Journal of Neurology, Neurosurgery, and Psychiatry最新文献

Background: The premanifest stage in carriers of hexanucleotide repeat expansions in the C9orf72 gene (C9RE) is associated with memory impairment. The present study examines whether the impairment is general across domains or disproportionately affects specific stimulus categories such as socioemotional events, and its underlying functional neuroanatomy.

Methods: This task-based fMRI-study included 21 premanifest C9RE (preC9RE) carriers and 24 controls. Participants encoded stimuli of (emotional and neutral) faces and houses, followed by a recognition task. Using univariate and multivoxel pattern analyses at whole-brain level and region-of-interest level, we investigated the neural change during encoding and retrieval processes, as well as the neural pattern similarity between encoding and retrieval.

Results: Compared with controls, the preC9RE group demonstrated poorer performance in memorising faces (U=104, p=0.002), while their ability to memorise houses remained intact. The preC9RE group exhibited distinct neural patterns in the anterior insula during face encoding compared with the controls (accuracy>0.765, p<0.05). During face retrieval, the preC9RE group showed an increased neural response to encoded faces versus new faces in the right anterior insula (U=394, p=0.015). Individuals with preC9RE exhibited reduced encoding-retrieval neural similarity in the salience network specifically related to face stimuli (U=120, p=0.023).

Conclusions: The findings reveal functional changes in the salience network related to impaired social memory at the premanifest stage of C9RE. The findings further underscore the high potential of multidimensional neural response patterns as a sensitive biomarker for neurodegenerative functional changes, and the salience network as biomarker for C9RE disease staging.

Background: The impact of body weight on disability progression rates among patients receiving ofatumumab was not evaluated yet.

Methods: Among patients from a multicentre prospective cohort, baseline demographics were compared among body mass index (BMI) quartiles as well as proportions of clinical relapses, MRI lesions and disability worsening during follow-up.

Results: 536 patients from four centres were included. Baseline demographics were evenly distributed among patients. Proportions of relapses and new/enlarging MRI lesions were comparable among BMI strata.Confirmed disability worsening was significantly more abundant among patients from the 4th BMI quartile (BMI ≥29.2 kg/m²; adjusted HR: 3.33 (95% CI: 1.72 to 6.42; p<0.001). Relapse-associated worsening was not substantially different among relapsing patients from different BMI strata (HR: 1.19 (95% CI: 0.40 to 3.52; p=0.750)). Yet, progression independent from relapse activity was more likely in patients from 4th BMI quartile (HR: 2.00 (95% CI: 1.47 to 2.70; p<0.001)).Body weight (4th body weight quartile: ≥84.5 kg) was not associated with disability worsening (adjusted HR: 1.91 (95% CI: 0.97 to 3.76; p=0.060). Ofatumumab serum levels were lower in patients with higher BMI as well.

Conclusions: Inflammatory disease outcomes did not differ but disability progression was more frequent in the highest BMI quartile (BMI >29.2 kg/m²). This was associated with lower ofatumumab serum levels. Since body weight itself was not predictive, we assume that body fat composition is critical for ofatumumab effectiveness.

Background: The ASCEND trial did not find benefit of natalizumab during secondary progressive multiple sclerosis compared with placebo; however, its open-label extension suggests this may be obscured by therapeutic lag.We aimed to compare the efficacy of natalizumab and interferon β-1a in slowing disease progression in secondary progressive multiple sclerosis after accounting for therapeutic lag.

Methods: We analysed pooled data from the ASCEND (natalizumab vs placebo) and SPECTRIMS (interferon β-1a vs placebo) trials. Cumulative hazards of 6-month confirmed disability progression during secondary progressive multiple sclerosis were compared using Cox proportional hazards models adjusted for confounding variables. We accounted for therapeutic lag in each patient based on baseline expanded disability status scale, annualised relapse rate and sex. Differences between SPECTRIMS and ASCEND placebo arms were used to adjust the differences between interferon β-1a and natalizumab arms.

Results: Baseline characteristics of 1156 patients were similar between SPECTRIMS and ASCEND cohorts, except for a higher proportion of older patients and lower relapse rates in the ASCEND trial. Natalizumab exhibited a lower cumulative hazard of disability progression compared with interferon β-1a (HR 0.15, 95% CI 0.08 to 0.29, p<0.0001). After adjusting for the difference in cumulative hazards between placebo groups (HR 0.36, 95% CI 0.20 to 0.63, p=0.0004), natalizumab remained associated with a lower hazard of disability progression compared with interferon β-1a (HR 0.42, 95% CI 0.22 to 0.77, p=0.0016).

Conclusion: After accounting for therapeutic lag and differences between ASCEND and SPECTRIMS trials, natalizumab, compared with interferon β-1a, reduces disability progression during secondary progressive multiple sclerosis.

