Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease

Niklas Mattsson, Ulf Andreasson, Henrik Zetterberg, Kaj Blennow, Michael W. Weiner, Paul Aisen, Arthur W. Toga, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Leslie M. Shaw, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew KullerMarc Raichle, David Holtzman, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, M. Marcel Mesulam, William Potter, Peter Snyder, Eli Lilly, Adam Schwartz, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Archana B. Balasubramanian, Jennifer Mason, Iris Sim, Danielle Harvey, Matthew Bernstein, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, Emily Rogalski, Sandra Weintraub, Borna Bonakdarpour, Alzheimer's Disease Neuroimaging Initiative

Research output: Contribution to journalArticle

132 Citations (Scopus)

Abstract

IMPORTANCE Existing cerebrospinal fluid (CSF) or imaging (tau positron emission tomography) biomarkers for Alzheimer disease (AD) are invasive or expensive. Biomarkers based on standard blood test results would be useful in research, drug development, and clinical practice. Plasma neurofilament light (NFL) has recently been proposed as a blood-based biomarker for neurodegeneration in dementias. OBJECTIVE To test whether plasma NFL concentrations are increased in AD and associated with cognitive decline, other AD biomarkers, and imaging evidence of neurodegeneration. DESIGN, SETTING, AND PARTICIPANTS In this prospective case-control study, an ultrasensitive assay was used to measure plasma NFL concentration in 193 cognitively healthy controls, 197 patients with mild cognitive impairment (MCI), and 180 patients with AD dementia from the Alzheimer's Disease Neuroimaging Initiative. The study dates were September 7, 2005, to February 13, 2012. The plasma NFL analysis was performed in September 2016. MAIN OUTCOMES AND MEASURES Associationswere tested between plasma NFL and diagnosis, Aβ pathologic features, CSF biomarkers of neuronal injury, cognition, brain structure, and metabolism. RESULTS Among 193 cognitively healthy controls, 197 patients with mild cognitive impairment, and 180 patients with AD with dementia, plasma NFL correlated with CSF NFL (Spearman ? = 0.59, P < .001). Plasma NFL was increased in patients with MCI (mean, 42.8 ng/L) and patients with AD dementia (mean, 51.0 ng/L) compared with controls (mean, 34.7 ng/L) (P < .001) and had high diagnostic accuracy for patients with AD with dementia vs controls (area under the receiver operating characteristic curve, 0.87, which is comparable to established CSF biomarkers). Plasma NFL was particularly high in patients with MCI and patients with AD dementia with Aβ pathologic features. High plasma NFL correlated with poor cognition and AD-related atrophy (at baseline and longitudinally) and with brain hypometabolism (longitudinally). CONCLUSIONS AND RELEVANCE Plasma NFL is associated with AD diagnosis and with cognitive, biochemical, and imaging hallmarks of the disease. This finding implies a potential usefulness for plasma NFL as a noninvasive biomarker in AD.

Original languageEnglish (US)
Pages (from-to)557-566
Number of pages10
JournalJAMA Neurology
Volume74
Issue number5
DOIs
StatePublished - May 2017

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Intermediate Filaments
Alzheimer Disease
Light
Biomarkers
Cerebrospinal Fluid
Dementia
Cognition
Hematologic Tests
Neuroimaging
ROC Curve
Positron-Emission Tomography
Brain Injuries
Atrophy

