Age- and brain region-associated alterations of cerebral blood flow in early Alzheimer's disease assessed in AβPP(SWE)/PS1(ΔE9) transgenic mice using arterial spin labeling

It has been suggested that cerebral blood flow (CBF) alterations may be involved in the pathogenesis of Alzheimer's disease (AD). However, how CBF changes with age has not been detailed in AD, particularly in its early stages. The objective of the present study was to evaluate CBF in four brain regions (the hippocampus, entorhinal cortex, frontoparietal cortex and thalamus) of mice in four age groups, to mimic the respective stages of AD in humans [2 months (pre-clinical), 3.5 months (sub-clinical), 5 months (early-clinical) and 8 months (mid-clinical)], to understand the age-associated changes in selected brain regions and to elucidate the underlying vascular mechanisms. CBF was measured using magnetic resonance imaging-arterial spin labelling (ASL) under identical conditions across the age groups of AβPP(SWE)/PS1(ΔE9) (APP/PS1) transgenic mice with AD. The results indicated age- and brain region-associated changes in CBF were associated with early AD. More precisely, an age-dependent increase in CBF (in the pre- and sub-clinical AD groups) was observed in the frontoparietal cortex and thalamus. Conversely, increased CBF demonstrated an age-dependent decline (in the early- and mid-clinical AD groups) in all examined brain regions. Among the regions, the thalamus had the greatest increase in CBF in the 2 and 3.5 months age groups, which was substantially different compared with the age-matched controls. An extension of vessel area was also noted to be age- and brain region-dependent. In particular, correlation analysis revealed significant associations of CBF with vessel area in the frontoparietal cortex and thalamus of APP/PS1 mice at ages 2 and 3.5 months, indicating that CBF increase may arise from vessel extension. The results of the present study suggested that ASL can detect age- and brain region-associated changes in CBF in mice with AD, and that ASL-measured CBF increase may be a potential diagnostic biomarker for early AD. The observation that CBF increase resulted from vessel extension may aid in the understanding of the vascular role in age-associated development of AD pathology, and provide preclinical evidence for AD patient management.