Systematic Review on Fractal Dimension of the Retinal Vasculature in Neurodegeneration and Stroke: Assessment of a Potential Biomarker

Abstract

Introduction: Ocular manifestations in several neurological pathologies accentuate the strong relationship between the eye and the brain. Retinal alterations in particular can serve as surrogates for cerebral changes. Offering a "window to the brain," the transparent eye enables non-invasive imaging of these changes in retinal structure and vasculature. Fractal dimension (FD) reflects the overall complexity of the retinal vasculature. Changes in FD could reflect subtle changes in the cerebral vasculature that correspond to preclinical stages of neurodegenerative diseases. In this review, the potential of this retinal vessel metric to serve as a biomarker in neurodegeneration and stroke will be explored.Methods: A literature search was conducted, following the PRISMA Statement 2009 criteria, in four large bibliographic databases (Pubmed, Embase, Web Of Science and Cochrane Library) up to 12 October 2019. Articles have been included based upon their relevance. Wherever possible, level of evidence (LOE) has been assessed by means of the Oxford Centre for Evidence-based Medicine Level of Evidence classification.Results: Twenty-one studies were included for qualitative synthesis. We performed a narrative synthesis and produced summary tables of findings of included papers because methodological heterogeneity precluded a meta-analysis. A significant association was found between decreased FD and neurodegenerative disease, mainly addressing cognitive impairment (CI) and dementia. In acute, subacute as well as chronic settings, decreased FD seems to be associated with stroke. Differences in FD between subtypes of ischemic stroke remain unclear. Conclusions:This review provides a summary of the scientific literature regarding the association between retinal FD and neurodegenerative disease and stroke. Central pathology is associated with a decreased FD, as a measure of microvascular network complexity. As retinal FD reflects the global integrity of the cerebral microvasculature, it is an attractive parameter to explore. Despite obvious concerns, mainly due to a lack of methodological standardization, retinal FD Lemmens et al.Retinal Fractals: Neurodegeneration and Stroke remains a promising non-invasive and low-cost diagnostic biomarker for neurodegenerative and cerebrovascular disease. Before FD can be implemented in clinic as a diagnostic biomarker, the research community should strive for uniformization and standardization.

Retinal microvasculature dysfunction is associated with Alzheimer’s disease and mild cognitive impairment

“…Since FD is a measure of vasculature branching pattern complexity, it may be a more relevant biomarker for the SCP than the DCP. Our finding is in keeping with previous publications on larger retinal vessels using fundus photographs, where AD and MCI participants demonstrated a loss of vessel complexity [35].…”

ROSE: A Retinal OCT-Angiography Vessel Segmentation Dataset and New Model

“…With the simultaneous occurrence of both neurodegeneration and microvascular changes in the brain, many studies [51], [54], [55] have suggested that the macula microvasculature may provide vital information on the changes in the cerebral microcirculation during the subclinical phase. Changes in the retinal capillary network may indicate the onset and progression of retinopathy, and fractal dimension (FD) is a wellknown measure for characterizing the geometric complexity of retinal vasculature that will be a promising biomarker for vascular diseases [56]- [58] as well as neurodegenerative [59] and cerebrovascular diseases [60]. In particular, Cheung et al [56] indicated that the conventional structural measures (e.g., branching angle and vascular tortuosity) represent only one of the many aspects of the retinal vascular geometry and are lack of single global measure that can summarize the branching pattern of the vasculature as a whole.…”

Retinal Microvascular Alterations in Alzheimer’s Disease and Mild Cognitive Impairment

“…Our nding is in keeping with previous publications on larger retinal vessels using fundus photographs, where AD and MCI participants demonstrated a loss of vessel complexity. [30] Perfusion density of large vessels It should be noted that although VD in SCP was decreased in participants with cognitive impairment, perfusion density of the large retinal vessels remained unchanged. Previous studies have examined retinal vessels from fundus photographs and reported alterations in the venular caliber in participants with AD.…”

“…Perfusion density of the large vessels were computed as the ratio between large vessel area per total imaged area in the annulus region of measurement. (6) FD represents the vessel complexity of the retinal vasculature [30] and was calculated within the annulus zone using the box counting method (Dbox) with the fractal analysis toolbox (TruSoft Benoit Pro 2.0, TruSoft International, Inc, St. Petersburg, FL). [31] Statistical analyses Primary outcomes were retinal VD, FD, and FAZ dimensions at SCP and DCP.…”