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Emerging Applications of Optical Coherence Tomography Angiography (OCTA) in neurological research
© The Author(s). 2018
Received: 9 February 2018
Accepted: 27 April 2018
Published: 12 May 2018
To review the clinical and research value of optical coherence tomography angiography (OCTA) in the field of neurology.
Current literature involving OCTA were reviewed through PubMed using the search terms “optical coherence tomography angiography”, with “multiple sclerosis”, “Alzheimer’s disease”, “optic neuropathy”, or other closely-related terms.
OCTA has been applied in research to advance our understanding of the pathobiology of neurological disorders. OCTA-derived blood flow and vessel density measures are altered in multiple sclerosis (MS), Alzheimer’s disease (AD), and various optic neuropathies (ON) in varying regions of the posterior segment vasculature of the eye. These emerging research findings support the occurrence of retinal vascular alterations across a host of neurological disorders and raise the possibility that vasculopathy can be clinically relevant since it contributes to the pathobiology of several neurological disorders.
OCTA may be beneficial for neurological research. Additional investigations using OCTA in neurological disorders will help to further validate its clinical and research utilities in terms of characterizing the role of vasculopathy in neurological disorders.
Optical coherence tomography angiography (OCTA) enables visualization of the ocular microvasculature through non-invasive, high-resolution enface and depth resolved imaging . First adapted from OCT and approved by the Food and Drug Administration (FDA) in 2015, OCTA provides structural and potentially functional information regarding the superficial and deep retina, as well as choroidal vasculature . Vessel alterations including but not limited to neovascularization , capillary loss , non-perfusion , increase in vessel tortuosity , and decrease in relative flow rates  have been reported with OCTA in various ocular pathological conditions such as age related macular degeneration , macular telangiectasia , artery and vein occlusions [10, 11], diabetic retinopathy , and glaucoma . Undetectable with commonly utilized ophthalmic tools such as traditional OCT and fundus photography, deeper, finer and more subtle vascular alterations are traditionally visualized through intravenous fluorescein angiography (IVFA), which requires the injection of a fluorescence dye . However, leakage of the dye related to the breakdown in the blood-retinal-barrier has been reported to potentially obscure capillary loss, vessel distortion, and early neovascularization [13, 14]. While indocyanine green angiography (ICGA) can potentially better visualize deeper regions of the chorioretinal vasculature, this technique still employs contrast-based injections [15–17]. Since OCTA may allow these obscured structures to be more clearly distinguished, and non-invasively without the use of contrast agents, the development of OCTA represents a major contribution towards advancing ophthalmic imaging in ocular disease diagnosis, monitoring and treatment [17, 18]. While OCTA utilization has been growing in ophthalmic clinical practices, a potential application of OCTA in the field of neurology has also been under active investigation. Benefiting from OCTA’s depth imaging capabilities, pial vessels in the cerebral microvasculature of mouse models can still be visualized in the setting of intact scalps . OCTA has also enabled rodent models of stroke and traumatic brain injury (TBI) to be studied in vivo. The real time analysis OCTA allows of the structural and potential functional alterations within the microvasculature have helped to further characterize disease complexes and more specifically, vascular components underlying the pathobiology of diseases, which could open up new therapeutic targets and avenues of clinical monitoring [20, 21]. Due to the lack of direct access, human cerebral microvascular alterations are difficult to non-invasively monitor in vivo. However, the brain can possibly be interrogated through the eyes since the vasculature of the retina and brain is similar in its anatomy and physiology [22, 23]. Furthermore, through the process of trans-synaptic degeneration, cerebral tissue injury may result in tissue degeneration of the optic nerves and retinal ganglion cells, which are supplied by the central retinal artery . Thus, structural and functional changes in the optic nerve and retina may hypothetically result in ocular vascular alterations. Using OCTA, non-invasive in vivo studies of neurological disorders through the human eye have emerged for multiple sclerosis (MS) [25–28], Alzheimer’s disease (AD) [29–31], and various optic neuropathies (ON) [32–36].
Algorithms and analysis
Owing to the fact that OCTA has traditional OCT function that can be used to acquire information on retinal structure, multiple layers can be identified so that the vasculature in the corresponding layers can be segmented . For example, in Optovue™, the OCT scan can be segmented into a number of composite layer regions, including the inner retina (from ganglion cell layer to inner plexiform layer), middle retina (from inner nuclear layer to outer plexiform layer), outer retina (from outer nuclear layer to external limiting membrane), choriocapillaris, and choroid . These regions on the OCTA can be analyzed for a number of vascular features. For instance, the presence of neovascularization , an increase in tortuosity , and areas of capillary loss  can be qualitatively analyzed. Additional features such as the area of the foveal avascular zone (FAZ), parafoveal region, regions of non-perfusion and relative density can be quantitatively determined either through the fractal analysis or pixel counting methods. The flow rate is the average decorrelation value of sequential B-scans on OCTA, which can be used as a surrogate for blood flow rates . Furthermore, Optovue™ includes an analysis package in its system that automatically analyzes the FAZ and vessel density in different retinal sub-regions.
OCTA findings in healthy volunteers have been critical for forming a solid foundation for the normative retinal and choroidal microvasculature, determining when abnormalities are present, and will ultimately play a central role in helping to guide future disease characterization and diagnosis. The mean relative parafoveal flow (flow index) and relative vessel coverage (decorrelation values) have been reported to significantly decrease with normal aging, while the FAZ area (determined by pixel counting) significantly increases in size with normal aging . The correlation between vessel and perfusion loss with increasing age in healthy vasculatures have been reported in prior studies using blue field stimulation , magnetic resonance imaging , and IVFA . However, analyses of the FAZ determined by fractal analysis, as opposed to pixel counting, did not find significant changes in the FAZ with age, which might be partially due to unadjusted magnification error . However, fractal dimension showed a relatively denser DVP in comparison to the SVP in relation to age-related changes [18, 54]. These findings are supported by previous research that analyzed human donor eyes through confocal microscopy in the perifoveal region . The FAZ area, which varies in size from person to person has been reported to be on average 0.32 ± 0.11 mm2 in size through pixel counting on angiograms generated with SSADA in a study of healthy volunteers (n = 144, age range 10–79 years) .
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS) where neurodegeneration primarily occurring because of inflammation is thought to be the principal substrate underlying disability. Post-mortem studies demonstrate that up to 99% of MS patients exhibit demyelinating plaques within their optic nerves, making optic nerve involvement a ubiquitous part of the MS disease process [57, 58]. Optic neuritis (ON) is the initial manifestation of MS in approximately 25% of patients and occurs in approximately 50% of patients at some point in the disease course . Since available treatments generally target the autoimmune and inflammatory aspects of MS and vary in effectiveness across patients , sensitive biomarkers for monitoring disease progression and therapeutic efficacy are desperately needed. OCT-derived retinal measures have emerged for this purpose, with the retina representing the most accessible component of the CNS. OCT identified thinning of the retinal nerve fiber layer (RNFL) and composite of the ganglion cell and inner plexiform layers (GCIP) in particular have become biomarkers of global CNS neurodegeneration in MS .
The etiology underlying the decrease in blood flow and density of the retinal vasculature in MS patients remain unclear. Accumulating evidence has determined that inflammation leads to loss of neurons in the inner retina. The reduced number of neurons, resulting in reduced metabolic demand, may result in reduced blood supply provided by the vessels of the SVP, which in turn supplies the DVP through anastomoses [25, 26]. Inflammation is thought to lead to mild alterations in vascular function, including endotheliopathy, and postulated to result in decreased perfusion and neuronal damage , although this pathologic disease mechanism remains to be definitively demonstrated. Interestingly, studies of the cerebral microvasculature in MS have revealed possible hypoperfusion in the normal appearing gray matter and white matter [61, 62]. A recent cross-sectional study of the Retinal Function Imager, an ophthalmic multimodal imaging modality, in relapsing remitting MS (RRMS) (n = 17) revealed reductions in retinal arteriolar and venular blood flow velocities as compared to healthy controls, although determinations with respect to underlying mechanisms of the observed findings or their relationships to ON history were not possible . In MS, it is also recognized that elevations in hypoxia inducible factors (indicating vascular compromise) occur in regions of neurodegeneration . Future studies employing easily performed OCTA with larger sample sizes, longitudinal follow up, and more focus on potential correlations to other MS biomarkers in the CNS will help further characterize aberrations in the retinal vasculature in MS and provide insights into MS disease mechanisms and even novel therapeutic strategies.
Alzheimer’s disease (AD), the most common cause of dementia , is a progressive neurodegenerative disorder that is more common with aging and characterized by an accumulation of misfolded protein, in particular amyloid-beta (AB) and neurofibrillary tangles (NFTs) . Prior to AD onset, patients often have mild cognitive impairment (MCI), during which cognitive function declines, but patients have sufficient cognitive function to perform their activities of daily living . AD has been associated with a number of vascular risk factors including stroke, diabetes mellitus, atherosclerosis, and hypertension . Moreover, cerebral hypoperfusion, increased cerebral vascular tortuosity, and decreased vascular density have been reported in AD patients [29, 68], which may indicate the presence of a vasculopathy in the pathogenesis of AD. This probable disease mechanism, while difficult to analyze directly due to the location of the brain within the skull, may be investigated through the retinal microvasculature. The retinal and cerebral vasculatures share similar embryonic, physiologic, and anatomic features [30, 63]. Furthermore, similar to the brain, AB accumulation was found in the retina in AD . Using OCT, thinning of the GCIP in the retina was suggested to be a potential biomarker of neurodegeneration and disease severity in AD .
Anterior ischemic optic neuropathy
Characterized by severe vision loss due to ischemia of the small vessels supplying the anterior portion of the optic nerve head, anterior ischemic optic neuropathy (AION) can be classified as arteritic (AAION) or non-arteritic (NAION) . Accounting for up to 15% of AION cases, AAION is caused by inflammation within arteries primarily as a result of underlying giant cell arteritis (temporal arteritis) . NAION is the more common form of AION and accounts for approximately 85% of AION cases. NAION is considered a form of small vessel disease, which usually occurs in patients with various risk factors such as hypertension, diabetes, or dyslipidemia. These factors are unrelated to inflammation . Furthermore, there is no consistently effective treatment method to prevent irreversible vision loss in NAION. While OCTA cannot differentiate between AAION and NAION, the regions of non-perfusion with ischemic boundaries can be clearly identified on OCTA of the optic disk .
