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Retinal Microvascular and Neurodegenerative Changes in Alzheimer’s Disease and Mild Cognitive Impairment Compared with Control Participants

Published:March 11, 2019DOI:https://doi.org/10.1016/j.oret.2019.02.002

      Purpose

      Evaluate and compare the retinal microvasculature in the superficial capillary plexus (SCP) in Alzheimer’s disease (AD), mild cognitive impairment (MCI), and cognitively intact controls using OCT angiography. OCT parameters were also compared.

      Design

      Cross-sectional study.

      Participants

      Seventy eyes from 39 AD participants, 72 eyes from 37 MCI participants, and 254 eyes from 133 control participants were enrolled.

      Methods

      Participants were imaged using Zeiss Cirrus HD-5000 with AngioPlex (Carl Zeiss Meditec, Dublin, CA) and underwent cognitive evaluation with Mini-Mental State Examination.

      Main Outcome Measures

      Vessel density (VD) and perfusion density (PD) in the SCP within the Early Treatment Diabetic Retinopathy Study 6-mm circle, 3-mm circle, and 3-mm ring were compared between groups. Foveal avascular zone (FAZ) area, central subfield thickness (CST), macular ganglion cell-inner plexiform layer (GC-IPL) thickness, and peripapillary retinal nerve fiber layer (RNFL) thickness were also compared.

      Results

      Alzheimer’s participants showed significantly decreased SCP VD and PD in the 3-mm ring (P = 0.001 and P = 0.002, respectively) and 3-mm circle (P = 0.003 and P = 0.004, respectively) and decreased SCP VD in the 6-mm circle (P = 0.047) compared with MCI and significantly decreased SCP VD and PD in the 3-mm ring (P = 0.008 and P = 0.004, respectively) and 3-mm circle (P = 0.015 and P = 0.009, respectively) and SCP PD in the 6-mm circle (P = 0.033) when compared with cognitively intact controls. There was no difference in SCP VD or PD between MCI and controls (P > 0.05). FAZ area and CST did not differ significantly between groups (P > 0.05). Alzheimer’s participants showed significantly decreased GC-IPL thickness over the inferior (P = 0.032) and inferonasal (P = 0.025) sectors compared with MCI and significantly decreased GC-IPL thickness over the entire (P = 0.012), superonasal (P = 0.041), inferior (P = 0.004), and inferonasal (P = 0.006) sectors compared to controls. MCI participants showed significantly decreased temporal RNFL thickness (P = 0.04) compared with controls.

      Conclusions

      Alzheimer’s participants showed significantly reduced macular VD, PD, and GC-IPL thickness compared with MCI and controls. Changes in the retinal microvasculature may mirror small vessel cerebrovascular changes in AD.

      Abbreviations and Acronyms:

      AD (Alzheimer’s disease), CST (central subfield thickness), ETDRS (Early Treatment Diabetic Retinopathy Study), FAZ (foveal avascular zone), GC-IPL (ganglion cell–inner plexiform layer), logMAR (logarithm of the minimum angle of resolution), MCI (mild cognitive impairment), MMSE (Mini-Mental State Examination), OCTA (OCT angiography), PD (perfusion density), PET (positron emission tomography), RNFL (retinal nerve fiber layer), SCP (superficial capillary plexus), VD (vessel density)
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      References

        • Hebert L.E.
        • Weuve J.
        • Scherr P.A.
        • Evans D.A.
        Alzheimer disease in the United States (2010–2050) estimated using the 2010 census.
        Neurology. 2013; 80: 1778-1783
        • Galton C.J.
        • Patterson K.
        • Xuereb J.H.
        • Hodges J.R.
        Atypical and typical presentations of Alzheimer’s disease: a clinical, neuropsychological, neuroimaging and pathological study of 13 cases.
        Brain. 2000; 123: 484-498
        • Gauthier S.
        • Reisberg B.
        • Zaudig M.
        • et al.
        Mild cognitive impairment.
        Lancet. 2006; 367: 1262-1270
        • Ward A.
        • Tardiff S.
        • Dye C.
        • Arrighi H.M.
        Rate of conversion from prodromal Alzheimer’s disease to Alzheimer’s dementia: a systematic review of the literature.
        Dement Geriatr Cogn Dis Extra. 2013; 3: 320-332
        • Grossman I.
        • Lutz M.W.
        • Crenshaw D.G.
        • et al.
        Alzheimer’s disease: diagnostics, prognostics and the road to prevention.
        EPMA J. 2010; 1: 293-303
        • Koronyo-Hamaoui M.
        • Koronyo Y.
        • Ljubimov A.V.
        • et al.
        Identification of amyloid plaques in retinas from Alzheimer’s patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model.
        Neuroimage. 2011; 54: S204-S217
        • Cheung C.Y.L.
        • Ong Y.T.
        • Ikram M.K.
        • et al.
        Microvascular network alterations in the retina of patients with Alzheimer’s disease.
        Alzheimers Dement. 2014; 10: 135-142
        • Patton N.
        • Aslam T.
        • MacGillivray T.
        • et al.
        Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: a rationale based on homology between cerebral and retinal microvasculatures.
        J Anat. 2005; 206: 319-348
        • London A.
        • Benhar I.
        • Schwartz M.
        The retina as a window to the brain-from eye research to CNS disorders.
        Nat Rev Neurol. 2013; 9: 44-53
        • Lad E.M.
        • Mukherjee D.
        • Stinnett S.S.
        • et al.
        Evaluation of inner retinal layers as biomarkers in mild cognitive impairment to moderate Alzheimer’s disease.
        PLoS One. 2018; 13e0192646
        • Yim C.
        • Cheung-Lui
        • Ong Y.T.L.
        • et al.
        Retinal ganglion cell analysis using high-definition optical coherence tomography in patients with mild cognitive impairment and Alzheimer’s disease.
        J Alzheimers Dis. 2015; 45: 45-56
        • Chan V.T.T.
        • Sun Z.
        • Tang S.
        • et al.
        Spectral domain-optical coherence tomography measurements in Alzheimer’s disease: a systematic review and meta-analysis.
        Ophthalmology. 2018; 126: 497-510
        • La Morgia C.
        • Ross-Cisneros F.N.
        • Koronyo Y.
        • et al.
        Melanopsin retinal ganglion cell loss in Alzheimer disease.
        Ann Neurol. 2016; 79: 90-109
        • Feke G.T.
        • Hyman B.T.
        • Stern R.A.
        • Pasquale L.R.
        Retinal blood flow in mild cognitive impairment and Alzheimer’s disease.
        Alzheimers Dement. 2015; 1: 144-151
        • Heringa S.M.
        • Bouvy W.H.
        • van den Berg E.
        • et al.
        Associations between retinal microvascular changes and dementia, cognitive functioning, and brain imaging abnormalities: a systematic review.
        J Cereb Blood Flow Metab. 2013; 33: 983-995
        • Smith E.E.
        • Greenberg S.M.
        Beta-amyloid, blood vessels, and brain function.
        Stroke. 2009; 40: 2601-2606
        • Brown W.R.
        • Thore C.R.
        Review: cerebral microvascular pathology in ageing and neurodegeneration.
        Neuropathol Appl Neurobiol. 2011; 37: 56-74
        • Frost S.
        • Kanagasingam Y.
        • Sohrabi H.
        • et al.
        Retinal vascular biomarkers for early detection and monitoring of Alzheimer’s disease.
        Transl Psychiatry. 2013; 3 (e233–e233)
        • Rosenfeld P.J.
        • Durbin M.K.
        • Roisman L.
        • et al.
        Zeiss AngioplexTM spectral domain optical coherence tomography angiography: technical aspects.
        Dev Ophthalmol. 2016; 56: 18-29
        • Bulut M.
        • Kurtuluş F.
        • Gözkaya O.
        • et al.
        Evaluation of optical coherence tomography angiographic findings in Alzheimer’s type dementia.
        Br J Ophthalmol. 2018; 102: 233-237
        • Jiang H.
        • Wei Y.
        • Shi Y.
        • et al.
        Altered macular microvasculature in mild cognitive impairment and Alzheimer disease.
        J Neuro-Ophthalmol. 2017; 38: 292-298
        • Mckhann G.M.
        • Knopman D.S.
        • Chertkow H.
        • et al.
        The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging and the Alzheimer’s Association workgroup.
        Alzheimers Dement. 2011; 7: 263-269
        • Albert M.S.
        • Dekosky S.T.
        • Dickson D.
        • et al.
        The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.
        Alzheimers Dement. 2011; 7: 270-279
        • Koronyo Y.
        • Biggs D.
        • Barron E.
        • et al.
        Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease.
        JCI Insight. 2017; 2: e93621
        • Durbin M.K.
        • An L.
        • Shemonski N.D.
        • et al.
        Quantification of retinal microvascular density in optical coherence tomographic angiography images in diabetic retinopathy.
        JAMA Ophthalmol. 2017; 135: 370
        • Triolo G.
        • Rabiolo A.
        • Shemonski N.D.
        • et al.
