Resting State Functional Connectivity Signature Differentiates Cognitively Normal from Individuals Who Convert to Symptomatic Alzheimer’s Disease

Article type: Research Article

Authors: Wisch, Julie K.^a | Roe, Catherine M.^{a; d} | Babulal, Ganesh M.^{a; d} | Schindler, Suzanne E.^{a; d} | Fagan, Anne M.^{c; d} | Benzinger, Tammie L.^{b; d} | Morris, John C.^{a; b; d} | Ances, Beau M.^{a; b; c; d; *}

Affiliations: [a] Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA | [b] Department of Radiology, Washington University in St. Louis St. Louis, MO, USA | [c] Hope Center, Washington University in Saint Louis, St. Louis, MO, USA | [d] Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA

Correspondence: [*] Correspondence to: Beau M. Ances, MD, PhD, MSc, Department of Neurology, Washington University in Saint Louis School of Medicine, Campus Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110, USA. Tel.: 314 747 8423; Fax: 314 747 8427; E-mail: [email protected].

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.

Keywords: Alzheimer’s disease, biomarkers, neuroimaging, observational studies

DOI: 10.3233/JAD-191039

Journal: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1085-1095, 2020