eLife, Journal Year: 2023, Volume and Issue: 12
Published: March 23, 2023
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron dysfunction and loss. A portion of ALS cases are caused mutation the proteasome shuttle factor
Language: Английский
EBioMedicine, Journal Year: 2023, Volume and Issue: 99, P. 104923 - 104923
Published: Dec. 14, 2023
BackgroundTau pathology correlates with and predicts clinical decline in Alzheimer's disease. Approved tau-targeted therapies are not available.MethodsADAMANT, a 24-month randomised, placebo-controlled, parallel-group, double-blinded, multicenter, Phase 2 trial (EudraCT2015-000630-30, NCT02579252) enrolled 196 participants disease; 119 included this post-hoc subgroup analysis. AADvac1, active immunotherapy against pathological tau protein. A machine learning model predicted likely Amyloid+Tau+ from baseline MRI. Statistical methods: MMRM for change cognition, function, neurodegeneration; linear regression associations between antibody response endpoints.ResultsThe prediction achieved PPV of 97.7% amyloid, 96.2% tau. the full analysis set (70 treatment 49 placebo) were classified as A+T+. trend CDR-SB 104-week (estimated marginal means [emm] = −0.99 points, 95% CI [−2.13, 0.13], p 0.0825]) ADCS-MCI-ADL (emm 3.82 [−0.29, 7.92], 0.0679) favour group was seen. Reduction seen plasma NF-L −0.15 log pg/mL, [−0.27, −0.03], 0.0139). Higher to AADvac1 related slowing on (rho −0.10, [−0.21, 0.01], 0.0376) ADL 0.15, [0.03, 0.27], 0.0201), slower brain atrophy 0.18–0.35, < 0.05 temporal volume, whole cortex, right left hippocampus).ConclusionsIn ML imputed or CSF identified A+T+, slowed AD-related an antibody-dependent manner. Larger anti-tau trials warranted.FundingAXON Neuroscience SE.
Language: Английский
Citations
23
Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 95, P. 102247 - 102247
Published: Feb. 27, 2024
Age-associated cerebral small vessel disease (CSVD) represents a clinically heterogenous condition, arising from diverse microvascular mechanisms. These lead to chronic cerebrovascular dysfunction and carry substantial risk of subsequent stroke vascular cognitive impairment in aging populations. Owing advances neuroimaging, vivo visualization vasculature abnormities detection CSVD, including lacunes, microinfarcts, microbleeds white matter lesions, is now possible, but remains resource-, skills- time-intensive approach. As result, there has been recent proliferation blood-based biomarker studies for CSVD aimed at developing accessible screening tools early stratification. However, good understanding the pathophysiological processes underpinning needed identify assess useful biomarkers. Here, we provide an overview associated with pathogenesis, endothelial injury dysfunction, neuroinflammation, oxidative stress, perivascular neuronal damage as well cardiovascular dysfunction. Then, review clinical key biomolecules involved aforementioned processes. Lastly, outline future trends directions discovery validation.
Language: Английский
Citations
15
International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(12), P. 6295 - 6295
Published: June 7, 2024
Neurological damage is the pathological substrate of permanent disability in various neurodegenerative disorders. Early detection this damage, including its identification and quantification, critical to preventing disease’s progression brain. Tau, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), as brain biomarkers, have potential improve diagnostic accuracy, disease monitoring, prognostic assessment, treatment efficacy. These biomarkers are released into cerebrospinal fluid (CSF) blood proportionally degree neuron astrocyte different neurological disorders, stroke, traumatic injury, multiple sclerosis, dementia, Parkinson’s disease. Here, we review how GFAP, NfL detected CSF crucial tools, well levels these used for differentiating a range diseases monitoring progression. We also discuss biosensor approach that allows real-time diseases. This combined system holds significant promise developing more specific accurate clinical tools can identify type stage human with greater precision.
Language: Английский
Citations
15
Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 147(1)
Published: March 25, 2024
Language: Английский
Citations
9
Translational Vision Science & Technology, Journal Year: 2025, Volume and Issue: 14(2), P. 24 - 24
Published: Feb. 25, 2025
The purpose of this study was to evaluate the relationship between serum and aqueous humor (AH) neurofilament light chain (NfL) determine whether NfL is elevated in patients undergoing ocular surgery who have glaucoma compared with those do not. In single-center, case-control study, we enrolled various types stages planned ophthalmic as part their routine care them without phacoemulsification for age-related cataract. We recruited 110 113 collected AH blood from these participants. Levels were quantified using Single-Molecule Array (Simoa) NF-light assay (Quanterix). Clinical information obtained by reviewing medical records. a model controlling age body mass index (BMI), significantly controls (P < 0.001). contrast, after age, BMI, Mini Mental Status Examination (MMSE) scores, not = 0.81). Although our findings validate marker glaucomatous neurodegeneration, no such evidence found NfL. levels may be molecular retinal ganglion cell health glaucoma; has limited utility monitoring neurodegeneration.
Language: Английский
Citations
1
Cell Reports, Journal Year: 2025, Volume and Issue: 44(3), P. 115382 - 115382
Published: March 1, 2025
Neurofilament light chain (NfL) is a neuron-specific cytoskeletal protein that provides structural support for axons and released into the extracellular space following neuronal injury. While NfL has been extensively studied as disease biomarker, underlying release mechanisms role in neurodegeneration remain poorly understood. Here, we find neurons secrete low baseline levels of NfL, while damage triggers calpain-driven proteolysis fragmented NfL. Secreted activates microglial cells, which can be blocked with anti-NfL antibodies. We utilize vivo single-cell RNA sequencing to profile brain cells after injection recombinant mouse hippocampus robust macrophage responses. Consistently, knockout mice ameliorate microgliosis delay symptom onset SOD1 model amyotrophic lateral sclerosis (ALS). Our results show activate myeloid is, thus, potential therapeutic target neurodegenerative diseases.
