Phosphorylated tau as a candidate biomarker for amyotrophic lateral sclerosis

Abstract

Importance: An increasingly varied clinical spectrum of cases with amyotrophic lateral sclerosis (ALS) has been identified, and objective criteria for clinical trial eligibility are necessary.

Objective: To develop a cerebrospinal fluid (CSF) biomarker sensitive and specific for the diagnosis of ALS.

Design, setting, and participants: A case-control study including 51 individuals with ALS and 23 individuals with a disorder associated with a 4-repeat tauopathy was conducted at an academic medical center.

Main outcomes and measures: The CSF level of tau phosphorylated at threonine 181 (ptau) and ratio of ptau to total tau (ttau).

Results: Using a cross-validation prediction procedure, we found significantly reduced CSF levels of ptau and the ptau:ttau ratio in ALS relative to 4-repeat tauopathy and to controls. In the validation cohort, the receiver operating characteristic area under the curve for the ptau:ttau ratio was 0.916, and the comparison of ALS with 4-repeat tauopathy showed 92.0% sensitivity and 91.7% specificity. Correct classification based on a low CSF ptau:ttau ratio was confirmed in 18 of 21 cases (86%) with autopsy-proved or genetically determined disease. In patients with available measures, ptau:ttau in ALS correlated with clinical measures of disease severity, such as the Mini-Mental State Examination (n = 51) and ALS Functional Rating Scale-Revised (n = 42), and regression analyses related the ptau:ttau ratio to magnetic resonance imaging (n = 10) evidence of disease in the corticospinal tract and white matter projections involving the prefrontal cortex.

Conclusions and relevance: The CSF ptau:ttau ratio may be a candidate biomarker to provide objective support for the diagnosis of ALS.

FIGURE 1

BOXPLOTS OF CSF ANALYTES PTAU NG/ML, TTAU NG/ML, AND PTAU:TTAU RATIO IN AMYOTROPHIC LATERAL SCLEROSIS, FOUR-REPEAT TAUOPATHY, AND HEALTHY SENIORS. NOTE. Dark lines in boxplots illustrate median CSF value, notches illustrate interquartile range (non-overlapping notches are significantly different), and error bars represent full range of data.

FIGURE 2

RECEIVER OPERATING CHARACTERISTIC CURVE ILLUSTRATING THE SENSITIVITY AND SPECIFICITY OF CSF PTAU, TTAU, AND PTAU:TTAU RATIO IN AMYOTROPHIC LATERAL SCLEROSIS RELATIVE TO FOUR-REPEAT TAUOPATHIES.

FIGURE 3

REDUCED WHITE MATTER FRACTIONAL ANISOTROPY IN AMYOTROPHIC LATERAL SCLEROSIS AND 4R-TAU, AND REGRESSIONS RELATING ADJUSTED CSF PTAU:TTAU RATIO TO FRACTIONAL ANISOTROPY. NOTE. Panel A: Right anterior view of anatomic distribution of reduced fractional anisotropy in ALS (q<0.05, FDR-corrected; green). Red areas indicate anatomic distribution of regressions relating adjusted ptau:ttau ratio to fractional anisotropy in corticospinal tract, prefrontal centrum semiovale, and body of corpus callosum (not illustrated). Panel B: Left anterior view of anatomic distribution of reduced fractional anisotropy in 4R-tau (q<0.005, FDR-corrected; green). Red areas indicate anatomic distribution of regressions relating adjusted ptau:ttau ratio to fractional anisotropy in midbrain, right uncinate (not illustrated).