This project aims to identify genetic causes of heritable movement disorders and define pathogenic mechanisms to improve diagnosis and enable targeted therapies. Parkinson’s disease, ataxias, spastic paraplegias, and dystonic or choreiform disorders are highly genetically heterogeneous, and many causative genes remain unknown. We will (1) recruit and characterize individuals and families with genetically unexplained movement disorders; (2) apply linkage/IBD analysis, next-generation sequencing, and CNV analysis to discover novel disease genes; and (3) investigate pathogenic mechanisms using patient tissues, induced pluripotent stem cell–derived neural and glial models, and Drosophila. Functional studies will focus on RAB39B, ATP6AP2, SAMD9L, and GBA, genes involved in endolysosomal trafficking and autophagy, pathways central to neurodegeneration. Integrated genomic, cellular, and model-organism approaches will define disease mechanisms, identify vulnerable cell types, and reveal therapeutic targets applicable across neurodegenerative disorders.
Patient Population: Older Adults
AD-protective regulatory APOE variation in ethnically diverse populations.
Variants in the apolipoprotein E (APOE) gene strongly influence Alzheimer’s disease (AD) risk, neuropathology, and longevity. The APOE ε4 allele confers the greatest genetic risk for AD in Europeans and Japanese populations and is associated with reduced lifespan, whereas the protective ε2 allele is enriched among centenarians. Notably, APOE ε4 risk is attenuated in individuals of African ancestry, who also show reduced neuropathologic burden. We hypothesize that ancestry-specific regulatory variation at the APOE locus alters risk allele dosage and contributes to these differences. Single-nucleus RNA-seq studies show reduced APOE ε4 expression in astrocytes of African carriers, but the underlying regulatory variants remain unknown. This proposal aims to define the APOE transcript repertoire in human brain (Aim 1) and functionally evaluate ancestry-enriched APOE variants for effects on transcription, splicing, and RNA processing (Aim 2) using targeted long-read RNA sequencing and multiplex reporter assays. This work will generate a regulatory map of APOE and identify variants that lower APOE expression and protect against AD.
Regulatory variation that affects splicing of the Alzheimer’s disease risk gene TREM2
Alzheimer’s disease (AD) risk is strongly influenced by genetic variation, much of which lies in noncoding regions that regulate gene expression and RNA splicing. Protein-coding variants explain only ~30% of AD heritability, highlighting the need to functionally characterize regulatory variants. TREM2 is a microglia-specific immune receptor in which heterozygous missense variants increase late-onset AD risk, while biallelic loss-of-function variants cause early-onset dementia. TREM2 undergoes alternative splicing, but its transcript repertoire and regulation in human brain remain poorly defined. We identified a novel splice isoform lacking exon 2 (Δe2) that encodes a truncated protein with altered activity. Preliminary data show that AD- and dementia-associated variants shift splicing toward Δe2, reducing functional TREM2 dosage. We will define TREM2 isoforms in human brain, functionally assess regulatory variants affecting splicing, and analyze interactions between cis-variants and trans-acting splicing factors altered in AD, using long-read RNA sequencing and high-throughput functional assays.
Discovering how a task-shifted Care Manager workforce of community health workers can address geriatric mental health
Older adults are less likely to receive the recommended standard of care for preventative services, chronic diseases and geriatric concerns such as complex care navigation. Late-life depression is a common chronic disease, and older adults face multiple barriers obtaining depression care from healthcare settings, especially if things like fragility, social needs, and transportation limit access to primary care. Offering depression care in non-traditional healthcare settings is one way to increase access. Community health workers (CHWs) are trusted community members who increase the health of communities through care coordination, health education and outreach. One approach is to task-shift the Care Manager (CM) role of a Collaborative Care framework to CHWs in the community. Global health work has demonstrated that non-clinicians can conduct low-intensity psychosocial interventions for depression. However, task-shifting the Care Manager role in a non-clinical setting requires additional skills and poses added challenges. We have gathered prior formative work among CHWs on what they think about being trained and supported in the skills of CM. We now seek to understand Collaborative Care stakeholders’ perspectives on this proposed role expansion of CHWs to CHW Care Managers (CHW-CMs) to understand how to design this role.
Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
Electroconvulsive therapy (ECT) is one of the most effective antidepressant non-invasive brain stimulation therapies for adults with major depression. However, a number of patients fail to respond despite adequate trials, and while clinically beneficial, ECT can produce adverse cognitive effects including amnesia, executive dysfunction, and verbal dysfluency.
In this prospective study, we propose the first investigation integrating multiple units of analysis including clinical and cognitive phenotyping, whole-brain neuroimaging, EEG, and E-field modeling to establish the mechanisms underlying ECT-induced antidepressant response (response biomarkers) and cognitive adverse effects (safety biomarkers), as well as to find the “sweet spot” of ECT dosing for optimal antidepressant benefit and cognitive safety. This proposal will result in a paradigm shift from “trial and error” approaches of ECT parameter selection to individualized, precision dosing to improve patient outcomes.
