Differences in Age-related Retinal and Cortical Atrophy Rates in Multiple Sclerosis

Abstract

Background and Objectives:The timing of neurodegeneration in MS remains unclear. It is critical to understand the dynamics of neuroaxonal loss if we hope to prevent or forestall permanent disability in MS. We therefore used a deeply phenotyped longitudinal cohort to assess and compare rates of neurodegeneration in retina and brain throughout the MS disease course.Methods:We analyzed 597 MS patients who underwent longitudinal OCT imaging annually for 4.5±2.4 years and 432 patients who underwent longitudinal MRI scans for 10±3.4 yrs, quantifying macular ganglion-cell–inner plexiform layer (GCIPL) volume and cortical gray matter (CGM) volume. To evaluate the rate of loss, linear mixed-effects modeling with subject-specific intercepts and slopes were fitted using restricted maximum likelihood estimation. The association between the slope of decline in the anatomical structure and the age of entry in the cohort (categorized by the MRI cohort’s age quartiles) was assessed by linear regression models.Results:The rate of CGM volume loss declined with increasing age of study entry (1.3%/year atrophy for the age of entry in the cohort <35 years; 1.1% for age >35 years and <41; 0.97% for age >41 years and <49; 0.9% for age >49 years) while the rate of GCIPL thinning was highest in patients in the youngest quartile, fell by more than 50% in the following age quartile, and then stabilized (0.7%/year thinning for the age of entry in the cohort <35 years; 0.29% for age >35 years and <41; 0.34% for age >41 years and <49; 0.33% for age >49 years).Conclusions:An age-dependent reduction in retinal and cortical volume loss rates during RRMS suggests deceleration in neurodegeneration in the earlier period of disease and further indicates that the period of greatest adaptive-immune-mediated inflammatory activity is also the period with the greatest neuroaxonal loss.

Synaptic injury in the inner plexiform layer of the retina is associated with progression in multiple sclerosis

“…In this study, we applied a translational approach to study the association between synaptic injury and progression in MS. First, we analyzed retinal signs of synaptic injury in an animal model of inflammatory demyelination and neurodegeneration (i.e., EAE), 23 finding evidence of synaptic loss within the IPL on the first day of symptoms and prior to worsening motor outcomes. To investigate the temporal relationship between synaptic loss and relentless MS disability, we then leveraged the University of California, San Francisco (UCSF) Expressions, Proteomics, Imaging, Clinical (EPIC) dataset that follows over 800 participants enrolled with more than 12 years of average follow-up with highly detailed assessments, including OCT. 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 We find that people with MS (PwMS) who develop SPMS show greater IPL loss using macular volume OCT as a sign of pronounced synaptic pathology. Our findings are supported by a proteome-wide analysis from MS patients enrolled in a randomized clinical trial that explored the pathophysiological mechanisms that might drive synaptic injury in PwMS.…”

“…When disease-modifying treatments were added to the analysis as a covariate, they were classified in tiers based on their efficacy, as already described. 29 All statistical analysis was performed using R version 3.6.3.…”

Deciphering multiple sclerosis disability with deep learning attention maps on clinical MRI

“…The importance of cortical GM for disease progression has been suggested in several studies, although the proposed underlying pathological mechanisms differ across studies. For instance, loss of cortical GM volume ( Cordano et al, 2022 ), microstructural cortical damage, reflected by increased total sodium concentration ( Collorone et al, 2021 ), or grey matter demyelination ( Gilmore et al, 2009 ), including the presence of visible lesions in the cortex ( Madsen et al, 2022 ), may all contribute to the accumulation of disability. Furthermore, the loss of the physiological balance between the cortical thickness of different areas has also been proposed as a process potentially leading to clinical dysfunction in MS ( Tur et al, 2018a , Tur et al, 2019 ).…”

Preventing Neurodegeneration in Multiple Sclerosis Is Required From the Earliest Stages of the Disease

“…In this issue of Neurology ®, the authors 9 provide robust evidence that cortical and retinal atrophy is more prominent in younger than older patients with MS, reinforcing the concept that neurodegeneration is an early phenomenon in the disease. They analyzed the Expression, Proteomics, Imaging, Clinical cohort from the University of California, San Francisco, including 597 people with MS with 5 years of optical coherence tomography (OCT) longitudinal assessments and 423 participants with 10 years of brain MRI follow-up.…”