White Matter Hyperintensity Localization and Severity in Association with PET Tau in Alzheimer Disease

Project Summary

Goal: The overall goal of this project is to evaluate the contributions of vascular disease and phosphorylated tau on structural connections within the brain to better characterize the progression of Alzheimer's disease (AD).  

Aim Summaries. To accomplish this goal, the aims focus on characterizing white matter damage in two different AD populations.  White matter damage is largely considered a secondary symptom of AD attributed to vascular dysfunction, but posthumous work has suggested loss in axonal integrity may more directly be influenced by AD pathology (phosphorylation of tau). Therefore, to better understand and characterize the loss of white matter in AD, the first aim focuses on individuals who develop AD later in life (late-onset Alzheimer’s disease, or LOAD) and are at greater risk of vascular dysfunction. These individuals often have multiple etiologies that associate with aging, including vascular-related comorbidities. The second aim focuses on individuals who are genetically predisposed to develop AD  (ie, autosomal dominant Alzheimer's disease), but much earlier in life. Individuals with these rare genetic profiles express far fewer behavioral signs of vascular dysfunction, suggesting white matter damage in this population is more directly influenced by AD pathology. The last aim involves comparing and contrasting the topography and severity of white matter damage in these populations to ascertain the contribution of vascular dysfunction to AD pathology. 

Innovation. One of the key pathological biomarkers in AD is the formation of neurofibrillary tangles that lead to neurodegeneration and cognitive decline.  Recent advancements in radioligands allows for the visualization of these filaments within the brain while the patient is still alive.  This study will incorporate this new tracer to better understand the AD pathology that associates with white matter damage. Healthy tau innately resides within the axons or white matter but after phosphorylation it migrates to the cell body where it forms tangles.  This migration is hypothesized to be detrimental to the underlying white matter integrity, suggesting improved detection of white matter damage may act as an early indicator of symptom onset.

Foreseeable Benefits. My future aspirations for this project are to expand our knowledge of the degenerative patterns of white matter damage from AD pathology.  Clarification in this area will allow for more inferences on how this disease spreads and improve clinicians’ ability to predict what regions are at risk of further decline in their patients.  Ideally, these techniques for quantifying white matter damage may act as an outcome measure for treatment interventions that specifically target misfolded tau.