Background: Autologous haematopoietic stem cell transplantation (AHSCT) has emerged as a highly effective treatment for relapsing-remitting multiple sclerosis (RRMS), though patient selection remains challenging. The degree to which disease-modifying therapies (DMTs) and procedure-related complications affect treatment outcomes is unclear. The objective of this study was to investigate the factors that might influence outcomes following AHSCT.

Methods: Data from the multicentre, retrospective cohort study Haematopoietic Stem Cell Transplantation for Treatment of Multiple Sclerosis in Sweden (AutoMS-Swe) were analysed, comprising 174 patients with RRMS who received AHSCT before 1 January 2020. Primary outcomes included inflammatory disease activity, confirmed disability worsening (CDW) and overall evidence of disease activity. Confirmed disability improvement was investigated as a secondary outcome. Associations between variables of interest and outcomes were assessed using univariable Cox proportional hazards models.

Results: Patients who received rituximab as the last DMT before AHSCT had a reduced hazard of inflammatory disease activity (HR 0.18, 95% CI 0.04 to 0.78). Epstein-Barr virus detection was associated with a higher hazard of inflammatory disease activity (HR 2.3, 95% CI 1.05 to 5.07). CDW was associated with longer disease durations (HR 1.09, 95% CI 1.00 to 1.19) and was negatively associated with gadolinium-enhancing lesions (HR 0.08, 95% CI 0.01 to 0.64). No CDW events occurred in treatment-naive patients.

Conclusions: Prior rituximab treatment appears to be protective against inflammatory activity after AHSCT. Disease duration and gadolinium-enhancing lesions are major determinants of disability following AHSCT.

Background: Can plasma biomarkers as well as cerebrospinal fluid (CSF) perform in the separation of amyloid-beta-positive (Aβ+) vs amyloid-beta-negative (Aβ-) groups across an age range seen in an NHS cognitive disorder clinic?

Methods: As part of the routine diagnostic investigation of 111 clinic patients who had contemporaneous blood and CSF samples taken, patients were categorised into Aβ+ and Aβ- groups based on their CSF in an Aβ42/40 ratio. We then evaluated four single molecule array (Simoa) Quanterix assays, quantifying single plasma analytes and ratios (p-tau217, p-tau217/Aβ42 ratio, p-tau181, p-tau181/Aβ42 ratio and Aβ42/40 ratio) in their ability to distinguish between these groups and the effect of age.

Results: The median (range) age of participants was 66 (55-79) years with 48 females (43.2%). The areas under the curve (AUC), not accounting for age, for the ability to discriminate Aβ+ from Aβ- groups were plasma p-tau217 AUC=0.94, Aβ42/40 AUC=0.78 and p-tau181 AUC=0.77. Combining p-tau217/Aβ42 increased the AUC to 0.97. The difference between the groups was influenced by age with less separation in older individuals: a significant negative interaction term between age and group for plasma p-tau217 concentrations (-0.037, p=0.013) and p-tau217/Aβ42 ratio (-0.007, p=0.008).

Conclusions: There was variable performance of plasma biomarkers to recapitulate the CSF assay. Both p-tau217 and p-tau217/Aβ42 showed excellent promise as surrogates of CSF amyloid status, although with slightly reduced performance in older individuals. There was poorer discriminatory ability for p-tau181 and Aβ42/40. Further research is needed to address potential age-related confounds.

Background: Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is a severe autoimmune disorder with high morbidity and mortality. Current treatments have limitations including relapse, highlighting the need for effective maintenance therapy. This study evaluates the efficacy and safety of mycophenolate mofetil (MMF) as long-term adjunctive therapy to first-line treatment in newly diagnosed patients with NMDARE.

Methods: We conducted a prospective, randomised, open-label trial in four academic centres in China. Patients aged 14 and older with acute NMDARE, who received first-line treatments within 2 weeks of presentation to the hospital and had a modified Rankin scale (mRS) score of 2 or more, were recruited. Participants were randomly assigned to receive first-line treatment with or without MMF (0.5 g two times per day for 24 months). Primary outcomes included relapse rates and time to relapse, with secondary outcomes including cognitive deficits, treatment response (the proportion of patients with≥1 point improvement in mRS within 4 weeks) and adverse events (AEs).

Results: Of 100 patients (52% female; median age 27), those in the MMF group had fewer relapses (5.9% vs 26.5%; p=0.006) and better treatment response (84.3% vs 65.3%; p=0.03). No significant difference was found in long-term functional prognosis at 12 and 24 months. However, MMF patients had less fatigue, cognitive impairment, depression and seizures. AEs were mild-to-moderate, with no deaths or anaphylactic reactions.

