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.

VL - 51 IS - 11 U1 - https://www.ncbi.nlm.nih.gov/pubmed/31636452?dopt=Abstract ER - TY - JOUR T1 - Novel genetic loci associated with hippocampal volume. JF - Nat Commun Y1 - 2017 A1 - Hibar, Derrek P A1 - Adams, Hieab H H A1 - Jahanshad, Neda A1 - Chauhan, Ganesh A1 - Stein, Jason L A1 - Hofer, Edith A1 - Renteria, Miguel E A1 - Bis, Joshua C A1 - Arias-Vasquez, Alejandro A1 - Ikram, M Kamran A1 - Desrivières, Sylvane A1 - Vernooij, Meike W A1 - Abramovic, Lucija A1 - Alhusaini, Saud A1 - Amin, Najaf A1 - Andersson, Micael A1 - Arfanakis, Konstantinos A1 - Aribisala, Benjamin S A1 - Armstrong, Nicola J A1 - Athanasiu, Lavinia A1 - Axelsson, Tomas A1 - Beecham, Ashley H A1 - Beiser, Alexa A1 - Bernard, Manon A1 - Blanton, Susan H A1 - Bohlken, Marc M A1 - Boks, Marco P A1 - Bralten, Janita A1 - Brickman, Adam M A1 - Carmichael, Owen A1 - M Mallar Chakravarty A1 - Chen, Qiang A1 - Ching, Christopher R K A1 - Chouraki, Vincent A1 - Cuellar-Partida, Gabriel A1 - Crivello, Fabrice A1 - den Braber, Anouk A1 - Doan, Nhat Trung A1 - Ehrlich, Stefan A1 - Giddaluru, Sudheer A1 - Goldman, Aaron L A1 - Gottesman, Rebecca F A1 - Grimm, Oliver A1 - Griswold, Michael E A1 - Guadalupe, Tulio A1 - Gutman, Boris A A1 - Hass, Johanna A1 - Haukvik, Unn K A1 - Hoehn, David A1 - Holmes, Avram J A1 - Hoogman, Martine A1 - Janowitz, Deborah A1 - Jia, Tianye A1 - Jørgensen, Kjetil N A1 - Karbalai, Nazanin A1 - Kasperaviciute, Dalia A1 - Kim, Sungeun A1 - Klein, Marieke A1 - Kraemer, Bernd A1 - Lee, Phil H A1 - Liewald, David C M A1 - Lopez, Lorna M A1 - Luciano, Michelle A1 - Macare, Christine A1 - Marquand, Andre F A1 - Matarin, Mar A1 - Mather, Karen A A1 - Mattheisen, Manuel A1 - McKay, David R A1 - Milaneschi, Yuri A1 - Muñoz Maniega, Susana A1 - Nho, Kwangsik A1 - Nugent, Allison C A1 - Nyquist, Paul A1 - Loohuis, Loes M Olde A1 - Oosterlaan, Jaap A1 - Papmeyer, Martina A1 - Pirpamer, Lukas A1 - Pütz, Benno A1 - Ramasamy, Adaikalavan A1 - Richards, Jennifer S A1 - Risacher, Shannon L A1 - Roiz-Santiañez, Roberto A1 - Rommelse, Nanda A1 - Ropele, Stefan A1 - Rose, Emma J A1 - Royle, Natalie A A1 - Rundek, Tatjana A1 - Sämann, Philipp G A1 - Saremi, Arvin A1 - Satizabal, Claudia L A1 - Schmaal, Lianne A1 - Schork, Andrew J A1 - Shen, Li A1 - Shin, Jean A1 - Shumskaya, Elena A1 - Smith, Albert V A1 - Sprooten, Emma A1 - Strike, Lachlan T A1 - Teumer, Alexander A1 - Tordesillas-Gutierrez, Diana A1 - Toro, Roberto A1 - Trabzuni, Daniah A1 - Trompet, Stella A1 - Vaidya, Dhananjay A1 - Van der Grond, Jeroen A1 - van der Lee, Sven J A1 - Van der Meer, Dennis A1 - van Donkelaar, Marjolein M J A1 - van Eijk, Kristel R A1 - van Erp, Theo G M A1 - Van Rooij, Daan A1 - Walton, Esther A1 - Westlye, Lars T A1 - Whelan, Christopher D A1 - Windham, Beverly G A1 - Winkler, Anderson M A1 - Wittfeld, Katharina A1 - Woldehawariat, Girma A1 - Wolf, Christiane A1 - Wolfers, Thomas A1 - Yanek, Lisa R A1 - Yang, Jingyun A1 - Zijdenbos, Alex A1 - Zwiers, Marcel P A1 - Agartz, Ingrid A1 - Almasy, Laura A1 - Ames, David A1 - Amouyel, Philippe A1 - Andreassen, Ole A A1 - Arepalli, Sampath A1 - Assareh, Amelia A A1 - Barral, Sandra A1 - Bastin, Mark E A1 - Becker, Diane M A1 - Becker, James T A1 - Bennett, David A A1 - Blangero, John A1 - van Bokhoven, Hans A1 - Boomsma, Dorret I A1 - Brodaty, Henry A1 - Brouwer, Rachel M A1 - Brunner, Han G A1 - Buckner, Randy L A1 - Buitelaar, Jan K A1 - Bulayeva, Kazima B A1 - Cahn, Wiepke A1 - Calhoun, Vince D A1 - Cannon, Dara M A1 - Cavalleri, Gianpiero L A1 - Cheng, Ching-Yu A1 - Cichon, Sven A1 - Cookson, Mark R A1 - Corvin, Aiden A1 - Crespo-Facorro, Benedicto A1 - Curran, Joanne E A1 - Czisch, Michael A1 - Dale, Anders M A1 - Davies, Gareth E A1 - De Craen, Anton J M A1 - de Geus, Eco J C A1 - De Jager, Philip L A1 - de Zubicaray, Greig I A1 - Deary, Ian J A1 - Debette, Stéphanie A1 - DeCarli, Charles A1 - Delanty, Norman A1 - Depondt, Chantal A1 - DeStefano, Anita A1 - Dillman, Allissa A1 - Djurovic, Srdjan A1 - Donohoe, Gary A1 - Drevets, Wayne C A1 - Duggirala, Ravi A1 - Dyer, Thomas D A1 - Enzinger, Christian A1 - Erk, Susanne A1 - Espeseth, Thomas A1 - Fedko, Iryna O A1 - Fernández, Guillén A1 - Ferrucci, Luigi A1 - Fisher, Simon E A1 - Fleischman, Debra A A1 - Ford, Ian A1 - Fornage, Myriam A1 - Foroud, Tatiana M A1 - Fox, Peter T A1 - Francks, Clyde A1 - Fukunaga, Masaki A1 - Gibbs, J Raphael A1 - Glahn, David C A1 - Gollub, Randy L A1 - Göring, Harald H H A1 - Green, Robert C A1 - Gruber, Oliver A1 - Gudnason, Vilmundur A1 - Guelfi, Sebastian A1 - Håberg, Asta K A1 - Hansell, Narelle K A1 - Hardy, John A1 - Hartman, Catharina A A1 - Hashimoto, Ryota A1 - Hegenscheid, Katrin A1 - Heinz, Andreas A1 - Le Hellard, Stephanie A1 - Hernandez, Dena G A1 - Heslenfeld, Dirk J A1 - Ho, Beng-Choon A1 - Hoekstra, Pieter J A1 - Hoffmann, Wolfgang A1 - Hofman, Albert A1 - Holsboer, Florian A1 - Homuth, Georg A1 - Hosten, Norbert A1 - Hottenga, Jouke-Jan A1 - Huentelman, Matthew A1 - Pol, Hilleke E Hulshoff A1 - Ikeda, Masashi A1 - Jack, Clifford R A1 - Jenkinson, Mark A1 - Johnson, Robert A1 - Jönsson, Erik G A1 - Jukema, J Wouter A1 - Kahn, René S A1 - Kanai, Ryota A1 - Kloszewska, Iwona A1 - Knopman, David S A1 - Kochunov, Peter A1 - Kwok, John B A1 - Lawrie, Stephen M A1 - Lemaître, Herve A1 - Liu, Xinmin A1 - Longo, Dan L A1 - Lopez, Oscar L A1 - Lovestone, Simon A1 - Martinez, Oliver A1 - Martinot, Jean-Luc A1 - Mattay, Venkata S A1 - McDonald, Colm A1 - McIntosh, Andrew M A1 - McMahon, Francis J A1 - McMahon, Katie L A1 - Mecocci, Patrizia A1 - Melle, Ingrid A1 - Meyer-Lindenberg, Andreas A1 - Mohnke, Sebastian A1 - Montgomery, Grant W A1 - Morris, Derek W A1 - Mosley, Thomas H A1 - Mühleisen, Thomas W A1 - Müller-Myhsok, Bertram A1 - Nalls, Michael A A1 - Nauck, Matthias A1 - Nichols, Thomas E A1 - Niessen, Wiro J A1 - Nöthen, Markus M A1 - Nyberg, Lars A1 - Ohi, Kazutaka A1 - Olvera, Rene L A1 - Ophoff, Roel A A1 - Pandolfo, Massimo A1 - Paus, Tomas A1 - Pausova, Zdenka A1 - Penninx, Brenda W J H A1 - Pike, G Bruce A1 - Potkin, Steven G A1 - Psaty, Bruce M A1 - Reppermund, Simone A1 - Rietschel, Marcella A1 - Roffman, Joshua L A1 - Romanczuk-Seiferth, Nina A1 - Rotter, Jerome I A1 - Ryten, Mina A1 - Sacco, Ralph L A1 - Sachdev, Perminder S A1 - Saykin, Andrew J A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Schofield, Peter R A1 - Sigursson, Sigurdur A1 - Simmons, Andrew A1 - Singleton, Andrew A1 - Sisodiya, Sanjay M A1 - Smith, Colin A1 - Smoller, Jordan W A1 - Soininen, Hilkka A1 - Steen, Vidar M A1 - Stott, David J A1 - Sussmann, Jessika E A1 - Thalamuthu, Anbupalam A1 - Toga, Arthur W A1 - Traynor, Bryan J A1 - Troncoso, Juan A1 - Tsolaki, Magda A1 - Tzourio, Christophe A1 - Uitterlinden, Andre G A1 - Hernández, Maria C Valdés A1 - van der Brug, Marcel A1 - van der Lugt, Aad A1 - van der Wee, Nic J A A1 - van Haren, Neeltje E M A1 - van 't Ent, Dennis A1 - van Tol, Marie-Jose A1 - Vardarajan, Badri N A1 - Vellas, Bruno A1 - Veltman, Dick J A1 - Völzke, Henry A1 - Walter, Henrik A1 - Wardlaw, Joanna M A1 - Wassink, Thomas H A1 - Weale, Michael E A1 - Weinberger, Daniel R A1 - Weiner, Michael W A1 - Wen, Wei A1 - Westman, Eric A1 - White, Tonya A1 - Wong, Tien Y A1 - Wright, Clinton B A1 - Zielke, Ronald H A1 - Zonderman, Alan B A1 - Martin, Nicholas G A1 - van Duijn, Cornelia M A1 - Wright, Margaret J A1 - Longstreth, W T A1 - Schumann, Gunter A1 - Grabe, Hans J A1 - Franke, Barbara A1 - Launer, Lenore J A1 - Medland, Sarah E A1 - Seshadri, Sudha A1 - Thompson, Paul M A1 - Ikram, M Arfan AB -The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

VL - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28098162?dopt=Abstract ER - TY - JOUR T1 - Regional correlations between [(11)C]PIB PET and post-mortem burden of amyloid-beta pathology in a diverse neuropathological cohort. JF - Neuroimage Clin Y1 - 2017 A1 - Seo, Sang Won A1 - Ayakta, Nagehan A1 - Grinberg, Lea T A1 - Sylvia Villeneuve A1 - Lehmann, Manja A1 - Reed, Bruce A1 - DeCarli, Charles A1 - Miller, Bruce L A1 - Rosen, Howard J A1 - Boxer, Adam L A1 - O'Neil, James P A1 - Jin, Lee-Way A1 - Seeley, William W A1 - Jagust, William J A1 - Rabinovici, Gil D AB -Imaging-pathological correlation studies show that in vivo amyloid-β (Aβ) positron emission tomography (PET) strongly predicts the presence of significant Aβ pathology at autopsy. We sought to determine whether regional PiB-PET uptake would improve sensitivity for amyloid detection in comparison with global measures (experiment 1), and to estimate the relative contributions of different Aβ aggregates to in vivo PET signal (experiment 2). In experiment 1, 54 subjects with [(11)C] PiB-PET during life and postmortem neuropathologic examination (85.2% with dementia, interval from PET to autopsy 3.1 ± 1.9 years) were included. We assessed Thal amyloid phase (N = 36) and CERAD score (N = 54) versus both global and regional PiB SUVRs. In experiment 2 (N = 42), PiB SUVR and post-mortem amyloid β burden was analyzed in five customized regions of interest matching regions sampled at autopsy. We assessed the relative contribution of neuritic plaques (NPs), diffuse plaques (DPs) and cerebral amyloid angiopathy (CAA) to regional PIB SUVR using multi-linear regression. In experiment 1, there were no differences in Area Under the Curve for amyloid phase ≥ A2 and CERAD score ≥ C2 between global and highest regional PiB SUVR (p = 0.186 and 0.230). In experiment 2, when NPs, DPs, and/or CAA were included in the same model, moderate to severe NPs were independently correlated with PiB SUVR in all regions except for the inferior temporal and calcarine ROI (β = 0.414-0.804, p < 0.05), whereas DPs were independently correlated with PiB SUVR in the angular gyrus ROI (β = 0.446, p = 0.010). CAA was also associated with PiB SUVR in the inferior temporal and calcarine ROI (β = 0.222-0.355, p < 0.05). In conclusion, global PiB-PET SUVR performed as well as regional values for amyloid detection in our cohort. The substrate-specific binding of PiB might differ among the brain specific regions.

VL - 13 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27981028?dopt=Abstract ER - TY - JOUR T1 - Validation of a Regression Technique for Segmentation of White Matter Hyperintensities in Alzheimer's Disease. JF - IEEE Trans Med Imaging Y1 - 2017 A1 - Dadar, Mahsa A1 - Pascoal, Tharick A. A1 - Manitsirikul, Sarinporn A1 - Misquitta, Karen A1 - Tartaglia, Carmela A1 - John CS Breitner A1 - Pedro Rosa-Neto A1 - Carmichael, Owen A1 - DeCarli, Charles A1 - Collins, D Louis AB -Segmentation and volumetric quantification of white matter hyperintensities (WMHs) is essential in assessment and monitoring of the vascular burden in aging and Alzheimer's disease (AD), especially when considering their effect on cognition. Manually segmenting WMHs in large cohorts is technically unfeasible due to time and accuracy concerns. Automated tools that can detect WMHs robustly and with high accuracy are needed. Here we present and validate a fully automatic technique for segmentation and volumetric quantification of WMHs in aging and AD. The proposed technique combines intensity and location features from multiple magnetic resonance imaging (MRI) contrasts and manually labeled training data with a linear classifier to perform fast and robust segmentations. It provides both a continuous subject specific WMH map reflecting different levels of tissue damage and binary segmentations. The method was used to detect WMHs in 80 elderly/AD brains (ADC dataset) as well as 40 healthy subjects at risk of AD (PREVENT-AD dataset). Robustness across different scanners was validated using 10 subjects from ADNI2/GO study. Voxel-wise and volumetric agreements were evaluated using Dice similarity index (SI) and intra-class correlation (ICC), yielding ICC=0.96, SI=0.62±0.16 for ADC dataset and ICC=0.78, SI=0.51±0.15 for PREVENT-AD dataset. The proposed method was robust in the independent sample yielding SI=0.64±0.17 with ICC=0.93 for ADNI2/GO subjects. The proposed method provides fast, accurate and robust segmentations on previously unseen data from different models of scanners, making it ideal to study WMHs in large scale multi-site studies.1.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/28422655?dopt=Abstract ER - TY - JOUR T1 - Novel genetic loci underlying human intracranial volume identified through genome-wide association. JF - Nat Neurosci Y1 - 2016 A1 - Adams, Hieab H H A1 - Hibar, Derrek P A1 - Chouraki, Vincent A1 - Stein, Jason L A1 - Nyquist, Paul A A1 - Renteria, Miguel E A1 - Trompet, Stella A1 - Arias-Vasquez, Alejandro A1 - Seshadri, Sudha A1 - Desrivières, Sylvane A1 - Beecham, Ashley H A1 - Jahanshad, Neda A1 - Wittfeld, Katharina A1 - van der Lee, Sven J A1 - Abramovic, Lucija A1 - Alhusaini, Saud A1 - Amin, Najaf A1 - Andersson, Micael A1 - Arfanakis, Konstantinos A1 - Aribisala, Benjamin S A1 - Armstrong, Nicola J A1 - Athanasiu, Lavinia A1 - Axelsson, Tomas A1 - Beiser, Alexa A1 - Bernard, Manon A1 - Bis, Joshua C A1 - Blanken, Laura M E A1 - Blanton, Susan H A1 - Bohlken, Marc M A1 - Boks, Marco P A1 - Bralten, Janita A1 - Brickman, Adam M A1 - Carmichael, Owen A1 - M Mallar Chakravarty A1 - Chauhan, Ganesh A1 - Chen, Qiang A1 - Ching, Christopher R K A1 - Cuellar-Partida, Gabriel A1 - Braber, Anouk Den A1 - Doan, Nhat Trung A1 - Ehrlich, Stefan A1 - Filippi, Irina A1 - Ge, Tian A1 - Giddaluru, Sudheer A1 - Goldman, Aaron L A1 - Gottesman, Rebecca F A1 - Greven, Corina U A1 - Grimm, Oliver A1 - Griswold, Michael E A1 - Guadalupe, Tulio A1 - Hass, Johanna A1 - Haukvik, Unn K A1 - Hilal, Saima A1 - Hofer, Edith A1 - Hoehn, David A1 - Holmes, Avram J A1 - Hoogman, Martine A1 - Janowitz, Deborah A1 - Jia, Tianye A1 - Kasperaviciute, Dalia A1 - Kim, Sungeun A1 - Klein, Marieke A1 - Kraemer, Bernd A1 - Lee, Phil H A1 - Liao, Jiemin A1 - Liewald, David C M A1 - Lopez, Lorna M A1 - Luciano, Michelle A1 - Macare, Christine A1 - Marquand, Andre A1 - Matarin, Mar A1 - Mather, Karen A A1 - Mattheisen, Manuel A1 - Mazoyer, Bernard A1 - McKay, David R A1 - McWhirter, Rebekah A1 - Milaneschi, Yuri A1 - Mirza-Schreiber, Nazanin A1 - Muetzel, Ryan L A1 - Maniega, Susana Muñoz A1 - Nho, Kwangsik A1 - Nugent, Allison C A1 - Loohuis, Loes M Olde A1 - Oosterlaan, Jaap A1 - Papmeyer, Martina A1 - Pappa, Irene A1 - Pirpamer, Lukas A1 - Pudas, Sara A1 - Pütz, Benno A1 - Rajan, Kumar B A1 - Ramasamy, Adaikalavan A1 - Richards, Jennifer S A1 - Risacher, Shannon L A1 - Roiz-Santiañez, Roberto A1 - Rommelse, Nanda A1 - Rose, Emma J A1 - Royle, Natalie A A1 - Rundek, Tatjana A1 - Sämann, Philipp G A1 - Satizabal, Claudia L A1 - Schmaal, Lianne A1 - Schork, Andrew J A1 - Shen, Li A1 - Shin, Jean A1 - Shumskaya, Elena A1 - Smith, Albert V A1 - Sprooten, Emma A1 - Strike, Lachlan T A1 - Teumer, Alexander A1 - Thomson, Russell A1 - Tordesillas-Gutierrez, Diana A1 - Toro, Roberto A1 - Trabzuni, Daniah A1 - Vaidya, Dhananjay A1 - Van der Grond, Jeroen A1 - Van der Meer, Dennis A1 - van Donkelaar, Marjolein M J A1 - van Eijk, Kristel R A1 - van Erp, Theo G M A1 - Van Rooij, Daan A1 - Walton, Esther A1 - Westlye, Lars T A1 - Whelan, Christopher D A1 - Windham, Beverly G A1 - Winkler, Anderson M A1 - Woldehawariat, Girma A1 - Wolf, Christiane A1 - Wolfers, Thomas A1 - Xu, Bing A1 - Yanek, Lisa R A1 - Yang, Jingyun A1 - Zijdenbos, Alex A1 - Zwiers, Marcel P A1 - Agartz, Ingrid A1 - Aggarwal, Neelum T A1 - Almasy, Laura A1 - Ames, David A1 - Amouyel, Philippe A1 - Andreassen, Ole A A1 - Arepalli, Sampath A1 - Assareh, Amelia A A1 - Barral, Sandra A1 - Bastin, Mark E A1 - Becker, Diane M A1 - Becker, James T A1 - Bennett, David A A1 - Blangero, John A1 - van Bokhoven, Hans A1 - Boomsma, Dorret I A1 - Brodaty, Henry A1 - Brouwer, Rachel M A1 - Brunner, Han G A1 - Buckner, Randy L A1 - Buitelaar, Jan K A1 - Bulayeva, Kazima B A1 - Cahn, Wiepke A1 - Calhoun, Vince D A1 - Cannon, Dara M A1 - Cavalleri, Gianpiero L A1 - Chen, Christopher A1 - Cheng, Ching-Yu A1 - Cichon, Sven A1 - Cookson, Mark R A1 - Corvin, Aiden A1 - Crespo-Facorro, Benedicto A1 - Curran, Joanne E A1 - Czisch, Michael A1 - Dale, Anders M A1 - Davies, Gareth E A1 - de Geus, Eco J C A1 - De Jager, Philip L A1 - de Zubicaray, Greig I A1 - Delanty, Norman A1 - Depondt, Chantal A1 - DeStefano, Anita L A1 - Dillman, Allissa A1 - Djurovic, Srdjan A1 - Donohoe, Gary A1 - Drevets, Wayne C A1 - Duggirala, Ravi A1 - Dyer, Thomas D A1 - Erk, Susanne A1 - Espeseth, Thomas A1 - Evans, Denis A A1 - Fedko, Iryna O A1 - Fernández, Guillén A1 - Ferrucci, Luigi A1 - Fisher, Simon E A1 - Fleischman, Debra A A1 - Ford, Ian A1 - Foroud, Tatiana M A1 - Fox, Peter T A1 - Francks, Clyde A1 - Fukunaga, Masaki A1 - Gibbs, J Raphael A1 - Glahn, David C A1 - Gollub, Randy L A1 - Göring, Harald H H A1 - Grabe, Hans J A1 - Green, Robert C A1 - Gruber, Oliver A1 - Gudnason, Vilmundur A1 - Guelfi, Sebastian A1 - Hansell, Narelle K A1 - Hardy, John A1 - Hartman, Catharina A A1 - Hashimoto, Ryota A1 - Hegenscheid, Katrin A1 - Heinz, Andreas A1 - Le Hellard, Stephanie A1 - Hernandez, Dena G A1 - Heslenfeld, Dirk J A1 - Ho, Beng-Choon A1 - Hoekstra, Pieter J A1 - Hoffmann, Wolfgang A1 - Hofman, Albert A1 - Holsboer, Florian A1 - Homuth, Georg A1 - Hosten, Norbert A1 - Hottenga, Jouke-Jan A1 - Pol, Hilleke E Hulshoff A1 - Ikeda, Masashi A1 - Ikram, M Kamran A1 - Jack, Clifford R A1 - Jenkinson, Mark A1 - Johnson, Robert A1 - Jönsson, Erik G A1 - Jukema, J Wouter A1 - Kahn, René S A1 - Kanai, Ryota A1 - Kloszewska, Iwona A1 - Knopman, David S A1 - Kochunov, Peter A1 - Kwok, John B A1 - Lawrie, Stephen M A1 - Lemaître, Herve A1 - Liu, Xinmin A1 - Longo, Dan L A1 - Longstreth, W T A1 - Lopez, Oscar L A1 - Lovestone, Simon A1 - Martinez, Oliver A1 - Martinot, Jean-Luc A1 - Mattay, Venkata S A1 - McDonald, Colm A1 - McIntosh, Andrew M A1 - McMahon, Katie L A1 - McMahon, Francis J A1 - Mecocci, Patrizia A1 - Melle, Ingrid A1 - Meyer-Lindenberg, Andreas A1 - Mohnke, Sebastian A1 - Montgomery, Grant W A1 - Morris, Derek W A1 - Mosley, Thomas H A1 - Mühleisen, Thomas W A1 - Müller-Myhsok, Bertram A1 - Nalls, Michael A A1 - Nauck, Matthias A1 - Nichols, Thomas E A1 - Niessen, Wiro J A1 - Nöthen, Markus M A1 - Nyberg, Lars A1 - Ohi, Kazutaka A1 - Olvera, Rene L A1 - Ophoff, Roel A A1 - Pandolfo, Massimo A1 - Paus, Tomas A1 - Pausova, Zdenka A1 - Penninx, Brenda W J H A1 - Pike, G Bruce A1 - Potkin, Steven G A1 - Psaty, Bruce M A1 - Reppermund, Simone A1 - Rietschel, Marcella A1 - Roffman, Joshua L A1 - Romanczuk-Seiferth, Nina A1 - Rotter, Jerome I A1 - Ryten, Mina A1 - Sacco, Ralph L A1 - Sachdev, Perminder S A1 - Saykin, Andrew J A1 - Schmidt, Reinhold A1 - Schofield, Peter R A1 - Sigurdsson, Sigurdur A1 - Simmons, Andy A1 - Singleton, Andrew A1 - Sisodiya, Sanjay M A1 - Smith, Colin A1 - Smoller, Jordan W A1 - Soininen, Hilkka A1 - Srikanth, Velandai A1 - Steen, Vidar M A1 - Stott, David J A1 - Sussmann, Jessika E A1 - Thalamuthu, Anbupalam A1 - Tiemeier, Henning A1 - Toga, Arthur W A1 - Traynor, Bryan J A1 - Troncoso, Juan A1 - Turner, Jessica A A1 - Tzourio, Christophe A1 - Uitterlinden, Andre G A1 - Hernández, Maria C Valdés A1 - van der Brug, Marcel A1 - van der Lugt, Aad A1 - van der Wee, Nic J A A1 - van Duijn, Cornelia M A1 - van Haren, Neeltje E M A1 - Van T Ent, Dennis A1 - van Tol, Marie-Jose A1 - Vardarajan, Badri N A1 - Veltman, Dick J A1 - Vernooij, Meike W A1 - Völzke, Henry A1 - Walter, Henrik A1 - Wardlaw, Joanna M A1 - Wassink, Thomas H A1 - Weale, Michael E A1 - Weinberger, Daniel R A1 - Weiner, Michael W A1 - Wen, Wei A1 - Westman, Eric A1 - White, Tonya A1 - Wong, Tien Y A1 - Wright, Clinton B A1 - Zielke, H Ronald A1 - Zonderman, Alan B A1 - Deary, Ian J A1 - DeCarli, Charles A1 - Schmidt, Helena A1 - Martin, Nicholas G A1 - De Craen, Anton J M A1 - Wright, Margaret J A1 - Launer, Lenore J A1 - Schumann, Gunter A1 - Fornage, Myriam A1 - Franke, Barbara A1 - Debette, Stéphanie A1 - Medland, Sarah E A1 - Ikram, M Arfan A1 - Thompson, Paul M AB -Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

