Bridel C, van Wieringen WN, Zetterberg H, Tijms BM, Teunissen CE, and the NFL Group, Alvarez-Cermeño JC, Andreasson U, Axelsson M, Bäckström DC, Bartos A, Bjerke M, Blennow K, Boxer A, Brundin L, Burman J, Christensen T, Fialová L, Forsgren L, Frederiksen JL, Gisslén M, Gray E, Gunnarsson M, Hall S, Hansson O, Herbert MK, Jakobsson J, Jessen-Krut J, Janelidze S, Johannsson G, Jonsson M, Kappos L, Khademi M, Khalil M, Kuhle J, Landén M, Leinonen V, Logroscino G, Lu CH, Lycke J, Magdalinou NK, Malaspina A, Mattsson N, Meeter LH, Mehta SR, Modvig S, Olsson T, Paterson RW, Pérez-Santiago J, Piehl F, Pijnenburg YA, Pyykkö OT, Ragnarsson O, Rojas JC, Romme Christensen J, Sandberg L, Scherling CS, Schott JM, Sellebjerg FT, Simone IL, Skillbäck T, Stilund M, Sundström P, Svenningsson A, Tortelli R, Tortorella C, Trentini A, Troiano M, Turner MR, van Swieten JC, Vågberg M, Verbeek MM, Villar LM, Visser PJ, Wallin A, Weiss A, Wikkelsø C, Wild EJ. Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis. JAMA Neurol. 2019 Jun 17; PubMed.
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Hospital de Sant Pau
I found this study particularly interesting because NfL in CSF (and probably in plasma) may be incorporated soon in clinical routine to the current biomarker panel. The strength of NfL is that, since it is only expressed in the nervous system, it can capture the global neuronal/axonal damage and translate it into one numerical value.
The interest of the study relies on the large sample size and diversity of diagnoses, and although (as the authors mention) there is no reference method for NfL, the fact that the authors only included those studies that used the assay from Uman Diagnostics.
It was quite surprising to see that the HIV group had the highest levels, followed by FTD/ALS (already known from other studies). This may be explained by the axonal damage in subcortical regions in these disorders but could also mean that neuroinflammation (which is particularly present in HIV) could be driving this increase.
The differences in sex in CSF NfL levels (males higher levels than females) were also intriguing (also observed in a large recent multicenter study by Lleó et al. 2019), because most biomarkers do not show detectable sex differences. Of note, this difference has not been observed in blood samples. The reasons for these differences remain to be investigated and therefore it will be important to take into account sex for defining specific cut-offs for some diseases.
The main potential clinical use of NfL however, relies not on its diagnostic potential (limited by the overlap seen between most of the disorders) but on its excellent correlation with progression of the disease in many conditions. In some diseases, such as AD, this offers the possibility of having diagnostic (Aβ42 and 40 and t-tau, p-tau) and prognostic markers (NfL) with one single procedure.
The value of NfL in CSF could be reinforced by the possibility of measuring NfL in blood samples, which are more accessible than CSF, in follow-up visits, precluding the need of repeating the lumbar puncture.
This study also suggest that NfL levels in CSF could be useful in certain particular scenarios, for example to in the differential diagnosis between AD and FTD (alone or in combination with others CSF markers, such sAPPβ, which is low in FTD and normal in AD (Alcolea et al., 2017) and between PD and atypical parkinsonisms.
Finally, I would like to mention how studies with CSF markers have shown distinct profiles between AD and FTD, with AD-neurodegeneration closely associated to tau and FTD-neurodegeneration more associated to NfL. This clearly shows that tau and NfL provide information on neurodegeneration that is, at least in part, different.
References:
Lleó A, Alcolea D, Martínez-Lage P, Scheltens P, Parnetti L, Poirier J, Simonsen AH, Verbeek MM, Rosa-Neto P, Slot RE, Tainta M, Izaguirre A, Reijs BL, Farotti L, Tsolaki M, Vandenbergue R, Freund-Levi Y, Verhey FR, Clarimón J, Fortea J, Frolich L, Santana I, Molinuevo JL, Lehmann S, Visser PJ, Teunissen CE, Zetterberg H, Blennow K. Longitudinal cerebrospinal fluid biomarker trajectories along the Alzheimer's disease continuum in the BIOMARKAPD study. Alzheimers Dement. 2019 Jun;15(6):742-753. Epub 2019 Apr 6 PubMed.
Alcolea D, Vilaplana E, Suárez-Calvet M, Illán-Gala I, Blesa R, Clarimón J, Lladó A, Sánchez-Valle R, Molinuevo JL, García-Ribas G, Compta Y, Martí MJ, Piñol-Ripoll G, Amer-Ferrer G, Noguera A, García-Martín A, Fortea J, Lleó A. CSF sAPPβ, YKL-40, and neurofilament light in frontotemporal lobar degeneration. Neurology. 2017 Jul 11;89(2):178-188. Epub 2017 Jun 7 PubMed.
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