Dementia with Lewy bodies: association of Alzheimer pathology with functional connectivity networks.

Dementia with Lewy bodies (DLB) is neuropathologically defined by the presence of α-synuclein aggregates, but many DLB cases show concurrent Alzheimer's disease (AD) pathology in the form of β-amyloid plaques and tau neurofibrillary tangles. The first objective of this study was to investigate the effect of AD co-pathology on functional network changes within the default mode network (DMN) in DLB. Secondly, we studied how the distribution of tau pathology measured with PET relates to functional connectivity in DLB. Twenty-seven DLB, 26 AD, and 99 cognitively unimpaired (CU) participants (balanced on age and sex to the DLB group) underwent tau-PET with AV-1451 (flortaucipir), β-amyloid-PET with Pittsburgh compound-B (PiB), and resting state (rs)-fMRI scans. The rs-fMRI data were used to assess functional connectivity within the posterior DMN. This was then correlated with overall cortical flortaucipir-PET and PiB-PET standardized uptake value ratio (SUVr). The strength of inter-regional functional connectivity was assessed using the Schaefer atlas. Tau-PET covariance was measured as the correlation in flortaucipir SUVr between any two regions across participants. The association between region-to-region functional connectivity and tau-PET covariance was assessed using linear regression. Additionally, we identified the region with highest and the region with lowest tau SUVrs (tau hot- and coldspot) and tested whether tau SUVr in all other brain regions was associated with the strength of functional connectivity to these tau hot- and coldspots. A reduction in posterior DMN connectivity correlated with overall higher cortical tau- (r=-0.39, p = 0.04) and amyloid-PET uptake (r=-0.41, p = 0.03) in the DLB group, i.e. DLB patients with more concurrent AD pathology showed a more severe loss of DMN connectivity. Higher functional connectivity between regions was associated with higher tau covariance in CU, AD, and DLB. Furthermore, higher functional connectivity of a target region to the tau hotspot (i.e. inferior/medial temporal cortex) was related to higher flortaucipir SUVRs in the target region whereas higher functional connectivity to the tau coldspot (i.e. sensory-motor cortex) was related to lower flortaucipir SUVr in the target region. Our findings suggest that a higher burden of AD co-pathology in DLB patients is associated with more AD-like changes in functional connectivity. Furthermore, we found an association between the brain's functional network architecture and the distribution of tau pathology which has recently been described in AD. We show that this relationship also exists in DLB patients, indicating that similar mechanisms of connectivity-dependent occurrence of tau pathology might be at work in both diseases.