Retinal and brain damage during multiple sclerosis course: inflammatory activity is a key factor in the first 5 years.
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ABSTRACT:
SUBMITTER: Pulido-Valdeolivas I
PROVIDER: S-EPMC7414206 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
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Retinal and brain damage during multiple sclerosis course: inflammatory activity is a key factor in the first 5 years.
Pulido-Valdeolivas Irene I Andorrà Magí M Gómez-Andrés David D Nakamura Kunio K Alba-Arbalat Salut S Lampert Erika J EJ Zubizarreta Irati I Llufriu Sara S Martinez-Heras Eloy E Solana Elisabeth E Sola-Valls Nuria N Sepulveda María M Tercero-Uribe Ana A Blanco Yolanda Y Camos-Carreras Anna A Sanchez-Dalmau Bernardo B Villoslada Pablo P Saiz Albert A Martinez-Lapiscina Elena H EH
Scientific reports 20200807 1
Understanding of the role of focal inflammation, a treatable feature, on neuro-axonal injury, is paramount to optimize neuroprotective strategy in MS. To quantify the impact of focal inflammatory activity on the rate of neuro-axonal injury over the MS course. We quantified the annualized rates of change in peripapillary retinal nerve fiber layer, ganglion cell plus inner plexiform layer (GCIPL), whole-brain, gray matter and thalamic volumes in patients with and without focal inflammatory activit ...[more]
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Project description:ImportanceBiomarkers to estimate long-term outcomes in patients with multiple sclerosis (MS) and to assign patients to individual treatment regimens are urgently needed.ObjectiveTo assess whether retinal layer volumes are correlated with immune cell subsets and immunoglobulin indices in the cerebrospinal fluid and whether retinal layer volumes alone or in combination with intrathecal variables are associated with worsening of disease in patients with relapsing-remitting MS.Design, setting, and participantsThis observational cohort study included 312 patients with relapsing-remitting MS in 2 independent cohorts (72 patients with short disease duration [cohort 1] and 240 patients with longer disease duration [cohort 2]) treated at a single German university hospital from April 15, 2013, through November 11, 2015.Main outcomes and measuresThe common ganglion cell and inner plexiform layer (GCIPL) and inner nuclear layer (INL) volumes were tested for association with the immunoglobulin indices and the frequencies of immune cells in the cerebrospinal fluid (including B cells, T cells, and natural killer cells) (cohort 1). Volumes of GCIPL alone (cohorts 1 and 2) or GCIPL corrected for intrathecal B-cell frequencies (cohort 1) were tested for their association with worsening disability.ResultsA total of 312 patients (212 women [67.9%] and 100 men [32.1%]; median age, 34.0 years [interquartile range (IQR), 28.0-42.0 years]) were available for analysis. In cohort 1 (50 women [69.4%] and 22 men [30.6%]; median age, 31.0 years [IQR, 26.3-38.3 years]), with short disease durations (median, 1.0 months [IQR, 1.0-2.0 months]), low GCIPL volumes were associated with increased intrathecal B-cell frequencies (median, 1.96% [IQR, 1.45%-4.20%]) and intrathecal IgG synthesis (median cerebrospinal fluid/serum IgG index, 0.78 [IQR, 0.53-1.07]). The INL volumes correlated with the frequencies of intrathecal CD56bright natural killer cells (r = 0.28; P = .007). Individuals with low GCIPL volumes (<1.99 mm3) had a 6.4-fold risk for worsening disability during follow-up compared with patients with higher GCIPL values (95% CI, 1.7-24.2; P = .007). This finding was reproduced in cohort 2 (162 women [67.5%] and 78 men [32.5%]; median age, 34.0 years [IQR, 29.0-42.0 years]) consisting of patients with longer disease durations (median, 36.0 months [IQR, 21.0-60.0 months]) (hazard ratio, 2.4; 95% CI, 1.2-4.8; P = .02). In both cohorts, INL volumes correlated with the prospective increase in T2 lesion load and the number of gadolinium-enhancing lesions.Conclusions and relevanceRetinal layers reflect different aspects of disease activity during MS. Loss of GCIPL is associated with intrathecal B-cell immunity and constitutes an independent risk factor for worsening disability, whereas high INL volumes are associated with activity on magnetic resonance imaging in the brain parenchyma. Thus, retinal optical coherence tomography might be a means to support stratification of patients with MS for different therapeutic regimens.
