Tauopathies, the most common of which is Alzheimer’s disease (AD), constitute the most crippling neurodegenerative threat to our aging population. Tauopathic patients have significant cognitive decline accompanied by irreversible and severe brain atrophy, and it is thought that neuronal dysfunction begins years before diagnosis. Our current understanding of tauopathies has yielded promising therapeutic interventions but have all failed in clinical trials. This is partly due to the inability to identify and intervene in an effective therapeutic window early in the disease process. A major challenge that contributes to the definition of an early therapeutic window is limited technologies. To address these challenges, we modified and adapted a manganese-enhanced magnetic resonance imaging (MEMRI) approach to provide sensitive and quantitative power to detect changes in broad neuronal function in aging mice. Considering that tau tangle burden correlates well with cognitive impairment in Alzheimer’s patients, we performed our MEMRI approach in a time course of aging mice and an accelerated mouse model of tauopathy. We measured significant changes in broad neuronal function as a consequence of age and, in transgenic mice, before the deposition of bona fide tangles. This MEMRI approach represents the first diagnostic measure of neuronal dysfunction in mice. Successful translation of this technology in the clinic could serve as a sensitive diagnostic tool for the definition of effective therapeutic windows.
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Funding for this work came from the University of Kentucky Alzheimer’s Disease Center (UK-ADC), which is supported by NIH/NIA P30 AG028383. JFA, SNF, AI, RAC. SEM, EM, DL, GKN, and EM, were supported by NIH/NINDS 1R01 NS091329-01, Alzheimer’s Association NIRG-14-322441, NIH/NCATS 5UL1TR000117-04, NIH/NIGMS 5P30GM110787, Department of Defense AZ140097, the University of Kentucky Epilepsy Center (EpiC), NIH/NIA P30 AG028383, and NIH/NIMHD L32 MD009205-01.
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Fontaine, Sarah N.; Ingram, Alexandria; Cloyd, Ryan A.; Meier, Shelby E.; Miller, Emily; Lyons, Danielle N.; Nation, Grant K.; Mechas, Elizabeth; Weiss, Blaine; Lanzillotta, Chiara; Di Domenico, Fabio; Schmitt, Frederick A.; Powell, David K.; Vandsburger, Moriel H.; and Abisambra, Jose Francisco, "Identification of Changes in Neuronal Function as a Consequence of Aging and Tauopathic Neurodegeneration Using a Novel and Sensitive Magnetic Resonance Imaging Approach" (2017). Sanders-Brown Center on Aging Faculty Publications. 124.