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Mattsson N, Cullen NC, Andreasson U, Zetterberg H, Blennow K. Association Between Longitudinal Plasma Neurofilament Light and Neurodegeneration in Patients With Alzheimer Disease. JAMA Neurol. 2019 Jul 1;76(7):791-799. PubMed.
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Washington University in St. Louis
Before we can say what utility NfL may have, we need to understand how levels of NfL discriminate between diseases states in a cross-sectional, one-off manner, as well as how it behaves over time. Understanding such a longitudinal change is critical for any biomarker that could be considered for a clinical trial.
The strengths of the current study are the large population, which is impressive, and the sheer amount of longitudinal data. In this large sample, the authors clearly demonstrate that, at the group level, rates of change in NfL increase with greater cognitive impairment as well as with worse biological profiles of Aβ, tau, and neurodegeneration. This result is consistent with what we have seen in autosomal-dominant AD. This study is about LOAD, but is always important to see results that are in agreement between LOAD and ADAD.
As to the clinical utility of NfL at an individual level, I think the jury is still out on that one. Although the current paper finds significant differences, there is a large degree of overlap in NfL rates of change between groups. Also, the vast majority of individuals in the study are showing positive annual rate of change in NfL values. This suggests that there could be a background amount of change in NfL associated with aging, making it problematic to pick up disease-related effects.
Still, the fact that NfL can be detected in blood makes it an excellent candidate biomarker. Such a low-cost measure, even with its limitations, could be a boon to noninvasively studying injury in the brain across neurodegenerative diseases.
View all comments by Brian GordonUCL
This is an important and timely study, which examines longitudinal plasma NfL data on large numbers of individuals at different stages of sporadic AD.
The findings appear consistent with what we and others have found previously in autosomal-dominant AD, with the concentration of NfL in blood beginning to rise early in the disease, and continuing to rise progressively thereafter, with plasma NfL appearing to reflect both disease severity and intensity. As the authors discuss, the potential availability of such a measure from a simple blood test, as opposed to requiring either CSF sampling or expensive imaging techniques, would be extremely valuble.
However, although statistically significantly different, longitudinal rates of change values show a lot of overlap between groups, particularly when comparing the MCI group to the cognitively unimpaired group, with very similar average group values (2.7 ng/L per year versus 2.4 ng/L per year). Also, it will also be interesting to examine individual trajectories over time, and how much longitudinal fluctuation/variation exists within individuals.
Therefore at the current time, while showing promise as a potential measure in trials to compare different groups over time, it remains unclear exactly how useful longitudinal measurement of plasma NfL may be when applied to individual patients to inform individual patient treatment decisions. Further studies will hopefully help to answer this question.
The study also reinforces what we already knew in terms of NfL measurement not being specific to AD, as it was strongly associated with amyloid-negative neurodegeneration also. Therefore I think, rather than being used diagnostically, its main utility in AD is likely to be in monitoring and assessment to identify those individuals most at risk of clinical decline in the near future, and in tracking subsequent neurodegenerative change.
View all comments by Philip WestonMayo Clinic
This paper is an important contribution to the field. Although previous studies examined plasma NfL and Alzheimer’s disease, there is a dearth of studies with serial measures of plasma NfL. Therefore, it was not known whether plasma NfL serially tracked with ongoing neurodegeneration over the clinical AD spectrum. The results of the current study highlight the potential utility of plasma NfL as a biomarker of neurodegeneration and disease progression. Such a biomarker, especially one that is blood-based, is particularly attractive as an endpoint for clinical trials and to determine rate of disease progression in the general population.
Although the results of this study are quite promising, a lot of research is still needed before plasma NfL is ready for the clinic in the context of AD. ADNI participants are very well characterized and have imaging and/or CSF. However, they are more similar to a clinical trials population than the general population.
For example, many participants with vascular disease were excluded from ADNI. This is important because NfL (plasma and CSF) has been shown to also be elevated in vascular dementia and stroke patients. It will be important to replicate the current study in a more general population that considers vascular pathology and vascular risk factors. It also is not well understood what other factors might affect plasma NfL levels, especially because it is thought to be a nonspecific neurodegeneration marker. This research will also be needed before plasma NfL can be used clinically.
View all comments by Michelle MielkeMake a Comment
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