CSF p-tau181 Increases in Patients with Neuronal Intranuclear Inclusion Disease without Amyloid Burden

Background and Objectives CSF tau phosphorylated at threonine 181 (p-tau181) is a widely used biomarker for Alzheimer’s disease (AD) and has recently been regarded to reflect amyloid-beta (Aβ) and/or p-tau deposition in the AD brain. Although it is important to know how this biomarker reacts in other neurocognitive diseases, CSF p-tau181 in patients with neuronal intranuclear inclusion disease (NIID) has not been studied. Methods CSF concentrations of p-tau181, total tau, amyloid-beta 1-42 (Aβ42), monoamine metabolites homovanillic acid (HVA), and 5-hydroxyindole acetic acid (5-HIAA) were compared between 12 patients with NIID, 120 patients with symptomatic AD biologically confirmed based on CSF biomarker profiles, and patients clinically diagnosed with other neurocognitive disorders (dementia with Lewy bodies [DLB], 24; frontotemporal dementia [FTD], 13; progressive supranuclear palsy [PSP], 21; and corticobasal syndrome [CBS], 13). Amyloid PET using Pittsburgh compound B (PiB) was performed in six NIID patients. Results CSF p-tau181 concentration was significantly higher in NIID (72.7 ± 24.8 pg/mL) compared to DLB, PSP, and CBS and was comparable between NIID and AD. CSF p-tau181 was above the cutoff value (50.0 pg/mL) in 11 of 12 NIID patients (91.7%). Within these patients, only two patients showed decreased CSF Aβ42, and these patients showed negative or mild local accumulation in PiB PET, respectively. PiB PET scans were negative in the remaining 4 patients tested. CSF HVA and 5-HIAA concentrations were significantly higher in patients with NIID compared to disease controls. Discussion CSF p-tau181 was increased in patients with NIID without amyloid accumulation. Although the deposition of p-tau has not been reported in NIID brains, molecular mechanism of tau phosphorylation or secretion of p-tau may be altered in NIID. ### Competing Interest Statement Atsushi Iwata receives research grants from Fujirebio, Inc. The remaining authors declare no disclosures relevant to the manuscript. ### Funding Statement This study was supported by Intramural Research Grant of TMGHIG to M.K. and K.K, AMED 22dk0207057h0001 to A.I., and KAKENHI 20H03587 and 21K19465 to A.I. ### 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: The study protocols were approved by the Institutional Review Board of the Tokyo Metropolitan Institute of Gerontology (approval No. 250217). The study protocol for genetic testing in neurodegenerative diseases were approved by the Institutional Review Board of the University of Tokyo (approval No. G1396). 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors