Biomarkers.

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.