To assess the association and discriminative performance of serum biomarkers with clinical disease progression and survival in patients with amyotrophic lateral sclerosis (ALS). This retrospective study, conducted at Houston Methodist Hospital, Houston, TX, used longitudinal serum samples collected between January 2018 and December 2022. A cohort of 100 patients with sporadic or familial ALS was randomly selected and assayed by ELISAs for biomarkers 4-hydroxy-2-nonenal (4-HNE), lipopolysaccharide binding protein (LBP), and neurofilament light chain (NfL) levels. Each biomarker was increased in patients. 4-HNE and LBP were increased at diagnosis and continued to increase as the disease progressed; both correlated with progression rates and survival. NfL was increased at diagnosis, then plateaued relatively. LBP correlated with ALSFRS-R at diagnosis; NfL did not correlate. 4-HNE and LBP were increased in bulbar onset patients who survived a shorter period of time; NfL levels for bulbar/limb onsets were not different. Receiver operating characteristic analyses with apparent and optimism-adjusted area-under-the-curve (AUC) demonstrated that 4-HNE and LBP discriminated rapid progression and survival, whereas NfL showed modest discrimination for rapid progression. The combination of biomarkers yielded improved AUCs as depicted in Venn diagrams across individual and combined biomarkers. 4-HNE, LBP, and NfL are biomarkers of lipid peroxidation, systemic inflammation, and axonal integrity. 4-HNE and LBP correlated with disease burden, disease progression, and survival. In the bulbar onset, survival was shortened and associated with increased 4-HNE and LBP. This exploratory longitudinal study suggests the utility of combining biomarkers to discriminate disease progression and survival and monitor clinical trial outcomes.
Cognitive impairment is a common non-motor symptom in Multiple Sclerosis (MS), negatively affecting autonomy and Quality of Life (QoL). Innovative rehabilitation strategies, such as semi-immersive virtual reality (VR) and computerized cognitive training (CCT), may offer advantages over traditional cognitive rehabilitation (TCR), particularly in terms of engagement, specificity, adaptability, and ecological validity. This study aimed to compare the efficacy of semi-immersive VR, CCT using the ERICA platform, and TCR on cognitive outcomes and depressive/anxiety symptoms in individuals with MS. Eighty-seven patients with MS and mild to moderate cognitive impairment were randomly assigned to three groups: VR-based training, CCT, or TCR. Each group underwent 24 individual sessions delivered regularly three times per week over 8 weeks. Neuropsychological assessments were conducted at baseline (T0) and post-intervention (T1), evaluating information processing speed (SDMT), memory (SRT, SPART), executive functions (WLG), emotional status (BDI, HRS-A), and QoL (MSQOL-54). All groups showed significant improvements in most cognitive and depressive (BDI)/anxiety symptoms (HRS-A) after the intervention. However, the VR group demonstrated significantly greater gains in executive functions, working memory, and QoL (MSQOL-54 Physical and Mental Composite scores) compared to both the CCT and TCR groups (p < 0.001). While the CCT group showed selective improvements in mood and working memory, its overall efficacy did not significantly differ from that of TCR. Semi-immersive VR represents an effective and engaging approach to cognitive rehabilitation in MS, likely due to its capacity to deliver multisensory, adaptive, and ecologically valid stimulation. Nonetheless, a tailored hybrid model integrating VR with conventional and computer-based strategies may further optimize outcomes and support functional independence in individuals with MS.
