Citation and Abstract


Fagan AM, Mintun MA, Shah AR, Aldea P, Roe CM, Mach RH, Marcus D, Morris JC, Holtzman DM. Cerebrospinal fluid tau and ptau181 increase with cortical amyloid deposition in cognitively normal individuals: Implications for future clinical trials of Alzheimer's disease EMBO Molecular Medicine. 2009 Nov 1;1(8-9):371-380.

 

REAGENTS/MATERIAL:
CSF samples were analysed for Ab42, total tau and phospho-tau181 (ptau181) by enzyme-linked immunosorbant assay (ELISA) (InnotestTM, Innogenetics, Ghent, Belgium). CSF Ab40 was assayed by ELISA (Cirrito et al, 2003), and plasma Ab1–40, Ab1–42 and Abx–40, Abx–42 were analysed by xMAP (bead-based) ELISA (Inno-Bia Plasma Ab Forms Multiplex AssayTM; Innogenetics, Ghent, Belgium). CSF Ab38 was analysed by an antibody-based electrochemiluminescence assay according to the manufacturer’s recommendations (MSD 96 well Multi-Array Human (6E10) Abeta 38 Ultra-Sensitive KitTM, Meso Scale Discovery, Gaithersburg, MD)

  ABSTRACT
Alzheimer's disease (AD) pathology is estimated to develop many years before detectable cognitive decline. Fluid and imaging biomarkers may identify people in early symptomatic and even preclinical stages, possibly when potential treatments can best preserve cognitive function. We previously reported that cerebrospinal fluid (CSF) levels of amyloid-42 (A42) serve as an excellent marker for brain amyloid as detected by the amyloid tracer, Pittsburgh compound B (PIB). Using data from 189 cognitively normal participants, we now report a positive linear relationship between CSF tau/ptau181 (primary constituents of neurofibrillary tangles) with the amount of cortical amyloid. We observe a strong inverse relationship of cortical PIB binding with CSF A42 but not for plasma A species. Some individuals have low CSF A42 but no cortical PIB binding. Together, these data suggest that changes in brain A42 metabolism and amyloid formation are early pathogenic events in AD, and that significant disruptions in CSF tau metabolism likely occur after A42 initially aggregates and increases as amyloid accumulates. These findings have important implications for preclinical AD diagnosis and treatment.