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

Molecular Neurodegeneration

Research Article

R. Ross Reichard¹  Aivi T. Nguyen¹  Jeffrey L. Dage²  Ronald C. Petersen³  David S. Knopman³  Jonathan Graff-Radford³  Tiffany N. Hicks Sirmans⁴  Melissa E. Murray⁴  Jessica F. Tranovich⁴  Christina M. Moloney⁴  Darren M. Rothberg⁴  Baayla D. C. Boon⁴  Naomi Kouri⁴  Billie J. Matchett⁴  Dennis W. Dickson⁴  Jeremy A. Syrjanen⁵  Heather J. Wiste⁵  Michelle M. Mielke⁶  Val J. Lowe⁷  Prashanthi Vemuri⁷  Clifford R. Jack⁷ 

[1] Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA;Department of Neurology, Indiana University, Indianapolis, IN, USA;Department of Neurology, Mayo Clinic, Rochester, MN, USA;Department of Neuroscience, Mayo Clinic Florida, 4500 San Pablo Road, 32224, Jacksonville, FL, USA;Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA;Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA;Wake Forest University School of Medicine, Winston-Salem, NC, USA;Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University School of Medicine, 525 Vine, 5th floor, 27157, Winston-Salem, NC, USA;Department of Radiology, Mayo Clinic, Rochester, MN, USA;

关键词: Alzheimer’s Disease;    Neuropathology;    Blood biomarker;    Phosphorylated Tau;    Neurofibrillary Tangles;    Amyloid-β;    Digital Pathology;   

DOI  :  10.1186/s13024-022-00578-0

 received in 2022-05-24, accepted in 2022-10-26,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundAdvances 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.MethodsWe 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.ResultsThe 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. R2 = 0.31) and 59% in plasma p-tau217 (Adj. R2 = 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/mm2 was not associated with plasma p-tau levels, a lower locus coeruleus neuron count/mm2 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. R2 = 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.ConclusionsHigher 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.

【 授权许可】

CC BY   
© The Author(s) 2022

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