In this study, we assessed retinal (layer) thickness measured with OCT as a non-invasive biomarker for neurodegeneration in PCA and tAD compared to control participants. To our knowledge, we are the first to report retinal thickness in PCA cases, the most common atypical phenotype of AD preferentially affecting parietal-occipital cortices involved in visual processing [10]. In contrast to earlier studies in AD, we found no evidence of overall differences in retinal thickness between controls and either patient group. Our findings thus strongly question the utility of cross-sectional retinal thickness measurements with OCT as a diagnostic biomarker of AD.
This sample represents one of the largest, well-characterized samples of both PCA and tAD that includes OCT imaging. As PCA primarily affects cortices involved in visual processing, this cohort is well positioned to test the hypothesis of retrograde atrophy originating from visual cortices. In addition to fulfilling clinical criteria, we performed additional analysis on patients with quantified neurodegeneration and patients with a CSF profile consistent with AD, to provide insight regarding effect sizes of retinal versus established biomarkers. Consistent with our findings in the overall cohort, our subgroup analysis showed that despite unequivocal neurodegeneration on MRI and amyloid positivity based on CSF, retinal (layer) thinning was not observed in tAD and PCA.
There are a number of considerations for the interpretation of results from the current study, as they were inconsistent with earlier studies showing retinal (layer) thinning in AD [3]. In the current cohort, both tAD and PCA patients were relatively young (mean age 65 years), as compared to previous studies (mean age 74 years) [3]. Despite similar underlying proteinopathies (β-amyloid, tau), clinico-radiological differences exist between patients with early and late onset AD (EOAD, LOAD) [28]. For example, atypical presentations are more common in EOAD (33% vs. 6%) and cortical atrophy patterns differ [28,29,30]. We previously found that retinal thickness did not discriminate EOAD from controls in a well-characterized sample from an independent center [31], consistent with other studies involving EOAD cases [32]. While it is possible that the retina is less affected in EOAD, differences between EOAD and LOAD could also be interpreted as an age effect or a synergistic effect between AD and age in LOAD cases. The current unique cohort enabled assessment of cases with AD pathology with minimal contribution of ageing and age-related comorbidities such as AMD and glaucoma [33]. Indeed, findings include robust associations between age and retinal measures rather than between AD and retinal measures. However, differentiating age from disease effects ultimately requires future studies directly comparing EOAD and LOAD.
Previous study samples have tended to comprise patients at more advanced stages of AD relative to the current sample, based on general measures of disease severity (MMSE score). Retinal thinning may occur late in the disease course, following cortical atrophy. In the current cohort, reliable discrimination of patient from control participants based on MMSE scores, structural neuro-imaging and CSF biomarkers queries the additive diagnostic value of cross-sectional OCT measurements in the clinic in the early to moderate stage of dementia.
The current study used the Optos OCT/SLO device. Direct comparison of different OCT devices is challenging, due to differences in scan area, axial resolution, imaging protocols, and segmentation methods between devices [34]. As our device is a SD-OCT scanner with similar resolution and acquisition times as previously reported OCT scanners, we do not expect this to have influenced results. In addition, as both patients and a large control sample were scanned with the same device, the current lack of evidence for between-group differences cannot be accounted for by discrepancies in measurements.
A limitation of our study is a relatively limited ophthalmological examination of participants, as no detailed eye examination was conducted, and therefore subtle, pre-clinical changes of glaucoma and diabetic retinopathy cannot completely be ruled out. OCT and fundus photographs from all our participants were, however, assessed for ophthalmological comorbidity by an independent ophthalmologist in order to establish any relevant pathology. Secondly, assessment of individual layer thickness of the macula could not be delineated with the OCT system used in this study, ruling out the possibility of establishing that different retinal layers changed in subtle ways without influencing total macular thickness. Future studies should assess the value of measuring individual macular layer thickness, including the RNFL. While representing a limitation of the current study, comparisons of individual or total macular layer thickness between amyloid proven EOAD, LOAD and control participants from the independent Amsterdam Dementia Cohort have not provided evidence of group differences [35]. Thirdly, MRI and CSF subgroup analyses were slightly underpowered to detect pairwise group differences, and conclusions from these analyses should be interpreted with caution. Fourthly, the focus of the current study was on relative biomarker differences in two patient groups compared to a control comparator group. However, particularly given the emergence of atrophy in healthy ageing, future studies might evaluate MRI and OCT measures over time, and study how these relate to purported biomarker group differences either cross-sectionally or longitudinally. Lastly, we did not systemically acquire information on vascular risk factors. As these may influence retinal thickness directly or through diabetes mellitus and hypertensive retinopathy, future studies should consider collecting these, thereby taking vascular risk factors into account as a possible confounder in the relationship between neurodegenerative disease and retinal thinning. Nevertheless, these limitations do not appear to be sufficient to challenge the lack of evidence of retinal (layer) thinning in AD and PCA participants in the presented study.
It is worth noting that retinal (layer) thickness is highly variable among the normal population [36]. Retinal (layer) thinning is a nonspecific finding and is affected by ageing [37], diabetes mellitus [38,39,40,41,42,43], AMD [44] and glaucoma [45], as well as in other neurodegenerative diseases such as Parkinson’s disease [46] and multiple sclerosis [47]. An additional, possibly small, disease effect from AD is therefore likely to be challenging to detect cross-sectionally. Longitudinal measurements might be more sensitive to detect such small disease effects and ‘normalize’ for interpersonal differences. In addition, future research should focus on molecular imaging of the retina in AD, such as tau, β-amyloid and neuro-inflammation. Molecular biomarkers could have a larger effect size and specificity like in CSF [48], and answer the need for therapeutic read-outs focused on pathological molecular pathways in AD. Presence of these molecular changes in the retina remains controversial, however, and needs confirmation in post-mortem cohorts [7, 49,50,51]. If proven unequivocally, emerging optical techniques such as fluorescent imaging [52], two-photon microscopy [53], (stimulated) Raman [54] and hyperspectral imaging [55] might be tools to image these molecular changes in the retina in vivo in the future.