Ob sich diese Maßnahmen über die Jahre flächendeckend etabliert haben, ist unklar. METHODE: Für die strukturbezogenen Analysen der Schlaganfallversorgung in Deutschland wurden alle relevanten dokumentierten Schlaganfälle (ICD-10) aus den Qualitätsberichten (QB) deutscher Krankenhäuser und eine repräsentative Stichprobe von Krankenversicherungsdaten (AOK) im Zeitraum von 2006 (QB)/2007 (AOK) bis 2017 verwendet. Diese Informationen wurden u. a. durch Angaben zu zertifizierten Stroke Units der Deutschen Schlaganfall-Gesellschaft (DSG) und Daten zur Führung von regionalen Schlaganfall-Registern der Arbeitsgemeinschaft Deutschsprachiger Schlaganfall-Register (ADSR) ergänzt. Zur Verfolgung der Veränderungen des Versor-gungsgeschehens im deutschen Bundesgebiet wurden die Daten mit geografischen Daten (Bundesamt für Kartographie und Geodäsie) verknüpft. Es erfolgten univariate Analysen der Daten und eine Trend-Analyse der verschiedenen qfM im Jahresverlauf (Konkordanzkoeffizient nach Kendall). ERGEBNISSE: Die QB Analysen zeigten einen Anstieg kodierter Schlaganfälle in Krankenhäusern mit qfM um 14-20%. In 2006 wurden 80% der Schlaganfälle (QB) in einem Krankenhaus mit min. einer qfM kodiert, in 2017 95%. Diese Entwicklungen spiegelten sich auch in den AOK-Routinedaten wider, wobei in 2007 89% und in 2017 97% der Patient:innen unter mindestens einer qfM behandelt wurden. Dabei waren in 2007 bei 55% der behandelnden Krankenhäuser qfM vorhanden, in 2017 bei 72%. SCHLUSSFOLGERUNG: Patient:innen werden inzwischen signifikant häufiger in Krankenhäusern mit Spezialisierung auf die Schlaganfallversorgung behandelt. Auch die verschiedenen qfM haben sich im Laufe der Jahre im gesamten Bundesgebet verbreitet, jedoch existieren noch Versorgungslücken, die geschlossen werden sollten, damit in Zukunft alle Patient:innen qualitativ hochwertig behandelt werden können. BACKGROUND: In order to optimize stroke care, various quality-enhancing measures (qfM) have been introduced in Germany in recent years to varying degrees across regions, with the aim of achieving the best possible quality of care. It is unclear whether these measures have become established nationwide over the years. METHOD: For the structural analyses of stroke care in Germany, all relevant documented strokes (ICD-10) from the quality reports (QB) of German hospitals and a representative sample of health insurance data (AOK) for the period from 2006 (QB)/2007 (AOK) to 2017 were used. This information was supplemented by data on certified stroke units from the German Stroke Society (DSG) and data on the maintenance of regional stroke registries from the Working Group of German-Speaking Stroke Registers (ADSR), among others. To track changes in patterns of care in Germany, the data were linked with geographic data (Federal Agency for Cartography and Geodesy). Univariate analyses of the data and a trend analysis of the different qfM over the year (Kendall concordance coefficient) were performed. RESULTS: The analyses (QB) showed an increase in coded strokes in hospitals with qfM between 14-20%. In 2006, 80% of strokes (QB) were coded in hospitals with at least one qfM and 95% in 2017. Comparing years, AOK data showed similar trends: in 2007, 89% of patients were treated in hospitals with at least one qfM and 97% in 2017. In 2007, 55% of treating hospitals had qfM and 72% in 2017. CONCLUSION: Meanwhile, patients are more often treated in hospitals that specialise in stroke care. In addition, the various qfM have spread across the nation over the years, but there are still gaps in care that should be addressed to ensure quality care for all patients in the future.

Associations between structure- and process-orientated measures and stroke long term mortality - an observational study based on routine data.

