CSF p-Tau181/Tau ratio to distinguish FTLD-TDP from FTLD-Tau

Background: To evaluate the CSF p-Tau181/Tau ratio to distinguish between the two main forms of frontotemporal lobar degeneration (FTLD): FTLD with TAR DNA-binding protein 43 (TDP-43) immunoreactive inclusions (FTLD-TDP) and FTLD with Tau inclusions (FTLD-Tau). Methods: Differences in the CSF p-Tau/t-Tau ratio were examined in patients with predictable Tau (n=27, as affected by Progressive Supranuclear Palsy) and TDP-43 (n=22, as carriers of mutations within Granulin gene, C9orf72 or affected by FTD with motor neuron disease) neuropathology. Cut-off values were determined to achieve highest values of sensitvity and specificity according to ROC curve analysis. Cut-off values were applied to a second cohort of cases with unpredictable underlying neuropathology, including behavioural variant FTD (bvFTD, n=82), corticobasal degeneration (CBS, n=40), agrammatic variant of primary progressive aphasia (avPPA, n=16), amyotrophic lateral sclerosis (ALS, n=12), and synucleopathies (Dementia with Lewy bodies, multiple system atrophy, n=16), and healthy controls (HC, n=37). Results: FTLD-TDP cases had reduced levels of p-Tau, and the cut-off value of <0.1305 (p/t-Tau ratio) allowed to differentiate FTLD-TDP from FTLD-Tau with 92.6% sensitivity and 77.3% specificity. In non-TDP disease, such as synucleopathies, ratio score was within normal range in 68.8% of cases, whilst in TDP disease, such as ALS, predicted neuropathology in almost 70% of cases. A TDP-like p/t-Tau ratio was found in 51.2% bvFTD, with a distribution consistent with previous clinicopathologic studies in FTLD, in 25% of CBS, and in 43.8% of avPPA patients. HC had a ratio within normal range in 73% of cases. Conclusions: A reliable biomarker that accurately predicts the FTLD neuropathology is urgently needed in the prospect of disease-modifying therapies that target the underlying pathological process. A reduced CSF p/t-Tau ratio represents a viable and reproducible biomarker to correctly distinguish FTLD-TDP and FTLD-Tau. Detecting an on-going TDP or Tau pathological process in FTLD has several implications for defining distinctive therapeutic approaches, guiding genetic screening and helping in patients' selection in future clinical trials.