CSF P-Tau181 and Other Biomarkers in Patients With Neuronal Intranuclear Inclusion Disease

Abstract

Background and objectives: CSF tau phosphorylated at threonine 181 (p-tau181) is a widely used biomarker for Alzheimer disease (AD) and has recently been regarded to reflect β-amyloid and/or p-tau deposition in the AD brain. Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by intranuclear inclusions in neurons, glial cells, and other somatic cells. Symptoms include dementia, neuropathy, and others. CSF biomarkers were not reported. The objective of this study was to investigate whether CSF biomarkers including p-tau181 are altered in patients with NIID.

Methods: This was a retrospective observational study. 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 Alzheimer clinical syndrome 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 6 patients with NIID.

Results: The mean age of patients with NIID, AD, DLB, FTD, PSP, and CBS was 71.3, 74.6, 76.8, 70.2, 75.5, and 71.9 years, respectively. CSF p-tau181 was significantly higher in NIID (72.7 ± 24.8 pg/mL) compared with 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 patients with NIID (91.7%). Within these patients, only 2 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. The proportion of patients with increased CSF p-tau181 and normal Aβ42 (A-T+) was significantly higher in NIID (75%) compared with DLB, PSP, and CBS (4.2%, 4.8%, and 7.7%, respectively). CSF HVA and 5-HIAA concentrations were significantly higher in patients with NIID compared with 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, the molecular mechanism of tau phosphorylation or secretion of p-tau may be altered in NIID.

Figure 1. AD-Related CSF Biomarkers in Patients With NIID and Disease Controls

(A) CSF p-tau181 was significantly higher in AD compared with DLB, FTD, PSP, and CBS, as previously reported. CSF p-tau181 was significantly higher in NIID compared with DLB, PSP, and CBS. (B) CSF Aβ42 was decreased in AD, DLB, and PSP. CSF Aβ42 was higher in NIID compared with AD, DLB, and PSP and was comparable to FTD and CBS. (C) CSF t-tau was significantly higher in AD compared with NIID, DLB, FTD, PSP, and CBS, as previously reported. CSF t-tau also showed a higher trend in NIID, although nonsignificant. (D) CSF p-tau181 and t-tau showed moderate correlation in NIID (r = 0.57), AD (r = 0.62), DLB (r = 0.50), and CBS (r = 0.37). The difference of CSF p-tau181 between NIID and AD was nonsignificant by ANCOVA adjusted by CSF t-tau (p = 0.56). * 0.01 ≤ p < 0.05; ** 0.001 ≤ p < 0.01; *** 0.0001 ≤ p < 0.001; **** p < 0.0001. Aβ42 = amyloid-beta 42; AD = Alzheimer disease; ANCOVA = analysis of covariance; CBS = corticobasal syndrome; DLB = dementia with Lewy body; FTD = frontotemporal dementia; NIID = neuronal intranuclear inclusion disease; p-tau181 = tau phosphorylated at threonine 181; PSP = progressive supranuclear palsy; t-tau = total tau.

Figure 2. AT(N) Classification in Patients With NIID and Disease Controls

(A) Scatter plot of CSF Aβ42 and p-tau181 levels of each patient. Quadrants are divided into A−T−, A+T−, A−T+, or A+T+ according to the presence of abnormal CSF Aβ42 (A) and p-tau181 (T) results using predetermined institutional cutoffs. (B) Bar graph showing the frequency of each AT(N) classification in each disease groups. The frequency of A−T+ was significantly higher in NIID compared with AD, DLB, PSP, and CBS. Bonferroni-adjusted p values are used. The number of independent tests was 15. Aβ42 = amyloid-beta 42; AD = Alzheimer disease; CBS = corticobasal syndrome; DLB = dementia with Lewy body; NIID = neuronal intranuclear inclusion disease; p-tau181 = tau phosphorylated at threonine 181; PSP = progressive supranuclear palsy.

Figure 3. CSF Monoamine Metabolites in Patients With NIID and Disease Controls

(A) CSF homovanillic acid (HVA) was significantly higher in NIID compared with AD, DLB, FTD, PSP, and CBS. CSF HVA was significantly lower in DLB compared with AD, as previously reported. (B) CSF 5-hydroxyindole acetic acid (5-HIAA) was significantly higher in NIID compared with AD, DLB, FTD, PSP, and CBS. CSF 5-HIAA was significantly lower in DLB compared with AD, as previously reported. ** 0.001 ≤ p < 0.01; *** 0.0001 ≤ p < 0.001; **** p < 0.0001. 5-HIAA = 5-hydroxyindole acetic acid; AD = Alzheimer disease; CBS = corticobasal syndrome; DLB = dementia with Lewy body; FTD = frontotemporal dementia; HVA = homovanillic acid; NIID = neuronal intranuclear inclusion disease; PSP = progressive supranuclear palsy.