title: Attenuation of functional hyperemia to visual stimulation in mild Alzheimer's disease and its sensitivity to cholinesterase inhibition.
abstract: 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.
authors.affiliation: Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, ON M5G 2M9, Canada. Electronic address: rjanik@sri.utoronto.ca.
authors.forename: Rafal
authors.initials: R
authors.lastname: Janik
authors.affiliation: Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
authors.forename: Lynsie A M
authors.initials: LA
authors.lastname: Thomason
authors.affiliation: Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, ON M5G 2M9, Canada.
authors.forename: Simone
authors.initials: S
authors.lastname: Chaudhary
authors.affiliation: Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Dorr
authors.affiliation: Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, ON M5G 2M9, Canada.
authors.forename: Amy
authors.initials: A
authors.lastname: Scouten
authors.affiliation: Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
authors.forename: Graeme
authors.initials: G
authors.lastname: Schwindt
authors.affiliation: Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.
authors.forename: Mario
authors.initials: M
authors.lastname: Masellis
authors.affiliation: Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, ON M5G 2M9, Canada; Department of Nerurosurgery and Pediatrics Neurosurgery, Medical University of Lublin, Aleje Raclawickie 1, 20-059 Lublin, Poland.
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Stanisz
authors.affiliation: Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Institute of Medical Sciences, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Medicine (Neurology), Sunnybrook Health Sciences Centre University of Toronto, Canada; Canadian Partnership for Stroke Recovery Sunnybrook Site, Canada.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Black
authors.affiliation: Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, ON M5G 2M9, Canada; Canadian Partnership for Stroke Recovery Sunnybrook Site, Canada.
authors.forename: Bojana
authors.initials: B
authors.lastname: Stefanovic
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D001921:Brain / Q000098:blood supply / Q000000981:diagnostic imaging / Q000473:pathology; D002560:Cerebrovascular Circulation; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D006940:Hyperemia / Q000097:blood / Q000000981:diagnostic imaging / Q000473:pathology / Q000628:therapy*; D008279:Magnetic Resonance Imaging; D008297:Male; D010775:Photic Stimulation
chemical_list: D002800:Cholinesterase Inhibitors
keywords: Arterial spin labeling MRI; Cholinesterase inhibitors; Early stage Alzheimer's disease; Functional hyperemia; Vascular impairment