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.

Reduced global brain metabolism but maintained vascular function in amnestic mild cognitive impairment

“…When the condition of the patient advances to the stage of AD, vascular deficits are likely to become more apparent. 17,40,41 Our findings of a reduction in brain tissue oxygen utilization in MCI cannot be attributed to a loss in brain volume, 8,42 as neither gray matter nor wholebrain volume showed a difference between the two groups. Similarly, the volume of WMHs did not show a difference.…”

Functional MRI technologies in the study of medication treatment effect on Alzheimer's disease

“…Without treatment, AD patients showed a significantly lower CBF and BOLD signal intensity than HC. After 6 months of ChEI treatment, a further CBF decline was seen in the occipital lobe during visual stimulation, whereas the CBF response was stabilized after 12 months of treatment …”

“…A subsequent study by Janik et al investigated changes of CBF and fMRI activation in mild AD during both rest and task phases using PCASL‐PWI. Without treatment, AD patients showed a significantly lower CBF and BOLD signal intensity than HC.…”

“…The PWI studies under review all used PCASL . The studies consistently suggested a treatment‐induced positive effect: a CBF increase in multiple brain regions (lateral temporal lobe, cingulate, and the white matter of posterior cingulate and prefrontal) that was clinically meaningful or CBF stabilization …”

Dysfunctional Sensory Modalities, Locus Coeruleus, and Basal Forebrain: Early Determinants that Promote Neuropathogenesis of Cognitive and Memory Decline and Alzheimer’s Disease

“…Visual-processing abnormalities are common in typical AD (Mentis et al 1996), and this correlates with evidence of a decline in the visual cortex hyperemia (Janik et al 2015). Hence, a significant deficit in the visual cortex hyperemia may occur despite the relative sparing of visual function in AD in its initial stage.…”