Journal of Neurology, Neurosurgery, and Psychiatry最新文献

Background: Multiple sclerosis (MS) progression independent of relapses is driven by brain innate immune cell activation. The aim of this study was to evaluate the association between chitinase-3-like protein 1 (CHI3L1), expressed in brain by astrocytes and microglia, measured from blood and smouldering inflammation measured using 18 kDa translocator protein (TSPO) positron emission tomography (PET) in patients with MS.

Methods: The study cohort included 55 patients with MS (25 progressive MS (PMS) and 30 relapsing remitting MS (RRMS)) and 17 healthy controls (HC). CHI3L1 was measured with commercial ELISA from plasma samples. A subcohort (44 MS and 9 HC) underwent TSPO-PET to assess [¹¹C]PK11195 distribution volume ratio (DVR) and MRI concurrent to blood sampling. These imaging outcomes were used in respective correlation and linear regression analyses.

Results: CHI3L1 concentration in plasma was higher in PMS (23.5 ng/mL) compared with HC (16.8 ng/mL, p=0.0055) and RRMS (19.3 ng/mL, p=0.049). CHI3L1 associated with brain [¹¹C]PK11195 DVR in all MS (standardised estimate 0.89, 95% CI 0.23 to 1.55, p=0.010) and in PMS (Spearman correlation ρ=0.58, 95% CI 0.058 to 0.86, p=0.032). Additionally, CHI3L1 was associated with smaller brain volume in both MS (-0.75, -1.38 to -0.11, p=0.023) and PMS (ρ=-0.56, -0.83 to -0.095, p=0.021). Furthermore, CHI3L1 was associated with Expanded Disability Status Scale (0.70, 0.12 to 1.28, p=0.019) and age (0.93, 0.37 to 1.48, p=0.002) among all patients with MS.

Conclusions: Association of CHI3L1 with glial activation and brain volume loss identifies plasma CHI3L1 as a promising biomarker for smouldering inflammation and MS progression-related pathology.

Background: Several prognostic models predict clinical outcomes in Guillain-Barré syndrome (GBS). Recently, neurofilament light chain (NfL) has emerged as a prognostic biomarker. We investigated the added prognostic value of NfL in serum (sNfL) and cerebrospinal fluid (cNfL) to models based on clinical factors predicting respiratory failure and inability to walk in GBS.

Methods: We included patients from a randomised placebo-controlled trial (second intravenous immunoglobulin dose in GBS). Serum was acquired at entry and week 1, 2, 4 and 12 and cerebrospinal fluid at entry. NfL levels were determined on a single molecule array. The additional prognostic value of NfL to the (modified) Erasmus GBS Outcome Score ((m)EGOS) and (modified) Erasmus GBS Respiratory Insufficiency Score was evaluated using logistic regression analyses.

Results: In total, 293 patients were included (74 (25%) mechanically ventilated, 38/275 (13%) unable to walk at 26 weeks). Higher sNfL at entry, week 1 and week 2 and cNfL at entry were associated with inability to walk at 4 and 26 weeks. Neither sNfL nor cNfL levels at entry were associated with respiratory failure. The EGOS and mEGOS improved after adding NfL (∆C-statistic range: 0.01-0.11), especially the models predicting outcome at 26 weeks. A new model predicting inability to walk at 26 weeks consisting of sNfL at entry, GBS disability score at entry and Medical Research Council sum score at week 2 performed best (C-statistic: 0.88 (95% CI 0.83 to 0.94)).

Conclusions: Addition of NfL may improve clinical prognostic models for the prediction of inability to walk, but not of respiratory failure.

Trial registration number: NTR2224/NL2107.

Background: Natalizumab is a highly effective drug for patients with relapsing-remitting multiple sclerosis (MS). A disadvantage of this treatment is the risk of progressive multifocal leukoencephalopathy in patients who are seropositive for the John Cunningham virus (JCV). JCV seroconversion rates increase under natalizumab treatment compared with non-natalizumab using controls. The aim of this study was to assess whether lower natalizumab trough concentrations are associated with reduced JCV seroconversion compared with higher natalizumab trough concentrations.

Methods: Two overlapping cohorts of patients treated with intravenous natalizumab in the Netherlands were combined for this study. JCV seroconversion was assessed during periods of high (≥15 µg/mL) and low (<15 µg/mL) natalizumab trough concentrations. Low trough concentrations were mainly the result of trough concentration guided personalised extended interval dosing (EID). The seroconversion rates during high and low trough concentrations were compared using a generalised linear mixed model with a Poisson link function.

