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      Retinal nerve fiber layer thickness predicts CSF amyloid/tau before cognitive decline

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          Abstract

          Background

          Alzheimer’s disease (AD) pathology precedes symptoms and its detection can identify at-risk individuals who may benefit from early treatment. Since the retinal nerve fiber layer (RNFL) is depleted in established AD, we tested whether its thickness can predict whether cognitively healthy (CH) individuals have a normal or pathological cerebrospinal fluid (CSF) Aß 42 (A) and tau (T) ratio.

          Methods

          As part of an ongoing longitudinal study, we enrolled CH individuals, excluding those with cognitive impairment and significant ocular pathology. We classified the CH group into two sub-groups, normal (CH-NAT, n = 16) or pathological (CH-PAT, n = 27), using a logistic regression model from the CSF AT ratio that identified >85% of patients with a clinically probable AD diagnosis. Spectral-domain optical coherence tomography (OCT) was acquired for RNFL, ganglion cell-inner plexiform layer (GC-IPL), and macular thickness. Group differences were tested using mixed model repeated measures and a classification model derived using multiple logistic regression.

          Results

          Mean age (± standard deviation) in the CH-PAT group (n = 27; 75.2 ± 8.4 years) was similar (p = 0.50) to the CH-NAT group (n = 16; 74.1 ± 7.9 years). Mean RNFL (standard error) was thinner in the CH-PAT group by 9.8 (2.7) μm; p < 0.001. RNFL thickness classified CH-NAT vs. CH-PAT with 87% sensitivity and 56.3% specificity.

          Conclusions

          Our retinal data predict which individuals have CSF biomarkers of AD pathology before cognitive deficits are detectable with 87% sensitivity. Such results from easy-to-acquire, objective and non-invasive measurements of the RNFL merit further study of OCT technology to monitor or screen for early AD pathology.

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          Most cited references36

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          Relationship between cognitive impairment and retinal morphological and visual functional abnormalities in Alzheimer disease.

          There is conflicting evidence as to whether Alzheimer disease (AD) is accompanied by loss of retinal ganglion cells. To evaluate this issue, we have used optical coherence tomography (OCT) to assess the thickness and volume of the retina. We have also sought to correlate our findings with visual function and cognitive impairment. We evaluated 28 eyes of 14 patients with AD and 30 eyes of 15 age-matched control subjects. In these two groups, we measured retinal nerve fiber layer (RNFL) thickness, macular thickness, and macular volume with OCT, visual function through latency of the pattern visual evoked potential (VEP) signal, and cognitive impairment through the Mini-Mental State Examination (MMSE). The parapapillary and macular RNFL thickness in all quadrants and positions of AD patients were thinner than in control subjects. The mean total macular volume of AD patients was significantly reduced as compared with control subjects (P < 0.05). Total macular volume and MMSE scores were significantly correlated. No significant difference was found in the latency of the VEP P100 of AD patients and control subjects. Our study confirms some other studies in showing that in AD patients there is a reduction of parapapillary and macular RNFL thickness and macular volume as measured by OCT. The reduction in macular volume was related to the severity of cognitive impairment.
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            Morphological and functional retinal impairment in Alzheimer's disease patients.

            Our study aims to assess the optic nerve fiber layer thickness in vivo, the function of the innermost retinal layer and whether a correlation exists between morphological and functional parameters in patients affected by Alzheimer's Disease (AD). Seventeen AD patients (mean age 70.37+/-6.1 years, best corrected visual acuity >8/10 with refractive error between +/-3 sf, intra-ocular pressure (IOP) 0.01) between NFL values and other PERG parameters (N35 implicit time, N35-P50 amplitude) were found. Our results suggest that in AD patients, there is a reduction of NFL thickness evaluated in vivo by OCT and this morphological abnormality is related to a retinal dysfunction as revealed by abnormal PERG responses.
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              Macular ganglion cell-inner plexiform layer: automated detection and thickness reproducibility with spectral domain-optical coherence tomography in glaucoma.

              To demonstrate the capability of SD-OCT to measure macular retinal ganglion cell-inner plexiform layer (GCIPL) thickness and to assess its reproducibility in glaucomatous eyes. Fifty-one glaucomatous eyes (26 mild, 11 moderate, 14 severe) of 51 patients underwent macular scanning using the Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA) macula 200×200 acquisition protocol. Five scans were obtained on 5 days within 2 months. The ganglion cell analysis (GCA) algorithm was used to detect the macular GCIPL and to measure the thickness of the overall average, minimum, superotemporal, superior, superonasal, inferonasal, inferior, and inferotemporal GCIPL. The reproducibility of the measurements was evaluated with intraclass correlation coefficients (ICCs), coefficients of variation (COVs), and test-retest standard deviations (TRTSDs). Segmentation and measurement of GCIPL thickness were successful in 50 of 51 subjects. All ICCs ranged between 0.94 and 0.98, but ICCs for average and superior GCIPL parameters (0.97-0.98) were slightly higher than for inferior GCIPL parameters (0.94-0.97). All COVs were <5%, with 1.8% for average GCIPL and COVs for superior GCIPL parameters (2.2%-3.0%) slightly lower than those for inferior GCIPL parameters (2.5%-3.6%). The TRTSD was lowest for average GCIPL (1.16 μm) and varied from 1.43 to 2.15 μm for sectoral GCIPL CONCLUSIONS: The Cirrus HD-OCT GCA algorithm can successfully segment macular GCIPL and measure GCIPL thickness with excellent intervisit reproducibility. Longitudinal monitoring of GCIPL thickness may be possible with Cirrus HD-OCT for assessing glaucoma progression.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Funding acquisitionRole: MethodologyRole: Writing – review & editing
                Role: MethodologyRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: Writing – review & editing
                Role: MethodologyRole: Writing – review & editing
                Role: MethodologyRole: Writing – review & editing
                Role: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                29 May 2020
                2020
                : 15
                : 5
                : e0232785
                Affiliations
                [1 ] Doheny Eye Institute, Los Angeles, CA, United States of America
                [2 ] Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America
                [3 ] Department of Medicine, Ophthalmology, University of Udine, Udine, Italy
                [4 ] Department of Clinical Sciences and Community Health, Ophthalmological Unit, IRCCS-Cà Granda Foundation—Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
                [5 ] Department of Ophthalmology, University of Ottawa, Ottawa, Ontario, Canada
                [6 ] Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
                [7 ] Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States of America
                [8 ] Department of Neurology, University of Southern California, Los Angeles, CA, United States of America
                [9 ] Cipher Biostatistics & Reporting, Reno, NV, United States of America
                [10 ] Huntington Medical Research Institutes, Pasadena, CA, United States of America
                University of Florida, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                ‡ These authors are joint senior authors on this work.

                Author information
                http://orcid.org/0000-0002-7923-8032
                Article
                PONE-D-20-02170
                10.1371/journal.pone.0232785
                7259639
                32469871
                245a9122-982c-46e1-816e-c1b8cfabc6d5
                © 2020 Asanad 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
                : 23 January 2020
                : 21 April 2020
                Page count
                Figures: 2, Tables: 2, Pages: 13
                Funding
                This study was funded by the Brain Aging Study from the L.K. Whittier Foundation (to MGH), National Institute of Aging P01 AG052350 (to BVZ) and National Institute of Aging P50 AG005142 (to HCC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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