Translational Outcomes Project in Neurotrauma (TOP-NT) Pre-Clinical Consortium Study: A Synopsis

Journal of Neurotrauma, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Traumatic brain injury (TBI) has long been a leading cause of death and disability, yet research failed to successfully translate findings from the pre-clinical, animal setting into clinic. One factor that contributes significantly this struggle is heterogeneity observed in clinical where patients present with injuries varying types, severities, comorbidities. Modeling highly varied population laboratory remains challenging. Given feasibility constraints, individual laboratories often focus on single types are limited an abridged set outcome measures. Furthermore, tend use different or methodologies one another, making it difficult compare studies identify which pre-clinical may be best suited for translation. The NINDS-funded Translational Outcomes Project Neurotrauma (TOP-NT) multi-site consortium designed address reproducibility, rigor, transparency development validation clinically relevant biomarkers TBI. current overview article provides detailed description infrastructure strategic approach undertaken by consortium. We outline TOP-NT strategy three goals: (1) selection cross-center biomarker tools, (2) data allow sharing reuse following findable, accessible, interoperable, reusable guidelines, (3) demonstration feasibility, conducting multi-center, trial TBI development. synthesized scientific analysis results efforts will topic future articles.

Language: Английский

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Serum neurofilament light chain: a novel biomarker for early diabetic sensorimotor polyneuropathy

Diabetologia, Journal Year: 2022, Volume and Issue: 66(3), P. 579 - 589

Published: Dec. 6, 2022

Abstract Aims/hypothesis No established blood-based biomarker exists to monitor diabetic sensorimotor polyneuropathy (DSPN) and evaluate treatment response. The neurofilament light chain (NFL), a blood of neuroaxonal damage in several neurodegenerative diseases, represents potential for DSPN. We hypothesised that higher serum NFL levels are associated with prevalent DSPN nerve dysfunction individuals recently diagnosed diabetes. Methods This cross-sectional study included 423 adults type 1 2 diabetes known duration less than year from the prospective observational German Diabetes Study cohort. was measured samples fasting participants multiplex approach using proximity extension assay technology. assessed by neurological examination, conduction studies quantitative sensory testing. Associations (defined according Toronto Consensus criteria) were estimated Poisson regression, while multivariable linear quantile regression models used assess associations function measures. In exploratory analyses, other biomarkers panel also analysed similarly NFL. Results found 16% sample. Serum increased age. After adjustment age, sex, waist circumference, height, HbA 1c , duration, type, cholesterol, eGFR, hypertension, CVD, use lipid-lowering drugs non-steroidal anti-inflammatory drugs, (RR [95% CI] per 1-normalised protein expression increase, 1.92 [1.50, 2.45], p <0.0001), slower motor (all <0.0001) ≤0.03) velocities, lower sural action ( =0.0004) thermal detection threshold warm stimuli =0.023 =0.004 hand foot, respectively). There no evidence between or Conclusions/interpretation Our findings provide new associating peripheral dysfunction. present advocates as Graphical abstract

Language: Английский

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Elevated serum neurofilament light chain levels in patients with neuropsychiatric systemic lupus erythematosus: a cross-sectional study

Lupus Science & Medicine, Journal Year: 2025, Volume and Issue: 12(1), P. e001309 - e001309

Published: Jan. 1, 2025

Background The neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and serum as a marker of neuronal damage may be potential biomarker neuropsychiatric involvement SLE (NPSLE). Methods 80 patients with were included. We obtained paired CSF samples from 48 (NPSLE n=32, non-NPSLE n=16) 31 controls. levels NfL determined using ELISA. Results Patients NPSLE demonstrated significantly higher compared the group (mean 31.68±36.63 pg/mL vs mean 16.75±12.48 pg/mL, respectively, p<0.05) controls 10.74±4.36 p<0.01). Notably, concentrations showed an upward trend 1600±2852 pg/mL) contrast to 393.4±191.9 509.7±358.5 pg/mL). Furthermore, positive correlation was observed between (R=0.8686, Elevated triacylglycerol concentrations, C reactive protein organ linked increased (p=0.002; p<0.001; p=0.036) (p=0.008; p=0.007; p<0.001) concentrations. In addition, we established significant intrathecal interleukin-6 (R=0.5118, p<0.05). Conclusion readily available SLE.

