Distinct neural processing of acute stress in major depression and borderline personality disorder

Background: Major depressive disorder (MDD) and borderline personality disorder (BPD) are highly prevalent and often comorbid psychiatric conditions, with abnormal processing of negative affect resulting from psychological stress. Characteristics of central processing of autonomic response to stress in each disorder are not clearly settled. Methods: We obtained whole brain 3T fMRI with concurrent skin conductance, respiration rate, and heart rate variability measures in a cohort of MDD (N=19), BPD (N=19) patients, and healthy (N=20) individuals. Experiments were conducted in resting conditions, during a control mental arithmetic task, during highly stressful mental arithmetic, and in the period immediately following psychological stress. Results: Widespread activation of central autonomic network (CAN) structures was observed during stress compared to a control task in the group of healthy participants, whereas CAN activation during stress was less intense in both BPD and MDD. Both patient groups displayed increased sympathetic and decreased parasympathetic activation compared to healthy subjects, as previously reported. The relationship between peripheral sympathetic or parasympathetic activity and simultaneous regional brain BOLD activity was similar in BPD patients and healthy subjects, and markedly different from that seen in MDD patients. Limitations: The sample size, the fact it belonged to a single study site, and low grade affective symptomatology in both patient groups limit the generalizability of the present findings. Conclusions: The diverging neurobiological signature in the homeostatic response to stress in MDD and BPD possibly represents a heuristically valuable candidate biomarker to help discern MDD and BPD patients.Fil: Villarreal, Mirta Fabiana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; ArgentinaFil: Wainsztein, Agustina Edith. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; ArgentinaFil: Alvarez Mercè, Rocío. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Goldberg, Ximena. Centro de Investigación Biomédica en Red de Salud Mental; EspañaFil: Castro, Mariana Nair. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Brusco, Luis Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Ladrón de Guevara, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Bodurka, Jerzy. Laureate Institute for Brain Research; Estados UnidosFil: Paulus, Martin. Laureate Institute for Brain Research; Estados UnidosFil: Menchón, José M.. Universidad de Barcelona. Hospital Duran I Reynals. Instituto de Investigación Biomédica de Bellvitge; España. Instituto de Salud Carlos III; España. Universidad de Barcelona; EspañaFil: Soriano Mas, Carles. Universidad de Barcelona. Hospital Duran I Reynals. Instituto de Investigación Biomédica de Bellvitge; España. Instituto de Salud Carlos III; España. Universitat Autònoma de Barcelona; EspañaFil: Guinjoan, Salvador Martín. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires; Argentina. Laureate Institute for Brain Research; Estados Unido

Novel genes and sex differences in COVID-19 severity.

Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10-22 and p = 8.1x10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10-8) and ARHGAP33 (p = 1.3x10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele