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

doi:10.1001/jamaneurol.2016.6117

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

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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.

Original language	English
Pages (from-to)	557-566
Number of pages	10
Journal	JAMA Neurology
Volume	74
Issue number	5
DOIs	https://doi.org/10.1001/jamaneurol.2016.6117
State	Published - May 2017

Bibliographical note

Funding Information:
Data collection (and sharing) for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (grant U01 AG024904 from the National Institutes of Health) and by the Department of Defense OD ADNI (award W81XWH-12-2-0012). The ADNI is funded by the National Institute on Aging and by the National Institute of Biomedical Imaging and Bioengineering, as well as through generous contributions from the following: AbbVie, Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Araclon, Biotech, BioClinica Inc, Biogen, Bristol-Myers Squibb, CereSpir Inc, Cogstate, Eisai Inc, Elan Pharmaceuticals Inc, Eli Lilly and Company, EuroImmun, F. Hoffmann-La Roche Ltd and its affiliated company Genentech Inc, Fujirebio Europe, GE Healthcare, IXICO Ltd, Janssen Alzheimer Immunotherapy Research & Development LLC, Johnson & Johnson Pharmaceutical Research & Development LLC, Lumosity, Lundbeck, Merck & Co Inc, Meso Scale Diagnostics LLC, NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corporation, Pfizer Inc, Piramal Imaging, Servier, Takeda Pharmaceutical Company, and Transition Therapeutics. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private-sector contributions are facilitated by the Foundation for the National Institutes of Health. The grantee organization is the Northern California Institute for Research and Education Inc, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. The ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of Southern California. This research was also supported by grants from the Swedish Alzheimer Foundation, the Greta and Johan Kock Foundation, the Thelma Zoega Foundation, the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson's Disease) at Lund University, Vinnova, the Swedish Research Council, the European Research Council, Swedish State Support for Clinical Research, and Frimurarestiftelsen.

Publisher Copyright:
© 2017 American Medical Association. All rights reserved.

ASJC Scopus subject areas

Clinical Neurology

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10.1001/jamaneurol.2016.6117

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@article{7ca2b02f1d144ac6bd25b8c18b92e5d0,

title = "Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease",

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 David Jones and Kejal Kantarci and Greg Jicha",

note = "Funding Information: Data collection (and sharing) for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (grant U01 AG024904 from the National Institutes of Health) and by the Department of Defense OD ADNI (award W81XWH-12-2-0012). The ADNI is funded by the National Institute on Aging and by the National Institute of Biomedical Imaging and Bioengineering, as well as through generous contributions from the following: AbbVie, Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Araclon, Biotech, BioClinica Inc, Biogen, Bristol-Myers Squibb, CereSpir Inc, Cogstate, Eisai Inc, Elan Pharmaceuticals Inc, Eli Lilly and Company, EuroImmun, F. Hoffmann-La Roche Ltd and its affiliated company Genentech Inc, Fujirebio Europe, GE Healthcare, IXICO Ltd, Janssen Alzheimer Immunotherapy Research & Development LLC, Johnson & Johnson Pharmaceutical Research & Development LLC, Lumosity, Lundbeck, Merck & Co Inc, Meso Scale Diagnostics LLC, NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corporation, Pfizer Inc, Piramal Imaging, Servier, Takeda Pharmaceutical Company, and Transition Therapeutics. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private-sector contributions are facilitated by the Foundation for the National Institutes of Health. The grantee organization is the Northern California Institute for Research and Education Inc, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. The ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of Southern California. This research was also supported by grants from the Swedish Alzheimer Foundation, the Greta and Johan Kock Foundation, the Thelma Zoega Foundation, the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson's Disease) at Lund University, Vinnova, the Swedish Research Council, the European Research Council, Swedish State Support for Clinical Research, and Frimurarestiftelsen. Publisher Copyright: {\textcopyright} 2017 American Medical Association. All rights reserved.",

year = "2017",

month = may,

doi = "10.1001/jamaneurol.2016.6117",

language = "English",

volume = "74",

pages = "557--566",

number = "5",

}

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 - Jones, David

AU - Kantarci, Kejal

AU - Jicha, Greg

N1 - Funding Information: Data collection (and sharing) for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (grant U01 AG024904 from the National Institutes of Health) and by the Department of Defense OD ADNI (award W81XWH-12-2-0012). The ADNI is funded by the National Institute on Aging and by the National Institute of Biomedical Imaging and Bioengineering, as well as through generous contributions from the following: AbbVie, Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Araclon, Biotech, BioClinica Inc, Biogen, Bristol-Myers Squibb, CereSpir Inc, Cogstate, Eisai Inc, Elan Pharmaceuticals Inc, Eli Lilly and Company, EuroImmun, F. Hoffmann-La Roche Ltd and its affiliated company Genentech Inc, Fujirebio Europe, GE Healthcare, IXICO Ltd, Janssen Alzheimer Immunotherapy Research & Development LLC, Johnson & Johnson Pharmaceutical Research & Development LLC, Lumosity, Lundbeck, Merck & Co Inc, Meso Scale Diagnostics LLC, NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corporation, Pfizer Inc, Piramal Imaging, Servier, Takeda Pharmaceutical Company, and Transition Therapeutics. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private-sector contributions are facilitated by the Foundation for the National Institutes of Health. The grantee organization is the Northern California Institute for Research and Education Inc, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. The ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of Southern California. This research was also supported by grants from the Swedish Alzheimer Foundation, the Greta and Johan Kock Foundation, the Thelma Zoega Foundation, the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson's Disease) at Lund University, Vinnova, the Swedish Research Council, the European Research Council, Swedish State Support for Clinical Research, and Frimurarestiftelsen. Publisher Copyright: © 2017 American Medical Association. All rights reserved.

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

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