Cognitive impairment in patients with multiple sclerosis is associated with atrophy of the inner retinal layers

Background: Inner retinal layer (IRL) atrophy is a potential biomarker for neurodegeneration in multiple sclerosis (MS). Objective: To investigate the relationship between cognitive impairment and IRL atrophy in MS. Methods: Cross-sectional study design, including 217 patients and 59 healthy controls. Subjects were investigated clinically, underwent retinal optical coherence tomography (OCT) and comprehensive cognitive assessments. The association between these modalities was evaluated by regression analyses. Results: Of the patients, 44.2% were cognitively impaired. In the absence of multiple sclerosis–associated optic neuritis (MSON), cognitively impaired patients had a significantly lower mean peripapillary retinal nerve fiber layer (pRNFL, Δ: 8.13 µm, p < 0.001) and mean macular ganglion cell–inner plexiform layer (mGCIPL, Δ: 11.50 µm, p < 0.001) thickness compared to cognitively preserved patients. There was a significant association between the presence of cognitive impairment and pRNFL (odds ratio (OR): 1.11, 95% confidence interval (CI): 1.04–1.18, p = 0.001) and mGCIPL (OR = 1.11, 95% CI = 1.05–1.18, p < 0.001) atrophy. This association was masked by the severe IRL atrophy seen following MSON. Conclusion: The strong relationship between cognitive impairment across multiple cognitive domains and atrophy of the pRNFL and mGCIPL in patients who never suffered from MSON suggests that OCT is useful in assessing central nervous system neurodegeneration in MS.

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Association of Retinal Layer Thickness With Cognition in Patients With Multiple Sclerosis

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000001018 ◽

2021 ◽

Vol 8 (4) ◽

pp. e1018

Author(s):

Sharon Jean Baetge ◽

Michael Dietrich ◽

Melanie Filser ◽

Alina Renner ◽

Nathalie Stute ◽

...

Keyword(s):

Multiple Sclerosis ◽

Layer Thickness ◽

Short Term Memory ◽

Cognitive Status ◽

Retinal Layer ◽

Inner Plexiform Layer ◽

Fiber Layer ◽

Related Factors ◽

Cross Sectional ◽

Potential Marker

ObjectiveRetinal layer thickness (RLT) measured by optical coherence tomography (OCT) is considered a noninvasive, cost-efficient marker of neurodegeneration in multiple sclerosis (MS). We aimed to investigate associations of RLT with cognitive performance and its potential as indicator of cognitive status in patients with MS by performing generalized estimating equation (GEE) analyses.MethodsIn this cross-sectional study, patients with at least mild signs of cognitive impairment were examined by OCT as well as by the Brief International Cognitive Assessment for MS and tests assessing attention and executive functions (Trail Making Test [TMT] A and B). Associations of these factors were investigated using GEE models controlling for demographic and disease-related factors and correcting for multiple testing.ResultsA total of 64 patients entered the study. In the final sample (n = 50 [n = 14 excluded due to missing data or drop-outs]; n = 44 relapsing-remitting MS and n = 6 secondary progressive MS, mean Expanded Disability Status Scale score = 2.59 [SD = 1.17], disease duration [median] = 7.34 [interquartile range = 12.1]), 36.0% were cognitively impaired. RLT of the macular retinal nerve fiber layer was associated with performance in TMT-B (β = −0.259). Analyses focusing on the upper and lower tertile of RLT additionally revealed associations between macular ganglion cell-inner plexiform layer and TMT-B and verbal short-term memory and learning, respectively.ConclusionIn patients with MS, at less advanced disease stages, RLT was especially associated with cognitive flexibility promoting OCT as a potential marker advocating further extensive neuropsychological examination.

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Ocular biomarkers for cognitive impairment in nonagenarians; a prospective cross-sectional study

10.21203/rs.2.10871/v1 ◽

2019 ◽

Author(s):

Jacoba Alida van de Kreeke ◽

Nienke Legdeur ◽

Maryam Badissi ◽

H. Ton Nguyen ◽

Elles Konijnenberg ◽

...

