Resting-state functional dynamics alterations relate to plasma amyloid markers and statistically explain memory impairments in the TgF344-AD model of Alzheimer’s disease

BACKGROUND: Resting-state functional MRI studies of Alzheimer's disease (AD) show lower functional connectivity (FC) of AD-relevant regions and resting-state networks in patients and transgenic rodent models at symptomatic stages. However, at early stages of the disease, both hyper and hypo connectivity has been reported. Traditional FC overlooks temporal fluctuations in connectivity and network dynamics at a short timescale captured by transient brain states such as co-activation patterns (CAPs). CAPs have been shown to be more sensitive than FC to detect early alterations in neurodegenerative diseases and therefore can shed light on hyper versus hypo connectivity observed at early stages. Moreover, how brain functional signatures of Alzheimer's disease are related to its behavioral and pathological markers and whether they have prognostic relevance remain scarcely investigated. METHODS: We acquired high temporal resolution resting-state functional MRI data in the TgF344-AD model rats and age-matched wild-type animals at 4 and 10 months of age corresponding to the pre-plaque and plaque stages, respectively and delineated brain functional alterations using FC and CAPs in the model animals. We also assessed the levels of amyloid beta (Aβ) in blood and working and reference memory performance in the same animals at the plaque stage and investigated their statistical relationship with pre-plaque and plaque-stage changes in FC and CAPs. RESULTS: TgF344-AD rats had significantly elevated blood Aβ levels, committed more working and reference memory errors and showed reduced hippocampal FC with the lateral cortical and default-mode-like network compared to wild-type animals at the plaque stage. FC at the pre-plaque stage did not differ between TgF344-AD and wild-type rats. TgF344-AD rats showed hyper- and hypo-activation in the default-mode-like-network and hippocampal regions at pre-plaque and plaque stages, respectively, in multiple CAPs. Blood Aβ levels were statistically explained more accurately by plaque-stage, than pre-plaque stage, FC values and CAP activations. CAP activations, especially at the pre-plaque stage, outperformed FC in accurate statistical explanation of memory impairments. CONCLUSION: Our findings demonstrate pre-plaque stage hyperconnectivity not in the traditional, static measure of functional connectivity but in transient, dynamic brain states and that these early brain functional signatures have prognostic relevance for memory deficits in a translational rat model of Alzheimer's disease.