Results: A total of 357 patients from 21 hospitals in the Netherlands were included. The annual seroconversion rate of 8.4% observed in patients during periods of high trough concentrations (n=226) was 2.32 times higher than the seroconversion rate of 4.8% in patients during periods of low trough concentrations (n=252) (95% CI=1.32 to 4.08, p=0.0035).

Conclusions: The seroconversion rate observed in patients with MS with low trough concentrations was substantially lower compared with those with high trough concentrations during natalizumab treatment. This emphasises the importance of personalised EID, where intervals between infusions are prolonged to achieve lower natalizumab trough concentrations, to increase drug safety.

Background: Due to the lack of long-term studies, this research aimed to explore the changes and predictors of autonomic dysfunction (AD) in people with multiple sclerosis (pwMS) over a 6-year period from disease onset.

Methods: Among the 121 pwMS cohort, 75 underwent autonomic function tests at baseline and year 6. Autonomic symptoms were assessed using the Composite Autonomic System Score-31 (COMPASS-31), while the results of autonomic tests were recorded using the Composite Autonomic Scoring Scale (CASS) at baseline and biennially over 6 years. Symptomatic dysautonomia was identified by a COMPASS-31 score greater than 7.913 and a CASS score greater than 0.

Results: No significant changes were noted in the COMPASS-31 and CASS scores from baseline to year 6. However, there was a significant decline in the cardiovagal index (p=0.001) and the sudomotor index (p=0.036 and p=0.001, respectively) at years 4 and 6, compared with baseline. The number of participants with symptomatic dysautonomia increased significantly from year 0 to 6 (14 (20.9%) vs 29 (39.2%), respectively; p=0.049). Multivariable logistic regression analysis revealed that experiencing a relapse during the 6 years increased the likelihood of symptomatic dysautonomia (Exp(B) 3.886, 95% CI 1.019 to 14.825, p=0.047). Conversely, transitioning to high-efficacy disease-modifying therapy (HET) reduced the probability of having a CASS score greater than 0 at year 6 (Exp(B) 0.221, 95% CI 0.067 to 0.734, p=0.014).

Conclusions: Dysfunction of the cardiovagal and sudomotor systems progresses alongside disease duration in pwMS. The early initiation of HET may help mitigate the risk of developing AD.

Background: Grey matter (GM) atrophy is associated with cognitive impairment (CI) in multiple sclerosis (MS). We aimed to investigate the predictive role of early regional GM damage for long-term CI.

Methods: A post-hoc cluster analysis was conducted on 175 patients with MS followed for 20 years from onset. Participants underwent a 1.5T-MRI scanning at diagnosis and after 2 years, and a comprehensive neuropsychological assessment after 20 years.

Results: Three clusters have been identified: cluster 1 (primarily patients with long-term normal cognition), cluster 2 (primarily patients with long-term mild CI) and cluster 3 (primarily patients with long-term severe CI). Five brain regions have been identified showing a significant difference in early atrophy from cluster 1 and both clusters 2 and 3: precuneus (1 vs 2: p<0.001, relative risk ratio (RRR)=4.9, 95% confidence intervals (95% CIs) =2.4-10.1; 1 vs 3: p<0.001, RRR=5.5, 95% CIs=3.1-9.7), insula (1 vs 2: p<0.001, RRR=4.1, 95% CIs=1.9-8.6; 1 vs 3: p<0.001, RRR=4.3, 95% CIs=2.5-7.5), parahippocampal gyrus (1 vs 2: p<0.001, RRR=3.2, 95% CIs=1.8-5.7; 1 vs 3: p<0.001, RRR=3.1, 95% CIs=2.1-4.6), cingulate gyrus (1 vs 2: p<0.001, RRR=3.0, 95% CIs=1.7-5.3; 1 vs 3: p<0.001, RRR=2.2, 95% CIs=1.6-5.3) and cerebellum (1 vs 2: p=0.027, RRR=2.6, 95% CIs=1.5-4.6; 1 vs 3: p<0.001, RRR=2.1, 95% CIs=1.5-2.9). Four additional brain regions showed a significant difference in terms of early atrophy between cluster 1 and cluster 3: precentral gyrus (p<0.001, RRR=7.3, 95% CIs=3.1-17.3), postcentral gyrus (p<0.001, RRR=4.6, 95% CIs=2.2-9.8), superior frontal gyrus (p<0.001, RRR=4.0, 95% CIs=2.0-8.0) and hippocampus (p<0.001, RRR=2.4, 95% CIs=1.6-3.6).

