Immunohistochemical labeling of ongoing axonal degeneration 10 days following cervical contusion spinal cord injury in the rat DOI Creative Commons
Anna Fusco, Sabhya Rana,

Marda L. Jorgenson

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 11, 2024

Abstract Study Design: Experimental Animal Objective To continue validating an antibody which targets epitope of neurofilament light chain (NF-L) only available during neurodegeneration and to utilize the describe pattern axonal degeneration 10 days post-unilateral C4 contusion in rat. Setting: University Florida Methods Sprague Dawley rats received either a unilateral 150kdyn (n = 6; n 3 females, males) or laminectomy control surgery 5; males, 2 females). Ten following SCI laminectomy, spinal cords brainstems were processed for immunohistochemistry. Serial cord brainstem cross-sections stained with degeneration-specific NF-L (MCA-6H63) dual labeled against C-terminus portion (NF-L-Ct), label healthy axons, amyloid precursor protein (APP), considered current “gold standard” identifying degenerating axons. The ongoing was assessed. Results Spinal from injured had punctate MCA-6H63 positive fibers pathological appearance, loss anti-NF-L-Ct co-labeling, frequent colocalization APP. Immunopositive abundant rostral caudal lesion white matter tracts that would be disrupted by contusion. This staining not observed tissue. Conclusions labels axons offers promising tool quantify degeneration.

Language: Английский

Neurofilaments as biomarkers in neurological disorders — towards clinical application DOI
Michael Khalil, Charlotte E. Teunissen, Sylvain Lehmann

et al.

Nature Reviews Neurology, Journal Year: 2024, Volume and Issue: 20(5), P. 269 - 287

Published: April 12, 2024

Language: Английский

Citations

111
Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis DOI
Ahmed Abdelhak, Pascal Benkert,

Sabine Schaedelin

et al.

JAMA Neurology, Journal Year: 2023, Volume and Issue: 80(12), P. 1317 - 1317

Published: Nov. 6, 2023

Importance Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity people MS (MS); however, data on the association between NfL level and have been conflicting. Objective To determine whether when levels elevated context confirmed worsening (CDW). Design, Setting, Participants This study included 2 observational cohorts: results from Expression, Proteomics, Imaging, Clinical (EPIC) at University California San Francisco (since 2004) were Swiss Multiple Sclerosis Cohort (SMSC), multicenter 8 centers since 2012. Data extracted EPIC April 2022 (sampling July 1, 2004, December 20, 2016) SMSC June 6, 2012, September 2, 2021). The cohorts tertiary centers. All participants both available study, no eligible excluded or declined participate. Exposure Association z scores CDW. Main Outcome Measures CDW was defined as Expanded Disability Status Scale (EDSS) that after 6 more months classified into associated clinical relapses (CDW-R) independent (CDW-NR). Visits relation events CDW(−2) for visits preceding event, CDW(−1) directly CDW(event) first diagnosis EDSS increase, confirmation visit. Mixed linear Cox regression models used evaluate dynamics assess future CDW, respectively. Results A total 3906 (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) 8901 (1290 41.2 [32.5-49.9] 850 [65.9%]) included. In CDW-R (EPIC, 36 events; SMSC, 93 events), 0.71 (95% CI, 0.35-1.07; P < .001) units higher CDW-R(−1) 0.32 0.14-0.49; compared stable samples. elevation could be detected CDW-NR 191 342 events) CDW-NR(−2) (EPIC: 0.23; 95% 0.01-0.45; = .04; SMSC: 0.28; 0.18-0.37; CDW-NR(−1) 0.27; 0.11-0.44; .001; 0.09; 0-0.18; .06). Those findings replicated subgroup relapsing-remitting MS. Time-to-event analysis within approximately 1 year (in 1-2 years). Conclusions Relevance cohort documents occurrence advance may hint potential window ongoing dynamic central nervous system pathology precedes

Language: Английский

Citations

42
Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy DOI Creative Commons
Jean Paul Chadarevian, Jonathan Hasselmann, Alina Lahian

et al.

Neuron, Journal Year: 2024, Volume and Issue: 112(16), P. 2686 - 2707.e8

Published: June 18, 2024

Microglia replacement strategies are increasingly being considered for the treatment of primary microgliopathies like adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). However, available mouse models fail to recapitulate diverse neuropathologies reduced microglia numbers observed in patients. In this study, we generated a xenotolerant model lacking fms-intronic regulatory element (FIRE) enhancer within Csf1r, which develops nearly all hallmark pathologies associated ALSP. Remarkably, transplantation human induced pluripotent stem cell (iPSC)-derived microglial (iMG) progenitors restores homeostatic signature prevents development spheroids, white matter abnormalities, reactive astrocytosis, brain calcifications. Furthermore, CRISPR-corrected ALSP-patient-derived iMG reverses pre-existing astrogliosis, calcification pathologies. Together accompanying study by Munro colleagues, our results demonstrate utility FIRE mice ALSP provide compelling evidence that could offer promising new therapeutic strategy perhaps other microglia-associated neurological disorders.

