Joanna Su Xian Chong1, Siwei Liu1, Yng Miin Loke2, Saima Hilal3, Mohammad Kamran Ikram4, Xin Xu3, Boon Yeow Tan5, Narayanaswamy Venketasubramanian6, Christopher Li-Hsian Chen7, Juan Zhou8
1Duke-NUS Medical School, Singapore, Singapore, 2Duke-NUS Medical school, Singapore, Singapore, 3Department of Pharmacology, National University Health System, Clinical Research Centre, Singapore, Singapore, 4Memory Ageing & Cognition Centre, National University Health System, Singapore, Singapore, Singapore, 5St Luke's Hospital, Singapore, Singapore, 6Raffles Hospital, Singapore, Singapore, 7National University of Singapore, Singapore, Singapore, 8Duke-National University of Singapore Medical School, Singapore, Singapore
Alzheimer's disease (AD) is a neurodegenerative disorder associated with large-scale disruptions in intrinsic brain functional connectivity (FC) . Notably, several AD studies have demonstrated reduced FC in the default mode network (DMN) [1-3], and such FC disruptions are evident even at prodromal stages . However, while FC changes have been widely documented in AD, little remains known about FC changes in patients with both AD and cerebrovascular disease (CeVD). CeVD frequently exists with AD  and has been associated with executive function decline  and FC disruptions in frontoparietal regions . Together, AD and CeVD are thought to have additive effects on cognitive decline: given the same clinical severity, AD patients exhibited more severe AD pathology than those comorbid with CeVD [5, 8]. Whether such additive effects of AD and CeVD also extend to FC changes at different disease stages remain to be seen.
Our study thus sought to examine FC changes in prodromal and clinical AD patients with and without CeVD . Given past findings, we hypothesize that AD patients with CeVD would show greater ECN FC disruptions (related to CeVD pathology) and lesser DMN FC disruptions (related to AD pathology) than those without CeVD at the same clinical severity. Additionally, we hypothesize that these FC changes would be present at the prodromal stages of AD.
Seed-based FC analyses were performed on task-free fMRI data from 199 participants  using regions of interests (ROIs) from core regions in the DMN (left posterior cingulate cortex; lPCC) and ECN (right dorsolateral prefrontal cortex; rDLPFC). Participants were from one of five groups: healthy controls (HC), cognitive impairment no dementia with CeVD (CIND+CeVD), CIND without CeVD (CIND), AD with CeVD (AD+CeVD) and AD without CeVD (AD). Individual DMN and ECN FC z-maps were obtained by computing Pearson's correlation between each voxel's BOLD time series and the mean time series of the DMN and ECN ROIs respectively, then converting correlation values to z-scores using Fisher's r-to-z transformation. Separate regression analyses were subsequently performed on the FC maps of each ROI to identify voxels showing group differences. Results were thresholded at a height threshold of p<.01 and a cluster-extent threshold of p<.05. Age, sex, education, handedness, ethnicity and voxelwise grey matter maps were included as nuisance covariates.
Both DMN and ECN showed divergent FC patterns in AD and AD+CeVD patients. In the DMN (Fig. 1A, 2A), AD patients showed widespread reductions in lPCC-posterior DMN FC compared to HC and AD+CeVD patients. By comparison, AD+CeVD patients showed only FC reductions in the cerebellum crus relative to HC.
As for the ECN (Fig. 1B, 2B), dissociations in ECN FC changes were also found between the two groups, particularly in the frontal regions. Compared to HC, AD patients showed reduced rDLPFC FC to both parietal and frontal ECN regions. In contrast, while AD+CeVD patients similarly showed reduced parietal FC relative to HC, they instead showed increased rDLPFC-frontal FC compared to both HC and AD patients. Importantly, these ECN FC changes were recapitulated in CIND and CIND+CeVD patients: CIND patients showed reduced parietal FC compared to HC, while CIND+CeVD patients showed reduced parietal FC and increased frontal FC compared to HC and CIND patients.
We found divergent FC changes between AD and AD+CeVD patients. AD patients, but not AD+CeVD patients, showed reductions in posterior DMN FC. In contrast, while both AD and AD+CeVD patients showed reduced parietal ECN FC compared to HC, only AD+CeVD patients showed increases in frontal ECN FC. Importantly, these distinct ECN FC changes were mirrored in prodromal AD patients with and without CeVD. Our findings support the idea that the pathology of AD patients with CeVD might reflect a combination of more severe CeVD and less severe AD network degeneration phenotype compared to those without CeVD.
Disorders of the Nervous System:
Alzheimer's Disease and Other Dementias 1
Disorders of the Nervous System Other
Modeling and Analysis Methods:
fMRI Connectivity and Network Modeling 2
Other - Alzheimer's Disease
1|2Indicates the priority used for review