Therapeutic Advances in Neurological Disorders最新文献

Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are autoimmune diseases characterized by immune-mediated damage to the central nervous system. Current treatments primarily focus on chronic immunosuppression. Immune tolerance induction offers a novel approach to restoring immune balance while minimizing systemic side effects. Central and peripheral immune tolerance mechanisms regulate autoreactive lymphocytes, ensuring immune homeostasis. Dysregulation of these pathways underpins NMOSD and MOGAD pathogenesis. Antigen-specific therapies targeting aquaporin-4 (AQP4) or myelin oligodendrocyte glycoprotein (MOG) autoantigens include peptide-based vaccines and nanoparticle delivery systems, promoting T cell anergy and regulatory T cell (Treg) expansion. Cell-based therapies utilizing ex vivo-expanded Tregs or regulatory B cells (Bregs) have shown promise in preclinical models but face challenges in clinical translation due to scalability and safety concerns. Gene-editing technologies such as CRISPR/Cas9 present opportunities to modulate immune pathways and restore tolerance, although delivery and off-target effects remain obstacles. Additionally, strategies addressing double-seronegative NMOSD, which lacks detectable autoantibodies, emphasize broad immune modulation rather than antigen specificity. While significant progress has been achieved, the transition to clinical application requires overcoming hurdles such as optimizing antigen delivery, ensuring long-term efficacy, and identifying reliable biomarkers. Advances in personalized medicine hold promise for achieving sustained remission, reducing dependency on immunosuppression, and improving patient outcomes in NMOSD and MOGAD. This review explores advancements in tolerance strategies, highlighting their potential in NMOSD and MOGAD.

Background: Cladribine, an oral prodrug, penetrates the blood-brain barrier, impacting biomarkers of disease progression within the central nervous system.

Objectives: Describe disease activity in cladribine tablets (CladT)-treated people with highly active relapsing multiple sclerosis (pwRMS) using clinical outcomes and biomarkers.

Design: MAGNIFY-MS was an open-label, single-arm, phase IV trial with four sub-studies. Participants were grouped by previous treatment (Tx); Tx-naïve versus Tx-experienced; those with previous exposure to second-line therapies were excluded. This analysis describes cerebrospinal fluid (CSF) and optical coherence tomography (OCT) sub-studies. CSF sub-study participants were stratified by the number of oligoclonal bands (OCBs) at baseline (≥2/≥4).

Methods: Logistic regression analysis is reported for no evidence of disease activity (NEDA)-3 and no evidence of progression or active disease (NEPAD) at Year (Y)1 and Y2, and annualized relapse rate (ARR) at Y2. Changes in intrathecal (OCBs, kappa free light chain [KFLC], immunoglobulin [Ig]G and IgM indices), OCT measures, and neuroaxonal degeneration (neurofilament light chain [NfL]) biomarkers are reported at baseline, month (M)12, and M24.

Results: MAGNIFY-MS included 270 pwRMS; 28 and 36 were included in the CSF and OCT sub-studies, respectively. In Y2, estimated rates of NEDA-3 were 64.1% overall and 69.1% in the Tx-naïve group. The estimated rate of NEPAD overall was 60.2% in Y2. The estimated ARR was 0.09 from baseline to M24 (Tx-naïve participants, 0.04). In participants with ≥2 OCBs at baseline (n = 17), 76.5% had OCB reduction or disappearance at least once in the study. KFLC and IgG indices were reduced at M24 versus baseline. Sustained reductions were observed in median NfL, while IgG and IgM remained within normal ranges for most participants. Mean OCT measurements showed no retinal nerve fiber thinning.

Conclusion: For CladT-treated pwRMS, disease activity and biomarkers of intrathecal inflammation and neuroaxonal damage were reduced versus baseline.

Trial registration: ClinicalTrials.gov identifier, NCT03364036. Date registered: June 12, 2017. Date first patient enrolled: May 28, 2018. https://clinicaltrials.gov/study/NCT03364036. Extension study ClinicalTrials.gov Identifier: NCT04783935. Date registered: March 05, 2021. Date first patient enrolled: March 10, 2021. https://clinicaltrials.gov/study/NCT04783935.

Neuropsychiatric symptoms, such as depression, anxiety, cognitive changes, apathy or hallucinations are common in patients with Parkinson's disease (PD). They can appear at any stage of the disease and some symptoms may even be a harbinger of PD. These neuropsychiatric complications often become more pronounced as PD progresses and may worsen particularly during 'off-periods'. Moreover, neuropsychiatric symptoms are also frequently seen in patients with addictive behaviours, collectively called impulse control disorders, where insight is particularly low. In this narrative review, non-pharmacological as well as experimental and pragmatic pharmacological approaches are outlined to provide a deeper understanding of the best treatment strategy for these patients. Early detection as well as a tailored multidisciplinary approach is necessary to improve symptoms and ultimately the quality of life for patients and their family members.

