Neurology® Neuroimmunology & Neuroinflammation最新文献

Background and objectives: In multiple sclerosis (MS), immune cells invade the CNS and destroy myelin. Macrophages contribute to demyelination and myelin repair, and their role in each process depends on their ability to acquire specific phenotypes in response to external signals. In this article, we assess whether defects in MS patient macrophage responses may lead to increased inflammation or lack of neuroregenerative effects.

Methods: CD14⁺CD16^- monocytes from patients with MS and healthy controls (HCs) were activated in vitro to obtain homeostatic-like, proinflammatory, and proregenerative macrophages. Macrophage activation profiles were assessed through RNA sequencing and metabolomics. Surface molecule expression of CD14, CD16, and HLA-DR and myelin phagocytic capacity were evaluated with flow cytometry. Macrophage supernatant capacity to influence oligodendrocyte precursor cell differentiation toward an astrocytic or oligodendroglia fate was also tested.

Results: We observed that MS patient monocytes ex vivo recapitulate their preferential activation toward the CD16⁺ phenotype, a subset of proinflammatory cells overrepresented in MS lesions. Functionally, MS patient macrophages display a decreased capacity to phagocytose human myelin and a deficit of processing myelin after ingestion. In addition, MS patient macrophage supernatant favors astrocytes over oligodendrocyte differentiation when compared with HC macrophage supernatant. Furthermore, even when exposed to homeostatic or proregenerative stimuli, MS patient macrophages uphold a proinflammatory transcriptomic profile with higher levels of cytokine/chemokine. Of interest, MS patient macrophages exhibit a distinct metabolic signature with a mitochondrial energy metabolism blockage. Transcriptomic data are further substantiated by metabolomics studies that reveal perturbations in the corresponding metabolic pathways.

Discussion: Our results show an intrinsic defect of MS patient macrophages, reminiscent of innate immune cell memory in MS, lifting macrophage importance in the disease and as potential therapeutic targets.

Background and objectives: Cognitive impairment (CI) in multiple sclerosis (MS) is frequent and determined by a complex interplay between inflammatory and neurodegenerative processes. We aimed to investigate whether CSF parvalbumin (PVALB), measured at the time of diagnosis, may have a prognostic role in patients with MS.

Methods: In this cohort study, CSF analysis of PVALB and Nf-L levels was performed on all patients at diagnosis (T0) and combined with physical, cognitive, and MRI assessment after an average of 4 years of follow-up (T4) from diagnosis. Cognitive performance was evaluated with a comprehensive neuropsychologic battery: both global (cognitively normal, CN, mildly CI, mCI, and severely CI, sCI) and domain cognitive status (normal/impaired in memory, attention/information processing speed, and executive functions) were considered. Cortical thickness and gray matter volume data were acquired using 3T MRI scanner.

Results: A total of 72 patients with MS were included. At diagnosis, PVALB levels were higher in those patients who showed a worsening physical disability after 4 years of follow-up (p = 0.011). CSF PVALB levels were higher in sCI patients than in CN (p = 0.033). Moreover, higher PVALB levels significantly correlated with worse global cognitive (p = 0.024) and memory functioning (p = 0.044). A preliminary clinical threshold for PVALB levels at diagnosis was proposed (2.57 ng/mL), which maximizes the risk of showing CI (in particular, sCI) at follow-up, with a sensitivity of 91% (specificity 30%). No significant results were found for these associations with Nf-L. In addition, patients with higher levels of PVALB at diagnosis showed higher cognitive (p = 0.024) and global fatigue (p = 0.043) at follow-up. Finally, higher PVALB levels also correlated significantly with more pronounced CTh/volume at T4 in the inferior frontal gyrus (p = 0.044), postcentral gyrus (p = 0.025), frontal pole (p = 0.042), transverse temporal gyrus (p = 0.008), and cerebellar cortex (p = 0.041) and higher atrophy (change T0-T4) in the right thalamus (p = 0.038), pericalcarine cortex (p = 0.009), lingual gyrus (p = 0.045), and medial frontal gyrus (p = 0.028).

Discussion: The significant association found between parvalbumin levels in the CSF at diagnosis and cognitive, clinical, and neuroradiologic worsening after 4 years of follow-up support the idea that parvalbumin, in addition to Nf-L, might represent a new potential prognostic biomarker, reflecting MS neurodegenerative processes occurring since early disease stages.

Background and objectives: Autoimmune encephalitis (AIE) and paraneoplastic neurologic syndromes (PNSs) encompass a heterogeneous group of antibody-associated disorders. Both the number of syndromes and commercially available antibody tests have increased considerably over the past decade. High-quality population-based data on epidemiology of these disorders and real-world performance of antibody tests are needed.

Methods: In this nationwide retrospective cohort study, we identified all serum and CSF samples tested for antibodies against intracellular antigens (IAs: Hu [ANNA1], Yo [PCA1], CV2 [CRMP5], Ri [ANNA2], Ma1, Ma2 [Ta], amphiphysin, GAD65, GFAP, KLHL11, CARP VIII) or extracellular antigens (EAs: NMDAR, LGI1, Caspr2, GABA-B-R, GABA-A-R, AMPAR, DPPX, GlyR, mGluR1, VGCC, IgLON5, Tr [DNER]) between January 2016 and December 2021 in the Netherlands. Nationwide coverage was guaranteed for all antibodies except anti-GAD65 and anti-VGCC. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV); obtained clinical information about patients who tested positive; assigned diagnosis of AIE/PNS according to diagnostic criteria; and calculated incidence rates for IA, EA, and individual antibody-associated syndromes.

Results: In the study period, 2,877 (9.5%) of 30,246 samples, belonging to 1,228 patients, tested positive. Sensitivity and specificity were high (>95%) to very high (>99%) for most tests in both serum and CSF. PPVs for several tests were moderate to poor, especially for serum testing of IA antibodies (25%-80%). Clinical data were available for 940 (76.5%) of 1,228 patients. A total of 578 AIE/PNS diagnoses were made. The incidence rate for AIE/PNS (per million person-years) increased from 4.70 (95% CI 3.72-5.85) in 2016 to 5.76 (4.69-7.00) in 2021. Overall, the incidence rate was 5.57 (5.13-6.05), 2.96 (2.64-3.31) for the EA and 2.61 (2.31-2.94) for the IA subgroup. The 4 most common AIE/PNS types were anti-NMDAR, anti-LGI1, anti-Hu, and anti-GAD65, together comprising almost two-thirds of all diagnoses (364/578, 63.0%).

Discussion: Most commercial antibody tests perform well overall, but important pitfalls remain. Although almost all tests had high specificity, PPV was only modest in the setting of these rare diseases and mass testing. We observe trends toward increasing incidence of antibody-associated AIE/PNS.

Background and objectives: Recent studies suggest that the choroid plexus (CP) may function as a site of access of inflammatory cells into the CNS in multiple sclerosis (MS). Pediatric-onset MS (POMS) is characterized by a high inflammatory burden, as evidenced by a high relapse rate and volume of T2 lesions, making patients with POMS an informative population to evaluate choroid plexus volume (CPV). The objectives of the study were (1) to evaluate CPV at symptom onset in participants with POMS compared with healthy controls (HCs); (2) to evaluate changes in CPV in the first year of disease in participants with POMS; and (3) to evaluate associations between CPV, brain volumes, relapse activity, and disability in participants with POMS.

Methods: Baseline 1.5T MRI scans were acquired from 23 participants with POMS and 23 age-matched and sex-matched HCs; 18 participants with POMS also had 12-month follow-up MRI scans. The CP of the lateral ventricles was segmented manually. CP and brain structure volumes were normalized for total intracranial volume. The number of relapses, T2 and gadolinium-enhancing T1 lesion counts, and Expanded Disability Status Scale (EDSS) scores at 12 months were also analyzed. Baseline CPVs were compared between groups using the Wilcoxon exact test, and CPV change from baseline to 12 months in participants with POMS was compared using the Wilcoxon signed-rank test. The relationship between CPV and brain volumetric measures, T2 lesion volumes, lesion count, number of relapses, and EDSS scores was assessed through Spearman correlation.

Results: The median normalized CPV was 1.51 × 10^-3 (interquartile range [IQR]: 1.32-1.76) in POMS baseline scans and 1.21 × 10^-3 (IQR: 1.1-1.47) in HC scans (p = 0.001). CPV did not significantly change at 12 months in the 18 participants with POMS with follow-up scans (p = 0.352). CPV in participants with POMS and HCs correlated with lateral ventricular volume (p = 0.012 for both groups) but did not correlate with brain and T2 lesion volumes or lesion count at baseline, nor with relapse activity or EDSS scores at 12 months in participants with POMS.