Hereditary spastic paraplegia (HSP) is a group of disorders characterized by progressive spasticity and lower limb weakness, with mutations in SPG4/SPAST being the most common cause. Detailed studies and clinical and molecular comparisons across different populations are missing. We examined the clinical, pathological, and genetic spectrum of the SPG4/SPAST gene in patients with HSP. The study involved 726 HSP patients recruited from Italy, Brazil, and Japan between 2001 and 2025, with analysis conducted in collaborative centers. SPG4/SPAST variants were identified using direct and next-generation sequencing. The pathogenicity of novel variants was confirmed through familial segregation and in silico analysis. Clinical and epidemiological differences were observed across populations, particularly in phenotype, age at onset, and disability, expanding the SPG4 clinical spectrum. Genetic analysis identified 52 pathogenic SPG4/SPAST mutations in 284 patients, including four novel variants. Several mutations were population-specific, and a possible founder effect was suggested for a recurrent variant in Italy. Dementia occurred in 44 HSP-SPG4 patients and was neuropathologically confirmed in four unrelated autopsied cases from four families comprising 28 individuals; atypical pathological features were observed in all four autopsied cases. Additionally, 18 patients with SPG4/SPAST mutations presented with thin corpus callosum and intellectual disability. In this study, we investigated pathogenic SPG4/SPAST variants in an international cohort of HSP patients from three continents. Our findings expand the clinical spectrum of HSP-SPG4, identifying a new type complicated by an atypical pathological form of dementia. Careful assessment of genotype-phenotype relationships offers insights into patient counseling and future research planning.
The aim of our study was to establish the prevalence of adverse events in a real-world setting in boys living with Duchenne muscular dystrophy (DMD) treated with givinostat as part of an Expanded Access Program (EAP) in Italy. The cohort included 90 ambulant boys, with age when treatment started between 6 and 23 years (mean 10.1 years, SD: 3.2 years) and with a follow up between 6.0 and 14.6 months (mean 10.6 months; SD 2.6 months). Platelets count decrease and triglyceride levels increase were the most common adverse events, followed by diarrhea. A dose reduction was needed in 38 of the 90 boys following thrombocytopenia (n = 34), diarrhea (n = 2), and hypertriglyceridemia (n = 4), with two of the boys presenting both thrombocytopenia and hypertriglyceridemia. Eleven of the 38 boys with initial dose reduction (10 with thrombocytopenia and 1 with hypertriglyceridemia) required an additional dose reduction for persistence of values outside the threshold, with one of them discontinuing treatment because of persistent hypertriglyceridemia even with the lowest dose. Our results confirm the safety profile observed in the pivotal study providing further evidence of the management of the drug in a real-world setting. In our experience, treatment with givinostat was well managed by maintaining a strict monitoring. This was facilitated by allowing families to perform blood tests in local labs, reducing the stress and burden of frequent visits to the hospital.
Although hippocampal sclerosis (TLE-HS) represents the most frequent cause of temporal lobe epilepsy (TLE), up to 30% of patients show no lesion on visual MRI inspection (TLE-MRIneg). These cases pose diagnostic and therapeutic challenges and are underrepresented in surgical series. We investigated whether TLE-MRIneg constitutes a distinct clinical and neuroanatomical entity compared to TLE-HS and aimed to identify subtypes within the TLE-MRIneg group. We analyzed MRI and clinical data from 209 patients with TLE and 102 healthy controls from the multicenter "3TLE project". Based on expert radiological review, 96 patients were classified as TLE-MRIneg and 76 as TLE-HS; the remaining 37 were excluded due to other focal lesions. We compared clinical characteristics and brain morphometry between TLE-MRIneg and TLE-HS and applied clustering techniques to detect TLE-MRIneg subtypes. Compared with TLE-HS, TLE-MRIneg was associated with later onset, shorter disease duration, and milder clinical presentation. TLE-HS patients exhibited widespread cortical and subcortical atrophy, while TLE-MRIneg showed only subtle cortical thinning. Cluster analysis revealed two subtypes of TLE-MRIneg: one characterized by ipsilateral amygdala enlargement (AE) and the other by diffuse cortical atrophy. These findings demonstrate that TLE-MRIneg represents a distinct clinical-imaging entity from TLE-HS. The identification of morphologically defined subtypes, particularly AE, highlights the heterogeneity of TLE-MRIneg and its potential clinical relevance. This work supports the use of advanced imaging and data-driven methods to improve diagnosis and guide individualized management in non-lesional epilepsies.