Conclusions: Cluster analysis identified the most specific brain regions whose early atrophy best distinguished future patients with CI. Long-term CI accumulation in MS can be predicted by early GM volume loss of specific cortical/deep GM regions.

Background: Three decades have passed since the initial approval of disease-modifying therapies (DMTs). Ongoing discussion is focused on fundamental aspects of the disease, highlighting a growing division between successes in managing relapsing multiple sclerosis (MS) and the persistent challenges posed by disease progression.

Methods: A cohort study on prospectively acquired data from the Italian MS register. The primary outcome was to describe the MS disease course from onset to secondary progression (SP) defined according to a data-driven algorithm over 30 years follow-up and according to five different eras of disease onset.

Results: A total cohort of 9958 patients was analysed; 1364 converted to SP after a mean of 8.5 (SD 5.5) years. A higher rate of patients converting to SP had never been exposed to DMTs (135, 9.9% vs 424, 5.2%) than non-converting ones. The treatment coverage was also lower in patients converting to SP than non-converting ones 58.4 (SD 31.5) vs 73.6 (SD 27.6).The SP incidence rate was 1.26 (95% CI 1.19 to 1.32) overall. The rates showed a downward trend among the different eras: from 1st era 1.98 (95% CI 1.73 to 2.27) to 5th era 1.15 (95% CI 0.97 to 1.35).In the multivariable Cox model, 10% increase of treatment coverage was associated to 19% lower risk to convert to SP (10%, HR 0.89, 95% CI 0.87 to 0.90).

Conclusions: This 30-year analysis suggests that SP conversion rates have decreased over time, partially explained by improvements in therapeutic coverage. Future research should adopt a multifaceted approach to develop more comprehensive models of disease progression.

Background and objectives: Biologically informative markers like glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) may help predict confirmed disability worsening (CDW) in multiple sclerosis (MS). However, data on the prognostic value of their blood concentrations in progressive MS (PMS) are limited, and there are substantial discrepancies in the published literature. This international collaboration uses individual participant data to define the prognostic value of serum GFAP and NfL in people with PMS (pwPMS).

Methods: Data were collected from BioMS-eu network centres and collaborating cohorts. pwPMS with primary progressive MS (PPMS) or secondary progressive MS (SPMS) with at least one GFAP value and at least three follow-up expanded disability status scale (EDSS) scores were included. The prognostic value of serum GFAP and NfL age- and sex-adjusted Z-scores for future CDW was evaluated using Cox regression models, accounting for sex, age, baseline disease duration and EDSS, and dominant treatment during follow-up.

Results: 1058 participants and 7530 encounters were included (median age 53 years (IQR: 44 to 59), 57% female, follow-up 4.6 years (2.9 to 8.4)) with median baseline GFAP of 0.74 (-0.10 to 1.55) and NfL of 0.64 (-0.36 to 1.51). 723 CDW events were recorded. Each GFAP Z-score increase was associated with ~10% higher CDW risk (adjusted HR (aHR) 1.107 (1.001 to 1.225), p=0.049). Results were mainly driven by SPMS participants (n=613, aHR 1.242 (1.073 to 1.438), p=0.004). Higher NfL Z-scores predicted CDW only in PPMS participants (1.236 (1.092 to 1.399), p=0.001).

Conclusions: GFAP was a prognostic indicator for future CDW in pwPMS, especially in pwSPMS. On the other hand, NfL was predictive of CDW only in pwPPMS.

Background: Immunoglobulin G₄ (IgG₄) related disease (RD) is a multisystem, immunologically mediated disease discovered within the last two decades. Within the nervous system, a broad range of both central and peripheral nervous system involvement has been reported. We aimed to systematically review the neurological manifestations of IgG₄-RD.

Aim: To identify the clinical presentation, radiological findings, diagnostic methods, treatment and outcomes for neurological manifestations of IgG₄-RD.

Methods: We systematically reviewed the literature to identify all reports of neurological manifestations of IgG₄-RD. Data on neurological manifestations, non-neurological manifestations, clinical presentation, radiological findings, diagnostic methods, treatment modalities and outcomes were extracted.

