Retinal thickness as potential biomarker in posterior cortical atrophy and typical Alzheimer’s disease

Abstract

Background Retinal thickness can be measured non-invasively with optical coherence tomography (OCT) and may offer compelling potential as a biomarker for Alzheimer’s disease (AD). Retinal thinning is hypothesized to be a result of retrograde atrophy and/or parallel neurodegenerative processes. Changes in the visual pathway are of particular interest in posterior cortical atrophy (PCA), the most common atypical AD phenotype predominantly affecting the parietal-occipital cortices. We therefore evaluated retinal thickness as non-invasive biomarker of neurodegeneration in well-characterized participants with posterior cortical atrophy (PCA) and typical Alzheimer’s disease (tAD). Methods Retinal thickness measures were acquired from 48 patient participants ( N = 25 PCA; N = 23 tAD) fulfilling consensus diagnostic criteria and 70 age-matched controls. Participants were recruited between 2014 and 2016. All participants underwent optical coherence tomography (OCT) imaging, including measurement of peripapillary retinal nerve fiber layer (pRNFL) thickness and total macular thickness (mRT). Participants did not show evidence of any significant ophthalmological conditions. Subgroup analyses were performed in participants with available MRI and CSF measures, providing evidence of neurodegeneration and underlying AD pathology respectively. Results There was no evidence of overall between-group differences in pRNFL thickness (mean PCA 98.7 ± 12.2; tAD 99.9 ± 8.7; controls 99.6 ± 10.0 μm, one-way analysis of variance (ANOVA) p = 0.92) or total mRT (mean PCA 266.9 ± 16.3; tAD 267.8 ± 13.6; controls 269.3 ± 13.6 μm, one-way ANOVA p = 0.75). Similarly, subgroup analysis with MRI biomarkers (PCA = 18, tAD = 17, controls = 31) showing neurodegeneration, and CSF biomarkers (PCA = 18, tAD = 14, controls = 13) supporting underlying AD pathology did not provide evidence of overall between-group differences in pRNFL or mRT measures (all p > 0.3). Conclusions Retinal thickness did not discriminate tAD and PCA from controls or from one another despite unequivocal differences on standard clinical, neuro-imaging and CSF measures. Findings from this well-characterized sample, including cases with PCA, do not support the hypothesis that retinal neurodegeneration, measured using conventional OCT, is a useful biomarker for AD or PCA.

Optical Coherence Tomography in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis

“…It is important to remember that MCI is a clinical construct that indicates a mildly abnormal cognitive profile, and the MCI designation alone does indicate whether there is AD pathological burden (i.e., amyloid (A), tau (T), or neurodegeneration (N). Given that recently published data from well-characterized cohorts that included amyloid biomarkers have not consistently shown differences in retinal OCT thickness measures between controls and AD, it is imperative that future studies use AD biomarkers, specifically A/T/N markers, to characterize participants ( 47 , 48 ). It is understood that amyloid accumulation in Alzheimer's disease precedes the onset of cognitive impairment by 15–20 years, and there is evidence that clinical signs and symptoms of cognitive impairment are driven by tau and brain atrophy (i.e., neurodegeneration) and not amyloid alone.…”

Rhodopsin: A Potential Biomarker for Neurodegenerative Diseases

“…In recent years, retinal thinning has become heavily associated with neurodegenerative diseases of the brain (Helmer et al, 2013;Sivak, 2013). There have been correlations established between retinal thinning and Alzheimer's disease (Chiquita et al, 2019;Cipollini et al, 2019;den Haan et al, 2019), Parkinson's disease (Ahn et al, 2018;Satue et al, 2018), Huntington's disease (Dhalla et al, 2019), Amyotrophic lateral sclerosis (Hubers et al, 2016;Mukherjee et al, 2017), and a case has been reported of reduced retinal thickness after an occipital lobe infarction (Tanito and Ohira, 2013). Given this, it is important that we consider exploring biomarkers of the retina as possible routes of monitoring and diagnosing these debilitating neurodegenerative diseases.…”

“…Should screening become possible at earlier stages, clinicians can better intervene in the progression of these diseases. Retinal alterations have recently been associated with numerous neurodegenerative diseases (Helmer et al, 2013;Sivak, 2013;Tanito and Ohira, 2013;Hubers et al, 2016;Mukherjee et al, 2017;Sudharsan et al, 2017;Ahn et al, 2018;Satue et al, 2018;Chiquita et al, 2019;Cipollini et al, 2019;den Haan et al, 2019;Dhalla et al, 2019). Rhodopsin, a G-protein coupled receptor in the rod cells of the retina is a biomarker associated with retinal thinning and degeneration (Cideciyan et al, 2005;Xiong and Bellen, 2013), suggesting its potential in the early detection and progression monitoring of neurodegenerative diseases.…”

Afferent and Efferent Visual Markers of Alzheimer’s Disease: A Review and Update in Early Stage Disease

“…Despite the presence of negative studies (Pillai et al, 2016 ; Poroy and Yucel, 2018 ; Sánchez et al, 2018 , 2020 ; den Haan et al, 2019 ), there is compelling evidence that significant retinal thinning occurs in AD dementia. AD patients are found to have significant thinning in the peripapillary retinal nerve fiber layer and macular sections containing ganglion cells such as the ganglion cell-inner plexiform layer, ganglion cell layer, and ganglion cell complex (Bambo et al, 2015 ; Cunha et al, 2016 ; Garcia-Martin et al, 2016 ; Ferrari et al, 2017 ; Kim and Kang, 2019 ).…”

“…Although the timeline of these changes is unclear, the proposed dynamic nature of the retina may partially explain negative OCT studies, which examine retinal thickness across pre-set areas. Negative studies may also be explained by non-psychometrically characterized controls (Poroy and Yucel, 2018 ; den Haan et al, 2019 ), comparatively younger AD cohorts in the context of no retinal differences in early-onset AD (Pillai et al, 2016 ; Haan et al, 2019a ), and use of different OCT devices (Poroy and Yucel, 2018 ; Sánchez et al, 2018 , 2020 ).…”