Lundbeck Foundation

Body-first Lewy body disease (LBD) is hypothesized to begin in the peripheral autonomic nervous system, years before nigrostriatal involvement. Isolated REM sleep behaviour disorder (iRBD) is considered prodromal body-first LBD, but the duration of the prodromal phase remains unknown. We aimed to determine the progression rate of cardiac sympathetic denervation using [123I]meta-iodobenzylguanidine (MIBG) scintigraphy and employ the resulting curves to estimate the prodromal period of body-first LBD. We analysed longitudinal MIBG and dopaminergic imaging data from three cohorts: early Parkinsons disease (PD) patients from KPD, Korea (KPD-PD; n=195); de novo PD (n=74) and iRBD (n=54) patients from the PACE cohort, Aarhus, Denmark; and DaT SPECT data from PPMI PD (n=426) and iRBD (n=37). Heart-to-mediastinum ratios (MIBG) and putamen-to-occipital ratios (DaT SPECT) were converted to percent of normal value (healthy control mean). Patients were binned into quartiles according to baseline imaging data and progression curves were constructed by using median decline rates within each quartile. Onset of cardiac sympathetic (peripheral) and nigrostriatal dopaminergic (central) neurodegeneration were determined for iRBD patients by back-extrapolation from baseline imaging values. Longitudinal MIBG trajectories were highly consistent across the KPD and PACE cohorts, showing a rapid early decline (~10%-points/year) followed by gradual slowing, reaching 50% of normal value after ~5 years and 25% after ~10 years. PACE-iRBD patients displayed severe baseline cardiac sympathetic loss (median 21.3% of normal), corresponding to an estimated onset of peripheral neurodegeneration 11.3 years prior to study enrolment. Dopaminergic decline was slightly slower, reaching 50% of normal value after ~8 years and 25% after ~15 years. PACE-iRBD patients exhibited mild baseline dopaminergic deficit (median 81.6% of normal), indicating onset of nigrostriatal degeneration 2.7 years prior to enrolment. Thus, cardiac sympathetic degeneration preceded nigrostriatal involvement by 8.6 years. Based on baseline dopaminergic degeneration in PACE-PD patients, predicted time to phenoconversion for PACE-iRBD patients was 8.4 years. The combined model estimated the total prodromal period in body-first LBD to exceed 19 years. In conclusion, our study suggests that cardiac sympathetic degeneration begins more than a decade before study enrolment in iRBD subjects and nearly two decades before LBD diagnosis. Therefore, MIBG scintigraphy is a robust biomarker for detecting the earliest measurable neurodegeneration of body-first LBD and may be integrated in biological staging of alfa-synucleinopathies. Furthermore, our findings have implications for drug trial design in SAA-positive individuals, and for identifying patients at the optimal window for disease-modifying therapies.

Asthma and recurrent wheeze in the first years of life represent a heterogeneous and poorly understood syndrome with a need to understand to what extent phenotypes reflect distinct underlying mechanisms. We sought to investigate whether specific genetic asthma mechanisms, represented by genetic risk loci, were associated with specific disease courses and asthma phenotypes. Known childhood asthma risk loci (GSDMB, CDHR3, FUT2, ABO, HLA-DQA1, IL33, IL1RL1, IL13, and TSLP) were analyzed in relation to redeemed prescriptions for asthma and allergy medication from birth to age 15 years in more than 23,000 children from the iPSYCH (Integrative Psychiatric Research) study. Gene variants were studied separately and as combined scores on the basis of putative similar mechanisms. Association with atopic and nonatopic asthma phenotypes was examined in more than 6000 children from the COPSAC (Copenhagen Prospective Study on Asthma in Childhood), BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiology), and CHILD (Canadian Healthy Infant Longitudinal Development) birth cohorts. GSDMB and CDHR3 were the strongest risk loci for asthma prescriptions in the first years of life, with effects continuing into school age, although with attenuating effect size. CDHR3 was characterized by associations present already in the first year of life and a strong interaction with GSDMB genotype. Suspected TH2-related loci were characterized by a slightly later onset around age 2 to 3 years, with increasing or stable effect size till age 15 years and increased risk of allergic rhinitis. GSDMB and CDHR3 were associated with early transient disease, whereas most other loci were associated with both persistent and late-onset disease and with both atopic and nonatopic asthma. Risk loci of early childhood asthma seem to involve different disease mechanisms as illustrated by their specific age-related effects. However, risk loci generally showed associations across classical age- and atopy-related phenotypes, suggesting that specific asthma mechanisms are not well captured by classical phenotyping.

