Neurology® Neuroimmunology & Neuroinflammation最新文献

Background and objectives: Anti-myelin-associated glycoprotein (anti-MAG) neuropathy is a chronic demyelinating neuropathy with deposits of IgM and sural nerve fiber demyelination. While growing evidence supports the critical role of IgG glycosylation in autoimmune diseases, IgM glycosylation profiles markedly differ from those of IgG but are largely neglected. The aim of this study was to characterize IgM N-glycosylation in patients with anti-MAG neuropathy and its involvement in anti-MAG pathogenicity.

Methods: IgM antibodies were isolated from patients with anti-MAG neuropathy (n = 17), asymptomatic patients with monoclonal gammopathy of undetermined significance (n = 8), and healthy donors ([HDs], n = 6). N-glycan analysis was performed using mass spectrometry. Binding to myelin-associated glycoprotein (MAG), complement (C1q), and IgM Fc receptors (Fcα/μR and DC-SIGN) was compared using ELISA between anti-MAG and MGUS IgM, before and after N-deglycosylation/desialylation. Finally, we assessed how IgM N-glycosylation influences cytokine production by monocyte-derived macrophages by measuring cytokine levels in culture supernatants.

Results: Anti-MAG IgM exhibited a unique glycosylation pattern, dominated by fucosylated, monosialylated N-glycan with a bisecting N-acetyl glucosamine (N-glycan 12), representing 48.5% of the total N-glycan pool, compared with 27.3% in MGUS IgM and 35.6% in HD IgM. We showed that deglycosylation and desialylation significantly reduced anti-MAG activity and C1q binding (average % of decrease 58.3 ± 18.8, p < 0.01, and 40.0 ± 19.9%, p < 0.05, respectively). Furthermore, anti-MAG IgM binding to C1q was significantly higher than that of MGUS IgM and HD IgM (p < 0.0001 and p < 0.001, respectively). Compared with MGUS IgM, anti-MAG IgM also significantly increased the production of proinflammatory cytokines IL-1, IL-6, IL-8, TNF-α, and IFN-Υ by macrophages, in a glycan-dependent manner (p < 0.01 to p < 0.001), with IL-8 being particularly elevated. Finally, we found that anti-MAG IgM bound more strongly Fcα/μ receptor and DC-SIGN compared with MGUS IgM (p < 0.05 and p = 0.06).

Discussion: This study uncovered a unique N-glycosylation pattern of anti-MAG IgM, crucial for its interaction with MAG and binding to C1q. Moreover, anti-MAG IgM increased the macrophage cytokine production, driven by their glycosylation. The increased IL-8 expression and anti-MAG IgM binding to C1q might open 2 potential therapeutic avenues: inhibiting IL-8 activity or targeting the complement pathway. In addition, the glycosylation and C1q binding of anti-MAG IgM could serve as biomarkers for monitoring this neuropathy.

Background and objectives: Long-term cognitive impairment is observed in 14%-32% of patients surviving community-acquired bacterial meningitis. We hypothesized that the impairment might be linked to secondary immune activation due to the development of neuronal autoantibodies, similar to postinfectious autoimmune encephalitis after viral encephalitis.

Methods: In this cross-sectional observational study, we included adult patients from a prospective, nationwide cohort study of community-acquired bacterial meningitis in the Netherlands, the MeninGene study. The presence of neuronal autoantibodies was evaluated in follow-up serum samples at 7 days, at 3 months, or over a year. Immunohistochemistry on complete rat brain slices was performed for the initial screening. If positive or ambiguous, immunocytochemistry using live primary rat hippocampal neurons and cell-based assays expressing extracellular targets were performed; immunoblots were used for intracellular targets.

Results: In total, 118 patients were included, of whom 24 of 100 (24%) had cognitive impairment and 14 of 109 (13%) had focal neurologic deficits at discharge. Causative pathogens were Streptococcus pneumoniae in 98 patients (83%), Neisseria meningitidis in 4 (3%), and other pathogens in 6 (5%); in 10 patients (9%), no causative pathogen was identified. Two of 118 patients (2%) had neuronal autoantibodies in follow-up serum: 1 had leucine-rich glioma inactivated 1 antibodies, and 1 had unspecified antibodies. None of the patients was positive for NMDA receptor antibodies.

Discussion: There was no clear evidence of postinfectious autoimmune encephalitis after bacterial meningitis. Therefore, acute brain damage caused by the infection itself seems to be the most plausible explanation for long-term cognitive impairment and neurologic disabilities.

Background and objectives: Multiple sclerosis (MS) is a chronic inflammatory disease coupled with neurodegenerative processes affecting both the white matter and gray matter (GM) in the CNS. Several histopathologic studies have reported a reduction in synaptic density in various areas of the brain. However, this pathologic feature is yet an unexplored entity among people with MS (pwMS). Therefore, we sought to investigate synaptic loss in vivo by quantifying the synaptic vesicle glycoprotein 2A using [¹¹C]UCB-J-PET imaging and to explore associations with clinical and cognitive measures.

Methods: Ten pwMS and 8 healthy controls (HCs) underwent high-resolution [¹¹C]UCB-J-PET imaging and MRI. SV2A availability was determined using the tissue-to-plasma concentration ratio at equilibrium (distribution volume; V_T). We furthermore explored associations between PET imaging results and clinical and cognitive measures in pwMS (assessed with the Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test [SDMT]). In addition, we considered volumetric, clinical, and cognitive measures during a 5-year period before PET imaging.

Results: Ten pwMS (7 women [70%], median [interquartile range] age, 53 [50-56]) years were compared with 8 HCs (6 women [75%]; age, 51 [50-70] years). PwMS had a significantly lower SV2A availability in the cortical GM (pwMS: mean [SD], V_T = 15.65 mL/cm³ [2.26]; HCs: V_T = 18.14 mL/cm³ [2.09]; p = 0.029, t test), as well as in several subcortical regions. Moreover, a lower SV2A availability in cortical GM correlated significantly with reduced SDMT values in pwMS (r = 0.071, p = 0.021; Spearman correlation coefficient). No association between physical disability (measured using EDSS) and SV2A availability was found.

Discussion: Using in vivo [¹¹C]UCB-J PET imaging, we provide evidence of reduced synaptic density in pwMS. Furthermore, the results reveal a link between synaptic loss and cognitive impairment. These findings highlight the potential of [¹¹C]UCB-J PET imaging as a promising tool for assessing clinically relevant aspects of GM pathology in MS.

Background and objectives: In multiple sclerosis (MS), neurodegeneration results from the interplay between disease-specific pathology and normal aging. Conventional MRI captures morphologic changes in neurodegeneration, while quantitative MRI (qMRI) provides biophysical measures of microstructural alterations. Combining these modalities may reveal how aging and pathology interact and contribute to disability progression in people with MS.

Methods: We analyzed cross-sectional and longitudinal morphometry data from 1,353 patients with MS and 3,462 healthy controls (HCs). In addition, cross-sectional qMRI data, available for 378 HCs and 169 patients with MS, were analyzed separately. Morphometric measures and quantitative metrics were used to estimate brain-predicted age differences (brain-PADs) with machine learning. We assessed the added value of quantitative metrics over a model based exclusively on morphometric measures in brain age prediction. We also investigated the associations of brain-PADs derived from conventional and qMRI-based predictive models with clinical disability, serum inflammatory biomarkers of neuroaxonal and astrocytic injury, and lesion burden.

Results: Models combining morphometry and qMRI data achieved the best performance (mean absolute error: 5.73), outperforming those based on qMRI (6.62) or morphometry alone (8.00). Cross-sectional and longitudinal morphometry-based brain-PAD correlated with clinical disability, serum neurofilament light chain, and serum glial fibrillary acidic protein levels (all p < 0.01), with significant longitudinal interactions with time (all p < 0.05). Cross-sectional qMRI-based brain-PAD correlated with white matter lesion count (p = 0.042, R² = 0.028) and paramagnetic rim lesion volume (p = 0.028, R² = 0.020).

Discussion: Integrating qMRI improves brain age predictions. Brain-PAD serves as an imaging biomarker to quantify MS-associated aging and track disability and neuroinflammation progression.

Background and objectives: Although disease-modifying therapies (DMTs) may suppress coronavirus disease 2019 (COVID-19) vaccine responses in people with multiple sclerosis (pwMS), limited data are available on the cumulative effect of additional boosters. Maturation of Spike immunoglobulin G (IgG) to target a greater diversity of SARS-CoV-2 variants, especially past the BA.1 variant, has not been reported. In addition, the prediction of variant-specific protection, given that Spike antibody testing is not performed routinely, remains a challenge. We, therefore, evaluated whether additional vaccine doses improved the breadth of cross-variant recognition to target emerging SARS-CoV-2 variants. Machine learning-based models were designed to predict variant-specific protection status.

