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P1‐024: INCREASED STREM‐2 IN AMYLOID‐POSITIVE PATIENTS WITH SUBJECTIVE COGNITIVE DECLINE
Author(s) -
Nordengen Kaja,
Henjum Kristi,
Selnes Per,
Nilsson Lars,
Fladby Tormod
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.025
Subject(s) - cerebrospinal fluid , cognitive decline , medicine , atrophy , dementia , amyloid (mycology) , etiology , disease , immunology , pathology
Background:Misfolded tau protein as intracellular neurofibrillary tangles (NFT) are a core pathology of Alzheimer disease (AD). However, the process leading to soluble tau release and insoluble aggregation represent complex biological processes with uncertain relationships to other AD pathologies and clinical symptoms. The objective of this study is to assess the longitudinal profile of multiple cerebrospinal fluid (CSF) phosphorylated tau sites in familial dominantly inherited AD (DIAD) in relation to cortical amyloid and the estimated age of symptom onset.Methods:We analyzed longitudinal Amyloid beta (Ab) PiB-PET and CSF by mass spectrometry (MS) and immunoassays in 115 participants (405 samples) at 50% risk of carrying a DIAD mutation enrolled in dominantly inherited AD study. CSF tau peptides and phosphorylated peptides at T181, S202, T205 and T217 were quantified. Multivariable, linear mixed effect models were used to estimate the rate of change for all measures in relation to the estimated years until symptom onset (EYO) and Pearson’s correlation to assess the cross-sectional association between measures. Results:Compared to mutation noncarriers, mutation carriers began cortical fibrillar Ab deposition and elevation of CSF tau T217 hyper phosphorylation at 19 and 21 years before the estimated year of onset (Figure, top/middle). Together with total tau levels, the rate of phosphorylation on T205 appeared to increase closer to symptom onset (not significant, Figure, bottom). MS and ELISA total tau levels were strongly correlated (r 1⁄4 0.96, p <0.05) and MS and ELISA p-tau181 p-tau181 (r 1⁄40.69, p < 0.05). Furthermore, both T217 and T205 phosphorylation rates were strongly inversely associated with cognitive decline (r1⁄4 -0.73 and -0.74; p< 0.05). Conclusions:These data suggest an evolution of soluble tau phosphorylated epitopes, first on T217 that coincides with the initial development of fibrillar Ab plaque pathology, followed T205, T181 (not shown), and then CSF total tau levels increase more closely to symptom onset (and, presumably, NFT development). These findings are important for a better understanding of the tau-pathology associated with neurodegeneration in AD, and suggest these phosphorylated tau epitopes may serve as a sensitive step-wise, non-Ab, AD biomarker of disease progression.