Retinal Neurodegeneration Measured With Optical Coherence Tomography and Neuroimaging in Alzheimer Disease: A Systematic Review

Optical coherence tomography (OCT) has enabled several retinal alterations to be detected in patients with Alzheimer disease (AD), alterations that could be potential biomarkers. However, the relationship between the retina and other biomarkers of AD has been underresearched. We gathered and analyzed the literature about the relationship between retinal and cerebral alterations detected via neuroimaging in patients with AD, mild cognitive impairment (MCI), and preclinical AD.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Retinal Neurodegeneration Measured With Optical Coherence Tomography and Neuroimaging in Alzheimer Disease: A Systematic Review Lina Carazo-Barrios, MD, Andrés Cabrera-Maestre, MD, Carmen Alba-Linero, MD, PhD, Mario Gutiérrez-Bedmar, MD, PhD, Francisco J. Garzón-Maldonado, MD, PhD, Vicente Serrano, MD, Carlos de la Cruz-Cosme, MD, PhD, Natalia García-Casares, MD, PhD Background: Optical coherence tomography (OCT) has enabled several retinal alterations to be detected in patients with Alzheimer disease (AD), alterations that could be potential biomarkers. However, the relationship between the retina and other biomarkers of AD has been underresearched. We gathered and analyzed the literature about the relationship between retinal and cerebral alterations detected via neuroimaging in patients with AD, mild cognitive impairment (MCI), and preclinical AD. Methods: This systematic review followed the PRISMA Statement guidelines through the 27 items on its checklist. We searched in PubMed, BVS, Scopus, and the Cochrane Library, using the keywords: Alzheimer’s disease, optical coherence tomography, white matter, cortex, atrophy, cortical thickness, neuroimaging, magnetic resonance imaging, and positron emission tomography. We included articles that studied the retina in relation to neuroimaging in patients with AD, MCI, and preclinical AD. We excluded studies without OCT, without neuroimaging, clinical cases, opinion articles, systematic reviews, and animal studies. Results: Of a total of 35 articles found, 23 were finally included. Although mixed results were found, most of these corroborate the relationship between retinal and brain disorders. Conclusions: More rigorous research is needed in the field, including homogenized, longitudinal, and prolonged followup studies, as well as studies that include all stages of AD. This will enable better understanding of the retina and its Departamento de Neurología (LC-B, FJG-M, VS, CdlC-C), Hospital Universitario Virgen de la Victoria de Málaga, Málaga, Spain; Facultad de Medicina (AC-M, CA-L, MG-B, NG-C), Universidad de Málaga, Málaga, Spain; Departamento de Oftalmología (CA-L), Hospital Universitario Virgen de la Victoria de Málaga, Málaga, Spain; Unidad de Neurologia Clinica (NG-C), Centro de Investigaciones Médico-Sanitarias (C.I.M.E.S), Malaga, Spain; and Instituto de Investigación Biomédica de Málaga (I.B.I.M.A) (CA-L, MG-B, FJG-M, CdlC-C, NG-C), Málaga, Spain. The authors report no conflicts of interest. Address correspondence to Natalia García-Casares, MD, PhD, Departamento de Medicina, Facultad de Medicina, Universidad de Málaga, Boulevard Louis Pasteur 32, C.P 29071 Málaga, Spain; E-mail: [e-mail] 116 implications in AD, leading to the discovery of retinal biomarkers that reflect brain alterations in AD patients in an accessible and noninvasive manner. Journal of Neuro-Ophthalmology 2023;43:116–125 doi: 10.1097/WNO.0000000000001673 © 2022 by North American Neuro-Ophthalmology Society A lzheimer disease (AD) is the most frequent cause of dementia (1). The disease has different stages (2), presenting an accumulation of beta-amyloid (Ab) and neurofibrillary tangles of hyperphosphorylated tau protein (pTau) (3– 6). Brain alterations have been found on neuroimaging with MRI and positron emission tomography (PET), as well as changes in the cerebrospinal fluid (CSF) (5,7,8), changes that are believed to begin 15–20 years before the onset of clinical symptoms of dementia (9–11). These biomarkers should allow new treatment strategies to be implemented in early stages of the disease before the damage becomes irreversible (10,12,13). The retina and optic nerve form part of the central nervous system. These structures migrate from the diencephalon during embryonic development, sharing structural and physiological similarities. Thus, the retina can be considered “a window through the brain” (14). Patients with AD can suffer from visual deterioration early in the disease, involving decreased visual acuity, abnormal pupillary reaction, or color perception impairment (12,15). Accordingly, retinal examination using optical coherence tomography (OCT) has been proposed to investigate changes associated with AD (16). Although a few retinal changes have been suggested in the literature, no consensus has yet been reached. Several meta-analyses (14,17,18) have suggested that OCT can be used to see retinal parameters, like macular volume/thickness, and the peripapillary retinal nerve fiber Carazo-Barrios et al: J Neuro-Ophthalmol 2023; 43: 116-125 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution layer (RNFL) thickness is reduced in patients with AD and mild cognitive impairment (MCI), including preclinical AD (19). Other authors, however, did not find these results (20,21). Vascular retinal alterations have also been described in patients with AD, both in central retinal vessels and in choroidal vessels (22). Capillary density (23,24), blood flow (25,26), and vessel oxygen saturation (26) are reduced in patients with AD, whereas the foveal avascular zone is enlarged (24). Several studies have also reported a reduction in choroidal thickness (17,24,27–29). Retinal neurovascular coupling shows an inverse correlation with Ab in CSF (30). Likewise, electroneurophysiological alterations measured with electroretinography (ERG) and visual evoked potentials (VEP) have been observed in patients with AD (31). However, limited evidence exists concerning the relationship between the retinal structure measured with OCT and neuroimaging in AD patients through the different stages of the disease (12). We aim to review this retina–brain relationship through the stages of AD and examine whether these retinal changes could potentially be used as biomarkers for AD. METHODS This systematic review was in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Declaration (32). We consulted PubMed, BVS, Scopus, and The Cochrane Library. The descriptors were Alzheimer’s disease, optical coherence tomography, white matter, cortex, atrophy, cortical thickness, neuroimaging, MRI, PET, and the Boolean operators AND and OR. The search included observational studies, in English and Spanish, with no defined date limitation. Three authors performed the search independently, reading the titles and the abstracts to discard those that did not meet the inclusion criteria, and the articles selected were then evaluated through a full-text reading. The articles finally selected were examined for a consensus. The inclusion criteria were studies researching retinal changes occurring in patients with AD through different stages of the disease related to neuroimaging findings with techniques such as MRI or PET. The exclusion criteria were single case studies, opinion articles, reviews, studies in animal models, low-quality studies, and those in a language other than Spanish or English. Studies that did not contain references to neuroimaging tests or OCT were discarded as well as those studies that, despite belonging to a similar subject, were performed on a population sample with normal cognitive status. After a thorough reading process, 23 of the 35 articles initially eligible were finally selected, as shown in the flowchart (Fig. 1). RESULTS Table 1 shows the 23 articles included. Of the 23 studies, 20 were cross sectional, and the other 3 were longitudinal Carazo-Barrios et al: J Neuro-Ophthalmol 2023; 43: 116-125 (13,15,33). The sample size was highly variable, ranging from 16 to 197 subjects. The ages ranged from 62 to 80 years. Correlation Between Ophthalmological Variables and Neuroimaging in Patients With Established Alzheimer Disease and Mild Cognitive Impairment The studies in this section presented samples of patients with AD, patients with other conditions like MCI, and a control group. Among these studies, some presented only MRI images, others used PET, or a combination of tests. OCT was the main test used to study the relationship with retinal structural alterations, but other ophthalmological variables were studied using angiographic OCT, fundus autofluorescence (FAF), VEP, or ERG. The relationship between the volume of different brain areas and retinal structural abnormalities was demonstrated by studies using MRI as the main neuroimaging test, described below. The parietal region was studied by Den Haan et al (34), finding a relationship between macular thickness and parietal atrophy as well as global cortical atrophy. In another study, Den Haan et al (35) found no differences in RNFL thickness and macular thickness when comparing patients with AD and patients with posterior cortical atrophy (PCA). Another study (36) showed an inverse correlation between venular tortuosity of the macula and white matter (WM) hyperintensities according to the Fazekas scale, although retinal vascular parameters did not discriminate between patients with AD and patients with a normal cognitive status. Total brain volume (TBV) was studied by Uchida et al (37), who found a correlation between TBV and photoreceptor outer segment volume. Zhao et al (38) found a similar relationship between perifoveal retinal thickness and TBV in patients with AD and MCI, as well as with the entorhinal cortex and hippocampus. The same authors found a relationship between hippocampal volume and macular RNFL thickness and P100 amplitude measured by VEP (39). Carazo-Barrios et al (12) showed a relationship between macular RNFL thickness and WM hyperintensities in the occipital region. Jorge et al (3) used MRI and PET with [11C]-Pittsburgh Compound B (PiB) tracer and found a correlation between the retinal inner plexiform layer and primary visual cortex (V1), which also showed greater Ab deposition. Finally, Alves et al (40) used diffusion tensor imaging (DTI) and described a relationship between visual tracts and the retina. Zhou et al (7) used DTI and found that the macular ganglion cell–inner plexiform layer (GC-IPL) was associated with a lower grey matter volume (GMV) as well as WM microstructure disruption. Using OCT angiography (OCT-A), Yoon et al (5) noted that brain ventricular volume was reduced in relation to 117 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Flowchart of the search strategy. retinal vascular parameters in patients with AD and MCI. Another study, also using OCT-A (41), found that retinal vascular pulsatility alterations were correlated with the cortical burden of Ab measured using PET. A few studies used various imaging techniques. Lee et al (41) measured brain cortical thickness and Ab deposition but did not find any relationship with retinal parameters. On the other hand, López-de-Eguileta et al (4) used PET to demonstrate macular and choroidal (10) thinning related to the positivity of PiB in patients with AD and MCI. Correlation Between Ophthalmological Variables and Neuroimaging in Patients With Preclinical Alzheimer Disease We analyzed 8 studies that examined a sample of participants with a healthy cognitive status but with risk factors for cognitive impairment, such as having first-degree relatives 118 suffering from AD, the presence of subjective cognitive complaints, or the presence of Ab in CSF or on PET using various radiotracers. Three of the studies are longitudinal and report a relationship between Ab brain deposition and different retinal structural alterations, like RNFL thinning (15), increased macular inner ring thickness (13), or a less significant reduction of this macular region (33) after a follow-up time of 27, 24, and 22 months, respectively. Van de Kreeke et al (42) presented 2 cross-sectional studies, in which the authors report a relationship between Ab deposition measured with PET and macular inner ring thickness or vascular density (43). This nonrelevant association between macular vascular density and Ab deposits in PET had already been described in a previous study (44). This study by O’Bryhim did, however, find an increase in foveal avascular zone thickness and a thinning of inner Carazo-Barrios et al: J Neuro-Ophthalmol 2023; 43: 116-125 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Carazo-Barrios et al: J Neuro-Ophthalmol 2023; 43: 116-125 Study Year/ Research Design Participants (n) Neuroimaging Test and Variables OphthalmoLogic Test Cognitive Tests Biomarkers Blood/CSF Ab+ (75.2) Ab2 (68.4) CDR No PET: [11C]-PiB MRI SS-OCT F-ERG MMSE CDT TMT HAM-D HAM-A No MRI 1.5T SD-OCT MMSE MoCA ADAS-cog SDS SAS ApoE 4 MRI 3T SD-OCT VEP F-ERG Preclinical AD Monozygotic twins (n = 145) (68.6) Ab+ (n = 16) vs Ab- (n = 129) MMSE No PET: SD-OCT Van de Kreeke et al Preclinical AD Monozygotic twins (44) (n = 124) (68.5) 2020 Cross sectional Ab+ (n = 13) vs Ab2 (n = 111) MMSE Preclinical AD Monozygotic twins (n = 165) (69.5) Ab+ (n = 18) vs Ab2 (n = 147) MMSE Byun et al (46) 2021 Cognitively Cross sectional normal n = 49 Ab+ = 16 Ab2 = 33 Carazo-Barrios et al (12) 2021 Cross sectional n = 32 AD (73.3) AD (n = 9) vs MCI (76.3) MCI (n = 9) vs CG (63.3) CG (n = 14) AD (70.2) Zhao et al (39) 2021 n = 59 Cross sectional AD (n = 17) vs MCI (68.4) MCI (n = 23) NC (66.6) vs CG (n = 19) Van de Kreekeet al (43) 2019Cross sectional 18F-flutemeta- mol No PET: OCT-A 18F-flutemeta- mol No PET: 18F-flutemetamol SD-OCT Ophthalmologic Variables Results Ab+ participants showed reduced inner nasal Total mRT and mRT layers macular thickness (P = 0.007) and RNFL GC-IPL thickness thickness (inferior quadrant, P = 0.003). pRNFL thickness Prolonged implicit time in F-ERG of Ab+ Functional parameters: participants (P = 0.002). Implicit time and F1 amplitude AD-related neurodegeneration related to thickness of GC-IPL (R = 0.41; P = 0.005) RNFL Linear tendency towards RNFL thinning (superior and temporal quadrants) related to worsening of cognitive impairment. Correlation between RNFL thinning (temporal quadrant left eye) and increase of WM hyperintensities (occipital lobe) (R = –0.58; P = 0.038). AD and MCI groups showed decreased P100 mRNFL amplitude (VEP) and delayed latency Visual pathways and (F-ERG) compared to the CG. photoreceptors amplitudes OCT revealed thinning of mRNFL in patients and latencies. with AD and MCI compared to the CG. Both mRNFL (R = 0.53; P , 0.001) and P100 amplitude (R = 0.37; P = 0.003) were related to a reduction of hippocampal volume in patients with AD and MCI. Total mRT and mRT layers At the start of the follow-up period and after 22 pRNFL months, no differences were found between the retina of both study groups. Participants with a high Ab burden at onset experienced a smaller reduction of inner ring IPL thickness (R = 0.26; P = 0.003) during follow-up period. Vascular Density Higher vascular density in Ab+ group compared FAZ to Ab-, but no differences in FAZ. Positive association between Ab deposits and inner ring macular vascular density (R = 0.51; P = 0.016); non-significant after due corrections. Total mRT and mRT layers No differences found in the retinas of Ab+ and pRNFL Ab- participants. Positive association between Ab burden and inner ring mRT (R = 0.92; P = 0.018), non-significant after due corrections. Conclusions Cognitively normal adults with cerebral Ab deposition have structural and functional retinal changes. Retinal biomarkers may be used as a screening tool for early detection of AD. WM hyperintensities in the visual cortex could provoke retrograde neuronal degeneration reflected in RNFL thickness, in patients with AD and MCI. mRNFL and P100 amplitude are related to the hippocampus, a structure particularly vulnerable to AD related changes. IPL changes could open future paths of research in preclinical AD. Retinal vascular density could be used as a biomarker for preclinical AD, but further research is needed. Retinal thickness is unable to discriminate between preclinical AD and healthy patients. Original Contribution Study Groups (Age) Van de Kreeke et al (33) 2020 Longitudinal (22 months) 119 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. General characteristics of the articles included in this review Participants (n) Study Groups (Age) Cognitive Tests Biomarkers Blood/CSF Neuroimaging Test and Variables OphthalmoLogic Test Ophthalmologic Variables Uchida et al (37) 2020 Cross sectional AD (64.7) n = 64 AD (n = 14) vs PD (62.9) PD (n = 19) vs CG (65.1) CG (n = 31) MocA WMS-IV HVLT-R No MRI 3T SD-OCT Total mRT and mRT layers Jorge et al (3) 2020 Cross sectional n = 37 AD (65.3) AD (n = 20) vs CG (66.3) CG (n = 17) MMSE MoCA CDR MRI 3T PET: [11C]-PiB [11C]PK11195 SD-OCT Total mRT and mRT layers López-de-Eguileta et al (10) 2020 Cross sectional n = 126 AD (n = 12) vs MCI (n = 51) vs CG (n = 63) n = 126 AD (n = 12) vs MCI (n = 51) vs CG (n = 63) n = 60 AD (n = 28) vs SVCI (n = 18) vs CG (n = 14) PET/CT: [11C]-PiB EDI-OCT Choroidal thickness López-de-Eguileta et al (4) 2019 Cross sectional Lee et al (42) 2020 Cross sectional Carazo-Barrios et al: J Neuro-Ophthalmol 2023; 43: 116-125 Marquié et al (13) 2020 Longitudinal (24 months) Results Conclusions TBV and hippocampal volume were reduced in External retinal layers could reflect a brain volume biomarker, both in AD patients compared to PD and CG. healthy patients and in A positive association between TBV and neurodegenerative diseases. external retinal segment volume (EZ-RPE) was found in the 3 study groups: AD (R = 0.53; P = 0.05), PD (R = 0.48; P = 0.04) and CG (R = 0.51; P,0.01). Patients with AD show a higher Ab burden in This retina–brain interaction could reflect retinal changes (IPL) V1 (measured with PiB-PET), without resulting from Ab deposit in V1, evidence of neuroinflammation (measured with PK11195-PET). contributing to early visual IPL was the only layer showing a positive deterioration in AD. correlation with V1 thickness (R = 0.60; P , 0.006) in AD patients. In different locations, the choroidal layer was Ab deposit, responsible for brain thinner (P = 0.020-0.045) in PiB+ patients angiopathy, could also cause (AD and MCI) when compared to CG. choroidal angiopathy and choroidal atrophy. AD (73.6) MCI (73.2) CG (73.3) No CSF: Ab1–40 Ab1–42 Ab42/ Ab40 pTau181 Ab42/pTau No AD and MCI (73.5) CG (73.3) No No PET/CT: [11C]-PiB SD-OCT Total mRT and mRT layers Retinal damage derived from Ab Macular RNFL (P,0.028; AUC = 0.652) and deposit can be detected in early GCC (P , 0.014; AUC = 0.699) were stages of AD. thinner in PiB+ patients (AD and MCI) when compared with healthy controls. AD (67.5) SVCI (77.0) CG (67.2) K-MMSE ApoE 4 OCT-A Peripapillary capillary density pRNFL MMSE ApoE4 MRI 3T PET: 18Fflorbetaben 18F-flutemeta mol PET: 18Fflorbetaben SD-OCT Total mRT and mRT layers pRNFL Retinal neurodegeneration (pRNFL) Peripapillary capillary density is reduced in does not reflect brain SVCI. No differences found in AD patients neurodegeneration. compared to CG. No association between pRNFL and cortical thickness or amyloid positivity was found in AD patients. After 24 months, 15 participants changed from Macular changes are present in preclinical AD, and can be SCI to MCI, but no retinal variables were detected using OCT and be found to be associated with the conversion. correlated to Ab burden. Ab+ participants showed thinner pRNFL at onset and at the end of the study, compared to Ab- participants. Inner nasal macular thickness increased in Ab+ group, and only this region was related to global Ab deposit, both at onset (OR = 1.08; P = 0.004) and after 24 months (OR = 1.06; P = 0.001). SCI (n = 129) Ab+ (64.2) Ab+ (n = 15) Ab2 (68.5) vs Ab- (n = 114) Original Contribution 120 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Study Year/ Research Design Carazo-Barrios et al: J Neuro-Ophthalmol 2023; 43: 116-125 Participants (n) Study Groups (Age) Biomarkers Blood/CSF ApoE 4 CSF: Ab1–42 Tau181 pTau pTau181/ Ab1-42 ratio CSF: Ab1–42 pTau181 pTau181/ Ab 1–42 ratio SD-OCT MRI PET: 18Fflorbetaben 18F-florbetapir 18Fflutemetamol [11C]-PiB MRI 3T SD-OCT Total mRT and mRT layers pRNFL Cortical thickness and macular Retinal thickness does not discriminate thickness are related (grey between AD and CG. matter), but cortical thickness is mRT was related to global cortical atrophy not related to pRNFL axons (white (P = 0.01) and parietal cortical atrophy matter). (P , 0.01) in the AD group. No relationship between pRNFL and cortical thickness was found. Total mRT pRNFL ApoE 4 CSF: Ab1–42 Tau181 pTau pTau181/ Ab1-42 ratio No OCT-A MRI EDI-OCT PET: 18Fflorbetaben 18F-florbetapir [11C]-PiB Vascular density FAZ Choroidal thickness Retinal thickness is not a reliable Retinal thickness (total mRT and pRNFL) cannot discriminate between CG and the biomarker for AD or PCA. rest. AD and PCA groups showed no relationship between retinal variables (mRT P = 0.75, pRNFL P = 0.92) and neuroimaging, despite individual differences. Retinal parameters could not No differences found in vascular density, discriminate AD