Language: Английский

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Adaptive structural changes in the motor cortex and white matter in Parkinson’s disease

Acta Neuropathologica, Journal Year: 2022, Volume and Issue: 144(5), P. 861 - 879

Published: Sept. 2, 2022

Parkinson's disease (PD) is a movement disorder characterized by the early loss of nigrostriatal dopaminergic pathways producing significant network changes impacting motor coordination. Recently three stages PD have been proposed (a silent period when begins, prodromal with subtle focal manifestations, and clinical PD) evidence that cortex abnormalities occur to produce PD[8]. We directly assess structural in primary corticospinal tract using parallel analyses longitudinal cross-sectional pathological cohorts thought represent different PD. 18F-FP-CIT positron emission tomography features identified patients idiopathic rapid-eye-movement sleep behaviour (n = 8) developed signs Longitudinal diffusion tensor imaging before after development showed higher fractional anisotropy compared controls, indicating adaptive networks concert dopamine loss. Histological white matter underlying progressive disorientation axons segmental replacement neurofilaments α-synuclein, enlargement myelinating oligodendrocytes increased density their precursors. There was no neurons or late pathologically confirmed although there were cortical increases neuronal neurofilament light chain myelin proteins association α-synuclein accumulation. Our results collectively provide direct impact on its output begins stage These become considerable as advances potentially contributing

Language: Английский

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Advances and challenges in modeling inherited peripheral neuropathies using iPSCs

Experimental & Molecular Medicine, Journal Year: 2024, Volume and Issue: 56(6), P. 1348 - 1364

Published: June 3, 2024

Abstract Inherited peripheral neuropathies (IPNs) are a group of diseases associated with mutations in various genes fundamental roles the development and function nerves. Over past 10 years, significant advances identifying molecular disease mechanisms underlying axonal myelin degeneration, acquired from cellular biology studies transgenic fly rodent models, have facilitated promising treatment strategies. However, no clinical has emerged to date. This lack highlights urgent need for more biologically clinically relevant models recapitulating IPNs. For both neurodevelopmental neurodegenerative diseases, patient-specific induced pluripotent stem cells (iPSCs) particularly powerful platform modeling preclinical studies. In this review, we provide an update on different vitro human IPN including traditional two-dimensional monoculture iPSC derivatives, recent complex iPSC-based systems using microfluidic chips, organoids, assembloids.

Language: Английский

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Mitochondrial Dynamics: Working with the Cytoskeleton and Intracellular Organelles to Mediate Mechanotransduction

Aging and Disease, Journal Year: 2023, Volume and Issue: 14(5), P. 1511 - 1511

Published: Jan. 1, 2023

Cells are constantly exposed to various mechanical environments; therefore, it is important that they able sense and adapt changes. It known the cytoskeleton plays a critical role in mediating generating extra- intracellular forces mitochondrial dynamics crucial for maintaining energy homeostasis. Nevertheless, mechanisms by which cells integrate mechanosensing, mechanotransduction, metabolic reprogramming remain poorly understood. In this review, we first discuss interaction between cytoskeletal components, followed annotation of membranous organelles intimately related dynamic events. Finally, evidence supporting participation mitochondria mechanotransduction corresponding alterations cellular conditions. Notable advances bioenergetics biomechanics suggest system composed mitochondria, system, regulated through dynamics, may be promising target further investigation precision therapies.

Language: Английский

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Neurofilament accumulations in amyotrophic lateral sclerosis patients’ motor neurons impair axonal initial segment integrity

Cellular and Molecular Life Sciences, Journal Year: 2023, Volume and Issue: 80(6)

Published: May 15, 2023

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease in adults with no curative treatment. Neurofilament (NF) level patient' fluids have recently emerged as prime biomarker of ALS progression, while NF accumulation MNs patients oldest and one best pathological hallmarks. However, way accumulations could lead to MN degeneration remains unknown. To assess study impact on MNs, we compared derived from induced pluripotent stem cells (iPSC) carrying mutations C9orf72, SOD1 TARDBP genes, three main genetic causes. We show that all mutant light (NF-L) chains rapidly accumulate soma, phosphorylated heavy/medium (pNF-M/H) pile up axonal proximal regions only C9orf72 MNs. Excitability abnormalities were also observed these latter demonstrate integrity initial segment (AIS), region action potential initiation responsible for maintaining integrity, impaired presence pNF-M/H establish a strong correlation between accumulations, an AIS distal shift, increased calibers modified repartition sodium channels. The results expand our understanding how dysregulate components cytoskeleton disrupt homeostasis. With recent cumulative evidence alterations are implicated different brain diseases, preserving important therapeutic implications ALS.

