Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity.

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20dimCD8+ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20dimCD8+ T cells had a greater contribution to treatment-associated changes in the CD8+ T cell pool than was the case for CD4+ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20dimCD8+ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19+CD24highCD38high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20dimCD8+ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8+ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

Lesion features on magnetic resonance imaging discriminate multiple sclerosis patients.

BACKGROUND: Magnetic resonance imaging (MRI) provides insight into various pathological processes in multiple sclerosis (MS) and may provide insight into patterns of damage among patients. OBJECTIVE: We sought to determine if MRI features have clinical discriminative power among a cohort of MS patients. METHODS: Ninety-six relapsing remitting and seven progressive MS patients underwent myelin water fraction (MWF) imaging and conventional MRI for cortical thickness and thalamic volume. Patients were clustered based on lesion level MRI features using an agglomerative hierarchical clustering algorithm based on principal component analysis (PCA). RESULTS: One hundred and three patients with 1689 MS lesions were analyzed. PCA on MRI features demonstrated that lesion MWF and volume distributions (characterized by 25th, 50th, and 75th percentiles) accounted for 87% of the total variability based on four principal components. The best hierarchical cluster confirmed two distinct patient clusters. The clustering features in order of importance were lesion median MWF, MWF 25th, MWF 75th, volume 75th percentiles, median individual lesion volume, total lesion volume, cortical thickness, and thalamic volume (all p values <0.01368). The clusters were associated with patient Expanded Disability Status Scale (EDSS) (n = 103, p = 0.0338) at baseline and at 5 years (n = 72, p = 0.0337). CONCLUSIONS: These results demonstrate that individual MRI features can identify two patient clusters driven by lesion-based values, and our unique approach is an analysis blinded to clinical variables. The two distinct clusters exhibit MWF differences, most likely representing individual remyelination capabilities among different patient groups. These findings support the concept of patient-specific pathophysiological processes and may guide future therapeutic approaches.

Quantitative susceptibility mapping identifies inflammation in a subset of chronic multiple sclerosis lesions.

Chronic active multiple sclerosis lesions, characterized by a hyperintense rim of iron-enriched, activated microglia and macrophages, have been linked to greater tissue damage. Post-mortem studies have determined that chronic active lesions are primarily related to the later stages of multiple sclerosis; however, the occurrence of these lesions, and their relationship to earlier disease stages may be greatly underestimated. Detection of chronic active lesions across the patient spectrum of multiple sclerosis requires a validated imaging tool to accurately identify lesions with persistent inflammation. Quantitative susceptibility mapping provides efficient in vivo quantification of susceptibility changes related to iron deposition and the potential to identify lesions harbouring iron-laden inflammatory cells. The PET tracer 11C-PK11195 targets the translocator protein expressed by activated microglia and infiltrating macrophages. Accordingly, this study aimed to validate that lesions with a hyperintense rim on quantitative susceptibility mapping from both relapsing and progressive patients demonstrate a higher level of innate immune activation as measured on 11C-PK11195 PET. Thirty patients were enrolled in this study, 24 patients had relapsing remitting multiple sclerosis, six had progressive multiple sclerosis, and all patients had concomitant MRI with a gradient echo sequence and PET with 11C-PK11195. A total of 406 chronic lesions were detected, and 43 chronic lesions with a hyperintense rim on quantitative susceptibility mapping were identified as rim+ lesions. Susceptibility (relative to CSF) was higher in rim+ (2.42 ± 17.45 ppb) compared to rim- lesions (-14.6 ± 19.3 ppb, P < 0.0001). Among rim+ lesions, susceptibility within the rim (20.04 ± 14.28 ppb) was significantly higher compared to the core (-5.49 ± 14.44 ppb, P < 0.0001), consistent with the presence of iron. In a mixed-effects model, 11C-PK11195 uptake, representing activated microglia/macrophages, was higher in rim+ lesions compared to rim- lesions (P = 0.015). Validating our in vivo imaging results, multiple sclerosis brain slabs were imaged with quantitative susceptibility mapping and processed for immunohistochemistry. These results showed a positive translocator protein signal throughout the expansive hyperintense border of rim+ lesions, which co-localized with iron containing CD68+ microglia and macrophages. In conclusion, this study provides evidence that suggests that a hyperintense rim on quantitative susceptibility measure within a chronic lesion is a correlate for persistent inflammatory activity and that these lesions can be identified in the relapsing patients. Utilizing quantitative susceptibility measure to differentiate chronic multiple sclerosis lesion subtypes, especially chronic active lesions, would provide a method to assess the impact of these lesions on disease progression.

Pituitary dendritic cells communicate immune pathogenic signals.

This study reveals the presence of dendritic cells (DCs) in the pituitary gland, which play a role in communicating immune activation to the hypothalamic pituitary adrenal (HPA) axis. Using enhanced yellow fluorescent protein (eyfp) expression as a reporter for CD11c, a marker of DCs, we demonstrate anatomically the presence of CD11c/eyfp+ cells throughout the pituitary. Flow cytometric analysis shows that the predominant cellular phenotype of pituitary CD11c/eyfp+ cells resembles that of non-lymphoid DCs. In vivo and in vitro immune challenge with lipopolysaccharide (LPS) stimulates these pituitary CD11c/eyfp+ DCs, but not eyfp(neg) cells, to increase levels of pro-inflammatory cytokines, IL-6, IL-1ß, and TNF-α. In vivo analysis of plasma glucocorticoid (GC) and adrenocorticotropic hormone (ACTH) levels at this early phase of the immune response to LPS suggest that pro-inflammatory cytokine production by DCs within the pituitary may activate the release of GCs from the adrenals via ACTH. Pituitary CD11c/eyfp+ cells also express annexin A1 (ANXA1), indicating a role in GC signal attenuation. In summary, our data demonstrate that a resident DC population of the pituitary gland coordinates GC release in the early phase of systemic immune activation, thereby providing an essential immune signaling sentinel for the initial shaping of the systemic immune response to LPS.

Impact of paramagnetic rim lesions on disability and race in multiple sclerosis: mediation analysis.

OBJECTIVE: Black American (BA) multiple sclerosis (MS) patients experience greater disability compared to White American (WA) patients. Here, we investigated the role of paramagnetic rim lesions (PRLs), a subset of chronic active lesions, on race-related disability in MS. METHODS: We conducted a retrospective observational study comparing BA and WA MS patients. PRLs were identified through Quantitative Susceptibility Mapping (QSM) MRI. A causal mediation analysis explored the impact of PRLs on the relationship between race and disability, as measured by the Expanded Disability Status Scale (EDSS). RESULTS: The prevalence of PRLs in BA patients with MS was higher at 55% compared to WA patients at 39% (p = 0.022). A higher percentage of PRLs among all white matter lesions was observed with BA (8.01%) patients compared to WA (3.4%) patients (p = 0.003). In a regression analysis, controlling for significant patient-level covariates and income-level demographics, the percentage of PRLs was, on average, 4.61 points higher for BA patients than for WA patients (p = 0.003). In a separate regression analysis, accounting for covariates, BA patients exhibited significantly higher EDSS scores (p < 0.001). Further analysis demonstrated that the percentage of PRLs was a mediator in the association between BA patients and greater disability (p = 0.031). Higher proportion of PRLs in BA population accounted for 14% of the total effect of race on disability. INTERPRETATION: BA patients exhibit greater disability, in part, due to their higher proportion of PRLs. This study underscores the substantial impact of chronic active lesions on disability outcomes in this specific minority MS patient population.

Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis.

Importance: Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that most closely reflects central nervous system biology. Objective: To identify CSF biological measures associated with progressive MS pathobiology. Design, Setting, and Participants: This cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023). Exposures: Test-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies. Main Outcomes and Measures: Twenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions [SELs]). Results: The test cohort (n = 131) included 100 patients with RMS (mean [SD] age, 36.6 [10.4] years; 68 [68%] female and 32 [32%] male; Expanded Disability Status Scale [EDSS] score, 0-5.5), and 31 patients with PPMS (mean [SD] age, 44.9 [7.4] years; 15 [48%] female and 16 [52%] male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years [range, 20-61 years]; 47 [69%] female and 21 [31%] male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = -0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = -0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002). Conclusions and Relevance: In this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression.

No Evidence of Disease Activity (NEDA) as a Clinical Assessment Tool for Multiple Sclerosis: Clinician and Patient Perspectives [Narrative Review].

The emergence of high-efficacy therapies for multiple sclerosis (MS), which target inflammation more effectively than traditional disease-modifying therapies, has led to a shift in MS management towards achieving the outcome assessment known as no evidence of disease activity (NEDA). The most common NEDA definition, termed NEDA-3, is a composite of three related measures of disease activity: no clinical relapses, no disability progression, and no radiological activity. NEDA has been frequently used as a composite endpoint in clinical trials, but there is growing interest in its use as an assessment tool to help patients and healthcare professionals navigate treatment decisions in the clinic. Raising awareness about NEDA may therefore help patients and clinicians make more informed decisions around MS management and improve overall MS care. This review aims to explore the potential utility of NEDA as a clinical decision-making tool and treatment target by summarizing the literature on its current use in the context of the expanding treatment landscape. We identify current challenges to the use of NEDA in clinical practice and detail the proposed amendments, such as the inclusion of alternative outcomes and biomarkers, to broaden the clinical information captured by NEDA. These themes are further illustrated with the real-life perspectives and experiences of our two patient authors with MS. This review is intended to be an educational resource to support discussions between clinicians and patients on this evolving approach to MS-specialized care.

Recent progress in multiple sclerosis (MS) has led to the development of new treatments, known as high-efficacy therapies. Compared with previous treatments, high-efficacy therapies are better at managing visible inflammation of the central nervous system, a main cause of worsening symptoms early on in people living with MS. Treatment with high-efficacy therapies means many people with MS may achieve better outcomes than previously possible. One such outcome is the set of criteria known as no evidence of disease activity (NEDA). Achieving NEDA-3, the most commonly used NEDA criteria, means that people exhibit no clinical relapses, no worsening of physical symptoms, and no visible disease activity on a magnetic resonance imaging scan. Researchers have studied NEDA as an outcome in MS clinical trials, but it may be useful in clinical practice as a tool for doctors to measure a person's disease progression and response to treatment. This could help to inform important decisions around treatment selection and improve overall care for people with MS. This review explores the available information about NEDA to understand its potential to support clinical decision-making and patient evaluations. We discuss the barriers to NEDA being used in clinical practice and the ways the criteria may change to capture a broader range of clinical information from the patient. These topics are presented alongside the real-life perspectives and experiences of our two patient authors with MS. This review is meant to be an educational resource to assist conversations about NEDA between clinicians and patients in everyday clinical practice.

Acute in vivo exposure to interferon-gamma enables resident brain dendritic cells to become effective antigen presenting cells.

Dendritic cells (DC) are the professional antigen presenting cells (APC) that bridge the innate and adaptive immune system. Previously, in a CD11c/EYFP transgenic mouse developed to study DC functions, we anatomically mapped and phenotypically characterized a discrete population of EYFP(+) cells within the microglia that we termed brain dendritic cells (bDC). In this study, we advanced our knowledge of the function of these cells in the CD11c/EYFP transgenic mouse and its chimeras, using acute stimuli of stereotaxically inoculated IFNgamma or IL-4 into the CNS. The administration of IFNgamma increased the number of EYFP(+)bDC but did not recruit peripheral DC into the CNS. IFNgamma, but not IL-4, upregulated the expression levels of major histocompatibility class II (MHC-II). In addition, IFNgamma-activated EYFP(+)bDC induced antigen-specific naïve CD4 T cells to proliferate and secrete Th1/Th17 cytokines. Activated bDC were also able to stimulate naïve CD8 T cells. Collectively, these data reveal the Th1 cytokine IFNgamma, but not the Th2 cytokine IL4, induces bDC to up-regulate MHC-II and become competent APC.

Quantitative susceptibility mapping versus phase imaging to identify multiple sclerosis iron rim lesions with demyelination.

