Investigator Grants

In 2014, the Texas Council on Alzheimer’s Disease and Related Disorders launched the inaugural Investigator Grant Program for the Texas Alzheimer’s Research and Care Consortium (TARCC), as part of the state-funded Darrell K Royal Texas Alzheimer’s Initiative. This grant program provided financial support to Texas researchers to promote novel research and discovery towards understanding biological mechanisms, improving diagnosis, and developing therapies for Alzheimer’s disease.

Since 2007 a four (4) member External Advisory Committee comprised of out-of-state distinguished, nationally prominent research scientists and medical doctors, led by Dr. Ron Petersen at Mayo Clinic, have regularly met with Steering Committee and Council representatives to conduct a detailed review of all TARCC scientific activities and grant awards to assure that the investments made by the Texas Legislature are advancing the best science of AD research.

In 2018, with a mature database of 3,670 cases accumulated by TARCC investigators across the state, the Council approved a transition from a cohort surveillance model to a grants-based program. The TARCC Investigator Grants Program aims to support the best science in the state while enhancing TARCC cohort data utilization and scientific productivity.

Professor
Department of Neurology and Neurotherapeutics
Peter O'Donnell Jr. Brain Institute
UT Southwestern

Email: [email protected]
Web: https://profiles.utsouthwestern.edu/profile/80056/john-hart.html

Title: Longitudinal Continuation of TARCC Hispanic Cohort

Project involves: UT Southwestern, UT Health Science Center San Antonio, Texas Tech Univ Health Science Center, and UT Dell

Despite being the most rapid growing ethnic group in Texas and the United States, little is known about risk factors for Alzheimer’s disease (AD) and related disorders in the Hispanic population. Previous investigations have been derived largely from studies of Hispanic subjects of Caribbean origin. Unfortunately, these data may have limited applicability to Hispanic individuals of non-Caribbean origin, which represents the largest Hispanic group in Texas. The cohort of Hispanic participants in TARCC represent one of the largest cohorts of Non-Caribbean Hispanic subjects and this proposal unites four of the previous sites that participated in the TARCC clinical cohort to continue to follow a significant number of the Hispanic subjects who were followed in TARCC. These subjects will receive the same neurological and neuropsychological testing that was previously administered in TARCC, with the addition now that every subject will receive a yearly structural MRI scan and we will recruit each subject to have a lumbar puncture (with a TARCC of 25% of the cohort) to measure a-beta-42, total tau, and phosphorylated tau.

Following aims are the scientific points to be addressed directly in this proposal by the data collected:
Aim 1. Assess the effectiveness of the CDR in the diagnosis of MCI and AD in the Hispanic population.
Aim 2. In the subset of individuals who converted from normal to MCI and MCI to AD during their enrollment
in TARCC, determine factors (demographical, neuropsychological, behavioral) that predict progression in diagnoses.
Aim 3. Verify via repeat testing of the Hispanic cohort whether factors derived from our pilot statistical analyses are still significant in this repeat testing sample. In this aim, the same variables (demographic, neurological, neuropsychological) that were used in the pilot analysis will be analyzed in this sample to determine if they remain significant for diagnostic classification in this repeat testing sample. In addition, several specific sub-aims relevant to this population to be explored are: a. Role of depressive symptom reporting on diagnostic classification in the Hispanic population. b. Utilize measures of intraindividual neuropsychological test performance variability on tests from multiple cognitive domains to add to models to improve diagnostic classification (Koscik et al., 2016).
Aim 4. Provide a continuing longitudinal cohort to collect neuroimaging markers, CSF biomarkers, and tracking
the Hispanic cohort of TARCC for neurodegenerative disease progression.
Aim 5.a. Use CSF amyloid-β1-42 and tau measures to define clinical phenotypes of normal and dementia to use in the model to determine if the same dimensions underlie diagnoses and differentiate between Hispanic diagnostic subgroups when CSF markers are used to define dementia in this population. We will compare LDA modelling results when using the CSF-based versus clinician-based diagnoses, and we will compare differences in classification rates between the two models. We hypothesize that the CSF biomarkers will be significant predictive factors in the model.
Aim 5.b. Add the CSF biomarkers to the original variables used in the preliminary study to predict clinically derived diagnosis for Hispanic subgroups and see if the addition of these CSF markers improve diagnostic classification. We hypothesize that the CSF biomarkers will be significant predictive factors in the model. We will compare classification accuracies obtained from LDA using demographic/neuropsychological and CSF data to accuracies obtained from just the demographic/neuropsychological data.
Aim 6. Add new structural MRI factors, particularly, hippocampal volume, global cortical thickness, and resting-state functional connectivity measures to determine if these factors improve the diagnostic classification accuracy for Hispanic participants. We will add MRI-based morphometric factors and standard seed-based assessments of functional connectivity, primarily, of the posterior cingulate in the default mode network and prefrontal cortex in the salience network to our predictive model to examine potential neural correlates of underlying differences between Hispanics diagnostic subgroups and to assess if these objective measures improve diagnostic accuracy beyond the existing demographic/neuropsychological data.
Aim 7. Examine diagnostic classification differences of classifications of Hispanic normal controls, MCI and AD participants using the available subsets of data separately and in combination. We will examine variability in classification accuracies using the full sets of demographic/cognitive, morphometric, resting-state fMRI connectivity, and CSF (Aß42, t-tau, and p-tau) data.

The general design of this study is to recruit a cohort of Hispanic participants previously enrolled in TARCC at each site to continue to acquire yearly neuropsychiatric examination, neuropsychological examination, and relevant questionnaires at each yearly visit and a one-time blood draw for genetics if the subject is a new recruit to TARCC, all will undergo MRI and a subset will provide CSF. The neuropsychiatric, neuropsychological, and questionnaire results will be used to derive diagnostic classifications (normal, MCI, AD) via weekly central consensus conference committee and clinicians from each site will participate via Skype/Zoom and this data will be used to address the proposed aims of this study and all data will be kept in central core facilities for other investigators to access for their studies (see also companion application).

2023 Postdoctoral Fellowship Grants

Recipient

Grant Title

Recipient: Salvatore Saieva, PhD
Title: Postdoctoral Fellow
Department: Neurology
University: The University of Texas Health Science Center at Houston

Email: [email protected]
Web: https://www.uth.edu/postdocs/profile.htm?profileinode=30087423-5402-4991-82ee-ebc124527496

Grant Title: Pathological characterization and seeding activity of Aß aggregates in eyes

Abstract: Alzheimer’s Disease (AD) pathology is mainly linked to CNS alterations, yet compelling evidence shows the contribution of peripheral tissues in AD progression. Aß deposits have been identified in peripheral tissues of AD patients, including skin, liver, and intestine, and Aß seeds can accelerate Aß brain deposition in mouse models when challenged through different routes of administration. Notably, our group recently demonstrated that the most efficient peripheral administration route of Aß seeds is through eye drops. This information is suggestive of an active crosstalk between brain and eyes in the context of AD. Interestingly, the presence of Aß deposits has been demonstrated in eyes of AD patients and mouse models. Therefore, investigating the biochemical, functional and pathological properties of ocular Aß deposits may be relevant to understand the mechanisms underlying AD onset and progression. Furthermore, growing evidence suggests that Aß peptides spread in the brain through mechanisms similar to prions, infectious particles shown to transmit disease in animals and humans. Relevant to this application, Creutzfeldt-Jakob disease can be transmitted in humans following eye surgeries inadvertently performed with prion-infected materials. The latter information, combined with our preliminary observations, raises concerns on potential inter-individual transmission of Aß through the ocular route. Moreover, mounting evidence suggests that Aß conformational variants, or strains, underlie the phenotype variability observed across AD patients, therefore their early detection can lead to more accurate prognosis and treatments; noteworthy, ocular markers and imaging methos of Aß in eyes are being explored as potential diagnostic tools. Our working hypothesis is that Aß deposits present in the eye share similar pathological properties compared to those in the brain, and that misfolded proteins in these two organs spread in a prion-like fashion. To test our hypothesis, we will characterize the biochemical and biological properties of eye’s misfolded Aß compared to their brain counterparts in human samples, and assess eye’s deposits seeding potentials. For this purpose, we will employ several techniques including histological analyses, biochemical assays in human eyes and brains, in vitro and in vivo seeding assays, behavioral testing of AD mouse models intracerebrally treated with eye and brain extracts from AD patients, and pathological characterizations of the same. In summary, this project can provide novel (non-incremental) evidence on the role of the eye in AD pathology, in particular: 1) identifying AD-relevant pathological events occurring simultaneously in eyes and in the brain, 2) prompting the development of potential innovative methods for AD diagnosis and assessment, 3) unveiling potential mechanisms associated with inter-individual transmission of amyloidosis, 4) encouraging the research for innovative and personalized therapies against AD.

Pathological characterization and seeding activity of Aß aggregates in eyes

Recipient: Vijay Kumar M J Rao, PhD
Title: Postdoctoral Fellow
Department: Neurology
University: The University of Texas Health Science Center at Houston

Email: [email protected]
Web: https://med.uth.edu/neurology/brains-research-laboratory/mccullough-lab-faculties/dr-andrey-tsvetkovs-lab/

Grant Title: The role of G4 helicase DHX36 in neuronal and astrocytic senescence

Abstract: Cellular senescence characterized by DNA damage, chromatin remodeling, dysfunctional autophagy, and metabolic reprogramming plays a crucial role in aging and age-related brain disorders such as Alzheimer’s disease (AD) and related dementias (ADRDs). During aging, brain cells such as neurons and astrocytes are subjected to a lot of internal stressors such as oxidative stress, DNA damage, accumulation of protein aggregates, and dysregulated gene expression, all contributing to senescence. Despite extensive research in aging and AD, it still remains elusive how brain cells respond to stressors and undergo senescence and whether there are differences in pathways between healthy aging and pathological conditions such as AD. Guanine-rich DNA and RNA can fold into non-canonical four-stranded structures called the G-quadruplex (G4s, G4-DNA, G4-RNA). G4-DNA plays important roles in transcription and replication. G4-RNA regulates various RNA functions including translation. G4 helicases unfold the G4-DNA/RNA structures and modulate G4 landscapes in cells. Overly stabilized G4-DNA induces genomic instability, whereas overly stabilized G4-RNA disrupts translation and other RNA-dependent processes, leading to cellular senescence. In our data, we found that brain samples from aged mice contain more G4s than those of young mice. Mice treated with a small molecule G4 stabilizer develop cognitive impairment and accelerated brain aging. Senescent astrocytes contain more G4-RNA compared to young astrocytes. G4-helicase DHX36, a major helicase that unfolds G4-DNA and G4-RNA, is upregulated in neurons in a mouse model of tauopathy-aged Tau P301S brains compared to aged control mice, likely indicating a compensatory mechanism to revert G4 stabilization. All these findings converge and lead us to hypothesize an important G4-dependent molecular mechanism of aging and senescence in the brain. We hypothesize that reverting G4 stabilization by DHX36 will prevent/reduce senescence phenotypes in the aged Tau P301S brain and in aged human astrocytes. The primary objective of the proposal is to investigate the functional role of DHX36 in mitigating senescent phenotypes in two cell types of the NVU—in neurons and astrocytes. In Aim 1, we will examine the role of neuronal DHX36 in rescuing neurodegenerative and vascular phenotypes in Tau P301S mice. In Aim 2, we will determine the role of DHX36 in modulating the mechanisms of senescence in young and aged human astrocytes. The synergistic interactions of G4s and G4 helicases across the various cellular mechanisms raise the optimism that effective targeting of G4s could exert novel findings to develop therapeutic strategies to combat pathology associated with aging. These studies will create a strong foundation to decode the vital functions of G4-DNA, G4-RNA, and G4 helicase DHX36 in regulating cellular senescence, brain aging, and pathology associated with neurological disorders, AD, and ADRDs.

The role of G4 helicase DHX36 in neuronal and astrocytic senescence

Recipient: Elizabeth Ochoa, PhD
Title: Postdoctoral Fellow
Department: Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases
University: University of Texas Health Science Center at San Antonio (UT Health San Antonio)

Email: [email protected]
Web: https://lsom.uthscsa.edu/physiology/postdoctoral-training/pathobiology-occlusive-vascular-disease/current-trainees/elizabeth-ochoa-2/

Grant Title: Investigating the selective vulnerability of the brainstem in ADRD

Abstract: Alzheimer’s disease and related dementias (ADRD) affect over 6 million individuals in the United States, and over 55 million globally. Deposition of disease-associated pathological hallmarks is often found in brainstem structures. The brainstem houses nuclei important for the control of cardiovascular and cardiopulmonary homeostasis, and data from the Framingham Heart Study identify factors such as altered heart rate variability and hypertension as risk factors for the development of ADRD. GWAS studies have identified APOE as a genetic risk modifier of ADRD, and reports indicate that APOE4 has implications in cardiovascular disease. Additionally, a recent report finds that the risk effect due to APOE4 can be blunted by African local genetic ancestry. While the dementia risk attributable to comorbidities and APOE is understood in cortical regions, selective vulnerability of brainstem nuclei to these risk factors remains unclear, especially in the context of diverse genetic ancestry. In addition, identified novel genetic variants from patients with neurodegenerative disease are yet to be investigated as mediators of selective vulnerability in the brainstem. In preliminary studies using 18-month-old mice with genetic knock-in of either APOE2, 3, or 4 allele I find that APOE differentially affects astrocyte transcriptomics in the brainstem when compared to the cortex. In mice with APOE4 knock-in, pathway analysis reveals that neurotoxic astrocyte genes are increased in the cortex while decreased in the brainstem. Based on these results and reports that identify region and disease-associated astrocyte genes, I hypothesize that dementia risk modifiers such as APOE status, diverse genetic ancestry, cardiovascular disease, and novel genetic variants differentially alter the expression of disease-associated astrocyte genes to dictate vulnerability of brainstem nuclei to neurodegenerative pathology. In this TARCC Postdoctoral Fellowship, I will test my hypothesis by combining studies in postmortem human tissue, TARCC database information, clinical findings, and functional genomics. Using histological methods alongside spatial transcriptomics, I will determine the expression of disease-associated astrocyte genes in the human brainstem (Aim 1) and quantify correlation between astrocyte gene expression, dementia risk factor (Aim 2), and novel genetic variant (Aim 3). My fellowship-supported development as a translational scientist will include formal training in bioinformatics, clinical shadowing in neuropsychology and genetic counseling, and model development of novel disease variants identified from patients using Drosophila melanogaster (Aim 3). The proposed studies and training will improve the current understanding of brainstem vulnerability in ADRD and foster future discovery of biomarkers and potential therapeutic strategies.

Investigating the selective vulnerability of the brainstem in ADRD

Cerebrovascular Dysfunction & Rejuvenation in Alzheimer's Disease Pathogenesis

Recipient: Jared Benge, PhD, ABPP
Title: Associate Professor
Department: Neurology
University: The University of Texas at Austin

Email: [email protected]
Web: https://dellmed.utexas.edu/directory/jared-benge-ph-d

Grant Title: Continuation of the Neuropsychology Fellowship Program at UT Dell Medical School

Abstract: Given the projected growth of the older adult population and need for dementia care services in Texas and beyond, postdoctoral training in neurodegenerative diseases is more important than ever before. The Adult Neuropsychology Postdoctoral Fellowship training program at The University of Texas (UT) at Austin Dell Medical School (DMS) was developed in 2020 with the goal to train clinician-scientists to help fill the large need for specialists in Alzheimer disease and related conditions (ADRD). This 2-year program follows the scientist-practitioner model, which specifies requirements in clinical training, research, and didactic programming, and is intended to be the final neuropsychology training experience that will prepare postdoctoral fellows for independent practice in neuropsychology and eventual board certification in clinical neuropsychology. Fellows in our training program have the opportunity to learn about the full spectrum of dementia care within an integrated practice setting and value-based care model at the Comprehensive Memory Center (CMC) at Mulva Clinic for the Neurosciences at UT Health Austin. Fellows participate in 2-3 neuropsychological evaluations per week and observe the typical practice of all team members which includes exposure to behavioral neurology, geriatric psychiatry, social work, and speech language therapy sessions all geared toward neurodegenerative disease diagnosis and management. Research is part of the daily clinic operations of the CMC, and one thematic area of study for the CMC is examining the effects of our technology on day to day functioning in those with ADRD. For the required TARCC-related research project, the fellow will help to develop measures of digital dyspraxia amongst older adults impacted by ADRD. To ensure successful completion of this project within the 2-year training period, the fellow will have 30% protected research time, access to clinical and research personnel needed to collect and enter data, and mentorship from faculty with expertise in developing and validating measures for use in ADRD. Finally, fellows participate in required weekly and monthly didactics and choose from a variety of optional didactics based on individual training needs and goals. They also are provided several opportunities for professional development that will prepare them well for a career as a board-certified clinical neuropsychologist and allow them to network with other neuropsychologists, researchers, and clinicians involved in dementia care in Texas.

Continuation of the Neuropsychology Fellowship Program at UT Dell Medical School

2023 Junior Investigator Research Grants

Recipient

Grant Title

Developing therapeutic inhibitor peptides for Alzheimer and related diseases

Recipient: Natalia Rocha, PhD, MSc
Title: Assistant Professor
Department: Neurology
University: The University of Texas Health Science Center at Houston

Email: [email protected]
Web: https://med.uth.edu/neurology/2022/10/31/natalia-pessoa-rocha-pharmd-msc-phd/

Grant Title: Biological validation of MBI as part of the ADRD spectrum

Abstract: Mild behavioral impairment (MBI) is a syndrome comprising sustained and impactful late-life neuropsychiatric symptoms (NPS) that are thought to represent early manifestations of ADRD. The MBI construct assumes that neurodegeneration can manifest as NPS before clinically defined cognitive impairment. Although the diagnostic criteria for MBI represent a clear advance in the definition of prodromal stages of AD, the concept of MBI as part of the AD spectrum still needs to be validated from clinical, epidemiologic, and neurobiological perspectives. With the escalating prevalence of AD in our aging society and the development of new therapeutics, including anti-amyloid immunotherapy, there is a critical need to identify patients as early as possible in the neurodegeneration process before substantial brain damage occurs. Our long-term goal is to identify individuals at the earliest symptomatic (behavioral) stages of AD. Our overall objective, which is the next step toward attaining our long-term goal, is to validate the construct of MBI in a neurobiological framework. Our central hypothesis is that individuals with MBI represent a clinically measurable stage of AD and thus will have evidence of AD pathophysiological changes, as confirmed by validated AD CSF markers. The central hypothesis will be tested by pursuing two specific aims: 1. Identify AD-related markers in biological fluids of individuals with MBI. 2. Ascertain the presence of ongoing neuroinflammation and neurodegeneration in individuals with MBI. Our approach will be to recruit individuals with MBI and analyze the AD CSF biomarker profile and novel in vitro seed amplification assays (SAAs) to detect the presence of soluble misfolded oligomeric forms of Aß (SA1). We will also quantify CSF levels of markers of inflammation (cytokines, C-reactive protein, YKL-40, sTREM-2) and neuronal/axonal and glial injury [NFL, S100B, and GFAP] (SA2). In parallel to assessing CSF, we will use blood samples to test less invasive ways to detect AD-related changes (SA1 & SA2). This proposal is innovative because: 1. It will use well-established markers of AD (i.e., CSF levels of Aß42, Tau, and pTau-181) and innovative methods (SAAs) to detect an AD profile in patients with MBI. 2. Besides analyzing CSF, we will also assess AD-related biomarkers and Aß oligomers in peripheral blood samples as a promising strategy aiming at less invasive ways. 3. Will leverage CSF and blood samples previously collected from a diverse, underrepresented population (for the AD and control groups). To create the MBI group, we will use an established cohort of individuals with NPS of late onset from the UT Geriatric Psychiatric Clinic. This contribution is significant because it will help identify individuals at a prodromal, behavioral stage of AD. Early detection and treatment of behavioral symptoms might, respectively, be relevant for participants’ selection for disease-modifying trials and reduce and/or delay cognitive decline.

Biological validation of MBI as part of the ADRD spectrum

Recipient: Rodney Ritzel, PhD
Title: Assistant Professor
Department: Neurology
University: The University of Texas Health Science Center at Houston

Email: [email protected]
Web: https://med.uth.edu/neurology/2022/10/31/rodney-ritzel-phd/

Grant Title: Cellular senescence as a sex-specific driver of amyloid pathology

Abstract: Women with Alzheimer’s disease (AD) exhibit greater cognitive vulnerability, faster cognitive decline, and increased brain volume loss compared to men. The hormonal shifts during menopause may elevate the risk of AD-related brain changes, as early menopause is associated with a higher risk of dementia later in life. The initiation of amyloid ß (Aß) pathology aligns with this unique life transition in women. Men and women exhibit different rates of biological aging over the lifetime, and patients with AD have older biological brain ages than their chronological age would predict. The decline in estrogen levels during menopause triggers profound changes in brain structure and higher cognitive function, with important implications for the immune system. Inflammation and immune dysregulation play a critical role in in the generation of Aß plaques and AD pathogenesis. As the primary drivers of inflamm-aging, senescent microglia represent important therapeutic targets, which if left unchecked, could worsen AD progression. Early phase clinical trials for AD are exploring senotherapeutics targeting senescent cells, but the efficacy of senolytic treatments, such as dasatinib plus quercetin (D+Q), has not been evaluated for both sexes, in preclinical models of amyloidosis, or at different stages of disease progression. This represents a major gap in understanding, and a potential barrier to translation. Our previous work shows the female sex is associated with increased microglial senescence and cognitive dysfunction in late-middle age. This informs our overall hypothesis that menopause induces premature immune senescence which promotes accelerated aging, amyloidosis, and subsequent cognitive decline in older females. This proposal will explore the role of biological aging in the pathogenesis and progression of AD and as a potential driver of sexually dimorphic outcomes. We will determine if the accumulation of senescent cells precedes amyloidopathy or vice versa, and whether males and females respond similarly to senolytic treatment. In our first aim, we will conduct preclinical testing of D+Q therapy in age- and sex-matched amyloid-bearing Tg2576 mice. Aim 1a will evaluate efficacy in pre-symptomatic mice to determine whether senescent cells contribute to AD pathogenesis. Aim 1b will evaluate efficacy in post-symptomatic mice to determine whether senescent cells drive Aß plaque formation and cognitive decline. In our second aim, we propose to utilize the TARCC biorepository to validate our preclinical findings. We hypothesize that the early emergence of senescent cells in the human brain (Aim 2a) and blood (Aim 2b) will be seen in patients with mild cognitive impairment (MCI) versus normal controls. We also predict that sex-specific senescence signatures will be more pronounced in AD patients compared to age-matched MCI samples, implicating cellular senescence as an important driver of disease progression.

