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.