Cerebral blood flow measured by arterial spin labeling MRI as a preclinical marker of Alzheimer's disease

Abstract

There is growing recognition that cerebral hypoperfusion is related to the pathogenesis of Alzheimer's disease (AD), implicating the measurement of cerebral blood flow (CBF) as a possible biomarker of AD. The ability to identify the earliest and most reliable markers of incipient cognitive decline and clinical symptoms is critical to develop effective preventive strategies and interventions for AD. Arterial spin labeling (ASL) magnetic resonance imaging (MRI) measures CBF by magnetically labeling arterial water and using it as an endogenous tracer. Studies using ASL MRI in humans indicate that CBF changes are present several years before the development of the clinical symptoms of AD. Moreover, ASL-measured CBF has been shown to distinguish between cognitively normal individuals, adults at risk for AD, and persons diagnosed with AD. Some studies indicate that CBF may even be sensitive for predicting cognitive decline and conversion to mild cognitive impairment and AD over time. Taken together, evidence suggests that the current staging models of AD biomarker pathology should incorporate early changes in CBF as a useful biomarker, possibly present even earlier than amyloid-β accumulation. Though still a research tool, ASL imaging is a promising non-invasive and reliable method with the potential to serve as a future clinical tool for the measurement of CBF in preclinical AD.

Keywords: Alzheimer's disease; arterial spin labeling; cerebral blood flow; cerebrovascular disorders; cognition; mild cognitive impairment; neuroimaging; neurovascular dysfunction; perfusion.

Figure 1

Summary of ASL studies showing CBF alterations in the preclinical, subclinical and clinical phases of AD. In the preclinical phase, which includes asymptomatic APOE ε4 carriers with or without a familial history of AD, there is evidence of hyperperfusion, especially in younger individuals [–37,40]. In the subclinical phase, which includes MCI, studies show both hyperperfusion and hypoperfusion, with some evidence of early CBF increases and later decreases [41]. The clinical phase includes AD, with most studies showing widespread decreases in CBF [18,19]. ** This figure has been adapted from [48].

Figure 2

Hypothetical model of the temporal ordering of physiological biomarkers of AD. This figure is adapted from [2] to include early alterations in CBF in the sequence of biomarkers across the continuum from normal aging to MCI to AD. Direction of CBF alteration is not specified because, as reviewed here, both hyper and hypoperfusion reflect abnormality in different stages of cognitive decline.