Neurofilament light protein in CSF and blood is associated with neurodegeneration and disease severity in Huntington’s disease R6/2 mice

Soylu-Kucharz, Rana; Sandelius, Åsa; Sjögren, Marie; Blennow, Kaj; Wild, Edward J.; Zetterberg, Henrik; Björkqvist, Maria

doi:10.1038/s41598-017-14179-1

Cited by 49 publications

(37 citation statements)

References 28 publications

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“…Experiments were carried out on 12, 16 and 18 weeks old male transgenic R6/2 HD mice (expressing exon 1 of the HD gene) 16 and their wild type (WT) littermates. 12 weeks correspond to early stage disease and 16/18 weeks to an early/mid stage disease in our colony of mice 17 . Mice were obtained through crossing heterozygous R6/2 males with WT females (F1 of CBAxC57BL/6J).…”

Section: Methodsmentioning

confidence: 75%

Increased intestinal permeability and gut dysbiosis in the R6/2 mouse model of Huntington’s disease

Stan

Soylu-Kucharz

Burleigh

et al. 2020

Sci Rep

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Huntington’s disease (HD) is a progressive, multifaceted neurodegenerative disease associated with weight loss and gut problems. Under healthy conditions, tight junction (TJ) proteins maintain the intestinal barrier integrity preventing bacterial translocation from the intestinal lumen to the systemic circulation. Reduction of TJs expression in Parkinson’s disease patients has been linked with increased intestinal permeability—leaky gut syndrome. The intestine contains microbiota, most dominant phyla being Bacteroidetes and Firmicutes; in pathogenic or disease conditions the balance between these bacteria might be disrupted. The present study investigated whether there is evidence for an increased intestinal permeability and dysbiosis in the R6/2 mouse model of HD. Our data demonstrate that decreased body weight and body length in R6/2 mice is accompanied by a significant decrease in colon length and increased gut permeability compared to wild type littermates, without any significant changes in the protein levels of the tight junction proteins (occludin, zonula occludens). Moreover, we found an altered gut microbiota in R6/2 mice with increased relative abundance of Bacteroidetes and decreased of Firmicutes. Our results indicate an increased intestinal permeability and dysbiosis in R6/2 mice and further studies investigating the clinical relevance of these findings are warranted.

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Section: Methodsmentioning

confidence: 75%

Increased intestinal permeability and gut dysbiosis in the R6/2 mouse model of Huntington’s disease

Stan

Soylu-Kucharz

Burleigh

et al. 2020

Sci Rep

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“…Thirdly, the small number of enrolled ALS patients may not be representative of the general population. In addition, NF-L is not a specific marker of ALS and has been shown to increase in a number of other conditions, including Alzheimer disease [24], progressive supranuclear palsy, frontotemporal dementia, and Huntington’s disease [25]; it would therefore have been very informative to have included non-ALS neurodegenerative diseases in this study.…”

Section: Discussionmentioning

confidence: 99%

Neurofilament Subunit L Levels in the Cerebrospinal Fluid and Serum of Patients with Amyotrophic Lateral Sclerosis

Gong

Gao

et al. 2018

Neurodegener Dis

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Background: There are no reliable biomarkers that could evaluate the disease burden in amyotrophic lateral sclerosis (ALS). Objectives: The aim of our study is to evaluate the changes in cerebrospinal fluid (CSF) and serum neurofilament subunit L (NF-L) in patients with ALS and to analyze the correlations between the levels of NF-L and clinical parameters. Method: CSF and serum samples were obtained from 80 ALS patients and 40 controls. The levels of NF-L in CSF and serum were assessed, and disease progression parameters including duration, revised ALS Functional Rating Scale (ALSFRS-r) score, disease progression rate (DPR), upper motor neuron (UMN) score, and survival were analyzed by registered neurologists. All samples were measured using a commercial enzyme-linked immunosorbent assay. Statistical analyses were performed using Prism software. Results: Compared to the controls, the ALS patients displayed significantly increased levels of NF-L; these values were negatively correlated with the ALSFRS-r score and positively correlated with the decrease in ALSFRS-r score, DPR, and UMN score. There was no correlation between levels of NF-L and duration. In addition, the cumulative survival rate in ALS patients with a low level of NF-L was higher than in patients with a high level of NF-L. Conclusions: NF-L levels increased in CSF and serum of patients with ALS. NF-L may thus be a neurodegenerative biomarker for predicting ALS severity and progression, and the survival of patients with this disease.

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“…There was a strong correlation between plasma and CSF NfL concentration, implying CNS origin of NfL detected in plasma (22). Subsequently we showed NfL in plasma predicts regional atrophy in disease-associated brain areas (23) and that NfL in CSF and blood is a potential translational biomarker in at least one mouse model of HD (24). However, our understanding of the potential value of NfL as a biomarker is limited by the lack of a large, wellphenotyped cohort in which to study it in both plasma and CSF.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington’s disease

et al. 2018

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Huntington's disease (HD) is a genetic progressive neurodegenerative disorder, caused by a mutation in the gene, for which there is currently no cure. The identification of sensitive indicators of disease progression and therapeutic outcome could help the development of effective strategies for treating HD. We assessed mutant huntingtin (mHTT) and neurofilament light (NfL) protein concentrations in cerebrospinal fluid (CSF) and blood in parallel with clinical evaluation and magnetic resonance imaging in premanifest and manifest HD mutation carriers. Among HD mutation carriers, NfL concentrations in plasma and CSF correlated with all nonbiofluid measures more closely than did CSF mHTT concentration. Longitudinal analysis over 4 to 8 weeks showed that CSF mHTT, CSF NfL, and plasma NfL concentrations were highly stable within individuals. In our cohort, concentration of CSF mHTT accurately distinguished between controls and HD mutation carriers, whereas NfL concentration, in both CSF and plasma, was able to segregate premanifest from manifest HD. In silico modeling indicated that mHTT and NfL concentrations in biofluids might be among the earliest detectable alterations in HD, and sample size prediction suggested that low participant numbers would be needed to incorporate these measures into clinical trials. These findings provide evidence that biofluid concentrations of mHTT and NfL have potential for early and sensitive detection of alterations in HD and could be integrated into both clinical trials and the clinic.

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Neurofilament light protein in CSF and blood is associated with neurodegeneration and disease severity in Huntington’s disease R6/2 mice

Cited by 49 publications

References 28 publications

Increased intestinal permeability and gut dysbiosis in the R6/2 mouse model of Huntington’s disease

Increased intestinal permeability and gut dysbiosis in the R6/2 mouse model of Huntington’s disease

Neurofilament Subunit L Levels in the Cerebrospinal Fluid and Serum of Patients with Amyotrophic Lateral Sclerosis

Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington’s disease

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