from controls, but choroidal thickness or FAZ between groups. vascular density could reflect brain WM hyperintensities (Fazekas score) microvascular alterations. showed an inverse association with vascular density of macular outer ring (P,0.01; b = –0.64) and vein tortuosity (P,0.01; b = –0.56) MRI 3T SD-OCT OCT-A ApoE 4 CSF: Ab1–40 Ab1–42 Ab42/ Ab4o pTau181 No MRI 3T: DTI PET: [11C]-PiB SD-OCT RNFL GCC-IPL FAZ Vascular density and perfusion Total mRT and mRT layers MRI 3T SD-OCT AD (65.0) n = 142 AD (n = 57) vs CG (67.9) CG (n = 85) MMSE Den Haanet al (35) 2019 Cross sectional AD (64.5) n = 48 AD (n = 23) vs PCA (67.0) PCA (n = 25) CG (66.3) vs CG (n = 70) MMSE Den Haanet al (36) 2019 Cross sectional n = 86 AD (65.4) AD (n = 48) vs CG (60.6) CG (n = 38) MMSE Yoon et al (5) 2019 Cross sectional n = 16 AD (n = 9) vs MCI (n = 7) MMSE AD (75.2) MCI (70.7) Neuroimaging Test and Variables Cognitive Tests Den Haanet al (34) 2019 Cross sectional Alves et al (40) 2019 n = 40 AD (66.4) Cross sectional AD (n = 17) vs CG (63.4) CG (n = 23) MMSE MocA CDR Tao et al (38) 2019 Cross sectional AD (71.4) n = 197 AD (n = 73) vs MCI (71.7) MCI (n = 51) CG (68.9) vs CG (n = 67) MMSE O’Bryhim et al (45) 2018 Cross sectional Preclinical AD Ab+ (73.5) Ab2 (75.4) n = 30) Ab+ (n = 14) vs Ab- (n = 16) CDR CSF: Ab42 OphthalmoLogic Test PET: OCT-A [11C]-PiB 18F-florbetapir Ophthalmologic Variables Total mRT and mRT layers pRNFL Total mRT and mRT layers FAZ Vascular density Results Conclusions Retinal vascular parameters could A correlation was found between vascular reflect microvascular brain density (r = –0.56; P = 0.028) and vascular alterations and brain volume. perfusion (r = –0.60; P = 0.016) with an increment of ILV in MCI and AD patients. INL thickness could reflect visual Retinal layer thickness was similar in both pathway WM tracts dysfunction in study groups. patients with AD. A reduction in AD was found in AD patients (WM alterations due to axon loss). Positive correlation between FA of visual pathway tracts and INL in AD patients (R = 0.42; P , 0.05). Thinning of macular GCC and pRNFL in AD and Inner retinal layer thickness could be a potential biomarker for AD. MCI patients compared to CG. Correlation between retinal thickness and brain volume (P , 0.05). Association between inner perifoveal thickness and hippocampus (R = 0.43; P , 0.01) and entorhinal cortex volume (R = 0.64; P , 0.01). Microvascular alterations are present -No changes in vascular density. in early stages of AD. -Increased FAZ thickness (P = 0.002) and decrease of inner foveal thickness (P = 0.03) found in patients with positive biomarkers (PET/CSF). Original Contribution 121 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Study Year/ Research Design Participants (n) Study Groups (Age) Carazo-Barrios et al: J Neuro-Ophthalmol 2023; 43: 116-125 Santos et al (15) 2018 Longitudinal (27 months) Preclinical AD Ab+ (68.3) Ab2 (64.6) (n = 56) Ab+ (n = 15) vs Ab2 (n = 41) Golzan et al (41) 2017Cross sectional n = 101 AD (n = 28) vs Preclinical AD (n = 23) vs CG (n = 50) Snyder et al (16) 2016 Cross sectional Preclinical AD Ab+ (62.3) Ab2 (65.5) (n = 63) Ab+ (n = 10) vs Ab2 (n = 53) Liu et al (7) 2016 Cross sectional n = 180 AD (n = 47) vs CIND (n = 68) vs CG (n = 65) AD (70) Preclinical AD (80) CG (79) AD (75.2) CIND 69.7) CG (65) Neuroimaging Test and Variables Cognitive Tests Biomarkers Blood/CSF OphthalmoLogic Test MMSE MAC-Q GMLT ISLT ApoE 4 PET: SD-OCT 18F-florbetapir MAC-Q MoCA No MRI PET: 18Fflorbetaben MMSE MAC-Q GMLT ISLT DASS ApoE 4 PET: SD-OCT 18F-florbetapir FAF Total mRT and mRT layers pRNFL Retinal inclusion bodies MMSE CDR No MRI 3T: DTI VBM GCC-IPL SD-OCT OCT-A SD-OCT Ophthalmologic Variables Total mRT and mRT layers pRNFL GCC pRNFL Vascular parameters Results Conclusions No differences between groups were found at onset, but after a 27 month follow-up, a reduction in mRNFL, ONL and IPL was observed in Ab+ patients compared to Abpatients. After a 27 month follow up period, only mRNFL volume reduction showed a linear correlation with Ab deposit (P = 0.017), after age correction. AD patients showed a greater thinning of GCC, but no association with Ab deposit was found. Correlation between retinal vascular pulsatility amplitude and cortical Ab burden. Arterial amplitudes