Alzheimer’s Disease Projection From Normal to Mild Dementia Reflected in Functional Network Connectivity: A Longitudinal Study

BACKGROUND: Alzheimer’s disease (AD) is the most common age-related problem and progresses in different stages, including mild cognitive impairment (early stage), mild dementia (middle-stage), and severe dementia (late-stage). Recent studies showed changes in functional network connectivity obtained from resting-state functional magnetic resonance imaging (rs-fMRI) during the transition from healthy aging to AD. By assuming that the brain interaction is static during the scanning time, most prior studies are focused on static functional or functional network connectivity (sFNC). Dynamic functional network connectivity (dFNC) explores temporal patterns of functional connectivity and provides additional information to its static counterpart. METHOD: We used longitudinal rs-fMRI from 1385 scans (from 910 subjects) at different stages of AD (from normal to very mild AD or vmAD). We used group-independent component analysis (group-ICA) and extracted 53 maximally independent components (ICs) for the whole brain. Next, we used a sliding-window approach to estimate dFNC from the extracted 53 ICs, then group them into 3 different brain states using a clustering method. Then, we estimated a hidden Markov model (HMM) and the occupancy rate (OCR) for each subject. Finally, we investigated the link between the clinical rate of each subject with state-specific FNC, OCR, and HMM. RESULTS: All states showed significant disruption during progression normal brain to vmAD one. Specifically, we found that subcortical network, auditory network, visual network, sensorimotor network, and cerebellar network connectivity decrease in vmAD compared with those of a healthy brain. We also found reorganized patterns (i.e., both increases and decreases) in the cognitive control network and default mode network connectivity by progression from normal to mild dementia. Similarly, we found a reorganized pattern of between-network connectivity when the brain transits from normal to mild dementia. However, the connectivity between visual and sensorimotor network connectivity decreases in vmAD compared with that of a healthy brain. Finally, we found a normal brain spends more time in a state with higher connectivity between visual and sensorimotor networks. CONCLUSION: Our results showed the temporal and spatial pattern of whole-brain FNC differentiates AD form healthy control and suggested substantial disruptions across multiple dynamic states. In more detail, our results suggested that the sensory network is affected more than other brain network, and default mode network is one of the last brain networks get affected by AD In addition, abnormal patterns of whole-brain dFNC were identified in the early stage of AD, and some abnormalities were correlated with the clinical score.