Cognitive reserve (CR), referring to the brain's adaptability to maintain functioning despite pathology, has been found to positively impact the clinical manifestations in schizophrenia and bipolar disorder. Here, we aimed to explore the protective role of CR in children at familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) compared with population-based controls (PBC). This study is part of The Danish High Risk and Resilience Study, a cohort study of 522 seven-year-old children at FHR-SZ (n = 202, 45.6% females) or FHR-BP (n = 120, 46.1% females) and PBC (n = 200, 46.2% females). CR was assessed using principal component analysis including information about child IQ, school performance, peer relations, physical leisure activities, developmental milestones, parental education and occupation, and family leisure activities. Clinical outcomes included child global functioning, lifetime psychopathology, and psychotic experiences. Neurocognitive outcomes included processing speed, sustained attention, verbal memory, visuospatial memory, verbal working memory, and set-shifting. Compared with PBC, CR was lower in children at FHR-SZ (p < 0.001, d = 0.73) and FHR-BP (p < 0.001, d = 0.51). Additionally, children at FHR-SZ had lower CR than FHR-BP (p = 0.042, d = 0.24). Across groups, CR was non-differentially and positively associated with global functioning (p < 0.001) and all neurocognitive outcomes (p ≤ 0.005) and negatively associated with psychopathology (p ≤ 0.007) and delusional psychotic experiences (p = 0.019). Children at high risk have lower CR already at an early developmental stage. CR may serve as a protective factor against the development of psychopathology and neurocognitive impairments, offering a potential target in preventative interventions aiming at altering the long-term trajectories for high-risk populations.

SummaryBackgroundFamily adversity and childhood abuse have been associated with an increased risk of homelessness in adulthood. However, to our knowledge, no population-based longitudinal studies have examined the association between out-of-home placement and subsequent homelessness, while accounting for psychiatric disorders and parental background. Thus, we aimed to investigate the association between out-of-home placement and psychiatric disorders during childhood or adolescence and homelessness later in life.MethodsWe used data from a nationwide, register-based birth cohort in Denmark from 1 January 1983 to 31 December 2003, who were alive at any point from 1 January 2001 to 31 December 2021. Children and adolescents (aged 0–17) were followed up from their 18th birthday for risk of homelessness. We investigated associations using national registers with information on homelessness and psychiatric disorders. We examined individuals with any out-of-home placement history with and without psychiatric disorders diagnosed up to age 18 according to the first episode of homelessness after age 18, defined as first contact with a shelter. We estimated the cumulative incidence function using an Aalen-Johansen estimator. Hazard ratios (HRs) for the association between out-of-home placement, psychiatric disorder, and homelessness were estimated by sex using Cox proportional-hazard regression analyses, adjusted for birth year, parental sociodemographic factors and psychiatric disorders. Additionally, we employed a stratified Cox model (stratified by mother) to examine the contribution of within-family covariates.FindingsThe study cohort included 1,226,130 Danish residents aged 18–39 years. Of these, 53,281 individuals (4·3%) had experienced out-of-home placement during childhood or adolescence. By age 39, 12·2% (95% CI 11·6–12·7) of males and 6·3% (95% CI 5·9–6·7) of females with a history of out-of-home placement experienced homelessness. This corresponds to a substantially increased risk compared to people without such a history, with adjusted HRs of 7·1 (95% CI 6·7–7·5) for males and 9·0 (8·2–9·8) for females. In sibling analyses restricted to 955,287 individuals and adjusted for birth year, out-of-home placement was associated with a 3-fold increased risk of homelessness compared to siblings without such a history (aHR 2·8 (95% CI 2·4–3·3) for males and aHR 3·2 (2·4–4·1) for females). Homelessness risk was even higher for individuals with a history of both out-of-home placement and psychiatric disorder, particularly when psychiatric diagnosis occurred after the first placement. In the full cohort, adjusted HRs were 11·8 (95% CI 10·8–13·0) for males and 19·3 (16·9–21·9) for females, compared to individuals with neither out-of-home placement nor psychiatric disorder.InterpretationIndividuals with a history of out-of-home placement are at higher risk of experiencing homelessness, particularly those with co-occurring psychiatric disorders. These findings highlight the need for targeted interventions and coordinated efforts across medical and social services to prevent homelessness.FundingFunded by a grant from the 10.13039/501100003554Lundbeck Foundation to SFN, F-61171-23-50 and the Independent Research Fund to SFN 10.46540/3162-00051B.

Background: Severe anorexia nervosa (AN) represents a subgroup of individuals with AN with prolonged illness duration and poor prognosis. Previous research has reported increased medication use in AN, but prescription patterns in severe AN remain unexplored. Methods: Utilizing Danish registers, this cohort study included 7,654 individuals diagnosed with AN. We assigned cases to severe AN or less-severe AN groups based on their AN Register-based Severity Index scores. First, we examined trajectories of medication use and compared prescription patterns between groups using logistic regression models. Second, common comorbidity profiles among individuals with severe AN were identified by latent class analysis for further between-group comparisons. Subgroup analyses were conducted to test alternative definitions of severe AN. Results: Compared to individuals with less-severe AN, those with severe AN were more likely to be prescribed various medications, including drugs targeting the alimentary tract (OR = 1.44), cardiovascular drugs (OR = 1.12), analgesics (OR = 1.18), and psychotropic drugs (OR = 2.89). Notably, the severe AN group was prescribed medications even in the absence of diagnosed comorbidities and with significantly higher frequencies compared to those with less-severe AN. Within the severe group, five clusters with distinct comorbidity profiles emerged, and we observed an increased use of medication compared to the comorbidity-free cluster. Conclusion: Our study highlights the higher medication use in individuals with severe AN and the association between medication use and comorbid conditions. These findings underscore the importance of comprehensive and specialized strategies for severe AN.

ABSTRACT Microglia response is proposed to be relevant in the neurogenerative process associated with alpha-synuclein (α-syn) pathology in Parkinson’s disease (PD). STING is a protein related to the immune sensing of DNA and autophagy, and it has been proposed to be involved in PD neurodegeneration. To investigate this, we injected 10 µg of murine pre-formed fibrils (PFFs) of α-syn (or monomeric and PBS as controls) into the striatum of wild-type (WT) and STING gt/gt mice, which lack functional STING. We examined motor behavior and brain pathology at 1- and 6-months post-injection. STING gt/gt mice showed more motor changes associated with PFF injection than WT mice. STING gt/gt mice had a differential immune response to PFF with early and sustained increased microglia numbers and higher macrophagic CD68 response, but milder changes in the expression of immune-relevant markers such as TLR2, TLR4, IL1b, and TREM2. However, the lack of STING did not induce changes in the extent of α-syn pathology nor the p62 accumulation seen in the model. Altogether, this resulted in a faster but similar degree of nigrostriatal dopaminergic degeneration after 6 months. Therefore, the data do not support a necessary role for STING in the α-syn induced nigral neuronal loss in the PFF-PD mouse model used here. However, the results suggest a functional relevance for STING in the brain response to the excess and aggregation of amylogenic proteins such as α-syn that can contribute to symptomatic changes.

The Southern Ocean is warming more rapidly than other parts of our planet. How this region's endemic biodiversity will respond to such changes can be illuminated by studying past events through genetic analyses of time-series data sets, including historic and fossil remains. Archaeological and subfossil remains show that the southern elephant seal (Mirounga leonina) was common along the coasts of Australia and New Zealand in the recent past. This species is now mostly confined to sub-Antarctic islands and the southern tip of South America. We analyzed ancient seal samples from Australia (Tasmania), New Zealand and the Antarctic mainland to examine how southern elephant seals have responded to a changing climate and anthropogenic pressures during the Holocene. Our analyses show that these seals formed part of a broader Australasian lineage, comprising seals from all sampled locations from the south Pacific sector of the Southern Ocean. Our study demonstrates that southern elephant seal populations have dynamically altered both range and population sizes under climatic and human pressures over surprisingly short evolutionary timeframes for such a large, long-lived mammal.

Evidence suggests that maternal health in pregnancy is associated with autism in the offspring. However, most diagnoses in pregnant women have not been examined, and the role of familial confounding remains unknown. Our cohort included all children born in Denmark between 1998 and 2015 (n = 1,131,899) and their parents. We fitted Cox proportional hazard regression models to estimate the likelihood of autism associated with each maternal prenatal ICD-10 diagnosis, accounting for disease chronicity and comorbidity, familial correlations and sociodemographic factors. We examined the evidence for familial confounding using discordant sibling and paternal negative control designs. Among the 1,131,899 individuals in our sample, 18,374 (1.6%) were diagnosed with autism by the end of follow-up. Across 236 maternal diagnoses we tested (prevalence ≥0.1%), 30 were significantly associated with autism after accounting for sociodemographic factors, disorder chronicity and comorbidity, and correction for multiple testing. This included obstetric, cardiometabolic and psychiatric disorders (for example, diabetes in pregnancy (hazard ratio (HR) 1.19, 95% confidence interval (CI) 1.08–1.31) and depression (HR 1.49, 95% CI 1.27–1.75)), previously shown to be associated with autism. Family-based analyses provided strong evidence for familial confounding in most of the observed associations. Our findings indicate pervasive associations between maternal health in pregnancy and offspring autism and underscore that these associations are largely attributable to familial confounding.