Neurodegeneration In Multiple Sclerosis Research Articles

Loss of Cells in the Retinal Ganglion Cell Layer as an Early Indication of Neurodegeneration in Multiple Sclerosis

Loss of Cells in the Retinal Ganglion Cell Layer as an Early Indication of Neurodegeneration in Multiple Sclerosis

Choroid plexus enlargement is associated with future periventricular neurodegeneration in multiple sclerosis

BackgroundThe choroid plexus (CP), located within the ventricles of the brain and the primary producer of cerebrospinal fluid, has been shown to be enlarged in patients with multiple sclerosis (MS) and linked to periventricular remyelination failure. Atrophied T2-lesion volume (aT2-LV), a promising neurodegenerative imaging marker in progressive MS (PMS), reflects the volume of periventricular lesions subsumed into cerebrospinal fluid over the follow-up. MethodsIn a cohort of 143 people with relapsing-remitting MS (RRMS) and 53 with PMS, we used 3T magnetic resonance imaging (MRI) to quantify CP volume (CPV) at baseline and aT2-LV over an average of 5.4 years of follow-up. Partial correlations, adjusting for age and sex, and linear regression analyses were used to assess the relationships between imaging measures. ResultsIn both cohorts, CPV was associated with aT2-LV in both the RRMS group (r = 0.329, p < 0.001) as well as the PMS group (r = 0.522, p < 0.001). In regression analyses predicting aT2-LV, ventricular volume (final adjusted R2 = 0.407, p < 0.001) explained additional variance beyond age, sex, and T2-lesion volume in the RRMS group while CPV (final adjusted R2 = 0.446, p = 0.009) was retained in the PMS group. ConclusionFindings from this study suggest that the CP enlargement is associated with future neurodegeneration, with a particularly relevant role in PMS.

Vulnerability of Thalamic Nuclei at CSF Interface During the Entire Course of Multiple Sclerosis.

Thalamic atrophy can be used as a proxy for neurodegeneration in multiple sclerosis (MS). Some data point toward thalamic nuclei that could be affected more than others. However, the dynamic of their changes during MS evolution and the mechanisms driving their differential alterations are still uncertain. We paired a large cohort of 1,123 patients with MS with the same number of healthy controls, all scanned with conventional 3D-T1 MRI. To highlight the main atrophic regions at the thalamic nuclei level, we validated a segmentation strategy consisting of deep learning-based synthesis of sequences, which were used for automatic multiatlas segmentation. Then, through a lifespan-based approach, we could model the dynamics of the 4 main thalamic nuclei groups. All analyses converged toward a higher rate of atrophy for the posterior and medial groups compared with the anterior and lateral groups. We also demonstrated that focal MS white matter lesions were associated with atrophy of groups of nuclei when specifically located within the associated thalamocortical projections. The volumes of the most affected posterior group, but also of the anterior group, were better associated with clinical disability than the volume of the whole thalamus. These findings point toward the thalamic nuclei adjacent to the third ventricle as more susceptible to neurodegeneration during the entire course of MS through potentiation of disconnection effects by regional factors. Because this information can be obtained even from standard T1-weighted MRI, this paves the way toward such an approach for future monitoring of patients with MS.

Role of ferroptosis in neuroimmunity and neurodegeneration in multiple sclerosis revealed by multi-omics data.

Previous studies have found that ferroptosis plays an important role in a variety of neurological diseases. However, the precise role of ferroptosis in the multiple sclerosis patients remains uncertain. We defined and validated a computational metric of ferroptosis levels. The ferroptosis scores were computed using the AUCell method, which reflects the enrichment scores of ferroptosis-related genes through gene ranking. The reliability of the ferroptosis score was assessed using various methods, involving cells induced to undergo ferroptosis by six different ferroptosis inducers. Through a comprehensive approach integrating snRNA-seq, spatial transcriptomics, and spatial proteomics data, we explored the role of ferroptosis in multiple sclerosis. Our findings revealed that among seven sampling regions of different white matter lesions, the edges of active lesions exhibited the highest ferroptosis score, which was associated with activation of the phagocyte system. Remyelination lesions exhibit the lowest ferroptosis score. In the cortex, ferroptosis score were elevated in neurons, relevant to a variety of neurodegenerative disease-related pathways. Spatial transcriptomics demonstrated a significant co-localization among ferroptosis score, neurodegeneration and microglia, which was verified by spatial proteomics. Furthermore, we established a diagnostic model of multiple sclerosis based on 24 ferroptosis-related genes in the peripheral blood. Ferroptosis might exhibits a dual role in the context of multiple sclerosis, relevant to both neuroimmunity and neurodegeneration, thereby presenting a promising and novel therapeutic target. Ferroptosis-related genes in the blood that could potentially serve as diagnostic and prognostic markers for multiple sclerosis.

HnRNP A1 dysfunction alters RNA splicing and drives neurodegeneration in multiple sclerosis (MS)

Neurodegeneration is the primary driver of disease progression in multiple sclerosis (MS) resulting in permanent disability, creating an urgent need to discover its underlying mechanisms. Herein, we establish that dysfunction of the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) results in differential of binding to RNA targets causing alternative RNA splicing, which contributes to neurodegeneration in MS and its models. Using RNAseq of MS brains, we discovered differential expression and aberrant splicing of hnRNP A1 target RNAs involved in neuronal function and RNA homeostasis. We confirmed this in vivo in experimental autoimmune encephalomyelitis employing CLIPseq specific for hnRNP A1, where hnRNP A1 differentially binds and regulates RNA, including aberrantly spliced targets identified in human samples. Additionally, dysfunctional hnRNP A1 expression in neurons caused neurite loss and identical changes in splicing, corroborating hnRNP A1 dysfunction as a cause of neurodegeneration. Collectively, these data indicate hnRNP A1 dysfunction causes altered neuronal RNA splicing, resulting in neurodegeneration in MS.

Systemic inflammation associates with and precedes cord atrophy in progressive multiple sclerosis.

In preclinical models of multiple sclerosis, systemic inflammation has an impact on the compartmentalized inflammatory process within the central nervous system and results in axonal loss. It remains to be shown whether this is the case in humans, specifically whether systemic inflammation contributes to spinal cord or brain atrophy in multiple sclerosis. Hence, an observational longitudinal study was conducted to delineate the relationship between systemic inflammation and atrophy using magnetic resonance imaging: the SIMS (Systemic Inflammation in Multiple Sclerosis) study. Systemic inflammation and progression were assessed in people with progressive multiple sclerosis (n = 50) over two and a half years. Eligibility criteria included: (i) primary or secondary progressive multiple sclerosis; (ii) age ≤ 70; and (iii) Expanded Disability Status Scale ≤ 6.5. First morning urine was collected weekly to quantify systemic inflammation by measuring the urinary neopterin-to-creatinine ratio using a validated ultra-performance liquid chromatography mass spectrometry technique. The urinary neopterin-to-creatinine ratio temporal profile was characterized by short-term responses overlaid on a background level of inflammation, so these two distinct processes were considered as separate variables: background inflammation and inflammatory response. Participants underwent MRI at the start and end of the study, to measure cervical spinal cord and brain atrophy. Brain and cervical cord atrophy occurred on the study, but the most striking change was seen in the cervical spinal cord, in keeping with the corticospinal tract involvement that is typical of progressive disease. Systemic inflammation predicted cervical cord atrophy. An association with brain atrophy was not observed in this cohort. A time lag between systemic inflammation and cord atrophy was evident, suggesting but not proving causation. The association of the inflammatory response with cord atrophy depended on the level of background inflammation, in keeping with experimental data in preclinical models where the effects of a systemic inflammatory challenge on tissue injury depended on prior exposure to inflammation. A higher inflammatory response was associated with accelerated cord atrophy in the presence of background systemic inflammation below the median for the study population. Higher background inflammation, while associated with cervical cord atrophy itself, subdued the association of the inflammatory response with cord atrophy. Findings were robust to sensitivity analyses adjusting for potential confounders and excluding cases with new lesion formation. In conclusion, systemic inflammation associates with, and precedes, multiple sclerosis progression. Further work is needed to prove causation since targeting systemic inflammation may offer novel treatment strategies for slowing neurodegeneration in multiple sclerosis.

Plasma antioxidant potential measured by total radical trapping antioxidant parameter in a cohort of multiple sclerosis patients.

Oxidative injury has been implicated as a mediator of demyelination, axonal damage, and neurodegeneration in multiple sclerosis (MS). There is a high demand for oxidative injury biomarkers. The aim of the study was to evaluate MS patients' plasma antioxidant potential using the total radical trapping parameter (TRAP) assay and examine its usefulness as an MS disease biomarker. A total number of 112 MS patients underwent an analysis of TRAP. In addition, plasma uric acid (UA) levels were analyzed. The neurological and radiological data were collected from patient records from Helsinki University Hospital during 2012-2013 when first-line injectables of moderate-efficacy, natalizumab (NTZ), and fingolimod (FTY) of high efficacy disease modifying therapies and in some cases azathioprine (AZT) were used to treat MS. TRAP values were negatively associated with expanded disability status scale (EDSS) score with p-value .052, β=-28. There was also a negative association in TRAP values between patients with no medication (n=22, TRAP mean 1255μmol/L (95% confidence interval [CI] 1136-1374)) and patients who received NTZ, p-value .020 (n=19, TRAP mean was 991μmol/L (95% CI 849-1133) or FTY treatment, p-value .030 (n=5, TRAP mean 982μmol/L (95% CI 55-1909). Due to a small sample size, these results were not significant after applying a false discovery rate correction at a 0.05 significance level but are worth highlighting. Men in the study had higher TRAP values, p-value=.001 (TRAP mean 1320±293μmol/L) than women (TRAP mean 1082±288μmol/L). UA was positively associated with TRAP values, p-value <.001 and UA levels in men (UA mean 334.5±62.6μmol/L) were higher compared to women (UA mean 240±55.8μmol/L), t-test p-value <.001. The significant difference in TRAP levels between genders, with men showing higher TRAP values than women, may be attributed to the variation in UA levels. Our findings suggest that lower plasma antioxidant potential is linked to more severe disability measured by EDSS scores. Patients treated with NTZ and FTY had reduced antioxidant power, which might be influenced by the active MS disease rather than the treatments themselves. The study reveals a strong positive correlation between UA levels and TRAP, particularly among women. However, men on average had better antioxidant potential than women. Neither the disease type nor the duration influences TRAP levels. While serving as a marker of antioxidant potential, plasma TRAP in MS patients does not reliably reflect overall oxidative stress (OS) and should not be solely used as an indicator of OS.

Exploring Vitreous Haze as a Potential Biomarker for Accelerated Glymphatic Outflow and Neurodegeneration in Multiple Sclerosis: A Cross-Sectional Study.

The glymphatic system removes neurodegenerative debris. The ocular glymphatic outflow is from the eye to the proximal optic nerve. In multiple sclerosis (MS), atrophy of the optic nerve increases the glymphatic outflow space. Here, we tested whether vitreous haze (VH) can provide novel insights into the relationship between neurodegeneration and the ocular glymphatic system in MS. This cross-sectional study comprised 315 persons with MS and 87 healthy controls (HCs). VH was quantified from optical coherence tomography (OCT) volume scans. Neurodegeneration was determined on three-dimensional T1 (3DT1) MRI, lesion detection on fluid-attenuated inversion (FLAIR), and layer thickness on OCT. Generalized estimating equations, corrected for age, were used to analyze associations between VH and metrics for neurodegeneration, demographics, and clinical scales. Group differences were determined between mild, moderate, and severe disability. On the group level, VH scores were comparable between MS and control (p = 0.629). In MS, VH scores declined with disease duration (β = -0.009, p = 0.004) and age (β = -0.007, p = 0.001). There was no relation between VH scores and higher age in HCs. In MS patients, VH was related to normalized gray (NGMV, β = 0.001, p = 0.011) and white matter volume (NWMV, β = 0.001, p = 0.003), macular ganglion cell-inner plexiform layer thickness (mGCIPL, β = 0.006, p < 0.001), and peripapillary retinal nerve fiber layer thickness (pRNFL, β = 0.004, p = 0.008). VH was significantly lower in severe compared to mild disability (mean difference -28.86%, p = 0.058). There is a correlation between VH on OCT and disease duration, more severe disability and lower brain volumes in MS. Biologically, these relationships suggest accelerated glymphatic clearance with disease-related atrophy.

Cerebral microvascular endothelial cell-derived extracellular vesicles regulate blood − brain barrier function

Autoreactive T lymphocytes crossing the blood-brain barrier (BBB) into the central nervous system (CNS) play a crucial role in the initiation of demyelination and neurodegeneration in multiple sclerosis (MS). Recently, extracellular vesicles (EV) secreted by BBB endothelial cells (BBB-EC) have emerged as a unique form of cell-to-cell communication that contributes to cerebrovascular dysfunction. However, the precise impact of different size-based subpopulations of BBB-EC-derived EV (BBB-EV) on the early stages of MS remains unclear. Therefore, our objective was to investigate the content and function of distinct BBB-EV subpopulations in regulating BBB integrity and their role in T cell transendothelial migration, both in vitro and in vivo. Our study reveals that BBB-ECs release two distinct size based EV populations, namely small EV (sEV; 30-150 nm) and large EV (lEV; 150-300 nm), with a significantly higher secretion of sEV during inflammation. Notably, the expression patterns of cytokines and adhesion markers differ significantly between these BBB-EV subsets, indicating specific functional differences in the regulation of T cell migration. Through in vitro experiments, we demonstrate that lEV, which predominantly reflect their cellular source, play a major role in BBB integrity loss and the enhanced migration of pro-inflammatory Th1 and Th17.1 cells. Conversely, sEV appear to protect BBB function by inducing an anti-inflammatory phenotype in BBB-EC. These findings align with our in vivo data, where the administration of sEV to mice with experimental autoimmune encephalomyelitis (EAE) results in lower disease severity compared to the administration of lEV, which exacerbates disease symptoms. In conclusion, our study highlights the distinct and opposing effects of BBB-EV subpopulations on the BBB, both in vitro and in vivo. These findings underscore the need for further investigation into the diagnostic and therapeutic potential of BBB-EV in the context of MS.

Spotlight on Trans-Synaptic Degeneration in the Visual Pathway in Multiple Sclerosis.

A putative mechanism of neurodegeneration in multiple sclerosis (MS) is trans-synaptic degeneration (TSD), whereby injury to a neuron leads to degeneration of synaptically connected neurons. The visual system is commonly involved in MS and provides an ideal model to study TSD given its well-defined structure. TSD may occur in an anterograde direction (optic neuropathy causing degeneration in the posterior visual pathway including the optic radiations and occipital gray matter) and/or retrograde direction (posterior visual pathway lesions causing retinal degeneration). In the current review, we discuss evidence supporting the presence of anterograde and retrograde TSD in the visual system in MS.

Validation of brain parenchyma sonography as a marker of neurodegeneration in multiple sclerosis