Cellular senescence as a sex-specific driver of amyloid pathology

Recipient: Vijayasree V Giridharan, PhD
Title: Assistant Professor
Department: Psychiatry and Behavioral Sciences
University: The University of Texas Health Science Center at Houston

Email: [email protected]
Web: https://med.uth.edu/psychiatry/2023/10/31/vijayasree-v-giridharan-phd/

Grant Title: Role of Innate lymphoid Cells in Alzheimer's Pathology

Abstract: Alzheimer's disease (AD) is a multifaceted neurodegenerative condition marked by gradual cognitive deterioration, memory loss, and behavioral changes. In the context of AD, disruptions in the immune system and inflammatory processes have emerged as significant factors in disease development. The exploration of immune pathways has shed light on their involvement in AD pathology. In the last decade, the identification and study of tissue-resident innate lymphoid cells (ILCs) have revolutionized our understanding of immune regulation in health and disease. ILCs demonstrate activation in response to the cytokines IL-33 or IL-25. When activated, a specific subset of ILCs, known as ILC2s, releases a combination of cytokines including IL-5, IL-4, and IL-13. This intricate cascade of events holds potential significance in the protection of the central nervous system (CNS). Recently, in aging, stroke, and Alzheimer’s mouse models functionally active ILC2 demonstrated a significant reduction in neuroinflammation and promotes cognition by releasing neuroprotective cytokines IL-5 and IL-13. Our preliminary finding shows the accumulation of quiescent ILC2 in the brain barrier (choroid plexus, CP) and a significant decline in memory in the infection model. Although studies investigated the role of ILC2 on cognition, the influence of ILC2 on amyloid and tau pathology is not explored yet. In this context, we hypothesize that increasing the activated ILC2 may improve cognitive function alleviate amyloid and tau pathology, and prevent AD progression. To test this hypothesis, in aim 1. We will test whether the expansion of ILC2 improves cognition and reduces amyloid pathology in the APP/PS1 mouse model. Aim 1: To test the role of ILC2 on cognition and amyloid pathology in experimental AD animal models. SA1.1. To test whether exogenously administering activated ILC2 attenuates amyloid plaques in APP/PS1 mice. SA1.2. To test whether ILC2 deficiency exacerbates amyloid pathology. Aim 2: To test the role of ILC2 on cognition and tau pathology in experimental AD animal models. SA2.1. To examine whether administering activated ILC2 ameliorates tau hyperphosphorylation in P301S mice. SA2.2. To investigate whether the absence of ILC2 worsens tau pathology. We will analyze the cognition using behavioral tasks, different subtypes of ILCs in CP, meninges, and brain using flow cytometry, neuroinflammation by evaluating inflammatory markers and glial cell activation, and AD pathology by evaluating amyloid (soluble and insoluble Aß40/42, 4G8), and tau levels using immunohistochemistry (4G8 and AT8) and ELISA assays. The outcome of this study will increase our understanding of the role of ILC2 in AD pathology further it could offer invaluable insights into potential therapeutic approaches for a range of dementia-related disorders.

Role of Innate lymphoid Cells in Alzheimer's Pathology

Recipient: Huihui Fan, PhD
Title: Assistant Professor
Department: Neurology
University: The University of Texas Health Science Center at Houston

Email: [email protected]
Web: https://med.uth.edu/neurology/2023/08/31/huihui-fan-mbbs-phd/

Grant Title: Harnessing DNA methylation patterns in TARCC cohort to reveal novel biomarkers