To (1) validate GAD65-ELISA detection and quantification for type 1 diabetes mellitus and autoimmune neurological diagnoses, (2) correlate ELISA results (reference range < 5 IU/mL) with established radioimmunoprecipitation assay (RIA; ≤ 0.02 nmol/L), and (3) define ELISA clinical utility and pitfalls. Serum performance for diabetes (FDA-cleared, undiluted) was verified, and neurological laboratory-developed serum and CSF dilution protocols were validated to extend the reportable range beyond > 250 IU/mL. ELISA and RIA values were correlated, including established neurological RIA cut-offs (serum ≥ 20 nmol/L; CSF any positive). ELISA met analytical criteria (precision, accuracy, sensitivity, specificity, reference range) in serum and CSF and was clinically equivalent to RIA for autoimmune diabetes. Neurological ELISA cut-offs were established at 10,000 IU/mL (serum) and 100 IU/mL (CSF). Precision was better below 10,000 IU/mL (CVs < 20%) than above (CVs 30.8% serum; 26.5% CSF). ELISA-RIA correlation and agreement was stronger below the neurological cut-off (R2 = 0.89) than above (R2 = 0.36). Positive agreement for RIA-defined neurological disease was 100% in serum and CSF; all serums were > 10,000 IU/mL. Clinical specificity was 97.5% in serum and 100% in CSF, exceeding reported RIA specificity. Screen results > 250 IU/mL spanned a wide range of dilution values; many were below the neurological cut-off. Most patients with paired serum/CSF positivity showed elevated GAD65 IgG indices. GAD65 ELISA and RIA have equivalent sensitivity for autoimmune diabetes and neurological testing, with higher specificity for ELISA. A serum cut-off of 10,000 IU/mL is informative but requires clinical context, and dilution of screen > 250 IU/mL samples is essential for neurological interpretation.
Oxysterols (cholestane-3β,5α,6β-triol and 7-ketocholesterol) and N-palmitoyl-O-phosphocholineserine (PPCS) are sensitive biomarkers for Niemann-Pick disease type C (NPC) screening. However, false-positive results occur, with a biomarker profile suggestive of NPC despite the absence of pathogenic variants in genes involved in NPC or other inborn errors of metabolism. To identify causes of false-positive biomarker profiles mimicking NPC. We conducted a multicenter retrospective study of 15 patients with false-positive oxysterols and PPCS profiles referred between 2017 and 2022 to two French NPC reference laboratories. Clinical data were collected via standardized chart review. The impact of Sertraline on NPC-like biological features was evaluated using the filipin test in fibroblasts and biomarker analysis in sertraline-treated patients. Thirteen of 15 patients with false-positive biomarkers were treated with sertraline. Two patients who discontinued sertraline showed normalization of biomarkers. The filipin test revealed that Sertraline disrupts intracellular cholesterol trafficking, a hallmark of NPC cellular features. Finally, among 47 sertraline-treated patients without NPC-suspicion, 26 (55%) had biomarker profile mimicking NPC. Sertraline use is frequently associated with elevated biomarkers that mimic NPC, representing a primary cause of false-positive results in NPC screening. Genetic analysis of NPC1 and NPC2 remains essential to confirm NPC diagnosis. Most sertraline-treated patients with false-positive biomarkers presented predominantly atypical psychiatric symptoms, though one exhibited a clinical picture highly suggestive of NPC following prolonged sertraline exposure. The long-term clinical effects of sertraline use need further evaluation.