BackgroundMultiple sclerosis (MS) is widely known to cause brain atrophy due to neurodegeneration. Neuroimaging investigations revealed a direct link between brain atrophy detected by MRI and impairment. Transcranial sonography is a safe, feasible and cost-effective imaging technique. In this study, we aimed to validate B-mode transcranial sonography (TCS) as a marker of neurodegeneration in MS. This study is the first study directed to set cut-off point for brain parenchyma measurement in Egyptian population. An observational, case–control study, conducted on 125 subjects; divided into 2 groups: first group, 71 healthy volunteers and patients’ group (54 patients) with relapsing–remitting multiple sclerosis (RRMS). All studied subjects were assessed using B-mode TCS. Transcranial sonography findings were categorized into: first, assessment of brain atrophy parameters by measuring diameter (cm) of third ventricle and both frontal horns of lateral ventricles. Then, the echogenicity of thalamus and brainstem structures (substantia nigra (SN), red nucleus) planimetric surface area (cm2) were assessed along with their abnormal echogenicity (cm2), while brainstem raphe was assessed semi-quantitatively for its echogenicity (intact or interrupted).ResultsQuantitative measures of brain atrophy: in normal control group the third ventricle diameter mean was 0.2 cm (± 0.08), right and left frontal horn diameter were 0.3 cm (± 0.13) and 0.28 cm (± 0.1), respectively, brain atrophy parameters could differentiate between MS patients and normal control group as a statistically significant (p< 0.001) larger ventricular diameter was found in MS patients. On the other hand, assessment of brain stem structures and thalamus showed no statistical significance between MS patients and normal control except in surface area of both red nuclei.ConclusionsBrain parenchymal sonography may be used as a tool in assessment of neurodegeneration in MS patients.

Optical coherence tomography with voxel-based morphometry: a new tool to unveil focal retinal neurodegeneration in multiple sclerosis.

Neurodegeneration is the main contributor to disability accumulation in multiple sclerosis. Previous studies in neuro-ophthalmology have revealed that neurodegeneration in multiple sclerosis also affects the neuro-retina. Optical coherence tomography has been used to measure thinning of retinal layers, which correlates with several other markers for axonal/neuronal loss in multiple sclerosis. However, the existing analytical tools have limitations in terms of sensitivity and do not provide topographical information. In this study, we aim to evaluate whether voxel-based morphometry can increase sensitivity in detecting neuroaxonal degeneration in the retina and offer topographical information. A total of 131 people with multiple sclerosis (41 clinically isolated syndrome, 53 relapsing-remitting and 37 progressive multiple sclerosis) and 50 healthy subjects were included. Only eyes with normal global peripapillary retinal nerve fibre layer thickness and no history of optic neuritis were considered. Voxel-based morphometry and voxel-wise statistical comparisons were performed on the following: (i) patients at different disease stages and 2) patients who experienced the first demyelination attack without subclinical optic neuritis, assessed by visual evoked potentials. Standard parameters failed to discern any differences; however, voxel-based morphometry-optical coherence tomography successfully detected focal macular atrophy of retinal nerve fibre layer and ganglion cell/inner plexiform layer, along with thickening of inner nuclear layer in patients who experienced the first demyelination attack (disease duration = 4.2 months). Notably, the atrophy pattern of the ganglion cell/inner plexiform layer was comparable across disease phenotypes. In contrast, the retinal nerve fibre layer atrophy spread from the optic nerve head to the fovea as the disease evolved towards the progressive phase. Furthermore, for patients who experienced the first neurological episode, the severity of retinal nerve fibre layer atrophy at entry could predict a second attack. Our results demonstrate that voxel-based morphometry-optical coherence tomography exhibits greater sensitivity than standard parameters in detecting focal retinal atrophy, even at clinical presentation, in eyes with no history of optic neuritis and with normal latency of visual evoked potentials. Thinning of the ganglion cell/inner plexiform layer primarily concentrated in nasal perifovea in all disease phenotypes, indicating selective vulnerability of retinal ganglion cells and their perifoveal axons. Conversely, the degree of retinal nerve fibre layer thinning seems to be related to the clinical course of multiple sclerosis. The findings suggest bidirectional neurodegeneration in the visual pathway. Voxel-based morphometry-optical coherence tomography shows potential as a valuable tool for monitoring neurodegeneration on a patient level and evaluating the efficacy of novel neuroprotective treatments.

Trans-synaptic degeneration in the optic pathway: Exploring the role of lateral geniculate nucleus in early stages of relapsing-remitting multiple sclerosis.

Optic pathway is considered an ideal model to study the interaction between inflammation and neurodegeneration in multiple sclerosis (MS). Optical Coherence Tomography (OCT) and 3.0 T magnetic resonance imaging (MRI) were acquired in 92 relapsing remitting (RR) MS at clinical onset. Peripapillary RNFL (pRNFL) and macular layers were measured. White matter (WM) and gray matter (GM) lesion volumes (LV), lateral geniculate nucleus (LGN) volume, optic radiations (OR) WM LV, thickness of pericalcarine cortex were evaluated. OCT and MRI control groups (healthy controls [HC]-OCT and HC-MRI) were included. A significant thinning of temporal pRNFL and papillo-macular bundle (PMB) was observed (p<0.001) in 16 (17%) patients presented with monocular optic neuritis (MSON+), compared to 76 MSON- and 30 HC (-15μm). In MSON-, PMB was reduced (-3μm) compared to HC OCT (p<0.05). INL total volume was increased both in MSON+ (p<0.001) and MSON- (p=0.033). Inner retinal layers volumes (macular RNFL, GCL and IPL) were significantly decreased in MSON+ compared to HC (p<0.001) and MSON- (p<0.001). Reduced GCL volume in the parafoveal ring was observed in MSON- compared to HCOCT (p < 0.05). LGN volume was significantly reduced only in MSON+ patients compared to HC-MRI (p<0.001) and MSON- (p<0.007). GCL, IPL and GCIP volumes associated with ipsilateral LGN volume in MSON+ and MSON-. Finally, LGN volume associated with visual cortex thickness with no significant difference between MSON+ and MSON-. Anterograde trans-synaptic degeneration is early detectable in RRMS presenting with optic neuritis but does not involve LGN.

The small molecule fibroblast growth factor receptor inhibitor infigratinib exerts anti-inflammatory effects and remyelination in a model of multiple sclerosis.

Fibroblast growth factors and receptors (FGFR) have been shown to modulate inflammation and neurodegeneration in multiple sclerosis (MS). The selective FGFR inhibitor infigratinib has been shown to be effective in cancer models. Here, we investigate the effects of infigratinib on prevention and suppression of first clinical episodes of myelin oligodendrocyte glycoprotein (MOG)35-55 -induced experimental autoimmune encephalomyelitis (EAE) in mice. The FGFR inhibitor infigratinib was given over 10days from the time of experimental autoimmune encephalomyelitis induction or the onset of symptoms. The effects of infigratinib on proliferation, cytotoxicity and FGFR signalling proteins were studied in lymphocyte cell lines and microglial cells. Administration of infigratinib prevented by 40% and inhibited by 65% first clinical episodes of the induced experimental autoimmune encephalomyelitis. In the spinal cord, infiltration of lymphocytes and macrophages/microglia, destruction of myelin and axons were reduced by infigratinib. Infigratinib enhanced the maturation of oligodendrocytes and increased remyelination. In addition, infigratinib resulted in an increase of myelin proteins and a decrease in remyelination inhibitors. Further, lipids associated with neurodegeneration such as lysophosphatidylcholine and ceramide were decreased as were proliferation of T cells and microglial cells. This proof of concept study demonstrates the therapeutic potential of targeting FGFRs in a disease model of multiple sclerosis. Application of oral infigratinib resulted in anti-inflammatory and remyelinating effects. Thus, infigratinib may have the potential to slow disease progression or even to improve the disabling symptoms of multiple sclerosis.

A Phase 1b, Open-Label Study to Evaluate the Safety and Tolerability of the Putative Remyelinating Agent, Liothyronine, in Individuals with MS

Thyroid hormones are essential during developmental myelination and may play a direct role in remyelination and repair in the adult central nervous system by promoting the differentiation of oligodendrocyte precursor cells into mature oligodendrocytes. Since tri-iodothyronine (T3) is believed to mediate the majority of important thyroid hormone actions, liothyronine (synthetic T3) has the potential to induce reparative mechanisms and limit neurodegeneration in multiple sclerosis (MS). We completed a phase 1b clinical trial to determine the safety and tolerability of ascending doses of liothyronine in individuals with relapsing and progressive MS. A total of 20 people with MS were enrolled in this single-center trial of oral liothyronine. Eighteen participants completed the 24-week study. Our study cohort included mostly women (11/20), majority relapsing MS (12/20), mean age of 46, and baseline median EDSS of 3.5. Liothyronine was tolerated well without treatment-related severe/serious adverse events or evidence of disease activation/clinical deterioration. The most common adverse events included gastrointestinal distress and abnormal thyroid function tests. No clinical thyrotoxicosis occurred. Importantly, we did not observe a negative impact on secondary clinical outcome measures. The CSF proteomic changes suggest a biological effect of T3 treatment within the CNS. We noted changes primarily in proteins associated with immune cell function and angiogenesis. Liothyronine appeared safe and was well tolerated in people with MS. A larger clinical trial will help assess whether liothyronine can promote oligodendrogenesis and enhance remyelination in vivo, limit axonal degeneration, or improve function.

