Development of an Innovative Vervet (Chlorocebus aethiops sabaeous) Model of Early Alzheimer’s-like Neuropathology and Symptomatology

Wake Forest University Health Sciences, Winston-Salem NC

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Abstract

This application is a Supplement to R24 AG073199 Development of a Vervet Model of Early AD-like Neuropathology & Symptomatology. The purpose of this supplement is to: A) exploit an unexpected opportunity that fits within the approved scope of work, the collection and analysis of specimens from a unique resource of type 2 diabetic vervets, which would be significantly delayed through the competitive supplement route; and B) take advantage of new brain imaging technology which has become available since the application was submitted that will facilitate the completion of the R24 specific aims: PET imaging of synaptic function and MRI imaging of CSF flow. Type 2 diabetes (T2D) increases with age and significantly increases Alzheimer's disease (AD) risk. Amyloid-β accumulates in the brains of human T2Ds and may involve impaired CSF clearance. Synaptic loss has been observed in a T2D mouse model. Vervet monkeys, an established model of early AD-like neuropathology, are also susceptible to T2D. We propose to add 8 T2Ds, to our aging vervet cohort and compare all phenotypes from the parent grant (behavioral, fluid biomarkers, imaging) in normal aging vervets with the T2Ds. We have recently developed two new methods to assess brain function that are particularly well-suited to neuropathologic changes with T2D: synaptic function with PET, and cerebrospinal fluid flow with MRI. Synapse loss is an early pathological change in AD. Neuropathological studies have reported lower synaptic densities in AD compared to controls. Synaptic vesicle glycoprotein 2A (SV2A) is expressed in all synapses. Changes in synaptic density in animal models and AD patients are currently studied using the SV2A-based PET radiotracer [18F]UCBH which we have recently characterized and optimized for vervets. We propose to assess the 15 older vervets in our R24 imaging cohort, and add a comparison group of 8 T2D. It is hypothesized that impaired clearance of amyloid-β and tau may promote AD neuropathology. Likewise, recent observations suggest a relationship between impaired clearance and prediabetes. However, no study has directly correlated CSF flow with AD pathophysiology in the living primate brain, and there is no validated method to measure clearance. In preliminary studies we observed subarachnoid space (SAS) CSF flow was negatively correlated with PET-determined gray matter amyloid-β deposition, and we have optimized the phase-contrast sequences for vervets. We propose to assess SAS CSF flow with longitudinal phase-contrast MRI in the 15 older vervets in our imaging cohort and add a comparison group of 8 T2Ds. We will test the hypotheses that neurocognitive decline will be accelerated in vervet T2D, and synaptic density and CSF flow will decline with age and be accelerated in T2D. This research will yield proof-of-concept data for new dynamic MRI and PET biomarkers that may better reflect AD-like pathophysiology, and provide critical data illuminating temporal changes in neuropathology that increase AD risk in T2D. These data will be used to support further research on AD risk in humans with and without T2D.