Language: Английский

Citations

23
Oligodendroglial fatty acid metabolism as a central nervous system energy reserve DOI Creative Commons
Ebrahim Asadollahi, Andrea Trevisiol, Aiman S. Saab

et al.

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(10), P. 1934 - 1944

Published: Sept. 9, 2024

Language: Английский

Citations

19
Oligodendrocytes and myelin limit neuronal plasticity in visual cortex DOI Creative Commons
Wendy Xin, Megumi Kaneko, Richard H. Roth

et al.

Nature, Journal Year: 2024, Volume and Issue: 633(8031), P. 856 - 863

Published: Aug. 21, 2024

Abstract Developmental myelination is a protracted process in the mammalian brain 1 . One theory for why oligodendrocytes mature so slowly posits that may stabilize neuronal circuits and temper plasticity as animals age 2–4 We tested this visual cortex, which has well-defined critical period experience-dependent 5 During adolescence, experience modulated rate of oligodendrocyte maturation cortex. To determine whether turn regulates plasticity, we genetically blocked differentiation adolescent mice. In adult mice lacking oligodendrogenesis, brief monocular deprivation led to significant decrease cortex responses deprived eye, reminiscent normally restricted adolescence. This enhanced functional was accompanied by greater turnover dendritic spines coordinated reductions spine size following deprivation. Furthermore, inhibitory synaptic transmission, gates at circuit level, diminished absence oligodendrogenesis. These results establish role shaping stabilization cortical support concept developmental acting brake on plasticity.

Language: Английский

Citations

13
CSF neurofilament light chain profiling and quantitation in neurological diseases DOI Creative Commons
Claire A. Leckey, John B. Coulton, Tatiana A. Giovannucci

et al.

Brain Communications, Journal Year: 2024, Volume and Issue: 6(3)

Published: Jan. 1, 2024

Abstract Neurofilament light chain is an established marker of neuroaxonal injury that elevated in CSF and blood across various neurological diseases. It increasingly used clinical practice to aid diagnosis monitor progression as outcome measure assess safety efficacy disease-modifying therapies the translational neuroscience field. Quantitative methods for neurofilament human biofluids have relied on immunoassays, which limited capacity describe structure protein how this might vary different neurodegenerative In study, we characterized quantified species neuroinflammatory diseases healthy controls using targeted mass spectrometry. We show quantitative immunoprecipitation–tandem spectrometry method developed study strongly correlates single-molecule array measurements broad spectrum was replicable centres. summary, created accurate cost-effective assay measuring a key biomarker research practice, can be easily multiplexed translated into laboratories screening monitoring disease or acute brain injury.

Language: Английский

Citations

8
Head-to-head comparison of four plasma neurofilament light chain (NfL) immunoassays DOI
Susan Ashrafzadeh‐Kian, Daniel Figdore,

Bethany J. Larson

et al.

Clinica Chimica Acta, Journal Year: 2024, Volume and Issue: 561, P. 119817 - 119817

Published: June 14, 2024

Language: Английский

Citations

5
Emerging Trends: Neurofilament Biomarkers in Precision Neurology DOI
Priti Sharma, Aditi Giri, Prabhash Nath Tripathi

et al.

Neurochemical Research, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 30, 2024

Language: Английский

Citations

5
Immunohistochemical labeling of ongoing axonal degeneration 10 days following cervical contusion spinal cord injury in the rat DOI
Anna Fusco, Sabhya Rana, Marda Jorgensen

et al.

Spinal Cord, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 3, 2025

Language: Английский

Citations

0
Neurofilament Light Chain under the Lens of Structural Mass Spectrometry DOI Creative Commons
Salomé Coppens, Dea Gogishvili,

Valentina Faustinelli

et al.

ACS Chemical Neuroscience, Journal Year: 2025, Volume and Issue: 16(2), P. 141 - 151

Published: Jan. 2, 2025

Neurofilament light chain (NfL) is an early nonspecific biomarker in neurodegenerative diseases and traumatic brain injury, indicating axonal damage. This work describes the detailed structural characterization of a selected primary calibrator with potential to be used future reference measurement procedure (RMP) development for accurate quantification NfL. As part described workflow, sequence, higher-order structure as well solvent accessibility, hydrogen-bonding profile were assessed under three different conditions KPBS, artificial cerebrospinal fluid, fluid presence human serum albumin. The results revealed that NfL structurally heterogeneous protein, eliciting large conformational flexibility. Its ensemble changed when it was diluted aqueous buffer versus surrogate matrix, (aCSF), and/or aCSF Various regions protection deprotection protein head, central helical, tail domains experienced altered accessibility changes caused by identified. Moreover, interfacial residues, which may play role direct interaction between albumin, emerged from hydrogen–deuterium exchange mass spectrometry (HDX-MS). These data pinpointed distinct participate such interaction. Overall, critical quality attributes measurements are provided. findings will ultimately inform ongoing biochemical clinical assay procedures manufacturing practices, giving careful consideration during sample handling method development.

Language: Английский

Citations

0