        Optical coherence tomography angiography macular and peripapillary vessel perfusion density in healthy subjects, glaucoma suspects, and glaucoma patients.
        Invest Ophthalmol Vis Sci. 2017; 58: 5713-5722
        • Masters B.R.
        Fractal analysis of the vascular tree in the human retina.
        Annu Rev Biomed Eng. 2004; 6: 427-452
        • Williams M.A.
        • McGowan A.J.
        • Cardwell C.R.
        • et al.
        Retinal microvascular network attenuation in Alzheimer’s disease.
        Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. 2015; 1: 229-235
        • Haritoglou C.
        • Rudolph G.
        • Hoops J.P.
        • et al.
        Retinal vascular abnormalities in CADASIL.
        Neurology. 2004; 62: 1202-1205
        • Ikram M.K.
        • Cheung C.Y.
        • Wong T.Y.
        • Chen C.P.L.H.
        Retinal pathology as biomarker for cognitive impairment and Alzheimer’s disease.
        J Neurol Neurosurg Psychiatry. 2012; 83: 917-922
        • de Carlo T.E.
        • Romano A.
        • Waheed N.K.
        • Duker J.S.
        A review of optical coherence tomography angiography (OCTA).
        Int J Retin Vitr. 2015; 1: 5
        • Henkind P.
        Radial peripapillary capillaries of the retina. I. Anatomy: human and comparative.
        Br J Ophthalmol. 1967; 51: 115-123
        • O’Bryhim B.
        • Apte R.S.
        • Kung N.
        • et al.
        Association of preclinical Alzheimer disease with optical coherence tomographic angiography findings.
        JAMA Ophthalmol. 2018; 136: 1242-1248
        • Fujiwara A.
        • Morizane Y.
        • Hosokawa M.
        • et al.
        Factors affecting foveal avascular zone in healthy eyes: an examination using swept-source optical coherence tomography angiography.
        PLoS One. 2017; 12e0188572
        • Ghassemi F.
        • Mirshahi R.
        • Bazvand F.
        • et al.
        The quantitative measurements of foveal avascular zone using optical coherence tomography angiography in normal volunteers.
        J Curr Ophthalmol. 2017; 29: 293-299
        • Cunha L.P.
        • Lopes L.C.
        • Costa-Cunha L.V.F.
        • et al.
        Macular thickness measurements with frequency domain-OCT for quantification of retinal neural loss and its correlation with cognitive impairment in Alzheimer disease.
        PLoS One. 2016; 11e0153830
        • den Haan J.
        • Verbraak F.D.
        • Visser P.J.
        • et al.
        Retinal thickness in Alzheimer’s disease: a systematic review and meta-analysis.
        Alzheimers Dement. 2018; 10: 49-55
        • Cunha J.P.
        • Proença R.
        • Dias-Santos A.
        • et al.
        OCT in Alzheimer’s disease: thinning of the RNFL and superior hemiretina.
        Graefes Arch Clin Exp Ophthalmol. 2017; 255: 1827-1835
        • Lee C.S.
        • Larson E.B.
        • Gibbons L.E.
        • et al.
        Associations between recent and established ophthalmic conditions and risk of Alzheimer’s disease.
        Alzheimers Dement. 2018; 15: 34-41
        • Lin I.-C.
        • Wang Y.-H.
        • Wang T.-J.
        • et al.
        Glaucoma, Alzheimer’s disease, and Parkinson’s disease: an 8-year population-based follow-up study.
        PLoS One. 2014; 9e108938
        • Guedes V.
        • Schuman J.S.
        • Hertzmark E.
        • et al.
        Optical coherence tomography measurement of macular and nerve fiber layer thickness in normal and glaucomatous human eyes.
        Ophthalmology. 2003; 110: 177-189
        • Blanks J.C.
        • Torigoe Y.
        • Hinton D.R.
        • Blanks R.H.
        Retinal pathology in Alzheimer’s disease. I. Ganglion cell loss in foveal/parafoveal retina.
        Neurobiol Aging. 1996; 17: 377-384
        • Williams P.A.
        • Thirgood R.A.
        • Oliphant H.
        • et al.
        Retinal ganglion cell dendritic degeneration in a mouse model of Alzheimer’s disease.
        Neurobiol Aging. 2013; 34: 1799-1806
        • Liu S.
        • Ong Y.-T.
        • Hilal S.
        • et al.
        The association between retinal neuronal layer and brain structure is disrupted in patients with cognitive impairment and Alzheimer’s disease.
        J Alzheimers Dis. 2016; 54: 585-595
        • Leite M.T.
        • Rao H.L.
        • Weinreb R.N.
        • et al.
        Agreement among spectral domain optical coherence tomography instruments for assessing retinal nerve fiber layer thickness.
        Am J Ophthalmol. 2011; 151: 85-92.e1
        • Curcio C.A.
        • Allen K.A.
        Topography of ganglion cells in human retina.
        J Comp Neurol. 1990; 300: 5-25
        • Larrieu S.
        • Letenneur L.
        • Orgogozo J.M.
        • et al.
        Incidence and outcome of mild cognitive impairment in a population-based prospective cohort.
        Neurology. 2002; 59: 1594-1599
        • Mufson E.J.
        • Binder L.
        • Counts S.E.
        • et al.
        Mild cognitive impairment: pathology and mechanisms.
        Acta Neuropathol. 2012; 123: 13-30
        • Cunha J.P.
        • Moura-Coelho N.
        • Proença R.P.
        • et al.
        Alzheimer’s disease: a review of its visual system neuropathology. Optical coherence tomography—a potential role as a study tool in vivo.
        Graefes Arch Clin Exp Ophthalmol. 2016; 254: 2079-2092
        • Aizenstein H.J.
        • Nebes R.D.
        • Saxton J.A.
        • et al.
        Frequent amyloid deposition without significant cognitive impairment among the elderly.
        Arch Neurol. 2008; 65: 1509
        • Okello A.
        • Koivunen J.
        • Edison P.
        • et al.
        Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study.
        Neurology. 2009; 73: 754-760