Multiple Sclerosis Brain Research Articles

The relation between BTK expression and iron accumulation of myeloid cells in multiple sclerosis.

Activation of Bruton's tyrosine kinase (BTK) has been shown to play a crucial role in the proinflammatory response of B cells and myeloid cells upon engagement with B cell, Fc, Toll-like receptor, and distinct chemokine receptors. Previous reports suggest BTK actively contributes to the pathogenesis of multiple sclerosis (MS). The BTK inhibitor Evobrutinib has been shown to reduce the numbers of gadolinium-enhancing lesions and relapses in relapsing-remitting MS patients. In vitro, BTK inhibition resulted in reduced phagocytic activity and modulated BTK-dependent inflammatory signaling of microglia and macrophages. Here, we investigated the protein expression of BTK and CD68 as well as iron accumulation in postmortem control (n = 10) and MS (n = 23) brain tissue, focusing on microglia and macrophages. MS cases encompassed active, chronic active, and inactive lesions. BTK+ and iron+ cells positively correlated across all regions of interests and, along with CD68, revealed highest numbers in the center of active and at the rim of chronic active lesions. We then studied the effect of BTK inhibition in the human immortalized microglia-like HMC3 cell line in vitro. In particular, we loaded HMC3 cells with iron-dextran and subsequently administered the BTK inhibitor Evobrutinib. Iron treatment alone induced a proinflammatory phenotype and increased the expression of iron importers as well as the intracellular iron storage protein ferritin light chain (FTL). BTK inhibition of iron-laden cells dampened the expression of microglia-related inflammatory genes as well as iron-importers, whereas the iron-exporter ferroportin was upregulated. Our data suggest that BTK inhibition not only dampens the proinflammatory response but also reduces iron import and storage in activated microglia and macrophages with possible implications on microglial iron accumulation in chronic active lesions in MS.

High Levels of Perivascular Inflammation and Active Demyelinating Lesions at Time of Death Associated with Rapidly Progressive Multiple Sclerosis Disease Course: A Retrospective Postmortem Cohort Study.

Analysis of postmortem multiple sclerosis (MS) tissues combined with in vivo disease milestones suggests that whereas perivascular white matter infiltrates are associated with demyelinating activity in the initial stages, leptomeningeal immune cell infiltration, enriched in B cells, and associated cortical lesions contribute to disease progression. We systematically examine the association of inflammatory features and white matter demyelination at postmortem with clinical milestones. In 269 MS brains, 20 sites were examined using immunohistochemistry for active lesions (ALs) and perivenular inflammation (PVI). In a subset of 22, a detailed count of CD20+ B cells and CD3+ T cells in PVIs was performed. ALs were detected in 22%, whereas high levels of PVI were detected in 52% of cases. ALs were present in 35% of cases with high levels of PVI. Shorter time from onset of progression to death was associated with increased prevalence and higher levels of PVI (both p < 0.0001). Shorter time from onset of progression to wheelchair use was associated with higher prevalence of ALs (odds ratio [OR] = 0.921, 95% confidence interval [CI] = 0.858-0.989, p = 0.0230) and higher level of PVI (OR = 0.932, 95% CI = 0.886-0.981, p = 0.0071). High levels of PVI were associated with meningeal inflammation and increased cortical demyelination and significantly higher levels of B lymphocytes within the PVI. ALs, a feature of early disease stage, persist up to death in a subgroup with high levels of PVI. These features link to a rapid progressive phase and higher levels of meningeal inflammation and B-cell infiltrates, supporting the hypothesis that chronic inflammation drives progression in MS. ANN NEUROL 2024;95:706-719.

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.

Promises of Lipid-Based Nanocarriers for Delivery of Dimethyl Fumarate to Multiple Sclerosis Brain.

Multiple sclerosis (MS) is a neurodegenerative autoimmune disorder of the central nervous system (CNS) infecting 2.5million people worldwide. It is the most common nontraumatic neurological impairment in young adults. The blood-brain barrier rupture for multiple sclerosis pathogenesis has two effects: first, during the onset of the immunological attack, and second, for the CNS self-sustained "inside-out" demyelination and neurodegeneration processes. In addition to genetic variations, environmental and lifestyle variables can also significantly increase the risk of developing MS. Dimethyl fumarate (DMF) and sphingosine-1-phosphate (S1P) receptor modulators that may pass the blood-brain barrier and have positive direct effects in the CNS with quite diverse mechanisms of action raise the possibility that a combination therapy could be successful in treating MS. Lipid nanocarriers are recognized as one of the best drug delivery techniques to the brain for effective brain delivery. Numerous scientific studies have shown that lipid nanoparticles can enhance the lipid solubility, oral bioavailability, and brain availability of the drugs. Nanolipidic carriers for DMF delivery could be derived through vitamin D, tocopherol acetate, stearic acid, quercetin, cell-mimicking platelet-based, and chitosan-alginate core-shell-corona-shaped nanoparticles. Clinical and laboratory diagnosis of MS can be performed mainly through magnetic resonance imaging. The advancements in nanotechnology have enabled the clinicians to cross the blood-brain barrier and to target the brain and central nervous system of the patient with multiple sclerosis.

How the immune response to a common virus may target the brain in multiple sclerosis

We discovered that the immune response to a common virus called Epstein-Barr virus may be linked to multiple sclerosis by cross-reacting with a protein in the body called alpha-crystallin B . People who reacted to this protein were more likely to develop the disease, and this finding is a step forward in our understanding of how this common virus may cause disease in some people.

Concurrent gliomas in patients with multiple sclerosis

BackgroundConcurrent malignant brain tumors in patients with multiple sclerosis (MS) constitute a rare but paradigmatic phenomenon for studying neuroimmunological mechanisms from both molecular and clinical perspectives.MethodsA multicenter cohort of 26 patients diagnosed with both primary brain tumors and multiple sclerosis was studied for disease localization, tumor treatment-related MS activity, and molecular characteristics specific for diffuse glioma in MS patients.ResultsMS neither predisposes nor protects from the development of gliomas. Patients with glioblastoma WHO grade 4 without isocitratdehydrogenase (IDH) mutations have a longstanding history of MS, whereas patients diagnosed with IDH-mutant astrocytoma WHO grade 2 receive multiple sclerosis diagnosis mostly at the same time or later. Concurrent MS is associated with a lesser extent of tumor resection and a worse prognosis in IDH-mutant glioma patients (PFS 32 vs. 64 months, p = 0.0206). When assessing tumor-intrinsic differences no distinct subgroup-defining methylation pattern is identified in gliomas of MS patients compared to other glioma samples. However, differential methylation of immune-related genetic loci including human leukocyte antigen locus on 6p21 and interleukin locus on 5q31 is found in MS patients vs. matched non-MS patients. In line, inflammatory disease activity increases in 42% of multiple sclerosis patients after brain tumor radiotherapy suggesting a susceptibility of multiple sclerosis brain tissue to pro-inflammatory stimuli such as ionizing radiation.ConclusionsConcurrent low-grade gliomas should be considered in multiple sclerosis patients with slowly progressive, expansive T2/FLAIR lesions. Our findings of typically reduced extent of resection in MS patients and increased MS activity after radiation may inform future treatment decisions.

Transient Receptor Potential Vanilloid 4-Dependent Microglial Function in Myelin Injury and Repair.

Microglia are found pathologically at all stages of multiple sclerosis (MS) lesion development and are hypothesized to contribute to both inflammatory injury and neuroprotection in the MS brain. Transient receptor potential vanilloid 4 (TRPV4) channels are widely expressed, play an important role as environmental sensors, and are involved in calcium homeostasis for a variety of cells. TRPV4 modulates myeloid cell phagocytosis in the periphery and microglial motility in the central nervous system. We hypothesized that TRPV4 deletion would alter microglia phagocytosis in vitro and lessen disease activity and demyelination in experimental autoimmune encephalitis (EAE) and cuprizone-induced demyelination. We found that genetic deletion of TRPV4 led to increased microglial phagocytosis in vitro but did not alter the degree of demyelination or remyelination in the cuprizone mouse model of MS. We also found no difference in disease in EAE following global or microglia-specific deletion of Trpv4. Additionally, lesioned and normal appearing white matter from MS brains exhibited similar TRPV4 expression compared to healthy brain tissue. Taken together, these findings indicate that TRPV4 modulates microglial activity but does not impact disease activity in mouse models of MS, suggesting a muted and/or redundant role in MS pathogenesis.

The Use of Artificial Intelligence in the Evaluation of Multiple Sclerosis Brain Lesions Through the Processing of MRI Images

The Use of Artificial Intelligence in the Evaluation of Multiple Sclerosis Brain Lesions Through the Processing of MRI Images

Blood-Brain Barrier and Neuronal Damage during Icans in Patients Treated with Anti-CD19 CAR-T Cells

Background Immune effector cell-associated neurotoxicity syndrome (ICANS) is the most frequent neurological toxicity occurring after treatment with chimeric antigen receptor T-cells (CAR-T), with a reported incidence of around 30-50% according to different settings and products. Clinical manifestations may widely range from dizziness to seizures, and tend to achieve response with high-dose steroids. The pathogenesis of ICANS is unclear; despite some data suggest a role for endothelial activation and impairment of the blood-brain barrier (BBB). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NFL) are reliable astroglial and axonal neuronal damage biomarkers, respectively. NFL provides structural support to neurons, while GFAP is crucial for astrocyte function and BBB maintenance. Elevated levels of NFL and GFAP in cerebrospinal fluid indicate BBB damage, aiding the diagnosis and monitoring of neurological conditions like multiple sclerosis and traumatic brain injury. Recently, preliminary studies reported that NFL serum levels correlate with the severity of neurotoxicity after CAR T-cell treatment. Aim and Methods In our study, we measured GFAP and NFL both at baseline and at day 7 in 34 patients with R/R B-cell malignancies treated with CD19 CAR-T cells (15 Axi-cel, 12 Tisa-cel, 7 Brexu-cel), and explored their association with clinically relevant neurological toxicities and markers of endothelial impairment. We have collected peripheral blood samples from patients treated with CD19-directed CAR-T cells at baseline and at every other day up to 14 days after CAR-T infusion. We have measured GFAP and NFL levels and compared them with clinical neurotoxicity and serum markers of endothelial damage or inflammatory activity. Results Elderly patients tended to have higher values of GFAP at day 0 and to raise those levels after CAR-T infusion. When measured after infusion, GFAP positively correlated with endothelial biomarkers such as von Willebrand factor (p=0.041) and sST2 (p=0.015) and got some trends with IL-2R (p=0.050) and SUPAR (p=0.074). NFL positively correlated with the vWF (p=0.021) and with the endothelial activation score mEASIX (p=0.015) (Figure 1A). Overall, 11/34 patients (33%) developed ICANS. Baseline GFAP and NFL values did not impact the subsequent development of CRS or ICANS. When compared to the baseline, an increase of NFL was observed in 50% of cases. Patients experiencing an increase in NFL values after CAR-T infusion were more likely to develop ICANS of higher grades (p=0.046, OR 4.14) and to receive treatment with steroids (p=0.023). The median increase of NFL in patients with ICANS was of 25% of baseline levels. When representing values measured after CAR-T infusion in a heatmap, it emerges that a profile with higher GFAP and NFL may describe patients with ICANS of a higher grade (Figure 1B). Conclusion To sum up, our data confirm a correlation between severe ICANS and elevated NFL and G-FAP serum levels. Interestingly, these data also correlate with markers of endothelial activation, suggesting an active role of BBB impairment - considered in both its components- and concomitant neuronal damage in the pathogenesis of ICANS.

Quantitative Analysis of S1PR1 Expression in the Postmortem Multiple Sclerosis Central Nervous System.

