Novel imaging biomarkers of neuroinflammation in Alzheimer's disease - Abstract Alzheimer's disease (AD) is a widespread global neurodegenerative disorder, accounting for the majority of dementia cases in the United States. With over 25 million people affected by the disease, this number is expected to double by 2050, primarily due to the growing aging population. The amyloid cascade hypothesis posits that the accumulation of amyloid-β in the brain triggers AD. However, the complexities of AD pathogenesis extend beyond this theory, with mounting evidence linking inflammatory markers and AD risk genes to innate immune functions, emphasizing the significant role of neuroinflammation. This study aims to develop and optimize noninvasive imaging biomarkers to track neuroinflammation in the early stages of AD and explore the intricate connections between neuroinflammation, brain glucose hypometabolism, and the progression of AD. The study proposes the use of deuterium-magnetic-resonance-spectroscopy (DMRS) and quantitative- exchanged-label-turnover MRS (qeltMRS) with deuterium-labeled acetate to track the temporal dynamics of neuroinflammation in AD. The research comprises three specific aims. Firstly, it focuses on investigating the relationship between astrocytic acetate metabolism and astrocyte reactivity in an adenovirus-induced reactive astrogliosis model, utilizing DMRS and qeltMRS. The hypothesis suggests a higher uptake and metabolism of acetate in reactive astrocytes, correlated with increased expression of the monocarboxylate transporter (MCT1) protein. Secondly, the study aims to characterize the spatiotemporal patterns of neuroinflammation and brain glucose hypometabolism in an AD mouse model, using DMRS and qeltMRS. The hypothesis proposes that in AD mice, reactive astrocytes and microglia will metabolize acetate predominantly over glucose, with upregulated MCT1 transporters and downregulated GLUT3 transporters compared to age-matched WT mice. Lastly, the research seeks to validate the efficiency of the methods by assessing the impact of a ketogenic diet on neuroinflammation in AD mice over a longitudinal study. The hypothesis anticipates a slower level of neuroinflammation in the treated AD mice compared to the untreated group. The innovation and potential impact of this research lie in providing a robust preclinical framework for understanding AD pathophysiology, enabling the detection of early pathological processes in vivo. Successful outcomes may contribute to the development of prognostic tools and personalized treatment strategies targeting neuroinflammation, ultimately translating findings into clinical applications for improved outcomes in human patients affected by AD.