Background: Serum glial fibrillary acidic protein (sGFAP) is a promising biomarker for multiple sclerosis (MS) disease progression. Elevated sGFAP levels are considered to reflect ongoing astrocyte-related pathology in the central nervous system.

Objectives: To study whether sGFAP levels associate with 18 kDa translocator protein (TSPO) availability in MS brain. TSPO is a mitochondrial molecule that is expressed by activated microglia and astrocytes.

Design: Cross-sectional multimodal biomarker correlation study.

Methods: We included 80 people with MS (66 relapsing-remitting and 14 progressive MS, 69% women), and 11 healthy control participants (73% women). sGFAP was measured using single molecule array (Simoa®) technology in combination with 3T magnetic resonance imaging and positron emission tomography (PET) using a TSPO-binding [¹¹C]PK11195 radioligand.

Results: sGFAP was higher among people with progressive MS (median 122 pg/ml) compared to healthy controls (median 59 pg/ml, p = 0.0002) or participants with relapsing-remitting MS (median 77 pg/ml, p = 0.0056). Among people with MS, higher sGFAP associated with higher volume of chronic lesions with increased TSPO activity (r = 0.36, p = 0.0011) and with thalamic TSPO activity (r = 0.30, p = 0.0069), as well as with T1 and T2 lesion loads (r = 0.38, 0.41, p = 0.0005, 0.0002, respectively). Smaller normal-appearing white matter (r = -0.36, p = 0.0009), cortical gray matter, and thalamus volumes (r = -0.39, p = 0.0003 for both) correlated with higher sGFAP. In regression analyses, the volume of TSPO-expressing lesions, together with age and MS disease-modifying treatment status, explained 27% of the variation in sGFAP.

Conclusion: sGFAP associates with adverse magnetic resonance imaging and PET imaging outcomes. The association between a high prevalence of TSPO-expressing white matter lesions and high sGFAP suggests that lesion-associated glial activity promotes MS progression partially via astrocyte-driven mechanisms. A combination of various soluble biomarkers and PET ligands for specific cell types may add to the understanding of progression-promoting cellular mechanisms in the brain.

Trial registration: ClinicalTrials.gov NCT03134716, NCT03368677, NCT04126772, NCT04239820, https://clinicaltrials.gov.

Background: Branch atheromatous disease (BAD) is a subtype of ischemic stroke associated with early neurological deterioration (END) and poor outcomes. Although BAD shares features with large artery atherosclerosis, optimal treatment strategies remain undefined.

Objectives: To assess the efficacy and safety of early dual antiplatelet therapy (DAPT) and high-intensity statins in reducing END and improving outcomes in BAD.

Design: A prospective, single-arm study with a historical control group.

Methods: This study reports the results of the Statin and Dual Antiplatelet Therapy in Preventing Early Neurological Deterioration in Branch Atheromatous Disease trial. Patients with BAD-related ischemic stroke were treated with aspirin, clopidogrel, and high-intensity statins within 24 h of symptom onset. Outcomes were compared with a historical control cohort treated with single antiplatelet therapy and moderate- or low-intensity statins. The primary outcome was the composite of END (defined as an National Institutes of Health Stroke Scale score increase ⩾2 points within 7 days) or recurrent stroke within 30 days. Secondary outcomes included severe END, functional outcomes at 90 days, and safety events.

Results: A total of 91 patients received intensive therapy and 285 received standard treatment. The primary endpoint occurred less frequently in the intensive group (34.1% vs 48.1%; adjusted risk ratio (aRR), 0.71; 95% confidence interval (CI), 0.52-0.98; p = 0.034). Intensive therapy significantly reduced END at 7 days (34.1% vs 47.0%; aRR, 0.73; 95% CI, 0.54-1.00; p = 0.049) but not recurrent stroke at 30 days (2.2% vs 1.8%; aRR, 1.16; 95% CI, 0.25-5.43). Good outcomes at 90 days (modified Rankin Scale ⩽2) were more common with intensive therapy (73.6% vs 57.2%; aRR, 1.27; 95% CI, 1.09-1.48; p = 0.002). Major bleeding and mortality did not differ between groups.

Conclusion: Early intensive therapy with DAPT and high-intensity statins significantly reduced END and improved recovery in BAD without compromising safety. Further studies are warranted to validate these findings.

Trial registration: ClinicalTrials.gov; Identifier: NCT04824911 (https://clinicaltrials.gov/study/NCT04824911).

Background: Serum glial fibrillary acidic protein (sGFAP) is associated with disease activity in aquaporin-4-immunoglobulin G-seropositive neuromyelitis optica spectrum disorders (AQP4-IgG+NMOSD). Serum neurofilament light chain (sNfL) is a biomarker for neuroaxonal damage. However, the association of sGFAP and sNfL with magnetic resonance imaging (MRI) volumes in AQP4-IgG+NMOSD is unclear.

Objectives: To investigate the associations of sGFAP and sNfL with brain MRI volumes in AQP4-IgG+NMOSD.

Design: Monocentric, retrospective, observational study.

Methods: In 33 clinically stable patients with AQP4-IgG+NMOSD, 17 patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and 15 healthy controls (HC), sGFAP and sNfL were measured at 2 (HC = 1) and 3-Tesla MRIs were obtained at 4 (HC = 1) yearly visits. Associations between biomarkers and MRI metrics were evaluated using linear models.

Results: In AQP4-IgG+NMOSD, but not in MOGAD and HC, higher sGFAP was associated with lower hippocampus (β = -2.0 (95% confidence interval: -3.4, -0.7), p = 0.004) and thalamus volumes (β = -2.5 (-4.3, -0.7), p = 0.006) and higher MRI cerebrospinal fluid volume (β = 1.8 (0.7, 3.2), p = 0.01), and, statistically less robust, with lower whole brain (β = -2.3 (-5.3, 0.8), p = 0.15) and gray matter volumes (β = -1.8 (-4.0, 0.4), p = 0.10). Furthermore, higher sGFAP (β = -0.06 (-0.11, -0.002), p = 0.04), but not sNfL (β = -0.02 (-0.08, 0.03), p = 0.38), was associated with percent brain volume change in AQP4-IgG+NMOSD.

Conclusion: The specific associations of sGFAP with brain MRI volumes corroborate sGFAP as a biomarker for disease activity in AQP4-IgG+NMOSD.

Background: Brain atrophy (BA) is a useful predictor of clinical outcomes in people with multiple sclerosis (PwMS). For this reason, MAGNIMS (Magnetic Resonance Imaging in Multiple Sclerosis), an expert consensus group, recommended that global brain volume loss (BVL) is included as a secondary outcome in therapeutic clinical trials. However, there has not been a recent review of the evidence of the association, or strength of association, between global BA and disability in PwMS.

Objectives: Our aim is to review articles from 2013 onward measuring the associations between percentage of brain volume loss (PBVL), normalized brain volumes (NBV) or normalized brain parenchymal volume (NBPV), and the Expanded Disability Status Scale (EDSS), or disability progression (DP) measured by EDSS in PwMS.

Design: Systematic review.

Methods: We searched Medline, Embase, Cochrane Library, Cochrane Clinical Register of Controlled Trials, Cochrane Database of Systematic Reviews and Cumulative Index to Nursing and Allied Health Literature for observational studies, clinical trials and modelling studies measuring the association between global BVL, PBVL, NBV or NBPV, and EDSS score or DP in PwMS. We included people with clinically isolated syndrome and excluded studies with a population greater than 20% primary progressive multiple sclerosis patients.

Results: We found 58 studies were eligible for the review. Most longitudinal studies (19/23) observed a significant association between global BVL and change in EDSS score or DP. Similarly the majority of cross-sectional studies (26/29) observed an association between baseline BV measures and EDSS. Most studies investigating the association between baseline brain volume (BV) measures and follow-up EDSS, that is, asking if baseline BV is a predictor of DP, or future EDSS score, did not find an association (4/15 observed an association).

Conclusion: Around a 1% (range 0.4%-1.3%) decrease in global BV per year was associated with DP, but caution in comparing studies is recommended due to variations in the definition of DP.

Background: Pediatric headache disorders are a significant public health issue, affecting school performance, social participation, and quality of life.

Objective: Our aim was to explore the age- and gender-related changes in the characteristics and burden of headaches from childhood to adolescence, with a focus on diagnostic shifts, frequency, intensity, and quality-of-life.

Design: We conducted a cross-sectional survey on five primary and secondary schools in the L'Aquila district, Italy.

Methods: Using the translated Italian version of the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation questionnaire, we collected data on headache frequency, intensity, duration, associated symptoms, and impact. Diagnoses were algorithmically assigned through International Classification of Headache Disorders, 3rd edition criteria. Statistical analyses examined the effects of age, gender, and their interaction on clinical and quality-of-life outcomes.

Results: In total, 431 students were included (mean age: 9.82 ± 2.28 years; range: 6-15; 52.9% female). Findings indicated that as children grow older, headaches become increasingly frequent, longer in duration, and more intensely experienced. The progression from primary to secondary school was accompanied by a transition in diagnosis, with undifferentiated headaches giving way to more specific categories, such as probable or definite migraine and, to a lesser extent, tension-type headache. Age-by-gender interactions revealed that older females experienced greater frequency and a more pronounced impact, while headache frequency affected quality of life with increasing age.

