Letournel, Franck

Abstract Background The quantification of Neurofilament Light chain (NfL) in blood and cerebrospinal fluid (CSF) has proven valuable for diagnosing and prognosing various neurological disorders, including Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, parkinsonism, multiple sclerosis, and ischemic damage. However, there is considerable variability in clinical and laboratory practices between centers, primarily due to different contexts of use (COU), analytical methods, and the application of cutoffs or scales. Additionally, for the same biochemical profile, the interpretation and reporting of results may vary from one center to another, raising concerns about the commutability of the tests. To date, no consensus has been reached among laboratories to define the most appropriate use of cutoffs or conclusions/comments based on NfL profiles. Method This international project involves 38 laboratories across 18 countries, all specialized in the biochemical diagnosis of neurological disorders. Using a questionnaire, we obtained descriptions from each center regarding their COU, pre‐analytical and analytical protocols (including the biological fluid and methods used to quantify NfL). Through a consensus approach, we developed a harmonized strategy for the use and reporting of NfL results across different centres according to their respective COU. Results Among the centers, 63% quantified NfL in the CSF, 87% in blood and 53% in both fluids. COU were as follow: frontotemporal dementia (71%), Alzheimer disease (71%), multiple sclerosis (61%), amyotrophic lateral sclerosis (61%), psychiatric syndrome (45%), Creutzfeldt‐Jakob disease (32%), Parkinson disease (39%), peripheral neuropathy (29%), traumatic brain injury (21%), Huntington's disease (13%), amyloid transthyretin related (11%) and cardiac arrest (8%). Most of the centers define pathological cutoffs based on publications (50%) and take age into account for this purpose (42%). Reporting is mostly transmitted through numeric results (95%). Conclusion Harmonizing cutoffs, reporting, and interpretation across various clinical contexts will facilitate the incorporation of this biomarker into routine clinical practice.

Abstract INTRODUCTION Neurofilament light chain (NfL) quantification aids in diagnosing and predicting neurological disorders, but clinical and laboratory practices vary across centers. Differences in result interpretation and reporting further challenge test commutability. This study aimed to review the global analytical and post‐analytical methods used for NfL measurement in routine clinical practice across different contexts. METHODS We established an international working group (WG) and distributed a survey to its members to gather information on context of use (COU), (pre) analytical methods, cutoff usage, as well as the interpretation and reporting of NfL measurements. RESULTS Among the centers, 63% measured NfL in cerebrospinal fluid (CSF), 87% in blood, and 53% in both. COU was widespread, with 50% defining pathological cutoffs based on publications and 42% considering age. Reporting was primarily done through numeric results (95%). DISCUSSION Harmonizing cutoffs, reporting, and interpretation across various clinical contexts will facilitate the incorporation of this biomarker into routine clinical practice. Highlights Unique international overview of current analytical and post‐analytical methods for neurofilament light chain (NfL) measurement in routine clinical practice. Tailored sheets for each neurological application. Strategies to harmonize cutoffs, reporting, and interpretation of NfL's measurement.

Background: Conflicting results from studies of Lewy-type α−synucleinopathy (LTS) in colonic biopsies of subjects with Parkinson’s disease (PD) prompted a two-part multicenter assessment. The first assessment, now published (Acta Neuropathol Commun 4 : 35, 2016), examined archived colonic biopsies and found that none of the tested methods was adequately sensitive or specific. Objective: As the amount of nervous tissue in typical colonic biopsies may be insufficient, and the clinical diagnosis of PD not completely accurate, the objective of the current study was to use instead full-thickness sections of sigmoid colon from autopsy-proven PD and normal subjects. Methods: Seven different immunohistochemical (IHC) methods were used, employing five different primary antibodies and four different combinations of epitope exposure and signal development protocols. Specific staining was defined as being restricted to morphological features consistent with neuronal elements. Stained slides from each subject were independently categorized as being positive or negative for LTS, and their density semi-quantitatively graded, by four raters blinded to diagnosis. Results: Agreement and mean diagnostic performance varied markedly between raters. With the two most accurate raters, 5 methods achieved diagnostic accuracies of 70% or greater; one method had 100% accuracy and 100% inter-rater agreement. The submucosa had the highest prevalence of pathological LTS staining, followed by the muscularis and mucosa. Conclusions: The major conclusion of this study is that, when sufficient submucosa and LTS is present, and when specific staining is defined as being consistent with neuronal morphology, adequately-trained raters may reliably distinguish PD colon from control using suitable IHC methods.