Erica Andreozzi’s Dissertation Defense: The Development of Multimodal Imaging Probes for Visualizing Neuroinflammation in Alzheimer’s Disease and Traumatic Brain Injury
Erica Andreozzi’s dissertation defense is this Friday at 10am in GBSF Auditorium. See below for more information.
Location: GBSF Auditorium
Time: Friday, August 10th, at 10 AM.
The Development of Multimodal Imaging Probes for Visualizing Neuroinflammation in Alzheimer’s Disease and Traumatic Brain Injury
Alzheimer’s disease (AD) and traumatic brain injury (TBI) are two significant neurodegenerative diseases whose delayed diagnosis limits the possibility of treatment. According to the Alzheimer’s Association, over 5.4 million Americans have AD, and with this number projected to increase to 115 million people worldwide by 2050, so will the annual cost to the U.S. economy, which currently exceeds 180 billion dollars. To date, absolute diagnosis of AD can only be made posthumously through confirmation of senile plaques in brain autopsy specimens; there are no clinical signs of AD apart from severe dementia and brain atrophy, which are only detectable at mid to late stages when neurological damage is already very pronounced. As with AD, TBI is also a leading neurodegenerative disease that continues to go undetected and undiagnosed, leaving ~80,500 TBI survivors with cognitive deficits that result in greater than $56.3 billion in U.S. annual costs each year. While there is evidence suggesting that such cognitive deficits can be improved through immediate rehabilitation and pharmacological intervention post TBI, the lack of diagnostic methods makes these therapies inadequate.
Thus, there is great interest in developing a method for early diagnosis of AD and TBI so that necessary treatment options can be employed and chronic, irreversible brain damaged can be prevented. Having identified activated microglia (immune cells of the brain) as contributors to the post-injury neuroinflammation that follows both AD and TBI, we have developed a novel, multimodal imaging probe targeted to activated microglia as a means of non-invasively diagnosing these diseases before the onset of cognitive deficits. Focusing on the key role of microglia in AD and TBI pathology, we aim to use multimodal (PET/MRI/optical) imaging of microglia to for diagnosis and characterization of associated neurodegeneration in order to inform the design of possible drugs.
We have synthesized and characterized a multimodal, biomolecular imaging probe, mal-BSA-DOTA(Gd+3/64Cu), that demonstrates targeting to activated microglia in vitro. The existence of the blood brain barrier (BBB), however, poses challenges for the delivery of this probe into the brain to evaluate in vivo targeting. While rat models of TBI are known to exhibit a compromised BBB, we needed to confirm this with imaging studies. Since AD animal models do no exhibit adequate BBB disruption, we investigated solid lipid nanoparticles (SLNs) as vehicles for brain delivery of our probe. SLNs are submicron colloidal carriers that have recently emerged serve as efficient, non-toxic, and versatile alternatives to liposomes and polymeric nanoparticles for delivery of drugs and contrast agents. Interested in positron emission tomography (PET) because of its high in vivo sensitivity and magnetic resonance imaging (MRI) because of its high in vivo resolution, we have functionalized SLNs to be able to evaluate their performance with PET and MRI. By incorporating a lipid chelator into the SLN architecture, we developed a method to radiolabel SLNs with 64Cu for noninvasive mapping of biodistribution in vivo using PET. Preliminary in vivo biodistribution of these SLNs (64Cu-SLNs) was evaluated in mice up to 48 hr post intravenous injection using PET, and these values were then compared to ex vivo biodistribution from gamma counting of organs. An additional modification of the SLNs included the loading of gadolinium (1,4,7,10-tetraazacyclododecane)-1,4,7,10-tetraacetate (Gd-DOTA), a T1-weighted contrast agent, into SLNs in order to produce a new category of stable T1-weighted MRI contrast agents that can be modified for slow release of cargo and multimodal functionality. Intracerebroventricular injection of these Gd-loaded SLNs into mice exhibited shortened T1 with enhanced contrast in vivo using T1-weighted MRI. By demonstrating the ability to functionalize SLNs for PET and MRI functionality, we believe that these nanocarriers can serve as stable, biocompatible vehicles for delivering microglial-targeted biomolecules to the brain for early diagnosis AD and TBI.