Elevated Cerebrospinal Fluid Total Tau in Niemann-Pick Disease Type C1: Correlation With Clinical Severity and Response to Therapeutic Interventions

Abstract

Niemann-Pick disease, type C1 (NPC1) is an inborn error of intracellular cholesterol transport. Impaired function of NPC1 leads to endolysosomal accumulation of unesterified cholesterol, which results in progressive neurodegeneration. Although the age of onset is variable, classical NPC1 is a pediatric disease. Identification of biomarkers that correlate with clinical phenotype and respond to therapeutic interventions will be essential for developing effective therapeutic interventions. Aβ peptides and Tau protein are primary components of amyloid plaques and neurofibrillary tangles, respectively, which are major pathological features in neurodegenerative disorders. Cerebrospinal fluid (CSF) levels of total Tau, a biomarker of axonal damage, were elevated ~3-fold (p < 0.0001) in 106 individuals with Niemann-Pick disease, type C1, relative to age-appropriate comparison samples. Baseline CSF total Tau levels correlated with clinical measures of disease severity. Specifically, CSF total Tau levels decreased with increased age of neurological onset (r_s = -0.42, FDR adj. p < 0.0001) and increased with increased Annual Severity Increment Score (r_s = 0.52, FDR adj. p < 0.0001). Baseline CSF total Tau levels were decreased 40% (p = 0.0066) in individuals being treated with miglustat, and longitudinal analysis substantiated this observation with a 40% decrease (p < 0.0001, 95% CI 32%-47.4%). Longitudinal analysis also showed a significant (p = 0.004) decrease of 19% (95% CI 7%-30%) in total Tau levels associated with intrathecal 2-hydroxypropyl-β-cyclodextrin therapy. These data show that CSF total Tau levels are significantly increased in individuals with NPC1, positively correlated with increased disease severity, and respond to therapeutic interventions.

Keywords: NPC1; Niemann‐Pick disease type C1; biomarker; cerebrospinal fluid; lysosomal disease, miglustat, adrabetadex; total Tau.

FIGURE 1

Baseline CSF total Tau levels. (A) Log₁₀ CSF total Tau levels were elevated (p < 0.0001, Mann–Whitney‐U test) in individuals with NPC1 relative to age‐appropriate non‐NPC1 comparison samples. Baseline CSF total Tau levels were significantly (p = 0.0066, Mann–Whitney‐U test) lower in individuals with NPC1 being treated with miglustat (Mig). (B) Log₁₀ CSF total Tau levels decreased (p < 0.0001, Kruskal–Wallis) toward normal when categorized by age of neurological onset category. (C) CSF log₁₀ P‐Tau(181) (ng/mL) in NPC1 and age‐appropriate comparison samples. (D) Plasma log₁₀ pTau(217) levels in control and NPC1 samples.

FIGURE 2

Spearman correlations between CSF total Tau levels and measures of clinical severity and disease burden in individuals with NPC1. Spearman correlations were determined for Age of Neurological Onset (A), Annualized Severity Index Score (B), 17‐domain NPC Neurological Severity Score (C), and 5‐domain NPC Neurological Severity Score (D). A significant negative association was observed for log₁₀ CSF total Tau levels and Age of Neurological onset. A significant positive association was observed for log₁₀ CSF total Tau and the Annualized Severity Index Score. Neither the concurrent 17‐ nor 5‐domain NPC Neurological Severity Scores were correlated with CSF total Tau levels.

FIGURE 3

Longitudinal analysis of CSF total Tau. Forest plot of fold change in total Tau levels with one unit increase in a covariate and 95% confidence intervals for the six covariates evaluated using a linear mixed effects model. Significant decreased total Tau levels were associated with both miglustat and intrathecal 2HPβCD therapy.