Multiple sclerosis (MS) is an immune-mediated disease that is characterized by demyelination and inflammation in the central nervous system (CNS). Previous studies demonstrated that sphingosine-1-phosphate receptor (S1PR) modulators effectively inhibit S1PR1 in immune cell trafficking and reduce entry of pathogenic cells into the CNS. Studies have also implicated a nonimmune, inflammatory role of S1PR1 within the CNS in MS. In this study, we explored the expression of S1PR1 in the development and progression of demyelinating pathology of MS by quantitative assessment of S1PR1 expression using our S1PR1-specific radioligand, [3H]CS1P1, in the postmortem human CNS tissues including cortex, cerebellum, and spinal cord of MS cases and age- and sex-matched healthy cases. Immunohistochemistry with whole slide scanning for S1PR1 and various myelin proteins was also performed. Autoradiographic analysis using [3H]CS1P1 showed that the expression of S1PR1 was statistically significantly elevated in lesions compared to nonlesion regions in the MS cases, as well as normal healthy controls. The uptake of [3H]CS1P1 in the gray matter and nonlesion white matter did not significantly differ between healthy and MS CNS tissues. Saturation autoradiography analysis showed an increased binding affinity (Kd) of [3H]CS1P1 to S1PR1 in both gray matter and white matter of MS brains compared to healthy brains. Our blocking study using NIBR-0213, a S1PR1 antagonist, indicated [3H]CS1P1 is highly specific to S1PR1. Our findings demonstrated the activation of S1PR1 and an increased uptake of [3H]CS1P1 in the lesions of MS CNS. In summary, our quantitative autoradiography analysis using [3H]CS1P1 on human postmortem tissues shows the feasibility of novel imaging strategies for MS by targeting S1PR1.

Use of immersive virtual reality for stress reduction during botulinum toxin injection for spasticity (RVTOX): a study protocol of a randomised control trial

IntroductionBotulinum toxin injection is a common way to help reduce spasticity in the body caused by central neurological damage such as cerebral stroke, multiple sclerosis or traumatic brain injury. The...

Lifespan neurodegeneration of the human brain in multiple sclerosis.

Atrophy related to multiple sclerosis (MS) has been found at the early stages of the disease. However, the archetype dynamic trajectories of the neurodegenerative process, even prior to clinical diagnosis, remain unknown. We modeled the volumetric trajectories of brain structures across the entire lifespan using 40,944 subjects (38,295 healthy controls and 2649 MS patients). Then, we estimated the chronological progression of MS by assessing the divergence of lifespan trajectories between normal brain charts and MS brain charts. Chronologically, the first affected structure was the thalamus, then the putamen and the pallidum (around 4 years later), followed by the ventral diencephalon (around 7 years after thalamus) and finally the brainstem (around 9 years after thalamus). To a lesser extent, the anterior cingulate gyrus, insular cortex, occipital pole, caudate and hippocampus were impacted. Finally, the precuneus and accumbens nuclei exhibited a limited atrophy pattern. Subcortical atrophy was more pronounced than cortical atrophy. The thalamus was the most impacted structure with a very early divergence in life. Our experiments showed that lifespan models of most impacted structures could be an important tool for future preclinical/prodromal prognosis and monitoring of MS.

DeepCONN: patch-wise deep convolutional neural networks for the segmentation of multiple sclerosis brain lesions

DeepCONN: patch-wise deep convolutional neural networks for the segmentation of multiple sclerosis brain lesions

Quantitative magnetic resonance mapping of the myelin bilayer reflects pathology in multiple sclerosis brain tissue.

Multiple sclerosis (MS) is a neuroinflammatory disease characterized by loss of myelin (demyelination) and, to a certain extent, subsequent myelin repair (remyelination). To better understand the pathomechanisms underlying de- and remyelination and to monitor the efficacy of treatments aimed at regenerating myelin, techniques offering noninvasive visualizations of myelin are warranted. Magnetic resonance (MR) imaging has long been at the forefront of efforts to visualize myelin, but it has only recently become feasible to access the rapidly decaying resonance signals stemming from the myelin lipid-protein bilayer itself. Here, we show that direct MR mapping of the bilayer yields highly specific myelin maps in brain tissue from patients with MS. Furthermore, examination of the bilayer signal behavior is found to reveal pathological alterations in normal-appearing white and gray matter. These results indicate promise for in vivo implementations of the myelin bilayer mapping technique, with prospective applications in basic research, diagnostics, disease monitoring, and drug development.

