How Connections in the Brain Break Down in Alzheimer's Disease

Jeremy Strain, PhD
Washington University (Saint Louis, MO)
Year Awarded:
2018
Grant Duration:
July 1, 2018 to June 30, 2020
Disease:
Alzheimer's Disease
Award Amount:
$149,029
Grant Reference ID:
A2018817F
Award Type:
Postdoctoral Fellowship
Award Region:
US Southern

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

Summary

Each of the aims of this project are directed at understanding how and where structural connections in the brain are damaged in two variants of Alzheimer's disease (AD). We discuss two known causes of white matter damage commonly seen in this population that can be detected by combining different neuroimaging and analytical techniques that we are capable of performing. This will improve our understanding of the biological correlates that characterize this disease and the subtle differences in progression between these two types of AD

Details

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. 

About the Researcher

I am a third-year postdoctoral research associate currently positioned at Washington University in St. Louis. My work has consisted of deciphering anatomical correlates of cognitive change. During my graduate studies at the University of Texas at Dallas, my research revolved around using structural imaging markers to differentiate between variants of dementia (Alzheimer disease and frontotemporal dementia, or FTD) to assist in clinical diagnosis. The bulk of this research was devoted to identifying localized regions of impaired white matter that uniquely coincided with FTD pathology. Additionally, I transitioned to studying the impact of concussions, but retained an emphasis on brain-behavior relationships.  As an initial member of the retired National Football League Concussion project, my work consists of understanding how traumatic events lead to chronic anatomical changes. Specifically, utilizing diffusion tensor imaging, white matter hyperintensities, and volumetrics, I investigated the role of concussion in the subsequent development of memory dysfunction. After completion of my PhD degree, I joined the lab of Dr. Beau Ances at Washington University. Under his tutelage I have applied the imaging techniques that I developed during my graduate training in combination with positron emission tomography (PET).  Acquiring this new skill set has expanded the utility of my former skills and led me to ask more specific questions regarding the association with disease progression and neurodegenerative outcomes.  For this work, I was awarded a Registration Fellowship to be an oral presenter at the recent Alzheimer Imaging Conference (2017).

Personal Story

Growing up, my rigor for academia was instilled very early on by my parents, who both are community college professors. However, as in most cases, my personal experiences and memories are what honed my career goals to affiliate with Alzheimer’s disease (AD) research. My initial interest in neuroscience was piqued during my first undergraduate neuroanatomy lecture. The professor put up a slide of a brain prior to dissection with the caption “My goal is to make you all appreciate the complexity of this ugly looking slab of meat.” In my case, he succeeded, and inspired me to seek out neuroscience labs that interested me. Around the same time my aunt was diagnosed with AD. The frequency of people knowing someone or related to someone with AD continues to grow, and I am no exception.  My aunt’s diagnosis was early and most of the canonical memory problems had not influenced her daily life.  This allowed her to enroll in several clinical trials in the hopes of some improvement, but to no avail. Upon my entering graduate school, her lucid days were becoming increasingly sparse. As her dementia progressed, our names and faces became foreign to her, but she would still show a glimpse of delight telling me her nephew was working on a cure. Although I can’t say my research will directly lead to something that profound, it always reassured me that she clung to hope. As fate would have it, my graduate advisor assigned me to assist a colleague of his on a project dedicated to understanding the connections of the brain in Alzheimer’s patients. At the time I didn’t realize the link between this new advisor and me, even though he became one of my top mentors. I learned later that he was actually the neurologist overseeing my aunt’s care and several of his nurses would express what a delight she was to work with. It is always invigorating when strangers share memories or experiences regarding our loved ones, even when they only fleetingly touched their lives. Although my aunt’s long battle with AD has ended, the hope she once expressed in me is the hope I have, that my work will assist in improving the standard of care for patients like her.

Don't miss out.
Receive research updates, inspiring stories, and expert advice
Keep me informed about: *
Please select at least one.
You must select at least one disease category.
Please enter your first name.
Please enter your last name.