Association of Cerebrospinal Fluid Neurofilament Light Protein with Risk of Mild Cognitive Impairment among Individuals Without Cognitive Impairment

Silke Kern, Jeremy A. Syrjanen, Kaj Blennow, Henrik Zetterberg, Ingmar Skoog, Margda Waern, Clinton E. Hagen, Argonde C. van Harten, David S. Knopman, Clifford R. Jack, Ronald C. Petersen, Michelle M. Mielke

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Importance: Accumulating data suggest that elevated cerebrospinal fluid (CSF) neurofilament light (NfL) and neurogranin (Ng) levels are associated with cognitive decline and may be useful markers of neurodegeneration. However, to our knowledge, previous studies have not assessed these CSF markers in the community, evaluated them with regards to risk of mild cognitive impairment (MCI), or compared their prognostic value with CSF total tau (T-tau) or phosphorylated tau (P-tau). Objective: To determine (1) whether CSF NfL and Ng levels were associated with risk of MCI, (2) the effect size of these markers compared with CSF T-tau or P-tau for risk of MCI, and (3) whether CSF amyloid-β (Aβ42) modified these associations. Design, Setting and Participants: The analyses included 648 participants without cognitive impairment who were enrolled into the prospective population-based Mayo Clinic Study of Aging between January 2004 and December 2015 with available CSF data and at least 1 follow-up visit. Participants were followed up for a median of 3.8 years (interquartile range, 2.6-5.4 years). The CSF NfL and Ng levels were measured using an in-house sandwich enzyme-linked immunosorbent assay. The CSF Aβ42, T-tau, and P-tau levels were measured with automated electrochemiluminescence immunoassays. Cox proportional hazards models, with age as the timescale, were used to assess the association between CSF NfL, Ng, Aβ42, T-tau, or P-tau with risk of MCI after adjusting for sex, education, apolipoprotein E genotype, and the Charlson comorbidity index. To examine CSF Aβ42 as an effect modifier, it was categorized into tertiles; the bottom tertile was defined as having elevated brain amyloid. Main Outcomes and Measures: Risk of MCI. Results: At baseline, the median age of the 648 participants without cognitive impairment was 72.3 years (range, 50.7-95.3 years) and 366 (56.5%) were men; 96 (14.8%) developed incident MCI. Compared with the bottom quartile, the top quartile of CSF NfL was associated with a 3.1-fold increased risk of MCI (hazard ratio, 3.13; 95% CI, 1.36-7.18) in multivariate models. Neither CSF T-tau, P-tau, nor Ng was associated with risk of MCI. There was no interaction between Aβ42 and CSF NfL for risk of MCI. Conclusions and Relevance: Elevated CSF NfL levels but not CSF T-tau, P-tau or Ng are a risk factor for MCI in a community population and are independent of brain amyloid.
Original languageEnglish
JournalJAMA Neurology
DOIs
Publication statusE-pub ahead of print - 2018

Cite this

Kern, Silke ; Syrjanen, Jeremy A. ; Blennow, Kaj ; Zetterberg, Henrik ; Skoog, Ingmar ; Waern, Margda ; Hagen, Clinton E. ; van Harten, Argonde C. ; Knopman, David S. ; Jack, Clifford R. ; Petersen, Ronald C. ; Mielke, Michelle M. / Association of Cerebrospinal Fluid Neurofilament Light Protein with Risk of Mild Cognitive Impairment among Individuals Without Cognitive Impairment. In: JAMA Neurology. 2018.
@article{5bd53d21aa4045a9894f355a721a4d37,
title = "Association of Cerebrospinal Fluid Neurofilament Light Protein with Risk of Mild Cognitive Impairment among Individuals Without Cognitive Impairment",
abstract = "Importance: Accumulating data suggest that elevated cerebrospinal fluid (CSF) neurofilament light (NfL) and neurogranin (Ng) levels are associated with cognitive decline and may be useful markers of neurodegeneration. However, to our knowledge, previous studies have not assessed these CSF markers in the community, evaluated them with regards to risk of mild cognitive impairment (MCI), or compared their prognostic value with CSF total tau (T-tau) or phosphorylated tau (P-tau). Objective: To determine (1) whether CSF NfL and Ng levels were associated with risk of MCI, (2) the effect size of these markers compared with CSF T-tau or P-tau for risk of MCI, and (3) whether CSF amyloid-β (Aβ42) modified these associations. Design, Setting and Participants: The analyses included 648 participants without cognitive impairment who were enrolled into the prospective population-based Mayo Clinic Study of Aging between January 2004 and December 2015 with available CSF data and at least 1 follow-up visit. Participants were followed up for a median of 3.8 years (interquartile range, 2.6-5.4 years). The CSF NfL and Ng levels were measured using an in-house sandwich enzyme-linked immunosorbent assay. The CSF Aβ42, T-tau, and P-tau levels were measured with automated electrochemiluminescence immunoassays. Cox proportional hazards models, with age as the timescale, were used to assess the association between CSF NfL, Ng, Aβ42, T-tau, or P-tau with risk of MCI after adjusting for sex, education, apolipoprotein E genotype, and the Charlson comorbidity index. To examine CSF Aβ42 as an effect modifier, it was categorized into tertiles; the bottom tertile was defined as having elevated brain amyloid. Main Outcomes and Measures: Risk of MCI. Results: At baseline, the median age of the 648 participants without cognitive impairment was 72.3 years (range, 50.7-95.3 years) and 366 (56.5{\%}) were men; 96 (14.8{\%}) developed incident MCI. Compared with the bottom quartile, the top quartile of CSF NfL was associated with a 3.1-fold increased risk of MCI (hazard ratio, 3.13; 95{\%} CI, 1.36-7.18) in multivariate models. Neither CSF T-tau, P-tau, nor Ng was associated with risk of MCI. There was no interaction between Aβ42 and CSF NfL for risk of MCI. Conclusions and Relevance: Elevated CSF NfL levels but not CSF T-tau, P-tau or Ng are a risk factor for MCI in a community population and are independent of brain amyloid.",
author = "Silke Kern and Syrjanen, {Jeremy A.} and Kaj Blennow and Henrik Zetterberg and Ingmar Skoog and Margda Waern and Hagen, {Clinton E.} and {van Harten}, {Argonde C.} and Knopman, {David S.} and Jack, {Clifford R.} and Petersen, {Ronald C.} and Mielke, {Michelle M.}",
year = "2018",
doi = "10.1001/jamaneurol.2018.3459",
language = "English",
journal = "JAMA Neurology",
issn = "2168-6149",
publisher = "American Medical Association",

}

Association of Cerebrospinal Fluid Neurofilament Light Protein with Risk of Mild Cognitive Impairment among Individuals Without Cognitive Impairment. / Kern, Silke; Syrjanen, Jeremy A.; Blennow, Kaj; Zetterberg, Henrik; Skoog, Ingmar; Waern, Margda; Hagen, Clinton E.; van Harten, Argonde C.; Knopman, David S.; Jack, Clifford R.; Petersen, Ronald C.; Mielke, Michelle M.

In: JAMA Neurology, 2018.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Association of Cerebrospinal Fluid Neurofilament Light Protein with Risk of Mild Cognitive Impairment among Individuals Without Cognitive Impairment

AU - Kern, Silke

AU - Syrjanen, Jeremy A.

AU - Blennow, Kaj

AU - Zetterberg, Henrik

AU - Skoog, Ingmar

AU - Waern, Margda

AU - Hagen, Clinton E.

AU - van Harten, Argonde C.

AU - Knopman, David S.

AU - Jack, Clifford R.

AU - Petersen, Ronald C.

AU - Mielke, Michelle M.

