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. Author manuscript; available in PMC: 2023 Feb 1.
Published in final edited form as: Mov Disord. 2022 Feb;37(2):436–437. doi: 10.1002/mds.28920

Reply to: “Age-adjusted serum neurofilament predicts cognitive decline in Parkinson’s disease (MARK-PD)”

Whitley W Aamodt 1, Alice S Chen-Plotkin 1
PMCID: PMC8979549  NIHMSID: NIHMS1767149  PMID: 35150470

We thank Dr. Buhmann and colleagues for evaluating the predictive value of serum neurofilament light chain protein (NfL) in their letter “Age-adjusted serum neurofilament predicts cognitive decline in Parkinson’s disease (MARK-PD)” (1).

In the MARK-PD cohort, serum NfL predicted cognitive decline based on a decrease of >2 points on the Montreal Cognitive Assessment (MoCA) (2). Authors also evaluated whether our optimal plasma NfL cut-point of 14.6 pg/mL (3) predicted cognitive decline in their cohort, hypothesizing that age-adjusted NfL percentiles, rather than an absolute NfL cut-point, may yield more consistent results. Indeed, Dr. Buhmann and colleagues found no association between serum NfL level and faster cognitive decline using our cut-point of 14.6 pg/mL. However, patients with NfL levels above an age-adjusted 95th percentile showed significantly faster cognitive decline after adjusting for age, sex, disease duration, and initial MoCA score.

There are notable differences in our study cohorts that make it difficult to compare findings directly. In their study, 21 patients with Parkinson’s disease (PD) showed evidence of cognitive decline defined by a decrease of >2 points on the MoCA over 1.40 [1.00-1.86] years of follow-up. In contrast, our NfL cut-point was based on 94 PD patients with normal cognition who were followed for 4.60 [0.9-10.8] years and underwent annual/biannual neuropsychological testing and expert clinical consensus (4) to determine clinical conversion to mild cognitive impairment or dementia. Thus, because NfL cut-points may differ based on choice of cognitive outcome measure or cognitive “event,” it is uncertain how to compare findings. We note, moreover, that Buhmann et al. quote a median value of 18 pmol/mL for serum NfL in their study (2). As NfL has a molecular weight of 70 kD, 18 pmol is equivalent to 1260 ng, which would mean that their median serum NfL value is 1,260,000 pg/mL, extremely high compared to values reported by many groups, including our own (3,5,6).

Despite differences, findings from both studies support the value of plasma/serum NfL in PD and underscore the importance of establishing absolute quantitation measures and more reliable cut-points for use across cohort studies. Given age-related increases in NfL over time in both PD patients and healthy controls (6,7), we agree that age-adjusted NfL percentiles may provide more consistent results in predictive models. Further studies are needed to explore the utility of age-adjusted NfL cut-points in predicting cognitive decline in PD.

Acknowledgements

We thank our patients and their families for their generosity in contributing to this research.

Funding Sources:

This research was supported by the NIH (RO1 NS115139, U19 AG062418, P50 NS053488, P30 AG010124, K23 NS11416, T32 NS061779), and a Biomarkers Across Neurodegenerative Diseases (BAND) grant from the Michael J. Fox Foundation/Alzheimer’s Association/Weston Institute. Alice Chen-Plotkin is additionally supported by the Parker Family Chair.

Footnotes

Relevant Financial Disclosures and Conflicts of Interest:

Authors report no disclosures or conflicts of interest relevant to this work.

References:

  • 1.Buhmann C, Lezius S, Potter-Nerger M, et al. Age-adjusted serum neurofilament predicts cognitive decline in Parkinson’s disease (MARK-PD). Mov Disord. 2021. [DOI] [PubMed] [Google Scholar]
  • 2.Niemann L, Lezius S, Maceski A, et al. Serum neurofilament is associated with motor function, cognitive decline and subclinical cardiac damage in advanced Parkinson’s disease (MARK-PD). Parkinsonism Relat Disord. 2021. Sep;90:44–48. [DOI] [PubMed] [Google Scholar]
  • 3.Aamodt WW, Waligorska T, Shen J, et al. Neurofilament Light Chain as a Biomarker for Cognitive Decline in Parkinson Disease. Mov Disord. 2021. Sep 4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Pigott K, Rick J, Xie SX, et al. Longitudinal study of normal cognition in Parkinson disease. Neurology. 2015;85(15):1276–1282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.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. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Mollenhauer B, Dakna M, Kruse N, et al. Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson’s Disease Progression. Mov Disord. 2020. Nov;35(11):1999–2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Khalil M, Pirpamer L, Hofer E, et al. Serum neurofilament light levels in normal aging and their association with morphologic brain changes. Nat Commun. 2020. Feb 10;11(1):812. [DOI] [PMC free article] [PubMed] [Google Scholar]

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