Central Nervous System Compartment Research Articles

Non-genomic ERα-AMPK signaling regulates sex-dependent Bcrp transport activity at the blood-brain barrier.

The blood-brain barrier (BBB) is an extensive capillary network that protects the brain from environmental and metabolic toxins while limiting drug delivery to the central nervous system (CNS). The ATP-Binding Cassette (ABC) transporter Breast cancer resistance protein (Bcrp) reduces drug delivery across the BBB by actively transporting its clinical substrates back into peripheral circulation before their entry into the CNS compartment. 17β-estradiol (E2)-elicited changes in Bcrp transport activity and expression have been documented previously. We report a novel signaling mechanism by which E2 decreases Bcrp transport activity in mouse brain capillaries (MBCs) via rapid non-genomic signaling through estrogen receptor α (ERα). We extended this finding to investigate the effects of different endocrine-disrupting compounds (EDCs) and selective estrogen receptor modulators (SERMs) on Bcrp transport function. We also demonstrate sex-dependent expression of Bcrp and E2-sensitive Bcrp transport activity at the BBB ex vivo. This work establishes an explanted tissue-based model by which to interrogate EDCs and SERMs as modulators of nongenomic estrogenic signaling with implications for sex and hormonal regulation of therapeutic delivery into the CNS.

Modeling the Simultaneous Dynamics of Proteins in Blood Plasma and the Cerebrospinal Fluid in Human In Vivo.

The analysis of protein dynamics or turnover in patients has the potential to reveal altered protein recycling, such as in Alzheimer's disease, and to provide informative data regarding drug efficacy or certain biological processes. The observed protein dynamics in a solid tissue or a fluid is the net result of not only protein synthesis and degradation but also transport across biological compartments. We report an accurate 3-biological compartment model able to simultaneously account for the protein dynamics observed in blood plasma and the cerebrospinal fluid (CSF) including a hidden central nervous system (CNS) compartment. We successfully applied this model to 69 proteins of a single individual displaying similar or very different dynamics in plasma and CSF. This study puts a strong emphasis on the methods and tools needed to develop this type of model. We believe that it will be useful to any researcher dealing with protein dynamics data modeling.

Modeling blood-brain barrier formation and cerebral cavernous malformations in human PSC-derived organoids

The human blood-brain barrier (hBBB) is a highly specialized structure that regulates passage across blood and central nervous system (CNS) compartments. Despite its critical physiological role, there are no reliable invitro models that can mimic hBBB development and function. Here, we constructed hBBB assembloids from brain and blood vessel organoids derived from human pluripotent stem cells. We validated the acquisition of blood-brain barrier (BBB)-specific molecular, cellular, transcriptomic, and functional characteristics and uncovered an extensive neuro-vascular crosstalk with a spatial pattern within hBBB assembloids. When we used patient-derived hBBB assembloids to model cerebral cavernous malformations (CCMs), we found that these assembloids recapitulated the cavernoma anatomy and BBB breakdown observed in patients. Upon comparison of phenotypes and transcriptome between patient-derived hBBB assembloids and primary human cavernoma tissues, we uncovered CCM-related molecular and cellular alterations. Taken together, we report hBBB assembloids that mimic the core properties of the hBBB and identify a potentially underlying cause of CCMs.

Microglia at the blood brain barrier in health and disease.

The blood brain barrier (BBB) plays a crucial role in maintaining brain homeostasis by selectively preventing the entry of substances from the peripheral blood into the central nervous system (CNS). Comprised of endothelial cells, pericytes, and astrocytes, this highly regulated barrier encompasses the majority of the brain's vasculature. In addition to its protective function, the BBB also engages in significant crosstalk with perivascular macrophages (MΦ) and microglia, the resident MΦ of the brain. These interactions play a pivotal role in modulating the activation state of cells comprising the BBB, as well as MΦs and microglia, themselves. Alterations in systemic metabolic and inflammatory states can promote endothelial cell dysfunction, reducing the integrity of the BBB and potentially allowing peripheral blood factors to leak into the CNS compartment. This may mediate activation of perivascular MΦs, microglia, and astrocytes, and initiate further immune responses within the brain parenchyma, suggesting neuroinflammation can be triggered by signaling from the periphery, without primary injury or disease originating within the CNS. The intricate interplay between the periphery and the CNS through the BBB highlights the importance of understanding the role of microglia in mediating responses to systemic challenges. Despite recent advancements, our understanding of the interactions between microglia and the BBB is still in its early stages, leaving a significant gap in knowledge. However, emerging research is shedding light on the involvement of microglia at the BBB in various conditions, including systemic infections, diabetes, and ischemic stroke. This review aims to provide a comprehensive overview of the current research investigating the intricate relationship between microglia and the BBB in health and disease. By exploring these connections, we hope to advance our understanding of the role of brain immune responses to systemic challenges and their impact on CNS health and pathology. Uncovering these interactions may hold promise for the development of novel therapeutic strategies for neurological conditions that involve immune and vascular mechanisms.

Therapeutic Plasma Exchange and Multiple Sclerosis Dysregulations: Focus on the Removal of Pathogenic Circulatory Factors and Altering Nerve Growth Factor and Sphingosine-1-Phosphate Plasma Levels.

Multiple sclerosis (MS) is predominantly an immune-mediated disease of the central nervous system (CNS) of unknown etiology with a possible genetic predisposition and effect of certain environmental factors. It is generally accepted that the disease begins with an autoimmune inflammatory reaction targeting oligodendrocytes followed by a rapid depletion of their regenerative capacity with subsequent permanent neurodegenerative changes and disability. Recent research highlights the central role of B lymphocytes and the corresponding IgG and IgM autoantibodies in newly forming MS lesions. Thus, their removal along with the modulation of certain bioactive molecules to improve neuroprotection using therapeutic plasma exchange (TPE) becomes of utmost importance. Recently, it has been proposed to determine the levels and precise effects of both beneficial and harmful components in the serum of MS patients undergoing TPE to serve as markers for appropriate TPE protocols. In this review we discuss some relevant examples, focusing on the removal of pathogenic circulating factors and altering the plasma levels of nerve growth factor and sphingosine-1-phosphate by TPE. Altered plasma levels of the reviewed molecular compounds in response to TPE reflect a successful reduction of the pro-inflammatory burden at the expense of an increase in anti-inflammatory potential in the circulatory and CNS compartments.

VE-cadherin in arachnoid and pia mater cells serves as a suitable landmark for in vivo imaging of CNS immune surveillance and inflammation

Meninges cover the surface of the brain and spinal cord and contribute to protection and immune surveillance of the central nervous system (CNS). How the meningeal layers establish CNS compartments with different accessibility to immune cells and immune mediators is, however, not well understood. Here, using 2-photon imaging in female transgenic reporter mice, we describe VE-cadherin at intercellular junctions of arachnoid and pia mater cells that form the leptomeninges and border the subarachnoid space (SAS) filled with cerebrospinal fluid (CSF). VE-cadherin expression also marked a layer of Prox1+ cells located within the arachnoid beneath and separate from E-cadherin+ arachnoid barrier cells. In vivo imaging of the spinal cord and brain in female VE-cadherin-GFP reporter mice allowed for direct observation of accessibility of CSF derived tracers and T cells into the SAS bordered by the arachnoid and pia mater during health and neuroinflammation, and detection of volume changes of the SAS during CNS pathology. Together, the findings identified VE-cadherin as an informative landmark for in vivo imaging of the leptomeninges that can be used to visualize the borders of the SAS and thus potential barrier properties of the leptomeninges in controlling access of immune mediators and immune cells into the CNS during health and neuroinflammation.

A Novel Multicellular Placental Barrier Model to Investigate the Effect of Maternal Aflatoxin B1 Exposure on Fetal-Side Neural Stem Cells.

Ingestion of food toxins such as aflatoxin B1 (AFB1) during pregnancy may impair fetal neurodevelopment. However, animal model results may not be accurate due to the species' differences, and testing on humans is ethically impermissible. Here, we developed an in vitro human maternal-fetal multicellular model composed of a human hepatic compartment, a bilayer placental barrier, and a human fetal central nervous system compartment using neural stem cells (NSCs) to investigate the effect of AFB1 on fetal-side NSCs. AFB1 passed through the HepG2 hepatocellular carcinoma cells to mimic the maternal metabolic effects. Importantly, even at the limited concentration (0.0641 ± 0.0046 μM) of AFB1, close to the national safety level standard of China (GB-2761-2011), the mixture of AFB1 crossing the placental barrier induced NSC apoptosis. The level of reactive oxygen species in NSCs was significantly elevated and the cell membrane was damaged, causing the release of intracellular lactate dehydrogenase (p < 0.05). The comet experiment and γ-H2AX immunofluorescence assay showed that AFB1 caused significant DNA damage to NSCs (p < 0.05). This study provided a new model for the toxicological evaluation of the effect of food mycotoxin exposure during pregnancy on fetal neurodevelopment.

Intrathecal nonspecific immunoglobulin synthesis in syphilitic infection

Intrathecal Ig synthesis is one of the characteristic laboratory features of neurosyphilis (caused by Treponema pallidum subspecies pallidum able to affect the central nervous system (CNS), but a persisting pathogen-driven immune response is problem of scar effect. This long-term Ig production within the CNS compartment even after timely and proper treatment remains unexplored. We hypothesized that a long-term current chronic inflammation in the CNS caused by syphilitic infection can be a trigger of nonspecific humoral immune response and the scar effect may result from non-specific B cell activation within the CNS in the absence of antigens. The MRZ reaction is a laboratory tool for detection of intrathecal nonspecific humoral immune reaction, which is poorly investigated in syphilis patient. The MRZ reaction (MRZR) is used as a marker of intrathecal nonspecific humoral immune response and is composed of the three antibody indices (AI) against neurotropic viruses: measles, rubella and varicella zoster virus. A positive MRZR, defined as an elevated AIs ( 1.5) against at least one or more viral agents, confirms diagnosis of a chronic or autoimmune disease involving CNS recently declared as a highly specific marker of multiple sclerosis. Insufficient data on neuroinfections motivated us to examine a hypothesis that a long-term chronic inflammation within the CNS compartment caused by syphilitic infection may be a trigger of intrathecal nonspecific humoral immune response. We assessed prevalence of positive MRZR in 147 patients with later-stage syphilis seropositive for MRZ viruses. Study group included 43 patients with first-time diagnosed neurosyphilis, 16 patients with a follow-up visit after neurosyphilis treatment, 88 patients with excluded neurosyphilis. There were no significant differences between categories of patients examined, and presence of positive MRZR was not associated with any demographic, clinical and laboratory characteristics. To sum up, our study (n = 147) showed that 27 patients (18%, 95% CI: 1225% ) were positive for intrathecal Ig production against one, two or three of the M, R, Z viruses, and bi- and tri-specific MRZR was present in 7 of 147 patients (5%, 95% CI: 210%). The data obtained evidence that frequency of the MRZR for syphilitic infection matches that of found in general population and a long-term current syphilitic infection affecting CNS seems to not be a trigger of a nonspecific intrathecal immune response. Among our patients, we also selected 43 patients with previously treated syphilitic infection without any neurological symptoms and excluded neurosyphilis diagnosis, so these patients can be considered as an apparently healthy group.

Patient-derived xenograft mouse models to investigate tropism to the central nervous system and retina of primary and secondary central nervous system lymphoma.

How and why lymphoma cells home to the central nervous system and vitreoretinal compartment in primary diffuse large B-cell lymphoma of the central nervous system remain unknown. Our aim was to create an in vivo model to study lymphoma cell tropism to the central nervous system. We established a patient-derived central nervous system lymphoma xenograft mouse model and characterised xenografts derived from four primary and four secondary central nervous system lymphoma patients using immunohistochemistry, flow cytometry and nucleic acid sequencing technology. In reimplantation experiments, we analysed dissemination patterns of orthotopic and heterotopic xenografts and performed RNA sequencing of different involved organs to detect differences at the transcriptome level. We found that xenografted primary central nervous system lymphoma cells home to the central nervous system and eye after intrasplenic transplantation, mimicking central nervous system and primary vitreoretinal lymphoma pathology, respectively. Transcriptomic analysis revealed distinct signatures for lymphoma cells in the brain in comparison to the spleen as well as a small overlap of commonly regulated genes in both primary and secondary central nervous system lymphoma. This in vivo tumour model preserves key features of primary and secondary central nervous system lymphoma and can be used to explore critical pathways for the central nervous system and retinal tropism with the goal to find new targets for novel therapeutic approaches.

Selective emergence of antibody-secreting cells in the multiple sclerosis brain.

Although distinct brain-homing B cells have been identified in multiple sclerosis (MS), it is unknown how these further evolve to contribute to local pathology. We explored B-cell maturation in the central nervous system (CNS) of MS patients and determined their association with immunoglobulin (Ig) production, T-cell presence, and lesion formation. Exvivo flow cytometry was performed on post-mortem blood, cerebrospinal fluid (CSF), meninges and white matter from 28 MS and 10 control brain donors to characterize B cells and antibody-secreting cells (ASCs). MS brain tissue sections were analysed with immunostainings and microarrays. IgG index and CSF oligoclonal bands were measured with nephelometry, isoelectric focusing, and immunoblotting. Blood-derived B cells were cocultured under T follicular helper-like conditions to evaluate their ASC-differentiating capacity invitro. ASC versus B-cell ratios were increased in post-mortem CNS compartments of MS but not control donors. Local presence of ASCs associated with a mature CD45low phenotype, focal MS lesional activity, lesional Ig gene expression, and CSF IgG levels as well as clonality. Invitro B-cell maturation into ASCs did not differ between MS and control donors. Notably, lesional CD4+ memory T cells positively correlated with ASC presence, reflected by local interplay with T cells. These findings provide evidence that local B cells at least in late-stage MS preferentially mature into ASCs, which are largely responsible for intrathecal and local Ig production. This is especially seen in active MS white matter lesions and likely depends on the interaction with CD4+ memory T cells. Stichting MS Research (19-1057 MS; 20-490f MS), National MS Fonds (OZ2018-003).

Breast Cancer Brain Metastases: Achilles' Heel in Breast Cancer Patients' Care.

Brain metastases (BM) significantly affect the prognosis as well as the quality of life of breast cancer (BC) patients. Although advancements in neurosurgical and radiotherapy techniques improve local control and symptom management, BM remains associated with a poor prognosis. In addition, the efficacy of currently approved systemic therapies in central nervous system (CNS) compartment is still limited, especially after progression on local therapy. The blood-brain barrier (BBB) has been recognized as amechanism of primary resistance to many chemotherapeutic agents and targeted therapies due to low drug penetration. Other mechanisms of primary and secondary resistance are still unclear and may vary across the BC subtypes. New small molecules have demonstrated efficacy in BM, in particular for the HER2-positive subtype, with a benefit in survival. A new era has begun in the field of BM, and many trials specifically designed for this population are currently ongoing. The BC research community needs to address this call with the final aim of improving the efficacy of systemic therapy in CNS compartment and ultimately preventing the occurrence of BM.

Noninvasive, Dynamic Risk Profiling of Primary Central Nervous System Lymphoma By Peripheral Blood Ctdna-Sequencing

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare subtype of aggressive B-cell lymphoma restricted to the CNS. Despite the use of intensive chemotherapeutic regimens, relapsed or refractory disease (r/r) occurs frequently and depicts a major challenge. Response assessment is usually based on magnetic resonance imaging (MRI), but highly limited due to insufficient discrimination between scar and active tumor tissue. Furthermore, serial biopsies are often not feasible. Accordingly, there is a high unmet medical need for noninvasive risk profiling strategies in PCNSL. Methods: We applied circulating tumor DNA (ctDNA) sequencing to n=101 blood samples of n=47 patients. Peripheral blood was collected before (pre, n=47), during (mid, n=27) and after (post, n=22) treatment. Sequencing of ctDNA in cerebrospinal fluid (CSF) was performed in 5 patients. Our ctDNA sequencing approach encompasses a targeted gene panel covering >350 genes or genetic regions and an in-house developed bioinformatic pipeline. In the current version, our pipeline shows improved sensitivity and specificity over our previously published version (Sobesky S et al. Med. 2021;2(10):1171-1193.e11), mainly due to the addition of duplex barcode information. Results: The total amount of cell-free DNA (cfDNA) in plasma was generally low (mean 22.3, range 1.4-208.5 ng/ml) as compared to patients with systemic disease. We hypothesized that cfDNA fragment length profiles and their dynamic changes can inform on outcome in PCNSL as has been recently shown for other lymphomas (Meriranta L et al. Blood. 2022;139(12):1863-1877). To this end, we extracted fragment lengths distributions from all cfDNA samples and used principal component analysis to discern fragment length profiles representative of certain types of samples and remission status. Pre-treatment samples contained higher proportions of short cfDNA fragments (133-173 base pairs (bp)) compared to samples obtained mid-treatment, post-treatment, and healthy controls. In contrast, CSF samples were enriched with ultra-short cfDNA fragments (61-97 bp), which were almost absent in all other samples. The detection of single nucleotide polymorphisms (SNP) and small insertions or deletions (InDel) was challenging compared to our previously published experience with Hodgkin lymphoma (Sobesky S et al. Med. 2021;2(10):1171-1193.e11). Nevertheless, we detected mutations in most samples, including recurring mutations in PCNSL-associated genes such as MYD88, PIM1 and CD79, though at a lower frequency than expected. The mean baseline ctDNA concentration was 1.7 (range 0-2.8) log haploid genome equivalents (hGE)/ml plasma. Interestingly, the ctDNA concentration was markedly increased in CSF samples. Higher average mutated allele frequency (mAF) in a plasma sample at baseline was associated with reduced progression-free survival (PFS) and overall survival (OS). Patients with a mAF > 1% showed impaired PFS and OS compared to < 1%. No events were observed in patients with mAF < 0.5% (17% of all patients). MRI-based response evaluation indicated partial response in most patients both mid- and post-treatment and thus failed to predict outcomes. Therefore, we assessed mutation-based tracking of peripheral residual disease (PRD). Persistence of PRD during treatment was associated with impaired PFS (median 3.7 vs. 26.9 months, p < 0.0001) and OS (median 4.7 months vs. not reached, p = 0.0009). We hypothesized that dynamic detection of PRD might complement baseline risk stratification by mAF alone. In our final model, baseline low risk patients (mAF low) became high risk when PRD was positive, and baseline high risk patients (mAF high) became low risk when PRD turned negative during treatment. Strikingly, this classification was highly predictive of both PFS (median 9.3 vs. 26.9 months, p = 0.0004, Fig. 1) and OS (median 10.3 months vs. not reached, p = 0.0010). Conclusions: Surprisingly large differences in fragment length profiles between ctDNA in blood and CSF might yield insight into ctDNA characteristics of both compartments in the context of PCNSL and ctDNA biology in the privileged central nervous system compartment in general. Despite challenges in consistently detecting pathognomonic genetic alterations, assessment of ctDNA-based PRD and fragmentation patterns has the potential to significantly improve treatment guidance in PCNSL patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dysbiosis of Gut Microbiota from the Perspective of the Gut-Brain Axis: Role in the Provocation of Neurological Disorders.

The gut-brain axis is a bidirectional communication network connecting the gastrointestinal tract and central nervous system. The axis keeps track of gastrointestinal activities and integrates them to connect gut health to higher cognitive parts of the brain. Disruption in this connection may facilitate various neurological and gastrointestinal problems. Neurodegenerative diseases are characterized by the progressive dysfunction of specific populations of neurons, determining clinical presentation. Misfolded protein aggregates that cause cellular toxicity and that aid in the collapse of cellular proteostasis are a defining characteristic of neurodegenerative proteinopathies. These disorders are not only caused by changes in the neural compartment but also due to other factors of non-neural origin. Mounting data reveal that the majority of gastrointestinal (GI) physiologies and mechanics are governed by the central nervous system (CNS). Furthermore, the gut microbiota plays a critical role in the regulation and physiological function of the brain, although the mechanism involved has not yet been fully interpreted. One of the emerging explanations of the start and progression of many neurodegenerative illnesses is dysbiosis of the gut microbial makeup. The present understanding of the literature surrounding the relationship between intestinal dysbiosis and the emergence of certain neurological diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis, is the main emphasis of this review. The potential entry pathway of the pathogen-associated secretions and toxins into the CNS compartment has been explored in this article at the outset of neuropathology. We have also included the possible mechanism of undelaying the synergistic effect of infections, their metabolites, and other interactions based on the current understanding.