BACKGROUND AND PURPOSE: To compare quantitative susceptibility mapping (QSM) and high-pass-filtered (HPF) phase imaging for (1) identifying chronic active rim lesions with more myelin damage and (2) distinguishing patients with increased clinical disability in multiple sclerosis. METHODS: Eighty patients were scanned with QSM for paramagnetic rim detection and Fast Acquisition with Spiral Trajectory and T2prep for myelin water fraction (MWF). Chronic lesions were classified based on the presence/absence of rim on HPF and QSM images. A lesion-level linear mixed-effects model with MWF as the outcome was used to compare myelin damage among the lesion groups. A multiple patient-level linear regression model was fit to establish the association between Expanded Disease Status Scale (EDSS) and the log of the number of rim lesions. RESULTS: Of 2062 lesions, 188 (9.1%) were HPF rim+/QSM rim+, 203 (9.8%) were HPF rim+/QSM rim-, and the remainder had no rim. In the linear mixed-effects model, HPF rim+/QSM rim+ lesions had significantly lower MWF than both HPF rim+/QSM rim- (p < .001) and HPF rim-/QSM rim- (p < .001) lesions, while the MWF difference between HPF rim+/QSM rim- and HPF rim-/QSM rim- lesions was not statistically significant (p = .130). Holding all other factors constant, the log number of QSM rim+ lesion was associated with EDSS increase (p = .044). The association between the log number of HPF rim+ lesions and EDSS was not statistically significant (p = .206). CONCLUSIONS: QSM identifies paramagnetic rim lesions that on average have more myelin damage and stronger association with clinical disability than those detected by phase imaging.

Disease correlates of rim lesions on quantitative susceptibility mapping in multiple sclerosis.

Quantitative susceptibility mapping (QSM), an imaging technique sensitive to brain iron, has been used to detect paramagnetic rims of iron-laden active microglia and macrophages in a subset of multiple sclerosis (MS) lesions, known as rim+ lesions, that are consistent with chronic active lesions. Because of the potential impact of rim+ lesions on disease progression and tissue damage, investigating their influence on disability and neurodegeneration is critical to establish the impact of these lesions on the disease course. This study aimed to explore the relationship between chronic active rim+ lesions, identified as having a hyperintense rim on QSM, and both clinical disability and imaging measures of neurodegeneration in patients with MS. The patient cohort was composed of 159 relapsing-remitting multiple sclerosis patients. The Expanded Disability Status Scale (EDSS) and Brief International Cognitive Assessment for Multiple Sclerosis, which includes both the Symbol Digit Modalities Test and California Verbal Learning Test-II, were used to assess clinical disability. Cortical thickness and thalamic volume were evaluated as imaging measures of neurodegeneration. A total of 4469 MS lesions were identified, of which 171 QSM rim+ (3.8%) lesions were identified among 57 patients (35.8%). In a multivariate regression model, as the overall total lesion burden increased, patients with at least one rim+ lesion on QSM performed worse on both physical disability and cognitive assessments, specifically the Symbol Digit Modalities Test (p = 0.010), California Verbal Learning Test-II (p = 0.030), and EDSS (p = 0.001). In a separate univariate regression model, controlling for age (p < 0.001) and having at least one rim+ lesion was related to more cortical thinning (p = 0.03) in younger patients (< 45 years). Lower thalamic volume was associated with older patients (p = 0.038) and larger total lesion burden (p < 0.001); however, the association did not remain significant with rim+ lesions (p = 0.10). Our findings demonstrate a novel observation that chronic active lesions, as identified on QSM, modify the impact of lesion burden on clinical disability in MS patients. These results support further exploration of rim+ lesions for therapeutic targeting in MS to reduce disability and subsequent neurodegeneration.

Brachial plexopathy as a complication of COVID-19.

COVID-19 affects a wide spectrum of organ systems. We report a 52-year-old man with hypertension and newly diagnosed diabetes mellitus who presented with hypoxic respiratory failure due to COVID-19 and developed severe brachial plexopathy. He was not treated with prone positioning respiratory therapy. Associated with the flaccid, painfully numb left upper extremity was a livedoid, purpuric rash on his left hand and forearm consistent with COVID-19-induced microangiopathy. Neuroimaging and electrophysiological data were consistent with near diffuse left brachial plexitis with selective sparing of axillary, suprascapular and pectoral fascicles. Given his microangiopathic rash, elevated D-dimers and paucifascicular plexopathy, we postulate a patchy microvascular thrombotic plexopathy. Providers should be aware of this significant and potentially under-recognised neurologic complication of COVID-19.

QSM is an imaging biomarker for chronic glial activation in multiple sclerosis lesions.

BACKGROUND: Inflammation in chronic active lesions occurs behind a closed blood-brain barrier and cannot be detected with MRI. Activated microglia are highly enriched for iron and can be visualized with quantitative susceptibility mapping (QSM), an MRI technique used to delineate iron. OBJECTIVE: To characterize the histopathological correlates of different QSM hyperintensity patterns in MS lesions. METHODS: MS brain slabs were imaged with MRI and QSM, and processed for histology. Immunolabeled cells were quantified in the lesion rim, center, and adjacent normal-appearing white matter (NAWM). Iron+ myeloid cell densities at the rims were correlated with susceptibilities. Human-induced pluripotent stem cell (iPSC)-derived microglia were used to determine the effect of iron on the production of reactive oxygen species (ROS) and pro-inflammatory cytokines. RESULTS: QSM hyperintensity at the lesion perimeter correlated with activated iron+ myeloid cells in the rim and NAWM. Lesions with high punctate or homogenous QSM signal contained no or minimally activated iron- myeloid cells. In vitro, iron accumulation was highest in M1-polarized human iPSC-derived microglia, but it did not enhance ROS or cytokine production. CONCLUSION: A high QSM signal outlining the lesion rim but not punctate signal in the center is a biomarker for chronic inflammation in white matter lesions.

Brain dendritic cells in ischemic stroke: time course, activation state, and origin.

The immune response to stroke is comprised of inflammatory and regulatory processes. One cell type involved in both innate and adaptive immunity is the dendritic cell (DC). A DC population residing in the healthy brain (bDC) was identified using a transgenic mouse expressing enhanced yellow fluorescent protein (EYFP) under the promoter for the DC marker, CD11c (CD11c/EYFP Tg). To determine if bDC are involved in the immune response to cerebral ischemia, transient (40 min) middle cerebral artery occlusion (MCAO) followed by 6, 24, or 72 h reperfusion was conducted in CD11c/EYFP Tg mice. Our results demonstrated that DC accumulated in the ischemic hemisphere at 24 h post-MCAO-reperfusion, particularly in the border region of the infarct where T lymphocytes accrued. To distinguish resident bDC from the infiltrating peripheral DC, radiation chimeras [1. wild type (WT) hosts restored with CD11c/EYFP Tg bone marrow (BM) or 2. CD11c/EYFP Tg hosts restored with WT BM] were generated and examined by immunocytochemistry. These data confirmed that DC populating the core of the infarct at 72 h were of peripheral origin, whereas those in the border region were comprised primarily of resident bDC. The brain resident (CD45 intermediate) cells of CD11c/EYFP Tg mice were analyzed by flow cytometry. Compared to microglia, bDC displayed increased major histocompatibility class II (MHC II) and co-stimulatory molecules following MCAO-reperfusion. High levels of MHC II and the co-stimulatory molecule CD80 on bDC at 72 h corresponded to peak lymphocyte infiltration, and suggested a functional interaction between these two immune cell populations.

Impact of Lesion Location on Longitudinal Myelin Water Fraction Change in Chronic Multiple Sclerosis Lesions.

BACKGROUND AND PURPOSE: To examine the impact of lesion location on longitudinal myelin water fraction (MWF) changes in chronic multiple sclerosis (MS) lesions. Relative hypoxia, due to vascular watershed regions of the cerebrum, has been implicated in lesion development but impact on ongoing demyelination is unknown. METHODS: Forty-eight patients with relapsing-remitting and secondary progressive MS had two MWF scans with fast acquisition, spiral trajectory, and T2prep (FAST-T2) sequence, at an interval of 2.0 (±.3) years. Lesion location was identified based upon cerebral lobe and relation to the ventricles. Change in MWF was assessed using a mixed effects model, controlling for lesion location and patient covariates. RESULTS: Average age was 42.3 (±12) years, mean disease duration was 9.7 (±9.1) years, and median Expanded Disability Status Score (EDSS) was 2.5 (±2.3). The majority of 512 chronic lesions was located in the frontal and parietal lobes (75.6%) and more often periventricular (44.7%). All occipital lesions were periventricular. The average lesion MWF decreased from baseline (.07 ± .03) to 2 years (.06 ±.03) P < .01. Lesions within the occipital lobe showed a significant reduction in MWF as compared to other lobes. CONCLUSIONS: Chronic lesions in the occipital lobe showed the greatest reduction in MWF. Neuroanatomical localization of lesions to the occipital horns of the lateral ventricles, a watershed region, may contribute to ongoing demyelination in this lesion type.