Language: Английский
Citations
1
Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)
Published: March 14, 2025
Abstract Alzheimer’s disease (AD) is neuropathologically characterized by the extracellular deposition of amyloid-β peptide (Aβ) and intraneuronal accumulation abnormal phosphorylated tau (τ)-protein (p-τ). Most frequently, these hallmark lesions are accompanied other co-pathologies in brain that may contribute to cognitive impairment, such as vascular lesions, transactive-response DNA-binding protein 43 (TDP-43), and/or α-synuclein (αSyn) aggregates. To estimate extent AD patients, several biomarkers have been developed. Specific tracers target visualize Aβ plaques, p-τ αSyn pathology or inflammation positron emission tomography. In addition imaging biomarkers, cerebrospinal fluid, blood-based biomarker assays reflecting AD-specific non-specific processes either already clinical use development. this review, we will introduce pathological brain, related discuss what respective determined at post-mortem histopathological analysis. It became evident initial stages plaque not detected with currently available biomarkers. Interestingly, precedes deposition, especially beginning when unable detect it. Later, takes lead accelerates pathology, fitting well known evolution measures over time. Some still lack clinically established today, TDP-43 cortical microinfarcts. summary, specific for AD-related pathologies allow accurate diagnosis based on pathobiological parameters. Although current excellent pathologies, they fail which analysis required. Accordingly, neuropathological studies remain essential understand development early stages. Moreover, there an urgent need co-pathologies, limbic predominant, age-related encephalopathy-related modify interacting p-τ. Novel approaches vesicle-based cryptic RNA/peptides help better future.
Language: Английский
Citations
1
Brain Communications, Journal Year: 2022, Volume and Issue: 4(2)
Published: Feb. 17, 2022
Neurofilament light is a well-established marker of both acute and chronic neuronal damage increased in multiple neurodegenerative diseases. However, the protein not well characterized brain tissue or body fluids, it unknown what neurofilament species are detected by commercial assays whether additional exist. We developed an immunoprecipitation-mass spectrometry assay using custom antibodies targeting various domains, including Coil 1A/1B rod domain (HJ30.13), 2B (HJ30.4) tail region (HJ30.11). utilized our to characterize CSF individuals with Alzheimer's disease dementia healthy controls. then validated quantitative version measured concentrations commercially available immunoassay from Uman diagnostics without dementia. Our validation cohort included samples 30 symptomatic amyloid-positive participants, 16 asymptomatic 10 amyloid-negative participants 25 identified at least three major CSF, N-terminal C-terminal truncations, fragment containing domain. No full-length was CSF. This contrasts tissue, which contained mostly fragment. observed increase compared controls, larger differences for some than others. The largest were fragments NfL165 (in 1B), NfL324 2B) NfL530 domain). correlated most NfL324. study provides comprehensive evaluation enables future investigations biology utility as biomarker.
Language: Английский
Citations
36
Transplantation and Cellular Therapy, Journal Year: 2022, Volume and Issue: 28(8), P. 426 - 445
Published: June 1, 2022
Alloreactive and autoimmune responses after allogeneic hematopoietic cell transplantation can occur in nonclassical chronic graft-versus-host disease (chronic GVHD) tissues organ systems or manifest atypical ways classical organs commonly affected by GVHD. The National Institutes of Health (NIH) consensus projects were developed to improve understanding classification the clinical features diagnostic criteria for Although still speculative whether manifestations are entirely due GVHD, these remain poorly captured current NIH project criteria. Examples include GVHD impacting system as immune mediated cytopenias, endothelial dysfunction, musculoskeletal system, central peripheral nervous kidneys, serous membranes. These purported may contribute significantly patient morbidity mortality. Most have received little study, particularly within multi-institutional prospective studies, limiting our their frequency, pathogenesis, relation This task force report provides an update on what is known not about while outlining a research framework future studies be undertaken next 3 7 years. We also provide provisional each manifestation, along with practical investigation strategies clinicians managing patients features.
Language: Английский
Citations
34
Journal of Clinical Neurology, Journal Year: 2022, Volume and Issue: 18(4), P. 401 - 401
Published: Jan. 1, 2022
Alzheimer's disease (AD) is the most-common cause of neurodegenerative dementia, and it characterized by abnormal amyloid tau accumulation, which indicates neurodegeneration. AD has mostly been diagnosed clinically. However, ligand-specific positron emission tomography (PET) imaging, such as PET, cerebrospinal fluid (CSF) biomarkers are needed to accurately diagnose AD, since they supplement shortcomings clinical diagnoses. Using that represent pathology essential (particularly when disease-modifying treatment available) identify corresponding targeted therapy for monitoring response. Although imaging CSF useful, their widespread use restricted high cost discomfort during lumbar puncture, respectively. Recent advances in blood shed light on future purposes. The β (Aβ)42/Aβ40 ratio concentrations phosphorylated at threonine 181 217, neurofilament were found Aβ, tau, neurodegeneration brain using automatic electrochemiluminescence technologies, single-molecule arrays, immunoprecipitation coupled with mass spectrometry, etc. These imminently expected be incorporated into practice predict, diagnose, determine stage AD. In this review we focus advancements measurement technologies promising approaching application. We also discuss current limitations, further investigations, perspectives use.
Language: Английский
Citations
34