Bruton's Tyrosine Kinase Inhibition in Multiple Sclerosis.

Purpose of ReviewMultiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with a chronic and often progressive disease course. The current disease-modifying treatments (DMTs) limit disease progression primarily by dampening immune cell activity in the peripheral blood or hindering their migration from the periphery into the CNS. New therapies are needed to target CNS immunopathology, which is a key driver of disability progression in MS. This article reviews Bruton’s Tyrosine Kinase Inhibitors (BTKIs), a new class of experimental therapy that is being intensely evaluated in MS. We focus on the potential peripheral and central mechanisms of action of BTKIs and their use in recent clinical trials in MS.Recent FindingsThere is evidence that some BTKIs cross the blood–brain barrier and may be superior to currently available DMTs at dampening the chronic neuroinflammatory processes compartmentalized within the CNS that contribute to progressive worsening in people withMS (pwMS). Recently, evobrutinib and tolebrutinib have shown efficacy in phase II clinical trials, and there are numerous ongoing phase III clinical trials of various BTKIs in relapsing and progressive forms of MS. Results from these clinical trials will be essential to understand the efficacy and safety of BTKIs across the spectrum of MS and keydifferences between specific BTKIs when treating pwMS.SummaryInhibition of BTK has emerged as an attractive strategy to target cells of the adaptive and innate immune system outside and within the CNS. BTKIs carry great therapeutic potential across the MS spectrum, where key pathobiology aspects seem confined to the CNS compartment.

COVID-19 causes neuronal degeneration and reduces neurogenesis in human hippocampus.

Recent investigations of COVID-19 have largely focused on the effects of this novel virus on the vital organs in order to efficiently assist individuals who have recovered from the disease. In the present study we used hippocampal tissue samples extracted from people who died after COVID-19. Utilizing histological techniques to analyze glial and neuronal cells we illuminated a massive degeneration of neuronal cells and changes in glial cells morphology in hippocampal samples. The results showed that in hippocampus of the studied brains there were morphological changes in pyramidal cells, an increase in apoptosis, a drop in neurogenesis, and change in spatial distribution of neurons in the pyramidal and granular layer. It was also demonstrated that COVID-19 alter the morphological characteristics and distribution of astrocyte and microglia cells. While the exact mechanism(s) by which the virus causes neuronal loss and morphology in the central nervous system (CNS) remains to be determined, it is necessary to monitor the effect of SARS-CoV-2 infection on CNS compartments like the hippocampus in future investigations. As a result of what happened in the hippocampus secondary to COVID-19, memory impairment may be a long-term neurological complication which can be a predisposing factor for neurodegenerative disorders through neuroinflammation and oxidative stress mechanisms.

Phase II randomized study comparing proton craniospinal irradiation with photon involved-field radiotherapy for patients with solid tumor leptomeningeal metastasis.