Methods: In a prospective observational cohort (n = 442), Spike IgG titers and live virus neutralization against D614, BA.1, BA.2, BA.5, XBB.1.1, XBB.1.5, and EG.5.1 variants were determined in 1,011 serum samples (0-12 months after 2-4 doses). Predictive protection models were developed by K-fold cross-validation on training and test data sets (random split 70:30).

Results: After primary vaccination, pwMS on immunosuppressive disease-modifying therapy (IMM-DMT) had 10-fold and 7.2-fold lower D614 Spike IgG titers than pwMS on low-efficacy (LE)-DMT and cladribine (p < 0.01). After 4 doses, pwMS on IMM-DMT had significantly lower Spike IgG titers, compared with pwMS on low-efficacy disease-modifying therapy, for D614 (p < 0.05), as well as BA.1, BA.2, BA.5, XBB.1, XBB.1.5, and EG.5.1(p < 0.01). The breadth of Spike IgG to recognize variants other than the cognate antigen increased after 4 doses of all DMTs. Although pwMS on IMM-DMT displayed reduced cross-variant recognition, a fourth dose resulted in a 2-4-fold increase in protection against newer variants and a reduction in two-thirds of pwMS without protective Spike IgG (p < 0.0001). Tixagevimab and cilgavimab did not induce additional cross-variant protection. Variant-specific predictive models of vaccine protection were influenced by treatment, time since primary vaccination, and age, with high sensitivity (99.4%, 95% CI 96.8-99.99) and specificity (72.0%, 95% CI 50.6-87.9) for XBB.1.5/EG.5.1 variants.

Discussion: Despite not eliciting adequate antibody response in pwMS on IMM-DMT, COVID-19 boosters improve the breadth of the humoral response against SARS-CoV-2 emerging variants. Vaccine protection can be predicted by statistical modeling.

Background and objectives: Comorbidities greatly influence the course of many diseases. However, systematic data on comorbidities in patients with autoimmune encephalitis (AE) are scarce. We aimed to characterize comorbidities in patients with common AE variants and assess their influence on outcome and occurrence of infectious complications.

Methods: This multicenter, retrospective cohort study analyzed adult patients with definite anti-N-methyl-d-aspartate receptor (NMDAR), anti-leucine-rich glioma-inactivated-1 (LGI1), anti-contactin-associated protein-like-2 (CASPR2), and anti-immunoglobulin-like cell adhesion molecule-5 (IgLON5) AE registered by the GErman NEtwork for REsearch on AuToimmune Encephalitis between June 2004 and July 2023. Preexisting conditions (PECs), secondary diagnoses, and infectious complications documented during hospitalization were analyzed. Outcome was evaluated using a modified Rankin Scale (mRS), with unfavorable outcome defined as mRS >2 after a minimum of 12 months of follow-up.

Results: Among 308 patients with AE (144 NMDAR-AE, 98 LGI1-AE, 47 CASPR2-AE, and 19 IgLON5-AE), nearly half had cardiovascular and metabolic/endocrine, one-third neurologic, and one-fifth psychiatric comorbidities. Accompanying autoimmunity was observed in 12.7%. Univariable analysis showed that the presence of ≥3 PECs (OR 2.80, 95% CI 1.57-4.92), especially cardiovascular (OR 1.93, 95% CI 1.09-3.30) and psychiatric PECs (OR 3.84, 95% CI 1.96-7.31), was associated with unfavorable outcome. Multivariable regression analysis confirmed psychiatric PECs as independent risk factors (OR 4.55, 95% CI 1.99-10.60). During hospitalization, 13.6% of patients developed severe infections, although these were not associated with unfavorable outcome (OR 1.94, 95% CI 0.97-3.89). AE disease severity (OR 5.41, 95% CI 1.38-27.67) and intensive care unit admission emerged as the only independent predictors of severe infections (OR 20.76, 95% CI 7.02-75.10).

Discussion: As premorbid psychiatric conditions are main factors associated with unfavorable outcomes, these patients would highly benefit from integrated interdisciplinary treatment centers, or at least heightened awareness of these factors. Concomitant autoimmunity affecting other organs is frequent and should be sought. The risk of severe infections during the acute phase of AE is moderate and, given their lack of effect on outcome, should not justify withholding appropriate immunotherapy, even in elderly patients with comorbidities. Future prognostic models should incorporate comorbidities, particularly psychiatric ones, to enhance risk assessment and guide personalized care strategies.

