Impact of Nitric Oxide Bioavailability on the Progressive Cerebral and Peripheral Circulatory Impairments During Aging and Alzheimer's Disease.

Massimo Venturelli,Ilaria Boscolo Galazzo,Ettore Muti,Nicola Smania,Stefano Tamburin,Mario Rende,Annamaria Stabile,Anna Pedrinolla,Cristina Fonte,Federico Schena,Francesca B Pizzini,Alessandra Pistilli,Lucia Crispoltoni

doi:10.3389/fphys.2018.00169

Massimo Venturelli, Ilaria Boscolo Galazzo + Show 11 more

Open Access

https://doi.org/10.3389/fphys.2018.00169

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Abstract

Advanced aging, vascular dysfunction, and nitric oxide (NO) bioavailability are recognized risk factors for Alzheimer's disease (AD). However, the contribution of AD, per se, to this putative pathophysiological mechanism is still unclear. To better answer this point, we quantified cortical perfusion with arterial spin labeling (PVC-CBF), measured ultrasound internal carotid (ICA), and femoral (FA) artery blood flow in a group of patients with similar age (~78 years) but different cognitive impairment (i.e., mild cognitive impairment MCI, mild AD-AD1, moderate AD-AD2, and severe AD-AD3) and compared them to young and healthy old (aged-matched) controls. NO-metabolites and passive leg-movement (PLM) induced hyperemia were used to assess systemic vascular function. Ninety-eight individuals were recruited for this study. PVC-CBF, ICA, and FA blood flow were markedly (range of 9–17%) and significantly (all p < 0.05) reduced across the spectrum from YG to OLD, MCI, AD1, AD2, AD3 subjects. Similarly, plasma level of nitrates and the values of PLM were significantly reduced (range of 8–26%; p < 0.05) among the six groups. Significant correlations were retrieved between plasma nitrates, PLM and PVC-CBF, CA, and FA blood flow. This integrative and comprehensive approach to vascular changes in aging and AD showed progressive changes in NO bioavailability and cortical, extracranial, and peripheral circulation in patients with AD and suggested that they are directly associated with AD and not to aging. Moreover, these results suggest that AD-related impairments of circulation are progressive and not confined to the brain. The link between cardiovascular and the central nervous systems degenerative processes in patients at different severity of AD is likely related to the depletion of NO.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia, with an attested prevalence of ∼24 million which is predicted to quadruplicate by 2050 (Reitz et al, 2011)
The cardiovascular and the central nervous system (CNS) changes have been postulated to occur in parallel during the progression of AD (Picano et al, 2014)
Dementia severity was assessed by means of the Mini Mental State Examination (MMSE) (Folstein et al, 1975) and the Clinical Dementia Rating scale (CDR) (Morris, 1993)

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia, with an attested prevalence of ∼24 million which is predicted to quadruplicate by 2050 (Reitz et al, 2011). From the vascular point of view, Aβ peptide accumulation in the tunica media and adventitia of cerebral blood vessels, a condition termed cerebral amyloid angiopathy (CAA), is associated with vessel smooth muscle cell degeneration, resulting in impaired cerebral circulation (Maier et al, 2014). Apart from this direct effect of Aβ accumulation in the cortical neurons and vessels, there is increasing evidence that AD is associated with several dysregulated processes, which affect brain and systemic circulation, suggesting that vascular dysfunction may play a role in the pathogenesis of AD (Iturria-Medina et al, 2016). The cardiovascular and the central nervous system (CNS) changes have been postulated to occur in parallel during the progression of AD (Picano et al, 2014)

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