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Mattsson, N., Andreasson, U., Zetterberg, H., Blennow, K., Weiner, M. W., Aisen, P., ... Alzheimer's Disease Neuroimaging Initiative (2017). Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurology, 74(5), 557-566. https://doi.org/10.1001/jamaneurol.2016.6117
Mattsson, Niklas ; Andreasson, Ulf ; Zetterberg, Henrik ; Blennow, Kaj ; Weiner, Michael W. ; Aisen, Paul ; Toga, Arthur W. ; Petersen, Ronald ; Jack, Clifford R. ; Jagust, William ; Trojanowki, John Q. ; Shaw, Leslie M. ; Beckett, Laurel ; Green, Robert C. ; Saykin, Andrew J. ; Morris, John ; Khachaturian, Zaven ; Sorensen, Greg ; Carrillo, Maria ; Kuller, Lew ; Raichle, Marc ; Holtzman, David ; Paul, Steven ; Davies, Peter ; Fillit, Howard ; Hefti, Franz ; Mesulam, M. Marcel ; Potter, William ; Snyder, Peter ; Lilly, Eli ; Schwartz, Adam ; Montine, Tom ; Thomas, Ronald G. ; Donohue, Michael ; Walter, Sarah ; Gessert, Devon ; Sather, Tamie ; Jiminez, Gus ; Balasubramanian, Archana B. ; Mason, Jennifer ; Sim, Iris ; Harvey, Danielle ; Bernstein, Matthew ; Borowski, Bret ; Gunter, Jeff ; Senjem, Matt ; Vemuri, Prashanthi ; Rogalski, Emily ; Weintraub, Sandra ; Bonakdarpour, Borna ; Alzheimer's Disease Neuroimaging Initiative. / Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. In: JAMA Neurology. 2017 ; Vol. 74, No. 5. pp. 557-566.
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abstract = "IMPORTANCE Existing cerebrospinal fluid (CSF) or imaging (tau positron emission tomography) biomarkers for Alzheimer disease (AD) are invasive or expensive. Biomarkers based on standard blood test results would be useful in research, drug development, and clinical practice. Plasma neurofilament light (NFL) has recently been proposed as a blood-based biomarker for neurodegeneration in dementias. OBJECTIVE To test whether plasma NFL concentrations are increased in AD and associated with cognitive decline, other AD biomarkers, and imaging evidence of neurodegeneration. DESIGN, SETTING, AND PARTICIPANTS In this prospective case-control study, an ultrasensitive assay was used to measure plasma NFL concentration in 193 cognitively healthy controls, 197 patients with mild cognitive impairment (MCI), and 180 patients with AD dementia from the Alzheimer's Disease Neuroimaging Initiative. The study dates were September 7, 2005, to February 13, 2012. The plasma NFL analysis was performed in September 2016. MAIN OUTCOMES AND MEASURES Associationswere tested between plasma NFL and diagnosis, Aβ pathologic features, CSF biomarkers of neuronal injury, cognition, brain structure, and metabolism. RESULTS Among 193 cognitively healthy controls, 197 patients with mild cognitive impairment, and 180 patients with AD with dementia, plasma NFL correlated with CSF NFL (Spearman ? = 0.59, P < .001). Plasma NFL was increased in patients with MCI (mean, 42.8 ng/L) and patients with AD dementia (mean, 51.0 ng/L) compared with controls (mean, 34.7 ng/L) (P < .001) and had high diagnostic accuracy for patients with AD with dementia vs controls (area under the receiver operating characteristic curve, 0.87, which is comparable to established CSF biomarkers). Plasma NFL was particularly high in patients with MCI and patients with AD dementia with Aβ pathologic features. High plasma NFL correlated with poor cognition and AD-related atrophy (at baseline and longitudinally) and with brain hypometabolism (longitudinally). CONCLUSIONS AND RELEVANCE Plasma NFL is associated with AD diagnosis and with cognitive, biochemical, and imaging hallmarks of the disease. This finding implies a potential usefulness for plasma NFL as a noninvasive biomarker in AD.",
author = "Niklas Mattsson and Ulf Andreasson and Henrik Zetterberg and Kaj Blennow and Weiner, {Michael W.} and Paul Aisen and Toga, {Arthur W.} and Ronald Petersen and Jack, {Clifford R.} and William Jagust and Trojanowki, {John Q.} and Shaw, {Leslie M.} and Laurel Beckett and Green, {Robert C.} and Saykin, {Andrew J.} and John Morris and Zaven Khachaturian and Greg Sorensen and Maria Carrillo and Lew Kuller and Marc Raichle and David Holtzman and Steven Paul and Peter Davies and Howard Fillit and Franz Hefti and Mesulam, {M. Marcel} and William Potter and Peter Snyder and Eli Lilly and Adam Schwartz and Tom Montine and Thomas, {Ronald G.} and Michael Donohue and Sarah Walter and Devon Gessert and Tamie Sather and Gus Jiminez and Balasubramanian, {Archana B.} and Jennifer Mason and Iris Sim and Danielle Harvey and Matthew Bernstein and Bret Borowski and Jeff Gunter and Matt Senjem and Prashanthi Vemuri and Emily Rogalski and Sandra Weintraub and Borna Bonakdarpour and {Alzheimer's Disease Neuroimaging Initiative}",
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Mattsson, N, Andreasson, U, Zetterberg, H, Blennow, K, Weiner, MW, Aisen, P, Toga, AW, Petersen, R, Jack, CR, Jagust, W, Trojanowki, JQ, Shaw, LM, Beckett, L, Green, RC, Saykin, AJ, Morris, J, Khachaturian, Z, Sorensen, G, Carrillo, M, Kuller, L, Raichle, M, Holtzman, D, Paul, S, Davies, P, Fillit, H, Hefti, F, Mesulam, MM, Potter, W, Snyder, P, Lilly, E, Schwartz, A, Montine, T, Thomas, RG, Donohue, M, Walter, S, Gessert, D, Sather, T, Jiminez, G, Balasubramanian, AB, Mason, J, Sim, I, Harvey, D, Bernstein, M, Borowski, B, Gunter, J, Senjem, M, Vemuri, P, Rogalski, E, Weintraub, S, Bonakdarpour, B & Alzheimer's Disease Neuroimaging Initiative 2017, 'Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease', JAMA Neurology, vol. 74, no. 5, pp. 557-566. https://doi.org/10.1001/jamaneurol.2016.6117

Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. / Mattsson, Niklas; Andreasson, Ulf; Zetterberg, Henrik; Blennow, Kaj; Weiner, Michael W.; Aisen, Paul; Toga, Arthur W.; Petersen, Ronald; Jack, Clifford R.; Jagust, William; Trojanowki, John Q.; Shaw, Leslie M.; Beckett, Laurel; Green, Robert C.; Saykin, Andrew J.; Morris, John; Khachaturian, Zaven; Sorensen, Greg; Carrillo, Maria; Kuller, Lew; Raichle, Marc; Holtzman, David; Paul, Steven; Davies, Peter; Fillit, Howard; Hefti, Franz; Mesulam, M. Marcel; Potter, William; Snyder, Peter; Lilly, Eli; Schwartz, Adam; Montine, Tom; Thomas, Ronald G.; Donohue, Michael; Walter, Sarah; Gessert, Devon; Sather, Tamie; Jiminez, Gus; Balasubramanian, Archana B.; Mason, Jennifer; Sim, Iris; Harvey, Danielle; Bernstein, Matthew; Borowski, Bret; Gunter, Jeff; Senjem, Matt; Vemuri, Prashanthi; Rogalski, Emily; Weintraub, Sandra; Bonakdarpour, Borna; Alzheimer's Disease Neuroimaging Initiative.

In: JAMA Neurology, Vol. 74, No. 5, 05.2017, p. 557-566.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease

AU - Mattsson, Niklas

AU - Andreasson, Ulf

AU - Zetterberg, Henrik

AU - Blennow, Kaj

AU - Weiner, Michael W.

AU - Aisen, Paul

AU - Toga, Arthur W.

AU - Petersen, Ronald

AU - Jack, Clifford R.

AU - Jagust, William

AU - Trojanowki, John Q.

AU - Shaw, Leslie M.

AU - Beckett, Laurel

AU - Green, Robert C.

AU - Saykin, Andrew J.

AU - Morris, John

AU - Khachaturian, Zaven

AU - Sorensen, Greg

AU - Carrillo, Maria

AU - Kuller, Lew

AU - Raichle, Marc

AU - Holtzman, David

AU - Paul, Steven

AU - Davies, Peter

AU - Fillit, Howard

AU - Hefti, Franz

AU - Mesulam, M. Marcel

AU - Potter, William

AU - Snyder, Peter

AU - Lilly, Eli

AU - Schwartz, Adam

AU - Montine, Tom

AU - Thomas, Ronald G.

AU - Donohue, Michael

AU - Walter, Sarah

AU - Gessert, Devon

AU - Sather, Tamie

AU - Jiminez, Gus

AU - Balasubramanian, Archana B.

