Attenuation of functional hyperemia to visual stimulation in mild Alzheimer's disease and its sensitivity to cholinesterase inhibition.

Despite the growing recognition of the significance of cerebrovascular impairment in the etiology and progression of Alzheimer's disease (AD), the early stage brain vascular dysfunction and its sensitivity to pharmacological interventions is still not fully characterized. Due to the early and aggressive treatment of probable AD with cholinesterase inhibitors (ChEI), which in and of themselves have direct effects on brain vasculature, the vast majority of hemodynamic measurements in early AD subjects reported hitherto have consequently been made only after the start of treatment, complicating the disentanglement of disease- vs. treatment-related effects on the cerebral vasculature. To address this gap, we used pseudo continuous arterial spin labeling MRI to measure resting perfusion and visual stimulation elicited changes in cerebral blood flow (CBF) and blood oxygenation dependent (BOLD) fMRI signal in a cohort of mild AD patients immediately prior to, 6months post, and 12months post commencement of open label cholinesterase inhibitor treatment. Although patients exhibited no gray matter atrophy prior to treatment and their resting perfusion was not distinguishable from that in age, education and gender-matched controls, the patients' visual stimulation-elicited changes in BOLD fMRI and blood flow were decreased by 10±4% (BOLD) and 23±2% (CBF), relative to those in controls. Induction of cholinesterase inhibition treatment was associated with a further, 7±2% reduction in patients' CBF response to visual stimulation, but it stabilized, at this new lower level, over the follow-up period. Likewise, MMSE scores remained stable during the treatment; furthermore, higher MMSE scores were associated with higher perfusion responses to visual stimulation. This study represents the initial step in disentangling the effects of AD pathology from those of the first line treatment with cholinesterase inhibitors on cerebral hemodynamics and supports the use of arterial spin labeling MRI for quantitative evaluation of the brain vascular function in mild Alzheimer's disease. The findings provide evidence of a pronounced deficit in the visual cortex hyperemia despite the relative sparing of visual function in early stage AD, its reduction with ChEI treatment induction, and its stabilization in the first year of cholinesterase inhibition treatment. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

Hemodynamic effects of cholinesterase inhibition in mild Alzheimer's disease.

PURPOSE: To evaluate the spatiotemporal progression of perfusion changes in early stages of Alzheimer's disease (AD), we imaged the perfusion response to pharmacological treatment in a group of mild AD patients and contrasted it to the perfusion of age-, sex-, and education-matched healthy volunteers over the same time interval. MATERIALS AND METHODS: We used pseudo continuous arterial spin labeling (PCASL) MRI for quantitative three-dimensional mapping of perfusion immediately before and 6 months after cholinesterase inhibitor treatment. RESULTS: Before treatment, patients were found hypoperfused relative to their healthy counterparts in the gray matter of lateral temporal lobe, posterior cingulate, and anterior cingulate as well as in the white matter of the posterior cingulate. Most of the cortical regions investigated and the white matter of posterior cingulate and prefrontal regions showed treatment-elicited increases in perfusion, which were not secondary to changes in regional tissue volume nor were they associated with improvement in either MMSE or ADAS-Cog scores, although lack of deterioration suggested a cognitive benefit. CONCLUSION: This study provides a hemodynamic profile of mild AD and sheds light on the perfusion changes related to prolonged cholinesterase inhibition in this early disease stage.

Efficient sampling of early signal arrival for estimation of perfusion and transit time in whole-brain arterial spin labeling.

Arterial spin labeling can be used to measure both cerebral perfusion and arterial transit time. However, accurate estimation of these parameters requires adequate temporal sampling of the arterial spin labeling difference signal. In whole-brain multislice acquisitions, two factors reduce the accuracy of the parameter estimates: saturation of labeled blood in transit and inadequate sampling of early difference signal in superior slices. Label saturation arises when slices are acquired inferior-to-superior such that slice selection in proximal slices spoils the label for a distal slice. Inadequate sampling arises when the time spent acquiring inferior slices is too long to allow early sampling of the difference signal in superior slices. A novel approach to multislice imaging is proposed to address these two issues. In round-robin arterial spin labeling, slices are acquired in a different order after every pair of control-label acquisitions. Round-robin arterial spin labeling enables the acquisitions of all slices across the same range of postlabel delays in a descending superior-to-inferior order. This eliminates the temporal sampling problem and greatly reduces label saturation. Arterial transit time estimates obtained for the whole brain with round-robin arterial spin labeling show better agreement with a single-slice acquisition than do conventional multislice acquisitions.