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.

Default-mode network (DMN) connectivity at rest is disrupted in Alzheimer's Disease (AD), but it is unknown whether this abnormality is a static feature, or if it varies across cognitive states. We measured DMN integrity in 16 patients with mild AD and 18 controls during resting state and a simple visual task. Patients showed resting-state deficits in the parahippocampal gyrus and posterior cingulate. No group differences were found during the task. Controls exhibited higher DMN connectivity of multiple regions during rest than task, while the patient group showed no modulation of the DMN between states. However, the relative degree of increased resting- versus task-state co-activation in the posterior cingulate and precuneus was predictive of mini-mental status exam (MMSE) scores in AD patients, while measures at rest or task alone were not associated with MMSE. These findings suggest that a resting state may be more suited to detecting DMN abnormalities in AD than a simple task. However, the degree of state-dependent modulation in the DMN may be a better predictor of the individual cognitive status than a single-state acquisition. This study demonstrates an apparent reduction in the capacity for DMN modulation in individuals with mild AD, the degree of which uniquely predicted cognitive status.

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.