OBJECTIVES: Various measures are used to improve the quality of stroke care. In Germany, these include concentrating treatment in specialized facilities (stroke units), mandatory quality comparisons of hospitals in some German states, and treatment according to prespecified structure and process specifications (neurological complex treatment 8-981 or 8-98b). These measures have previously only been analyzed individually and regarding short-term patient outcomes. This study analyzes these measures in combination, considering patients' comorbidities as well as stroke severity in a longitudinal perspective. MATERIALS/METHODS: Analyses were based on data from 243,415 insurees of Germany's biggest health insurance (AOK) admitted to hospitals between 2007 and 2017 with cerebral infarction. Mortality risk was calculated using Cox regressions adjusted for various covariates. Kaplan-Meier analyses were differentiated by treatment site (stroke unit/external quality assurance/ Federal State Consortium of Quality Assurance Hesse - LAGQH) were performed, followed by log-rank tests and p-value adjustment. Trend analyses were performed for treatment types in combination with treatment sites. RESULTS: All analyses showed significant advantages for patients who received Neurological Complex Treatment, especially when the treatment was performed under external quality assurance conditions and/or in stroke units. There was an increasing frequency of specialized stroke treatment. CONCLUSIONS: Quality-enhancing structures and processes are associated with a lower mortality risk after stroke. There appears to be evidence of a cascading benefit from the implementation of neurological complex treatment, external quality assurance, and ultimately, stroke units. Consecutively, care should be concentrated in hospitals that meet these specifications. However, since measures are often applied in combination, it remains unclear which specific measures are crucial for patient outcome.

Results of the prospective multicenter SoLKiD cohort study indicate bio-psycho-social outcome risks to kidney donors 12 months after donation.

The outcome after living kidney donation was assumed to be comparable to that of the general population. However, recent register studies reveal negative changes in kidney function, quality of life and fatigue. Avoiding methodological issues of previous studies, the Safety of the Living Kidney Donor (SoLKiD) cohort study analyzed the outcome of donors in a multicenter and interdisciplinary fashion. Donor data were collected pre-donation and two-, six- and 12-months post-donation in 20 German transplantation centers. Primary parameters were kidney function, quality of life, and fatigue. Secondary endpoints were blood pressure, hemoglobin, hemoglobin A1c, body mass index, depression and somatization. Parameters were analyzed with non-parametric statistical tests and a mixed model regression for changes in time, their clinical relevance and interaction encompassing 336 donors with mean age of 52 years. Most of the physical secondary parameters, depression, and quality of life showed little or no changes and regained their pre-donation level. Kidney function decreased significantly with a 37% loss of glomerular filtration rate and an increase of donors with chronic kidney disease stage 3 from 1.5% pre-donation to about 50%. Donors consistently showed increased fatigue and somatization. Mental fatigue increased from 10.6% to 28.1%. The main influencing factors for decreased kidney function and increased fatigue were their respective pre-donation levels, and donor age for kidney function and subject stress level in fatigue. Thus, our study showed that a significant number of donors developed clinically relevant changes in physical and mental health and emphasizes the urgent need to inform potential donors about these risks.

Intrathecal Immunoglobulin M Synthesis is an Independent Biomarker for Higher Disease Activity and Severity in Multiple Sclerosis.

OBJECTIVE: We aimed to determine in relapsing multiple sclerosis (MS) whether intrathecal synthesis of immunoglobulin (Ig) M and IgG is associated with outcomes reflecting inflammatory activity and chronic worsening. METHODS: We compared cerebrospinal fluid analysis, clinical and magnetic resonance imaging data, and serum neurofilament light chain (sNfL) levels at baseline and follow-up in 530 patients with relapsing MS. Patients were categorized by the presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgGIF and IgMIF ). Relationships with the time to first relapse, sNfL concentrations, T2-weighted (T2w) lesions, MS Severity Score (MSSS), and time to initiation of high-efficacy therapy were analyzed in covariate-adjusted statistical models. RESULTS: By categorical analysis, in patients with IgMIF the median time to first relapse was 28 months shorter and MSSS on average higher by 1.11 steps compared with patients without intrathecal immunoglobulin synthesis. Moreover, patients with IgMIF had higher sNfL concentrations, more new/enlarging T2w lesions, and higher total T2w lesion counts (all p ≤ 0.01). These associations were absent or equally smaller in patients who were positive for only OCGB or OCGB/IgGIF . Furthermore, quantitative analyses revealed that in patients with IgMIF ≥ median, the time to first relapse and to initiation of high-efficacy therapy was shorter by 32 and by 203 months, respectively (both p < 0.01), in comparison to patients with IgMIF < median. Dose-dependent associations were also found for IgMIF but not for IgGIF with magnetic resonance imaging-defined disease activity and sNfL. INTERPRETATION: This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. ANN NEUROL 2021;90:477-489.

Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group.

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.

Brain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders : Evidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group.

Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = -0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.

Borrelia multiplex: a bead-based multiplex assay for the simultaneous detection of Borrelia specific IgG/IgM class antibodies.

BACKGROUND: Lyme borreliosis (LB) is the most common tick-borne infectious disease in the northern hemisphere. The diagnosis of LB is usually made by clinical symptoms and subsequently supported by serology. In Europe, a two-step testing consisting of an enzyme-linked immunosorbent assay (ELISA) and an immunoblot is recommended. However, due to the low sensitivity of the currently available tests, antibody detection is sometimes inaccurate, especially in the early phase of infection, leading to underdiagnoses. METHODS: To improve upon Borrelia diagnostics, we developed a multiplex Borrelia immunoassay (Borrelia multiplex), which utilizes the new INTELLIFLEX platform, enabling the simultaneous dual detection of IgG and IgM antibodies, saving further time and reducing the biosample material requirement. In order to enable correct classification, the Borrelia multiplex contains eight antigens from the five human pathogenic Borrelia species known in Europe. Six antigens are known to mainly induce an IgG response and two antigens are predominant for an IgM response. RESULTS: To validate the assay, we compared the Borrelia multiplex to a commercial bead-based immunoassay resulting in an overall assay sensitivity of 93.7% (95% CI 84.8-97.5%) and a specificity of 96.5% (95%CI 93.5-98.1%). To confirm the calculated sensitivity and specificity, a comparison with a conventional 2-step diagnostics was performed. With this comparison, we obtained a sensitivity of 95.2% (95% CI 84.2-99.2%) and a specificity of 93.0% (95% CI 90.6-94.7%). CONCLUSION: Borrelia multiplex is a highly reproducible cost- and time-effective assay that enables the profiling of antibodies against several individual antigens simultaneously.

Framework and baseline examination of the German National Cohort (NAKO).

The German National Cohort (NAKO) is a multidisciplinary, population-based prospective cohort study that aims to investigate the causes of widespread diseases, identify risk factors and improve early detection and prevention of disease. Specifically, NAKO is designed to identify novel and better characterize established risk and protection factors for the development of cardiovascular diseases, cancer, diabetes, neurodegenerative and psychiatric diseases, musculoskeletal diseases, respiratory and infectious diseases in a random sample of the general population. Between 2014 and 2019, a total of 205,415 men and women aged 19-74 years were recruited and examined in 18 study centres in Germany. The baseline assessment included a face-to-face interview, self-administered questionnaires and a wide range of biomedical examinations. Biomaterials were collected from all participants including serum, EDTA plasma, buffy coats, RNA and erythrocytes, urine, saliva, nasal swabs and stool. In 56,971 participants, an intensified examination programme was implemented. Whole-body 3T magnetic resonance imaging was performed in 30,861 participants on dedicated scanners. NAKO collects follow-up information on incident diseases through a combination of active follow-up using self-report via written questionnaires at 2-3 year intervals and passive follow-up via record linkages. All study participants are invited for re-examinations at the study centres in 4-5 year intervals. Thereby, longitudinal information on changes in risk factor profiles and in vascular, cardiac, metabolic, neurocognitive, pulmonary and sensory function is collected. NAKO is a major resource for population-based epidemiology to identify new and tailored strategies for early detection, prediction, prevention and treatment of major diseases for the next 30 years.

