Persistent Resting-State fMRI Hyperconnectivity as a Risk Factor for Alzheimers Disease After TBI
Abstract
Background: Amyloid (Abeta) plaques are one of the defining features of Alzheimer’s disease (AD), but increased levels of soluble Abeta can already be observed several years before plaque build-up and the appearance of clinical symptoms. Recent findings in animal models of AD and cognitively intact subjects with increased risk for AD indicate that increased levels of soluble Abeta cause paroxysmal abnormal neuronal firing or network hypersynchrony when plaques are still absent. Normal neuronal activity plays an important role in the control of Abeta production, degradation, and transport between neurons. Therefore, Abeta-induced abnormal neuronal firing could have a decisive role in facilitating Abeta build-up and deposition in the brain. Increased Abeta brain levels and hyperexcitability in the form of network hypersynchrony with an increased risk for epileptic seizures are also well-known features of acute and chronic traumatic brain injury (TBI). A new approach for dynamic resting state functional magnetic resonance imaging (fMRI) analysis made it possible to detect episodes of abnormal paroxysmal hyperconnectivity whose duration was positively correlated with Abeta load and gray matter loss and negatively with memory performance in two independent populations of cognitively intact and impaired but non-demented subjects with and without increased brain Abeta without a history of TBI. These preliminary findings suggest that these paroxysmal Abeta-associated hyperconnectivity episodes could represent the fMRI equivalent of the paroxysmal network hypersynchrony observed in animal models. The overall hypothesis to be investigated in the proposed project is that Abeta-associated paroxysmal hyperconnectivity episodes thought to represent the task-free fMRI equivalent of paroxysmal network hypersynchrony play a decisive role in the progression from preclinical to clinical AD. A critical role for network hypersynchrony could also explain why TBI is a risk factor for the development of AD in later life since impaired Abeta clearance and permanently altered neuronal excitability favoring paroxysmal network hypersynchrony have been shown to be features of the chronic stage of TBI. Patients with a history of TBI whose task-free fMRI shows paroxysmal hyperconnectivity episodes are therefore expected to have a higher risk to develop AD in later life, i.e., have higher Abeta plaque loads and worse cognitive abilities, than those who do not show this abnormality. The successful completion of this project could result in a non-invasive biomarker that is able to detect a “proxy” of a harmful action of oligomeric Abeta that plays a crucial role in the development of clinical AD before Abeta positron emission tomography (PET) becomes positive. This would allow the identification of subjects with and without history of TBI who are at risk to develop AD at a very early stage of the disease. Considering that it was possible to suppress Abeta-associated network hypersynchrony and epileptic activity in AD animal models and cognitively impaired patients with antiepileptic drugs, this might not only pave the way to a potentially disease-modifying treatment at a very early stage of the disease but also provide a means to monitor and individually adjust such a therapy. The first aim is to identify paroxysmal hyperconnectivity episodes in subjects with a history of TBI and to investigate their relationship with cognition, Abeta load, and TBI severity. Task-free fMRI data from about 80 subjects with and without a history of TBI from the Department of Defense Alzheimer Disease Neuroimaging Initiative (DoD-ADNI) project will be identified and analyzed with the newly developed dynamic analysis approach that was used to detect Abeta-associated hyperconnectivity episodes in patients with preclinical AD. The characteristics of these connectivity states will be compared with those of the paroxysmal hyperconnectivity state observed in previou
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910841
Entities
People
- Susanne G Mueller
Organizations
- United States Army
- University of California, San Francisco