Selective Impairment of Long-Range Default Mode Network Functional Connectivity as a Biomarker for Preclinical Alzheimer’s Disease in People with Down Syndrome

Article type: Research Article

Authors: DiProspero, Natalie D.^{a; b} | Keator, David B.^c | Phelan, Michael^d | van Erp, Theo G.M.^e | Doran, Eric^e | Powell, David K.^f | Van Pelt, Kathryn L.^g | Schmitt, Frederick A.^{g; h} | Head, Elizabethⁱ | Lott, Ira T.^e | Yassa, Michael A.^{a; b; c; *}

Affiliations: [a] Department of Neurobiology and Behavior, University of California, Irvine, CA, USA | [b] Center for the Neurobiology of Learning and Memory, University of California, Irvine, CA, USA | [c] Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA | [d] Institute for Memory Impairments and Neurological Disorders, UC Irvine, CA, USA | [e] Department of Pediatrics, University of California, Irvine Medical Center, Orange, CA, USA | [f] Department of Neuroscience, University of Kentucky Medical Center, Lexington, KY, USA | [g] Sanders-Brown Center on Aging, University of Kentucky Medical Center, Lexington, KY, USA | [h] Department of Neurology, University of Kentucky Medical Center, Lexington, KY, USA | [i] Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA

Correspondence: [*] Correspondence to: Michael A. Yassa, PhD, 1418 Biological Sciences 3, University of California, Irvine, Irvine, CA 92697, USA. Tel.: +1 949 824 1687; E-mail: [email protected].

Abstract: Background:Down syndrome (DS) is associated with increased risk for Alzheimer’s disease (AD). In neurotypical individuals, clinical AD is preceded by reduced resting state functional connectivity in the default mode network (DMN), but it is unknown whether changes in DMN connectivity predict clinical onset of AD in DS. Objective:Does lower DMN functional connectivity predict clinical onset of AD and cognitive decline in people with DS? Methods:Resting state functional MRI (rsfMRI), longitudinal neuropsychological, and clinical assessment data were collected on 15 nondemented people with DS (mean age = 51.66 years, SD = 5.34 years, range = 42-59 years) over four years, during which 4 transitioned to dementia. Amyloid-β (Aβ) PET data were acquired on 13 of the 15 participants. Resting state fMRI, neuropsychological, and clinical assessment data were also acquired on an independent, slightly younger unimpaired sample of 14 nondemented people with DS (mean age = 44.63 years, SD = 7.99 years, range = 38–61 years). Results:Lower functional connectivity between long-range but not short-range DMN regions predicts AD diagnosis and cognitive decline in people with DS. Aβ accumulation in the inferior parietal cortex is associated with lower regional DMN functional connectivity. Conclusion:Reduction of long-range DMN connectivity is a potential biomarker for AD in people with DS that precedes and predicts clinical conversion.

Keywords: Alzheimer’s disease, biomarkers, default mode network, dementia, Down syndrome, functional connectivity, resting state functional magnetic resonance imaging

DOI: 10.3233/JAD-210572

Journal: Journal of Alzheimer's Disease, vol. 85, no. 1, pp. 153-165, 2022