Discussion: CPV measured at baseline is greater in participants with POMS than in HCs. Baseline CPV did not predict higher disease activity or worse neurologic outcomes over 1 year. While higher CPV may be an early feature of inflammation in MS, its strong correlation with ventricular volumes could also reflect enlargement secondary to the mechanical attachment of CP to the ventricular wall.

Background and objectives: The 2022 International Consortium for Optic Neuritis diagnostic criteria for optic neuritis (ON) include optical coherence tomography (OCT). The diagnostic value of intereye difference (IED) metrics is high for ON in patients with multiple sclerosis and aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders, but unknown in myelin oligodendrocyte glycoprotein antibody-associated ON (MOG-ON).

Methods: A multicenter validation study was conducted on the published IED cutoff values (>4% or >4 μm in the macular ganglion cell and inner plexiform layer [mGCIP] or >5% or >5 μm in the peripapillary retinal nerve fiber layer [pRNFL]) in individuals with MOG-ON and age-matched and sex-matched healthy controls (HCs). Structural data were acquired with Spectralis spectral-domain OCT >6 months after ON. We calculated sensitivity, specificity, and receiver operating characteristics for both intereye percentage (IEPD) and absolute difference (IEAD).

Results: A total of 66 individuals were included (MOG-ON N = 33; HCs N = 33). ON was unilateral in 20 and bilateral in 13 subjects. In the pooled analysis, the mGCIP IEPD was most sensitive (92%), followed by the mGCIP IEAD (88%) and pRNFL (84%). The same pattern was found for the specificity (mGCIP IEPD 82%, IEAD 82%; pRNFL IEPD 82%, IEAD 79%).In subgroup analyses, the diagnostic sensitivity was higher in subjects with unilateral ON (>99% for all metrics) compared with bilateral ON (61%-78%).

Discussion: In individuals with MOG-ON, the diagnostic accuracy of OCT-based IED metrics for ON was high, especially of mGCIP IEPD.

Classification of evidence: This study provides Class III evidence that the intereye difference on OCT can distinguish between those with MOG and normal controls.

Background and objectives: Recovery of vision after acute optic neuritis (AON) is critical to improving the quality of life of people with demyelinating diseases. The objective of the study was to prospectively assess the changes in visual acuity, retinal layer thickness, and cortical visual network in patients with AON to identify the predictors of permanent visual disability.

Methods: We studied a prospective cohort of 88 consecutive patients with AON with 6-month follow-up using high and low-contrast (2.5%) visual acuity, color vision, retinal thickness from optical coherence tomography, latencies and amplitudes of multifocal visual evoked potentials, mean deviation of visual fields, and diffusion-based structural (n = 53) and functional (n = 19) brain MRI to analyze the cortical visual network. The primary outcome was 2.5% low-contrast vision, and data were analyzed with mixed-effects and multivariate regression models.

Results: We found that after 6 months, low-contrast vision and quality of vision remained moderately impaired. The thickness of the ganglion cell layer at baseline was a predictor of low-contrast vision 6 months later (ß = 0.49 [CI 0.11-0.88], p = 0.012). The structural cortical visual network at baseline predicted low-contrast vision, the best predictors being the betweenness of the right parahippocampal cortex (ß = -036 [CI -0.66 to 0.06], p = 0.021), the node strength of the right V3 (ß = 1.72 [CI 0.29-3.15], p = 0.02), and the clustering coefficient of the left intraparietal sulcus (ß = 57.8 [CI 12.3-103.4], p = 0.015). The functional cortical visual network at baseline also predicted low-contrast vision, the best predictors being the betweenness of the left ventral occipital cortex (ß = 8.6 [CI: 4.03-13.3], p = 0.009), the node strength of the right intraparietal sulcus (ß = -2.79 [CI: -5.1-0.4], p = 0.03), and the clustering coefficient of the left superior parietal lobule (ß = 501.5 [CI 50.8-952.2], p = 0.03).

Discussion: The assessment of the visual pathway at baseline predicts permanent vision disability after AON, indicating that damage is produced early after disease onset and that it can be used for defining vision impairment and guiding therapy.