Language: Английский

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Brain-Biomarker Changes in Body Fluids of Patients with Parkinson’s Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(13), P. 10932 - 10932

Published: June 30, 2023

Parkinson's disease (PD) is an incurable neurodegenerative that rarely diagnosed at early stage. Although the understanding of PD-related mechanisms has greatly improved over last decade, diagnosis PD still based on neurological examination through identification motor symptoms, including bradykinesia, rigidity, postural instability, and resting tremor. The phase characterized by subtle symptoms with a misdiagnosis rate approximately 16-20%. difficulty in recognizing implications for potential use novel therapeutic approaches. For this reason, it important to discover brain biomarkers can indicate dopaminergic dysfunction their changes body fluids, such as saliva, urine, blood, or cerebrospinal fluid (CSF). CFS-based test, invasiveness sampling major limitation, whereas other fluids are easier obtain could also allow population screening. Following crucial role alpha-synuclein (α-syn) pathology PD, very large number studies have summarized its fluids. However, methodological problems led poor diagnostic/prognostic value protein alternative currently being investigated. aim paper therefore summarize alternatives α-syn, particularly those change nigrostriatal areas biofluids, focus and, eventually, saliva urine.

Language: Английский

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Bisphenol S impairs mitochondrial function by targeting Myo19/oxidative phosphorylation pathway contributing to axonal and dendritic injury

Environment International, Journal Year: 2024, Volume and Issue: 186, P. 108643 - 108643

Published: April 1, 2024

Exposure to bisphenol S (BPS) is known adversely affect neuronal development. As pivotal components of polarization, axons and dendrites are indispensable structures within neurons, crucial for the maintenance nervous system function. Here, we investigated impact BPS exposure on axonal dendritic development both in vivo vitro. Our results revealed that during pregnancy lactation led a reduction complexity, density, length prefrontal cortex (PFC) offspring. Employing RNA sequencing technology elucidate underlying mechanisms damage induced by BPS, Kyoto Encyclopedia Genes Genomes (KEGG) analysis highlighted significant alteration oxidative phosphorylation (OXPHOS) pathway, essential mitochondrial Subsequent experiments demonstrate BPS-induced impairment function, including damaged morphology, decreased adenosine triphosphate (ATP) superoxide dismutase (SOD) levels, increased reactive oxygen species malondialdehyde (MDA). These alterations coincided with downregulated expression OXPHOS pathway-related genes (ATP6V1B1, ATP5K, NDUFC1, NDUFC2, NDUFA3, COX6B1) Myosin 19 (Myo19). Notably, Myo19 overexpression restored dysfunction alleviating inhibition pathway. Consequently, this amelioration was associated injury observed cultured neurons PFC.

Language: Английский

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Neurofilaments in health and Charcot-Marie-Tooth disease

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: Dec. 18, 2023

Neurofilaments (NFs) are the most abundant component of mature neurons, that interconnect with actin and microtubules to form cytoskeleton. Specifically expressed in nervous system, NFs present particularity within Intermediate Filament family being formed by four subunits, neurofilament light (NF-L), medium (NF-M), heavy (NF-H) proteins α-internexin or peripherin. Here, we review current knowledge on NF neurofilaments, from their domain structures model assembly dynamics transport degradation along axon. The formation filament its behaviour regulated various determinants, including post-transcriptional (miRNA RBP proteins) post-translational (phosphorylation ubiquitination) modifiers. Altogether, complex set modifications enable neuron establish a stable but elastic array constituting structural scaffold axon, while permitting local expression providing necessary fulfil demands respond stimuli injury. Thus, addition roles mechano-resistance, radial axonal outgrowth nerve conduction, control microtubule dynamics, organelle distribution neurotransmission at synapse. We discuss how studies neurodegenerative diseases aggregation shed biology NFs. In particular, NEFL NEFH genes mutated Charcot-Marie-Tooth (CMT) disease, common inherited neurological disorder peripheral system. clinical features CMT forms (axonal CMT2E, CMT2CC; demyelinating CMT1F; intermediate I-CMT) symptoms affecting central system (CNS) will allow us further investigate physiological brain. NF-CMT mouse models exhibit degrees sensory-motor deficits associated CNS symptoms. Cellular systems brought findings regarding dominant effect NF-L mutants transport, although these have been recently challenged. Neurofilament detection without recessive is puzzling, calling for re-examination which indispensable assembly. Overall, fundamental translational fields feeding each-other increase also challenge our biology, develop therapeutic avenues aggregation.

Language: Английский

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