Global neuropathologic severity of Alzheimer's disease and locus coeruleus vulnerability influences plasma phosphorylated tau levels.

Autor: Murray ME; Department of Neuroscience, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. murray.melissa@mayo.edu., Moloney CM; Department of Neuroscience, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Kouri N; Department of Neuroscience, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Syrjanen JA; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA., Matchett BJ; Department of Neuroscience, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Rothberg DM; Department of Neuroscience, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Tranovich JF; Department of Neuroscience, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Sirmans TNH; Department of Neuroscience, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Wiste HJ; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA., Boon BDC; Department of Neuroscience, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Nguyen AT; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Reichard RR; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Dickson DW; Department of Neuroscience, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA., Lowe VJ; Department of Radiology, Mayo Clinic, Rochester, MN, USA., Dage JL; Department of Neurology, Indiana University, Indianapolis, IN, USA., Petersen RC; Department of Neurology, Mayo Clinic, Rochester, MN, USA., Jack CR Jr; Department of Radiology, Mayo Clinic, Rochester, MN, USA., Knopman DS; Department of Neurology, Mayo Clinic, Rochester, MN, USA., Vemuri P; Department of Radiology, Mayo Clinic, Rochester, MN, USA., Graff-Radford J; Department of Neurology, Mayo Clinic, Rochester, MN, USA., Mielke MM; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA. mmielke@wakehealth.edu.; Wake Forest University School of Medicine, Winston-Salem, NC, USA. mmielke@wakehealth.edu.; Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University School of Medicine, 525 Vine, 5th floor, Winston-Salem, NC, 27157, USA. mmielke@wakehealth.edu.
Jazyk: angličtina
Zdroj: Molecular neurodegeneration [Mol Neurodegener] 2022 Dec 27; Vol. 17 (1), pp. 85. Date of Electronic Publication: 2022 Dec 27.
DOI: 10.1186/s13024-022-00578-0
Abstrakt: Background: Advances in ultrasensitive detection of phosphorylated tau (p-tau) in plasma has enabled the use of blood tests to measure Alzheimer's disease (AD) biomarker changes. Examination of postmortem brains of participants with antemortem plasma p-tau levels remains critical to understanding comorbid and AD-specific contribution to these biomarker changes.
Methods: We analyzed 35 population-based Mayo Clinic Study of Aging participants with plasma p-tau at threonine 181 and threonine 217 (p-tau181, p-tau217) available within 3 years of death. Autopsied participants included cognitively unimpaired, mild cognitive impairment, AD dementia, and non-AD neurodegenerative disorders. Global neuropathologic scales of tau, amyloid-β, TDP-43, and cerebrovascular disease were examined. Regional digital pathology measures of tau (phosphorylated threonine 181 and 217 [pT181, pT217]) and amyloid-β (6F/3D) were quantified in hippocampus and parietal cortex. Neurotransmitter hubs reported to influence development of tangles (nucleus basalis of Meynert) and amyloid-β plaques (locus coeruleus) were evaluated.
Results: The strongest regional associations were with parietal cortex for tau burden (p-tau181 R = 0.55, p = 0.003; p-tau217 R = 0.66, p < 0.001) and amyloid-β burden (p-tau181 R = 0.59, p < 0.001; p-tau217 R = 0.71, p < 0.001). Linear regression analysis of global neuropathologic scales explained 31% of variability in plasma p-tau181 (Adj. R 2  = 0.31) and 59% in plasma p-tau217 (Adj. R 2  = 0.59). Neither TDP-43 nor cerebrovascular disease global scales independently contributed to variability. Global scales of tau pathology (β-coefficient = 0.060, p = 0.016) and amyloid-β pathology (β-coefficient = 0.080, p < 0.001) independently predicted plasma p-tau217 when modeled together with co-pathologies, but only amyloid-β (β-coefficient = 0.33, p = 0.021) significantly predicted plasma p-tau181. While nucleus basalis of Meynert neuron count/mm 2 was not associated with plasma p-tau levels, a lower locus coeruleus neuron count/mm 2 was associated with higher plasma p-tau181 (R = -0.50, p = 0.007) and higher plasma p-tau217 (R = -0.55, p = 0.002). Cognitive scores (Adj. R 2  = 0.25-0.32) were predicted by the global tau scale, but not by the global amyloid-β scale or plasma p-tau when modeled simultaneously.
Conclusions: Higher soluble plasma p-tau levels may be the result of an intersection between insoluble deposits of amyloid-β and tau accumulation in brain, and may be associated with locus coeruleus degeneration.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje