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1. Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis

Author

Bridel, C. (Claire), Van Wieringen, W.N. (Wessel N.), Zetterberg, H. (Henrik), Tijms, B.M. (Betty M.), Teunissen, C.E. (Charlotte), Álvarez-Cermeño, J.C. (José C), Andreasson, U. (Ulf), Axelsson, M. (Markus), Bäckström, D.C. (David C.), Bartos, A. (Ales), Bjerke, M. (Maria), Blennow, K. (Kaj), Boxer, A.L. (Adam), Brundin, L. (Lou), Burman, J. (Joachim), Christensen, T. (Tove), Fialová, L. (Lenká), Forsgren, L. (Lars), Frederiksen, H., Gisslén, M. (Magnus), Gray, E. (Elizabeth), Gunnarsson, M. (Martin), Hall, S. (Sara), Hansson, O. (Oskar), Herbert, M.K. (Megan K.), Jakobsson, J. (Joel), Jessen-Krut, J. (Jan), Janelidze, S. (Shorena), Johannsson, G., Jonsson, M. (Michael), Kappos, L. (Ludwig), Khademi, M. (Mohsen), Khalil, M. (Michael), Kuhle, J. (Jens), Landén, M. (Mikael), Leinonen, V. (Ville), Logroscino, G. (Giancarlo), Lu, C.-H. (Ching-Hua), Lycke, J. (Jan), Magdalinou, N. (Nadia), Malaspina, A. (Andrea), Mattsson, N. (Niklas), Meeter, L.H.H. (Lieke), Mehta, S.R. (Sanjay R.), Modvig, S. (Signe), Olsson, T., Paterson, R.W. (Ross W.), Pérez-Santiago, J. (Josué), Piehl, F. (Fredrik), Pijnenburg, Y.A.L. (Yolande), Pyykkö, O.T. (Okko T.), Ragnarsson, O. (Oskar), Rojas, J.C. (Julio C.), Romme Christensen, J. (Jeppe), Sandberg, L. (Linda), Scherling, C.S. (Carole S.), Schott, J.M. (Jonathan M.), Sellebjerg, F. (Finn), Simone, I.L. (Isabella L.), Skillbäck, T. (Tobias), Stilund, M. (Morten), Sundström, P. (Peter), Svenningsson, A. (Anders), Tortelli, R. (Rosanna), Tortorella, C. (Carla), Trentini, A. (Alessandro), Troiano, M. (Maria), Turner, M.R. (Martin R.), Swieten, J.C. (John) van, Vågberg, M. (Mattias), Verbeek, M.M. (Marcel), Villar, L.M. (Luisa María), Visser, P. (Pim), Wallin, A. (Anders), Weiss, A. (Andreas), Wikkelsø, C. (Carsten), Wild, E.J. (Edward J.), Bridel, C. (Claire), Van Wieringen, W.N. (Wessel N.), Zetterberg, H. (Henrik), Tijms, B.M. (Betty M.), Teunissen, C.E. (Charlotte), Álvarez-Cermeño, J.C. (José C), Andreasson, U. (Ulf), Axelsson, M. (Markus), Bäckström, D.C. (David C.), Bartos, A. (Ales), Bjerke, M. (Maria), Blennow, K. (Kaj), Boxer, A.L. (Adam), Brundin, L. (Lou), Burman, J. (Joachim), Christensen, T. (Tove), Fialová, L. (Lenká), Forsgren, L. (Lars), Frederiksen, H., Gisslén, M. (Magnus), Gray, E. (Elizabeth), Gunnarsson, M. (Martin), Hall, S. (Sara), Hansson, O. (Oskar), Herbert, M.K. (Megan K.), Jakobsson, J. (Joel), Jessen-Krut, J. (Jan), Janelidze, S. (Shorena), Johannsson, G., Jonsson, M. (Michael), Kappos, L. (Ludwig), Khademi, M. (Mohsen), Khalil, M. (Michael), Kuhle, J. (Jens), Landén, M. (Mikael), Leinonen, V. (Ville), Logroscino, G. (Giancarlo), Lu, C.-H. (Ching-Hua), Lycke, J. (Jan), Magdalinou, N. (Nadia), Malaspina, A. (Andrea), Mattsson, N. (Niklas), Meeter, L.H.H. (Lieke), Mehta, S.R. (Sanjay R.), Modvig, S. (Signe), Olsson, T., Paterson, R.W. (Ross W.), Pérez-Santiago, J. (Josué), Piehl, F. (Fredrik), Pijnenburg, Y.A.L. (Yolande), Pyykkö, O.T. (Okko T.), Ragnarsson, O. (Oskar), Rojas, J.C. (Julio C.), Romme Christensen, J. (Jeppe), Sandberg, L. (Linda), Scherling, C.S. (Carole S.), Schott, J.M. (Jonathan M.), Sellebjerg, F. (Finn), Simone, I.L. (Isabella L.), Skillbäck, T. (Tobias), Stilund, M. (Morten), Sundström, P. (Peter), Svenningsson, A. (Anders), Tortelli, R. (Rosanna), Tortorella, C. (Carla), Trentini, A. (Alessandro), Troiano, M. (Maria), Turner, M.R. (Martin R.), Swieten, J.C. (John) van, Vågberg, M. (Mattias), Verbeek, M.M. (Marcel), Villar, L.M. (Luisa María), Visser, P. (Pim), Wallin, A. (Anders), Weiss, A. (Andreas), Wikkelsø, C. (Carsten), and Wild, E.J. (Edward J.)

Abstract

Importance: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date. Objectives: To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions. Data Sources: PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC. Study Selection: Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex. Data Extraction and Synthesis: Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept. Main Outcome and Measure: The cNfL levels adjusted for age and sex across diagnoses. Results: Data were collected for 10059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL incr

Published
2019
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2. Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Author

Meeter, L.H.H. (Lieke), Gendron, T.F. (Tania F.), Sias, A.C. (Ana C.), Jiskoot, L.C. (Lize), Russo, S.P. (Silvia P.), Donker Kaat, L. (Laura), Papma, J.M. (Janne), Panman, J.L. (Jessica), Ende, E.L. (Emma) van der, Dopper, E.G.P. (Elise), Franzen, S. (Sanne), Graff, C. (Caroline), Boxer, A.L. (Adam), Rosen, H.J. (Howard J.), Sánchez-Valle, R. (Raquel), Galimberti, D. (Daniela), Pijnenburg, Y.A.L. (Yolande), Benussi, L. (Luisa), Ghidoni, R. (Roberta), Borroni, B. (Barbara), Laforce, R. (Robert), del Campo, M. (Marta), Teunissen, C.E. (Charlotte), Thornton, A.S. (Andrew), Rojas, J.C. (Julio C.), Coppola, D. (Domenico), Geschwind, H., Rademakers, S. (Suzanne), Karydas, A.M. (Anna M.), Öijerstedt, L. (Linn), Scarpini, E. (Elio), Binetti, G. (Giuliano), Padovani, A. (Alessandro), Cash, D.M. (David M.), Dick, K.M. (Katrina M.), Bocchetta, M. (Martina), Miller, B.L. (Bruce Lars), Rohrer, J.D. (Jonathan), Petrucelli, L. (Leonard), Swieten, J.C. (John) van, Lee, S.E. (Suzee E.), Meeter, L.H.H. (Lieke), Gendron, T.F. (Tania F.), Sias, A.C. (Ana C.), Jiskoot, L.C. (Lize), Russo, S.P. (Silvia P.), Donker Kaat, L. (Laura), Papma, J.M. (Janne), Panman, J.L. (Jessica), Ende, E.L. (Emma) van der, Dopper, E.G.P. (Elise), Franzen, S. (Sanne), Graff, C. (Caroline), Boxer, A.L. (Adam), Rosen, H.J. (Howard J.), Sánchez-Valle, R. (Raquel), Galimberti, D. (Daniela), Pijnenburg, Y.A.L. (Yolande), Benussi, L. (Luisa), Ghidoni, R. (Roberta), Borroni, B. (Barbara), Laforce, R. (Robert), del Campo, M. (Marta), Teunissen, C.E. (Charlotte), Thornton, A.S. (Andrew), Rojas, J.C. (Julio C.), Coppola, D. (Domenico), Geschwind, H., Rademakers, S. (Suzanne), Karydas, A.M. (Anna M.), Öijerstedt, L. (Linn), Scarpini, E. (Elio), Binetti, G. (Giuliano), Padovani, A. (Alessandro), Cash, D.M. (David M.), Dick, K.M. (Katrina M.), Bocchetta, M. (Martina), Miller, B.L. (Bruce Lars), Rohrer, J.D. (Jonathan), Petrucelli, L. (Leonard), Swieten, J.C. (John) van, and Lee, S.E. (Suzee E.)

Abstract

Objective: To evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72-associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume. Methods: We measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel-wise analyses. Results: Poly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus. Interpretation: This study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72-associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

Published
2018
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