VL - 19 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27694991?dopt=Abstract ER - TY - JOUR T1 - β-amyloid, hippocampal atrophy and their relation to longitudinal brain change in cognitively normal individuals. JF - Neurobiol Aging Y1 - 2016 A1 - Fletcher, Evan A1 - Sylvia Villeneuve A1 - Maillard, Pauline A1 - Harvey, Danielle A1 - Reed, Bruce A1 - Jagust, William A1 - DeCarli, Charles KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Amyloid beta-Peptides KW - Atrophy KW - Cerebral Amyloid Angiopathy KW - Cognition KW - Cohort Studies KW - Female KW - Hippocampus KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Regression Analysis AB -Recent literature has examined baseline hippocampal volume and extent of brain amyloidosis to test potential synergistic effects on worsening cognition and extent of brain atrophy. Use of hippocampal volume in prior studies was based on the notion that limbic circuit degeneration is an early manifestation of the Alzheimer's Disease (AD) pathophysiology. To clarify these interactions early in the AD process, we tested the effects of amyloid and baseline normalized hippocampal volume on longitudinal brain atrophy rates in a group of cognitively normal individuals. Results showed that the combination of elevated β-amyloid and baseline hippocampal atrophy is associated with increased rates specific to the limbic circuit and splenium. Importantly, this atrophy pattern emerged from a voxelwise analysis, corroborated by regression models over region of interests in native space. The results are broadly consistent with previous studies of the effects of amyloid and baseline hippocampal atrophy in normals, while pointing to accelerated atrophy of AD-vulnerable regions detectable at the preclinical stage.

VL - 40 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26973117?dopt=Abstract ER - TY - JOUR T1 - Delphi definition of the EADC-ADNI Harmonized Protocol for hippocampal segmentation on magnetic resonance. JF - Alzheimers Dement Y1 - 2015 A1 - Boccardi, Marina A1 - Bocchetta, Martina A1 - Apostolova, Liana G A1 - Barnes, Josephine A1 - Bartzokis, George A1 - Corbetta, Gabriele A1 - DeCarli, Charles A1 - deToledo-Morrell, Leyla A1 - Firbank, Michael A1 - Ganzola, Rossana A1 - Gerritsen, Lotte A1 - Henneman, Wouter A1 - Killiany, Ronald J A1 - Malykhin, Nikolai A1 - Pasqualetti, Patrizio A1 - Jens C Pruessner A1 - Redolfi, Alberto A1 - Robitaille, Nicolas A1 - Soininen, Hilkka A1 - Tolomeo, Daniele A1 - Wang, Lei A1 - Watson, Craig A1 - Wolf, Henrike A1 - Duvernoy, Henri A1 - Duchesne, Simon A1 - Jack, Clifford R A1 - Frisoni, Giovanni B KW - Alzheimer Disease KW - Atrophy KW - Consensus KW - Delphi Technique KW - Hippocampus KW - Humans KW - Image Processing, Computer-Assisted KW - Imaging, Three-Dimensional KW - Internationality KW - Magnetic Resonance Imaging KW - Neuroimaging AB -**BACKGROUND: **This study aimed to have international experts converge on a harmonized definition of whole hippocampus boundaries and segmentation procedures, to define standard operating procedures for magnetic resonance (MR)-based manual hippocampal segmentation.

**METHODS: **The panel received a questionnaire regarding whole hippocampus boundaries and segmentation procedures. Quantitative information was supplied to allow evidence-based answers. A recursive and anonymous Delphi procedure was used to achieve convergence. Significance of agreement among panelists was assessed by exact probability on Fisher's and binomial tests.

**RESULTS: **Agreement was significant on the inclusion of alveus/fimbria (P = .021), whole hippocampal tail (P = .013), medial border of the body according to visible morphology (P = .0006), and on this combined set of features (P = .001). This definition captures 100% of hippocampal tissue, 100% of Alzheimer's disease-related atrophy, and demonstrated good reliability on preliminary intrarater (0.98) and inter-rater (0.94) estimates.

**DISCUSSION: **Consensus was achieved among international experts with respect to hippocampal segmentation using MR resulting in a harmonized segmentation protocol.

**BACKGROUND: **An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance.

**METHODS: **Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web-platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T.

**RESULTS: **The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001).

**CONCLUSIONS: **The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.

Amyloid-β, a hallmark of Alzheimer's disease, begins accumulating up to two decades before the onset of dementia, and can be detected in vivo applying amyloid-β positron emission tomography tracers such as carbon-11-labelled Pittsburgh compound-B. A variety of thresholds have been applied in the literature to define Pittsburgh compound-B positron emission tomography positivity, but the ability of these thresholds to detect early amyloid-β deposition is unknown, and validation studies comparing Pittsburgh compound-B thresholds to post-mortem amyloid burden are lacking. In this study we first derived thresholds for amyloid positron emission tomography positivity using Pittsburgh compound-B positron emission tomography in 154 cognitively normal older adults with four complementary approaches: (i) reference values from a young control group aged between 20 and 30 years; (ii) a Gaussian mixture model that assigned each subject a probability of being amyloid-β-positive or amyloid-β-negative based on Pittsburgh compound-B index uptake; (iii) a k-means cluster approach that clustered subjects into amyloid-β-positive or amyloid-β-negative based on Pittsburgh compound-B uptake in different brain regions (features); and (iv) an iterative voxel-based analysis that further explored the spatial pattern of early amyloid-β positron emission tomography signal. Next, we tested the sensitivity and specificity of the derived thresholds in 50 individuals who underwent Pittsburgh compound-B positron emission tomography during life and brain autopsy (mean time positron emission tomography to autopsy 3.1 ± 1.8 years). Amyloid at autopsy was classified using Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria, unadjusted for age. The analytic approaches yielded low thresholds (standard uptake value ratiolow = 1.21, distribution volume ratiolow = 1.08) that represent the earliest detectable Pittsburgh compound-B signal, as well as high thresholds (standard uptake value ratiohigh = 1.40, distribution volume ratiohigh = 1.20) that are more conservative in defining Pittsburgh compound-B positron emission tomography positivity. In voxel-wise contrasts, elevated Pittsburgh compound-B retention was first noted in the medial frontal cortex, then the precuneus, lateral frontal and parietal lobes, and finally the lateral temporal lobe. When compared to post-mortem amyloid burden, low proposed thresholds were more sensitive than high thresholds (sensitivities: distribution volume ratiolow 81.0%, standard uptake value ratiolow 83.3%; distribution volume ratiohigh 61.9%, standard uptake value ratiohigh 62.5%) for CERAD moderate-to-frequent neuritic plaques, with similar specificity (distribution volume ratiolow 95.8%; standard uptake value ratiolow, distribution volume ratiohigh and standard uptake value ratiohigh 100.0%). A receiver operator characteristic analysis identified optimal distribution volume ratio (1.06) and standard uptake value ratio (1.20) thresholds that were nearly identical to the a priori distribution volume ratiolow and standard uptake value ratiolow. In summary, we found that frequently applied thresholds for Pittsburgh compound-B positivity (typically at or above distribution volume ratiohigh and standard uptake value ratiohigh) are overly stringent in defining amyloid positivity. Lower thresholds in this study resulted in higher sensitivity while not compromising specificity.

VL - 138 IS - Pt 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25953778?dopt=Abstract ER -