[P1.088] Phosphorylated Tau Is a Candidate Biomarker for Amyotrophic Lateral Sclerosis

Murray Grossman,1Lauren Elman,2Leo McCluskey,1Corey McMillan,1Ashley Boller,1John Powers,1Katya Rascovsky,1William Hu,3Leslie Shaw,1David Irwin,1Virginia Lee,1John Trojanowski1
1Philadelphia, PA, USA, 2Merion Station, PA, USA, 3Atlanta, GA, USA

OBJECTIVE: We sought to develop a cerebrospinal fluid (CSF) biomarker sensitive and specific for the diagnosis of amyotrophic lateral sclerosis (ALS).
BACKGROUND: An increasingly varied clinical spectrum of cases with amyotrophic lateral sclerosis (ALS) has been identified, and objective criteria for clinical trial eligibility must be established. Examinations of brain pathological samples show very low levels of phosphorylated tau in ALS compared to patients with progressive supranuclear palsy and other four-repeat tauopathies (4R-tau).
DESIGN/METHODS: A cohort of clinically-diagnosed ALS (N=51) and 4R-tau (N=23) individuals participated in a lumbar puncture. CSF was interrogated using standard procedures for levels of tau phosophorylated at threonine 181 (ptau), total tau (ttau), and ratio of ptau to total tau (pau:ttau). Most ALS patients had a Mini Mental State Exam (MMSE) and ALS Functional Rating Scale-Revised (FRS), and a subset of patients had MRI (n=10 ALS) or known pathology (n=21).
RESULTS: Using a cross-validation prediction procedure, we found significantly reduced CSF levels of ptau and ptau:ttau in ALS relative to 4R-tau 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 to 4R-tau showed sensitivity=92% and specificity=91.7%. Correct classification based on low CSF ptau:ttau was confirmed in 18 of 21 cases with known pathology. ptau:ttau in ALS correlated with clinical measures of disease severity including MMSE and FRS, and regression analyses related ptau:ttau to MRI evidence of disease in the corticospinal tract and white matter projections involving prefrontal cortex.
CONCLUSION: CSF ptau:ttau yields sensitive and specific differential diagnosis of ALS and therefore may be a candidate biomarker for the objective diagnosis of ALS.
STUDY SUPPORTED BY: AG032953, AG017586, AG043503, NS044266, AG038490, AG053488, and the Wyncote Foundation
Category - Neuromuscular and Clinical Neurophysiology (EMG): ALS/Anterior Horn Diseases

Monday, April 28, 2014 3:00 PM

P1: Poster Session I: Anterior Horn Cell Disease: Pathogenesis and Pathology (3:00 PM-6:30 PM)


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