Julie K Wisch1, Catherine M Roe1,2, Ganesh M Babulal1,2, Suzanne E Schindler1,2, Anne M Fagan3,2, Tammie L Benzinger4,2, John C Morris1,4,2, Beau M Ances1,4,3,2. 1. Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA. 2. Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. 3. Hope Center, Washington University in Saint Louis, St. Louis, MO, USA. 4. Department of Radiology, Washington University in St. Louis St. Louis, MO, USA.
Abstract
BACKGROUND: Changes in resting state functional connectivity (rs-fc) occur in Alzheimer's disease (AD), but few longitudinal rs-fc studies have been performed. Most studies focus on single networks and not a global measure of rs-fc. Although the amyloid tau neurodegeneration (AT(N)) framework is increasingly utilized by the AD community, few studies investigated when global rs-fc signature changes occur within this model. OBJECTIVE: 1) Identify a global rs-fc signature that differentiates cognitively normal (CN) individuals from symptomatic AD. 2) Assess when longitudinal changes in rs-fc occur relative to conversion to symptomatic AD. 3) Compare rs-fc with amyloid, tau, and neurodegeneration biomarkers. METHODS: A global rs-fc signature composed of intra-network connections was longitudinally evaluated in a cohort of cognitively normal participants at baseline (n = 335). Biomarkers, including cerebrospinal fluid (Aβ42 and tau), structural magnetic resonance imaging, and positron emission tomography were obtained. RESULTS: Global rs-fc signature distinguished CN individuals from individuals who developed symptomatic AD. Changes occurred nearly four years before conversion to symptomatic AD. The global rs-fc signature most strongly correlated with markers of neurodegeneration. CONCLUSION: The global rs-fc signature changes near symptomatic onset and is likely a neurodegenerative biomarker. Rs-fc changes could serve as a biomarker for evaluating potential therapies for symptomatic conversion to AD.
BACKGROUND: Changes in resting state functional connectivity (rs-fc) occur in Alzheimer's disease (AD), but few longitudinal rs-fc studies have been performed. Most studies focus on single networks and not a global measure of rs-fc. Although the amyloid tau neurodegeneration (AT(N)) framework is increasingly utilized by the AD community, few studies investigated when global rs-fc signature changes occur within this model. OBJECTIVE: 1) Identify a global rs-fc signature that differentiates cognitively normal (CN) individuals from symptomatic AD. 2) Assess when longitudinal changes in rs-fc occur relative to conversion to symptomatic AD. 3) Compare rs-fc with amyloid, tau, and neurodegeneration biomarkers. METHODS: A global rs-fc signature composed of intra-network connections was longitudinally evaluated in a cohort of cognitively normal participants at baseline (n = 335). Biomarkers, including cerebrospinal fluid (Aβ42 and tau), structural magnetic resonance imaging, and positron emission tomography were obtained. RESULTS: Global rs-fc signature distinguished CN individuals from individuals who developed symptomatic AD. Changes occurred nearly four years before conversion to symptomatic AD. The global rs-fc signature most strongly correlated with markers of neurodegeneration. CONCLUSION: The global rs-fc signature changes near symptomatic onset and is likely a neurodegenerative biomarker. Rs-fc changes could serve as a biomarker for evaluating potential therapies for symptomatic conversion to AD.
Authors: Anne M Fagan; Mark A Mintun; Robert H Mach; Sang-Yoon Lee; Carmen S Dence; Aarti R Shah; Gina N LaRossa; Michael L Spinner; William E Klunk; Chester A Mathis; Steven T DeKosky; John C Morris; David M Holtzman Journal: Ann Neurol Date: 2006-03 Impact factor: 10.422
Authors: R C Petersen; R O Roberts; D S Knopman; Y E Geda; R H Cha; V S Pankratz; B F Boeve; E G Tangalos; R J Ivnik; W A Rocca Journal: Neurology Date: 2010-09-07 Impact factor: 9.910
Authors: John C Morris; Suzanne E Schindler; Lena M McCue; Krista L Moulder; Tammie L S Benzinger; Carlos Cruchaga; Anne M Fagan; Elizabeth Grant; Brian A Gordon; David M Holtzman; Chengjie Xiong Journal: JAMA Neurol Date: 2019-03-01 Impact factor: 18.302
Authors: Yi Su; Tyler M Blazey; Abraham Z Snyder; Marcus E Raichle; Daniel S Marcus; Beau M Ances; Randall J Bateman; Nigel J Cairns; Patricia Aldea; Lisa Cash; Jon J Christensen; Karl Friedrichsen; Russ C Hornbeck; Angela M Farrar; Christopher J Owen; Richard Mayeux; Adam M Brickman; William Klunk; Julie C Price; Paul M Thompson; Bernadino Ghetti; Andrew J Saykin; Reisa A Sperling; Keith A Johnson; Peter R Schofield; Virginia Buckles; John C Morris; Tammie L S Benzinger Journal: Neuroimage Date: 2014-12-05 Impact factor: 6.556
Authors: Emma Lawrence; Carolin Vegvari; Alison Ower; Christoforos Hadjichrysanthou; Frank De Wolf; Roy M Anderson Journal: J Alzheimers Dis Date: 2017 Impact factor: 4.472
Authors: Clifford R Jack; David A Bennett; Kaj Blennow; Maria C Carrillo; Billy Dunn; Samantha Budd Haeberlein; David M Holtzman; William Jagust; Frank Jessen; Jason Karlawish; Enchi Liu; Jose Luis Molinuevo; Thomas Montine; Creighton Phelps; Katherine P Rankin; Christopher C Rowe; Philip Scheltens; Eric Siemers; Heather M Snyder; Reisa Sperling Journal: Alzheimers Dement Date: 2018-04 Impact factor: 21.566
Authors: Peng Wang; Ru Kong; Xiaolu Kong; Raphaël Liégeois; Csaba Orban; Gustavo Deco; Martijn P van den Heuvel; B T Thomas Yeo Journal: Sci Adv Date: 2019-01-09 Impact factor: 14.136
Authors: Peter R Millar; Beau M Ances; Brian A Gordon; Tammie L S Benzinger; Anne M Fagan; John C Morris; David A Balota Journal: Neurobiol Aging Date: 2020-08-18 Impact factor: 4.673
Authors: Omar H Butt; Karin L Meeker; Julie K Wisch; Suzanne E Schindler; Anne M Fagan; Tammie L S Benzinger; Carlos Cruchaga; David M Holtzman; John C Morris; Beau M Ances Journal: Alzheimers Dement Date: 2021-05-18 Impact factor: 21.566
Authors: Ningxin Dong; Changyong Fu; Renren Li; Wei Zhang; Meng Liu; Weixin Xiao; Hugh M Taylor; Peter J Nicholas; Onur Tanglay; Isabella M Young; Karol Z Osipowicz; Michael E Sughrue; Stephane P Doyen; Yunxia Li Journal: Front Aging Neurosci Date: 2022-05-03 Impact factor: 5.750