Community resilience to late life depression among first generation Asian Indian immigrants in the greater Seattle area (The CREED Seattle Study)
Asian Indians, are one of the fastest growing ethnic groups in the country, growing from 1.9 million (2000) to 4.6 million (2020). With a median household income of $119,000, Asian Indians are highly educated (43% have a postgraduate degree), are proficient English speakers (82%) and are often touted as a “model minority”. While these data create an impression of general well-being and success, there is limited information on the mental health of this community, as most research tends to aggregate results of the Asian population. Aging and age related mental health issues, especially late life depression in the community, in particular, has been under-studied. As culture exerts a significant influence on psychiatric morbidity, it is likely that this population has unique drivers to late life syndromic and subsyndromal depression beyond what is known from typical studies. Additionally, migration related, as well as acculturative stress, may provide unique influences. However, immigrant Indian communities are known for community engagement, providing large social networks and support which may reduce risk for depression. As a result, it is possible that higher risk resulting from immigration related stress might be mitigated by social engagement. This project will study older first-generation Asian Indians in the Greater Seattle Area to study the association between community engagement and depression symptoms.
Family and Caregiver Training and Support Program (FACTS) pilot
We know from decades of research that caregiver involvement, including family and non‐family members, in a patient’s mental health treatment can make a tremendous difference in the trajectory of their loved one’s life by supporting recovery, reducing relapse, and decreasing mental health crises. Family and caregiver involvement also decreases provider stress, improves caregiver well-being, and can lead to lower patient healthcare utilization and costs. But despite their importance, many family members and caregivers struggle to engage in the kind of support that can benefit the patient and themselves. They often lack access to education, resources, or skills to step into this critical role despite a desire to help. Our initiative intends to develop a pilot Family and Caregiver Training and Support Program (FACTS) program that aims to decrease barriers to caregiver involvement and improve caregiver support.
Our team will develop online training that will include an orientation to having a loved one who is psychiatrically hospitalized and will teach families and caregivers practical communication skills while their loved one is in our care. These topics would be relevant regardless of a patient’s diagnosis and will be adapted from existing evidence‐based models. The pilot will be tested with caregivers of patients hospitalized at the new Center for Behavioral Health and Learning and we will proactively integrate input and feedback from participants to inform program improvements along the way.
We will also build a public-facing website to host FACTS training materials as well as mental health information and resources that we will curate for accuracy and reliability. We expect the FACTS pilot content will serve as a foundation for additional offerings that will include diagnosis specific skills trainings as well opportunities for in-person sessions and Family Peer Support programming.
Immune changes with neuropsychiatric symptoms in dementia
Though the focus of most research on dementia is the pathogenesis of cognitive deficits, neuropsychiatric symptoms (NPS) are identified in >90% of those afflicted, resulting in hastened cognitive decline, worsened general health, reduced patient and caregiver quality of life, sooner institutionalization, and increased mortality. Affective symptoms, including depression, are the most common NPS in Alzheimer’s Disease (AD), and are present in over half of patients. Using the in-depth clinical phenotyping of participants in the National Alzheimer’s Coordinating Center (NACC) with matched plasma samples, we propose to determine the correlation between select cytokines/chemokines and T-cell differentiation with depression in dementia.
Spanish-language lay-delivered Behavioral Activation in senior centers
This supplement seeks to expand the Collaborative R01 on Lay-delivered Behavioral Activation in Senior Centers for clients whose preferred language is Spanish. The aims are to translate DMFB intervention materials and and test the effect of Spanish DMFB in comparison to professionally-delivered BA (Clinician BA) among older senior center clients on increased activity level and decreased depressive symptoms.
Using neurocomputational modeling to track memory decline
The most salient and debilitating aspect of dementia is memory loss. Unfortunately, memory loss is also the most difficult to quantify because it relies on doctor-administered tests that cannot be repeated very often. Without frequent and accurate measurements, it is difficult for clinicians to make reliable diagnoses, for patients and their caretakers to prepare in advance and for researchers to better understand the relationship between brain changes and cognitive decline.
This project will recruit 100 patients who are just beginning to experience memory loss as well as 100 healthy controls. Their memory function will be measured weekly through a brief, online test that can be accessed through any device and performed in less than 10 minutes. Data from the test will be fed to a computer model that simulates how fast memories fade in each patient’s brain, and the parameter that represents each patient’s speed of forgetting will be tracked over time. While the model simulates the patient, it also adapts the difficulty of the weekly task, ensuring it remains engaging but doable as memory declines.
The weekly estimates will provide the first, detailed trajectories of how fast memory declines over time in healthy aging and in different forms of dementia. The trajectory of the rate of forgetting will be used to analyze MRI data, producing precise associations between different types of memory loss and different types of brain damage.
