Search Results (127)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration with limited treatment options. In this study, we investigated the pathological role of microRNA-485-3p (miR-485-3p) in ALS, particularly its regulation of PGC-1α, a transcriptional coactivator essential for mitochondrial function and neuroprotection. We also evaluated the therapeutic potential of BMD-001S, a nanoparticle-based formulation encapsulating an antisense oligonucleotide targeting miR-485-3p. Our results demonstrated that miR-485-3p expression was significantly elevated in both SOD1^G93A-expressing HMC3 microglial cells and in the spinal cords of SOD1^G93A transgenic mice at late disease stages, implicating its contribution to ALS pathogenesis. Intravenous administration of BMD-001S effectively reduced miR-485-3p levels and restored PGC-1α mRNA and PGC-1α protein expression in the spinal cord. These molecular changes were associated with notable therapeutic outcomes, including reduced SOD1 protein aggregation, decreased neuroinflammation, and lower neurofilament light chain concentrations in cerebrospinal fluid. Moreover, BMD-001S treatment was associated with improvements in electrophysiological parameters and preservation of neuromuscular junction integrity during the observation period in SOD1^G93A transgenic mice. Taken together, these findings suggest that miR-485-3p/PGC-1α pathway is a promising therapeutic target in ALS and support the potential of BMD-001S as a novel treatment strategy for the disease. Full article

Background: Alcohol use disorder (AUD) is associated with chronic heavy or repeated binge alcohol abuse, which can cause alcohol-related brain damage (ARBD) marked by neurobehavioral, cognitive, and motor deficits. The anterior frontal lobe and cerebellar vermis are two of the major targets of ARBD in humans with AUD and in experimental alcohol exposed models. Alcohol’s neurotoxic and neurodegenerative effects include impairments in signaling through insulin and insulin-like growth factor (IGF) pathways that regulate energy metabolism. This human AUD study was inspired by a recent report suggesting that dysfunction of the frontal lobe incretin network in experimental ARBD is linked to known impairments in brain insulin/IGF signaling. Objective: The overarching goal was to investigate whether AUD is associated with dysfunction of the brain’s incretin network, focusing on the cerebellum and frontal lobe. Methods: Fresh frozen postmortem cerebellar vermis and anterior frontal lobe tissues from adult male AUD (n = 6) and control (n = 6) donors were processed for protein extraction. Duplex enzyme-linked immunosorbent assays (ELISAs) were used to assess immunoreactivity to neurofilament light chain (NfL) as a marker of neurodegeneration. A multiplex ELISA was used to measure immunoreactivity to a panel of gut hormones, including incretin polypeptides. Results: AUD was associated with significantly increased NfL immunoreactivity in both the cerebellar vermis and anterior frontal lobe. However, the patterns of AUD-related alterations in gut hormone immunoreactivity differed regionally. AUD reduced pancreatic polypeptide immunoreactivity in the cerebellar vermis, and GIP, GLP-1, leptin, and ghrelin in the frontal lobe. Conclusions: (1) Increased NfL may serve as a useful biomarker of neurodegeneration in AUD. (2) AUD’s adverse effects on neuroendocrine signaling networks differ in the cerebellar vermis and anterior frontal region, although both are significant targets of ARBD. (3) The finding of AUD-associated reductions in frontal lobe GIP and GLP-1 suggests that therapeutic targeting with incretin receptor agonists may help restore energy metabolism and neurobehavioral and cognitive functions linked to their networks. Full article

Repeated exposure to low-level blast overpressure (BOP) during controlled detonations is an emerging occupational health concern for military breachers and Special Operations Forces personnel, given accumulating evidence that chronic exposure may produce subtle, subclinical neurotrauma. This study derived a latent neuroinjury construct integrating three complementary domains of brain health—post-concussive symptoms, working-memory performance, and circulating biomarkers—to determine whether breachers exhibit coherent patterns of neurobiological alteration. Symptom severity was assessed using the Rivermead Post-Concussion Questionnaire (RPQ), and working memory was assessed with the N-Back task and a panel of thirteen neuroproteomic biomarkers was measured reflecting astroglial activation, neuronal and axonal injury, oxidative stress, inflammatory signaling, and neurotrophic regulation. Experienced Canadian Armed Forces breachers with extensive occupational BOP exposure were compared with unexposed controls. Bayesian latent-variable modeling provided probabilistic evidence for a chronic, subclinical neurobiological signal, with the strongest contributions arising from self-reported symptoms and smaller but consistent contributions from the biomarker domain. Working-memory performance did not load substantively on the latent factor. Several RPQ items and circulating biomarkers showed robust loadings, and the latent neuroinjury factor was elevated in breachers relative to controls (97% posterior probability). The pattern is broadly consistent with subclinical neurobiological stress in the absence of measurable cognitive impairment, suggesting early or compensated physiological alterations rather than overt dysfunction. This multidomain, biomarker-informed framework provides a mechanistically grounded and scalable approach for identifying subtle neurobiological strain in military personnel routinely exposed to repetitive low-level blast. It may offer value for risk stratification, operational health surveillance, and the longitudinal monitoring of neurobiological change in high-risk occupations. Full article

Creutzfeldt–Jakob disease (CJD) is a rare but devastating neurodegenerative disorder characterized by the pathological misfolding of the cellular prion protein (PrP^C) into the pathogenic isoform-scrapie prion protein (PrP^Sc), ultimately leading to fatal outcomes. Cerebrospinal fluid (CSF) biomarkers play a pivotal role in early diagnosis, longitudinal monitoring, and prognostic assessment, thereby enhancing the clinical management of this challenging disease. This review summarizes the established CSF biomarkers, 14-3-3 protein, tau protein (total tau), phosphorylated tau isoforms, α-synuclein, neurofilament light chain (Nfl), S100B, neuron-specific enolase (NSE), and phosphorylated neurofilament heavy chain (pNFH), highlighting typical sensitivity ranges (14-3-3 ~70–85%; RT-QuIC > 90%) and subtype-dependent performance variation. We further dissect limitations related to assay variability, inter-laboratory cut-off inconsistencies, and reduced specificity in non-prion dementias. Looking ahead, we discuss emerging multi-omics discovery, integration of CSF with blood-based biomarkers and imaging signatures, and AI-enabled diagnostic modeling. We propose a three-tier biomarker framework combining Real-Time Quaking-Induced Conversion (RT-QuIC) as a confirmatory assay, tau/NfL/pNFH as injury-severity indicators, and multi-omics-derived signatures for early detection and prognosis stratification. Full article

Background/Objectives: Alzheimer’s disease (AD) is the leading cause of dementia, which is an inevitable consequence of aging. Early detection of AD, or detection during the pre-AD stage, is beneficial, as it enables timely intervention to reduce modifiable risk factors, which may help prevent or delay the progression to dementia. On the one hand, plasma biomarkers have demonstrated great promise in predicting cognitive decline. On the other hand, in recent years, ocular imaging features, particularly the thickness of retinal layers measured by spectral-domain optical coherence tomography (SD-OCT), are emerging as possible non-invasive, non-contact surrogate markers for early detection and monitoring of neurodegeneration. This pilot study aims to identify retinal layer thickness changes across the entire retina linked to plasma AD biomarkers in cognitively healthy (CH) elderly individuals at risk for AD. Methods: Eleven CH individuals (20 eyes total) were classified in the pre-AD stage by plasma β-amyloid (Aβ)42/40 ratio < 0.10 and underwent SD-OCT. A deep-learning-derived automated algorithm was used to segment retinal layers on OCT (with manual correction when needed). Multiple layer thicknesses throughout the entire retina (including the inner retina, the outer retina, and the choroid) were measured in the inner ring (1–3 mm) and outer ring (3–6 mm) of the Early Treatment Diabetic Retinopathy Study (ETDRS). Relationships between retinal layers and plasma biomarkers were analyzed by ridge regression/bootstrapping. Results: Results showed that photoreceptor inner segment (PR-IS) thinning had the largest size effect with neurofilament light chain. Additional findings revealed thinning or thickening of the other retinal layers in association with increasing levels of glial fibrillary acidic protein and phosphorylated tau at threonine 181 and 217 (p-tau181 and p-tau217). Conclusions: This pilot study suggests that retinal layer-specific signatures exist, with PR-IS thinning as the largest effect, indicating neurodegeneration in pre-AD. Further research is needed to confirm the findings of this pilot study using larger longitudinal pre-AD cohorts and comparative analyses with healthy aging adults. Full article

Traumatic brain injury (TBI) is a major global health concern and a leading cause of mortality and disability. Head computed tomography (CT) remains indispensable for the detection of intracranial hemorrhage; however, its indiscriminate use in mild trauma increases radiation exposure, cumulative oncogenic risk, and healthcare costs. Consequently, there is growing interest in tools capable of improving sensitivity in mild or early-stage TBI. Protein-based biomarkers are promising complements to conventional assessment. Molecules such as glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), S100 calcium-binding protein B (S100B), and neurofilament light chain (NfL) reflect astroglial activation, neuronal injury, and axonal damage, enabling objective evaluation of neurotrauma. Beyond protein biomarkers, metabolomic and lipidomic approaches capture alterations associated with early metabolic distress, oxidative stress, mitochondrial dysfunction, and membrane disruption following TBI. High-resolution mass spectrometry studies have identified reproducible metabolite and lipid signatures correlating with injury severity and functional outcomes. Longitudinal profiling further reveals dynamic metabolic trajectories that distinguish secondary injury progression from stabilization, supporting predictive modeling and risk stratification. Together, these advances pave the way toward precision medicine in neurotrauma. Nevertheless, variability in assay performance and sampling timing continues to limit widespread clinical adoption. Future research should prioritize methodological standardization, analytical validation, and the integration of multi-omic data with machine learning–based predictive models. Full article

The COVID-19 pandemic has demonstrated that its effects go far beyond the initial respiratory illness, with many survivors experiencing lasting neurological problems. Some patients develop a condition known as Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), which includes current issues such as reduced cognitive function, chronic headaches, depression, neuropathic pain, and sensory disturbances. These symptoms can severely disrupt daily life and overall well-being. In this narrative review, we provide an overview of current understanding regarding the neurological effects of COVID-19, with a focus on Long COVID. We discuss possible underlying mechanisms, including direct viral invasion of the nervous system, immune-related damage, and vascular complications. We also summarize findings from cohort studies and meta-analyses that explore the causes, symptom patterns, and frequency of these neurological issues. Approximately one-third of people who have had COVID-19 report neurological symptoms, especially those who experienced severe illness or were infected with pre-Omicron variants. Emerging research has identified potential biomarkers such as neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) that may help in diagnosis. Treatment approaches under investigation include antiviral medications, nutraceuticals, and comprehensive rehabilitation programs. Factors like older age, existing health conditions, and genetic differences in ACE2 and TMPRSS2 genes may affect an individual’s risk. To effectively address these challenges, current research is essential to improve diagnostic methods, develop targeted treatments, and enhance rehabilitation strategies. Ultimately, a coordinated, multidisciplinary effort is crucial to reduce the neurological impact of Long COVID and support better recovery for patients. Full article

Disability accumulation in multiple sclerosis often occurs independent of relapses and inflammatory activity, yet reliable predictors for early progression remain limited. Our aim was to evaluate the utility of baseline fluid and optical coherence tomography (OCT) biomarkers for predicting early disability progression in newly diagnosed relapsing–remitting MS (RRMS). We performed a monocentric observational cohort study on 72 RRMS patients that were enrolled within 6 months of diagnosis and followed for 2 years. Baseline serum and cerebrospinal fluid (CSF) samples were analyzed for neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (CHI3L1). Confirmed disability progression at 1 year (1yCDP) was defined by either an increase in Expanded Disability Status Scale or a ≥20% worsening on Nine-Hole Peg Test or Timed 25-Foot Walk. Seventeen patients (23.6%) developed 1yCDP. Elevated baseline CSF GFAP (OR = 5.79, 95% CI 1.72–19.45; p = 0.005) and CSF CHI3L1 thickness (OR = 4.14, 95% CI 1.49–11.49; p = 0.006) and reduced ganglion cell-inner plexiform layer (GCIPL) thickness (OR = 0.90, 95% CI 0.84–0.97; p = 0.006) independently predicted 1yCDP. A multivariate model including age, CSF GFAP and GCIPL achieved AUC = 0.831, with a sensitivity of 87.5% and specificity of 61.5%. This study provides evidence that baseline patient profiling using CSF GFAP, CSF CHI3L1 and GCIPL thickness may help predict early disability progression in RRMS. Full article

This study identifies a significant association among blood-based biomarkers of traumatic brain injury (TBI) and the Marshall CT classification of TBI (MCTC) scores, but not with Glasgow Coma Scale (GCS) scores. We aimed to determine whether GCS and MCTC scores relate to glial fibrillary acid protein (GFAP), ubiquitin carboxy hydrolase-1 (UCH-L1), tau, neurofilament light chain (NfL), and phosphorylated tau (p-tau231) concentrations following acute TBIs. Participants included patients from 20 trauma centers across 12 regional sites in the United States and Canada with an initial CT scan within 6 h after TBI and GCS scores of 3 to 12. Blood samples collected upon hospital arrival were analyzed for biomarker concentrations (pg/mL). Concentrations from 271 patients with GCS ≥ 9 were compared to 145 with GCS ≤ 9. Samples from 347 patients with MCTC < 3 were compared to 70 with MCTC ≥ 3. No significant differences in GCS groups were found (p’s > 0.5), while MCTC groups differed significantly (p’s < 0.001). Higher concentrations of plasma GFAP, NfL, and p-tau231 correlated with MCTC scores > 3, with no associations with GCS. Future research might show an application in individual risk assessments to improve triaging of TBI patients. Full article