Effects of Ibudilast on Retinal Atrophy in Progressive Multiple Sclerosis Subtypes: Post Hoc Analyses of the SPRINT-MS Trial.

Ganglion cell + inner plexiform layer (GCIPL) thinning, measured by optical coherence tomography (OCT), reflects global neurodegeneration in multiple sclerosis (MS). Atrophy of the inner (INL) and outer nuclear layer (ONL) may also be prominent in progressive MS (PMS). The phase 2, SPRINT-MS trial found reduced brain atrophy with ibudilast therapy in PMS. In this post hoc analysis of the SPRINT-MS trial, we investigate (1) retinal atrophy (2) differences in response by subtype and (3) associations between OCT and MRI measures of neurodegeneration. In the multicenter, double-blind SPRINT-MS trial, participants with secondary progressive MS (SPMS) or primary progressive MS (PPMS) were randomized to ibudilast or placebo. OCT and MRI data were collected every 24 weeks for 96 weeks. Extensive OCT quality control and algorithmic segmentation produced consistent results across Cirrus HD-OCT and Spectralis devices. Primary endpoints were GCIPL, INL, and ONL atrophy, assessed by linear mixed-effects regression. Secondary endpoints were associations of OCT measures, brain parenchymal fraction, and cortical thickness, assessed by partial Pearson correlations. One hundred thirty-four PPMS and 121 SPMS participants were included. GCIPL atrophy was 79% slower in the ibudilast (-0.07 ± 0.23 µm/y) vs placebo group (-0.32 ± 0.20 µm/y, p = 0.003). This effect predominated in the PPMS cohort (ibudilast: -0.08 ± 0.29 µm/y vs placebo: -0.60 ± 0.29 µm/y, a decrease of 87%, p < 0.001) and was not detected in the SPMS cohort (ibudilast: -0.21 ± 0.28 µm/y vs placebo: -0.14 ± 0.27 µm/y, p = 0.55). GCIPL, INL, and ONL atrophy rates correlated with whole brain atrophy rates across the cohort (r = 0.27, r = 0.26, and r = 0.20, respectively; p < 0.001). Power calculations from these data show future trials of similar size and design have ≥80% power to detect GCIPL atrophy effect sizes of approximately 40%. Ibudilast treatment decreased GCIPL atrophy in PMS, driven by the PPMS cohort, with no effect seen in SPMS. Modulated atrophy of retinal layers may be detectable in sample sizes smaller than the SPRINT-MS trial and correlate with whole brain atrophy in PMS, further highlighting their utility as outcomes in PMS. This study provides Class II evidence that ibudilast reduces composite ganglion cell + inner plexiform layer atrophy, without reduction of inner or outer nuclear layer atrophy, in patients with primary progressive MS but not those with secondary progressive MS.

Detection of grey matter microstructural substrates of neurodegeneration in multiple sclerosis.

