Search Results (229)

Pediatric seronegative immune-mediated cerebellar ataxia (IMCA) remains a poorly defined and often under-recognized diagnosis, particularly in young children, where symptoms are frequently misattributed to self-limited post-infectious processes. We report the case of a 2.5-year-old girl who presented with acute-onset ataxia (mSARA score: 14). Cerebrospinal fluid analysis revealed pleocytosis and positive oligoclonal bands, while serial brain imaging and extensive autoantibody panels were unremarkable. However, indirect immunohistochemistry (TIIF/IHC) demonstrated a positive intracellular signal in cerebellar Purkinje cells, supporting the diagnosis of isolated seronegative IMCA. The patient showed sustained clinical improvement with prolonged corticosteroid therapy (mSARA score: 1). To date, only a few similar cases have been reported in the literature. It remains unclear whether these presentations fall within the spectrum of autoimmune encephalitis (AIE) or represent a distinct pediatric phenotype, potentially expanding the age range of primary autoimmune cerebellar ataxia previously described in adults. We recommend incorporating TIIF/IHC into the diagnostic workup of both isolated and combined pediatric cerebellar ataxia syndromes to support diagnosis and guide individualized treatment. Additionally, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are emerging as promising biomarkers in this context and warrant further investigation. Full article

Lipid debris generated after ischemic stroke overwhelms myeloid cells, leading to foam cell-like dysfunction and chronic neuroinflammation. 2-hydroxypropyl-β-cyclodextrin (HPβCD), a cholesterol-mobilizing agent, has been shown to improve recovery and reduce chronic inflammation after stroke by enhancing lipid processing and cholesterol efflux in infarcts. To identify plasma biomarkers of HPβCD activity and gain mechanistic insight into lipid pathway modulation, aged (21-month-old) male mice underwent the distal middle cerebral artery occlusion + hypoxia (DH) model of stroke and received 2 g/kg HPβCD twice daily beginning 1 d after stroke. Plasma metabolomic and lipidomic profiling was performed 4 d after stroke using untargeted (Global Discovery) and targeted (Complex Lipid, Oxysterols, and Lipid Mediators of Inflammation) panels. Acute neuroprotection was assessed by magnetic resonance imaging (MRI) quantification of infarct, ventricle, and hippocampus volumes 2 d after stroke and by plasma neurofilament light (NfL) levels 4 d after stroke. HPβCD treatment did not provide acute neuroprotection; however, HPβCD did induce distinct plasma metabolomic and lipidomic signatures, including decreases in sphingolipids, cholesterol, long-chain fatty acids, 4β-hydroxycholesterol, 7-dehydrocholesterol, and 8-dehydrocholesterol and increases in 27-hydroxycholesterol and 7α-hydroxy-3-oxo-4-cholestenoic acid (7-HOCA), consistent with enhanced cholesterol efflux and metabolism. Pro-inflammatory oxylipins were also suppressed by HPβCD treatment. These results support the role of HPβCD in promoting lipid debris clearance and suppressing inflammatory lipid pathways after stroke and, together with prior studies demonstrating improved long-term recovery, highlight HPβCD as a biomarker-supported therapeutic candidate for stroke recovery. Full article

Atypical parkinsonian disorders—progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA)—are rare, rapidly progressive neurodegenerative syndromes characterized by distinct molecular pathologies, heterogeneous clinical phenotypes, and limited therapeutic options. Accurate diagnosis remains a major clinical challenge, especially during early and prodromal phases, due to overlap with Parkinson’s disease (PD), phenotypic evolution, and the absence of reliable stand-alone biomarkers. Misclassification delays prognosis, impairs patient care, and hinders clinical trial design. This review synthesizes advances from 2015 to 2025 in clinical, imaging, and biomarker-based diagnosis of PSP, CBD, and MSA. We examine their phenotypic spectra, neuropathological substrates, and epidemiological trends, and critically evaluate the diagnostic performance and translational potential of emerging tools—including quantitative MRI morphometry, second-generation tau and α-synuclein PET ligands, neurophysiological markers such as video-oculography and autonomic testing, and fluid biomarkers such as neurofilament light chain. Persistent diagnostic barriers are identified, from phenotypic mimicry and pathological pleomorphism to the limited specificity of molecular assays and inequitable access to advanced technologies. We propose tiered, multimodal diagnostic algorithms that integrate structured clinical phenotyping with quantitative imaging, molecular diagnostics, systemic risk profiling, and autopsy-linked validation. Such biology-anchored approaches could enable diagnosis years before classical features emerge, improve patient stratification for disease-modifying trials, and lay the foundation for precision medicine in atypical parkinsonian disorders. A paradigm shift from descriptive nosology to mechanistically grounded frameworks is essential to accelerate early intervention and transform the clinical management of these devastating diseases. Full article

Background and Objectives: Neuromyelitis optica spectrum disorder (NMOSD) and MOG antibody-associated disease (MOGAD) are distinct autoimmune demyelinating disorders of the central nervous system, characterized by different pathological and clinical features. Reliable biomarkers are essential for accurate diagnosis and monitoring of disease activity. Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are promising candidates, reflecting astrocytic and axonal damage, respectively. Materials and Methods: To investigate the relationship between astroglial (GFAP) and neuronal (NfL) protein levels in the peripheral blood, 89 plasma samples were analyzed using Simoa immunoassays. The concentrations of pNfL and pGFAP were measured in three groups: AQP4-IgG-positive NMOSD patients (n = 18), MOGAD patients (n = 12), and healthy controls (HCs, n = 19). Statistical analyses assessed group differences, correlations, and the predictive value of biomarkers for disease activity. Results: Both NMOSD and MOGAD patients exhibited elevated pNfL compared with controls, indicating neuroaxonal injury. No significant differences in pNfL, pGFAP, or pGFAP/pNfL ratios were observed between patient groups. The pGFAP levels and the pGFAP/pNfL ratio were significantly higher in NMOSD patients, particularly during attacks, indicating prominent astrocyte damage. Correlations revealed associations between biomarker levels, disability, and disease duration. pNfL demonstrated high accuracy in predicting recent relapses (AUC = 0.906), whereas pGFAP showed moderate predictive capacity (AUC = 0.638). Elevated pNfL and pGFAP levels were associated with an increased likelihood of relapse within six months. Conclusions: Plasma NfL and GFAP are promising biomarkers for assessing tissue injury and disease activity in NMOSD and MOGAD. NfL predicts relapses, while GFAP primarily reflects astrocytic damage in NMOSD. Longitudinal studies are warranted to validate these biomarkers and establish clinical thresholds for disease management. Full article

Background: Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders marked by progressive corticospinal tract dysfunction and wide phenotypic variability. Their genetic heterogeneity has so far limited the identification of biomarkers that are broadly applicable across different subtypes. Objective: We aim to define a balanced review on the use of biomarkers in HSP. Methods: This review focuses on fluid biomarkers already available in clinical or research settings—primarily validated in other neurodegenerative diseases—and assesses their potential translation to the HSP context. Biomarkers such as neurofilament light chain, brain-derived tau, glial fibrillary acidic protein, and soluble TREM2 reflect key converging mechanisms of neurodegeneration, including axonal damage, neuronal loss, and glial activation. These shared downstream pathways represent promising targets for disease monitoring in HSP, independently of the underlying genetic mutation. Results: An integrative framework of fluid biomarkers could assist in defining disease progression and stratify patients in both clinical and research settings. Moreover, recent advances in ultrasensitive assays and remote sampling technologies, such as dried blood spot collection, offer concrete opportunities for minimally invasive, longitudinal monitoring. When combined with harmonized multicenter protocols and digital infrastructure, these tools could support scalable and patient-centered models of care. Conclusions: The integration of already available biomarkers into the HSP field may accelerate clinical translation and offer a feasible strategy to overcome the challenges posed by genetic and clinical heterogeneity. Full article

This study evaluated serum neurofilament light chain (NfL) as a biomarker for spinal cord diseases in dogs, including 46 healthy dogs and 76 with conditions, such as intervertebral disc herniation (IVDH), syringomyelia (SM), fibrocartilaginous embolism (FCE), and acute non-compressive nucleus pulposus extrusion (ANNPE). There was a significant difference in serum NfL levels between healthy dogs (12.55 pg/mL) and those with spinal cord diseases (91.10 pg/mL; p < 0.0001). The NfL level in dogs with SM (50.7 pg/mL) was significantly lower than that in dogs with IVDH (99.3 pg/mL; p = 0.012) and those with other diseases, including FCE and ANNPE (241.0 pg/mL; p = 0.002). The area under the curve for differentiating between dogs with spinal cord diseases and healthy dogs was 0.91, with an optimal NfL cutoff value of 30.31 pg/mL (sensitivity of 80.68%; specificity of 91.30%). For dogs with IVDH treated solely with medication, the serum NfL levels in the Poor and Static group (180.0 pg/mL) were significantly higher than those in the Partial and Good group (81.30 pg/mL) (p = 0.03). Serum NfL is a promising biomarker for neuroaxonal injury, aiding in differentiating SM from other spinal cord diseases and evaluating treatment response. Full article