Background/Objectives: Myotonic dystrophy type 1 (DM1) is a multisystem disorder that affects the central nervous system. Despite previous studies, blood-based biomarkers have not been sufficiently characterized. This study investigated plasma neurofilament light chain (NfL), phosphorylated tau (p-tau181), amyloid-β (Aβ42/40), and glial fibrillary acidic protein (GFAP) in a Japanese cohort with DM1 to assess their potential as biomarkers. Methods: Forty patients with genetically confirmed DM1 were enrolled in this study. Plasma NfL, p-tau181, Aβ42/40, and GFAP were quantified using single-molecule array technology. Clinical and genetic variables, including age, CTG repeat size, Mini-Mental State Examination (MMSE) score, modified Rankin Scale (mRS) score, and creatine kinase levels, were analyzed for correlations. Results: NfL and p-tau181 were significantly elevated in patients with DM1 compared with controls, with 95% exceeding the p-tau181 cut-off. NfL was moderately correlated with age, age at onset, and mRS, and no significant associations were observed between p-tau181 and other biomarkers, although a correlation was noted with serum creatine kinase. Conclusions: These findings support that NfL is a marker of disease severity in DM1 and identified plasma p-tau181 as a potential novel biomarker. While the mechanisms underlying the increased p-tau181 levels remain unclear, they may reflect DM1-related pathologies in the brain and possibly in skeletal muscle. Study limitations include a small sample size and lack of age-matched controls, highlighting the need for longitudinal validation. This study demonstrates the utility of NfL and suggests that p-tau181 is an emerging biomarker for DM1, supporting future work toward biomarker-guided monitoring and therapeutic evaluation. Full article

Background: Biomarker analysis in neurodegeneration with brain iron accumulation (NBIA) can offer valuable insights into the disease’s pathology and natural history. Methods: Twenty-five patients with C19orf12 mutations causing mitochondrial membrane protein-associated neurodegeneration (MPAN), 12 patients with PANK2 mutations causing pantothenate kinase-associated neurodegeneration (PKAN), and 30 age- and gender-matched controls were studied. Serum levels of MMP-9, S100B, ICAM-1, E- and P-selectins, total α-synuclein, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), Tau, ubiquitin-C-terminal hydrolase-L1 (UCH-L1), and brain-derived neurotrophic factor (BDNF) were measured. Clinical status was evaluated with dedicated rating scales. Results: Compared to the control group, MPAN patients had significantly higher serum levels of nearly all biomarkers, except BDNF. NfL, GFAP, and UCH-L1, were elevated by 5, 2, and 3.5 times, respectively. PKAN patients showed no significant differences in GFAP, UCH-L1, and S100B levels compared to controls. However, NfL and Tau levels were increased by 3 and 1.8 times, respectively. A correlation was observed between disease severity and levels of NfL, Tau, and UCH-L1 in MPAN, and GFAP, Tau, and UCH-L1 in PKAN. Conclusions: Patients with MPAN and PKAN showed increased levels of neurodegeneration biomarkers. Elevated inflammation and blood–brain barrier dysfunction biomarkers were specific to MPAN patients. Full article

Ischemic stroke remains a leading cause of mortality and long-term disability worldwide, with prognosis influenced by heterogeneous biological and neuroanatomical factors. In the past decade, numerous possible biomarkers—molecular, imaging, and electrophysiological—have been investigated to improve outcome prediction and guide rehabilitation strategies and main objectives. Among them, neurofilament light chain (NFL), a cytoskeletal protein released during neuroaxonal injury, has become an effective marker of the severity of the neurological condition and the integrity of the neurons. Additional circulating biomarkers, including thioredoxin, netrin-1, omentin-1, bilirubin, and others, have been linked to oxidative stress, angiogenesis, neuroprotection, and regenerative processes. Meanwhile, innovations in electrophysiology (EEG and TMS-based predictions) and neuroimaging (diffusion tensor imaging, corticospinal tract lesion load, and functional connectivity) add some additional perspectives on the possibility for brain recovery. This work is a narrative synthesizing evidence from PubMed, Scopus, and Web of Science between 2015 and 2025, including both clinical and experimental studies addressing stroke biomarkers and outcome prediction. The review outlines a framework for the integration of multimodal biomarkers to support precision medicine and individualized rehabilitation in stroke. Full article

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

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