Understanding therapeutic efficacy of calorie restriction in Alzheimer's disease: dynamic rsfMRI and vascular reactivity as biomarkers in an AD rat model

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive decline in cognitive function associated with Aβ -peptide plaques and neurofibrillary tangles. Because aging is the major risk factor for AD, and dietary energy restriction can retard aging processes in the brain, researchers have been testing the hypothesis that caloric restriction (CR) regimens can protect against cognitive decline. The exact mechanisms through which CR promotes health and lifespan are still not fully understood. Nevertheless, numerous studies were designed to unravel the responses to CR. There is increasing evidence that synaptic defects affect synaptic transmission mechanisms. These synaptic transmission deficits may influence the functional connectivity (FC) in the brain, by impairing communication between brain regions. FC can be measured using resting state functional MRI (rsfMRI), and is defined as the temporal correlation between low frequency fluctuations in the BOLD fMRI signal in distinct brain areas. RsfMRI has identified default mode and task positive network disruptions as promising biomarkers for AD. Recently, the rsfMRI field has seen a shift from 'static' BOLD signal analysis to more time-resolved dynamic analysis. Dynamic rsfMRI is a state-of-the-art approach, which has revealed new insights into the macro-scale organization of functional networks. While CR is already known to influence memory performance, tauopathy and Aβ plaque formation, AD patients also have cerebral amyloid angiopathy (CAA), which influences vascular reactivity and therefore neurovascular coupling. It is of interest to identify these early markers of pathology progression using non-invasive imaging, as well as monitor the effect of CR on CAA, cerebral blood flow (CBF) and vascular reactivity using arterial spin labeling. In contrast to the BOLD signal which depends on the local cerebral metabolic rate of oxygen, CBF and cerebral blood volume, pCASL provides an absolute measure that only reflects CBF and hence enables to further disentangle the BOLD response and associated FC analysis. An alternative to dietary CR are nutrients that mimic these beneficial effects on brain aging (CR mimetics). These compounds mimic the biochemical and functional effects of CR without the need to reduce energy intake. In this project, we will combine dynamic rsfMRI, pCASL and behavioral tests in a TgF344-AD rat model, which recapitulates the major hallmarks of AD. We postulate the hypotheses that early decreases in (dynamic) FC and CBF may be potential prognostic biomarkers of the long-term outcome (memory and neuropsychiatric deficits) in this AD rat model; that FC and CBF at the time point when behavioural deficits occur, may be predictive biomarkers of the therapy (i.e. CR); that CR alleviates both memory and neurovascular deficits in this AD rat model; and that CR mimetics provide a therapeutic alternative with the same effects on memory and vascular reactivity.

Keywords:ALZHEIMER'S DISEASE, MRI (FUNCTIONAL)

Disciplines:Cognitive neuroscience, Neurophysiology