Journal of Neurology, Neurosurgery, and Psychiatry最新文献

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.

Background: Smoking is a significant risk factor for neurological disorders, yet its global impact on these conditions remains underexplored.

Methods: Using Global Burden of Diseases 2021 data, we analysed trends in age-standardised disability-adjusted life-years (DALYs) and deaths attributable to smoking from 1990 to 2021 for three neurological disorders: stroke, Alzheimer's disease and other dementias, and Multiple Sclerosis. Socioeconomic disparities were assessed using the lope index of inequality and the relative concentration index. Bayesian age-period-cohort models were employed to forecast smoking-attributable burden through 2050.

Results: Between 1990 and 2021, annual smoking-attributable DALYs and death rates slightly declined by -1.93% and -1.92%, respectively, but absolute numbers continued to rise, from 26.10 million to 30.18 million DALYs and from 0.93 million to 1.15 million deaths. Older adults (aged 60 and above) experienced the greatest burden, contributing 58.15% of DALYs and 75.57% of deaths in 2021. Smoking-attributable stroke was increasingly concentrated in low sociodemographic index regions, whereas disparities in dementias and multiple sclerosis were more pronounced in socioeconomically advantaged regions, particularly for multiple sclerosis.

Conclusions: This study identified an age-specific burden and widening disparities for neurological disorders attributable to smoking, with older adults disproportionately experiencing an escalating impact. Targeted prevention and equitable healthcare access tailored for older adults are critical to mitigating smoking-attributable neurological health loss.

Background: We aimed to investigate the prodromal phase of multiple sclerosis (MS) by investigating annual sickness absence rates before MS onset.

Methods: A retrospective cohort study was conducted using Sweden's linked clinical and health administrative data. We identified MS cases via a validated algorithm using International Classification of Diseases (ICD) diagnostic codes for MS ('administrative cohort') or registration in the Swedish MS registry ('clinical cohort'). MS onset was defined as the first MS/demyelinating disease ICD code (administrative cohort) or, for the clinical cohort, MS symptom onset date, if earlier. Cases were matched with up to five controls from the general population with no MS/demyelinating disease history. Yearly sickness absence rates up to 18 years pre-MS onset were compared using negative binomial regression with generalised estimating equations.

Results: The administrative/clinical cohorts comprised 8618/6361 MS cases and 43 072/31 776 controls. Sickness absence rate ratios were significantly elevated from 6 years before MS onset in the administrative cohort and 2 years before in the clinical cohort. The adjusted rate ratios peaked in the year pre-MS onset, reaching 2.59 (95% CI 2.40 to 2.79) in the administrative cohort and 1.19 (95% CI 1.06 to 1.34) in the clinical cohort. We also observed age-related and sex-related differences primarily in the year before MS onset, with males and older individuals exhibiting higher rate ratios.

Conclusions: We observed a significant increase in sickness absence spells in individuals on the path to developing MS. Investigating sick leave patterns may provide a unique and broad perspective on the health trajectories of chronic conditions like MS.

Background: Benign multiple sclerosis (MS), characterised by minimal disability despite long disease duration, remains poorly understood in terms of its determinants and prognostic implications. While lifestyle factors have been implicated in modifying disease progression, their role in distinguishing benign and non-benign MS remains unclear.

Methods: We conducted a comparative analysis of patients with benign (n=2040) and non-benign MS (n=4283) using data from Swedish nationwide case-control studies with long-term follow-up. Logistic regression models were used to analyse associations between a history of infectious mononucleosis (IM) and lifestyle factors (smoking, body mass index, fish consumption and sun exposure habits) and the likelihood of benign MS. Additionally, Cox regression was used to follow patients with benign MS from the 15-year mark onward, identifying factors associated with the transition to non-benign MS over time.

Results: The odds of having benign MS were reduced in association with a history of IM (OR 0.54, 95% CI 0.45 to 0.65), adolescent overweight and obesity (OR 0.69, 95% CI 0.56 to 0.85 and 0.46, 95% CI 0.32 to 0.66, respectively) and infrequent fish consumption (OR 0.72, 95% CI 0.60 to 0.88). Similar associations were observed for the risk of transitioning from benign to non-benign MS over time.

Conclusions: A history of IM and modifiable lifestyle factors significantly influence the probability of a benign disease course in MS. These findings underscore the potential for targeted lifestyle interventions to improve MS outcomes. Further research is needed to elucidate the mechanisms by which a past IM infection can continue to influence MS progression long after the initial infection.

Background: The link between low-density lipoprotein cholesterol (LDL-C) levels and dementia risk is poorly understood, with conflicting evidence on the role of LDL-C and the impact of statin therapy on cognitive outcomes. Thus, we aimed to examine the association between low-density LDL-C levels and the risk of dementia and assess the influence of statin therapy.

Methods: We retrospectively analysed data from 11 university hospitals participating in the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). Participants with a prior diagnosis of dementia or those with <180 days of observation before cohort inclusion, and those included in both cohorts were excluded. The primary outcome was all-cause dementia, with the secondary outcome being Alzheimer's disease-related dementia (ADRD). The study utilised 1:1 propensity score matching to compare individuals with LDL-C levels below 70 mg/dL (1.8 mmol/L) against those with levels above 130 mg/dL (3.4 mmol/L), resulting in a primary analysis cohort of 108 980 matched patients. Secondary analyses further examined LDL-C thresholds below 55 mg/dL (1.4 mmol/L) and the influence of statin use.

Results: The LDL-C levels below 70 mg/dL (1.8 mmol/L) were associated with a 26% reduction in the risk of all-cause dementia and a 28% reduction in the risk of ADRD, compared with levels above 130 mg/dL (3.4 mmol/L). For LDL-C levels below 55 mg/dL (1.4 mmol/L), there was an 18% risk reduction for both outcomes. Among those with LDL-C <70 mg/dL (<1.8 mmol/L), statin use was associated with a 13% reduction in all-cause dementia risk and a 12% decrease in ADRD risk compared with non-users.

Conclusion: Low LDL-C levels (<70 mg/dL (<1.8 mmol/L)) are significantly associated with a reduced risk of dementia, including ADRD, with statin therapy providing additional protective effects. These findings support the necessity of targeted lipid management as a preventive strategy against dementia, indicating the importance of personalised treatment approaches.

Frontotemporal degeneration (FTD) is a group of neurodegenerative disorders affecting behaviour, language and executive functions. FTD is a common cause of early-onset dementia, but there are no FDA-approved treatments or established biomarkers for diagnosing and tracking these conditions, making early and accurate diagnosis challenging during life. Recent advances in retinal imaging, particularly through technologies like optical coherence tomography (OCT), have emerged as promising tools for identifying potential biomarkers for FTD and related neurodegenerative diseases. The retina, being an accessible extension of the central nervous system, has shown abnormalities that might serve as indicators of forms of FTD. Retinal imaging has revealed changes such as thinning of specific retinal layers that could correlate with molecular forms of FTD, Alzheimer's disease and other neurodegenerative diseases. These advances highlight the potential of retinal imaging to not only aid in diagnosis but also differentiate between various neurodegenerative conditions. Emerging data on retinal tissue analysis with immunohistochemistry and other techniques further support the potential of retinal biomarkers, though further studies are required to validate and refine these findings. Future advancements in retinal imaging technologies, along with longitudinal and autopsy-validated studies, are crucial for enhancing diagnostic capabilities and understanding FTD-related pathologies within the retina.