Nanomedicine strategies for central nervous system (CNS) diseases

The blood-brain barrier (BBB) is a crucial part of brain anatomy as it is a specialized, protective barrier that ensures proper nutrient transport to the brain, ultimately leading to regulating proper brain function. However, it presents a major challenge in delivering pharmaceuticals to treat central nervous system (CNS) diseases due to this selectivity. A variety of different vehicles have been designed to deliver drugs across this barrier to treat neurodegenerative diseases, greatly impacting the patient’s quality of life. The two main types of vehicles used to cross the BBB are polymers and liposomes, which both encapsulate pharmaceuticals to allow them to transcytose the cells of the BBB. For Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and glioblastoma brain cancer, there are a variety of different nanoparticle treatments in development that increase the bioavailability and targeting ability of existing drugs or new drug targets to decrease symptoms of these diseases. Through these systems, nanomedicine offers a new way to target specific tissues, especially for the CNS, and treat diseases without the systemic toxicity that often comes with medications used currently.

Two-carba cyclic phosphatidic acid treatment promotes phenotypic switch from M1 to M2 microglia and prevents behavioral abnormalities in a mouse model of neuropsychiatric systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease associated with the production of double-stranded DNA (dsDNA) antibodies and other antibodies that predominantly affects women with a wide range of lesions. Although neuropsychiatric lupus erythematosus (NPSLE), characterized by neuropsychiatric symptoms related to cerebrovascular diseases or depression, ranks high in severity, no specific treatment has been defined. Two-carba cyclic phosphatidic acid (2ccPA), a derivative of cyclic phosphatidic acid, was isolated from the true slime mold Physarum polycephalum in 1992. 2ccPA treatment suppresses neuroinflammation and promotes tissue repair in mouse multiple sclerosis and traumatic brain injury models. In this study, we performed behavioral tests on MRL/lpr mice as an NPSLE model. MRL/lpr mice showed increased depression-like behaviors compared with control mice, which were significantly suppressed by 2ccPA treatment. The expression of CD68, an M1 phenotypic marker of microglia, was significantly elevated in the prefrontal cortex and hippocampus of MRL/lpr mice, which was significantly suppressed by 2ccPA treatment. In contrast, the expression of Arginase1, an M2 phenotypic marker of microglia, was significantly increased by 2ccPA treatment. Compared to control mice, MRL/lpr mice showed higher plasma levels of anti-dsDNA antibodies, which are mainly involved in SLE pathogenesis. 2ccPA treatment decreased these levels in the MRL/lpr mice. These results suggest that 2ccPA treatment suppresses behavioral abnormalities by promoting a microglial phenotypic switch from M1 to M2 in MRL/lpr mice.

Accelerometry applications and methods to assess standing balance in older adults and mobility-limited patient populations: a narrative review.

Accelerometers provide an opportunity to expand standing balance assessments outside of the laboratory. The purpose of this narrative review is to show that accelerometers are accurate, objective, and accessible tools for balance assessment. Accelerometry has been validated against current gold standard technology, such as optical motion capture systems and force plates. Many studies have been conducted to show how accelerometers can be useful for clinical examinations. Recent studies have begun to apply classification algorithms to accelerometry balance measures to discriminate populations at risk for falls. In addition to healthy older adults, accelerometry can monitor balance in patient populations such as Parkinson's disease, multiple sclerosis, and traumatic brain injury. The lack of software packages or easy-to-use applications have hindered the shift into the clinical space. Lack of consensus on outcome metrics has also slowed the clinical adoption of accelerometer-based balance assessments. Future studies should focus on metrics that are most helpful to evaluate balance in specific populations and protocols that are clinically efficacious.

