Phosphorylated Tau as a Candidate Biomarker for Amyotrophic Lateral Sclerosis

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