Quantitative Assessment of the Retina Using OCT and Associations with Cognitive Function

doi:10.1016/j.ophtha.2019.05.021

Ophthalmology

Volume 127, Issue 1, January 2020, Pages 107-118

https://doi.org/10.1016/j.ophtha.2019.05.021 Get rights and content

Purpose

To determine the association of retinal thickness with cognitive function in Japanese persons.

Design

Cross-sectional, population-based survey.

Participants

A total of 1293 Japanese persons aged 65 to 86 years who resided in the Saku area in the Japan Public Health Center–Based Prospective Study participated in the eye and mental health screening.

Methods

Participants underwent comprehensive ophthalmic assessment, including fundus photography, measurement of intraocular pressure, and determination of refraction status. We assessed the thickness of the macular retinal nerve fiber layer (mRNFL), ganglion cell-inner plexiform layer (GC-IPL), and ganglion cell complex (GCC, which includes the retinal nerve fiber layer and GC-IPL), and the full thickness in the macula and peripapillary retinal nerve fiber layer (ppRNFL) using spectral-domain (SD) OCT. Cognitive tests consisted of the Mini-Mental State Examination, Wechsler Memory Scale Revised logical memory I/II subtest, clock drawing test, and Clinical Dementia Rating Scale. These were used to designate the participants in the following 3 groups: Normal, those with mild cognitive impairment (MCI), and those with dementia. Multivariable logistic regression models were used to analyze associations between retinal thickness and cognitive function after adjusting potential confounding factors.

Main Outcome Measures

Association of retinal thickness with cognitive function.

Results

Among the 1293 potential subjects, 114 were excluded for a diagnosis of depression, 64 were excluded for retinal disease, and 140 were excluded for scanning errors or suboptimal OCT images. The remaining 975 participants (mean age, 73.2 years) were included in this analysis. Significant differences were found in the 3 groups in all layers and GCC thickness, but not in ppRNFL thickness. After adjusting for age, sex, educational status, and refraction, full macular thickness and GCC thickness were inversely associated with the presence of dementia, but ppRNFL thickness was not. Furthermore, GC-IPL, GCC, and full macular thicknesses were all associated with the presence of dementia in the inferior sectors.

Conclusions

Macular thickness was associated with the presence of dementia, but ppRNFL was not. Our results suggest that OCT measurements of the macula could be superior to those of the ppRNFL in assessing neurodegenerative changes and a potentially useful diagnostic biomarker of cognitive function.

Section snippets

Study Population

This study was a cross-sectional population-based survey conducted in one of the Japan Public Health Center Study areas¹¹ (the Saku Public Health Center catchment area, Nagano Prefecture, Japan). The present study population comprised residents in the area, and there were 12 219 participants (6172 men, 6047 women) aged 40 to 59 years at the beginning of the study in 1990. We excluded those who moved out of the region, died, or did not respond to subsequent questionnaires. Therefore, 8827

Results

Among the 1293 potential subjects, 114 were excluded for a diagnosis of depression, 64 were excluded for retinal disease, and 140 were excluded for scanning errors or suboptimal OCT images. The remaining 975 participants (mean age, 73.2±5.5 years; 427 male [43.8%] and 548 female [56.2%]) were included in this analysis. Among them, 6 participants previously diagnosed as having dementia were included in this analysis; 5 were diagnosed with dementia, and 1 was diagnosed with MCI. Also,

Discussion

We found that GCC and macular thicknesses were associated with the presence of dementia, but ppRNFL thickness was not, in our sample. The presence of MCI was not associated with any OCT measurements. Although MCI is generally regarded as a preceding stage of dementia, it may include a wide range of spectrums. Furthermore, GC-IPL, GCC, and full macular thicknesses were all associated with the presence of dementia in the inferior sectors.

A postmortem study showed that RGC loss in the macula was

Acknowledgments

The authors acknowledge Yasuhiro Makihara and Yukiko Miyasaka, other psychiatrists, and medical staff for technical assistance, and thank all staff members in the Saku area for extensive efforts to conduct the survey.

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Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Mild cognitive impairment (MCI) is a critical transitional stage between normal cognition and dementia, for which early detection is crucial for timely intervention. Retinal imaging has been shown as a promising potential biomarker for MCI. This study aimed to develop a dual-stream attention neural network to classify individuals with MCI based on multi-modal retinal images. Our approach incorporated a cross-modality fusion technique, a variable scale dense residual model, and a multi-classifier mechanism within the dual-stream network. The model utilized a residual module to extract image features and employed a multi-level feature aggregation method to capture complex context information. Self-attention and cross-attention modules were utilized at each convolutional layer to fuse features from optical coherence tomography (OCT) and fundus modalities, resulting in multiple output losses. The neural network was applied to classify individuals with MCI, Alzheimer's disease, and control participants with normal cognition. Through fine-tuning the pre-trained model, we classified community-dwelling participants into two groups based on cognitive impairment test scores. To identify retinal imaging biomarkers associated with accurate prediction, we used the Gradient-weighted Class Activation Mapping technique. The proposed method achieved high precision rates of 84.96% and 80.90% in classifying MCI and positive test scores for cognitive impairment, respectively. Notably, changes in the optic nerve head on fundus photographs or OCT images among patients with MCI were not used to discriminate patients from the control group. These findings demonstrate the potential of our approach in identifying individuals with MCI and emphasize the significance of retinal imaging for early detection of cognitive impairment.
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With increasing age, structural changes occur in the eye and brain. Neuronal death, inflammation, vascular disruption, and microglial activation are among many of the pathological changes that can occur during ageing. Furthermore, ageing individuals are at increased risk of developing neurodegenerative diseases in these organs, including Alzheimer’s disease (AD), Parkinson’s disease (PD), glaucoma and age-related macular degeneration (AMD). Although these diseases pose a significant global public health burden, current treatment options focus on slowing disease progression and symptomatic control rather than targeting underlying causes. Interestingly, recent investigations have proposed an analogous aetiology between age-related diseases in the eye and brain, where a process of chronic low-grade inflammation is implicated. Studies have suggested that patients with AD or PD are also associated with an increased risk of AMD, glaucoma, and cataracts. Moreover, pathognomonic amyloid-β and α-synuclein aggregates, which accumulate in AD and PD, respectively, can be found in ocular parenchyma. In terms of a common molecular pathway that underpins these diseases, the nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) inflammasome is thought to play a vital role in the manifestation of all these diseases. This review summarises the current evidence regarding cellular and molecular changes in the brain and eye with age, similarities between ocular and cerebral age-related diseases, and the role of the NLRP3 inflammasome as a critical mediator of disease propagation in the eye and the brain during ageing.
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To assess the association of inner retinal thickness with prevalent dementia and regional brain atrophy in a general older population of Japanese.
Population-based, cross-sectional study.
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The thicknesses of the inner retinal layers, namely, the ganglion cell-inner plexiform layer (GC-IPL) and retinal nerve fiber layer (RNFL)—were measured by swept-source OCT (SS-OCT). The association of these retinal thicknesses with the risk of the presence of dementia was estimated using restricted cubic splines and logistic regression models. Regional brain volumes were estimated separately by applying 2 different methods: voxel-based morphometry (VBM) and analysis by FreeSurfer software. The associations of GC-IPL and RNFL thickness with each brain regional volume were analyzed using multiple regression analysis.
Prevalent dementia and regional brain atrophy.
Among the study participants, 61 participants (5.7%) were diagnosed with dementia. The likelihood of the presence of dementia significantly increased with lower GC-IPL thickness after adjusting for potential confounders (odds ratio, 1.62 [95% confidence interval, 1.30–2.01] per 1 standard deviation decrement in the GC-IPL thickness), but no significant association was observed with RNFL thickness. In the VBM analyses with the multivariable adjustment, lower GC-IPL thickness was significantly associated with lower volume of known brain regions related to cognitive functions (i.e., the hippocampus, amygdala, entorhinal area, and parahippocampal gyrus) and visual functions (i.e., the cuneus, lingual gyrus, and thalamus). Meanwhile, the volume of the thalamus significantly decreased with lower RNFL thickness, but none of the brain regions related to cognitive function exhibited a volume change in association with RNFL thickness. The sensitivity analysis using FreeSurfer analysis also showed that lower GC-IPL thickness was significantly associated with lower regional brain volume/intracranial volume of the hippocampus, amygdala, cuneus, lingual gyrus, and thalamus.
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The HDES 230 and the HKES31 used the RTVue OCT (Optovue, Inc). The JPHCES32 and NS 233 used the Nidek RS-3000 Advance OCT (NIDEK Co, Ltd). The UEMS34 used the Nidek RS-3000 OCT (NIDEK Co, Ltd).
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: See Commentary on page 119.

: Supplemental material available at www.aaojournal.org.

: Financial Disclosure(s): The author(s) have made the following disclosure(s): M.M.: Grants and personal fees – Daiichi Sankyo, Takeda Yakuhin, Tsumura; Personal fees – Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, Fuji Film RI Pharma, Janssen Pharmaceutical, Mochida Pharmaceutical, MSD, Nippon Chemipher, Novartis Pharma, Ono Yakuhin, Otsuka Pharmaceutical, Pfizer, Yoshitomi Yakuhin; Grants – Pfizer, Shionogi, Tanabe Mitsubishi, outside the submitted work.

: Supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan (KAKENHI, JP26460778 [to M.S.]). The cohort study was originally supported by the National Cancer Center Research and Development Fund.

: HUMAN SUBJECTS: Human subjects were included in this study. The human ethics committees at the National Cancer Center Japan and Keio University School of Medicine approved the study. All research adhered to the tenets of the Declaration of Helsinki. All participants provided informed consent.

: No animal subjects were used in this study.

: Author Contributions:

: Conception and design: Sasaki

: Data collection: Ito, Sasaki, Takahashi, Nozaki, Matsuguma, Motomura, Ui, Shikimoto, Yuki, Sawada, Mimura, Tsubota, Tsugane

: Analysis and interpretation: Sasaki, Mimura, Kawasaki, Tsubota

: Obtained funding: Sasaki

: Overall responsibility: Ito, Sasaki

^∗: Y.I. and M.S. contributed equally to this work as first authors.

View full text

Original ArticleQuantitative Assessment of the Retina Using OCT and Associations with Cognitive Function

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Section snippets

Study Population

Results

Discussion

Acknowledgments

Neurosci Lett

Prog Retin Eye Res

Clin Neurophysiol

Alzheimers Dement (Amst)

J Psychiatr Res

Neurobiol Aging

Brain Res

Alzheimers Dement (Amst)

Biochim Biophys Acta

J Neurol Sci

Epidemiology of Alzheimer disease

Nat Rev Neurol

Optical coherence tomography in Alzheimer’s disease and other neurodegenerative diseases

Front Neurol

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

J Neuroophthalmol

Time domain and spectral domain optical coherence tomography in multiple sclerosis: a comparative cross-sectional study

Mult Scler

Detection of macular ganglion cell loss in glaucoma by Fourier-domain optical coherence tomography

Ophthalmology

Retinal nerve fiber layer measures and cognitive function in the EPIC-Norfolk Cohort Study

Invest Ophthalmol Vis Sci

The JPHC study: design and some findings on the typical Japanese diet

Jpn J Clin Oncol

The APOSTEL recommendations for reporting quantitative optical coherence tomography studies

Neurology

The Wechsler Memory Scale-Revised: psychometric characteristics and clinical application

Neuropsychol Rev

Original Article
Quantitative Assessment of the Retina Using OCT and Associations with Cognitive Function