@article {8206, title = {Genetic architecture of subcortical brain structures in 38,851 individuals.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Nov}, pages = {1624-1636}, abstract = {

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

}, issn = {1546-1718}, doi = {10.1038/s41588-019-0511-y}, author = {Satizabal, Claudia L and Adams, Hieab H H and Hibar, Derrek P and White, Charles C and Knol, Maria J and Stein, Jason L and Scholz, Markus and Sargurupremraj, Muralidharan and Jahanshad, Neda and Roshchupkin, Gennady V and Smith, Albert V and Bis, Joshua C and Jian, Xueqiu and Luciano, Michelle and Hofer, Edith and Teumer, Alexander and van der Lee, Sven J and Yang, Jingyun and Yanek, Lisa R and Lee, Tom V and Li, Shuo and Hu, Yanhui and Koh, Jia Yu and Eicher, John D and Desrivi{\`e}res, Sylvane and Arias-Vasquez, Alejandro and Chauhan, Ganesh and Athanasiu, Lavinia and Renter{\'\i}a, Miguel E and Kim, Sungeun and Hoehn, David and Armstrong, Nicola J and Chen, Qiang and Holmes, Avram J and den Braber, Anouk and Kloszewska, Iwona and Andersson, Micael and Espeseth, Thomas and Grimm, Oliver and Abramovic, Lucija and Alhusaini, Saud and Milaneschi, Yuri and Papmeyer, Martina and Axelsson, Tomas and Ehrlich, Stefan and Roiz-Santia{\~n}ez, Roberto and Kraemer, Bernd and H{\r a}berg, Asta K and Jones, Hannah J and Pike, G Bruce and Stein, Dan J and Stevens, Allison and Bralten, Janita and Vernooij, Meike W and Harris, Tamara B and Filippi, Irina and Witte, A Veronica and Guadalupe, Tulio and Wittfeld, Katharina and Mosley, Thomas H and Becker, James T and Doan, Nhat Trung and Hagenaars, Saskia P and Saba, Yasaman and Cuellar-Partida, Gabriel and Amin, Najaf and Hilal, Saima and Nho, Kwangsik and Mirza-Schreiber, Nazanin and Arfanakis, Konstantinos and Becker, Diane M and Ames, David and Goldman, Aaron L and Lee, Phil H and Boomsma, Dorret I and Lovestone, Simon and Giddaluru, Sudheer and Le Hellard, Stephanie and Mattheisen, Manuel and Bohlken, Marc M and Kasperaviciute, Dalia and Schmaal, Lianne and Lawrie, Stephen M and Agartz, Ingrid and Walton, Esther and Tordesillas-Gutierrez, Diana and Davies, Gareth E and Shin, Jean and Ipser, Jonathan C and Vinke, Louis N and Hoogman, Martine and Jia, Tianye and Burkhardt, Ralph and Klein, Marieke and Crivello, Fabrice and Janowitz, Deborah and Carmichael, Owen and Haukvik, Unn K and Aribisala, Benjamin S and Schmidt, Helena and Strike, Lachlan T and Cheng, Ching-Yu and Risacher, Shannon L and P{\"u}tz, Benno and Fleischman, Debra A and Assareh, Amelia A and Mattay, Venkata S and Buckner, Randy L and Mecocci, Patrizia and Dale, Anders M and Cichon, Sven and Boks, Marco P and Matarin, Mar and Penninx, Brenda W J H and Calhoun, Vince D and Chakravarty, M Mallar and Marquand, Andre F and Macare, Christine and Kharabian Masouleh, Shahrzad and Oosterlaan, Jaap and Amouyel, Philippe and Hegenscheid, Katrin and Rotter, Jerome I and Schork, Andrew J and Liewald, David C M and de Zubicaray, Greig I and Wong, Tien Yin and Shen, Li and S{\"a}mann, Philipp G and Brodaty, Henry and Roffman, Joshua L and de Geus, Eco J C and Tsolaki, Magda and Erk, Susanne and van Eijk, Kristel R and Cavalleri, Gianpiero L and van der Wee, Nic J A and McIntosh, Andrew M and Gollub, Randy L and Bulayeva, Kazima B and Bernard, Manon and Richards, Jennifer S and Himali, Jayandra J and Loeffler, Markus and Rommelse, Nanda and Hoffmann, Wolfgang and Westlye, Lars T and Vald{\'e}s Hern{\'a}ndez, Maria C and Hansell, Narelle K and van Erp, Theo G M and Wolf, Christiane and Kwok, John B J and Vellas, Bruno and Heinz, Andreas and Olde Loohuis, Loes M and Delanty, Norman and Ho, Beng-Choon and Ching, Christopher R K and Shumskaya, Elena and Singh, Baljeet and Hofman, Albert and van der Meer, Dennis and Homuth, Georg and Psaty, Bruce M and Bastin, Mark E and Montgomery, Grant W and Foroud, Tatiana M and Reppermund, Simone and Hottenga, Jouke-Jan and Simmons, Andrew and Meyer-Lindenberg, Andreas and Cahn, Wiepke and Whelan, Christopher D and van Donkelaar, Marjolein M J and Yang, Qiong and Hosten, Norbert and Green, Robert C and Thalamuthu, Anbupalam and Mohnke, Sebastian and Hulshoff Pol, Hilleke E and Lin, Honghuang and Jack, Clifford R and Schofield, Peter R and M{\"u}hleisen, Thomas W and Maillard, Pauline and Potkin, Steven G and Wen, Wei and Fletcher, Evan and Toga, Arthur W and Gruber, Oliver and Huentelman, Matthew and Davey Smith, George and Launer, Lenore J and Nyberg, Lars and J{\"o}nsson, Erik G and Crespo-Facorro, Benedicto and Koen, Nastassja and Greve, Douglas N and Uitterlinden, Andr{\'e} G and Weinberger, Daniel R and Steen, Vidar M and Fedko, Iryna O and Groenewold, Nynke A and Niessen, Wiro J and Toro, Roberto and Tzourio, Christophe and Longstreth, William T and Ikram, M Kamran and Smoller, Jordan W and van Tol, Marie-Jose and Sussmann, Jessika E and Paus, Tom{\'a}{\v s} and Lema{\^\i}tre, Herv{\'e} and Schroeter, Matthias L and Mazoyer, Bernard and Andreassen, Ole A and Holsboer, Florian and Depondt, Chantal and Veltman, Dick J and Turner, Jessica A and Pausova, Zdenka and Schumann, Gunter and van Rooij, Daan and Djurovic, Srdjan and Deary, Ian J and McMahon, Katie L and M{\"u}ller-Myhsok, Bertram and Brouwer, Rachel M and Soininen, Hilkka and Pandolfo, Massimo and Wassink, Thomas H and Cheung, Joshua W and Wolfers, Thomas and Martinot, Jean-Luc and Zwiers, Marcel P and Nauck, Matthias and Melle, Ingrid and Martin, Nicholas G and Kanai, Ryota and Westman, Eric and Kahn, Ren{\'e} S and Sisodiya, Sanjay M and White, Tonya and Saremi, Arvin and van Bokhoven, Hans and Brunner, Han G and V{\"o}lzke, Henry and Wright, Margaret J and van {\textquoteright}t Ent, Dennis and N{\"o}then, Markus M and Ophoff, Roel A and Buitelaar, Jan K and Fern{\'a}ndez, Guill{\'e}n and Sachdev, Perminder S and Rietschel, Marcella and van Haren, Neeltje E M and Fisher, Simon E and Beiser, Alexa S and Francks, Clyde and Saykin, Andrew J and Mather, Karen A and Romanczuk-Seiferth, Nina and Hartman, Catharina A and DeStefano, Anita L and Heslenfeld, Dirk J and Weiner, Michael W and Walter, Henrik and Hoekstra, Pieter J and Nyquist, Paul A and Franke, Barbara and Bennett, David A and Grabe, Hans J and Johnson, Andrew D and Chen, Christopher and van Duijn, Cornelia M and Lopez, Oscar L and Fornage, Myriam and Wardlaw, Joanna M and Schmidt, Reinhold and DeCarli, Charles and De Jager, Philip L and Villringer, Arno and Debette, Stephanie and Gudnason, Vilmundur and Medland, Sarah E and Shulman, Joshua M and Thompson, Paul M and Seshadri, Sudha and Ikram, M Arfan} } @article {8287, title = {Association of CD14 with incident dementia and markers of brain aging and injury.}, journal = {Neurology}, volume = {94}, year = {2020}, month = {2020 01 21}, pages = {e254-e266}, abstract = {

