Cerebrovascular disease influences brain network connectivity in prodromal and clinical AD

Presented During:

Monday, June 18, 2018: 3:21 PM  - 3:33 PM 
Singapore Convention Center  
Room: Summit 1  

Submission No:


Submission Type:

Abstract Submission 


Ashwati Vipin1, Yng Miin Loke1, Siwei Liu1, Saima Hilal2, Hee Youn Shim1, Xin Xu2, Boon Yeow Tan3, Narayanaswamy Venketasubramanian4, Christopher Li-Hsian Chen2, Juan Zhou1


1Duke-National University of Singapore Medical School, Singapore, Singapore, 2Memory Aging and Cognition Centre; National University Health System, Singapore, Singapore, 3St Luke's Hospital, Singapore, Singapore, 4Raffles Hospital, Singapore, Singapore



Alzheimer's disease (AD) with concomitant cerebrovascular disease (CeVD), a leading cause of age-related cognitive impairment, is thought to be associated with distinct neurodegenerative patterns[1]. The network-based degeneration hypothesis suggests that the disease-related spread of degeneration follows a pattern based on existing brain networks[2]. Indeed, the default mode network (DMN) and executive control network (ECN) play important roles in AD and CeVD[3, 4]. Both functional connectivity (FC) and white matter structural connectivity (SC) network disruptions have been illustrated in AD and CeVD separately[5, 6]. In fact, recent findings from our group using single DMN/ECN seeds reveal distinct DMN and ECN neural network changes indicating differential underlying pathology in AD patients with and without CeVD[7]. Nonetheless, given the multiple DMN and ECN core regions, the effect of CeVD on their network connectivity in AD and amnestic mild cognitive impairment (aMCI) using simultaneous FC and SC approaches remains to be elucidated. We thus used a hypothesis-driven multiple seed-based approach to concurrently assess FC and SC changes within and between DMN and ECN in aMCI and AD subjects with and without CeVD. We hypothesized that non-CeVD groups would show greater DMN FC damage, especially in temporal DMN regions, associated with memory impairment while CeVD participants would show greater ECN FC damage, corresponding to attention and executive function impairment. We predict that such network divergence patterns would be less evident in SC.


We assessed neuroimaging and clinical data from 65 healthy controls (HCs), 39 aMCI, 50 aMCI+CeVD, 47 AD and 47 AD+CeVD from a previously published cohort[7] following quality control. For seed-based FC and SC analyses, we defined 9 seeds, covering core DMN and core ECN regions based on previous work[7-9]. Preprocessing of fMRI and DTI images was conducted following our previous protocol[7, 10]. Individual-level seed-based intrinsic connectivity networks were obtained from all seeds and compared between groups thresholded at a height of p<0.01 and cluster-extent of p<0.05. For SC analyses, we carried out probabilistic fibre tractography on all seeds (FSL, PANDA) and tested group differences in SC probability. To assess the association between network SC/FC measures and cognition, we ran a step-wise multiple regression model across CeVD and non-CeVD subjects separately (SPSS).


We demonstrate divergent DMN and ECN FC changes in CeVD and non-CeVD subjects. Compared to HCs, intra-DMN hippocampal FC reductions were observed in both AD and AD+CeVD, with intra-DMN parietal FC increases in AD+CeVD and aMCI+CeVD but decreases in AD subjects. Intra-DMN medial prefrontal-parietal FC was reduced in AD but increased in AD+CeVD and aMCI+CeVD. As predicted, intra-ECN frontal FC increases and frontoparietal FC decreases occurred in CeVD but not non-CeVD subjects (Fig.1A). aMCI subjects did not show any intra-network FC changes. Such FC alterations related with cognitive impairment in a dissociative manner (Fig.2): intra-DMN parietal FC reductions and anterior DMN FC increases related to worse cognition primarily in non-CeVD groups while frontal intra-ECN FC increases and frontoparietal decreases related to worse cognition primarily in CeVD groups. Additionally, CeVD and non-CeVD groups showed overlapping and distinct alterations in inter-network DMN-ECN FC depending on disease severity. In contrast to FC changes, CeVD groups had greater network SC damage compared to non-CeVD groups at both prodromal and clinical stages (Fig.1B). Network SC damage was associated with worse cognition (p<0.05).
Supporting Image: Fig1Legend-modified3.png
   ·Distinct default mode network and executive control network functional and structural connectivity changes in subjects with and without cerebrovascular disease.
Supporting Image: Fig2Legend-modified.png
   ·Intra-DMN FC relates to memory and attention function impairment in subjects without CeVD while Intra-ECN FC relates to executive function and memory in subjects with CeVD.


Patients with and without CeVD had distinct network FC phenotypes underlying cognitive impairment. Moreover, CeVD was associated with early SC deterioration in prodromal AD. Our findings highlight the value of concurrent SC and FC neuroimaging to reveal early changes and distinct pathology in mixed AD and CeVD.

Disorders of the Nervous System:

Alzheimer's Disease and Other Dementias 1

Imaging Methods:

Diffusion MRI
Multi-Modal Imaging 2

Modeling and Analysis Methods:

fMRI Connectivity and Network Modeling


Cerebrovascular Disease
White Matter
Other - Alzheimer's disease

1|2Indicates the priority used for review