were increased (R = 0.33; P , 0.01) whereas venous amplitudes were reduced (R = 0.4; P,0.001). Increment of IPL volume in Ab+ patients, correlated to retinal inclusion bodies surface area. In Ab+ patients, retinal inclusion bodies surface area (identified using FAF) showed a correlation with Ab burden (P , 0.05). Decreased integrity of WM and GMV in CIND and AD compared to CG was found. A thinning of GCC-IPL was associated with decreased WM integrity and reduced GMV in different regions (P , 0.005). This association was only observed in CG and not in CIND and AD patients. mRNFL thinning is the earliest retinal alteration associated with AD, and is related to Ab burden. Correlation between retinal vascular alterations and Ab burden supports the possibility of an underlying vascular mechanism in AD. In early AD, IPL changes and their association with retinal inclusion bodies, could reflect neocortical amyloid deposit. Retina and normal brain degeneration could have a pathophysiological relationship in healthy aging. This relationship could be interrupted in AD. Ab, amyloid beta; PCA, posterior cortical atrophy; ADAS-cog, Alzheimer’s Disease Assessment Scale2014cognitive subscale; ApoE, Apolipoprotein E4; GCC, ganglion cell complex; CDR, clinical dementia rating; CDT, Clock-Drawing Test; RNFL, retinal nerve fiber layer; ONL, outer nuclear layer; INL, inner nuclear layer; IPL, inner plexiform layer; AD, axial diffusivity; DASS, depression anxiety stress scale; MCI, mild cognitive impairment; CIND, cognitive impairment without dementia; SCI, subjective cognitive impairment; SVCI, subcortical vascular cognitive impairment; AD, Alzheimer’s disease; EDI-OCT, enhanced depth imaging optical coherence tomography; AUC, area under the curve; PD, Parkinson’s Disease; FAF, fundus autofluorescence; FAZ, foveal avascular zone; FA, fractional anisotropy; F-ERG, flash electroretinography; CG, control group; GMLT, groton maze learning test; GMV, grey matter volume; HAM-A, hamilton anxiety rating scale; HAM-D, hamilton depression rating scale; HVLT-R, Hopkins Verbal Learning Test - Revised; ISLT, international shopping list task; DTI, diffusion tensor imaging; K-MMSE, MMSE korean version; CSF, cerebrospinal fluid; MAC-Q, memory complaints questionnaire; mRNFL, macular retinal nerve fiber layer; MMSE, Mini-Mental State Examination; MocA, montreal cognitive assessment; mRT, macular retinal thickness; OCT-A, optical coherence tomography angiography; pRNFL, peripapillary retinal nerve fiber layer; PET, positron emission tomography; VEP, visual evoked potentials; MRI, mRI; SAS, Zung Self-Rating Anxiety Scale; SDS, Zung Self-Rating Depression Scale; SD-OCT, spectral domain optical coherence tomography; SS-OCT, Swept-Source Optical Coherence Tomography; T, tesla; CT, computerized tomography; TMT, trail making test; VBM, Voxel-based morphometry; TBV, total brain volume; ILV, inferolateral ventricle; V1, primary visual cortex; WM, white matter; WMS-IV, Wechsler memory Scale fourth edition; EZ-RPE, Ellipsoid Zone - Retinal Pigment Epithelium; [11C]-PiB, Pittsburgh compound B (Carbon 11). Original Contribution 122 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Study Year/ Research Design Original Contribution foveal thickness in participants with positive biomarkers (PET/CSF). Additionally, Byun et al (45) demonstrated structural and functional retinal changes in cognitively normal adults. Finally, Snyder et al (16) used FAF to detect an increase in the surface area of retinal inclusion bodies as a function of Ab burden in participants with preclinical AD. DISCUSSION We analyzed studies that explored the relationship between the retinal structure and neuroimaging tests in patients with AD and MCI, plus preclinical AD. Most of the studies included corroborate the relationship. Although retinal changes related to brain Ab deposition have been documented using PET/CT (4), most of the studies used MRI. A relationship between the retinal structure and decreased brain volume has been reported for TBV (34,37,38) and the volume of particularly vulnerable regions, such as the hippocampus (38,39), entorhinal cortex (38), and parietal lobe (34). Regarding the relationship between the retina and brain visual pathways, an increment in WM hyperintensities has been