The Utility of Cerebral Blood Flow as a Biomarker of Preclinical Alzheimer's Disease

Abstract

There is accumulating evidence suggesting that changes in brain perfusion are present long before the clinical symptoms of Alzheimer's disease (AD), perhaps even before amyloid-β accumulation or brain atrophy. This evidence, consistent with the vascular hypothesis of AD, implicates cerebral blood flow (CBF) in the pathogenesis of AD and suggests its utility as a biomarker of preclinical AD. The extended preclinical phase of AD holds particular significance for disease modification, as treatment would likely be most effective in this early asymptomatic stage of disease. This highlights the importance of identifying reliable and accurate biomarkers of AD that can differentiate normal aging from preclinical AD prior to clinical symptom manifestation. Cerebral perfusion, as measured by arterial spin labeling magnetic resonance imaging (ASL-MRI), has been shown to distinguish between normal controls and adults with AD. In addition to demonstrating diagnostic utility, CBF has shown usefulness as a tool for identifying those who are at risk for AD and for predicting subtle cognitive decline and conversion to mild cognitive impairment and AD. Taken together, this evidence not only implicates CBF as a useful biomarker for tracking disease severity and progression, but also suggests that ASL-measured CBF may be useful for identifying candidates for future AD treatment trials, especially in the preclinical, asymptomatic phases of the disease.

Keywords: Alzheimer’s disease; Arterial spin labeling; Cerebral blood flow; Mild cognitive impairment; Neuroimaging; Perfusion.

Figures

Fig.1

Modified from Wierenga et al (2012). Analysis of variance results demonstrating an interaction of cognitive status (cognitively normal, MCI) and APOE genotype (ε3, ε4) for CBF with corresponding graphical presentation of significant CBF differences. Increased CBF in the left parahippocampal and fusiform gyrus was correlated only with verbal memory for cognitively normal (CN) ε4 adults and increased CBF in the left medial frontal gyrus was only correlated with verbal memory for MCI ε4 adults. This suggests a compensatory response that may shift from posterior to anterior cortices to overcome pathologic encroachments as the disease progresses. Results are thresholded and clustered (protecting a whole-brain voxelwise P < 0.05; red: P < 0.05, orange: P < 0.025, yellow: P < 0.01). Error bars represent the standard error of the mean. Results are overlaid onto sagittal slices of a high-resolution anatomical image averaged across all participants (L: left; R: right; C: cluster; PHG/ FG: parahippocampal gyrus/fusiform gyrus).

Fig.2

Receiver operating characteristic curve (ROC) demonstrating the ability of CBF to differentiate cognitive decliners from those who remained cognitively stable. ASL relative CBF in posterior cingulate cortex (PCC) enabled discrimination of deteriorated cognitive function (dCON) (P < .001) from stable cognitive function (sCON); however, there was no difference between deteriorated cognitive function and mild cognitive impairment (not shown). Published in: Aikaterini Xekardaki; Cristelle Rodriguez; Marie-Louise Montandon; Simona Toma; Eline Tombeur; François R. Herrmann; Dina Zekry; Karl-Olof Lovblad; Frederik Barkhof; Panteleimon Giannakopoulos; Sven Haller; Radiology 2015, 274, 490–499. DOI: 10.1148/radiol.14140680

Fig.3

Hypothetical model of the temporal ordering of physiological biomarkers of AD modified from Wierenga et al. (2014). This figure is adapted from Jack et al. (2010) 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.