Results: We identified 393 cases from 297 publications meeting the inclusion criteria. Hypertrophic pachymeningitis, IgG₄-related orbital disease and hypophysitis are the most common neurological manifestations of IgG₄-RD. Diagnostic evaluation involves testing for concomitant non-neurological manifestations, an MRI with gadolinium contrast, measurement of serum IgG₄ levels and a biopsy with specific staining for IgG₄ positive plasma cells. Treatment with corticosteroids leads to favourable outcomes.

Conclusions: IgG₄-RD is an emerging neurological disease that can manifest in multiple ways within the nervous system. It is important to recognise as treatment is often successful.

Background: Associations between comorbidity and reduced persistence to disease-modifying therapies (DMTs) in multiple sclerosis (MS) have been identified. Limited information is available regarding the association of comorbidity with safety outcomes. The study objective was to evaluate the association of comorbidities with safety outcomes and persistence.

Methods: We conducted a two-stage meta-analysis of individual participant data from phase III clinical trials of MS DMTs. Individual comorbidities and comorbidity burden, defined as the sum of all comorbidities (n=15), were examined. Safety outcomes, defined using adverse event (AE) data, were reviewed to identify specific AEs of interest, including infection; treatment-emergent autoimmune disease; cancer; elevated transaminases and lymphopenia. We also examined any early trial discontinuation.

Results: We included 17 clinical trials representing 16 794 MS participants. Over a 2-year follow-up, the pooled proportion of AEs was 64% (95% CI 59.4% to 68.9%) and the majority were infection AEs. Increasing comorbidity burden was associated with an increased rate of AEs (rate ratio (95% CI) 1: 1.13 (1.09 to 1.17); 2: 1.19 (1.14 to 1.23); ≥3: 1.25 (1.18 to 1.33)) compared with those with no comorbidity. When pooled across trials, early discontinuation affected 17% of participants (95% CI 13.8% to 20.9%). A higher risk of trial discontinuation was associated with higher comorbidity burden (2: 1.23 (1.07 to 1.42); ≥3: 1.19 (1.01 to 1.40)) compared with those with no comorbidity. Psychiatric disorders were associated with trial discontinuation.

Conclusions: Higher comorbidity burden is associated with increased risk of experiencing safety outcomes and early DMT discontinuation among individuals with MS enrolled in clinical trials of MS-DMTs, highlighting the important role of comorbidities in the safety and persistence of DMTs.

Background: Contact sports, including rugby union, are associated with higher rates of neurodegenerative dementia, due to various underlying pathologies such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). New ultrasensitive multiplexed immunoassays may clarify disease mechanisms after repetitive head impacts (RHI) and traumatic brain injury, potentially aiding risk-stratification, early diagnosis and dementia treatment.

Methods: Midlife participants in the ABHC cohort underwent plasma biomarker quantification (NULISA - NUcleic acid Linked Immuno-Sandwich Assay; n=124 markers), 3T MRI, trauma exposure ascertainment and phenotyping. Regressions quantified exposure-specific protein expression, relationship to trauma (including position) and brain atrophy, using cluster analysis to test correlates of traumatic encephalopathy syndrome (TES).

Results: 197 former elite rugby players and 33 controls were assessed. 24 (12.2%) met criteria for TES but none had dementia. Ex-players returned reduced plasma glial fibrillary acidic protein (GFAP), kallikrein-6 (KLK6) and synaptosomal-associated protein 25 (SNAP25). Ex-forwards specifically showed reduced plasma beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), amyloid beta-38 (Aβ38), and increased phospho-tau₁₈₁ (p-tau₁₈₁). KLK6 was lower in ex-backs than controls. No biomarkers related to career duration, concussion load or regional brain volume, nor did clustering relate to TES.

Conclusions: Ex-players showed distinctive plasma biomarker changes, more prominently in ex-forwards, possibly reflecting greater RHI exposure. Plasma KLK6, an endothelial serine protease, was reduced across the ex-player group, with potential diagnostic or prognostic utility in future. Reduced GFAP and SNAP25 in ex-forwards has an uncertain basis, while elevated p-tau-₁₈₁ more so than p-tau₂₁₇ points towards non-AD tau pathology. Our findings motivate longitudinal characterisation, including comparison with other neurodegenerative diseases.