Objectives: Social dysfunction is one of the most common signs of major neuropsychiatric disorders. The Default Mode Network (DMN) is crucially implicated in both psychopathology and social dysfunction, although the transdiagnostic properties of social dysfunction remains unknown. As part of the pan-European PRISM (Psychiatric Ratings using Intermediate Stratified Markers) project, we explored cross-disorder impact of social dysfunction on DMN connectivity. Methods: We studied DMN intrinsic functional connectivity in relation to social dysfunction by applying Independent Component Analysis and Dual Regression on resting-state fMRI data, among schizophrenia (SZ; N=48), Alzheimer disease (AD; N=47) patients and healthy controls (HC; N=55). Social dysfunction was operationalised via the Social Functioning Scale (SFS) and De Jong-Gierveld Loneliness Scale (LON). Results: Both SFS and LON were independently associated with diminished DMN connectional integrity within rostromedial prefrontal DMN subterritories (pcorrected range=0.02–0.04). The combined effect of these indicators (Mean.SFS + LON) on diminished DMN connectivity was even more pronounced (both spatially and statistically), independent of diagnostic status, and not confounded by key clinical or sociodemographic effects, comprising large sections of rostromedial and dorsomedial prefrontal cortex (pcorrected =0.01). Conclusions: These findings pinpoint DMN connectional alterations as putative transdiagnostic endophenotypes for social dysfunction and could aid personalised care initiatives grounded in social behaviour ; The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. This publication reflects only the author's views and neither the IMI 2JU nor EFPIA nor the European Commission are liable for any use that may be made of the ...
Altres ajuts: This work was in part supported by the Canadian Consortium on Neurodegeneration in Aging (E.R., M.Z.), the ALS Canada-Brain Canada Hudson Grant (J.R., E.R., L.Z.), James Hunter ALS Initiative and the Temerty Family Foundation (L.Z., J.R.), Alzheimer's Society grant #284 (R.F.), Argentine National Research Council (CONICET) (EIS), ALS Canada Clinical Research Fellowship (R.S.), National Institutes of Health (NIH) R35 NS097261, P50 AG016574, P01 NS084974 (RR), P50 AG016574 (N.R.G., D.W.D., J.E.P., B.F.B., R.C.P.), NIH P01 NS084974 (D.W.D.), NIH P01 AG019724 (B.L.M., W.W.S.), JPND PreFrontALS (733051042), JPND RiMOD (733051024), Memorabel-FTD (733050103) (J.C.v-S), the Flemish Government initiated Impulse Program on Networks for Dementia Research (VIND), the Methusalem Excellence Program, the Research Foundation Flanders (FWO) and the University of Antwerp Research Fund (C.V.B., J.v-d-Z.), NIH P01-AG-017586 (V.V.D.), "Investissements d'avenir" ANR-10-IAIHU-06, Assistance Publique-Hôpitaux de Paris (Clinical Research and Development Department), Programme Hospitalier de Recherche Clinique, FTLD-exome RCAOM-12123, the ANR-PRTS PREV-DEMALS project (I.L.B.), an MRC Clinician Scientist Fellowship (MR/M008525/1), the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH), the MRC UK GENFI grant (MR/M023664/1) (J.D.R.), Swedish Research Council (Dnr 521-2010-3134, 529-2014-7504, 2015-02926), Alzheimer foundation Sweden, Brain Foundation Sweden, Swedish FTD Initiative, Swedish Brain Power, Karolinska Institutet doctoral funding, Gamla tjänarinnor, Stohnes foundation, Dementia foundation Sweden and the Stockholm County Council (ALF project) (CG), Ricerca Corrente, Italian Ministry of Health (G.R., G.B., L.B.), a National Health & Medical Research Council of Australia (NHMRC) Boosting Dementia Research Leadership Fellowship (1138223) (C.D.S.), NHMRC Senior Principal Research Fellowship (1079679) (G.M.H.), NHMRC Senior Research Fellowship (1103258) (O.P.), Fondazione CRF Grant 2015.0722, Fondo ...
In: Gao , Y , Wang , T , Yu , X , Ferrari , R , Hernandez , D G , Nalls , M A , Rohrer , J D , Ramasamy , A , Kwok , J B J , Dobson-Stone , C , Brooks , W S , Schofield , P R , Halliday , G M , Hodges , J R , Piguet , O , Bartley , L , Thompson , E , Haan , E , Hernández , I , Ruiz , A , Boada , M , Borroni , B , Padovani , A , Cruchaga , C , Cairns , N J , Benussi , L , Binetti , G , Ghidoni , R , Forloni , G , Albani , D , Galimberti , D , Fenoglio , C , Serpente , M , Scarpini , E , Clarimón , J , Lleó , A , Blesa , R , Waldö , M L , Nilsson , K , Nilsson , C , Mackenzie , I R A , Hsiung , G Y R , Mann , D M A , Grafman , J , Morris , C M , Attems , J , Griffiths , T D , McKeith , I G , Thomas , A J , Pietrini , P , Huey , E D , Wassermann , E M , Baborie , A , Jaros , E , Tierney , M C , Pastor , P , Razquin , C , Ortega-Cubero , S , Alonso , E , Perneczky , R , Diehl-Schmid , J , Alexopoulos , P , Kurz , A , Rainero , I , Rubino , E , Pinessi , L , Rogaeva , E , George-Hyslop , P S , Rossi , G , Tagliavini , F , Giaccone , G , Rowe , J B , Schlachetzki , J C M , Uphill , J , Collinge , J , Mead , S , Danek , A , Van Deerlin , V M , Grossman , M , Trojanowski , J Q , van der Zee , J , Cruts , M , Van Broeckhoven , C , Cappa , S F , Leber , I , Hannequin , D , Golfier , V , Vercelletto , M , Brice , A , Nacmias , B , Sorbi , S , Bagnoli , S , Piaceri , I , Nielsen , J E , Hjermind , L E , Riemenschneider , M , Mayhaus , M , Ibach , B , Gasparoni , G , Pichler , S , Gu , W , Rossor , M N , Fox , N C , Warren , J D , Spillantini , M G , Morris , H R , Rizzu , P , Heutink , P , Snowden , J S , Rollinson , S , Richardson , A , Gerhard , A , Bruni , A C , Maletta , R , Frangipane , F , Cupidi , C , Bernardi , L , Anfossi , M , Gallo , M , Conidi , M E , Smirne , N , Rademakers , R , Baker , M , Dickson , D W , Graff-Radford , N R , Petersen , R C , Knopman , D , Josephs , K A , Boeve , B F , Parisi , J E , Seeley , W W , Miller , B L , Karydas , A M , Rosen , H , van Swieten , J C , Dopper , E G P , Seelaar , H , Pijnenburg , Y A L , Scheltens , P , Logroscino , G , Capozzo , R , Novelli , V , Puca , A A , Franceschi , M , Postiglione , A , Milan , G , Sorrentino , P , Kristiansen , M , Chiang , H H , Graff , C , Pasquier , F , Rollin , A , Deramecourt , V , Lebouvier , T , Kapogiannis , D , Ferrucci , L , Pickering-Brown , S , Singleton , A B , Hardy , J , Momeni , P , Zhao , H , Zeng , P & International FTD-Genomics Consortium (IFGC) 2020 , ' Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis ' , Scientific Reports , vol. 10 , no. 1 , 12184 . https://doi.org/10.1038/s41598-020-68848-9
We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.
25 páginas, 6 figuras, 2 tablas ; 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. ; This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government's LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Not ; Peer reviewed