OBJECTIVE: To test the hypothesis that the inflammatory marker plasma soluble CD14 (sCD14) associates with incident dementia and related endophenotypes in 2 community-based cohorts.

METHODS: Our samples included the prospective community-based Framingham Heart Study (FHS) and Cardiovascular Health Study (CHS) cohorts. Plasma sCD14 was measured at baseline and related to the incidence of dementia, domains of cognitive function, and MRI-defined brain volumes. Follow-up for dementia occurred over a mean of 10 years (SD 4) in the FHS and a mean of 6 years (SD 3) in the CHS.

RESULTS: We studied 1,588 participants from the FHS (mean age 69 {\textpm} 6 years, 47\% male, 131 incident events) and 3,129 participants from the CHS (mean age 72 {\textpm} 5 years, 41\% male, 724 incident events) for the risk of incident dementia. Meta-analysis across the 2 cohorts showed that each SD unit increase in sCD14 was associated with a 12\% increase in the risk of incident dementia (95\% confidence interval 1.03-1.23; = 0.01) following adjustments for age, sex, ε4 status, and vascular risk factors. Higher levels of sCD14 were associated with various cognitive and MRI markers of accelerated brain aging in both cohorts and with a greater progression of brain atrophy and a decline in executive function in the FHS.

CONCLUSION: sCD14 is an inflammatory marker related to brain atrophy, cognitive decline, and incident dementia.

}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000008682}, author = {Pase, Matthew P and Himali, Jayandra J and Beiser, Alexa S and DeCarli, Charles and McGrath, Emer R and Satizabal, Claudia L and Aparicio, Hugo J and Adams, Hieab H H and Reiner, Alexander P and Longstreth, W T and Fornage, Myriam and Tracy, Russell P and Lopez, Oscar and Psaty, Bruce M and Levy, Daniel and Seshadri, Sudha and Bis, Joshua C} } @article {9417, title = {Sleep Architecture, Obstructive Sleep Apnea, and Cognitive Function in Adults.}, journal = {JAMA Netw Open}, volume = {6}, year = {2023}, month = {2023 Jul 03}, pages = {e2325152}, abstract = {

IMPORTANCE: Good sleep is essential for health, yet associations between sleep and dementia risk remain incompletely understood. The Sleep and Dementia Consortium was established to study associations between polysomnography (PSG)-derived sleep and the risk of dementia and related cognitive and brain magnetic resonance imaging endophenotypes.

OBJECTIVE: To investigate association of sleep architecture and obstructive sleep apnea (OSA) with cognitive function in the Sleep and Dementia Consortium.

DESIGN, SETTING, AND PARTICIPANTS: The Sleep and Dementia Consortium curated data from 5 population-based cohorts across the US with methodologically consistent, overnight, home-based type II PSG and neuropsychological assessments over 5 years of follow-up: the Atherosclerosis Risk in Communities study, Cardiovascular Health Study, Framingham Heart Study (FHS), Osteoporotic Fractures in Men Study, and Study of Osteoporotic Fractures. Sleep metrics were harmonized centrally and then distributed to participating cohorts for cohort-specific analysis using linear regression; study-level estimates were pooled in random effects meta-analyses. Results were adjusted for demographic variables, the time between PSG and neuropsychological assessment (0-5 years), body mass index, antidepressant use, and sedative use. There were 5946 participants included in the pooled analyses without stroke or dementia. Data were analyzed from March 2020 to June 2023.

EXPOSURES: Measures of sleep architecture and OSA derived from in-home PSG.

MAIN OUTCOMES AND MEASURES: The main outcomes were global cognitive composite z scores derived from principal component analysis, with cognitive domains investigated as secondary outcomes. Higher scores indicated better performance.

RESULTS: Across cohorts, 5946 adults (1875 females [31.5\%]; mean age range, 58-89 years) were included. The median (IQR) wake after sleep onset time ranged from 44 (27-73) to 101 (66-147) minutes, and the prevalence of moderate to severe OSA ranged from 16.9\% to 28.9\%. Across cohorts, higher sleep maintenance efficiency (pooled β per 1\% increase, 0.08; 95\% CI, 0.03 to 0.14; P < .01) and lower wake after sleep onset (pooled β per 1-min increase, -0.07; 95\% CI, -0.13 to -0.01 per 1-min increase; P = .02) were associated with better global cognition. Mild to severe OSA (apnea-hypopnea index [AHI] >=5) was associated with poorer global cognition (pooled β, -0.06; 95\% CI, -0.11 to -0.01; P = .01) vs AHI less than 5; comparable results were found for moderate to severe OSA (pooled β, -0.06; 95\% CI, -0.11 to -0.01; P = .02) vs AHI less than 5. Differences in sleep stages were not associated with cognition.

CONCLUSIONS AND RELEVANCE: This study found that better sleep consolidation and the absence of OSA were associated with better global cognition over 5 years of follow-up. These findings suggest that the role of interventions to improve sleep for maintaining cognitive function requires investigation.

}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2023.25152}, author = {Pase, Matthew P and Harrison, Stephanie and Misialek, Jeffrey R and Kline, Christopher E and Cavuoto, Marina and Baril, Andree-Ann and Yiallourou, Stephanie and Bisson, Alycia and Himali, Dibya and Leng, Yue and Yang, Qiong and Seshadri, Sudha and Beiser, Alexa and Gottesman, Rebecca F and Redline, Susan and Lopez, Oscar and Lutsey, Pamela L and Yaffe, Kristine and Stone, Katie L and Purcell, Shaun M and Himali, Jayandra J} }