| S-EPMC5822191 | biostudies-literature
Project description:Multiple Sclerosis (MS) is an autoimmune disease driving inflammatory and degenerative processes that damage the central nervous system (CNS). However, it is not well understood how these events interact and evolve to evoke such a highly dynamic and heterogeneous disease. We established a hypothesis whereby the variability in the course of MS is driven by the very same pathogenic mechanisms responsible for the disease, the autoimmune attack on the CNS that leads to chronic inflammation, neuroaxonal degeneration and remyelination. We propose that each of these processes acts more or less severely and at different times in each of the clinical subgroups. To test this hypothesis, we developed a mathematical model that was constrained by experimental data (the expanded disability status scale [EDSS] time series) obtained from a retrospective longitudinal cohort of 66 MS patients with a long-term follow-up (up to 20 years). Moreover, we validated this model in a second prospective cohort of 120 MS patients with a three-year follow-up, for which EDSS data and brain volume time series were available. The clinical heterogeneity in the datasets was reduced by grouping the EDSS time series using an unsupervised clustering analysis. We found that by adjusting certain parameters, albeit within their biological range, the mathematical model reproduced the different disease courses, supporting the dynamic CNS damage hypothesis to explain MS heterogeneity. Our analysis suggests that the irreversible axon degeneration produced in the early stages of progressive MS is mainly due to the higher rate of myelinated axon degeneration, coupled to the lower capacity for remyelination. However, and in agreement with recent pathological studies, degeneration of chronically demyelinated axons is not a key feature that distinguishes this phenotype. Moreover, the model reveals that lower rates of axon degeneration and more rapid remyelination make relapsing MS more resilient than the progressive subtype. Therefore, our results support the hypothesis of a common pathogenesis for the different MS subtypes, even in the presence of genetic and environmental heterogeneity. Hence, MS can be considered as a single disease in which specific dynamics can provoke a variety of clinical outcomes in different patient groups. These results have important implications for the design of therapeutic interventions for MS at different stages of the disease.
| S-EPMC5657613 | biostudies-literature
Project description:Microbial communities reside in healthy tissues but are often disrupted during disease. Bacterial genomes and proteins are detected in brains from humans, nonhuman primates, rodents and other species in the absence of neurological disease. We investigated the composition and abundance of microbiota in frozen and fixed autopsied brain samples from patients with multiple sclerosis (MS) and age- and sex-matched nonMS patients as controls, using neuropathological, molecular and bioinformatics tools. 16s rRNA sequencing revealed Proteobacteria to be the dominant phylum with restricted diversity in cerebral white matter (WM) from MS compared to nonMS patients. Both clinical groups displayed 1,200-1,400 bacterial genomes/cm3 and low bacterial rRNA:rDNA ratios in WM. RNAseq analyses showed a predominance of Proteobacteria in progressive MS patients' WM, associated with increased inflammatory gene expression, relative to a broader range of bacterial phyla in relapsing-remitting MS patients' WM. Although bacterial peptidoglycan (PGN) and RNA polymerase beta subunit immunoreactivities were observed in all patients, PGN immunodetection was correlated with demyelination and neuroinflammation in MS brains. Principal component analysis revealed that demyelination, PGN and inflammatory gene expression accounted for 86% of the observed variance. Thus, inflammatory demyelination is linked to an organ-specific dysbiosis in MS that could contribute to underlying disease mechanisms.