AU - Mason, Jennifer

AU - Sim, Iris

AU - Harvey, Danielle

AU - Bernstein, Matthew

AU - Borowski, Bret

AU - Gunter, Jeff

AU - Senjem, Matt

AU - Vemuri, Prashanthi

AU - Rogalski, Emily

AU - Weintraub, Sandra

AU - Bonakdarpour, Borna

AU - Alzheimer's Disease Neuroimaging Initiative

PY - 2017/5

Y1 - 2017/5

N2 - IMPORTANCE Existing cerebrospinal fluid (CSF) or imaging (tau positron emission tomography) biomarkers for Alzheimer disease (AD) are invasive or expensive. Biomarkers based on standard blood test results would be useful in research, drug development, and clinical practice. Plasma neurofilament light (NFL) has recently been proposed as a blood-based biomarker for neurodegeneration in dementias. OBJECTIVE To test whether plasma NFL concentrations are increased in AD and associated with cognitive decline, other AD biomarkers, and imaging evidence of neurodegeneration. DESIGN, SETTING, AND PARTICIPANTS In this prospective case-control study, an ultrasensitive assay was used to measure plasma NFL concentration in 193 cognitively healthy controls, 197 patients with mild cognitive impairment (MCI), and 180 patients with AD dementia from the Alzheimer's Disease Neuroimaging Initiative. The study dates were September 7, 2005, to February 13, 2012. The plasma NFL analysis was performed in September 2016. MAIN OUTCOMES AND MEASURES Associationswere tested between plasma NFL and diagnosis, Aβ pathologic features, CSF biomarkers of neuronal injury, cognition, brain structure, and metabolism. RESULTS Among 193 cognitively healthy controls, 197 patients with mild cognitive impairment, and 180 patients with AD with dementia, plasma NFL correlated with CSF NFL (Spearman ? = 0.59, P < .001). Plasma NFL was increased in patients with MCI (mean, 42.8 ng/L) and patients with AD dementia (mean, 51.0 ng/L) compared with controls (mean, 34.7 ng/L) (P < .001) and had high diagnostic accuracy for patients with AD with dementia vs controls (area under the receiver operating characteristic curve, 0.87, which is comparable to established CSF biomarkers). Plasma NFL was particularly high in patients with MCI and patients with AD dementia with Aβ pathologic features. High plasma NFL correlated with poor cognition and AD-related atrophy (at baseline and longitudinally) and with brain hypometabolism (longitudinally). CONCLUSIONS AND RELEVANCE Plasma NFL is associated with AD diagnosis and with cognitive, biochemical, and imaging hallmarks of the disease. This finding implies a potential usefulness for plasma NFL as a noninvasive biomarker in AD.

AB - IMPORTANCE Existing cerebrospinal fluid (CSF) or imaging (tau positron emission tomography) biomarkers for Alzheimer disease (AD) are invasive or expensive. Biomarkers based on standard blood test results would be useful in research, drug development, and clinical practice. Plasma neurofilament light (NFL) has recently been proposed as a blood-based biomarker for neurodegeneration in dementias. OBJECTIVE To test whether plasma NFL concentrations are increased in AD and associated with cognitive decline, other AD biomarkers, and imaging evidence of neurodegeneration. DESIGN, SETTING, AND PARTICIPANTS In this prospective case-control study, an ultrasensitive assay was used to measure plasma NFL concentration in 193 cognitively healthy controls, 197 patients with mild cognitive impairment (MCI), and 180 patients with AD dementia from the Alzheimer's Disease Neuroimaging Initiative. The study dates were September 7, 2005, to February 13, 2012. The plasma NFL analysis was performed in September 2016. MAIN OUTCOMES AND MEASURES Associationswere tested between plasma NFL and diagnosis, Aβ pathologic features, CSF biomarkers of neuronal injury, cognition, brain structure, and metabolism. RESULTS Among 193 cognitively healthy controls, 197 patients with mild cognitive impairment, and 180 patients with AD with dementia, plasma NFL correlated with CSF NFL (Spearman ? = 0.59, P < .001). Plasma NFL was increased in patients with MCI (mean, 42.8 ng/L) and patients with AD dementia (mean, 51.0 ng/L) compared with controls (mean, 34.7 ng/L) (P < .001) and had high diagnostic accuracy for patients with AD with dementia vs controls (area under the receiver operating characteristic curve, 0.87, which is comparable to established CSF biomarkers). Plasma NFL was particularly high in patients with MCI and patients with AD dementia with Aβ pathologic features. High plasma NFL correlated with poor cognition and AD-related atrophy (at baseline and longitudinally) and with brain hypometabolism (longitudinally). CONCLUSIONS AND RELEVANCE Plasma NFL is associated with AD diagnosis and with cognitive, biochemical, and imaging hallmarks of the disease. This finding implies a potential usefulness for plasma NFL as a noninvasive biomarker in AD.

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Mattsson N, Andreasson U, Zetterberg H, Blennow K, Weiner MW, Aisen P et al. Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurology. 2017 May;74(5):557-566. https://doi.org/10.1001/jamaneurol.2016.6117