Serum Neurofilament light correlates with CADASIL disease severity and survival

Gido Gravesteijn, Julie W. Rutten, Inge M. W. Verberk, Stefan Böhringer, Michael K. Liem, Jeroen van der Grond, Annemieke Aartsma-Rus, Charlotte E. Teunissen, Saskia A. J. Lesnik Oberstein

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Objective: To validate whether serum Neurofilament Light-chain (NfL) levels correlate with disease severity in CADASIL, and to determine whether serum NfL predicts disease progression and survival. Methods: Fourty-one (pre-) manifest individuals with CADASIL causing NOTCH3 mutations and 22 healthy controls were recruited from CADASIL families. At baseline, MRI-lesion load and clinical severity was determined and serum was stored. Disease progression was measured in 30/41 patients at 7-year follow-up, and survival of all individuals was determined at 17-year follow-up. Serum NfL levels were quantified using an ultra-sensitive molecule array. Generalized estimated equation regression (GEE) was used to analyze association between serum NfL, MRI-lesion load, disease severity, and disease progression. With GEE-based Cox regression, survival was analyzed. Results: At baseline, serum NfL levels correlated with MRI-lesion load [lacune count (s = 0.64, P = 0.002), brain atrophy (r = −0.50, P = 0.001), and microbleed count (s = 0.48, P = 0.044)], cognition [CAMCOG (s = −0.45, P = 0.010), MMSE (r = −0.61, P = 0.003), GIT (r = −0.61, P < 0.001), TMT-A (r = 0.70, P < 0.001)) and disability (mRS (r = 0.70, P = 0.002)]. Baseline serum NfL predicted 7-year changes in disability (B = 0.34, P < 0.001) and cognition (CAMCOG B = −4.94, P = 0.032), as well as 17-year survival. Higher NfL levels were associated with increased mortality (HR=1.8 per twofold increase in NfL levels, P = 0.006). Interpretation: Serum NfL levels correlate with disease severity, disease progression and 17-year survival in CADASIL patients. Serum NfL is a promising biomarker to monitor and predict disease course in CADASIL, as well as potentially assessing therapeutic response in future clinical trials.
Original languageEnglish
Pages (from-to)46-56
Number of pages11
JournalAnnals of Clinical and Translational Neurology
Volume6
Issue number1
Early online date2018
DOIs
Publication statusPublished - 1 Jan 2019

Cite this

Gravesteijn, G., Rutten, J. W., Verberk, I. M. W., Böhringer, S., Liem, M. K., van der Grond, J., ... Lesnik Oberstein, S. A. J. (2019). Serum Neurofilament light correlates with CADASIL disease severity and survival. Annals of Clinical and Translational Neurology, 6(1), 46-56. https://doi.org/10.1002/acn3.678
Gravesteijn, Gido ; Rutten, Julie W. ; Verberk, Inge M. W. ; Böhringer, Stefan ; Liem, Michael K. ; van der Grond, Jeroen ; Aartsma-Rus, Annemieke ; Teunissen, Charlotte E. ; Lesnik Oberstein, Saskia A. J. / Serum Neurofilament light correlates with CADASIL disease severity and survival. In: Annals of Clinical and Translational Neurology. 2019 ; Vol. 6, No. 1. pp. 46-56.
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title = "Serum Neurofilament light correlates with CADASIL disease severity and survival",
abstract = "Objective: To validate whether serum Neurofilament Light-chain (NfL) levels correlate with disease severity in CADASIL, and to determine whether serum NfL predicts disease progression and survival. Methods: Fourty-one (pre-) manifest individuals with CADASIL causing NOTCH3 mutations and 22 healthy controls were recruited from CADASIL families. At baseline, MRI-lesion load and clinical severity was determined and serum was stored. Disease progression was measured in 30/41 patients at 7-year follow-up, and survival of all individuals was determined at 17-year follow-up. Serum NfL levels were quantified using an ultra-sensitive molecule array. Generalized estimated equation regression (GEE) was used to analyze association between serum NfL, MRI-lesion load, disease severity, and disease progression. With GEE-based Cox regression, survival was analyzed. Results: At baseline, serum NfL levels correlated with MRI-lesion load [lacune count (s = 0.64, P = 0.002), brain atrophy (r = −0.50, P = 0.001), and microbleed count (s = 0.48, P = 0.044)], cognition [CAMCOG (s = −0.45, P = 0.010), MMSE (r = −0.61, P = 0.003), GIT (r = −0.61, P < 0.001), TMT-A (r = 0.70, P < 0.001)) and disability (mRS (r = 0.70, P = 0.002)]. Baseline serum NfL predicted 7-year changes in disability (B = 0.34, P < 0.001) and cognition (CAMCOG B = −4.94, P = 0.032), as well as 17-year survival. Higher NfL levels were associated with increased mortality (HR=1.8 per twofold increase in NfL levels, P = 0.006). Interpretation: Serum NfL levels correlate with disease severity, disease progression and 17-year survival in CADASIL patients. Serum NfL is a promising biomarker to monitor and predict disease course in CADASIL, as well as potentially assessing therapeutic response in future clinical trials.",
author = "Gido Gravesteijn and Rutten, {Julie W.} and Verberk, {Inge M. W.} and Stefan B{\"o}hringer and Liem, {Michael K.} and {van der Grond}, Jeroen and Annemieke Aartsma-Rus and Teunissen, {Charlotte E.} and {Lesnik Oberstein}, {Saskia A. J.}",
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journal = "Annals of Clinical and Translational Neurology",
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Gravesteijn, G, Rutten, JW, Verberk, IMW, Böhringer, S, Liem, MK, van der Grond, J, Aartsma-Rus, A, Teunissen, CE & Lesnik Oberstein, SAJ 2019, 'Serum Neurofilament light correlates with CADASIL disease severity and survival' Annals of Clinical and Translational Neurology, vol. 6, no. 1, pp. 46-56. https://doi.org/10.1002/acn3.678

Serum Neurofilament light correlates with CADASIL disease severity and survival. / Gravesteijn, Gido; Rutten, Julie W.; Verberk, Inge M. W.; Böhringer, Stefan; Liem, Michael K.; van der Grond, Jeroen; Aartsma-Rus, Annemieke; Teunissen, Charlotte E.; Lesnik Oberstein, Saskia A. J.

In: Annals of Clinical and Translational Neurology, Vol. 6, No. 1, 01.01.2019, p. 46-56.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Serum Neurofilament light correlates with CADASIL disease severity and survival

AU - Gravesteijn, Gido

AU - Rutten, Julie W.

AU - Verberk, Inge M. W.

AU - Böhringer, Stefan

AU - Liem, Michael K.

AU - van der Grond, Jeroen

AU - Aartsma-Rus, Annemieke

AU - Teunissen, Charlotte E.

AU - Lesnik Oberstein, Saskia A. J.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Objective: To validate whether serum Neurofilament Light-chain (NfL) levels correlate with disease severity in CADASIL, and to determine whether serum NfL predicts disease progression and survival. Methods: Fourty-one (pre-) manifest individuals with CADASIL causing NOTCH3 mutations and 22 healthy controls were recruited from CADASIL families. At baseline, MRI-lesion load and clinical severity was determined and serum was stored. Disease progression was measured in 30/41 patients at 7-year follow-up, and survival of all individuals was determined at 17-year follow-up. Serum NfL levels were quantified using an ultra-sensitive molecule array. Generalized estimated equation regression (GEE) was used to analyze association between serum NfL, MRI-lesion load, disease severity, and disease progression. With GEE-based Cox regression, survival was analyzed. Results: At baseline, serum NfL levels correlated with MRI-lesion load [lacune count (s = 0.64, P = 0.002), brain atrophy (r = −0.50, P = 0.001), and microbleed count (s = 0.48, P = 0.044)], cognition [CAMCOG (s = −0.45, P = 0.010), MMSE (r = −0.61, P = 0.003), GIT (r = −0.61, P < 0.001), TMT-A (r = 0.70, P < 0.001)) and disability (mRS (r = 0.70, P = 0.002)]. Baseline serum NfL predicted 7-year changes in disability (B = 0.34, P < 0.001) and cognition (CAMCOG B = −4.94, P = 0.032), as well as 17-year survival. Higher NfL levels were associated with increased mortality (HR=1.8 per twofold increase in NfL levels, P = 0.006). Interpretation: Serum NfL levels correlate with disease severity, disease progression and 17-year survival in CADASIL patients. Serum NfL is a promising biomarker to monitor and predict disease course in CADASIL, as well as potentially assessing therapeutic response in future clinical trials.

AB - Objective: To validate whether serum Neurofilament Light-chain (NfL) levels correlate with disease severity in CADASIL, and to determine whether serum NfL predicts disease progression and survival. Methods: Fourty-one (pre-) manifest individuals with CADASIL causing NOTCH3 mutations and 22 healthy controls were recruited from CADASIL families. At baseline, MRI-lesion load and clinical severity was determined and serum was stored. Disease progression was measured in 30/41 patients at 7-year follow-up, and survival of all individuals was determined at 17-year follow-up. Serum NfL levels were quantified using an ultra-sensitive molecule array. Generalized estimated equation regression (GEE) was used to analyze association between serum NfL, MRI-lesion load, disease severity, and disease progression. With GEE-based Cox regression, survival was analyzed. Results: At baseline, serum NfL levels correlated with MRI-lesion load [lacune count (s = 0.64, P = 0.002), brain atrophy (r = −0.50, P = 0.001), and microbleed count (s = 0.48, P = 0.044)], cognition [CAMCOG (s = −0.45, P = 0.010), MMSE (r = −0.61, P = 0.003), GIT (r = −0.61, P < 0.001), TMT-A (r = 0.70, P < 0.001)) and disability (mRS (r = 0.70, P = 0.002)]. Baseline serum NfL predicted 7-year changes in disability (B = 0.34, P < 0.001) and cognition (CAMCOG B = −4.94, P = 0.032), as well as 17-year survival. Higher NfL levels were associated with increased mortality (HR=1.8 per twofold increase in NfL levels, P = 0.006). Interpretation: Serum NfL levels correlate with disease severity, disease progression and 17-year survival in CADASIL patients. Serum NfL is a promising biomarker to monitor and predict disease course in CADASIL, as well as potentially assessing therapeutic response in future clinical trials.

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