2000 Background: Leptomeningeal metastasis (LM) is associated with limited survival and treatments. Photon involved-field radiotherapy (IFRT) is the standard of care radiotherapy (RT) but benefits are limited. We hypothesized that proton craniospinal irradiation (pCSI) encompassing the central nervous system (CNS) compartment would result in superior CNS disease control compared to IFRT. Methods: We conducted a randomized phase 2 study comparing pCSI vs. IFRT in patients with non-small cell lung cancer (NSCLC) or breast cancer LM. Eligibility criteria included radiographic and/or cytologic LM and Karnofsky performance status (KPS) ≥ 60. Patients were stratified by histology (breast vs. NSCLC) and systemic disease (active vs. stable) and were randomized in a 2:1 ratio of pCSI:IFRT. Patients with all other solid tumor histologies were enrolled to an exploratory pCSI arm. RT was 3Gy x 10 fractions for all patients. The primary endpoint is CNS progression-free survival (CNS PFS), defined as time from randomization to CNS progression (POD); secondary endpoints include overall survival (OS) and treatment-related adverse events (TAEs). A target of 81 patients to compare pCSI and IFRT was designed with a one-sided alpha of 0.025 and a power of 0.8 based on stratified log-rank test. Analysis is based on intent-to-treat. Results: From 4/2020-10/2021, 42 and 21 patients were randomized to pCSI and IFRT, respectively. Baseline factors were not different: median age was 56 vs. 61 years (p = 0.5); both cohorts included 57% NSCLC and 52% with active systemic disease. At median follow up of 7.1 months, 25 patients had CNS POD (pCSI = 9 [21%], IFRT = 16 [76%]) and 28 died (pCSI = 15 [36%], IFRT = 13 [62%]). At planned interim analysis, significant benefit in CNS PFS was observed with pCSI (median = 7.5 months, 95% CI: 6.6-NA) vs. IFRT (median = 2.0, 95% CI: 1.0-5.1, p &lt; 0.001). As a result, the Data and Safety Monitoring Committee recommended early discontinuation of the trial. In addition, OS benefit with pCSI (median = 8.2 months, 95% CI: 7.4-NA) vs. IFRT (median = 4.9 months, 95% CI: 3.1-NA, p = 0.04) was observed. In a multivariable analysis including age, KPS and stratification factors, CNS PFS and OS benefit for pCSI remained significant. Grade 3 non-heme TAEs occurred in 3 patients with pCSI and 5 with IFRT. For the exploratory pCSI cohort, 35 patients enrolled, the median age was 61, 20 (57%) had active systemic disease and ovarian (7 [20%]) was the most common histology. At median follow up of 9.6 months, 7 (20%) had CNS POD and 20 (57%) died. Median CNS PFS was 5.4 months (95% CI: 4.8-9.1), OS was 6.6 months (95% CI: 5.4-12.1) and 4 patients had Grade 3 TAEs. Conclusions: In this trial, the first randomized study of RT for LM, we demonstrated improved CNS PFS of pCSI compared to IFRT, meeting the primary endpoint. pCSI also had a significant OS benefit. Grade 3 toxicities were comparable. Clinical trial information: NCT04343573.

CNS-associated T-lymphocytes in a mouse model of Hereditary Spastic Paraplegia type 11 (SPG11) are therapeutic targets for established immunomodulators

Pharmacological targeting of neuroinflammation in distinct models of genetically mediated disorders of the central nervous system (CNS) has been shown to attenuate disease outcome significantly. These include mouse models mimicking distinct subtypes of neuronal ceroid lipofuscinoses (NCL, CLN diseases) as well as hereditary spastic paraplegia type 2 (HSP/SPG2). We here show in a model of another, complicated HSP form (SPG11) that there is neuroinflammation in distinct compartments of the diseased CNS. Using a proof-of-principle experiment, we provide evidence that genetically targeting the adaptive immune system dampens disease progression including gait disturbance, demonstrating a pathogenic impact of neuroinflammation. Translating these studies into a clinically applicable approach, we show that the established immunomodulators fingolimod and teriflunomide significantly attenuate the neurodegenerative phenotype and improve gait performance in the SPG11 model, even when applied relatively late during disease progression. Particularly abnormalities in gait coordination, representing ataxia, could be attenuated, while features indicative of reduced strength during walking did not respond to treatment. Our study identifies neuroinflammation by the adaptive immune system as a robust and targetable disease amplifier in a mouse model of SPG11 and may thus pave the way for a translational approach in humans implicating approved immunomodulators.

Mechanisms of coronavirus infectious disease 2019-related neurologic diseases.