Background and objectives: Acetylcholine receptor (AChR) autoantibodies contribute to myasthenia gravis (MG) pathogenesis through 3 mechanisms: complement activation, receptor internalization, and acetylcholine (ACh) binding site blocking. Recently approved therapies target these autoantibodies by inhibiting the complement pathway or blocking the neonatal Fc receptor, reducing IgG autoantibody levels. However, these approaches have limitations: complement inhibitors do not address complement-independent mechanisms, and FcRn blockers only target IgG. Understanding how different pathogenic mechanisms, isotypes, and IgG subclasses are represented in the AChR autoantibody repertoire could lead to more precise application of therapeutics. To address this, we used advanced live cell-based assays to study autoantibody heterogeneity in longitudinally collected patient samples.

Methods: Serum samples (N = 210) from 50 AChR IgG+ generalized MG patients collected longitudinally over 2 years were evaluated using a set of cell-based assays to measure complement activation, receptor internalization, ACh binding site blocking, and the frequency of the IgM and IgA isotypes and IgG subclasses.

Results: In cross-sectional samples, IgA and IgM autoantibodies co-occurred with IgG in 10% and 12% of patients, respectively. In addition, 4% of patients had all 3 isotypes (IgA, IgM, and IgG) present simultaneously. AChR-IgG1 was found in 67.4%, followed by IgG3 (21.7%) and IgG2 (17.4%). Complement was active in 84.8%, followed by AChR internalization (63%) and blocking (30.4%). Complement and AChR internalization were simultaneously active in 45.6%, complement and blocking were active in 10.8%, and all 3 pathomechanisms were active in 17.4%. Blocking alone was active in only 2.1%; AChR internalization alone was not found. Autoantibody binding capacity was associated with the magnitude of complement activation and AChR internalization. Temporal fluctuations of autoantibody binding capacity and the associated pathogenic mechanisms were observed. Pathogenic mechanisms were not associated with disease severity in cross-sectional analyses. However, longitudinally, disease severity measures followed a similar trend to the AChR autoantibody repertoire and mediated pathogenic mechanisms in some individuals, but not others.

Discussion: These findings highlight subsets of patients with MG with autoantibodies that can mediate pathogenic mechanisms or include isotypes that some therapeutics may not effectively target. Consequently, we suggest incorporating comprehensive autoantibody profiling into future MG clinical trials to further investigate potential associations with treatment outcomes.

Background and objectives: Immune checkpoint inhibitors (ICIs) are oncologic treatments that may trigger or worsen paraneoplastic neurologic syndromes (PNSs). This study describes patients with CV2/CRMP5-PNS treated by ICI, compares the post-ICI group with ICI-naïve patients with CV2/CRMP5-PNS, and estimates the overall survival of ICI-treated patients with CV2/CRMP5-PNS, Hu-PNS, and Ma2-PNS.

Methods: The medical records of patients positive for anti-CV2/CRMP5 antibodies were retrospectively reviewed at the French Reference Centre to identify those treated with ICI (2016-2024). Patients with a preexisting PNS were described separately from those with post-ICI PNS; the latter were then compared with ICI-naïve patients with CV2/CRMP5-PNS diagnosed in the same study period. An overall survival analysis between ICI-treated patients with CV2/CRMP5-PNS, Hu-PNS, and Ma2-PNS was performed.

Results: Fourteen patients with CV2/CRMP5-PNS treated with ICIs were included. Eight patients [median age, 73 years (range: 60-87); 87.5% men] developed post-ICI PNS after a median of 3.5 ICI cycles (range: 1-7). The frequency and distribution of clinical phenotypes (isolated neuropathy [n = 3] or a multifocal neurologic involvement [encephalopathy, limbic syndrome, brainstem syndrome, cerebellar syndrome, ocular syndrome, neuropathy, and/or dysautonomia; n = 5]) were similar to those of ICI-naïve CV2/CRMP5-PNS (n = 48). The frequency of severe presentations (modified Rankin Scale [mRS] score > 3) at diagnosis was similar between post-ICI patients and ICI-naïve patients with CV2/CRMP5-PNS (63% vs 48%, p = 0.7) and slightly higher at last visit in post-ICI patients (88% vs 54%, p = 0.12). Anti-CV2/CRMP5 antibodies were undetectable in the only patient with a pre-ICI serum sample. Among the 6 patients with preexisting CV2/CRMP5-PNS [median age, 66 years (range: 54-79); 50% men] who received ICIs, PNS symptoms worsened in 5 (83%) [median mRS increase of 1.5 points (range: 1-3)]. The median overall survival (22 months) was significantly longer in the ICI-treated patients with CV2/CRMP5-PNS compared with the Hu-PNS and Ma2-PNS groups (4 months and 8 months, respectively, p = 0.0069).

Discussion: ICIs may trigger the onset and exacerbate the progression of CV2/CRMP5-PNS. Post-ICI forms are clinically undistinguishable but possibly more severe than their ICI-naïve counterparts. Increased surveillance is needed in identifying preexisting PNSs, with extreme caution when considering ICI treatment. Post-ICI-induced PNSs have variable prognosis according to the associated onconeural autoantibodies.

Background and objectives: Anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (anti-AMPAR) encephalitis manifests as limbic encephalitis in adults and is often associated with cancer. Although some reports suggest that it may occur in children, the clinical features in this population, as well as the prognostic factors and long-term outcomes in children and adults, are unknown.

Methods: We performed a retrospective, international collaborative study of patients with anti-AMPAR encephalitis. Clinical information was reviewed, together with data from published pediatric patients. Clinical features of children and adults were compared with nonparametric tests. Survival rates (Kaplan-Meier curves) were compared using log-rank tests. Prognostic factors of poor outcome (modified Rankin Scale score >2) were identified using logistic regression models.

Results: A total of 115 patients were included, of whom 84 (71 adults, 13 children) had only AMPAR antibodies and 31 (27 adults, 4 children) had additional concurrent neural antibodies. Among patients with AMPAR antibodies alone, tumors were identified in 37 adults (56%) and none of the children (p < 0.0001). Children were more likely than adults to have behavioral/psychiatric symptoms (5/13, 39%, vs 8/71, 11%, p = 0.026) at onset, cerebellar dysfunction (6/13, 46%, vs 7/68, 10% p = 0.005) or movement disorders (5/13, 39%, vs 8/67, 12%, p = 0.032) during the disease course, and extratemporal brain MRI lesions (4/9, 44%, vs 5/44, 11%, p = 0.035). Among 34 patients with prolonged follow-up (>24 months), long-term neurocognitive sequelae were reported in 23 (68%), all adults. Failure to respond to first-line immunotherapy at multivariable analysis predicted a poor outcome (OR 8.0, 95% CI 1.1-59.2, p = 0.043). Among the 31 patients with concurrent neural autoantibodies, 22 (79%) had a tumor; those with high-risk antibodies had lower survival rates (p = 0.008).

Discussion: Children and adults with anti-AMPAR encephalitis show distinct clinical-radiologic features. At long-term follow-up, 68% of patients, all adults, have neurologic sequelae, with failure to respond to first-line immunotherapy being associated with worse outcomes.

Background and objectives: The reasons for people with multiple sclerosis (MS) to access emergency services are understudied in the era of high-efficacy disease-modifying therapies (DMTs). Many people with MS live with multiple comorbidities and/or experience social determinants of health, which may affect their emergency department (ED) use. The aim of this study was to identify the reasons and risk factors for ED visits among patients with known MS, including sociodemographic characteristics, comorbidity burden, and DMT efficacy category.

Methods: A retrospective case-control study was conducted at the Massachusetts General Hospital, Boston. Patients with MS were analyzed in a 1:2 ratio of cases (patients with at least one ED visit) and controls (no ED visits) during the study time frame June 2019-December 2023. Regression models were constructed to assess the association of predefined variables-sex, age, race, insurance type, comorbidities as a Charlson Comorbidity Index (CCI), and DMT efficacy category-with the likelihood of an ED visit.

Results: Of 1,462 evaluated people with MS, 900 were randomly selected and included: 300 cases and 600 controls. Most patients were female (70.7% cases, 74.7% controls) and White (79.0% cases, 87.2% controls). Cases had a higher mean CCI score (0.83 points) compared with controls (0.05 points). Many people with MS were not taking a DMT (64.3% cases, 39.5% controls). ED utilization showed that 52.0% of patients had a single visit, with COVID-19 being the most common diagnosis (4.2%). 10.3% of people with MS who went to the ED had more than 5 visits during the study time frame. In a multivariable model, higher CCI score was the strongest predictor of ED visits (odds ratio [OR] = 4.23, p < 0.001). No DMT use (OR = 2.56, p < 0.001) and having public or no insurance (OR = 1.99, p < 0.001) each increased the likelihood of an ED visit while identifying as a racial minority led to a lower likelihood of an ED visit (OR = 0.48, p = 0.006).

Discussion: Specific risk factors for ED use occur in people with known MS. Comprehensive management of comorbidities and clinical pathways to reassess the high number of people with MS in the ED who do not take a DMT should be considered.