Conclusions: This study provides Class II evidence that long-term adjunctive treatment of MMF to first-line treatment of NMDARE resulted in a lower risk of relapse and was well tolerated beyond the 24 months of treatment.

Trial registration number: ChiCTR2100044362.

Background: Emerging evidence indicates that diet, including fish consumption, may play a role in the development and progression of multiple sclerosis (MS). We aimed to investigate the influence of fish consumption on disability progression in MS.

Methods: Incident cases from the population-based case-control study Epidemiological Investigation of MS (n=2719), with data on fish intake and Expanded Disability Status Scale (EDSS) outcomes, were categorised by fish consumption and followed up to 15 years post-diagnosis through the Swedish MS registry. A digital follow-up questionnaire in 2021 assessed changes in fish intake over time (n=1719). Cox regression models, adjusted for clinical and demographic variables, were used to evaluate 24-week confirmed disability worsening (CDW), and progression to EDSS 3 and EDSS 4.

Results: Higher total consumption of lean and oily fish at diagnosis was associated with a reduced risk of CDW (HR 0.66, 95% CI 0.51 to 0.86), EDSS 3 (HR 0.55, 95% CI 0.39 to 0.79) and EDSS 4 (HR 0.57, 95% CI 0.33 to 0.96) compared with low consumption. These associations showed significant trends and remained consistent after further adjustment for various lifestyle factors. The protective effects were more pronounced among patients who maintained consistent fish consumption during the follow-up period.

Conclusions: Our findings suggest that higher fish consumption is associated with more favourable MS disability progression, supporting diet as a potentially modifiable factor. Replication and validation are needed before transfer to practice.

Background: Alexithymia, a personality trait characterised by difficulty in identifying and expressing emotions, may contribute to the onset and clinical presentation of functional motor disorders (FMDs), although this association remains underexplored.

Methods: From the Italian Registry of FMDs, we selected individuals recruited between November 2011 and January 2023, diagnosed with FMD according to Gupta and Lang criteria and assessed for various neurological and psychological features with validated rating scales. The main statistical analysis included regression models using the Toronto Alexithymia Scale 20 items as an explanatory variable for a set of clinical measures, adjusting for sociodemographic factors and correcting for multiple testing.

Results: In a cohort of 483 individuals, 20.7% had possible alexithymia and 31.5% had definite alexithymia. Higher levels of alexithymia were strongly associated with increased severity of depression (β=0.31, p<0.001), anxiety (β=0.32, p<0.001), general psychological distress (β=-0.27, p<0.001), fatigue (β=0.05, p<0.001) and pain (β=0.32, p<0.001) and moderately associated with a slower onset of FMD (β=0.02, p=0.003). Subscale analyses revealed that difficulties identifying feelings contributed most to these associations. No significant association was observed with motor symptom severity.

Conclusions: Emotional processing difficulties of individuals with FMD and alexithymia might increase their vulnerability to mental health problems, pain and fatigue, possibly aggravating the overall prognosis. Further research is needed to elucidate the underlying mechanisms linking alexithymia to FMD and to explore the efficacy of interventions targeting emotional awareness and regulation in this population and to prevent long-term mental health burdens.

Background: A growing arsenal of treatment options for relapsing multiple sclerosis (RMS) emphasises the need for early prognostic biomarkers. While evidence for individual markers exists, comprehensive analyses at the time of diagnosis are sparse.

Methods: Brain and spinal cord lesion numbers, cerebrospinal fluid parameters, initial symptoms, and Expanded Disability Status Scale (EDSS) score were determined at the time of diagnosis. Confirmed disability accumulation (CDA), defined as a sustained EDSS increase over 6 months, was determined during a 5-year follow-up. All-subsets multivariable logistic regression was performed to identify predictors of CDA. Model performance was assessed via receiver operating characteristic analysis, and individual risks were calculated. Analyses were repeated with progression independent of relapse activity (PIRA) as an outcome.

Results: 113/417 (27.1%) people with RMS experienced CDA on follow-up. Intrathecal IgG synthesis, a higher number of spinal cord lesions, age and polysymptomatic manifestation were identified as independent predictors of CDA. The resulting prediction model yielded an area under the curve (AUC) of 0.75 with a 95% CI of 0.70 to 0.80. Individuals exceeding the optimal thresholds for the three most significant predictors had a 61.8% likelihood of experiencing CDA, whereas those below all three thresholds had a CDA rate of 4.5%. The only significant baseline predictor differentiating PIRA from relapse-associated worsening was a higher number of spinal cord lesions (AUC=0.64, 95% CI 0.54 to 0.74).

Conclusions: Intrathecal IgG synthesis, spinal cord lesion number, age and polysymptomatic manifestation are independent predictors of early CDA in newly diagnosed RMS.