Distinct and joint effects of low and high levels of Aβ and tau deposition on cortical thickness

Abstract

Alzheimer's disease (AD) is defined by the presence of Amyloid-β (Aβ), tau, and neurodegeneration (ATN framework) in the human cerebral cortex. Prior studies have suggested that Aβ deposition can be associated with both cortical thinning and thickening. These contradictory results may be due to small sample sizes, the presence versus absence of tau, and limited detectability in the earliest phase of protein deposition, which may begin in young adulthood and cannot be captured in studies enrolling only older subjects. In this study, we aimed to find the distinct and joint effects of Aβ and tau on neurodegeneration during the progression from normal to abnormal stages of pathologies that remain incompletely understood. We used 18F-MK6240 and 18F-Florbetaben/18F-Florbetapir positron emission tomography (PET) and magnetic resonance imaging (MRI) to quantify tau, Aβ, and cortical thickness in 529 participants ranging in age from 20 to 90. We applied a novel partial volume correction technique based on the absence of proteinopathy in young controls to optimize spatial resolution. Aβ/tau abnormality was defined at 95th percentile of the normal distribution of global Ab/tau observed in young participants. We performed multiple regression analyses to assess the distinct and joint effects of Aβ and tau on cortical thickness. Using 529 participants (83 young, 394 healthy older, 52 MCI) we showed that normal levels of Aβ deposition were significantly associated with increased cortical thickness regardless of the amount of tau (e.g., left entorhinal cortex with t>3.241). The relationship between tau deposition and neurodegeneration was more complex: abnormal levels of tau were associated with cortical thinning in several regions of the brain (e.g., left entorhinal with t<-2.80 and left insula with t<-3.202), as expected based on prior neuroimaging and neuropathological studies. Surprisingly, however, normal levels of tau were found to be associated with cortical thickening. Moreover, at abnormal levels of Aβ and tau, the resonance between them, defined as their correlation throughout the cortex, was associated strongly with cortical thinning when controlling for their additive effect. We confirm prior findings of an association between Aβ deposition and cortical thickening and suggest this may also be the case in the earliest stages of deposition in normal aging. We discuss potential pathophysiologic processes underlying this effect such as inflammation and hyperactivation (excitotoxicity). We also illustrate that resonance between high levels of Aβ and tau uptake is strongly associated with cortical thinning, emphasizing the effects of Aβ/tau synergy in AD pathogenesis.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study did not receive any funding

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The datasets of this study are approved by two Institutional Review Boards. One in Columbia University Irving Medical Center and another one in Weill Cornell medicine.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Data Availability

The data for this project are confidential but may be obtained with Data Use Agreements with the Weill Cornell Medicine and Columbia University Irving Medical Center. Researchers interested in access to the data may contact Dr. Razlighi at qrr4001@med.cornell.edu. It can take some weeks to negotiate data use agreements and gain access to the data.

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