reported in the occipital lobe (12), with a higher Ab burden in V1 (3) and on DTI (40). Using OCT, certain studies have found that retinal layers, such as the RNFL, ganglion cell layer (GCL), or inner plexiform layer (IPL), experience a reduction in their thickness in relation to a reduction in brain volume of certain areas, like the medial temporal lobe and occipital lobe (8,46) and the hippocampus (47). In addition, they found an association with the central cingulate cortex (48). The Rotterdam Study (49), and a more recent study using DTI (50), found an association between retinal layers and a reduction in GMV of the hypothalamus, occipital lobe, and thalamus, as well as a reduction in white matter volume of the optic radiations. The authors of a longitudinal trial (51) concluded that a thinner ganglion cell complex and IPL (GCCIPL) was associated with dementia, and a thinner RNFL at baseline was associated with an increased risk of developing dementia. Méndez-Gómez et al (52) found an association between an increased RNFL thickness and better MRI-DTI variables in regions pertaining to the visual pathways. OCT variants, like OCT-A or enhanced depth imaging OCT, have shown the relationship between retinal vascular alterations and the brain, either using MRI (5,36) or PET (10,53), in patients with AD, MCI, or preclinical AD (44). Other ophthalmological tests used to assess the retina–brain relationship are FAF (16), VEP, and ERG (39); even a computer-assisted analysis was able to relate retinal vascular parameters (54,55). Longitudinal trials using PET have demonstrated that the retinal structure is altered even in preclinical AD, and these alterations can be detected with OCT (13,15,33). Different mechanisms could explain the retina–brain relationship in AD. Ab and Tau deposition could affect Carazo-Barrios et al: J Neuro-Ophthalmol 2023; 43: 116-125 the visual pathway by causing retrograde neuronal degeneration of the optic nerve and deterioration of the retinal sublayers (17). Another mechanism may be a common Ab and fibrillar Tau deposition that could simultaneously affect the retina and the brain (49). However, it is unclear whether Ab is present in the retina of patients with AD (22), and the mechanisms are not fully understood. Other studies, however, found no significant results concerning the relationship between the retina and neuroimaging data, with some finding no relationship (35,37,41). Our systematic review has a few limitations. The discrepancies found may be due to non-homogeneous populations and the design of the study (56), the variability in neuroimaging tests used, the use of different radiotracers, or OCT variants, as well as the use of other ophthalmological tests. Further research is needed ensuring homogenized, longitudinal, follow-up studies, including all the stages of AD and combining different brain and ophthalmological tests (30,56,57). Conclusion This review studied the relationship between retinal structural changes and brain alterations in AD through its different stages. The majority of the studies included show results that support the relationship between retinal structural alterations measured using OCT and neuroimaging alterations through the different stages of AD. Thinning of RNFL or choroidal thickness are associated with a reduction in brain cortical volume, an increase in WM hyperintensities, and an increase in Ab deposition, among others. However, certain studies show conflicting results, and there are important discrepancies, such as lack of homogeneity of the studies, making it difficult to establish conclusive results. STATEMENT OF AUTHORSHIP Conception and design: N. García-Casares, C. Alba-Linero, C. de la Cruz Cosme; acquisition of data: L. Carazo-Barrios, A. CabreraMaestre, F. J. Garzón-Maldonado, V. Serrano; analysis and interpretation of data: N. García-Casares, F. J. Garzón-Maldonado, V. Serrano, M. Gutiérrez-Bedmar. drafting the manuscript: L. CarazoBarrios, A. Cabrera-Maestre, N. García-Casares; revising the manuscript for intellectual content: C. Alba-Linero, C. de la CruzCosme, N. García-Casares, M. Gutiérrez-Bedmar; final approval of the completed manuscript: all the authors have approved the final manuscript. REFERENCES 1. 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