Resting State Abnormalities of the Default Mode Network in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis

Article type: Research Article

Authors: Eyler, Lisa T.^{a; b; *} | Elman, Jeremy A.^a | Hatton, Sean N.^{a; c} | Gough, Sarah^a | Mischel, Anna K.^a | Hagler, Donald J.^d | Franz, Carol E.^a | Docherty, Anna^e | Fennema-Notestine, Christine^{a; d} | Gillespie, Nathan^f | Gustavson, Daniel^a | Lyons, Michael J.^g | Neale, Michael C.^f | Panizzon, Matthew S.^a | Dale, Anders M.^{c; d} | Kremen, William S.^{a; h}

Affiliations: [a] Department of Psychiatry, University of California San Diego, San Diego, CA, USA | [b] Desert Pacific Mental Illness Research Education and Clinical Center, VA San Diego Healthcare System, San Diego, CA, USA | [c] Department of Neurosciences, University of California San Diego, San Diego, CA, USA | [d] Department of Radiology, University of California San Diego, San Diego, CA, USA | [e] Departments of Psychiatry & Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA | [f] Departments of Psychiatry and Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA | [g] Department of Psychology, Boston University, Boston, MA, USA | [h] Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, San Diego, CA, USA

Correspondence: [*] Correspondence to: Lisa T. Eyler, PhD, Professor of Psychiatry, Mail Code 0931, 9500 Gilman Drive, La Jolla, CA 92093 0931, USA. Tel.: +1 858 534 9451; E-mail: [email protected].

Abstract: Background:Large-scale brain networks such as the default mode network (DMN) are often disrupted in Alzheimer’s disease (AD). Numerous studies have examined DMN functional connectivity in those with mild cognitive impairment (MCI), a presumed AD precursor, to discover a biomarker of AD risk. Prior reviews were qualitative or limited in scope or approach. Objective:We aimed to systematically and quantitatively review DMN resting state fMRI studies comparing MCI and healthy comparison (HC) groups. Methods:PubMed was searched for relevant articles. Study characteristics were abstracted and the number of studies showing no group difference or hyper- versus hypo-connnectivity in MCI was tallied. A voxel-wise (ES-SDM) meta-analysis was conducted to identify regional group differences. Results:Qualitatively, our review of 57 MCI versus HC comparisons suggests substantial inconsistency; 9 showed no group difference, 8 showed MCI > HC and 22 showed HC > MCI across the brain, and 18 showed regionally-mixed directions of effect. The meta-analysis of 31 studies revealed areas of significant hypo- and hyper-connectivity in MCI, including hypoconnectivity in the posterior cingulate cortex/precuneus (z = –3.1, p < 0.0001). Very few individual studies, however, showed patterns resembling the meta-analytic results. Methodological differences did not appear to explain inconsistencies. Conclusions:The pattern of altered resting DMN function or connectivity in MCI is complex and variable across studies. To date, no index of DMN connectivity qualifies as a useful biomarker of MCI or risk for AD. Refinements to MCI diagnosis, including other biological markers, or longitudinal studies of progression to AD, might identify DMN alterations predictive of AD risk.

Keywords: Alzheimer’s disease, default mode network, functional connectivity, mild cognitive impairment, posterior cingulate cortex, resting state functional magnetic resonance imaging

DOI: 10.3233/JAD-180847

Journal: Journal of Alzheimer's Disease, vol. 70, no. 1, pp. 107-120, 2019