Evaluation of Neurofilament Light Chain as a Biomarker of Neurodegeneration in X-Linked Childhood Cerebral Adrenoleukodystrophy

Wang, Hongge; Davison, Matt; Kramer, Martin; Qiu, Weiliang; Gladysheva, Tatiana; Chiang, Ruby M. S.; Kayatekin, Can; Nascene, David; Taghizadeh, Leyla A.; King, Carina J; Nolan, Erin E.; Gupta, Ashish; Orchard, Paul J.; Lund, Troy C.

doi:10.3390/cells11050913

Cited by 7 publications

(6 citation statements)

References 32 publications

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“…Increased NfL is described to be correlated with the development of motor neurological disorders or retinopathy in premature infants (Goeral et al, 2021 ; Sjöbom et al, 2021 ). The value of NfL in CSF and blood also appears to be associated with the severity of inherited diseases with neurological impairment, such as SMA (Johannsen et al, 2021 ; Nitz et al, 2021 ), cerebral adrenoleukodystrophy (Wang et al, 2022 ) or mitochondrial diseases (Sofou et al, 2019 ). Finally, NfL could be relevant for monitoring treatment response (Ru et al, 2019 ).…”

Section: Nfl and Neurological Damagesmentioning

confidence: 99%

Neurofilaments contribution in clinic: state of the art

Delaby

Bousiges²,

Bouvier

et al. 2022

Front. Aging Neurosci.

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Neurological biomarkers are particularly valuable to clinicians as they can be used for diagnosis, prognosis, or response to treatment. This field of neurology has evolved considerably in recent years with the improvement of analytical methods, allowing the detection of biomarkers not only in cerebrospinal fluid (CSF) but also in less invasive fluids like blood. These advances greatly facilitate the repeated quantification of biomarkers, including at asymptomatic stages of the disease. Among the various informative biomarkers of neurological disorders, neurofilaments (NfL) have proven to be of particular interest in many contexts, such as neurodegenerative diseases, traumatic brain injury, multiple sclerosis, stroke, and cancer. Here we discuss these different pathologies and the potential value of NfL assay in the management of these patients, both for diagnosis and prognosis. We also describe the added value of NfL compared to other biomarkers currently used to monitor the diseases described in this review.

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Section: Nfl and Neurological Damagesmentioning

confidence: 99%

Neurofilaments contribution in clinic: state of the art

Delaby

Bousiges²,

Bouvier

et al. 2022

Front. Aging Neurosci.

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“…Since VLCFA levels are not correlated with neurodegenerative involvements and since brain MRI is not easy to manage, there is an urgent need for prognostic biomarkers to evaluate disease progression and improve the follow-up of patients ( Honey et al, 2021 ). Recent studies identified and evaluated neurofilament light chain as a potential biomarker for cALD ( Weinhofer et al, 2021 ; Wang et al, 2022 ). In this study, we identified 5 proteins of the DAM signature which are over secreted by the mutant cells that could virtually represent relevant biomarkers of disease progression.…”

Section: Discussionmentioning

confidence: 99%

Peroxisomal defects in microglial cells induce a disease-associated microglial signature

Raas

Tawbeh

Tahri-Joutey

et al. 2023

Front. Mol. Neurosci.

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Microglial cells ensure essential roles in brain homeostasis. In pathological condition, microglia adopt a common signature, called disease-associated microglial (DAM) signature, characterized by the loss of homeostatic genes and the induction of disease-associated genes. In X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disease, microglial defect has been shown to precede myelin degradation and may actively contribute to the neurodegenerative process. We previously established BV-2 microglial cell models bearing mutations in peroxisomal genes that recapitulate some of the hallmarks of the peroxisomal β-oxidation defects such as very long-chain fatty acid (VLCFA) accumulation. In these cell lines, we used RNA-sequencing and identified large-scale reprogramming for genes involved in lipid metabolism, immune response, cell signaling, lysosome and autophagy, as well as a DAM-like signature. We highlighted cholesterol accumulation in plasma membranes and observed autophagy patterns in the cell mutants. We confirmed the upregulation or downregulation at the protein level for a few selected genes that mostly corroborated our observations and clearly demonstrated increased expression and secretion of DAM proteins in the BV-2 mutant cells. In conclusion, the peroxisomal defects in microglial cells not only impact on VLCFA metabolism but also force microglial cells to adopt a pathological phenotype likely representing a key contributor to the pathogenesis of peroxisomal disorders.

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“…A significant correlation was shown between the plasma and CSF levels of NfL, and a very good association was also found between the plasma NfL level and the MRI Loes score. Moreover, 9 of the 11 patients with cALD who were assessed pre- and post-HSCT showed a decrease in plasma NfL levels at 1 year post-HSCT [ 134 ]. In the same line, the results from the ADVANCE clinical study on plasma biomarker data showed that NfL levels were significantly increased at week 96 in placebo patients with cerebral lesion progression, supportive of a drug effect on reducing axonal degeneration by leriglitazone [ 120 ].…”

Section: Using Leriglitazone For the Treatment Of Neurodegenerative D...mentioning

confidence: 99%

Development of PPARγ Agonists for the Treatment of Neuroinflammatory and Neurodegenerative Diseases: Leriglitazone as a Promising Candidate

Pizcueta

Vergara

Emanuele

et al. 2023

IJMS

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Increasing evidence suggests that the peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, plays an important role in physiological processes in the central nervous system (CNS) and is involved in cellular metabolism and repair. Cellular damage caused by acute brain injury and long-term neurodegenerative disorders is associated with alterations of these metabolic processes leading to mitochondrial dysfunction, oxidative stress, and neuroinflammation. PPARγ agonists have demonstrated the potential to be effective treatments for CNS diseases in preclinical models, but to date, most drugs have failed to show efficacy in clinical trials of neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease. The most likely explanation for this lack of efficacy is the insufficient brain exposure of these PPARγ agonists. Leriglitazone is a novel, blood–brain barrier (BBB)-penetrant PPARγ agonist that is being developed to treat CNS diseases. Here, we review the main roles of PPARγ in physiology and pathophysiology in the CNS, describe the mechanism of action of PPARγ agonists, and discuss the evidence supporting the use of leriglitazone to treat CNS diseases.

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Evaluation of Neurofilament Light Chain as a Biomarker of Neurodegeneration in X-Linked Childhood Cerebral Adrenoleukodystrophy

Cited by 7 publications

References 32 publications

Neurofilaments contribution in clinic: state of the art

Neurofilaments contribution in clinic: state of the art

Peroxisomal defects in microglial cells induce a disease-associated microglial signature

Development of PPARγ Agonists for the Treatment of Neuroinflammatory and Neurodegenerative Diseases: Leriglitazone as a Promising Candidate

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