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      Impaired retinal microcirculation in patients with Alzheimer’s disease

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          Abstract

          The goal of this study was to determine the retinal blood flow rate (BFR) and blood flow velocity (BFV) of pre-capillary arterioles and post-capillary venules in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Forty patients (20 AD and 20 MCI) and 21 cognitively normal (CN) controls with a similar age range (± 5 yrs) were recruited. A retinal function imager (RFI) was used to measure BFRs and BFVs of arterioles and venules in the macular region. The thickness of the ganglion cell-inner plexiform layer (GCIPL) was measured using Zeiss Cirrus optical coherence tomography. Macular BFRs in AD group were 2.64 ± 0.20 nl/s (mean ± standard deviation) in arterioles and 2.23 ± 0.19 nl/s in venules, which were significantly lower than in MCI and CN groups (P < 0.05). In addition, BFRs in MCI were lower than in CN in both arterioles and venules (P < 0.05). The BFV of the arterioles was 3.20 ± 1.07 mm/s in AD patients, which was significantly lower than in CN controls (3.91 ± 0.77 mm/s, P = 0.01). The thicknesses of GCIPL in patients with AD and MCI were significantly lower than in CN controls (P < 0.05). Neither BFV nor BFR in arterioles and venules was related to age, GCIPL thickness, mini mental state examination (MMSE) score and disease duration in patients with AD and MCI (P > 0.05). The lower BFR in both arterioles and venules in AD and MCI patients together with the loss of GCIPL were evident, indicating the impairment of the two components in the neurovascular-hemodynamic system, which may play a role in disease progression.

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          GPOWER: A general power analysis program

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            Cerebral autoregulation.

            Autoregulation of blood flow denotes the intrinsic ability of an organ or a vascular bed to maintain a constant perfusion in the face of blood pressure changes. Alternatively, autoregulation can be defined in terms of vascular resistance changes or simply arteriolar caliber changes as blood pressure or perfusion pressure varies. While known in almost any vascular bed, autoregulation and its disturbance by disease has attracted particular attention in the cerebrovascular field. The basic mechanism of autoregulation of cerebral blood flow (CBF) is controversial. Most likely, the autoregulatory vessel caliber changes are mediated by an interplay between myogenic and metabolic mechanisms. Influence of perivascular nerves and most recently the vascular endothelium has also been the subject of intense investigation. CBF autoregulation typically operates between mean blood pressures of the order of 60 and 150 mm Hg. These limits are not entirely fixed but can be modulated by sympathetic nervous activity, the vascular renin-angiotensin system, and any factor (notably changes in arterial carbon dioxide tension) that decreases or increases CBF. Disease states of the brain may impair or abolish CBF autoregulation. Thus, autoregulation is lost in severe head injury or acute ischemic stroke, leaving surviving brain tissue unprotected against the potentially harmful effect of blood pressure changes. Likewise, autoregulation may be lost in the surroundings of a space-occupying brain lesion, be it a tumor or a hematoma. In many such disease states, autoregulation may be regained by hyperventilatory hypocapnia. Autoregulation may also be impaired in neonatal brain asphyxia and infections of the central nervous system, but appears to be intact in spreading depression and migraine, despite impairment of chemical and metabolic control of CBF. In chronic hypertension, the limits of autoregulation are shifted toward high blood pressure. Acute hypertensive encephalopathy, on the other hand, is thought to be due to autoregulatory failure at very high pressure. In long-term diabetes mellitus there may be chronic impairment of CBF autoregulation, probably due to diabetic microangiopathy.
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              Regulation of retinal blood flow in health and disease.

              Optimal retinal neuronal cell function requires an appropriate, tightly regulated environment, provided by cellular barriers, which separate functional compartments, maintain their homeostasis, and control metabolic substrate transport. Correctly regulated hemodynamics and delivery of oxygen and metabolic substrates, as well as intact blood-retinal barriers are necessary requirements for the maintenance of retinal structure and function. Retinal blood flow is autoregulated by the interaction of myogenic and metabolic mechanisms through the release of vasoactive substances by the vascular endothelium and retinal tissue surrounding the arteriolar wall. Autoregulation is achieved by adaptation of the vascular tone of the resistance vessels (arterioles, capillaries) to changes in the perfusion pressure or metabolic needs of the tissue. This adaptation occurs through the interaction of multiple mechanisms affecting the arteriolar smooth muscle cells and capillary pericytes. Mechanical stretch and increases in arteriolar transmural pressure induce the endothelial cells to release contracting factors affecting the tone of arteriolar smooth muscle cells and pericytes. Close interaction between nitric oxide (NO), lactate, arachidonic acid metabolites, released by the neuronal and glial cells during neural activity and energy-generating reactions of the retina strive to optimize blood flow according to the metabolic needs of the tissue. NO, which plays a central role in neurovascular coupling, may exert its effect, by modulating glial cell function involved in such vasomotor responses. During the evolution of ischemic microangiopathies, impairment of structure and function of the retinal neural tissue and endothelium affect the interaction of these metabolic pathways, leading to a disturbed blood flow regulation. The resulting ischemia, tissue hypoxia and alterations in the blood barrier trigger the formation of macular edema and neovascularization. Hypoxia-related VEGF expression correlates with the formation of neovessels. The relief from hypoxia results in arteriolar constriction, decreases the hydrostatic pressure in the capillaries and venules, and relieves endothelial stretching. The reestablished oxygenation of the inner retina downregulates VEGF expression and thus inhibits neovascularization and macular edema. Correct control of the multiple pathways, such as retinal blood flow, tissue oxygenation and metabolic substrate support, aiming at restoring retinal cell metabolic interactions, may be effective in preventing damage occurring during the evolution of ischemic microangiopathies.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Project administrationRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: ValidationRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: Project administrationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                2 February 2018
                2018
                : 13
                : 2
                : e0192154
                Affiliations
                [1 ] Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, United States of America
                [2 ] Evelyn F. McKnight Brain Institute, Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States of America
                [3 ] Department of Ophthalmology, Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
                [4 ] Zhongshan Ophthalmic Centre, Sun Yat-sen University, Guangzhou, Guangdong, China
                [5 ] National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States of America
                Ehime University Graduate School of Medicine, JAPAN
                Author notes

                Competing Interests: Dr. Jianhua Wang is a member of scientific advisory board of Optical Imaging Ltd. All other authors have no proprietary interest in any materials or methods. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0002-4269-4851
                Article
                PONE-D-17-25545
                10.1371/journal.pone.0192154
                5796702
                29394263
                34cf5c35-c44e-4239-a64a-726305508a88
                © 2018 Jiang et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 6 July 2017
                : 17 January 2018
                Page count
                Figures: 5, Tables: 1, Pages: 12
                Funding
                Funded by: North America Neuroophthalmology society
                Award ID: NANOS pilot grant
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100007049, Evelyn F. McKnight Brain Research Foundation;
                Award Recipient :
                Funded by: National Institutes of Health (US)
                Award ID: Center Grant P30 EY014801
                Funded by: Research for Prevent blindness
                This study was supported by the North American Neuro-ophthalmology Society, McKnight Brain Institute, NIH Center Grant P30 EY014801, and a grant from Research to Prevent Blindness (RPB).
                Categories
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