# Plasma p-tau species are elevated in presymptomatic and symptomatic neuronal intranuclear inclusion disease

## TL;DR

Plasma p-tau levels are elevated in both presymptomatic and symptomatic neuronal intranuclear inclusion disease, suggesting their potential as biomarkers.

## Contribution

This study identifies plasma p-tau species as potential biomarkers for neuronal intranuclear inclusion disease (NIID), including presymptomatic stages.

## Key findings

- P-tau217, p-tau231, p-tau181, α-syn, NfL, and GFAP levels are elevated in NIID patients compared to healthy controls.
- P-tau species and GFAP are also upregulated in presymptomatic NIID individuals.
- P-tau217 is associated with cognitive scores and distinct tau deposition patterns in NIID without Aβ pathology.

## Abstract

Neuronal intranuclear inclusion disease (NIID), caused by GGC repeat expansions in NOTCH2NLC, is a neurodegenerative disease frequently involved with cognitive impairment. Limited studies have focused on the biomarkers alteration in patients with NIID and presymptomatic NIID (preNIID) individuals. The clinical overlap between NIID and AD drives the exploration of plasma biomarker alterations in NIID and preNIID.

Cohorts 1 (87 patients with NIID, 147 individuals with Alzheimer's disease [AD], and 110 healthy controls [HCs]) and 2 (26 individuals with preNIID and 26 HCs) were included. Eight plasma biomarkers including amyloid-β (Aβ) 40, Aβ42, neurofilament light (NfL), α-synuclein (α-syn), phosphorylated tau protein 181 (p-tau181), p-tau217, p-tau231, and glial fibrillary acidic protein (GFAP) were detected. Neuropsychological scores, magnetic resonance imaging measures, Aβ positron emission tomography (Aβ-PET), and tau-PET were analysed.

P-tau217, p-tau231, p-tau181, α-syn, NfL, and GFAP levels were elevated in patients with NIID compared with HCs; p-tau species and GFAP were also upregulated in preNIID. P-tau species, particularly p-tau217, effectively distinguished NIID/preNIID from HCs (AUC 0.814/0.848), but failed to differentiate NIID from AD. The level of p-tau217 was associated with MMSE and FAB scores in dementia-dominant subtype, and the level of GFAP correlated to white matter volume. A tau-PET study revealed distinct tau deposition on the occipital lobe and temporal pole in NIID without Aβ pathology.

The significant changes of p-tau levels and prominent tau deposition highlight tau pathology involvement in NIID. Elevated plasma p-tau species in preNIID/NIID indicate their potential as biomarkers for NIID.

This study was supported by the 10.13039/501100001809National Natural Science Foundation of China (82394421, 82394420, 82371866, 82371434); the 10.13039/501100012166National Key R&D Program of China (2022ZD0213700); Natural Science Foundation of Hunan Province (2023JJ10097, 2025JJ40089, 2023JJ40948).