Hyaluronan hydrates and compartmentalises the CNS/PNS extracellular matrix and provides niche environments conducive to the optimisation of neuronal activity.

The central nervous system/peripheral nervous system (CNS/PNS) extracellular matrix is a dynamic and highly interactive space-filling, cell-supportive, matrix-stabilising, hydrating entity that creates and maintains tissue compartments to facilitate regional ionic micro-environments and micro-gradients that promote optimal neural cellular activity. The CNS/PNS does not contain large supportive collagenous and elastic fibrillar networks but is dominated by a high glycosaminoglycan content, predominantly hyaluronan (HA) and collagen is restricted to the brain microvasculature, blood-brain barrier, neuromuscular junction and meninges dura, arachnoid and pia mater. Chondroitin sulphate-rich proteoglycans (lecticans) interactive with HA have stabilising roles in perineuronal nets and contribute to neural plasticity, memory and cognitive processes. Hyaluronan also interacts with sialoproteoglycan associated with cones and rods (SPACRCAN) to stabilise the interphotoreceptor matrix and has protective properties that ensure photoreceptor viability and function is maintained. HA also regulates myelination/re-myelination in neural networks. HA fragmentation has been observed in white matter injury, multiple sclerosis, and traumatic brain injury. HA fragments (2 × 105 Da) regulate oligodendrocyte precursor cell maturation, myelination/remyelination, and interact with TLR4 to initiate signalling cascades that mediate myelin basic protein transcription. HA and its fragments have regulatory roles over myelination which ensure high axonal neurotransduction rates are maintained in neural networks. Glioma is a particularly invasive brain tumour with extremely high mortality rates. HA, CD44 and RHAMM (receptor for HA-mediated motility) HA receptors are highly expressed in this tumour. Conventional anti-glioma drug treatments have been largely ineffective and surgical removal is normally not an option. CD44 and RHAMM glioma HA receptors can potentially be used to target gliomas with PEP-1, a cell-penetrating HA-binding peptide. PEP-1 can be conjugated to a therapeutic drug; such drug conjugates have successfully treated dense non-operative tumours in other tissues, therefore similar applications warrant exploration as potential anti-glioma treatments.

Influence of cardiorespiratory fitness and MRI measures of neuroinflammation on hippocampal volume in multiple sclerosis

BackgroundThe hippocampus is a clinically relevant region where neurogenesis and neuroplasticity occur throughout the whole lifespan. Neuroinflammation and cardiorespiratory fitness (CRF) may influence hippocampal integrity by modulating the processes promoting...

Brain and cognitive reserve mitigate balance dysfunction in multiple sclerosis.

Approximately two-thirds of patients with multiple sclerosis (MS) complain different degrees of balance dysfunction, but some of them are able to withstand considerable disease burden without an overt balance impairment. Here, we tested the hypothesis that brain and cognitive reserve lessen the effect of MS-related tissue damage on balance control. We measured the postural sway of 148 patients and 74 sex- and age-matched healthy controls by force platform under different conditions reflecting diverse neuro-pathological substrates of balance dysfunction: eyes opened (EO), eyes closed (EC), and while performing the Stroop test, i.e., dual-task (DT). Lesion volumes on T2-hyperintense and T1-hypointense sequences, and normalized brain volume provided estimations of MS-related tissue damage in patients with MS. Hierarchical linear regressions explored the protective effect against the MS-related tissue damage of intracranial volume and educational attainment (proxies for brain and cognitive reserve, respectively) on balance. Larger intracranial volume and high educational attainment mitigated the detrimental effect of MS-related tissue damage on postural sway under EO (adjusted-R2=0.20 and 0.27, respectively, p<0.01) and DT (adjusted-R2=0.22 and 0.30, respectively, p<0.06) conditions. Neither educational level nor brain size was associated with postural sway under EC condition. Our findings suggest a protective role of brain and cognitive reserve even on balance, an outcome that relies on both motor control and higher order processing resources. The lack of a protective effect on postural sway under EC condition confirms that this latter outcome is closer associated with spinal cord rather than brain damage.