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Original Investigation
January 2016

Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression

Author Affiliations
  • 1Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
  • 2Department of Molecular Neuroscience, University College London Institute of Neurology, London, England
  • 3Department of Veterans Affairs Medical Center, University of California, San Francisco
  • 4Center for Imaging of Neurodegenerative Diseases, University of California, San Francisco
  • 5Department of Radiology and Biomedical Imaging, University of California, San Francisco
  • 6Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden
  • 7Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia
JAMA Neurol. 2016;73(1):60-67. doi:10.1001/jamaneurol.2015.3037

Importance  The extent to which large-caliber axonal degeneration contributes to Alzheimer disease (AD) progression is unknown. Cerebrospinal fluid (CSF) neurofilament light (NFL) concentration is a general marker of damage to large-caliber myelinated axons.

Objective  To test whether CSF NFL concentration is associated with cognitive decline and imaging evidence of neurodegeneration and white matter change in AD.

Design, Setting, and Participants  A commercially available immunoassay was used to analyze CSF NFL concentration in a cohort of patients with AD (n = 95) or mild cognitive impairment (MCI) (n = 192) and in cognitively normal individuals (n = 110) from the Alzheimer’s Disease Neuroimaging Initiative. The study dates were January 2005 to December 2007. The NFL analysis was performed in November 2014.

Main Outcomes and Measures  Correlation was investigated among baseline CSF NFL concentration and longitudinal cognitive impairment, white matter change, and regional brain atrophy within each diagnostic group.

Results  Cerebrospinal fluid NFL concentration (median [interquartile range]) was higher in the AD dementia group (1479 [1134-1842] pg/mL), stable MCI group (no progression to AD during follow-up; 1182 [923-1687] pg/mL), and progressive MCI group (MCI with progression to AD dementia during follow-up; 1336 [1061-1693] pg/mL) compared with control participants (1047 [809-1265] pg/mL) (P < .001 for all) and in the AD dementia group compared with the stable MCI group (P = .01). In the MCI group, a higher CSF NFL concentration was associated with faster brain atrophy over time as measured by changes in whole-brain volume (β = −4177, P = .003), ventricular volume (β = 1835, P < .001), and hippocampus volume (β = −54.22, P < .001); faster disease progression as reflected by decreased Mini-Mental State Examination scores (β = −1.077, P < .001) and increased Alzheimer Disease Assessment Scale cognitive subscale scores (β = 2.30, P < .001); and faster white matter intensity change (β = 598.7, P < .001).

Conclusions and Relevance  Cerebrospinal fluid NFL concentration is increased by the early clinical stage of AD and is associated with cognitive deterioration and structural brain changes over time. This finding corroborates the contention that degeneration of large-caliber axons is an important feature of AD neurodegeneration.