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Tau kinetics in Alzheimer disease and primary tauopathies
Author(s) -
Sato Chihiro,
Horie Kanta,
Barthelemy Nicolas R.,
Patterson Bruce W.,
Gordon Brian A.,
Benzinger Tammie L.S.,
Mallipeddi Nipun,
Sullivan Melissa,
Li Melody,
Lloyd LaKisha,
Elbert Donald L.,
Wright Brenton A.,
Day Gregory S.,
Davis Albert A.,
Rohrer Jonathan D.,
Paterson Ross W.,
Ghoshal Nupur,
Bateman Randall J.
Publication year - 2020
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 - 10.1002/alz.039109
Subject(s) - progressive supranuclear palsy , frontotemporal dementia , cerebrospinal fluid , tauopathy , positron emission tomography , alzheimer's disease , tau protein , corticobasal degeneration , pathology , tau pathology , neurodegeneration , psychology , neuroscience , medicine , dementia , disease , nuclear medicine
Background Understanding tau kinetics in the human central nervous system is critical for evaluating the effects of tau‐targeted therapies and designing clinical trials against tau in Alzheimer disease (AD) and other primary tauopathies. We hypothesized that tau production or clearance is altered in tauopathies and measured tau kinetics in AD and in a small set of participants with Progressive Supranuclear Palsy (PSP), Corticobasal Syndrome (CBS), or from Frontotemporal Dementia (FTD)‐ MAPT families. Methods In vivo human tau Stable Isotope Labeling Kinetics (SILK) were performed in 65 participants including 10 young normal controls, 23 age‐matched controls, 16 AD and 16 primary tauopathies (2 PSP, 4 CBS, 10 MAPT mutation family). Briefly, participants received 16hr intravenous infusion of 13 C 6 ‐leucine and cerebrospinal fluid (CSF) was collected from five lumbar punctures over 120 days. Labeled tau was measured with mass spectrometry to obtain kinetic curves of tau. Production and clearance rates were calculated and compared across different tauopathies. CSF amyloid beta (Aβ), amyloid and tau Positron Emission Tomography (PET) imaging were measured in a subset of participants, and analyzed for correlation with SILK measures. Results First, we confirmed the reproducibility of previous results (Sato et al., 2018) and demonstrated that tau production rates increased with amyloid measured by PET or CSF Aβ. Second, CSF tau concentration correlated with CSF Aβ 40 and Aβ 42 in primary tauopathies but only with Aβ 40 in those with abnormal Aβ levels. Third, 2 PSP patients had slower clearance of tau with tau half‐lives approximately 1.5‐2.5 times longer than other cohorts. Tau Fractional Synthesis Rate also negatively correlated with tau concentration in primary tauopathies, and CBS and FTD‐ MAPT had different slopes, suggesting that they may have different kinetics. Conclusions The results from this study provide mechanistic insights into differences between AD and other primary tauopathies, which may be targeted differently when developing therapies against tau metabolism. In vivo tau kinetics can help evaluate the efficacy of tau‐targeted therapies and provide information for designing clinical trials targeting tau.