Long-term outcomes of stroke unit care in older stroke patients: a retrospective cohort study.

BACKGROUND: older patients are less frequently treated in stroke units (SUs). Clinicians do not seem convinced that older patients benefit from specialised treatment in SU similarly to younger patients. OBJECTIVE: our study aimed to compare older patients' long-term outcomes with and without SU treatment. METHODS: this study used routinely collected health data of 232,447 patients admitted to hospitals in Germany between 2007 and 2017 who were diagnosed with ischaemic stroke (ICD 10 I63). The sample included 29,885 patients aged ≥90 years. The outcomes analysed were 10-, 30- and 90-day, and 1-, 3- and 5-year mortality and the combinations of death or recurrence, inpatient treatment and increase in long-term care needs. Bivariate chi-square tests and multivariable logistic regression analyses were used, adjusting for the covariates age, sex, co-morbidity, long-term care needs before stroke and socioeconomic status of the patients' region of origin. RESULTS: between 2007 and 2017, 57.1% of patients aged <90 years and 49.6% of those aged ≥90 years were treated in a SU. The 1-year mortality rate of ≥90-year-olds was 56.9 and 61.9% with and without SU treatment, respectively. The multivariable-adjusted risk of death in ≥90-year-olds with SU treatment was odds ratio (OR) = 0.67 (95% confidence interval [CI] = 0.62-0.73) 10 days after the initial event and OR = 0.76 (95% CI = 0.71-0.82) 3 years after stroke. CONCLUSIONS: even very old patients with stroke benefit from SU treatment in the short and long term. Therefore, SU treatment should be the norm even in older patients.

Associations of major depressive disorder and related clinical characteristics with 25-hydroxyvitamin D levels in middle-aged adults.

Background: Vitamin D deficiency has been suggested to contribute to the onset of depression, but published results are inconsistent. The aims of this study were 1) to compare serum 25-hydroxyvitamin D (25(OH)D) levels in patients with depression and non-depressed controls and 2) to examine whether distinct subtypes and symptom severity of depression may vary in their association with 25(OH)D.Methods: The study involved cross-sectional data of n=1169 participants from the BiDirect Study (n=639 patients with clinically diagnosed major depressive disorder (MDD), n=530 controls). Serum 25(OH)D was measured via LS-MS/MS. We performed analysis of covariance to evaluate adjusted means of 25(OH)D levels and multinomial logistic regression to assess the association of depression and its clinical characteristics, namely distinct subtypes and symptom severity, with 25(OH)D status (adjusted for age, sex, education, season of blood sample collection, and lifestyle factors).Results: In total, 45.0% of the participants had adequate 25(OH)D levels (≥20 ng/ml), whereas 24.9% had a deficiency (<12 ng/ml). Patients with MDD had lower 25(OH)D levels than controls (16.7 vs. 19.6 ng/ml, p<0.001). Patients with atypical depression had the lowest levels (14.6 ng/ml). Symptom severity was inversely related to 25(OH)D. Moreover, patients with MDD had a more than 2-times higher odds of 25(OH)D deficiency than controls. Atypical depression showed the highest odds of deficiency.Conclusions: The results support that patients with depression have lower 25(OH)D concentrations than non-depressed individuals. Distinct subtypes, particularly the atypical subtype, may play a special role in this context. Therefore, depression heterogeneity should be considered in future research.

Associations Between Outcome Resilience and Sociodemographic Factors, Childhood Trauma, Personality Dimensions and Self-Rated Health in Middle-Aged Adults.

BACKGROUND: We examined how sociodemographic factors, childhood trauma, personality dimensions, and self-rated health were associated with outcome resilience and how different stressors influenced depressive symptoms. METHODS: An outcome resilience score for 213 adults was derived by means of a residualization approach. Associations between outcome resilience and sociodemographic and personality factors were evaluated using linear regression. In addition, associations between log-transformed depressive symptoms and the stressors were analyzed using multiple linear regression. A Pearson correlation coefficient between self-rated health and outcome resilience was also computed. RESULTS: Higher neuroticism was negatively and higher conscientiousness was positively associated with outcome resilience. Better self-rated health was associated with higher outcome resilience. Somatic disease events and onset of chronic mental disorders were associated with more depressive symptoms. CONCLUSIONS: Outcome resilience was significantly related to neuroticism, conscientiousness, and self-rated health. Strong associations between depressive symptoms and the stressors somatic disease event, and chronic mental disorder were observed.

Female Stroke: Sex Differences in Acute Treatment and Early Outcomes of Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Men and women are differently affected by acute ischemic stroke (AIS) in many aspects. Prior studies on sex disparities were limited by moderate sample sizes, varying years of data acquisition, and inconsistent inclusions of covariates leading to controversial findings. We aimed to analyze sex differences in AIS severity, treatments, and early outcome and to systematically evaluate the effect of important covariates in a large German stroke registry. METHODS: Analyses were based on the Stroke Registry of Northwestern Germany from 2000 to 2018. We focused on admission-stroke severity and disability, acute recanalization treatment, and early stroke outcomes. Potential sex divergences were investigated via odds ratio (OR) using logistic regression models. Covariates were introduced in 3 steps: (1) base models (age and admission year), (2) partially adjusted models (additionally corrected for acute stroke severity and recanalization treatment), (3) fully adjusted models (additionally adjusted for onset-to-admission time interval, prestroke functional status, comorbidities, and stroke cause). Models were separately fitted for the periods 2000 to 2009 and 2010 to 2018. RESULTS: Data from 761 106 patients with AIS were included. In fully adjusted models, there were no sex differences with respect to treatment with intravenous thrombolysis (2000-2009: OR, 0.99 [95% CI, 0.94-1.03]; 2010-2018: OR, 1.0 [0.98-1.02]), but women were more likely to receive intraarterial therapy (2010-2018: OR, 1.12 [1.08-1.15]). Despite higher disability on admission (2000-2009: OR, 1.10 [1.07-1.13]; 2010-2018: OR, 1.09 [1.07-1.10]), female patients were more likely to be discharged with a favorable functional outcome (2003-2009: OR, 1.05 [1.02-1.09]; 2010-2018: OR, 1.05 [1.04-1.07]) and experienced lower in-hospital mortality (2000-2009: OR, 0.92 [0.86-0.97]; 2010-2018: OR, 0.91 [0.88-0.93]). CONCLUSIONS: Female patients with AIS have a higher chance of receiving intraarterial treatment that cannot be explained by clinical characteristics, such as age, premorbid disability, stroke severity, or cause. Women have a more favorable in-hospital recovery than men because their higher disability upon admission was followed by a lower in-hospital mortality and a higher likelihood of favorable functional outcome at discharge after adjustment for covariates.

Serum neurofilament light and tau as prognostic markers for all-cause mortality in the elderly general population-an analysis from the MEMO study.

BACKGROUND: Neurofilament light chain (NfL) is a cytoskeletal protein component whose release into blood is indicative of neuronal damage. Tau is a microtubule-associated protein in neurons and strongly associated with overall brain degeneration. NfL and tau levels are associated with mortality in different neurological diseases, but studies in the general population are missing. We investigated whether NfL and tau serum levels could serve as prognostic markers for overall mortality in elderly individuals without pre-defined neurological conditions. Further, we investigated the cross-sectional associations between NfL, tau, neuropsychological functioning, and brain structures. METHODS: In 1997, 385 inhabitants of Augsburg who were aged 65 years and older were included in the Memory and Morbidity in Augsburg Elderly (MEMO) study. They participated in a face-to-face medical interview including neuropsychological tests and magnetic resonance imaging (MRI) of the brain. NfL and tau were measured from non-fasting blood samples using highly sensitive single molecule array assays. To assess the prognostic accuracy of the biomarkers, concordance statistics based on the predicted 5-year survival probabilities were calculated for different Cox regression models. Associations between the biomarkers and the neuropsychological test scores or brain structures were investigated using linear or logistic regression. RESULTS: NfL (HR 1.27, 95% CI [1.14-1.42]) and tau (1.20 [1.07-1.35]) serum levels were independently associated with all-cause mortality. NfL, but not tau, increased the prognostic accuracy when added to a model containing sociodemographic characteristics (concordance statistic 0.684 [0.612-0.755] vs. 0.663 [0.593-0.733]), but not when added to a model containing sociodemographic characteristics and brain atrophy or neuropsychological test scores. NfL serum levels were cross-sectionally associated with neuropsychological test scores and brain structures. CONCLUSIONS: The association between NfL serum levels and brain atrophy and neuropsychological performance in individuals without overt neurological disease is similar to that seen in patients with neurodegenerative diseases. These findings support the concept of a continuum of physiological aging and incipient, subclinical pathology, and manifest disease. NfL, but not tau, serum levels might serve as a prognostic marker for all-cause mortality if no other clinical information is available.

Identification of Restless Legs Syndrome Genes by Mutational Load Analysis.

OBJECTIVE: Restless legs syndrome is a frequent neurological disorder with substantial burden on individual well-being and public health. Genetic risk loci have been identified, but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes, we searched for highly significant mutational burden in candidate genes. METHODS: We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions. The burden of low-frequency and rare variants was assessed, and in addition, an algorithm (binomial performance deviation analysis) was established to estimate independently the sequence variation in the probe binding regions from the variation in sequencing depth. RESULTS: Highly significant results (considering the number of genes in the genome) of the conventional burden test and the binomial performance deviation analysis overlapped significantly. Fourteen genes were highly significant by one method and confirmed with Bonferroni-corrected significance by the other to show a differential burden of low-frequency and rare variants in restless legs syndrome. Nine of them (AAGAB, ATP2C1, CNTN4, COL6A6, CRBN, GLO1, NTNG1, STEAP4, VAV3) resided in the vicinity of known restless legs syndrome loci, whereas 5 (BBS7, CADM1, CREB5, NRG3, SUN1) have not previously been associated with restless legs syndrome. Burden test and binomial performance deviation analysis also converged significantly in fine-mapping potentially causative domains within these genes. INTERPRETATION: Differential burden with intragenic low-frequency variants reveals putatively causative genes in restless legs syndrome. ANN NEUROL 2020;87:184-193.

Effect of applying inclusion and exclusion criteria of phase III clinical trials to multiple sclerosis patients in routine clinical care.

BACKGROUND: Newly approved, drug-modifying therapies are associated with still unknown adverse events, although clinical trials leading to approval have strict inclusion and exclusion criteria and analyse safety and efficacy. OBJECTIVES: The aim of this study was to analyse the eligibility of multiple sclerosis (MS) patients treated in routine care into the phase III clinical trial of the respective drug. METHODS: In total, 3577 MS patients with 4312 therapies were analysed. Patients with primary-progressive MS were excluded. Inclusion and exclusion criteria of phase III clinical trials in relapsing-remitting MS were adopted and subsequently applied. A comparison in clinical and sociodemographic characteristics was made between patient who met the criteria and those who did not. RESULTS: 83% of registered patients would not have been eligible to the respective phase III clinical trial. Relapse was the single most frequent criterion not fulfilled (74.7%), followed by medication history (21.2%). CONCLUSION: The majority of MS patients treated in routine care would not have met clinical trials criteria. Thus, the efficacy and safety of therapies in clinical trials can differ from those in the real world. Broader phase III inclusion criteria would increase their eligibility and contribute to a better generalizability of the results in clinical trials.