Other optic neuropathies
Summary of significant optical coherence tomography angiography findings in neurological disorders *
Wang et al. (2014) 
flow index - ONH
0.140 ± 0.020
0.160 ± 0.010
Spain et al. (2017) 
flow index - ONH
Feucht et al. (2017) 
vessel density % - SVP
vessel density % - SVP
vessel density % - DVP
vessel density % - DVP
Lanzillo et al. (2017) 
vessel density % - parafovea IS
50.96 ± 5.33
51.71 ± 5.82
vessel density % - macula
48.71 ± 4.44
53.08 ± 3.31
Bulut et al. (2017) 
area (mm 2 ) - FAZ
0.47 ± 0.18
0.33 ± 0.08
vessel density % - macula
45.50 ± 3.85
48.67 ± 3.29
Jiang et al. (2017) 
vessel density - SVP
vessel density - DVP
vessel density - DVP SN
Fard et al. (2018) 
vessel density % - PC
30.1 ± 6
42.3 ± 2.3
Song et al. (2017) 
vessel density % - PC
52.07 ± 7.68
58.68 ± 3.16
Ling et al. (2017) 
nonperfusion area % - ONH
17.84 ± 6.18
8.61 ± 1.65
Resulting from elevated intra-cranial pressure that may be idiopathic in etiology or secondary to numerous causes including but not limited to intracranial masses for example, papilledema –is swelling of the optic discs – that usually occurs bilaterally. Vision loss is uncommon in early papilledema, but decreased visual acuity and visual field loss is often profound in advanced papilledema . Using OCT, papilledema has also been shown to be associated with a significant increase in disc volume due to overall swelling, but also degeneration of the inner retinal layers in the setting of chronic papilledema . OCTA demonstrated an increased visibility of the peripapillary vascular network in chronic papilledema, which reveal an increased diameter of vessels along with an increase in vessel density . Additional studies with a quantitative measurement of the microvasculature for perfusion density will be necessary to further characterize the role of vascular alternations in the progression of papilledema.
OCTA is an advanced ophthalmic imaging technique that can non-invasively generate angiograms with depth information for the posterior segment of the eye. The subsequent measures of retinal vascular structure and indirect blood flow enable the detection of alterations in the structure and function of the vasculature in the retina, including the microvasculature that can be qualitatively and quantitatively analyzed. It is worthwhile to note limitations of the OCTA, including the lack of an industry standard for image processing, segmentation of vessel layers, and quantitative analysis. Furthermore, anatomical variables such as individual differences in blood flow and position of vessels may cause variability between subjects, both especially for qualitative and quantitative studies. Nevertheless, while the field of view is relatively small in comparison to other ophthalmic techniques such as FA, ICGA, and RFI [11, 17, 75], significant findings have been identified in a number of potentially sight-threatening ophthalmic disorders . Capable of non-invasively imaging microvascular features that may be obscured or undetectable in other ophthalmic imaging techniques, OCTA utilization is growing across a host of neurological disorders (including cerebrovascular diseases) and contributing towards advancing our understanding of operative disease mechanisms as well as the potential identification of novel biomarkers, which could collectively lead to novel therapeutic targets/strategies in the future. Blood flow or vessel density was reported to be decreased in MS, AD, and ON in various regions of the posterior segment vasculature. These emerging research findings suggest a role for vascular alterations in the pathobiology of these diseases, although it is unclear if and to what magnitude these changes may contribute to disease progression. Further investigations with larger sample sizes, assessment of greater regions of the vasculature, and additional OCTA parameters may help to characterize these neurological disorders and determine the true utility of OCTA in the field of neurology.
We thank Dr. Hong Jiang MD, PhD, of the Bascom Palmer Eye Institute at the University of Miami for providing the images used for Fig. 5.
This review article was supported in part by a grant (RG-1606-08768) from the National Multiple Sclerosis Society to SS.
Peter Calabresi has received personal honorariums for consulting from Biogen and Disarm Therapeutics. He is PI on research grants to Johns Hopkins from MedImmune, Annexon, and Genzyme.
Shiv Saidha has received consulting fees from Medical Logix for the development of CME programs in neurology and has served on scientific advisory boards for Biogen-Idec, Genzyme, Genentech Corporation, EMD Serono & Novartis. He is the PI of investigator-initiated studies funded by Genentech Corporation and Biogen Idec, and received support from the Race to Erase MS foundation. He has received equity compensation for consulting from JuneBrain LLC, a retinal imaging device developer. He is also the site investigator of a trial sponsored by MedDay Pharmaceuticals.
Liang Wang, Olwen Murphy, and Natalia Gonzalez Caldito do not have any disclosures.
LW and SS were the major contributors in writing the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The authors declare that they have no competing interests.
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