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JAMA Neurol. 2016 Jan;73(1):60-7. doi: 10.1001/jamaneurol.2015.3037.

Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression.

Collaborators (466)

Weiner MW, Aisen P, Weiner M, Aisen P, Petersen R, Jack CR Jr, Jagust W, Trojanowki JQ, Toga AW, Beckett L, Green RC, Saykin AJ, Morris J, Shaw LM, Khachaturian Z, Sorensen G, Carrillo M, Kuller L, Raichle M, Paul S, Davies P, Fillit H, Hefti F, Holtzman D, Mesulam M, Potter W, Snyder P, Schwartz A, Green RC, Montine T, Petersen R, Aisen P, Thomas RG, Donohue M, Walter S, Gessert D, Sather T, Jiminez G, Balasubramanian AB, Mason J, Sim I, Beckett L, Harvey D, Donohue M, Jack CR Jr, Bernstein M, Fox N, Thompson P, Schuff N, DeCArli C, Borowski B, Gunter J, Senjem M, Vemuri P, Jones D, Kantarci K, Ward C, Jagust W, Koeppe RA, Foster N, Reiman EM, Chen K, Mathis C, Landau S, Morris JC, Cairns NJ, Householder E, Taylor-Reinwald L, Shaw LM, Trojanowki JQ, Lee V, Korecka M, Figurski M, Toga AW, Crawford K, Neu S, Saykin AJ, Foroud TM, Potkin S, Shen L, Faber K, Kim S, Nho K, Weiner MW, Thal L, Khachaturian Z, Thal L, Buckholtz N, Weiner MW, Snyder PJ, Potter W, Paul S, Albert M, Frank R, Khachaturian Z, Hsiao J, Kaye J, Quinn J, Silbert L, Lind B, Carter R, Dolen S, Schneider LS, Pawluczyk S, Beccera M, Teodoro L, Spann BM, Brewer J, Vanderswag H, Fleisher A, Heidebrink JL, Lord JL, Petersen R, Mason SS, Albers CS, Knopman D, Johnson K, Doody RS, Villanueva-Meyer J, Chowdhury M, Rountree S, Dang M, Stern Y, Honig LS, Bell KL, Ances B, Morris JC, Carroll M, Creech ML, Franklin E, Mintun MA, Schneider S, Oliver A, Marson D, Griffith R, Clark D, Geldmacher D, Brockington J, Roberson E, Love MN, Grossman H, Mitsis E, Shah RC, deToledo-Morrell L, Duara R, Varon D, Greig MT, Roberts P, Albert M, Onyike C, D'Agostino D 2nd, Kielb S, Galvin JE, Cerbone B, Michel CA, Pogorelec DM, Rusinek H, de Leon MJ, Glodzik L, De Santi S, Doraiswamy P, Petrella JR, Borges-Neto S, Wong TZ, Coleman E, Arnold SE, Karlawish JH, Wolk D, Clark CM, Smith CD, Jicha G, Hardy P, Sinha P, Oates E, Conrad G, Lopez OL, Oakley M, Simpson DM, Porsteinsson AP, Goldstein BS, Martin K, Makino KM, Ismail M, Brand C, Mulnard RA, Thai G, Mc-Adams-Ortiz C, Womack K, Mathews D, Quiceno M, Levey AI, Lah JJ, Cellar JS, Burns JM, Swerdlow RH, Brooks WM, Apostolova L, Tingus K, Woo E, Silverman DH, Lu PH, Bartzokis G, Graff-Radford NR, Parfitt F, Kendall T, Johnson H, Farlow MR, Hake AM, Matthews BR, Brosch JR, Herring S, Hunt C, van Dyck CH, Carson RE, MacAvoy MG, Varma P, Chertkow H, Bergman H, Hosein C, Black S, Stefanovic B, Caldwell C, Hsiung GY, Feldman H, Mudge B, Assaly M, Finger E, Pasternack S, Rachisky I, Trost D, Kertesz A, Bernick C, Munic D, Mesulam MM, Lipowski K, Weintraub S, Bonakdarpour B, Kerwin D, Wu CK, Johnson N, Sadowsky C, Villena T, Turner RS, Johnson K, Reynolds B, Sperling RA, Johnson KA, Marshall G, Yesavage J, Taylor JL, Lane B, Rosen A, Tinklenberg J, Sabbagh MN, Belden CM, Jacobson SA, Sirrel SA, Kowall N, Killiany R, Budson AE, Norbash A, Johnson