Abstract: Alzheimer's disease (AD) is the main cause of dementia among adults aged 65 and older and characterized by the accumulation of amyloid and dysfunctional tau protein in the brain along with the final development of dementia. As indicated by brain imaging, accumulation of amyloid precedes the hallmark symptoms of AD by more than a decade, necessitating the urgency of developing early diagnostic markers of its onset and progression, particularly for new therapeutics that aim to modify disease process. As the population of older adults grows around the world, the incidence of AD is also intensifying. However, not all people = 65 years old are affected equally. Compared to other ethnic groups, Latinos = 65 years of age are about 1.5 times more likely than non-Hispanic Whites to develop Alzheimer’s and other dementias and are projected to have the steepest increase in AD in the next few decades. Some of the known and suspected risk factors for AD, for example advanced age and vascular disease risk factors (i.e., diabetes and hypertension), predominantly present in Latinos, may lead to their greater risks. Sex is another major risk factor for AD. Currently, 2 out of 3 AD patients are females. Latinos of Mexican descent are the largest ethnic group in the United States and the fastest-growing group in Texas, however, very little is known regarding AD in this population. Here, we propose to leverage the unique and novel strength of the TARCC (The Texas Alzheimer’s Research and Care Consortium) cohort to uncover novel peripheral DNA methylation biomarkers in Hispanic patients with mild cognitive impairment (MCI) and AD. Approximately 35% of the TARCC cohort are of Hispanic ethnicity and were studied longitudinally. We will profile and deliver the very first matched peripheral blood cell and plasma-based DNA methylome in Hispanic participants with MCI, AD, and age-matched normal controls (NC). Sex and comorbidities (i.e., hypertension and diabetes) will be evenly balanced for profiling and accounted for in downstream marker discoveries. Differentially methylated loci will be identified by comparing patients with MCI or AD to NC. DNA methylation quantitative trait loci will be identified using both case-control (i.e., MCI or AD vs. NC) and longitudinal design (MCI to AD conversion). Potential novel and unique biomarkers will be identified and validated by cross-referencing with and further filtered using peripheral biomarkers derived from large-cohort studies with non-Hispanic participants that are publicly available. Plasma-based circulating DNA methylome will be deconvoluted against the most comprehensive reference to date, by utilizing supervised deep neural network approach. Plasma-based central system-derived unique CpG loci associated with MCI and/or AD will be cross-referenced with and further filtered using brain-derived markers from patients with non-Hispanic ethnicity to identify potential and unique markers for Hispanic patients.

Harnessing DNA methylation patterns in TARCC cohort to reveal novel biomarkers

Recipient: Kristin Wilmoth, PhD
Title: Assistant Professor
Department: Psychiatry
University: The University of Texas Southwestern Medical Center (UT Southwestern)

Email: [email protected]
Web: https://profiles.utsouthwestern.edu/profile/413313/kristin-wilmoth.html

Grant Title: Enhancing Healthcare-Embedded Support for Care Partners of Adults with Alzheimer

Abstract: Demographic shifts in the older adult population are anticipated to create an immense need for care partners, rendering care partner support/training essential to public health. Dementia care partner support interventions that are culturally competent are crucial in light of growing U.S. diversity. Problem-solving training (PST), which teaches a self-management strategy derived from problem-solving psychotherapy, is a support intervention that our team culturally adapted for Latin American Spanish-speaking dementia care partners from diverse countries of origin. A lack of pre-implementation research has stalled the adoption of PST into healthcare settings. In fact, few support interventions for dementia care partners have bridged the translational gap from research into healthcare practice. Given healthcare is a novel setting for PST, better understanding of key healthcare stakeholders’ perspectives would guide implementation strategies. Understanding contextual factors is particularly needed for care partners from traditionally underserved populations in order to foster equitable access. The proposed study applies the Exploration and Preparation phases of the EPIS implementation science framework. The objectives of Aim 1 and 2 are to explore outer and inner characteristics, respectively, to inform PST implementation for care partners in Alzheimer’s disease and related dementias. Aim 1 will conduct a focus group on barriers/facilitators to clinic access for healthcare disparities populations (outer context). Aim 2 will collect quantitative surveys and qualitative interviews surrounding implementation engagement/climate within healthcare staff (inner context). The objectives of Aim 3 are to prepare for implementation. Aim 3 will create a situational assessment using mixed methods findings from Aims 1 and 2. Findings will inform adoption and scale-up of healthcare-embedded PST for dementia care partners. This study will pave the way for future pragmatic clinical trials of healthcare-embedded PST, such as a hybrid effectiveness-implementation trial. The proposed project is significant in that it represents the next step toward supporting dementia care partners during routine care.

Enhancing Healthcare-Embedded Support for Care Partners of Adults with Alzheimer

Recipient: Murali Vijayan, PhD
Title: Assistant Professor
Department: Internal Medicine
University: Texas Tech University Health Sciences Center

Email: [email protected]
Web: https://www.depts.ttu.edu/onehealth/faculty/murali-vijayan.php