| S-EPMC5125007 | biostudies-literature
Project description:The diagnosis of multiple sclerosis is based on a combination of clinical and paraclinical tests. The potential contribution of retinal optical coherence tomography (OCT) has been recognized. We tested the feasibility of OCT measures of retinal asymmetry as a diagnostic test for multiple sclerosis at the community level. In this community-based study of 72 120 subjects, we examined the diagnostic potential of the inter-eye difference of inner retinal OCT data for multiple sclerosis using the UK Biobank data collected at 22 sites between 2007 and 2010. OCT reporting and quality control guidelines were followed. The inter-eye percentage difference (IEPD) and inter-eye absolute difference (IEAD) were calculated for the macular retinal nerve fibre layer (RNFL), ganglion cell inner plexiform layer (GCIPL) complex and ganglion cell complex. Area under the receiver operating characteristic curve (AUROC) comparisons were followed by univariate and multivariable comparisons accounting for a large range of diseases and co-morbidities. Cut-off levels were optimized by ROC and the Youden index. The prevalence of multiple sclerosis was 0.0023 [95% confidence interval (CI) 0.00229-0.00231]. Overall the discriminatory power of diagnosing multiple sclerosis with the IEPD AUROC curve (0.71, 95% CI 0.67-0.76) and IEAD (0.71, 95% CI 0.67-0.75) for the macular GCIPL complex were significantly higher if compared to the macular ganglion cell complex IEPD AUROC curve (0.64, 95% CI 0.59-0.69, P = 0.0017); IEAD AUROC curve (0.63, 95% CI 0.58-0.68, P < 0.0001) and macular RNFL IEPD AUROC curve (0.59, 95% CI 0.54-0.63, P < 0.0001); IEAD AUROC curve (0.55, 95% CI 0.50-0.59, P < 0.0001). Screening sensitivity levels for the macular GCIPL complex IEPD (4% cut-off) were 51.7% and for the IEAD (4 μm cut-off) 43.5%. Specificity levels were 82.8% and 86.8%, respectively. The number of co-morbidities was important. There was a stepwise decrease of the AUROC curve from 0.72 in control subjects to 0.66 in more than nine co-morbidities or presence of neuromyelitis optica spectrum disease. In the multivariable analyses greater age, diabetes mellitus, other eye disease and a non-white ethnic background were relevant confounders. For most interactions, the effect sizes were large (partial ω2 > 0.14) with narrow confidence intervals. In conclusion, the OCT macular GCIPL complex IEPD and IEAD may be considered as supportive measurements for multiple sclerosis diagnostic criteria in a young patient without relevant co-morbidity. The metric does not allow separation of multiple sclerosis from neuromyelitis optica. Retinal OCT imaging is accurate, rapid, non-invasive, widely available and may therefore help to reduce need for invasive and more costly procedures. To be viable, higher sensitivity and specificity levels are needed.
| S-EPMC7880665 | biostudies-literature
Project description:ObjectiveThe brain reserve hypothesis links larger maximal lifetime brain growth (MLBG, estimated with intracranial volume [ICV]) with lower risk for cognitive decline/dementia. We examined whether larger MLBG is also linked to less physical disability progression over 5 years in a prospective sample of treatment-naive patients with multiple sclerosis (MS).MethodsPhysical disability was measured with the Expanded Disability Status Scale (EDSS) at baseline and 5-year follow-up in 52 treatment-naive Serbian patients with MS. MRI measured disease burden (cerebral atrophy, T2 lesion volume) and MLBG: a genetically determined, premorbid (established during adolescence, stable thereafter) patient characteristic estimated with ICV (adjusted for sex). Logistic regression tested whether MLBG (smaller vs larger) predicts disability progression (stable vs worsened) independently of disease burden.ResultsDisability progression was observed in 29 (55.8%) patients. Larger MLBG predicted lower risk for progression (odds ratio 0.13, 95% confidence interval 0.02-0.78), independently of disease burden. We also calculated absolute change in EDSS scores, and observed that patients with smaller MLBG showed worse EDSS change (0.91 ± 0.71) than patients with larger MLBG (0.42 ± 0.87).ConclusionsLarger MLBG was linked to lower risk for disability progression in patients with MS over 5 years, which is the first extension of the brain reserve hypothesis to physical disability. MLBG (ICV) represents a clinically available metric that may help gauge risk for future disability in patients with MS, which may advance the science and practice of early intervention. Potential avenues for future research are discussed.
