Depressive Symptoms, Proteins Aβ and Tau, and Neuronal Network Activity in Prodromal and Early Alzheimer’s Disease

Jennifer R. Gatchel, MD, PhD
McLean Hospital/Massachusetts General Hospital (Belmont, MA)

Mentors

Reisa A. Sperling, MD
Massachusetts General Hospital/Brigham and Women's Hospital
Gad A. Marshall, MD
Massachusetts General Hospital/Brigham and Women's Hospital
Diego A. Pizzagalli, PhD
McLean Hospital
Brent P. Forester, MD
McLean Hospital
Year Awarded:
2016
Grant Duration:
July 1, 2016 to June 30, 2018
Disease:
Alzheimer's Disease
Award Amount:
$100,000
Grant Reference ID:
A2016434F
Award Type:
Postdoctoral Fellowship
Award Region:
US Northeastern

This grant is made possible by a bequest from the Howlett Revocable Trust.

Jennifer R. Gatchel, MD, PhD

Depressive Symptoms and Tau PET Imaging in Early Alzheimer's Disease

Summary

In Alzheimer’s disease (AD), changes occur not only in a person’s memory and thinking, but also in their mood and behavior. Symptoms such as depression, apathy and withdrawal are common and distressing to patients and their families, and can be just as debilitating, if not more so, than changes in memory and thinking. These psychiatric and behavioral symptoms may occur very early in the disease process, in the “pre-Alzheimer’s” disease stage, when a person may have the AD proteins, amyloid beta (Aβ) and tau, in their brains, but before they have developed overt signs of the disease. There is currently not a clear understanding of why and how these debilitating psychiatric and behavioral symptoms occur, and there are few effective treatments. In this project we will be visualizing Aβ in the brains of older adults, and now, due to an exciting new technology developed in our group, for the first time we also will be able to visualize tau protein in the brains of living older adults. This project will be vital by 1) allowing us to see how mild psychiatric and behavioral symptoms relate to build up of Aβ, tau, and brain pathway changes in normal older adults and those in the pre-Alzheimer’s and early AD stages; and 2) providing important information about patterns of psychiatric and behavioral symptoms that may help us to identify those older adults most at risk. The results will pave the way for developing more effective treatments and prevention strategies for AD.

Details

In Alzheimer’s disease (AD), early changes occur not only in a person’s memory and thinking, but also in their mood and behavior. Symptoms such a depression, apathy and withdrawal are common and distressing to patients and their families, and can be just as debilitating, if not more so, than changes in memory and thinking. These changes in mood and behavior also can contribute to disease progression. The goal of my project is to investigate whether specific brain changes, including both the accumulation of two of the main AD associated proteins, — amyloid beta (Aβ) and tau, and associated changes in connections between neurons, might underlie these symptoms in early AD.

As Aim 1, I am investigating the association between mood symptoms of dysphoria (feeling unwell or unhappy), anhedonia (diminished ability to experience pleasure), and apathy (loss of interest and withdrawal) and accumulation of the AD- associated proteins tau and Aβ in the brains of living older adults who are cognitively normal and those with early AD. This project will make use of an innovative imaging technology, that of tau and Aβ positron emission tomography (PET) imaging, that allows us to visualize both the quantity and localization of these two proteins in the brains of living older adults. I predict that in healthy older adults, those who have more pronounced mood symptoms will have greater accumulation of tau in the medial temporal brain region (the initial site of early tau accumulation) and that in older adults with early AD, more severe mood symptoms will be associated with tau accumulation in broader brain regions that have been implicated in regulating the expression of these symptoms—the anterior cingulate cortex, the dorsolateral prefrontal cortex, and the orbitofrontal cortex.  I also predict that across all subjects, this association will be greater in older adults with higher brain Aβ.

As Aim 2, in parallel studies, in the same groups of older adults, I am investigating the association between mood symptoms and brain network connectivity changes (changes in groups of neurons that are connected at rest). I predict that increased severity of mood symptoms will be associated with decreased connectivity within a brain network active during task-related activities, and that this association will also relate to the severity of amyloid and tau protein accumulation.

As Aim 3, I am investigating how changes in mood symptoms relate to changes in memory and thinking in cognitively normal adults and in early AD dementia. I predict that greater severity of depression, anhedonia, and apathy will be associated with worse memory and worse planning and task-shifting functions (executive function) across all subjects.

In this highly innovative project, I will visualize amyloid accumulation and also incorporate an exciting new technology recently developed in our research group that will allow us for the first time to visualize, in parallel fashion, both Aβ and tau protein in the brains of living older adults, and relate accumulation of both proteins to changes in mood and other neuropsychiatric symptoms. Indeed, this is the first study we are aware of that will allow us to probe how psychiatric and behavioral symptoms relate to build up of Aβ, tau, and brain pathway changes in living, cognitively normal older adults and those in the pre-Alzheimer’s and early AD stages. As such, it has promise to shed new light on the brain-based changes underlying these symptoms in aging and early AD dementia.

By taking this approach, my project is explicitly translational in nature, and has promise for translation of research findings to clinical practice. Given that mood and other neuropsychiatric symptoms may occur in preclinical AD and early AD dementia, the proposed study may contribute to defining the association of these symptoms with Aβ and tau burden and cognitive changes, thus providing a window for delaying or preventing disease onset.  In addition, neuropsychiatric symptoms, both in cognitively normal elderly and those in the early AD spectrum, are devastating from a personal and public health perspective.  By investigating and better characterizing the mechanisms of these symptoms, my study has the potential to inform the development of more targeted and effective treatments, thus reducing enormous personal and societal burdens associated with AD.

About the Researcher

: I am a research-oriented geriatric psychiatrist who is focused on studying the pathophysiology of psychiatric symptoms in aging and in AD, with the goal of developing more effective treatments to alleviate patient suffering. I have utilized molecular biology, mouse models, genetics, neuropharmacology, and now clinical research and neuroimaging modalities to study how degenerative processes may impact neural circuitry to give rise to disease, and how to best identify and treat those at risk. I trained in the Medical Scientist Program at Baylor College of Medicine, earning an MD and a PhD in neuroscience while working with Dr. Huda Y. Zoghbi to studying mechanisms of neurodegeneration in mouse models of two neurodegenerative diseases. During this time, I obtained NIH research funding (T32 and individual F30), published my work in leading journals (Proceedings of the National Academy of Sciences, Nature Reviews Genetics, and Nature Genetics), and gained local and national recognition for my expertise. I went on to pursue residency in adult psychiatry in the top-ranked Massachusetts General Hospital (MGH)/McLean Hospital Residency Program, where I was selected to participate in the residency’s Research Concentration Program. During my final year of residency, I served as a Chief Resident and received the Thomas P. Hackett award in recognition of the resident who has contributed the most to the academic spirit of the Department of Psychiatry.

Following residency I completed additional specialized clinical training in geriatric psychiatry in the Partners Healthcare Geriatric Psychiatry Clinical Fellowship Program (2014-2015). During that fellowship, I continued to investigate mood and cognitive symptoms in late life and in AD under the mentorship of Drs. Reisa A. Sperling, Gad A. Marshall, Keith A. Johnson, Brent P. Forester, and Diego A. Pizzagalli.

My training experiences investigating mechanisms of brain-behavior relationships have led to several peer-reviewed publications, chapters in leading textbooks, and presentations at the Society of Biological Psychiatry, the American College of Neuropsychopharmacology, and the American Association for Geriatric Psychiatry annual meetings. I am a former American College of Psychiatry P.R.I.T.E. fellow, and was recognized as an Honors Scholar (American Association for Geriatric Psychiatry) and Webb Fellow (Academy of Psychosomatic Medicine). In addition, I am the recipient of the Harvard Medical School Department of Psychiatry Dupont Warren Research Fellowship and Livingston Award, the 2016 American Association for Geriatric Psychiatry Member in Training Research Award, and the 2016 Alzheimer’s Association Neuropsychiatric Symptoms in Neurodegenerative Disease New Investigator Award. When not carrying out research or clinical work in the care of geriatric patients with mood, anxiety, and cognitive symptoms, I serve in leadership roles in medical student, resident, and fellow geriatric psychiatry education.

Personal Story

I have a longstanding interest in improving the lives of elderly patients and their families, and that is what led me to pursue a career as a physician scientist in geriatric psychiatry, studying neuropsychiatric symptoms in Alzheimer’s disease (AD). My passion for this area originated from experiences growing up and watching my grandmother, an Italian immigrant and one of my primary caregivers, struggle with both the cognitive symptoms and the behavioral manifestations of neurodegenerative disease. I went on to earn an MD/PhD in the Baylor College of Medicine Medical Scientist Training Program, working with Dr. Huda Y. Zoghbi to study molecular mechanisms of neurodegeneration in mouse models of two spinocerebellar ataxias. I developed a fundamental curiosity for mechanisms underlying neurodegenerative processes and ways to halt neuronal dysfunction. Through the mentorship of Drs. Sperling, Marshall, Johnson and Forester I have carried out preliminary work in the Harvard Aging Brain Study (HABS), a longitudinal study of cognitively normal older adults that incorporates clinical and cutting-edge human brain imaging technology.

My body of clinical work and observations in geriatric mood and cognitive disorders, combined with my expertise in molecular neurodegeneration have led me to probe the role of proteins, such as tau, in contributing to the devastating neuropsychiatric symptoms in cognitively normal older adults and in those with AD dementia. These symptoms are debilitating to patients and caregivers alike, and there are currently few/limited effective treatment strategies. My BrightFocus project builds on my preliminary work to investigate the association between depressive and other neuropsychiatric symptoms and AD biomarkers (in particular brain amyloid and tau) in cognitively normal elderly and across the AD dementia spectrum. The support of BrightFocus Foundation and the generosity of donors will provide a critical foundation for future grant submissions to the National Institutes of Health, and allow me to investigate the association of depressive and neuropsychiatric symptoms with AD biomarkers across time. It is my hope to develop an independent clinical research niche in this area, with the goal of developing better prevention and treatment strategies.

Although my grandmother ultimately lost her battle with neurodegenerative disease, my memories of her provide the motivation to help other older adults like her, and continue to drive my interests in advocating for patients with dementia and their families, promoting healthy brain aging and positive mental health, and training the next generation of geriatric psychiatrists and clinician researchers. I enjoy giving talks on these topics in the community and to fellow clinicians and scientists across all disciplines. As I work towards these goals, I am forever indebted to BrightFocus Foundation donors for helping to make these life-long visions a reality.

Publications

Gatchel JR, Rabin JS, Buckley RF, Locascio JJ, Quiroz YT, Yang HS, Vannini P, Amariglio RE, Rentz DM, Properzi M, Donovan NJ, Blacker D, Johnson KA, Sperling RA, Marshall GA; Harvard Aging Brain Study. Longitudinal Association of Depression Symptoms With Cognition and Cortical Amyloid Among Community-Dwelling Older Adults. JAMA Netw Open. 2019 Aug 2;2(8):e198964. doi: 10.1001/jamanetworkopen.2019.8964. PubMed PMID: 31397865 PubMed Icon Google Scholar Icon

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