Black African and Latino/a identity correlates with increased plasmablasts in MS.

OBJECTIVE: To determine the influence of self-reported Black African and Latin American identity on peripheral blood antibody-secreting cell (ASC) frequency in the context of relapsing-remitting MS. METHODS: In this cross-sectional study, we recruited 74 subjects with relapsing-remitting MS and 24 age-, and self-reported ethno-ancestral identity-matched healthy donors (HDs) to provide peripheral blood study samples. Subjects with MS were either off therapy at the time of study draw or on monthly natalizumab therapy infusions. Using flow cytometry, we assessed peripheral blood mononuclear cells for antibody-secreting B-cell subsets. RESULTS: When stratified by self-reported ethno-ancestry, we identified significantly elevated frequencies of circulating plasmablasts among individuals with MS identifying as Black African or Latin American relative to those of Caucasian ancestry. Ethno-ancestry-specific differences in ASC frequency were observed only among individuals with MS. By contrast, this differential was not observed among HDs. ASCs linked with poorer MS prognosis and active disease, including IgM+- and class-switched CD138+ subsets, were among those significantly increased. CONCLUSION: The enhanced peripheral blood plasmablast signature revealed among Black African or Latin American subjects with MS points to distinct underlying mechanisms associated with MS immunopathogenesis. This dysregulation may contribute to the disease disparity experienced by patient populations of Black African or Latin American ethno-ancestry.

A Multi-Ligand Imaging Study Exploring GABAergic Receptor Expression and Inflammation in Multiple Sclerosis.

PURPOSE: The γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter and essential for normal brain function. The GABAergic system has been shown to have immunomodulatory effects and respond adaptively to excitatory toxicity. The association of the GABAergic system and inflammation in patients with multiple sclerosis (MS) remains unknown. In this pilot study, the in vivo relationship between GABAA binding and the innate immune response is explored using positron emission tomography (PET) with [11C] flumazenil (FMZ) and [11C]-PK11195 PET (PK-PET), a measure of activated microglia/macrophages. PROCEDURES: Sixteen MS patients had dynamic FMZ-PET and PK-PET imaging. Ten age-matched healthy controls (HC) had a single FMZ-PET. GABAA receptor binding was calculated using Logan reference model with the pons as reference. Distribution of volume ratio (VTr) for PK-PET was calculated using image-derived input function. A hierarchical linear model was fitted to assess the linear association between PK-PET and FMZ-PET among six cortical regions of interest. RESULTS: GABAA receptor binding was higher throughout the cortex in MS patients (5.72 ± 0.91) as compared with HC (4.70 ± 0.41) (p = 0.002). A significant correlation was found between FMZ binding and PK-PET within the cortex (r = 0.61, p < 0.001) and among the occipital (r = 0.61, p = 0.012), parietal (r = 0.49, p = 0.041), and cingulate (r = 0.32, p = 0.006) regions. CONCLUSIONS: A higher GABAA receptor density in MS subjects compared with HC was observed and correlated with innate immune activity. Our observations demonstrate that immune-driven GABAergic abnormalities may be present in MS.

Distribution of vitamin D binding protein expressing neurons in the rat hypothalamus.

We observed immunostaining for vitamin D binding protein (DBP) in rat hypothalamus. Part of the supraoptic and of the paraventricular neurons showed DBP immunoreactivity, in part colocalized with Arg-vasopressin. DBP was also observed in widespread axonal projections throughout the lateral hypothalamus, the median eminence and the posterior pituitary lobe. A portion of ependymal cells, the choroids plexus epithelium and some of the endocrine cells in the anterior pituitary lobe contained DBP immunoreactivity. In situ hybridization of semithin sections with a synthetic oligonucleotide probe to DBP mRNA resulted in staining of magnocellular hypothalamic neurons, but not of ependymal cells or anterior lobe cells. Our observations indicate an intrinsic expression of DBP in the rat hypothalamus. DBP may be synthesized and transported along with the classical neurohypophyseal hormones. The multiple locations of DBP-expressing neurons indicate multiple functional properties: DBP may be released from in the posterior lobe, it may act as a hypophyseotropic factor and as a central neuroactive substance.

Comparison of two different methods of image analysis for the assessment of microglial activation in patients with multiple sclerosis using (R)-[N-methyl-carbon-11]PK11195.

Chronic active multiple sclerosis (MS) lesions have a rim of activated microglia/macrophages (m/M) leading to ongoing tissue damage, and thus represent a potential treatment target. Activation of this innate immune response in MS has been visualized and quantified using PET imaging with [11C]-(R)-PK11195 (PK). Accurate identification of m/M activation in chronic MS lesions requires the sensitivity to detect lower levels of activity within a small tissue volume. We assessed the ability of kinetic modeling of PK PET data to detect m/M activity in different central nervous system (CNS) tissue regions of varying sizes and in chronic MS lesions. Ten patients with MS underwent a single brain MRI and two PK PET scans 2 hours apart. Volume of interest (VOI) masks were generated for the white matter (WM), cortical gray matter (CGM), and thalamus (TH). The distribution volume (VT) was calculated with the Logan graphical method (LGM-VT) utilizing an image-derived input function (IDIF). The binding potential (BPND) was calculated with the reference Logan graphical method (RLGM) utilizing a supervised clustering algorithm (SuperPK) to determine the non-specific binding region. Masks of varying volume were created in the CNS to assess the impact of region size on the various metrics among high and low uptake regions. Chronic MS lesions were also evaluated and individual lesion masks were generated. The highest PK uptake occurred the TH and lowest within the WM, as demonstrated by the mean time activity curves. In the TH, both reference and IDIF based methods resulted in estimates that did not significantly depend on VOI size. However, in the WM, the test-retest reliability of BPND was significantly lower in the smallest VOI, compared to the estimates of LGM-VT. These observations were consistent for all chronic MS lesions examined. In this study, we demonstrate that BPND and LGM-VT are both reliable for quantifying m/M activation in regions of high uptake, however with blood input function LGM-VT is preferred to assess longitudinal m/M activation in regions of relatively low uptake, such as chronic MS lesions.

Induction of disease remission with one cycle of alemtuzumab in relapsing-remitting MS.

OBJECTIVE: To investigate a single-course treatment with alemtuzumab in patients with relapsing-remitting multiple sclerosis. METHODS: We performed a retrospective chart review of all patients diagnosed with RRMS who were treated with alemtuzumab at our MS center and who had at least 12 month follow-up since the first dose. Data on radiological and clinical relapse were collected for the 2 years prior to patients' first dose of alemtuzumab and were tracked until the time of analysis. RESULTS: In the 2 years prior to first dose of alemtuzumab, 82.8% of the 29 patients had a new lesion on MRI and/or a clinical relapse, with an ARR of 0.67. In the mean 24.7 month follow-up after the first dose of alemtuzumab, 17.2% of patients displayed new disease activity and the ARR was 0.08. 4 out of 5 patients who relapsed did so within 12 month post-first infusion and received a second dose. Of the 24 patients who did not relapse, 8 received a second dose at 1 year and 16 did not. 5 out of all 29 patients developed thyroid disorder. CONCLUSIONS: Given that 96% of patients who did not relapse in the first 12 months following the initial dose of alemtuzumab remained relapse-free regardless of receiving a second course of drug, our data suggests that induction of disease remission for some patients might occur following just one dose of alemtuzumab. With further study, these data could support modification of the current therapy regimen.

MRI in the assessment and monitoring of multiple sclerosis: an update on best practice.

Magnetic resonance imaging (MRI) has developed into the most important tool for the diagnosis and monitoring of multiple sclerosis (MS). Its high sensitivity for the evaluation of inflammatory and neurodegenerative processes in the brain and spinal cord has made it the most commonly used technique for the evaluation of patients with MS. Moreover, MRI has become a powerful tool for treatment monitoring, safety assessment as well as for the prognostication of disease progression. Clinically, the use of MRI has increased in the past couple decades as a result of improved technology and increased availability that now extends well beyond academic centers. Consequently, there are numerous studies supporting the role of MRI in the management of patients with MS. The aim of this review is to summarize the latest insights into the utility of MRI in MS.