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Background: Among the Alzheimer's disease (AD) biomarkers measured in blood, phosphorylated forms of tau (p-tau) have been shown to exhibit a particularly high diagnostic potential. Here, we performed a comprehensive method comparison study, followed by evaluation of the diagnostic performance of eight recent plasma p-tau immunoassays targeting different tau phosphorylation sites, different tau fragments, and that are measured by two distinct platforms., Methods: We enrolled a cohort of 40 patients with AD at the stage of dementia (AD-dem) characterized by positive CSF A + T + profile, and a control group of 40 cognitively healthy participants (Control), to conduct a comprehensive method comparison for three plasma p-tau181 and five plasma p-tau217 assays run on the Simoa ® HD-X™ or Lumipulse ® G600II/G1200 platforms. Design of the compared assays differed in regard to: (1) tau phosphorylation site targeted by the capture antibody (T181 or T217), and (2) epitope of the pan-tau detector antibody (N-terminal or mid-region). For each of the assays we determined precision and analytical sensitivity parameters and used Passing-Bablok regression and Bland-Altman plots for pairwise comparison of p-tau181 or p-tau217 assays. Subsequently, we evaluated the diagnostic accuracy of all the assays for discrimination between AD-dem and Control groups., Results: We found a strong, positive correlation between all the measurements. Fixed and/or proportional bias was observed for each of compared p-tau181 assay pairs or p-tau217 assay pairs. While both plasma p-tau181 and p-tau217 levels were significantly increased in AD-dem vs. Control groups as measured by all assays, higher median concentration AD-dem/Control fold change and AUC values were observed for p-tau217 (assays range: fold change 3.72-6.74, AUC 0.916-0.956) compared with p-tau181 (assays range 1.81-2.94, AUC 0.829-0.909), independently of the platform used. No significant differences were observed between diagnostic performance of p-tau181 assays or p-tau217 assays targeting tau N-terminus or mid-region., Conclusions: Although all plasma p-tau measurements enabled discrimination between clinical groups, p-tau217 assays showed the highest robustness, independently of the pan-tau detector antibody targeting N-terminal or mid-region, and independently of the platform used. Considering the observed method disagreement in measured absolute concentrations, we stress the need for development of certified reference material, harmonizing measurements across different platforms., Competing Interests: Declarations. Ethics approval and consent to participate: All participants gave written informed consent to use medical data and biomaterial for research purposes. Ethical approval of the Amsterdam UMC VUmc medical ethical committee was in place, and the study was performed in accordance with the Helsinki Declaration of 1975. Consent for publication: Not applicable. Competing interests: JV, CL, MVL, and ES are employees of ADx NeuroSciences, part of the Fujirebio group. NB and MV are employees of Fujirebio Europe. AJ is an employee of ALZpath, Inc and has stock options. CET is employed by Amsterdam UMC and she has grants or contracts for Research of the European Commission (Marie Curie International Training Network, grant agreement No. 860197 (MIRIADE), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434) EPND ( IMI 2 Joint Undertaking (JU), grant No. 101034344) and JPND (bPRIDE), National MS Society (Progressive MS alliance), Alzheimer Drug Discovery Foundation, Alzheimer Association, Health Holland, the Dutch Research Council (ZonMW), including TAP-dementia, a ZonMw funded project (#10510032120003) in the context of the Dutch National Dementia Strategy, Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands. CET is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). CET is also a contract researcher for ADx Neurosciences, AC-Immune, Aribio, Axon Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly Fujirebio, Grifols, Instant Nano Biosensors, Merck, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Siemens, Toyama, Vivoryon, and the European Commission. CET has received payment or honoraria from Roche, Novo Nordisk, and Grifols, where all payments were made to her institution. CET also serves on editorial boards of Medidact Neurologie/Springer; and in Neurology: Neuroimmunology & Neuroinflammation. She is editor of Alzheimer Research and Therapy. Research programs of Wiesje van der Flier (WF) have been funded by ZonMW, NWO, EU-JPND, EU-IHI, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, Eisai, Combinostics. WF holds the Pasman chair. WF is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). WF is recipient of TAP-dementia (www.tap-dementia.nl), receiving funding from ZonMw (#10510032120003). TAP-dementia receives co-financing from Avid Radiopharmaceuticals, Roche, and Amprion. All funding is paid to her institution.WF has been an invited speaker at Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, European Brain Council. All funding is paid to her institution.WF is consultant to Oxford Health Policy Forum CIC, Roche, Biogen MA Inc, and Eisai. All funding is paid to her institution. WF participated in advisory boards of Biogen MA Inc, Roche, and Eli Lilly. WF is member of the steering committee of EVOKE/EVOKE+ (NovoNordisk). All funding is paid to her institution.WF is member of the steering committee of PAVE, and Think Brain Health. WF was associate editor of Alzheimer, Research & Therapy in 2020/2021. WF is associate editor at Brain. Inge M.W.Verberk received a speaker honorarium from Quanterix, which was paid directly to her institution. All the other authors have nothing to disclose., (© 2024. The Author(s).)

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, characterized by progressive neuromuscular degeneration resulting from mutations in the survival motor neuron ( SMN1 ) gene. The availability of disease-modifying therapies for SMA therapies highlights the pressing need for easily accessible and cost-effective blood biomarkers to monitor treatment response and for better disease management. Additionally, the wide implementation of newborn genetic screening programs in Western countries enables presymptomatic diagnosis of SMA and immediate treatment administration. However, the absence of monitoring and prognostic blood biomarkers for neurodegeneration in SMA hinders effective disease management. Neurofilament light protein (NfL) is a promising biomarker of neuroaxonal damage in SMA and reflects disease progression in children with SMA undergoing treatment. Recently, the European Medicines Agency issued a letter of support endorsing the potential utilization of NfL as a biomarker of pediatric neurological diseases, including SMA. Within this review, we comprehensively assess the potential applications of NfL as a monitoring biomarker for disease severity and treatment response in pediatric-onset SMA. We provide reference ranges for normal levels of serum based NfL in neurologically healthy children aged 0-18 years. These reference ranges enable accurate interpretation of NfL levels in children and can accelerate the implementation of NfL into clinical practice., (© 2024 the author(s), published by De Gruyter, Berlin/Boston.)