Ante mortem CSF tau levels correlate with post mortem tau pathology in FTLD

ABSTRACT

Objective: To test the hypotheses that 1) antemortem cerebrospinal fluid tau levels correlate with postmortem tau pathology in frontotemporal lobar degeneration and 2) tauopathy patients have higher phosphorylated-tau levels compared to TDP-43 proteinopathy patients while accounting for Alzheimer's disease co-pathology.

Methods: Patients had autopsy-confirmed frontotemporal lobar degeneration with tauopathy (n=31), TDP-43 proteinopathy (n=49), or Alzheimer's disease (n=26) with antemortem cerebrospinal fluid. Cerebrospinal fluid tau levels were compared between groups and correlated with digital histology measurement of postmortem tau pathology averaged from three cerebral regions (angular gyrus, mid-frontal cortex, anterior cingulate gyrus). Multivariate linear regression tested the association of ante mortem cerebrospinal fluid tau levels with post mortem tau pathology adjusting for demographics.

Results: Multivariate regression found an independent association of ante mortem cerebrospinal fluid phosphorylated tau levels with post mortem cerebral tau pathology in frontotemporal lobar degeneration (Beta=1.3, 95%CI=0.2-2.4, p<0.02). After excluding patients with coincident Alzheimer-associated tau pathology accompanying sporadic frontotemporal lobar degeneration, we found lower cerebrospinal fluid phosphorylated tau levels in the TDP-43 group (median=7.4 pg/ml, IQR=6.0,12.3, n=26) compared to the tauopathy group (median=12.5 pg/ml, IQR=10.7,15.0, n=23; Z=2.6,p<0.01).

Interpretation: Cerebrospinal fluid phosphorylated-tau levels are positively associated with cerebral tau burden in frontotemporal lobar degeneration. In vivo detection of Alzheimer's disease co-pathology in sporadic frontotemporal lobar degeneration patients may help stratify clinical cohorts with pure neuropathology in which low cerebrospinal fluid phosphorylated-tau levels may have diagnostic utility to distinguish TDP-43 proteinopathy from tauopathy. Autopsy-confirmed samples are critical for frontotemporal lobar degeneration biomarker development and validation. This article is protected by copyright. All rights reserved.

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