| S-EPMC4887124 | biostudies-literature
Project description:ObjectiveMultiple sclerosis (MS) is a common demyelinating central nervous system disease. MRI methods that can quantify myelin loss are needed for trials of putative remyelinating agents. Quantitative magnetization transfer MRI introduced the macromolecule proton fraction (MPF), which correlates with myelin concentration. We developed an alternative approach, Simultaneous-Multi-Angular-Relaxometry-of-Tissue (SMART) MRI, to generate MPF. Our objective was to test SMART-derived MPF metric as a potential imaging biomarker of demyelination.MethodsTwenty healthy control (HC), 11 relapsing-remitting MS (RRMS), 22 progressive MS (PMS), and one subject with a biopsied tumefactive demyelinating lesion were scanned at 3T using SMART MRI. SMART-derived MPF metric was determined in normal-appearing cortical gray matter (NAGM), normal-appearing subcortical white matter (NAWM), and demyelinating lesions. MPF metric was evaluated for correlations with physical and cognitive test scores. Comparisons were made between HC and MS and between MS subtypes. Furthermore, correlations were determined between MPF and neuropathology in the biopsied person.ResultsSMART-derived MPF in NAGM and NAWM were lower in MS than HC (p < 0.001). MPF in NAGM, NAWM and lesions differentiated RRMS from PMS (p < 0.01, p < 0.001, p < 0.001, respectively), whereas lesion volumes did not. MPF in NAGM, NAWM and lesions correlated with the Expanded Disability Status Scale (p < 0.01, p < 0.001, p < 0.001, respectively) and nine-hole peg test (p < 0.001, p < 0.001, p < 0.01, respectively). MPF was lower in the histopathologically confirmed inflammatory demyelinating lesion than the contralateral NAWM and increased in the biopsied lesion over time, mirroring improved clinical performance.InterpretationSMART-derived MPF metric holds potential as a quantitative imaging biomarker of demyelination and remyelination.
| S-EPMC9539387 | biostudies-literature
Project description:As the burden of neurodegenerative diseases increases, time-limited clinic encounters do not allow quantification of complex neurological functions. Patient-collected digital biomarkers may remedy this, if they provide reliable information. However, psychometric properties of digital tools remain largely un-assessed. We developed a smartphone adaptation of the cognitive test, the Symbol-Digit Modalities Test (SDMT) by randomizing the test's symbol-number codes and testing sequences. The smartphone SDMT showed comparable psychometric properties in 154 multiple sclerosis (MS) patients and 39 healthy volunteers (HV). E.g., smartphone SDMT achieved slightly higher correlations with cognitive subscores of neurological examinations and with brain injury measured by MRI (R2 = 0.75, Rho = 0.83, p < 0.0001) than traditional SDMT. Mathematical adjustment for motoric disability of the dominant hand, measured by another smartphone test, compensates for the disadvantage of touch-based test. Averaging granular home measurements of the digital biomarker also increases accuracy of identifying true neurological decline.