As of January 8, 2022, a global pandemic caused by infection with severe acute respiratory syndrome coronavirus (SARS-CoV)-2, a new RNA virus, has resulted in 304,896,785 cases in over 222 countries and regions, with over 5,500,683 deaths (www.worldometers.info/coronavirus/). Reports of neurological and psychiatric symptoms in the context of coronavirus infectious disease 2019 (COVID-19) range from headache, anosmia, and dysgeusia, to depression, fatigue, psychosis, seizures, delirium, suicide, meningitis, encephalitis, inflammatory demyelination, infarction, and acute hemorrhagic necrotizing encephalopathy. Moreover, 30-50% of COVID-19 survivors develop long-lasting neurologic symptoms, including a dysexecutive syndrome, with inattention and disorientation, and/or poor movement coordination. Detection of SARS-CoV-2 RNA within the central nervous system (CNS) of patients is rare, and mechanisms of neurological damage and ongoing neurologic diseases in COVID-19 patients are unknown. However, studies demonstrating viral glycoprotein effects on coagulation and cerebral vasculature, and hypoxia- and cytokine-mediated coagulopathy and CNS immunopathology suggest both virus-specific and neuroimmune responses may be involved. This review explores potential mechanistic insights that could contribute to COVID-19-related neurologic disease. While the development of neurologic diseases during acute COVID-19 is rarely associated with evidence of viral neuroinvasion, new evidence suggests SARS-CoV-2 Spike (S) protein exhibits direct inflammatory and pro-coagulation effects. This, in conjunction with immune dysregulation resulting in cytokine release syndrome (CRS) may result in acute cerebrovascular or neuroinflammatory diseases. Additionally, CRS-mediated loss of blood-brain barrier integrity in specific brain regions may contribute to the expression of proinflammatory mediators by neural cells that may impact brain function long after resolution of acute infection. Importantly, host co-morbid diseases that affect vascular, pulmonary, or CNS function may contribute to the type of neurologic disease triggered by SARS-COV-2 infection. Distinct effects of SARS-CoV-2 S protein and CNS compartment- and region-specific responses to CRS may underlie acute and chronic neuroinflammatory diseases associated with COVID-19.

Mechanisms of Entry Into the Central Nervous System by Neuroinvasive Pathogens.

The literature on neurological manifestations, cerebrospinal fluid analyses, and autopsies in patients with COVID-19 continues to grow. The proposed mechanisms for neurological disease in patients with COVID-19 include indirect processes such as inflammation, microvascular injury, and hypoxic-ischemic damage. An alternate hypothesis suggests direct viral entry of SARS-CoV-2 into the brain and cerebrospinal fluid, given varying reports regarding isolation of viral components from these anatomical sites. PubMed, Google Scholar databases, and neuroanatomical textbooks were manually searched and reviewed. We provide clinical concepts regarding the mechanisms of viral pathogen invasion in the central nervous system (CNS); advances in our mechanistic understanding of CNS invasion in well-known neurotropic pathogens can aid in understanding how viruses evolve strategies to enter brain parenchyma. We also present the structural components of CNS compartments that influence viral entry, focusing on hematogenous and transneuronal spread, and discuss this evidence as it relates to our understanding of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Although there is a paucity of data supporting direct viral entry of SARS-CoV-2 in humans, increasing our knowledge of the structural components of CNS compartments that block viral entry and pathways exploited by pathogens is fundamental to preparing clinicians and researchers for what to expect when a novel emerging virus with neurological symptoms establishes infection in the CNS, and how to design therapeutics to mitigate such an infection.

Novel contributors to B cell activation during inflammatory CNS demyelination; An oNGOing process

Over the past two decades, the development of targeted immunotherapeutics for relapsing-remitting multiple sclerosis has been successfully orchestrated through the efficacious modulation of neuroinflammatory outcomes demonstrated in the experimental autoimmune encephalomyelitis (EAE) model. In this model, the focus of developing immunomodulatory therapeutics has been demonstrated through their effectiveness in modifying the pro-inflammatory Th1 and Th17-dependent neuropathological outcomes of demyelination, oligodendrocytopathy and axonal dystrophy. However, recent successful preclinical and clinical trials have advocated for the significance of B cell-dependent immunopathogenic responses and has led to the development of novel biologicals that target specific B cell phenotypes. In this context, a new molecule, B-cell activating factor (BAFF), has emerged as a positive regulator of B cell survival and differentiation functioning through various signaling pathways and potentiating the activity of various receptor complexes through pleiotropic means. One possible cognate receptor for BAFF includes the Nogo receptor (NgR) and its homologs, previously established as potent inhibitors of axonal regeneration during central nervous system (CNS) injury and disease. In this review we provide current evidence for BAFF-dependent signaling through the NgR multimeric complex, elucidating their association within the CNS compartment and underlying the importance of these potential pathogenic molecular regulators as possible therapeutic targets to limit relapse rates and potentially MS progression.