Elevated levels of CSF p‐tau212 in FTLD‐Tau

Abstract Background Phosphorylated‐tau (p‐tau) biomarkers are typically specific for Alzheimer’s disease (AD) and are less elevated in the cerebrospinal fluid (CSF) of frontotemporal lobar degeneration (FTLD) type tau (FTLD‐tau). FTLD is a pathologically and clinically heterogenous neurodegenerative disorder, and we currently lack biomarkers to differentiate the two major pathological subtypes 1) FTLD‐tau, where pathological tau aggregation is observed or 2) FTLD‐TDP, where TAR‐DNA binding protein 43 (TDP‐43) is linked with the disease development and progression. Because FTD clinical phenotype does not predict pathology, biomarkers sensitive to FTLD‐tau are needed to provide a biological diagnosis in life. In this study, we test CSF p‐tau212 in patients with autopsy‐ or mutation‐confirmed FTLD‐tau and FTLD‐TDP without AD pathology; clinically healthy individuals without cognitive impairment and autopsy‐confirmed Lewy body disease with alpha‐synuclein (αSyn) were included as reference groups. Method Autopsies were performed at the University of Pennsylvania in the Center for Neurodegenerative Disease Research. Definite diagnosis was based on autopsy results or determined genetically. Using SIMOA technology, we tested p‐tau212 in 51 healthy controls, 33 FTLD‐Tau, 36 FTLD‐TDP and 13 αSyn (Figure 1). For further analysis we excluded individuals with evidence of AD pathology: intermediate/high AD neuropathologic change (ADNC), Thal phase ≥2, or CSF β‐amyloid 1‐42 ≤192. Wilcoxon test was used to compare groups. In brain regions sampled at autopsy, pathological tau burden was rated using a semi‐quantitative 5‐point scale; Spearman correlations tested associations between p‐tau212 and tau burden by region. Result CSF p‐tau212 was significantly increased in FTLD‐Tau when compared to healthy controls, people with FTLD‐TDP and people with αSyn pathology (Figure 2). Results remained significant when people with evidence of AD pathology were excluded. P‐tau212 measurements strongly correlated with tau burden across multiple brain regions (Figure 3). Average correlation was r=0.57, p<0.0001. Conclusion CSF p‐tau212 is strong candidate biomarker to differentiate FTLD‐tau from FTLD‐TDP and αSyn.