Cognitive Intervention Effects Vary as a Function of Plasma Neurofilament Light Chain Levels: A PICMOR Randomized Controlled Trial

Background There is a difference in the neuronal state of individuals. However, this has not been taken into consideration in most intervention studies. Recent advances in analytical technologies in hematological examination enabled us to evaluate neuronal states in a relatively convenient manner. Objective Using these advanced technologies, we aimed to investigate whether cognitive intervention effects vary as a function of levels of blood-based biomarkers, such as neurofilament light chain (NfL), since plasma NfL could be a biomarker of neurodegenerative diseases including Alzheimer’s disease. Methods In this study, we employed a group conversation-based intervention methodology named Photo-Integrated Conversation Moderated by Robots (PICMOR), which has been shown to improve verbal fluency in older adults. To examine the possibility of varying effects of this intervention method according to the neuronal state of each individual, we conducted a randomized controlled trial (UMIN Clinical Trials Registry number: UMIN000036599) and investigated how longitudinal changes in cognitive performance, such as verbal fluency, vary with the NfL level measured at the baseline. Results As the main result, positive intervention effects of PICMOR on verbal fluency were observed in individuals with lower level of NfL, which indicate a relatively intact neuronal state, whereas negative intervention effects were identified in individuals with higher NfL level. Conclusion Our findings suggest that cognitive intervention effects vary depending on level of Nfl in the plasma. Thus, future intervention studies should take into account the neuronal status of the participants to examine intervention effects. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial UMIN Clinical Trials Registry number: UMIN000036599 ### Funding Statement This study was funded by JSPS KAKENHI (Grant Numbers: JP18KT0035, JP19H01138, JP19K14489, JP20H05022, JP20H05574, JP20K19471, JP22H04872, JP22H00544) and the Japan Science and Technology Agency (Grant Numbers: JPMJCR20G1, JPMJPF2101, and JPMJMS2237). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Board of RIKEN gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors