Paramagnetic rim lesions are associated with pathogenic CSF profiles and worse clinical outcomes in multiple sclerosis: a retrospective cross-sectional study

Background and Objective: Paramagnetic rims have been observed as a feature of some MS lesions on susceptibility-sensitive MRI and indicate ongoing inflammation, principally consisting of compartmentalized activated microglia/macrophages. We investigated clinical, MRI, and intrathecal (cerebrospinal fluid, CSF) associations of paramagnetic rim lesions (PRL) using 3T MRI in MS. Methods: This is a retrospective, cross-sectional analysis of patients at a single neuroimmunology clinic. All patients had standardized 3T MRI using a multiecho T2*-weighted sequence with susceptibility postprocessing (SWAN protocol, GE) as part of the inclusion criteria. SWAN-derived filtered phase maps and corresponding T2-FLAIR images were manually reviewed by one expert rater blinded to clinical data, and PRL were determined based on qualitative assessment of hypointense paramagnetic edges on corresponding T2-hyperintense lesions. Descriptive statistics, t-tests, ANOVA, and linear regression determined demographic, clinical, MRI, and intrathecal profile associations with the presence of one or more PRL. Results: One hundred and forty-seven (147) MS patients were included in this analysis (2 clinically isolated syndrome, 118 relapsing-remitting, 14 secondary progressive, 13 primary progressive). Baseline mean age was 48.8 years, disease duration 12.8 years, and median EDSS 2, with 79% women. Seventy-five percent of patients were receiving a disease-modifying therapy, and 79 patients (54%) had available cerebrospinal fluid (CSF) analysis. Sixty-three patients (43%) had at least 1 PRL. PRL status (presence or absence) did not vary by sex or EDSS but was associated with younger age (51 vs 46 years; p=0.01) and shorter disease duration (14.5 vs 10.5 years; p=0.01). PRL status was also associated with worse disease (MS severity score: 2.8 vs 3.7; p=0.05) and blood-brain barrier disruption as determined by higher protein and pathologically elevated albumin quotient, as well as the presence of CSF oligoclonal bands (all p≤0.05); there was no association with immunoglobulin index or synthesis rate. PRL status was additionally associated with higher burden of T2-hyperintense cerebral lesion volume (T2LV), higher age-adjusted cerebral brain volume loss (especially of gray matter), and poorer performance on multiple clinical measures, including the 9-hole peg test and symbol digit modalities test (but not timed 25-foot walk speed). Clinical and intrathecal profiles remained associated with PRL after adjustment for age and in many cases T2LV as well. Sensitivity analyses limited to subgroups of patients without disease activity at the time of CSF sampling remained supportive of results. Patients with PRL were being treated with higher-efficacy disease-modifying therapies at the time of the data query. Conclusions: PRL, an emerging noninvasive biomarker of chronic cerebral neuroinflammation in MS, are confirmed to be associated with greater disease severity and newly shown to be associated with intrathecal inflammation and blood-brain-barrier disruption.

Microglial replacement in the aged brain restricts neuroinflammation following intracerebral hemorrhage

Aged microglia display augmented inflammatory activity after neural injury. Although aging is a risk factor for poor outcome after brain insults, the precise impact of aging-related alterations in microglia on neural injury remains poorly understood. Microglia can be eliminated via pharmacological inhibition of the colony–stimulating factor 1 receptor (CSF1R). Upon withdrawal of CSF1R inhibitors, microglia rapidly repopulate the entire brain, leading to replacement of the microglial compartment. In this study, we investigated the impact of microglial replacement in the aged brain on neural injury using a mouse model of intracerebral hemorrhage (ICH) induced by collagenase injection. We found that replacement of microglia in the aged brain reduced neurological deficits and brain edema after ICH. Microglial replacement-induced attenuation of ICH injury was accompanied with alleviated blood-brain barrier disruption and leukocyte infiltration. Notably, newly repopulated microglia had reduced expression of IL-1β, TNF-α and CD86, and upregulation of CD206 in response to ICH. Our findings suggest that replacement of microglia in the aged brain restricts neuroinflammation and brain injury following ICH.

NMDAR1 autoantibodies amplify behavioral phenotypes of genetic white matter inflammation: a mild encephalitis model with neuropsychiatric relevance

Encephalitis has an estimated prevalence of ≤0.01%. Even with extensive diagnostic work-up, an infectious etiology is identified or suspected in <50% of cases, suggesting a role for etiologically unclear, noninfectious processes. Mild encephalitis runs frequently unnoticed, despite slight neuroinflammation detectable postmortem in many neuropsychiatric illnesses. A widely unexplored field in humans, though clearly documented in rodents, is genetic brain inflammation, particularly that associated with myelin abnormalities, inducing primary white matter encephalitis. We hypothesized that “autoimmune encephalitides” may result from any brain inflammation concurring with the presence of brain antigen-directed autoantibodies, e.g., against N-methyl-D-aspartate-receptor NR1 (NMDAR1-AB), which are not causal of, but may considerably shape the encephalitis phenotype. We therefore immunized young female Cnp−/− mice lacking the structural myelin protein 2′-3′-cyclic nucleotide 3′-phosphodiesterase (Cnp) with a “cocktail” of NMDAR1 peptides. Cnp−/− mice exhibit early low-grade inflammation of white matter tracts and blood–brain barrier disruption. Our novel mental-time-travel test disclosed that Cnp−/− mice are compromised in what–where–when orientation, but this episodic memory readout was not further deteriorated by NMDAR1-AB. In contrast, comparing wild-type and Cnp−/− mice without/with NMDAR1-AB regarding hippocampal learning/memory and motor balance/coordination revealed distinct stair patterns of behavioral pathology. To elucidate a potential contribution of oligodendroglial NMDAR downregulation to NMDAR1-AB effects, we generated conditional NR1 knockout mice. These mice displayed normal Morris water maze and mental-time-travel, but beam balance performance was similar to immunized Cnp−/−. Immunohistochemistry confirmed neuroinflammation/neurodegeneration in Cnp−/− mice, yet without add-on effect of NMDAR1-AB. To conclude, genetic brain inflammation may explain an encephalitic component underlying autoimmune conditions.

Reversible brain edema in experimental cerebral malaria is associated with transcellular blood-brain barrier disruption and delayed microhemorrhages

Brain swelling occurs in cerebral malaria (CM) and may either reverse or result in fatal outcome. It is currently unknown how brain swelling in CM reverses, as investigations have been hampered by inadequate animal models. In this study, we show that reversible brain swelling in experimental murine cerebral malaria (ECM) can be induced reliably after single vaccination with radiation-attenuated sporozoites as revealed by in vivo high-field (9.4T) magnetic resonance imaging. Our results provide evidence that parenchymal fluid increase and consecutive brain swelling results from transcellular blood-brain barrier disruption (BBBD), as revealed by electron microscopy. This mechanism enables reversal of brain swelling but does not prevent persistent focal brain damage, evidenced by microhemorrhages, in areas of most severe BBBD. In a cohort of 27 pediatric and adult CM patients (n=4 fatal, n=23 non-fatal) two out of four fatal CM patients (50%) and 8 out of 23 non-fatal CM patients (35%) showed microhemorrhages on MRI at clinical field strength of 1.5T, emphasizing the translational potential of the experimental model.

SARS-CoV-2 as a Trigger in the Development of Tourette’s-Like Symptoms: A Case Report

Background: Reports have been surfacing surrounding CNS-associated symptoms in individuals affected by coronavirus disease 19 (COVID-19). Tourette syndrome is a neuropsychiatric disorder with usual onset in childhood. Gut microbiota can affect central physiology and function via the microbiota-gut-brain axis. The authors of this case report describe Tourette’s-like symptoms in a patient resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection disrupting gut microbiota. Case Presentation: This case involves a 16-year-old female that developed acute onset Tourette’s-like symptoms along with neuropsychiatric symptoms after exposure to and infection from SARS-CoV-2. The patient had negative nasopharyngeal (NP) real-time reverse transcription-PCR (RT-PCR) tests for SARS-CoV-2 on five occasions from August of 2020 through June of 2021. The patient’s symptoms continued to worsen over the next six months until next-generation sequencing (NGS) revealed SARS-CoV-2 in her stool. Repair of the gastrointestinal microbiota, treatment with nutraceutical and pharmaceutical agents, as well as alterations in her surroundings resulted in dramatic improvement in the microbiome and a significant reduction of symptoms.Discussion: The use of RT-PCR testing to determine the presence or absence of SARS-CoV-2 may be inadequate and inaccurate for individuals that have been exposed to the virus. In addition, the impact of SARS-CoV-2 infection to the GI tract may cause significant havoc in the gut microbiota which may lead to disruption of the blood brain barrier, disruption to the gut- microbiome-brain axis, and neurological symptoms. Additional testing, eradication of infectious agents, as well as restoration of the gut microbiome are needed to effectively manage and treat this condition.