| S-EPMC7904910 | biostudies-literature
Project description:ObjectiveRetrograde trans-synaptic neuroaxonal degeneration is considered a key pathological factor of subclinical retinal neuroaxonal damage in multiple sclerosis (MS). We aim to evaluate the longitudinal association of optic radiation (OR) lesion activity with retinal neuroaxonal damage and its role in correlations between retinal and brain atrophy in people with clinically isolated syndrome and early MS (pweMS).MethodsEighty-five pweMS were retrospectively screened from a prospective cohort (Berlin CIS cohort). Participants underwent 3T magnetic resonance imaging (MRI) for OR lesion volume and brain atrophy measurements and optical coherence tomography (OCT) for retinal layer thickness measurements. All pweMS were followed with serial OCT and MRI over a median follow-up of 2.9 (interquartile range: 2.6-3.4) years. Eyes with a history of optic neuritis prior to study enrollment were excluded. Linear mixed models were used to analyze the association of retinal layer thinning with changes in OR lesion volume and brain atrophy.ResultsMacular ganglion cell-inner plexiform layer (GCIPL) thinning was more pronounced in pweMS with OR lesion volume increase during follow-up compared to those without (Difference: -0.82 μm [95% CI:-1.49 to -0.15], p = 0.018). Furthermore, GCIPL thinning correlated with both OR lesion volume increase (β [95% CI] = -0.27 [-0.50 to -0.03], p = 0.028) and brain atrophy (β [95% CI] = 0.47 [0.25 to 0.70], p < 0.001). Correlations of GCIPL changes with brain atrophy did not differ between pweMS with or without OR lesion increase ( η p 2 = 5.92e-7 , p = 0.762).InterpretationFaster GCIPL thinning rate is associated with increased OR lesion load. Our results support the value of GCIPL as a sensitive biomarker reflecting both posterior visual pathway pathology and global brain neurodegeneration.
| S-EPMC10791029 | biostudies-literature
Project description:There is a well-known relationship between MS and damage to the optic nerve, but advanced, quantitative MR imaging methods have not been applied to large cohorts. Our objective was to determine whether a short imaging protocol (< 10 minutes), implemented with standard hardware, could detect abnormal water diffusion in the optic nerves of patients with MS.We examined water diffusion in human optic nerves via DTI in the largest MS cohort reported to date (104 individuals, including 38 optic nerves previously affected by optic neuritis). We also assessed whether such abnormalities are associated with loss of visual acuity (both high and low contrast) and damage to the retinal nerve fiber layer (assessed via optical coherence tomography).The most abnormal diffusion was found in the optic nerves of patients with SPMS, especially in optic nerves previously affected by optic neuritis (19% drop in FA). DTI abnormalities correlated with both retinal nerve fiber layer thinning (correlation coefficient, 0.41) and loss of visual acuity, particularly at high contrast and in nerves previously affected by optic neuritis (correlation coefficient, 0.54). However, diffusion abnormalities were overall less pronounced than retinal nerve fiber layer thinning.DTI is sensitive to optic nerve damage in patients with MS, but a short imaging sequence added to standard clinical protocols may not be the most reliable indicator of optic nerve damage.
| S-EPMC3190034 | biostudies-literature
Project description:BackgroundThe association of peripapillary retinal nerve fibre layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness with neurodegeneration in multiple sclerosis (MS) is well established. The relationship of the adjoining inner nuclear layer (INL) with inflammatory disease activity is less well understood.ObjectiveThe objective of this paper is to investigate the relationship of INL volume changes with inflammatory disease activity in MS.Methods In this longitudinal, multi-centre study, optical coherence tomography (OCT) and clinical data (disability status, relapses and MS optic neuritis (MSON)) were collected in 785 patients with MS (68.3% female) and 92 healthy controls (63.4% female) from 11 MS centres between 2010 and 2017 and pooled retrospectively. Data on pRNFL, GCIPL and INL were obtained at each centre.ResultsThere was a significant increase in INL volume in eyes with new MSON during the study (N = 61/1562, β = 0.01 mm3, p < .001). Clinical relapses (other than MSON) were significantly associated with increased INL volume (β = 0.005, p = .025). INL volume was independent of disease progression (β = 0.002 mm3, p = .474).ConclusionOur data demonstrate that an increase in INL volume is associated with MSON and the occurrence of clinical relapses. Therefore, INL volume changes may be useful as an outcome marker for inflammatory disease activity in MSON and MS treatment trials.
| S-EPMC6728683 | biostudies-literature