Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders

Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2–3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies

Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity

Background: Activated phosphoinositide-3-kinase d syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking. Objectives: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain of-function (GOF) disease; and identify predictors of severity in APDS. Methods: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs. Results: The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS. Conclusions: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients. (J Allergy Clin Immunol 2023;152:984-96.

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large‐scale studies. In response, we used cross‐sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Consortium to infer age‐related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta‐analysis and one‐way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3–90 years

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Consortium to examine age‐related trajectories inferred from cross‐sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3–90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter‐individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age‐related morphometric patterns

A prospective outcome study of patients with profound combined immunodeficiency (P-CID)

This is a prospective outcome study of patients with profound combined immunodeficiency (P-CID) (study number DRKS00000497). Combined immunodeficiencies (CID) are a heterogeneous group of inherited immune disorders with impaired T-cell development and (or) function manifesting through increased susceptibility to infections and (or) immune dysregulation. They can be delineated from severe CID (SCID) by their manifestation beyond the first year of life. Profound CID (P-CID) is a potentially life-threatening form of CID, in which stem cell transplant (SCT) is a relevant consideration at diagnosis. The primary objective of the study is to provide natural history data on patients with P-CID, irrespective of whether they undergo hematopoietic stem cell transplant (HSCT) or not. The goals are to determine survival, the frequency of severe events, and quality of life (QOL) 5 years after study inclusion. The secondary objective is to develop a risk model for P-CID patients. The model is developed from a set of clinical and laboratory parameters obtained at diagnosis, at study inclusion, and yearly thereafter. The tertiary objectives of this study are to determine the effects of donor, recipient, and treatment factors on the outcome of HSCT. The goal is to determine the quality of engraftment and immunological reconstitution and to determine the effects of these parameters on clinical outcome. The main hypothesis is that P-CID patients undergoing early HSCT have a better 5-year survival rate than patients who undergo late HSCT or are not transplanted. This is a prospective multi-centre international cohort study (observational study). Enrolled patients will be evaluated and treated according to local institutional protocols. They will receive comparable baseline and follow-up evaluations across all participating centres, irrespective of the therapeutic strategy at the individual site. There will be at least 6 study visits (scheduled yearly) for all patients. Because of the variable history prior to study inclusion, a morbidity score is determined for each patient at study visit 1. For those patients undergoing HSCT, an additional 6 month post-HSCT visit will be scheduled. The study visits will document immunological parameters, severe events including major infections, and major manifestations of immune dysregulation, severe transplant-related events, and QOL. </jats:p

Near Adult Heights and Predictions of Prospective Adult Heights using Automated and Conventional Greulich-Pyle Bone Age Determinations in children with chronic endocrine diseases

Abstract Calculation of prospective adult heights (PAH) is associated with considerable bone age interrater variability. Therefore, the new PAH method based on automated bone age (BA) determination (BoneXpert™) was compared to the conventional PAH method by Bayley- Pinneau (BP) based on BA determination according to Greulich and Pyle (GP) and to observed near adult heights. Heights and near adult heights were measured in 82 patients (48 females) with chronic endocrinopathies at age of 10.45 ± 2.12 years and at time of transition to adult care (17.98 ± 3.02 years). Further, BA were assessed according to conventional GP - by three experts- and by BoneXpert™. PAH were calculated using conventional BP tables and BoneXpert™. The conventional and the automated BA determinations revealed a mean difference of 0.25 ± 0.72 years (p = 0.0027). The automated PAH by BoneXpert™ were 156.96 ± 0.86 cm in females and 171.75 ± 1.6 cm in males compared to 153.95 ± 1.12 cm in females and 169.31 ± 1.6 cm in males by conventional BP, respectively, and in comparison to near adult heights 156.38 ± 5.84 cm in females and 168.94 ± 8.18 cm in males, respectively. Conclusion: BA ratings and adult height predictions by BoneXpert™ in children with chronic endocrinopathies abolish rater dependent variability and enhance reproducibility of estimates thereby refining care in growth disorders. Conventional methods may outperform automated analyses in specific cases.</jats:p