PL, Obisesan TO, Wolday S, Allard J, Lerner A, Ogrocki P, Tatsuoka C, Fatica P, Fletcher E, Maillard P, Olichney J, DeCarli C, Carmichael O, Kittur S, Borrie M, Lee TY, Bartha R, Johnson S, Asthana S, Carlsson CM, Potkin SG, Preda A, Nguyen D, Tariot P, Burke A, Trncic N, Fleisher A, Reeder S, Bates V, Capote H, Rainka M, Scharre DW, Kataki M, Adeli A, Zimmerman EA, Celmins D, Brown AD, Pearlson GD, Blank K, Anderson K, Flashman LA, Seltzer M, Hynes ML, Santulli RB, Sink KM, Gordineer L, Williamson JD, Garg P, Watkins F, Ott BR, Querfurth H, Tremont G, Salloway S, Malloy P, Correia S, Rosen HJ, Miller BL, Perry D, Mintzer J, Spicer K, Bachman D, Finger E, Pasternak S, Rachinsky I, Rogers J, Kertesz A, Drost D, Pomara N, Hernando R, Sarrael A, Schultz SK, Ponto LL, Shim H, Smith KE, Relkin N, Chaing G, Lin M, Ravdin L, Smith A, Raj BA, Fargher K, Weiner MW, Aisen P, Weiner M, Aisen P, Petersen R, Green RC, Harvey D, Jack CR Jr, Jagust W, Morris JC, Saykin AJ, Shaw LM, Toga AW, Trojanowki JQ, Neylan T, Grafman J, Green RC, Montine T, Weiner M, Petersen R, Aisen P, Thomas RG, Donohue M, Gessert D, Sather T, Davis M, Morrison R, Jiminez G, Neylan T, Hayes J, Finley S, Harvey D, Donohue M, Jack CR Jr, Bernstein M, Borowski B, Gunter J, Senjem M, Kantarci K, Ward C, Jagust W, Koeppe RA, Foster N, Reiman EM, Chen K, Landau S, Morris JC, Cairns NJ, Householder E, Shaw LM, Trojanowki JQ, Lee V, Korecka M, Figurski M, Toga AW, Crawford K, Neu S, Saykin AJ, Foroud TM, Potkin S, Shen L, Faber K, Kim S, Nho K, Weiner MW, Friedl K, Schneider LS, Pawluczyk S, Beccera M, Brewer J, Vanderswag H, Stern Y, Honig LS, Bell KL, Fleischman D, Arfanakis K, Shah RC, Duara R, Varon D, Greig MT, Doraiswamy P, Petrella JR, James O, Porsteinsson AP, Goldstein B, Martin KS, Mulnard RA, Thai G, McAdams-Ortiz C, Mintzer J, Massoglia D, Brawman-Mintzer O, Sadowsky C, Martinez W, Villena T, Jagust W, Landau S, Rosen H, Perry D, Turner RS, Behan K, Reynolds B, Sperling RA, Johnson KA, Marshall G, Sabbagh MN, Jacobson SA, Sirrel SA, Obisesan TO, Wolday S, Allard J, Johnson SC, Fruehling J, Harding S, Peskind ER, Petrie EC, Li G, Yesavage JA, Taylor JL, Furst AJ, Chao S, Relkin N, Chaing G, Ravdin L.

Author information

1
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden2Department of Molecular Neuroscience, University College London Institute of Neurology, London, Engla.
2
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
3
Department of Veterans Affairs Medical Center, University of California, San Francisco4Center for Imaging of Neurodegenerative Diseases, University of California, San Francisco5Department of Radiology and Biomedical Imaging, University of California, San.
4
Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia.
5
Department of Veterans Affairs Medical Center, University of California, San Francisco.

Abstract

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.

PMID:
26524180
PMCID:
PMC5624219
DOI:
10.1001/jamaneurol.2015.3037
[Indexed for MEDLINE]
Free PMC Article

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