Neuroaxonal damage underlies permanent disability in various neurological conditions, both neuroautoimmune and neurodegenerative. It is crucial to accurately quantify and monitor axonal injury using biomarkers to evaluate disease progression and treatment effectiveness and offer prognostic insights. Neurofilaments (NFs), and especially neurofilament light chain (NfL), show promise for this purpose, as their levels increase with neuroaxonal damage in both cerebrospinal fluid and blood, independent of specific causal pathways. Recent advances in ultrasensitive immunoassays enable the reliable detection of NFs in blood, transforming them from research tools into clinically applicable measures. In multiple sclerosis (MS), serum NfL correlates with disease activity, treatment response, and long-term disability, and may complement MRI in monitoring subclinical progression. In MS, NfL is primarily emerging as a marker of disease activity and treatment response; in amyotrophic lateral sclerosis (ALS), it has progressed further, being integrated into clinical trials as a pharmacodynamic endpoint and considered by regulatory agencies as a drug development tool. Additionally, NFs are increasingly being investigated in Alzheimer’s disease, frontotemporal dementia, and other neurodegenerative disorders, though their disease specificity is limited. Ongoing challenges include older and novel assay harmonization, normative range interpretation, biological and analytical variability, and integration with other molecular and imaging biomarkers. This critical narrative review synthesizes the existing literature on NFs as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers and discusses their role in therapeutic development and precision medicine in neuroautoimmune and neurodegenerative diseases. Full article

Background: Blast-induced spinal cord injuries (bSCI) account for 75% of all combat-related spinal trauma and are associated with long-term functional impairments. However, limited studies have evaluated the neuropathological outcomes in the spinal cord following blast exposure. Objectives In this study, we aimed to determine the acute and sub-acute neuropathological changes in the spinal cord of ferrets after blast exposure. Methods: An advanced blast simulator was used to expose ferrets to tightly coupled repeated blasts. The Catwalk XT system was used to detect gait performances in ferrets at 24 h and 1 month post-blast exposure. After euthanasia, the cervical spinal cord samples were collected at 24 h or 1 month post-blast. A quantitative real-time polymerase chain reaction was performed to evaluate changes in the gene expression of multiple Toll-like Receptors (TLR), Cyclooxygenase (COX-1 and COX-2) enzymes and cytokines. Western blotting was performed to investigate markers of axonal injury (Phosphorylated-Tau, pTau; Phosphorylated Neurofilament Heavy Chain, pNFH; and Neurofilament Light Chain present in degenerating neurons, NFL-degen) and neuroinflammation (Glial Fibrillary Acidic Protein, GFAP; and Ionized Calcium Binding Adaptor Molecule, Iba-1). Results: Blast exposure significantly affected the gait performances in ferrets, especially at 24 h post-blast. Multiple TLRs, COX-2, Interleukin-1-beta (IL-1β), Interleukin-6 (IL-6), and Tumor Necrosis Factor-α (TNF-α) were significantly upregulated in the spinal cord at 24 h after blast exposure. Although only TLR3 was significantly upregulated at 1 month, non-significant increases in TLR1 and TLR2 were observed in the spinal cord at 1 month post-blast. Phosphorylation of Tau at serine (Ser396 and Ser404) and threonine (Thr205) increased in the spinal cord at 24 h and 1 month post-blast exposure. The increased expression of pNFH and NFL-degen proteins was evident at both time points. The expression of GFAP, but not Iba-1, significantly increased at 24 h and 1 month following blast exposure. Conclusions: Our results indicate that blast exposure causes acute and sub-acute neuroinflammation and associated axonal injury in the cervical spinal cord. These data further suggest that inhibition of TLRs and/or COX-2 enzyme might offer protection against blast-induced injuries to the spinal cord. Full article

