SP #7: MR and PET for Neurodegenerative Disease

MR and PET for Neurodegenerative Disease

Significance:

Treatments for AD currently available provide largely symptomatic relief with only minor effects on the course of the disease; hence, there is an urgent need for better therapeutic interventions [1,2]. Besides immunomodulation, numerous other approaches are being studied, which include anti-Amyloid β aggregation agents, secretase inhibitors/modulators blocking Aβ production, tau aggregation blockers, agents targeting mitochondria, stem cell therapies and various neuroprotective strategies [3,4]. One of the greatest hopes for an intervention that will significantly impact disease progression in the near future comes from immunization approaches. Two possible methods to improve congophilic angiopathy (CAA) and tau pathology include activating the innate immune system via TLR9 stimulation and the inhibition of Aβ/apoE binding.

Aim:

In this study, we will determine the efficacy of these two treatments by observing the changes in the CAA burden longitudinally in vivo with ultrasmall superparamagnetic iron oxide (USPIO) amyloid binding particles for μMRI on a subset of Tg mice.  

Approach:

The Aβ 1-42 peptide will be synthesized in the W.M. Keck Facility at Yale University. Details of synthesis, purification, and sequence verification will be determined as described previously [5,6]. The USPIO nanoparticles (10mgFe/ml, Ocean Nanotech) will be linked to Aβ1-42 peptide and PEG using standard EDC/NHS coupling methods [5]. Each batch of Aβ-PEG-USPIO particles will have its binding affinity to free Aβ peptides determined by ELISA [5,7,8]. We will also determine that each batch of Aβ-PEG-USPIO particles is non-toxic in N2a mouse neuroblastoma cells (ATCC line CCL-131) using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) Cell Proliferation Assay (Promega, Madison, WI) and compared to the known toxicity of Aβ1-42 [9,10].

All of the MRI scans will be performed on the NYUSOM 7T micro-MRI system. For in vivo µMRI a modified 3D spoiled gradient recalled multi-echo (SPGRME) sequence will be used to acquire an additional self-gated signal on the readout dephasing gradient within each TR.  Figure 1 illustrates the voxel based morphometry (VBM) analysis that will be performed.  The ex vivo µMRIs of 12 APP/PS1 Tg mice injected with USPIO-PEG-Aß were compared to the ex vivo µMRIs of 9 APP/PS1 mice injected with USPIO alone. Areas of difference (p<0.01) on the coronal images are shown and correspond to the distribution of amyloid lesions. There are no differences between the two groups of Tg mice in the cerebellum where there are no amyloid deposits.

BTRC Resources Utilized:

TR&D#2: Central to this project is the development of amyloid imaging technology in Tg mice at 7T. It is hoped that this pre-clinical data will ultimately motivate extension of our methods to non-human primates and humans.

TR&D #3: In other projects in the Wisniewski lab, a number of different therapeutic approaches are being developed for prion disease. Among these is the use of amyloid binding agents that cross the blood brain barrier (BBB). We have found that a number of amyloidophilic agents that bind to both AD plaques, AD vessel amyloid and prion amyloid deposits are also therapeutically active for prion disease [11]. In unpublished data we have found that these amyloid binding compounds are able to behaviourally rescue AD 3xTg mice, with a reduction in both amyloid and tau related pathology. These amyloid binding compounds are also ideal PET ligands. Therefore, in collaboration with TR&D #3 co-PI Dr. Ding we plan to radiolabel these therapeutic amyloidophilic compounds and use them for PET. We also have access to a library of hundreds of styryl based amyloid binding, BBB permeable compounds [11,12], which we plan to use develop PET ligands which may more specifically bind either neurofibrillary tangles (NFT) or oligomers. The latter may be more useful for making the diagnosis of AD, since both the levels of NFTs and oligomers correlate better with the clinical/cognitive status of patients, in comparison to amyloid plaque burden [13]. In R01 NS073502 the Wisniewski lab is developing therapeutic strategies that specifically target pathological oligomeric structures [14,15]. Hence BTRC expertise will be important for the development of imaging biomarkers that can follow oligomer levels.

These developments, which extend the reach of the current service project, will clearly take advantage both of the radiochemistry facility and the μPET/CT scanner associated with the BTRC.  Concerns raised in the critiques about the availability of a μPET scanner and the ability to synthesize the proposed agents at the CAI2R facility were “alleviated at the site visit,” and indeed our μPET/CT scanner is now operational.

Principal Investigator: 

Sponsors

Latest Updates

Philanthropic Support

We gratefully acknowledge generous support for radiology research at NYU Langone Medical Center from:
 
• The Big George Foundation
• Raymond and Beverly Sackler
• Bernard and Irene Schwartz

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