Multiple sclerosis features complex pathological changes in grey matter that begin early and eventually lead to diffuse atrophy. Novel approaches to image grey-matter microstructural alterations in vivo are highly sought after and would enable more sensitive monitoring of disease activity and progression. This cross-sectional study aimed to assess the sensitivity of high-gradient diffusion MRI for microstructural tissue damage in cortical and deep grey matter in people with multiple sclerosis and test the hypothesis that reduced cortical cell body density is associated with cortical and deep grey-matter volume loss. Forty-one people with multiple sclerosis (age 24-72, 14 females) and 37 age- and sex-matched healthy controls were scanned on a 3 T Connectom MRI scanner equipped with 300 mT/m gradients using a multi-shell diffusion MRI protocol. The soma and neurite density imaging model was fitted to high-gradient diffusion MRI data to obtain estimates of intra-neurite, intra-cellular and extra-cellular signal fractions and apparent soma radius. Cortical and deep grey-matter microstructural imaging metrics were compared between multiple sclerosis and healthy controls and correlated with grey-matter volume, clinical disability and cognitive outcomes. People with multiple sclerosis showed significant cortical and deep grey-matter volume loss compared with healthy controls. People with multiple sclerosis showed trends towards lower cortical intra-cellular signal fraction and significantly lower intra-cellular and higher extra-cellular signal fractions in deep grey matter, especially the thalamus and caudate, compared with healthy controls. Changes were most pronounced in progressive disease and correlated with the Expanded Disability Status Scale, but not the Symbol Digit Modalities Test. In multiple sclerosis, normalized thalamic volume was associated with thalamic microstructural imaging metrics. Whereas thalamic volume loss did not correlate with cortical volume loss, cortical microstructural imaging metrics were significantly associated with thalamic volume, and not with cortical volume. Compared with the short diffusion time (Δ = 19 ms) achievable on the Connectom scanner, at the longer diffusion time of Δ = 49 ms attainable on clinical scanners, multiple sclerosis-related changes in imaging metrics were generally less apparent with lower effect sizes in cortical and deep grey matter. Soma and neurite density imaging metrics obtained from high-gradient diffusion MRI data provide detailed grey-matter characterization beyond cortical and thalamic volumes and distinguish multiple sclerosis-related microstructural pathology from healthy controls. Cortical cell body density correlates with thalamic volume, appears sensitive to the microstructural substrate of neurodegeneration and reflects disability status in people with multiple sclerosis, becoming more pronounced as disability worsens.

Trans-synaptic degeneration as a mechanism of neurodegeneration in multiple sclerosis.

Trans-synaptic degeneration as a mechanism of neurodegeneration in multiple sclerosis.

Utility of the visual system to monitor neurodegeneration in multiple sclerosis.

Neurodegeneration occurs early in the multiple sclerosis (MS) disease course and is an important driver of permanent disability. Current immunomodulatory therapies do not directly target neuronal health; thus, there is a critical need to develop neuroprotective strategies in MS. Outcome measures in clinical trials primarily evaluate disease activity and clinical disability scores rather than measures of neurodegeneration. The visual system provides a noninvasive correlate of brain atrophy and neuronal function through structural and functional exams. Furthermore, optic nerve axons and their respective neuronal cell bodies in the retina, in addition to their synaptic input to the thalamus, provide a distinct anatomy to investigate neurodegenerative processes. This review discusses the utility of the visual system as an early output measure of neurodegeneration in MS as well as an important platform to evaluate neuroprotective strategies in preclinical models.

NAT8L mRNA oxidation is linked to neurodegeneration in multiple sclerosis

RNA oxidation has been implicated in neurodegeneration, but the underlying mechanism for such effects is unclear. Extensive RNA oxidation occurs within the neurons in multiple sclerosis (MS) brains. Here, we identified selectively oxidized mRNAs in neuronal cells that pertained to neuropathological pathways. N-acetyl aspartate transferase 8 like (NAT8L) is one such transcript, whose translation product enzymatically synthesizes N-acetyl aspartic acid (NAA), a neuronal metabolite important for myelin synthesis. We reasoned that impediment of translation of an oxidized NAT8L mRNA will result in a reduction in its cognate protein, thus lowering the NAA level. This hypothesis is supported by our studies on cells, an animal model, and postmortem human MS brain. Reduced brain NAA level hampers myelin integrity making neuronal axons more susceptible to damage, which contributes to MS neurodegeneration. Overall, this work provides a framework for a mechanistic understanding of the link between RNA oxidation and neurodegeneration.