Autopsy studies have shown that Alzheimer’s disease (AD) often coexists with cerebrovascular injury, affecting cognitive outcomes and the effectiveness of anti-amyloid-beta (Aβ) drugs. No fluid biomarkers of cerebrovascular injury have been identified yet. We investigated the association between white matter hyperintensities (WMH) severity and fluid biomarkers, including cerebrospinal fluid (CSF) neurofilament light chain and plasma placental growth factor (PlGF) levels. This study included 242 patients from memory clinics. Magnetic resonance imaging (MRI), CSF, and plasma samples were collected. Patients were classified as AD+ or non-AD based on the CSF Aβ42/Aβ40 ratio. In the discovery cohort (79 AD+ and 20 non-AD patients with 3D-T1 images), we analyzed the association between WMH volume and plasma PlGF. In the validation cohort (54 AD+ patients without 3D-T1 images), we analyzed the association between WMH grading and plasma PlGF. Among AD+ patients in the discovery cohort, plasma PlGF levels remained significantly associated with WMH volume and grading after adjusting for age, sex, and global cognition. Among the AD+ patients in the validation cohort, the high-PlGF (above median) group had significantly greater WMH volumes and a higher number of patients with a high WMH grading than the low-PlGF (below median) group. Plasma PlGF is a promising marker of cerebrovascular injury in AD. Full article

Vascular dementia (VaD) represents the second-most common dementia type after Alzheimer’s disease since it results from complications of cerebrovascular disease. Mixed pathologies combining vascular and neurodegenerative processes are the rule rather than exception in elderly dementia patients. The condition known as VaD includes various types of vascular damage that affect both large and small blood vessels in the brain which results in cerebral hypoperfusion, blood–brain barrier disruption, glymphatic dysfunction, and molecular cascades causing neuronal damage. The mechanisms of VaD include endothelial dysfunction, oxidative stress, chronic neuroinflammation, impaired glymphatic clearance, white matter demyelination, and synaptic failure. The disease susceptibility of individuals depends on genetic factors which include NOTCH3 mutations and vascular risk polymorphisms. The diagnostic field uses neuroimaging tools and fluid biomarkers such as neurofilament light chain, inflammatory markers, and Aβ/tau ratios for mixed pathology. The current practice of vascular risk management combines with new therapeutic approaches that use phosphodiesterase inhibitors for cerebral perfusion and NLRP3 inflammasome inhibitors for neuroinflammation, senolytics for cellular senescence, and remyelination agents for white matter repair. However, the majority of new treatment methods remain investigational with limited Phase III data. Future medical treatment development will depend on precision medicine approaches which use biomarker-guided treatment selection and combination strategies targeting multiple pathological mechanisms. Full article

This study investigated the associations among age, physical activity level, knee muscle function, and neuromuscular junction (NMJ) biomarkers in a cohort of 80 middle-aged and young men residing in the Republic of Korea. Despite comparable levels of physical activity between the groups, the middle-aged participants exhibited significantly higher body fat percentage, elevated levels of the neurodegeneration marker neurofilament light chain (NfL), and a marked decline in lower-extremity muscle function compared to their younger counterparts. Advancing age was negatively associated with knee extensor peak torque, body weight–normalized torque (BW/PT), and the rate of torque development at 0.18 s (RTD@0.18s). In contrast, higher physical activity levels were positively correlated with certain indicators of muscle function and were associated with lower circulating concentrations of the NMJ degeneration marker, C-terminal agrin fragment (CAF). These findings suggest that neuromuscular decline and muscle function deterioration may begin as early as middle age. The results underscore the importance of implementing tailored exercise regimens and lifestyle interventions to preserve neuromuscular health and prevent early-onset muscle loss. Full article

Objective: We aimed to explore associations between plasma neurofilament light chain (pNfL) and cognition through patient-reported outcomes (PROs) in multiple sclerosis (MS). Methods: In this cross-sectional study, we included 211 people with MS (PwMS) and collected data from pNfL (fully automated chemiluminescent enzyme immunoassay), EDSS, education, cognition (the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT II), and Brief Visuospatial Memory Test–Revised (BVMT-R)), the Modified Fatigue Impact Scale (MFIS), Beck Depression Inventory (BDI-II), Beck Anxiety Inventory (BAI), and Pittsburgh Sleep Quality Index (PSQI). Results: On multivariate linear regression models, higher educational attainment was significantly associated with lower pNfL (high school: Coeff = −0.22, 95% CI = −0.41 to −0.04, p = 0.019; university: Coeff = −0.22, 95% CI = −0.42 to −0.02, p = 0.030). In logistic regression models, the likelihood of having pNfL levels above normal thresholds increased by 56% for each one-point increment in the EDSS score (OR = 1.56, 95% CI = 1.23 to 1.98, p < 0.001) and was 2.5 times greater in individuals with impaired SDMT (OR = 2.50, 95% CI = 2.20 to 5.21, p = 0.014). No statistically significant associations were observed between pNfL and CVLT-II, BVMT-R, BDI-II, MFIS, BAI, or PSQI. Conclusions: Neuro-axonal damage in people with MS manifests clinically as increased disability and reduced attention and processing speed. However, these effects may be mitigated by greater brain resilience, as suggested by the protective role of higher educational attainment. The PROs assessed in this study showed no significant associations with pNfL levels, possibly due to measurement errors and heterogeneity, with limited sensitivity to neuro-axonal damage. Full article

Mild traumatic brain injury (mTBI) remains a clinical challenge, particularly in cases with normal computed tomography (CT) findings but persistent or evolving symptoms. Conventional diagnostic approaches relying solely on clinical criteria and neuroimaging often lack adequate sensitivity and may lead to unnecessary radiation exposure. Recent advances in biomarker research have identified several blood-based proteins such as glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), S100 calcium-binding protein B (S100B), Tau protein, neuron-specific enolase (NSE), and neurofilament light chain (NFL) as potential tools for improving diagnostic precision and guiding clinical decisions. In this study, we synthesize current evidence evaluating the diagnostic and prognostic utility of these biomarkers using sensitivity, specificity, negative predictive value (NPV), and area under the receiver operating characteristic curve (AUC). GFAP and UCH-L1 have shown high sensitivity in detecting intracranial lesions and are now FDA-cleared for emergency department triage within 12 h of injury. While S100B remains widely investigated, its low specificity limits its application beyond select clinical scenarios (i.e., in patients without polytrauma). Additionally, Tau, NSE, and NFL are emerging as prognostic markers, with studies suggesting associations with persistent symptoms and long-term neurocognitive outcomes. Overall, the integration of biomarker-based data into clinical workflows may enhance early mTBI diagnosis, reduce reliance on imaging, and enable individualized follow-up and prognostic stratification. Future research should refine optimal sampling windows and explore multimarker panels to maximize diagnostic and prognostic performance. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative condition representing the most common cause of dementia and currently affects millions of people worldwide. The clinical presentation includes memory impairment, cognitive decline, and neuropsychiatric symptoms, reflecting pathological hallmarks such as β-amyloid (Aβ) plaques, neurofibrillary tangles, synaptic dysfunction, and neuroinflammation. Despite being the gold standard for detecting amyloid and tau pathologies in vivo, cerebrospinal fluid (CSF) biomarkers and positron emission tomography (PET) imaging are not widely used in the clinical setting because of invasiveness, high costs, and restricted accessibility. Recent advances in blood-based biomarkers offer a promising and minimally invasive tool for early detection, diagnosis, and monitoring of AD. Ultra-sensitive analytical platforms, including single-molecule arrays (Simoa) and immunoprecipitation-mass spectrometry, now enable reliable quantification of plasma Aβ isoforms, phosphorylated tau variants (p-Tau181, p-Tau217, p-Tau231), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). In addition, blood biomarkers reflecting oxidative stress, neuroinflammation, synaptic disruption and metabolic dysfunction are under active investigation. This narrative review synthesizes current evidence on blood-based biomarkers in AD, emphasizing their biological relevance, diagnostic accuracy, and clinical applications. Finally, we highlight forthcoming challenges, such as standardization, and future directions, including the use of artificial intelligence in precision medicine. Full article

Risdiplam is an orally administered small molecule that modifies the mRNA splicing of SMN2 for the treatment of spinal muscular atrophy (SMA). Its use is approved in presymptomatic patients diagnosed by neonatal screening with early and severe forms with two copies of SMN2, but we do not have real data on the evolution of oral treatment in this early phenotype of SMA. We present two cases treated at one month of life with a follow-up of 12 months and discuss their different evolutions and the causes of this. Familial adherence to treatment is important, as discontinuation can convert an early form of presymptomatic SMA to symptomatic. Molecular biomarkers such as plasma monitoring of neurofilament light chain (pNf-L) should be considered in the follow-up of early forms of SMA and may support the decision to change treatment in infants with SMA. Full article