PY - 2018

Y1 - 2018

N2 - Importance: Accumulating data suggest that elevated cerebrospinal fluid (CSF) neurofilament light (NfL) and neurogranin (Ng) levels are associated with cognitive decline and may be useful markers of neurodegeneration. However, to our knowledge, previous studies have not assessed these CSF markers in the community, evaluated them with regards to risk of mild cognitive impairment (MCI), or compared their prognostic value with CSF total tau (T-tau) or phosphorylated tau (P-tau). Objective: To determine (1) whether CSF NfL and Ng levels were associated with risk of MCI, (2) the effect size of these markers compared with CSF T-tau or P-tau for risk of MCI, and (3) whether CSF amyloid-β (Aβ42) modified these associations. Design, Setting and Participants: The analyses included 648 participants without cognitive impairment who were enrolled into the prospective population-based Mayo Clinic Study of Aging between January 2004 and December 2015 with available CSF data and at least 1 follow-up visit. Participants were followed up for a median of 3.8 years (interquartile range, 2.6-5.4 years). The CSF NfL and Ng levels were measured using an in-house sandwich enzyme-linked immunosorbent assay. The CSF Aβ42, T-tau, and P-tau levels were measured with automated electrochemiluminescence immunoassays. Cox proportional hazards models, with age as the timescale, were used to assess the association between CSF NfL, Ng, Aβ42, T-tau, or P-tau with risk of MCI after adjusting for sex, education, apolipoprotein E genotype, and the Charlson comorbidity index. To examine CSF Aβ42 as an effect modifier, it was categorized into tertiles; the bottom tertile was defined as having elevated brain amyloid. Main Outcomes and Measures: Risk of MCI. Results: At baseline, the median age of the 648 participants without cognitive impairment was 72.3 years (range, 50.7-95.3 years) and 366 (56.5%) were men; 96 (14.8%) developed incident MCI. Compared with the bottom quartile, the top quartile of CSF NfL was associated with a 3.1-fold increased risk of MCI (hazard ratio, 3.13; 95% CI, 1.36-7.18) in multivariate models. Neither CSF T-tau, P-tau, nor Ng was associated with risk of MCI. There was no interaction between Aβ42 and CSF NfL for risk of MCI. Conclusions and Relevance: Elevated CSF NfL levels but not CSF T-tau, P-tau or Ng are a risk factor for MCI in a community population and are independent of brain amyloid.

AB - Importance: Accumulating data suggest that elevated cerebrospinal fluid (CSF) neurofilament light (NfL) and neurogranin (Ng) levels are associated with cognitive decline and may be useful markers of neurodegeneration. However, to our knowledge, previous studies have not assessed these CSF markers in the community, evaluated them with regards to risk of mild cognitive impairment (MCI), or compared their prognostic value with CSF total tau (T-tau) or phosphorylated tau (P-tau). Objective: To determine (1) whether CSF NfL and Ng levels were associated with risk of MCI, (2) the effect size of these markers compared with CSF T-tau or P-tau for risk of MCI, and (3) whether CSF amyloid-β (Aβ42) modified these associations. Design, Setting and Participants: The analyses included 648 participants without cognitive impairment who were enrolled into the prospective population-based Mayo Clinic Study of Aging between January 2004 and December 2015 with available CSF data and at least 1 follow-up visit. Participants were followed up for a median of 3.8 years (interquartile range, 2.6-5.4 years). The CSF NfL and Ng levels were measured using an in-house sandwich enzyme-linked immunosorbent assay. The CSF Aβ42, T-tau, and P-tau levels were measured with automated electrochemiluminescence immunoassays. Cox proportional hazards models, with age as the timescale, were used to assess the association between CSF NfL, Ng, Aβ42, T-tau, or P-tau with risk of MCI after adjusting for sex, education, apolipoprotein E genotype, and the Charlson comorbidity index. To examine CSF Aβ42 as an effect modifier, it was categorized into tertiles; the bottom tertile was defined as having elevated brain amyloid. Main Outcomes and Measures: Risk of MCI. Results: At baseline, the median age of the 648 participants without cognitive impairment was 72.3 years (range, 50.7-95.3 years) and 366 (56.5%) were men; 96 (14.8%) developed incident MCI. Compared with the bottom quartile, the top quartile of CSF NfL was associated with a 3.1-fold increased risk of MCI (hazard ratio, 3.13; 95% CI, 1.36-7.18) in multivariate models. Neither CSF T-tau, P-tau, nor Ng was associated with risk of MCI. There was no interaction between Aβ42 and CSF NfL for risk of MCI. Conclusions and Relevance: Elevated CSF NfL levels but not CSF T-tau, P-tau or Ng are a risk factor for MCI in a community population and are independent of brain amyloid.

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