Transient global amnesia (TGA) is a striking model of isolated amnesia. While hippocampal lesions are well described, the network-level mechanisms and the precise neuropsychological profile remain debated. Our objective was thus to characterize functional and neuropsychological correlates of acute TGA and their longitudinal evolution. Prospective, single-center case-control study of 20 patients with acute TGA and 20 age- and sex-matched healthy controls. All participants completed neuropsychological testing and underwent structural and functional MRI at three time points: acute phase (< 24 h from onset), day 3, and 3 months. Primary outcomes were neuropsychological performance across episodic, semantic, and metamemory domains and resting-state fMRI connectivity within the episodic memory network. Secondary outcomes were functional connectivity within the Default Mode (DMN), Executive (ECN), and Salience (SN) networks. A total of 40 participants were included (20 patients with TGA, mean age 65.5 years, 45% women; 20 controls, mean age 64.3 years, 45% women). In patients, median delay from symptoms' onset to MRI was 6.67 h. Neuropsychologically, patients showed profound multimodal anterograde amnesia during the acute phase, resolving by 3 months. This deficit was largely isolated, sparing semantic memory and metamemory. Structurally, small bilateral lesions were present in most patients. Functionally, acute hypoconnectivity was observed within the extended hippocampal system, particularly between parahippocampal and cingulate cortices, normalizing by 3 months. No consistent disruption was found in large-scale networks (default mode, executive control, salience). TGA is associated with transient, selective hypoconnectivity within the mesiotemporal-cingulate episodic memory network, aligning with previous reports and further precising the functional anatomy. The finding of a profound anterograde amnesia was replicated and its recovery timecourse was elucidated. Semantic memory and metamemory remain preserved, clarifying inconsistencies in prior reports. These findings suggest that TGA reflects a transient limbic dysconnectivity syndrome rather than a diffuse network disorder, reconciling structural lesions with clinical and functional data.
Plasma p-217tau is a minimally invasive but specific biomarker for diagnosing Alzheimer's disease (AD). However, its disease specificity remains to be clinically evaluated. We validated the reliability of the p-217tau biomarker in 12 other neurological diseases. Plasma p-217tau levels were measured in 298 participants, consisting of 81 AD patients, 204 patients with 12 other neurological diseases, and 13 healthy and cognitively unimpaired controls (HCU), using an assay system from Meso Scale Diagnostics. Cerebrospinal fluid (CSF) tau and Aß levels were simultaneously evaluated in AD, amyotrophic lateral sclerosis (ALS), and idiopathic normal pressure hydrocephalus (iNPH). Plasma p-217tau levels increased in AD with the clinical stage, but also in ALS and iNPH, leading to them having decreased sensitivity and specificity for diagnosing AD. No increases in plasma p-217tau levels were seen in possible tauopathies or synucleinopathies. CSF and plasma p-217tau levels were strongly correlated in AD, but not in ALS. The plasma p-217tau/CSF p-217tau ratio was inversely higher in ALS than in AD. Active and chronic denervation potentials were associated with plasma p-217tau levels. In iNPH, plasma p-217tau was associated with cognitive dysfunction, but not with gait disturbance or urinary incontinence. CSF p-181tau, total tau, and Aß1-40 levels and the Aß1-40/1-42 ratio were reduced in iNPH. ALS and iNPH are two major pitfalls for the clinical application of plasma p-217tau as a biomarker of AD. Lower motor neuron injury in ALS and cognitive dysfunction in iNPH were both found to be associated with elevated plasma p-217tau levels.
Considerable efforts have been dedicated to developing effective treatments for post-stroke executive impairment (PSEI), among which repetitive transcranial magnetic stimulation (rTMS) has shown great potential. This study aimed to investigate the therapeutic effects of high-frequency rTMS on working memory (WM) and response inhibition (RI) of executive functions in PSEI patients and the potential neural mechanisms. In a randomized, double-blind trial, 10 Hz rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC) in 32 PSEI patients for 10 days, who were divided into real and sham rTMS groups. The Stroop color-word test (SCWT), digit span test (DST), and functional near-infrared spectroscopy (fNIRS) were used for assessment before and after the intervention. Resting-state functional connectivity (rsFC) and graph theory methods were used to analyze changes in brain function. Compared to the sham rTMS group, the real rTMS group showed significant reductions in SCWT response time (F = 4.223, p = 0.049) and improvements in DST forward scores (F = 4.739, p = 0.037) after the intervention. Moreover, the real rTMS group demonstrated significant enhancements in rsFC from left DLPFC to the right DLPFC (F = 8.538, p = 0.007) and the right posterior parietal cortex (F = 9.905, p = 0.004), as well as in the Degree Centrality of the left DLPFC (F = 7.144, p = 0.012), which were respectively significantly correlated with reduced SCWT response time and increased DST forward scores. High-frequency rTMS effectively improves WM and RI performance in patients with PSEI, which may be attributed to the remodeling of specific connectivity patterns and enhancement of local communication efficiency within the frontoparietal network.
Chimeric antigen receptor (CAR) T-cell therapy has been investigated in neurological diseases, encompassing both central nervous system malignancies and autoimmune disorders, thereby extending its application beyond hematological cancers. This scoping review evaluates CAR T-cell therapy applications in neurological conditions, assessing therapeutic efficacy, safety profiles, and neurotoxicity management strategies. A literature search across four databases (January 2020-December 2025) identified 33 studies meeting the inclusion criteria, encompassing original and secondary research from international centers. CAR T-cell therapy demonstrated promising efficacy across diverse neurological conditions. In glioblastoma trials, 44% of patients (n = 128) achieved partial or complete clinical/radiographic responses with favorable safety profiles. Moreover, compelling results emerged from neuromyelitis optica spectrum disorder studies, in which 92% of patients (11/12) achieved sustained relapse-free remission over a median follow-up of 5.5 months. Multiple sclerosis, myasthenia gravis, and stiff-person syndrome cases exhibited excellent treatment tolerance without significant immune effector cell-associated neurotoxicity syndrome (ICANS), which is a major concern affecting 27% of patients with hematological malignancies. Overall, CAR T-cell therapy emerges as a novel therapeutic strategy in neurology, encompassing both oncological and autoimmune conditions. Toxicity profiles in neurological CAR T-cell applications differ substantially from those observed in hematologic malignancies, underscoring the need for condition-specific risk assessment frameworks and customized management approaches. Future research should prioritize larger multicenter trials with extended follow-up to establish definitive efficacy and safety profiles in neurological indications.
Collaterals are crucial factors that influence the infarct growth rate (IGR). We aimed to determine whether a comprehensive multimodal collateral score (MCS), incorporating collateral assessment at the arterial, tissue, and venous levels, is associated with functional independence and provides incremental prognostic value over individual IGR metrics. Arterial collaterals were assessed using multiphase CT-angiography (mCTA), ranging from 0 to 5; tissue-level collaterals were evaluated on CT-perfusion by the hypoperfusion intensity ratio (HIR), ranging from 0 to 1; and venous outflow was measured on mCTA with the comprehensive venous outflow (CVO) score, ranging from 0 to 8. These metrics were used to develop the multimodal collateral score (MCS), which encompasses good mCTA collaterals (score 4-5), HIR (< 0.4), and CVO (range 4-8). The MCS ranges from 0 to 3, where 0 indicates no favorable collaterals, 1 means only one good collateral metric among the used ones, 2 signifies just two favorable collateral metrics differently combined among the used ones, and 3 represents the sum of all good collateral metrics. Multivariable logistic and ordinal regression analyses identified clinical and radiological factors independently associated with clinical outcomes (modified Rankin scale 0-2 at 90 days, ordinal mRS at 90 days). Overall, 615 acute ischemic stroke patients treated with thrombectomy within 24 h from symptom onset between January 2017 and December 2023 were included: the median age was 77 [IQR = 67-84], 320 (52%) were females, and 307 (50%) achieved functional independence. The MCS grades of 2 (aOR 2.92 [95% CI = 1.70-5.03]) and 3 (aOR 5.35 [95% CI = 3.03-9.44]) were independently associated with functional independence. The MCS was also independently associated with 90-day ordinal mRS (adjusted common odds ratio [acOR] 1.73 [95% CI = 1.51-2.01] per 1-point increase). The AUC of the MCS for predicting functional independence was 0.71 (95% CI = 0.66-0.75), which was superior to the other IGR metrics (p < 0.001). MCS was a strong, independent predictor of favorable functional outcomes and demonstrated significantly superior prognostic performance compared with individual IGR metrics.
Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is the most severe late-onset condition caused by a premutation in the FMR1 gene, characterized by expanded CGG triplet repeats of 55-200. Clinical presentations of FXTAS, including gait ataxia, kinetic tremor, cognitive decline, and rare Parkinsonism, are linked to white matter degeneration, predominantly in the middle cerebellar peduncles. Underlying pathophysiological mechanisms involve the sequestration of CGG-binding proteins due to elevated FMR1 mRNA and repeat-associated non-AUG (RAN)-initiated translation. Outside of the full presentation of FXTAS, some FMR1 premutation carriers exhibit only isolated clinical changes occurring in this syndrome. This study explored the relationship of molecular predictors of disease, either with these isolated features in patients who did not meet diagnostic criteria for FXTAS or with diagnosable FXTAS. 176 male (N = 111) and female (N = 65) premutation carriers were separated into three groups based on neurological/cognitive examination data: asymptomatic, non-syndromic/presenting isolated changes, and syndromic-FXTAS. These categories were then separately correlated with CGG repeat length and FMR1 mRNA expression levels. Regression and distributions' analyses showed that the most consistent associations of both genomic markers were with neurological severity rankings, followed by a binary definition of FXTAS status. Among other minor presentations, Parkinsonism and cognitive impairment were significantly correlated with CGG size in male samples. This data provides evidence for a linear relationship between FMR1 CGG size and mRNA levels, as well as both syndromic and non-syndromic forms of neurological manifestations, which represent aspects of the premutation-linked neurodegenerative process that persist with advancing age.
Posterior Cortical Atrophy (PCA) is a distinct dementia syndrome primarily affecting spatial abilities and visual processing. It is associated with degeneration in the posterior part of the brain. PCA is subclassified into PCA-pure and PCA-plus syndromes based on consensus criteria. To address this, the PCA Asia Workgroup was established to study PCA in Asian countries. The Asia PCA Workgroup collected demographic and clinical data, including symptoms and signs, from PCA patients. Patients were classified into PCA-pure (solely meeting PCA criteria) and PCA-plus (additional features of other neurodegenerative syndromes). The frequency of clinical presentations, symptoms, and signs was compared to the consensus classification estimation and the meta-analysis of published data. PCA-pure (76.2%) was the most common subtype, with earlier onset (80.95%) and distinct early prominent deficit of executive/memory > visual disturbances which is different from the consensus study has estimated and the meta-analysis of published data. PCA-Lewy body disease (PCA-DLB) exhibited higher frequencies of attention deficits, visual hallucinations, cognitive fluctuations, and rigidity compared to PCA-pure. This study reveals the real-world clinical presentation of PCA syndrome in an Asian population, emphasizing the differences from consensus estimations and the meta-analysis of published data. Further research is needed to validate these findings and compare them with real clinical data from PCA patients of other ethnicities, in order to gain a comprehensive understanding of PCA worldwide.
Stereoelectroencephalography-guided radiofrequency thermocoagulation (SEEG-RFTC) has emerged as a safe and effective minimally invasive treatment for children with drug-resistant focal epilepsy. Although evidence from real-world studies remains limited, numerous pediatric cases have demonstrated promising outcomes. This retrospective study aimed to evaluate the seizure outcomes of SEEG-RFTC in pediatric patients and identify predictive factors associated with seizure freedom. A retrospective observational study was conducted across two epilepsy centers, including 111 children with drug-resistant epilepsy who underwent SEEG-RFTC. Postoperative outcomes were assessed primarily by the rate of seizure freedom at the last follow-up (minimum 1 year). Potential predictive factors were analyzed through comparisons of clinical, neuroimaging, electrophysiological, and etiological variables. All patients were followed for at least 1 year post-procedure, with 73 (65.8%) achieving seizure freedom. Among 46 patients with focal cortical dysplasia, the seizure-free rate was 80.4%. In 10 patients with hippocampus sclerosis, 6 (60%) were seizure-free at the final follow-up. Statistical analysis identified the course of illness (p < 0.01) and positron emission tomography (PET) findings (p = 0.01) as significant predictors of seizure freedom. SEEG-RFTC is a safe procedure that yields favorable outcomes in a substantial proportion of pediatric patients with drug-resistant focal epilepsy. The duration of epilepsy and PET characteristics are significantly associated with the likelihood of achieving seizure freedom. These findings highlight the potential of SEEG-RFTC as a valuable therapeutic option in this population.
X-linked adrenoleukodystrophy (X-ALD) is a neurometabolic disorder caused by pathogenic variants in ABCD1, leading to slowly progressive spinal cord disease in nearly all affected men. Sensitive biomarkers to quantify disease severity and predict progression are needed for clinical care and trial design. Plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are promising biomarkers reflecting axonal and astroglial injury. This study evaluated their prognostic value for spinal cord disease progression in X-ALD. In a prospective, seven-year longitudinal study, 66 adult male X-ALD patients without cerebral involvement were followed. Plasma NfL and GFAP were measured using single-molecule array (Simoa) technology. Patients were stratified by baseline biomarker levels using cohort-based fourth-quartile cut-offs (NfL < 15.7 vs. ≥ 15.7 pg/mL; GFAP < 78.7 vs. ≥ 78.7 pg/mL). Age-adjusted NfL residuals were calculated from baseline log-transformed NfL regressed on age. Longitudinal trajectories of the EDSS, SSPROM, and 6-MWT were analyzed using linear mixed-effect models. High baseline NfL was associated with faster EDSS progression (p < 0.001) and steeper SSPROM decline, with differences emerging within the first year. Overall plasma NfL levels remained stable over time (p = 0.111). Age-adjusted NfL residuals showed significant slope differences between the mean and high (+1 SD) and very high (+2 SD) groups. GFAP stratification showed limited prognostic value, with only a significant decline in both groups for SSPROM. Baseline plasma NfL is a robust prognostic biomarker for spinal cord disease progression in adult X-ALD and supports its use for patient stratification in clinical trials, whereas GFAP shows limited standalone utility.
Retrograde trans-synaptic degeneration (rTSD) from posterior visual pathway lesions in multiple sclerosis (MS) is characterized by hemi-macular ganglion cell-inner plexiform layer (GCIPL) thinning and contralateral visual field loss. We investigated associations between rTSD, paramagnetic rim lesions (PRL), and longitudinal visual disability in people with MS (pwMS) using a novel optical coherence tomography (OCT) based biomarker of rTSD. PwMS, non-MS neurological disease controls, and healthy controls underwent OCT, multiparametric brain MRI, and clinical assessments. A quantitative rTSD index was developed to capture hemispheric GCIPL asymmetry, with absolute values reflecting rTSD severity. Generalized linear models were used to investigate MRI and clinical predictors of rTSD. Longitudinal changes in rTSD were evaluated using mixed-effects linear regression models. A total of 170 pwMS and 49 controls were included. PwMS had higher rTSD than healthy (p = 0.006) and non-MS controls (p = 0.009). African American race (p = 0.02) and longer disease duration (p = 0.005) were associated with higher baseline rTSD. PRL in the optic radiations (OR) was linked to a 4.5-fold increase in rTSD (p = 0.037; n = 37) and -1.18 dB reduction in hemifield sensitivity (p = 0.018). Longitudinally, each unit/year progression in rTSD was associated with a -0.07 dB/year decline in hemifield sensitivity (p = 0.005) and a 10.8-fold increase in the odds of expanded disability status scale score progression (p = 0.022). Higher body mass index was associated with faster rTSD progression longitudinally (p = 0.02). PRL in the OR, African American race, disease duration, and higher BMI are associated with rTSD in pwMS. Longitudinal increase in rTSD is associated with worsening visual loss and clinical disability progression in MS. ClinicalTrials.gov identifier: NCT05204459.
Central nervous system (CNS) inflammatory demyelinating syndromes, including multiple sclerosis (MS), aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), occasionally overlap. Some patients remain double-seronegative, showing atypical features that challenge current classifications. To better characterize the phenotypic spectrum of antibody-negative atypical inflammatory demyelinating disorders (AIDD) using unsupervised clustering. We retrospectively analyzed 316 patients (MS = 164, AQP4 + NMOSD = 36, double-seronegative NMOSD = 21, MOGAD = 15, AIDD = 80) followed between 2010 and 2023. Principal component analysis and k-means clustering were applied to AIDD cases using clinical, demographic, and radiological data. AIDD patients had lower disability and fewer corpus callosum and posterior fossa lesions than MS and NMOSD. Three clusters emerged: (1) myelitis-predominant with unmatched CSF oligoclonal bands and longitudinally extensive spinal lesions, (2) brainstem-dominant with recurrent brainstem attacks, and (3) optic neuritis-dominant with recurrent LEON meeting MS dissemination criteria. Treatment patterns differed; rituximab was most frequent. Double-seronegative AIDD represents a heterogeneous clinical spectrum. Unsupervised clustering provides a data-driven framework for refining phenotypic classification and may support biomarker and therapeutic development in antibody-negative CNS demyelination.
Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels are believed to reflect mainly acute and chronic disease processes in multiple sclerosis (MS), respectively. In this study, we investigated whether dimethyl fumarate (DMF) and rituximab (RTX) differentially affect these biomarkers. RIFUND-MS was a 2-year, rater-blinded, 1:1 randomized controlled multicenter trial comparing DMF and RTX in relapsing-remitting multiple sclerosis (RRMS). Serum samples for analysis of sNFL and sGFAP were collected at baseline and 0, 6, 12 and 24. Log-transformed biomarker data were analyzed with linear mixed models, based on intention to treat (ITT), per protocol (PP) and accounting for therapy switches. Cox proportional hazards models were performed to evaluate progression outcomes. Of 200 participants, 197 were analyzed. Based on ITT, sNfL decreased significantly in both arms from baseline to month 24; by 50.7% (CI 43.7%-56.8%; p < 0.001) with RTX, and by 46.4% (CI 38.6%-53.2%; p < 0.001) with DMF, no differences between treatments (global p-value: ITT = 0.06; PP = 0.08; switch group = 0.15). In contrast, sGFAP remained stable in RTX (3.6% decrease; CI -7.8%-13.8%, p = 0.81) but decreased with DMF (18.4%; CI 8.5%-27.2%; p < 0.001). Global analyses favored DMF (ITT = 0.02; PP = 0.004; switch group = 0.74). The risk of progression independent of relapse and MRI activity (PIRMA) was higher with RTX (HR 3.3, CI 1.1-10, p = 0.04). Both RTX and DMF reduced sNfL levels, consistent with suppression of acute inflammatory disease activity. However, only DMF was associated with a sustained reduction in sGFAP and a lower risk of non-inflammatory disability progression. These findings suggest that DMF may exert additional effects on astrocyte-related or compartmentalized CNS pathology beyond peripheral immune modulation.
Imaging and postmortem studies indicate that abnormalities in monoaminergic neurotransmission contribute to cognitive impairment in Parkinson's disease (PD). However, it remains uncertain if cerebrospinal fluid (CSF) monoamine metabolites can serve as biomarkers of cognitive decline in early PD. We therefore examined associations of CSF 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3,4-dihydroxyphenylglycol (DOPEG), and 5-hydroxyindoleacetic acid (5-HIAA) with baseline Montreal Cognitive Assessment (MoCA) scores and with longitudinal rates of change. Ninety-five patients with early PD and fifty-six demographically matched healthy controls (HCs) were included from the Parkinson's Progression Markers Initiative cohort. Baseline CSF concentrations of monoamine metabolites were measured by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). In PD patients, multivariable linear regression and linear mixed-effects models were used to evaluate the cross-sectional and longitudinal associations, respectively, between baseline CSF metabolites and MoCA scores. To facilitate comparison, the levels of monoamine metabolites were converted into Z-scores to attain standardized β coefficients. Compared with HCs, PD patients had lower baseline CSF concentrations of DOPAC, HVA, and 5-HIAA. After adjustment for relevant covariates, any standardized CSF metabolite was not associated with baseline MoCA scores. Lower baseline CSF DOPAC and HVA were significantly associated with more rapid cognitive decline over time (z-DOPAC: β = 0.17, p < 0.001; z-HVA: β = 0.14, p = 0.009). Neither DOPEG nor 5-HIAA was associated with longitudinal cognitive decline. Taken together, our results indicated that baseline CSF DOPAC and HVA may serve as promising longitudinal predictors of cognitive decline in patients with PD.