The Effects of Gene Mutations on Default Mode Network in Familial Alzheimer’s Disease

Article type: Research Article

Authors: Li, Xiaozhen^{a; b} | Westman, Eric^b | Thordardottir, Steinunn^{c; d} | Ståhlbom, Anne Kinhult^{c; d} | Almkvist, Ove^{b; e} | Blennow, Kaj^f | Wahlund, Lars-Olof^{b; *} | Graff, Caroline^{c; d}

Affiliations: [a] Department of Radiology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, China | [b] Division of Clinical Geriatrics, Center for Alzheimer Disease Research, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Huddinge, Sweden | [c] Division of Neurogeriatrics, Center for Alzheimer Disease Research, Department of NVS, Karolinska nstitutet, Huddinge, Sweden | [d] Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Huddinge, Sweden | [e] Department of Psychology, Stockholm University, Stockholm, Sweden | [f] Clinical Neurochemistry Lab, Sahlgrenska University Hospital, Gothenburg, Sweden

Correspondence: [*] Correspondence to: Lars-Olof Wahlund, Division of Clinical Geriatrics, Center for Alzheimer Disease Research, Department of NVS, Karolinska Institutet, Novum, 5th Floor, Blickagången 6, 141 57 Huddinge, Sweden. Fax: +46 8 585 85 470; E-mail: [email protected].

Abstract: Familial Alzheimer’s disease (FAD) mutations have very high penetrance but age at onset and rate of disease progression differ. Neuroimaging and cerebrospinal fluid (CSF) examinations in mutation carriers (MCs) may provide an opportunity to identify early biomarkers that can be used to track disease progression from presymptomatic to the dementia stages of disease. The default mode network (DMN) is a resting state neuronal network composed of regions known to associate with amyloid deposition in AD. We hypothesized that functional connectivity in the DMN might change at pre-clinical stages in FAD MCs and correlate with changes in CSF biomarkers as a consequence of AD brain pathology. To test the hypothesis, we compared the functional connectivity in DMN between pre-MCs/MCs and non-carriers (NCs). No significant differences between pre-MCs and NCs were observed. When comparing all MCs with NCs, significant decreased functional connectivity in the right inferior parietal lobule, right precuneus, and left posterior cingulate cortex were found. We also found statistically significant correlations between CSF amyloid-β 42 and tau protein levels and average Z-score, a resting-state functional MRI measurement reflecting the degree of the correlation between a given voxel’s time courses and the time courses corresponding to DMN, from the region with statistical difference. The observed disruption of DMN and pathological levels of AD CSF-biomarkers in FAD MCs are similar to the changes described in sporadic AD, which give further support that amyloid and tau pathology impairs neuronal and synaptic function.

Keywords: Cerebrospinal fluid biomarkers, default mode network, familial Alzheimer’s disease, mutation carrier, resting-state functional MRI, synaptic function

DOI: 10.3233/JAD-160730

Journal: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 327-334, 2017