Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study

Lu, Ching‐Hua; Petzold, Axel; Topping, Jo; Allen, Kezia; Macdonald‐Wallis, Corrie; Clarke, Jan; Pearce, Neil; Kuhle, Jens; Giovannoni, Gavin; Fratta, Pietro; Sidle, Katie; Fish, Mark; Orrell, Richard W.; Howard, RS; Greensmith, Linda; Malaspina, Andrea

doi:10.1136/jnnp-2014-307672

Cited by 96 publications

(128 citation statements)

References 35 publications

Supporting

Mentioning

107

Contrasting

Order By: Relevance

“…Phosphorylated neurofilament heavy chain appears elevated at stable levels throughout the disease [19][20][21][22][23][24][25][26]. Neurofilament light chain in cerebrospinal fluid (CSF) appears to increase as ALS progresses [19,[27][28][29][30][31].…”

Section: Toward Novel Outcome Measures and Biomarkers In Als Trialsmentioning

confidence: 99%

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

2015

View full text Add to dashboard Cite

The last 2 decades have seen a surge in the number of amyotrophic lateral sclerosis (ALS) clinical trials with the hope of finding successful treatments. Clinical trialists aim to repurpose existing drugs and test novel compounds to target potential ALS disease pathophysiology. Recent technological advancements have led to the discovery of new causative genetic agents and modes of delivering potential therapy, calling for increasingly sophisticated trial design. The standard ALS clinical trial design may be modified depending on study needs: type of therapy; route of therapy delivery; phase of therapy development; applicable subpopulation; market availability of therapy; and utility of telemedicine. Novel biomarkers of diagnostic, predictive, prognostic, and pharmacodynamic value are undergoing development and validation for use in clinical trials. Design modifications build on the traditional clinical trial design and may be employed in either the learning or confirming trial phase. Novel designs aim to minimize patient risk, study duration, and sample size, while improving efficiency and promoting statistical power to herald an exciting era for clinical research in ALS.

show abstract

Section: Toward Novel Outcome Measures and Biomarkers In Als Trialsmentioning

confidence: 99%

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

2015

View full text Add to dashboard Cite

show abstract

“…Some examples of these approaches, albeit from targeted analyses, have been performed [38,105,169], and have been discussed throughout this review. These studies require large sample sizes consisting of patients with ALS, neurologic disease controls, and healthy controls, in order to assess how particular biomarkers change over time.…”

Section: Current Status and Future Directionsmentioning

confidence: 99%

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Bowser

2017

Neurotherapeutics

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease with no effective treatment. Drug development has been hampered by the lack of biomarkers that aid in early diagnosis, demonstrate target engagement, monitor disease progression, and can serve as surrogate endpoints to assess the efficacy of treatments. Fluid-based biomarkers may potentially address these issues. An ideal biomarker should exhibit high specificity and sensitivity for distinguishing ALS from control (appropriate disease mimics and other neurologic diseases) populations and monitor disease progression within individual patients. Significant progress has been made using cerebrospinal fluid, serum, and plasma in the search for ALS biomarkers, with urine and saliva biomarkers still in earlier stages of development. A few of these biomarker candidates have demonstrated use in patient stratification, predicting disease course (fast vs slow progression) and severity, or have been used in preclinical and clinical applications. However, while ALS biomarker discovery has seen tremendous advancements in the last decade, validating biomarkers and moving them towards the clinic remains more elusive. In this review, we highlight biomarkers that are moving towards clinical utility and the challenges that remain in order to implement biomarkers at all stages of the ALS drug development process.

show abstract

“…High levels of pNfH in CSF have been described as a biomarker for sALS [22,23]. Plasma NfH levels and disease progression show a close correlation [36].…”

Section: Morphological Studies Of Wobbler Mouse Dorsal Root Ganglia Smentioning

confidence: 99%

Morphological Studies of Wobbler Mouse Dorsal Root Ganglia Show Neurofilamental Disorders

Ott¹,

Dahlke²,

Saberi³

et al. 2017

J Neurol Exp Neurosci

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with three described forms: The abundant, sporadic ALS (sALS) with approximately 90% of cases, the familial ALS (fALS) with 5-10%, and the very rare juvenile ALS (jALS) group, which is statistically less relevant. The wobbler mouse, a model for sALS, has been in the focus of research for many decades. Due to symptoms strongly resembling the human ALS pathology, the α-motor neurons (αMN) have received the most attention. With regard to pathological cellular processes, particularly those of impaired axonal transport, neuronal tissues in general should be examined. Dorsal root ganglia (DRG) cells are equipped with extremely long axons. Thus, we expected them to be an excellent target for analyzing the cellular mechanisms underlying the disease. In this study, an analysis of the distribution of heavy neurofilaments (NfH) in the perikarya and peripheral nerves of dorsal root ganglia cells from wobbler mice was performed. Here, we demonstrate that sensory neurons are also affected in wobbler mice during the progression of the disease, showing signs of degeneration like those described in the αMN. Furthermore, a highly impaired distribution of neurofilaments and a high number of phosphorylated heavy neurofilaments (pNfH) were observed, not only in large light neurons (LLN), but also in the small dark neurons (SDN) of wobbler mouse DRGs. The accumulation of pNfH in DRG as well as the loss of NfH in their axons are promising links to studies promoting high levels of pNfH in the cerebrospinal fluid (CSF) as an early hallmark of ALS in humans. KeywordsDorsal root ganglia, Amyotrophic lateral sclerosis, Wobbler, Neurofilaments, Neurodegeneration IntroductionNeurological diseases, and in particular motor neuron diseases (MND), have a great impact on a patient's quality of life. ALS is a common MND with an incidence of 1-3 cases per 100.000 per year and a prevalence of 3-8 per 100.000, with men being more often affected than women. The average survival is 3 years after the onset of ALS symptoms, typically between the ages of 55 to 60 [1]. Many pathological mechanisms have already been well investigated in animal models with ALS-like phenotypes, however comparison to the human ALS pathology is difficult. A treatment substantially modifying the diseases progression is still lacking. The well-known degeneration of the upper and lower motor neurons are common in the murine models as well as in humans. This

show abstract

Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study

Cited by 96 publications

References 35 publications

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis

Morphological Studies of Wobbler Mouse Dorsal Root Ganglia Show Neurofilamental Disorders

Contact Info

Product

Resources

About