Overall Project Goal Summary

Alzheimer’s disease (AD) dementia is a devastating illness with no cure. Treatments targeting known pathologic hallmarks of AD dementia, such as amyloid-beta (Ab), in symptomatic participants have proved largely fruitless and other potential disease targets or strategies warrant exploration. We propose to use neuroinflammation PET to guide new ways of treating AD. We anticipate that the significance of this work will be improvement of AD dementia treatment.

Alzheimer’s Disease Dementia and Neuroinflammation

 Ab alone is not sufficient to cause AD dementia and data from both autopsy and imaging studies show that amyloid deposition can be found in cognitively unimpaired elderly people. Neuroinflammation in AD may involve the activation of microglia by Ab. In the absence of foreign stimuli, microglial cells are in a resting state. When activated, they have the capability release pro-inflammatory cytokines including interleukin-1beta (IL-1b), IL-12, tumor necrosis factor-a (TNF-a), IL-6, and TNF-alpha among others. These pro-inflammatory processes induce direct neuronal death, decreased synaptic function, and inhibition of hippocampal neurogenesis.

The failure of anti-inflammatory drugs in clinical trials has been intriguing given these compelling biologic data. Potential explanations could include targeting the incorrect pathology or challenges in identifying who to treat. Maximizing the chance of treatment success includes a combination of optimal timing and appropriate treatment selection.

PET imaging of Neuroinflammation

PET imaging is the only way to directly visualize neuroinflammation in vivo. PET imaging of neuroinflammation has developed over many years and the field has produced a modest body of studies with small numbers of participants. Neuroinflammation imaging may help us understand the role of neuroinflammation in AD dementia.

Research Plan

In this project we propose to investigate neuroinflammation using PET in our unique cohort of participants in the Mayo Clinic Study of Aging (MCSA), a population-based study of 50-90 year old participants and other cohorts. We have a large research PET facility performing 1400 research human PET scans per year and a complete PET research team. Assessing neuroinflammation in a large cohort has not been done. We have the unique opportunity to assess the potential relationships of neuroinflammation and AD pathology utilizing our well-characterized aging population and our well-established dementia PET research program.

Objectives:

1.  Understand the impact of neuroinflammation on AD dementia and its implications for the design of clinical trials.

2.  Describe the association of neuroinflammation and cognitive change.

3.  Acquire data that can help treat neuroinflammation components of AD dementia.