Conclusion: Findings highlight gender-specific developmental trends in headache, characterized by increased frequency, intensity, and diagnostic clarity from childhood to adolescence. The burden of headache, particularly among older students, underscores the need for early recognition and age-appropriate interventions.

Background: Myasthenia gravis (MG) is a rare autoimmune neuromuscular disease characterized by fluctuating muscle weakness and a variable clinical course. While sex differences in MG onset and progression are well documented, the extent to which these disparities affect quality of life (QoL)-particularly through fatigue and psychological burden-remains unexplored.

Objectives: To systematically evaluate gender differences in QoL among MG patients and assess whether psychological factors and fatigue contribute to these disparities.

Design: A systematic review and meta-analysis were conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines.

Data sources and methods: Searches were performed in PubMed, Embase, and PsycINFO from inception through February 2025. Eligible studies included adult MG patients with QoL outcomes stratified by gender. QoL scores were synthesized using a random-effects model. Psychological and fatigue-related variables were examined qualitatively.

Results: Twelve studies (N = 4744; 2889 women, 1855 men) met the criteria for the systematic review, and five studies (N = 3765) were included in the meta-analysis. Women consistently reported lower QoL compared to men. The initial pooled analysis showed a moderate but non-significant effect (Hedges' g = 0.319, p = 0.0812; I² = 94.96%). Sensitivity analysis (excluding an outlier study) reduced heterogeneity (I² = 0%) and revealed a significant gender effect (Hedges' g = 0.440, p < 0.001), with women experiencing significantly poorer QoL. Psychological comorbidities-particularly depression and anxiety-and higher levels of fatigue were more prevalent among female patients and consistently associated with lower QoL.

Conclusion: Women with MG experience significantly reduced QoL, partially attributable to higher fatigue and psychological burden. These findings underscore the need for gender-sensitive approaches in MG management, including routine psychological screening and fatigue interventions. Future research should adopt standardized assessment tools and explore the impact of hormonal life stages on MG outcomes.

Trial registration: PROSPERO CRD420251011446.

Background: Dual antiplatelet therapy (DAPT) is a cornerstone of secondary prevention in patients with minor ischemic stroke or high-risk transient ischemic attack. The effectiveness and safety of DAPT may differ between patients with posterior (PCI) and anterior circulation infarct (ACI).

Objectives: We aimed to compare short-term outcomes following DAPT between mild-to-moderate stroke patients with PCI versus ACI.

Design: Propensity-matched analysis from a prospective real-world multicentric cohort study (READAPT).

Methods: We included patients with noncardioembolic mild-to-moderate stroke (National Institute of Health Stroke Scale of 0-10) who initiated DAPT within 48 h of symptom onset. Patients were categorized into ACI or PCI based on the infarct(s) location on brain neuroimaging. The primary effectiveness outcome was the 90-day risk of ischemic stroke or other vascular events. The secondary effectiveness outcomes were the 90-day modified Rankin Scale (mRS) score distribution, 24-h early neurological improvement or deterioration, and all-cause mortality. The safety outcomes included the 90-day risk of any bleedings and 24-h hemorrhagic transformation.

Results: We matched 281 PCI patients with 651 ACI patients. The 90-day risk of ischemic stroke or other vascular events was low and similar between PCI and ACI groups (3.1% vs 2.9%, respectively; hazard ratio 0.98, (95% confidence interval (CI) 0.45-2.14); p = 0.845). Patients with PCI had worse 90-day mRS ordinal distribution compared to those with ACI (odds ratio 1.18 (95% CI 1.01-1.39); p = 0.046). There were no differences in other secondary outcomes. Safety outcomes had low incidence and did not differ between groups (any bleedings: 3.2% vs 2.6%; 24-h hemorrhagic transformation: 1.8% vs 1.2%). We found no differences in the risk of ischemic stroke or other vascular events between patients with PCI and ACI across subgroups defined by sex, age, presumed stroke etiology, stroke severity, prestroke mRS, hypertension, diabetes, acute reperfusion therapies, DAPT loading dose, or presence of symptomatic intracranial stenosis.

Conclusion: Our findings suggest that effectiveness and safety outcomes after DAPT in patients with mild-to-moderate noncardioembolic ischemic stroke are consistent regardless of infarct location in the anterior or posterior circulation territory. However, patients with PCI may experience worse short-term functional outcome.

Trial registration: URL: www.clinicaltrials.gov; Unique identifier: NCT05476081.