Keyword(s):

Cognitive Impairment ◽

Layer Thickness ◽

Cross Sectional Study ◽

Fundus Photography ◽

Cognitively Impaired ◽

Retinal Layer ◽

Sectional Study ◽

Fiber Layer ◽

Cross Sectional ◽

Nerve Fiber Layer Thickness

Abstract Background: Ocular imaging receives much attention as a source of potential biomarkers for dementia. In the present study, we analyze these ocular biomarkers in cognitively impaired and healthy participants in a population aged over 90 years (= nonagenarian), and elucidate the effects of age on these biomarkers. Methods: For this prospective cross-sectional study, we included individuals from the EMIF-AD 90+ study, consisting of a cognitively healthy (N=67) and cognitively impaired group (N=33), and the EMIF-AD PreclinAD study, consisting of cognitively healthy controls aged ≥60 (N=198). Participants underwent Optical Coherence Tomography (OCT) and fundus photography of both eyes. OCT was used to asses total and individual inner retinal layer thickness in the macular region (Early Treatment Diabetic Retinopathy Study circles) as well as peripapillary retinal nerve fiber layer thickness, fundus images were analyzed with Singapore I Vessel Assessment to obtain 7 retinal vascular parameters. Values for both eyes were averaged. Differences in ocular biomarkers between the 2 nonagenarian groups were analyzed using linear regression, differences between the individual nonagenarian groups and controls were analyzed using generalized estimating equations. Results: Ocular biomarkers did not differ between the healthy and cognitively impaired nonagenarian groups. Both nonagenarian groups differed in most ocular biomarkers from the younger controls. Conclusion: Ocular biomarkers were not associated with cognitive impairment in nonagenarians, making their use as a screening tool for dementing disorders in this group limited. However, ocular biomarkers were significantly associated with chronological age, which were very similar to those ascribed to occur in Alzheimer’s Disease.

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Ocular biomarkers for cognitive impairment in nonagenarians; a prospective cross-sectional study

10.21203/rs.2.10871/v2 ◽

2020 ◽

Author(s):

Jacoba Alida van de Kreeke ◽

Nienke Legdeur ◽

Maryam Badissi ◽

H. Ton Nguyen ◽

Elles Konijnenberg ◽

...

Keyword(s):

Cognitive Impairment ◽

Layer Thickness ◽

Cross Sectional Study ◽

Fundus Photography ◽

Cognitively Impaired ◽

Retinal Layer ◽

Sectional Study ◽

Fiber Layer ◽

Cross Sectional ◽

Nerve Fiber Layer Thickness

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Serum ceramide levels are altered in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458520971816 ◽

2020 ◽

pp. 135245852097181

Author(s):

Angeliki G Filippatou ◽

Mohammed Moniruzzaman ◽

Elias S Sotirchos ◽

Kathryn C Fitzgerald ◽

Grigorios Kalaitzidis ◽

...

Keyword(s):

Multiple Sclerosis ◽

Plexiform Layer ◽

Small Sample ◽

Sphingolipid Metabolism ◽

Retinal Layer ◽

Inner Plexiform Layer ◽

Fiber Layer ◽

Spectral Domain Oct ◽

Disability Status ◽

Small Sample Sizes

Background: Sphingolipids are myelin components and inflammatory signaling intermediates. Sphingolipid metabolism may be altered in people with multiple sclerosis (PwMS), but existing studies are limited by small sample sizes. Objectives: To compare the levels of serum ceramides between PwMS and healthy controls (HCs) and to determine whether ceramide levels correlate with disability status, as well as optical coherence tomography (OCT)-derived rates of retinal layer atrophy. Methods: We performed targeted lipidomics analyses for 45 ceramides in PwMS ( n = 251) and HCs ( n = 68). For a subset of PwMS, baseline and 5-year Expanded Disability Status Scale (EDSS) assessments ( n = 185), or baseline and serial spectral-domain OCT ( n = 180) were assessed. Results: Several ceramides, including hexosylceramides, lactosylceramides, and dihydroceramides, were altered in PwMS compared with HCs. Higher levels of Cer16:0 were associated with higher odds of EDSS worsening at 5 years in univariable (odds ratio (OR) = 3.84, 95% confidence interval (CI) = 1.41–10.43) and multivariable analyses accounting for age, sex, and race (OR = 2.97, 95% CI = 1.03–8.59). Each 1 ng/mL higher concentration of Hex-Cer22:0 and DH-HexCer22:0 was associated with accelerated rates (μm/year) of ganglion cell + inner plexiform layer (–0.138 ± 0.053, p = 0.01; –0.158 ± 0.053, p = 0.003, respectively) and peripapillary retinal nerve fiber layer thinning (–0.305 ± 0.107, p = 0.004; –0.358 ± 0.106, p = 0.001, respectively). Conclusion: Ceramide levels are altered in PwMS and may be associated with retinal neurodegeneration and physical disability.

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Tracking changes over time in retinal nerve fiber layer and ganglion cell-inner plexiform layer thickness in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458514523498 ◽

2014 ◽

Vol 20 (10) ◽

pp. 1331-1341 ◽

Cited By ~ 54

Author(s):

Divya Narayanan ◽

Han Cheng ◽

Karlie N Bonem ◽

Roberto Saenz ◽

Rosa A Tang ◽

...

Keyword(s):

Multiple Sclerosis ◽

Ganglion Cell ◽

Layer Thickness ◽

Plexiform Layer ◽

Inner Plexiform Layer ◽

Fiber Layer ◽

Cross Sectional ◽

Permanent Disability ◽

Progressive Neurodegeneration

Background: Neurodegeneration plays an important role in permanent disability in multiple sclerosis (MS). Objective: The objective of this paper is to determine whether progressive neurodegeneration occurs in MS eyes without clinically evident inflammation. Methods: Retinal nerve fiver layer thickness (RNFLT) and ganglion cell-inner plexiform layer thickness (GCIPT) were measured using Cirrus optical coherence tomography (OCT) in 133 relapsing–remitting MS (RRMS) patients (149 non-optic neuritis (ON), 97 ON eyes, last ON ≥6 months). Ninety-three patients were scanned at two visits. Percentages of abnormal GCIPT vs RNFLT (<5% of machine norms) in cross-sectional data were compared. Relations between RNFLT/GCIPT and MS duration (cross-sectional) and follow-up time (longitudinal) were assessed. Results: GCIPT was abnormal in more eyes than RNFLT (27% vs 16% p = 0.004 in non-ON, 82% vs 72% p = 0.007 in ON). RNFLT and GCIPT decreased with MS duration by −0.49 µm/yr ( p = 0.0001) and −0.36 ( p = 0.005) for non-ON; −0.52 ( p = 0.003) and −0.41 ( p = 0.007) for ON. RNFLT and GCIPT decreased with follow-up time by −1.49 µm/yr ( p < 0.0001) and −0.53 ( p = 0.004) for non-ON, −1.27 ( p = 0.002) and −0.49 ( p = 0.04) for ON. Conclusions: In RRMS eyes without clinically evident inflammation, progressive loss of RNFLT and GCIPT occurred, supporting the need for neuroprotection in addition to suppression of autoimmune responses and inflammation.

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Inner and outer retinal layer thickness alterations in pediatric and juvenile craniopharyngioma

Scientific Reports ◽

10.1038/s41598-021-82107-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ga-In Lee ◽

Kyung-Ah Park ◽

Sei Yeul Oh ◽

Doo-Sik Kong ◽

Sang Duk Hong

Keyword(s):

Layer Thickness ◽

Outer Nuclear Layer ◽

Plexiform Layer ◽

Visual Field Defects ◽

Retinal Layer ◽

Inner Plexiform Layer ◽

Healthy Controls ◽

Fiber Layer ◽

Photoreceptor Layer ◽

Chiasmal Compression

AbstractWe evaluated postoperative retinal thickness in pediatric and juvenile craniopharyngioma (CP) patients with chiasmal compression using optical coherence tomography (OCT) auto-segmentation. We included 18 eyes of 18 pediatric or juvenile patients with CP and 20 healthy controls. Each thickness of the macular retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer, outer plexiform layer, outer nuclear layer, and photoreceptor layer was compared between the CP patients and healthy controls. There was significant thinning in the macular RNFL (estimates [μm], superior, − 10.68; inferior, − 7.24; nasal, − 14.22), all quadrants of GCL (superior, − 16.53; inferior, − 14.37; nasal, − 24.34; temporal, − 9.91) and IPL (superior, − 11.45; inferior, − 9.76; nasal, − 15.25; temporal, − 4.97) in pediatric and juvenile CP patients postoperatively compared to healthy control eyes after adjusting for age and refractive errors. Thickness reduction in the average and nasal quadrant of RNFL, GCL, and IPL was associated with peripapillary RNFL thickness, and reduced nasal quadrant GCL and IPL thicknesses were associated with postoperative visual field defects. In pediatric and juvenile patients with CP, decreased inner retinal layer thickness following chiasmal compression was observed. The changes in retinal structures were closely related to peripapillary RNFL thinning and functional outcomes.

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Evidence of subclinical quantitative retinal layer abnormalities in AQP4-IgG seropositive NMOSD

Multiple Sclerosis Journal ◽

10.1177/1352458520977771 ◽

2020 ◽

pp. 135245852097777

Author(s):

Angeliki G Filippatou ◽

Eleni S Vasileiou ◽

Yufan He ◽

Kathryn C Fitzgerald ◽

Grigorios Kalaitzidis ◽

...

Keyword(s):

Ganglion Cell ◽

Outer Nuclear Layer ◽

Sensitivity Analyses ◽

Retinal Layer ◽

Inner Plexiform Layer ◽

Fiber Layer ◽

Foveal Thickness ◽

Cross Sectional ◽

Photoreceptor Layer ◽

History Of

Background: Prior studies have suggested that subclinical retinal abnormalities may be present in aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive neuromyelitis optica spectrum disorder (NMOSD), in the absence of a clinical history of optic neuritis (ON). Objective: Our aim was to compare retinal layer thicknesses at the fovea and surrounding macula between AQP4-IgG+ NMOSD eyes without a history of ON (AQP4-nonON) and healthy controls (HC). Methods: In this single-center cross-sectional study, 83 AQP4-nonON and 154 HC eyes were studied with spectral-domain optical coherence tomography (OCT). Results: Total foveal thickness did not differ between AQP4-nonON and HC eyes. AQP4-nonON eyes exhibited lower outer nuclear layer (ONL) and inner photoreceptor segment (IS) thickness at the fovea (ONL: −4.01 ± 2.03 μm, p = 0.049; IS: −0.32 ± 0.14 μm, p = 0.029) and surrounding macula (ONL: −1.98 ± 0.95 μm, p = 0.037; IS: −0.16 ± 0.07 μm, p = 0.023), compared to HC. Macular retinal nerve fiber layer (RNFL: −1.34 ± 0.51 μm, p = 0.009) and ganglion cell + inner plexiform layer (GCIPL: −2.44 ± 0.93 μm, p = 0.009) thicknesses were also lower in AQP4-nonON compared to HC eyes. Results were similar in sensitivity analyses restricted to AQP4-IgG+ patients who had never experienced ON in either eye. Conclusions: AQP4-nonON eyes exhibit evidence of subclinical retinal ganglion cell neuronal and axonal loss, as well as structural evidence of photoreceptor layer involvement. These findings support that subclinical anterior visual pathway involvement may occur in AQP4-IgG+ NMOSD.

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Morphology of Inner Retina in Rhesus Monkeys of Various Ages: A Comparative Study

Journal of Ophthalmology ◽

10.1155/2019/7089342 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Jingfei Chen ◽

Qihui Luo ◽

Chao Huang ◽

Wen Zeng ◽

Ping Chen ◽

...

Keyword(s):

Rhesus Monkeys ◽

Morphological Structure ◽

Plexiform Layer ◽

Bipolar Cells ◽

Growth Stages ◽

Retinal Layer ◽

Inner Plexiform Layer ◽

Fiber Layer ◽

Inner Retina ◽

Biological Studies

Purpose. To investigate the changes of thickness in each layer, the morphology and density of inner neurons in rhesus monkeys’ retina at various growth stages, thus contribute useful data for further biological studies. Methods. The thickness of nerve fiber layer (NFL), the whole retina, inner plexiform layer (IPL), and outer plexiform layer (OPL) of rhesus monkeys at different ages were observed with hematoxylin and eosin (H&E) staining. The morphology and the density of inner neurons of rhesus monkey retina were detected by immunofluorescence. Results. The retina showed the well-known ten layers, the thickness of each retinal layer in rhesus monkeys at various ages increased rapidly after infant, and the retina was the thickest in adulthood, but the retinal thickness stop growing in senescent. Quantitative analysis showed that the maximum density of inner neurons was reached in adolescent, and then, the density of inner neurons decreased in adults and senescent retinas. And some changes in the morphology of rod bipolar cells have occurred in senescent. Conclusions. The structure of retina in rhesus monkeys is relatively immature at infant, and the inner retina of rhesus monkeys is mature in adolescent, while the thickness of each retinal layer was the most developed in the adult group. There was no significant change in senescence for the thickness of each retinal layer, but the number of the neurons in our study has a decreasing trend and the morphological structure has changed.

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Mechanisms of Network Changes in Cognitive Impairment in Multiple Sclerosis

Neurology ◽

10.1212/wnl.0000000000012834 ◽

2021 ◽

pp. 10.1212/WNL.0000000000012834

Author(s):

Danka Jandric ◽

Ilona Lipp ◽

David Paling ◽

David Rog ◽

Gloria Castellazzi ◽

...

Keyword(s):

Multiple Sclerosis ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Cognitive Impairment ◽

Functional Connectivity ◽

Resting State ◽

Structural Connectivity ◽

Cognitively Impaired ◽

Anatomical Connectivity ◽

Cross Sectional

Background and Objectives:Cognitive impairment in multiple sclerosis (MS) is associated with functional connectivity abnormalities. While there have been calls to use functional connectivity measures as biomarkers there remains to be a full understanding of why they are affected in MS. In this cross-sectional study we tested the hypothesis that functional network regions may be susceptible to disease-related ‘wear-and-tear’ and that this can be observable on co-occuring abnormalities on other MR metrics. We tested whether functional connectivity abnormalities in cognitively impaired MS patients co-occur with either 1) overlapping, 2) local, or 3) distal changes in anatomical connectivity and cerebral blood flow abnormalities.Methods:Multimodal 3T MRI and assessment with the Brief Repeatable Battery of Neuropsychological tests was performed in 102 relapsing-remitting MS patients and 27 healthy controls. MS patients were classified as cognitively impaired if they scored ≥1.5 standard deviations below the control mean on ≥2 tests (n=55), or else cognitively preserved (n=47). Functional connectivity was assessed with Independent Component Analysis and dual regression of resting-state fMRI images. Cerebral blood flow maps were estimated and anatomical connectivity was assessed with anatomical connectivity mapping and fractional anisotropy of diffusion-weighted MRI. Changes in cerebral blood flow and anatomical connectivity were assessed within resting state networks that showed functional connectivity abnormalities in cognitively impaired MS patients.Results:Functional connectivity was significantly decreased in the anterior and posterior default mode networks and significantly increased in the right and left frontoparietal networks in cognitively impaired relative to cognitively preserved MS patients (TFCE-corrected at p≤0.05, two-sided). Networks showing functional abnormalities showed altered cerebral blood flow and anatomical connectivity locally and distally but not in overlapping locations.Discussion:We provide the first evidence that FC abnormalities are accompanied with local cerebral blood flow and structural connectivity abnormalities but also demonstrate that these effects do not occur in exactly the same location. Our findings suggest a possibly shared pathological mechanism for altered functional connectivity in brain networks in MS.

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Macula structural and vascular differences in glaucoma eyes with and without high axial myopia

10.1101/2021.09.02.21263045 ◽

2021 ◽

Author(s):

Jasmin Rezapour ◽

Christopher Bowd ◽

Jade Dohleman ◽

Akram Belghith ◽

James A. Proudfoot ◽

...

Keyword(s):

Ganglion Cell ◽

Axial Length ◽

Plexiform Layer ◽

Positive Association ◽

Mean Deviation ◽

Ganglion Cell Complex ◽

Inner Plexiform Layer ◽

Fiber Layer ◽

Cross Sectional ◽

Axial Myopia

AbstractAimsTo assess the thickness of various retinal layers, and the superficial vessel density (sVD) in the macula of glaucomatous eyes and their associations with axial length (AL) and visual field mean deviation (VFMD) to identify parameters useful for glaucoma management in myopic eyes.Methods248 glaucoma patients (401 eyes) participating in the Diagnostic Innovations in Glaucoma Study observational cohort representing 3 axial myopia groups (non-myopia: n=146 eyes; mild myopia: n=208 eyes; high myopia (AL>26 mm): n=47 eyes) who completed macular OCT and OCT-Angiography imaging were included. The cross-sectional associations of AL and VFMD with the thickness of the ganglion cell inner plexiform layer (GCIPL), macular retinal nerve fiber layer (mRNFL), ganglion cell complex (GCC), sVD and macular choroidal thickness (mCT) were evaluated.ResultsThinner Global GCIPL and GCC were significantly associated with worse VFMD (R2=35.1%; and R2=33.4%; respectively p<0.001), but not with AL (all p>0.350). Thicker mRNFL showed a weak association with increasing AL (R2=3.4%; p=0.001) and a positive association with VFMD (global R2=20.5%; p<0.001). Lower sVD was weakly associated with increasing AL (R2=2.3%; p=0.016) and more strongly associated with more severe glaucoma VFMD (R2=31.8%; p<0.001). Thinner mCT was associated with increasing AL (R2=17.3% p<0.001) and not associated with VFMD (P=0.262). mRNFL was thickest while mCT was thinnest in all sectors of high myopic eyes.ConclusionsGCIPL and GCC thinned with increasing severity of glaucoma but were not significantly associated with axial length. GCIPL and GCC thickness may be useful clinical parameters to identify glaucoma in myopic eyes.

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