Early Detection of Alzheimer s Disease by Relayed NOE CEST MRI
Abstract
Alzheimer s disease (AD) is the most common cause of dementia, and currently, more than 5 million people have AD in the United States alone. The accumulation of neuritic plaques comprised of amyloid-beta (Aß) peptides and neurofibrillary tangles (NFT) of hyperphosphorylated tau are the major histopathological hallmarks of Alzheimer s disease. Therefore, the detection of the aggregated proteins involved in AD is expected to be a promising strategy for the early diagnosis of the disease, and is also important for dynamically monitoring the effects of new therapeutic agents on the clearance of the aggregated proteins. Magnetic resonance imaging (MRI) is commonly applied to visualize the medial temporal lobe (MTL) structures in the brain as a core diagnostic feature of AD, but still has limited molecular imaging methods available due to the its low sensitivity. Recently, chemical exchange saturation transfer (CEST) MRI has shown potential in detecting low-concentration proteins through the water signal used for imaging, and has demonstrated the possibility of monitoring protein aggregation in solutions. However, the capability of detecting Aß and NFT accumulation in AD disease by protein CEST MRI has not been implemented and verified. With this proposal, we attempt to develop and verify a CEST MRI biomarker from aliphatic protons in proteins, named as relayed nuclear Overhauser enhancements-CEST (rNOE-CEST). The rNOE-CEST contrast will be mapped using a new MRI technique based on the ultra-short echo time (UTE) MRI, which will allow us to map rNOE-CEST signal with sufficient sensitivity but immune to motions, and suppress the magnetization transfer contrast (MTC) and direct water saturation (DS) interferences. If successful, this new technique should provide a MRI biomarker that may play a pivotal role for the evaluation of protein misfolding and aggregation during early stages of AD, information that will have important diagnostic and therapeutic implications. We recently developed a new CEST technique, UTE-CEST, which is able to obtain high-resolution rNOE-CEST MRI insensitive to motion. We hypothesize that the rNOE-CEST signal detected by CEST-UTE on AD mouse is associated with the Aß and NFT accumulation due to the line broadening of amide and aliphatic proton signal in proteins introduced by protein aggregation. The optimized UTE-CEST method will be applied on two AD mouse models to verify that the technique is sensitive enough to detect the early protein aggregation seen in AD disease. Upon the successful completion of this proposal, we anticipate developing a new clinic-ready MRI technique that detect and evaluate the AD-associated protein aggregation.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810797
Entities
People
- Jiadi Xu
Organizations
- Kennedy Krieger Institute
- United States Army