Neurofilament Light Chain as Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Verde, Federico; Otto, Markus; Silani, Vincenzo

doi:10.3389/fnins.2021.679199

Cited by 93 publications

(81 citation statements)

References 102 publications

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“…We subsequently tried to perform a second search for studies relating to FTD; however, the number of studies found was too small to allow a meta-analysis to be performed. It should also be mentioned that the clinical, pathological, and genetic features of FTD exhibit marked heterogeneity [ 37 ]. Furthermore, the prevalence of FTD is lower than that of AD, which affects subject recruitment.…”

Section: Discussionmentioning

confidence: 99%

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Meta-analysis of cerebrospinal fluid neuron-specific enolase levels in Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy

et al. 2021

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Background This study examined the usefulness of cerebrospinal fluid (CSF) neuron-specific enolase (NSE) levels as a candidate biomarker of neurodegeneration in Alzheimer’s disease (AD), Parkinson’s disease (PD), PD with dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Methods We performed a systematic search of PubMed, the Cochrane Library, Scopus, and Google Scholar to find studies that measured CSF NSE levels in AD, PD, DLB, and/or MSA. For each disease, we pooled all available data and performed a meta-analysis, and meta-regression analyses of age and sex were conducted if the main analysis found a significant association. Results Twenty studies were included (13 for AD, 8 for PD/PDD/DLB, and 4 for MSA). Significantly elevated CSF NSE levels were detected in AD (Hedges’ g = 0.822, 95% confidence interval [95% CI] 0.332 to 1.311, p = 0.0010), but the data exhibited high heterogeneity (I2 = 88.43%, p < 0.001). The meta-regression analysis of AD showed that age (p < 0.001), but not sex, had a significant effect on CSF NSE levels. A meta-analysis of the pooled data for PD/PDD/DLB did not show any significant changes in the CSF NSE level, but a sub-group analysis of PDD/DLB revealed significantly elevated CSF NSE levels (Hedges’ g = 0.507, 95% CI 0.020 to 0.993, p = 0.0412). No significant changes in CSF NSE levels were detected in MSA. Conclusions The CSF NSE level may be a useful biomarker of neurodegeneration in AD and PDD/DLB. Age was found to affect the CSF NSE levels of AD patients.

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Section: Discussionmentioning

confidence: 99%

“…Furthermore, the prevalence of FTD is lower than that of AD, which affects subject recruitment. Further studies of FTD are needed, and identifying other markers of the disease, such as neurofilament light chain, would also be helpful [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis of cerebrospinal fluid neuron-specific enolase levels in Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy

et al. 2021

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“…Accumulations of neurofilaments are a pathological feature of several neurodegenerative diseases ( Didonna and Opal, 2019 ), including amyotrophic lateral sclerosis (ALS), Alzheimer’s, and Parkinson’s diseases. Moreover, NFL as a highly abundant protein in neurons shows promise as a serum biomarker for neuronal disruption in various neurological diseases, such as ALS ( Verde et al, 2021 ) and multiple sclerosis ( Ferreira-Atuesta et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Neurofilament Light Regulates Axon Caliber, Synaptic Activity, and Organelle Trafficking in Cultured Human Motor Neurons

Sainio

Rasila

Molchanova

et al. 2022

Front. Cell Dev. Biol.

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Neurofilament light (NFL) is one of the proteins forming multimeric neuron-specific intermediate filaments, neurofilaments, which fill the axonal cytoplasm, establish caliber growth, and provide structural support. Dominant missense mutations and recessive nonsense mutations in the neurofilament light gene (NEFL) are among the causes of Charcot–Marie–Tooth (CMT) neuropathy, which affects the peripheral nerves with the longest axons. We previously demonstrated that a neuropathy-causing homozygous nonsense mutation in NEFL led to the absence of NFL in patient-specific neurons. To understand the disease-causing mechanisms, we investigate here the functional effects of NFL loss in human motor neurons differentiated from induced pluripotent stem cells (iPSC). We used genome editing to generate NEFL knockouts and compared them to patient-specific nonsense mutants and isogenic controls. iPSC lacking NFL differentiated efficiently into motor neurons with normal axon growth and regrowth after mechanical axotomy and contained neurofilaments. Electrophysiological analysis revealed that motor neurons without NFL fired spontaneous and evoked action potentials with similar characteristics as controls. However, we found that, in the absence of NFL, human motor neurons 1) had reduced axonal caliber, 2) the amplitude of miniature excitatory postsynaptic currents (mEPSC) was decreased, 3) neurofilament heavy (NFH) levels were reduced and no compensatory increases in other filament subunits were observed, and 4) the movement of mitochondria and to a lesser extent lysosomes was increased. Our findings elaborate the functional roles of NFL in human motor neurons. NFL is not only a structural protein forming neurofilaments and filling the axonal cytoplasm, but our study supports the role of NFL in the regulation of synaptic transmission and organelle trafficking. To rescue the NFL deficiency in the patient-specific nonsense mutant motor neurons, we used three drugs, amlexanox, ataluren (PTC-124), and gentamicin to induce translational read-through or inhibit nonsense-mediated decay. However, the drugs failed to increase the amount of NFL protein to detectable levels and were toxic to iPSC-derived motor neurons.

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“…In addition to serving as therapeutic targets, these cryptic exon inclusion events can simultaneously be harnessed as biomarkers for diagnosis and prognosis and for evaluating the efficacy of experimental therapeutics 11 . In ALS, several candidate fluid biomarkers have been reported, such as vascular endothelial growth factor (VEGF), 37 neurofilament light chain protein (NfL) 38 and urinary p75 ECD 39 . However, because these likely reflect neurodegeneration in an unspecific way, rather than being specific to ALS or FTD, none of them is definitive 40,41 .…”

Section: Cryptic Exons As Novel Biomarker Candidatesmentioning

confidence: 99%

Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers

Akiyama

Koike

Petrucelli

et al. 2022

Clinical & Translational Med

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating human neurodegenerative diseases. A hallmark pathological feature of both diseases is the depletion of the RNA‐binding protein TDP‐43 from the nucleus in the brain and spinal cord of patients. A major function of TDP‐43 is to repress the inclusion of cryptic exons during RNA splicing. When it becomes depleted from the nucleus in disease, this function is lost, and recently, several key cryptic splicing targets of TDP‐43 have emerged, including STMN2 , UNC13A , and others. UNC13A is a major ALS/FTD risk gene, and the genetic variations that increase the risk for disease seem to do so by making the gene more susceptible to cryptic exon inclusion when TDP‐43 function is impaired. Here, we discuss the prospects and challenges of harnessing these cryptic splicing events as novel therapeutic targets and biomarkers. Deciphering this new cryptic code may be a touchstone for ALS and FTD diagnosis and treatment.

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Neurofilament Light Chain as Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Cited by 93 publications

References 102 publications

Meta-analysis of cerebrospinal fluid neuron-specific enolase levels in Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy

Meta-analysis of cerebrospinal fluid neuron-specific enolase levels in Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy

Neurofilament Light Regulates Axon Caliber, Synaptic Activity, and Organelle Trafficking in Cultured Human Motor Neurons

Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers

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