Grant Title: VDAC1 and mitophagy regulation in Alzheimer's Disease

Abstract: Alzheimer's disease (AD) is a late-onset, neurodegenerative disease characterized by a progressive decline of memory and cognitive functions and changes in behavior and personality. AD results in the irreversible loss of neurons, particularly in the learning and memory regions of the brain. The earliest symptoms of AD, which affect a large percentage of people, have been linked to mitochondrial abnormalities. Recently, we provided the first genetic crossing study to report the beneficial effects of reduced voltage dependent anion channel 1 (VDAC1) in AD. Further, our study observations provided protective effects of VDAC1 against P-Tau-induced mitochondrial dysfunction and defective mitophagy in TAU mice (P301L strain). However, the relationship between VDAC1 and mitophagy remains unclear. In this proposal, we propose to elucidate the role of reduced VDAC1 in preventing the progression of AD by promoting mitochondrial quality through mitophagy. Preliminary findings from our lab suggested that there is an increase in mitochondrial fragmentation and a reduction in mitochondrial biogenesis, synaptic function, mitophagy, and autophagy in 6-month-old Tau mice. These changes were reversed in the 6-month-old VDAC1+/-/Tau mice, suggesting that a reduction of VDAC1 may decrease the production of phosphorylated tau, reduce mitochondrial dysfunction, maintain mitochondrial dynamics, and enhance mitophagy, autophagy, mitochondrial biogenesis and synaptic activity. We also found that a partial reduction of VDAC1 (i) reduces the interaction of phosphorylated Tau with VDAC1, (ii) alters the interaction of HK1 and HK2 with VDAC1, (iii) triggers PINK1-PARKIN- Mediated mitophagy in 6-month- old, double mutant (VDAC1+/-/TAU) mice relative to TAU mice. The mechanisms underlying reduced VDAC1 remain to be elucidated in the proposed research, and the effect of VDAC1 on mitochondrial quality through mitophagy mechanisms of Tau mice will be determined. In Aim 1 of this project, we will determine whether reduced VDAC1 maintains mitophagy and their cargo receptor expressions in an in vitro AD model. In Aim 2, we will determine the molecular mechanisms of VDAC1 and mitophagy in an in vivo AD model. Mitophagy controls mitochondrial quality and quantity and it is the primary mechanism regulating mitochondrial energy metabolism, self-repair, and renewal. The nature of the interaction between mitophagy and mitochondrial energetic activity in AD is a topic that has been debated for a long time but has not yet been fully explored. Our project is designed to provide i) a causative link between VDAC1 and mitophagy in an AD model and ii) the protective effects of reduced VDAC1 against P-Tau mitochondrial toxicities in TAU mice. In addition, we expect that the findings derived from this work will provide new evidence to develop VDAC1 as a therapeutic strategy for AD.

VDAC1 and mitophagy regulation in Alzheimer's Disease

Recipient: Youngran Kim, PhD
Title: Assistant Professor
Department: Management, Policy and Community Health
University: The University of Texas Health Science Center at Houston

Email: [email protected]
Web: https://sph.uth.edu/faculty/#KDqYtmktY8dJ91A4QeRS5A==

Grant Title: Impact of FDA approval of brexpiprazole for agitation in Alzheimer's disease

Abstract: Agitation is among the most common and challenging aspects of care in patients with dementia due to Alzheimer’s disease (AD). It commonly occurs in combination with symptoms of aggression toward self or others, causing greater caregiver burden, and higher risk of nursing home placement. Therefore, safe and effective treatment of agitation is a high priority to improve patients’ quality of life, reduce the burden on their caregivers, and allow patients to live with their families in the community longer. While antipsychotics have been commonly used off-label to manage agitation in people with AD, particularly those in nursing homes, none of the antipsychotics was approved by the U.S. Food and Drug Administration (FDA) until recently. In May 2023, brexpiprazole (atypical antipsychotic drug) was granted supplemental approval and became the first FDA-approved treatment for agitation associated with dementia due to AD. The availability of an FDA-approved treatment option may have several implications for dementia care in patients with AD. As brexpiprazole stands as the sole approved antipsychotic drug in the US for treating agitation in people with AD, it is likely to become a prominently favored pharmacological therapy among clinicians, patients, and families, potentially surpassing other antipsychotics. This shift may lead to an overall increase in antipsychotic drug use among elderly patients, reversing years of federal and state efforts to reduce the widespread use of antipsychotics in residential care homes. Furthermore, the prescription cost for brexpiprazole is significantly higher compared to commonly used antipsychotics. Importantly, the drug’s approval was based on only two phase 3 randomized clinical trials with predominantly white participants (95%), raising safety concerns. Therefore, it is crucial to evaluate the impact of the first FDA-approved antipsychotic medication to treat agitation associated with AD in terms of utilization, cost, and long-term safety outcomes. The proposed research will focus on Medicare beneficiaries with AD in Texas using Texas Medicare claims data 2016-2024 with three specific aims: 1) examine changes in antipsychotic prescriptions overall and by drug type, provider specialty and type, and residential setting, 2) assess changes in the cost of antipsychotic prescriptions and healthcare expenditures overall and by service type, and 3) determine the safety of brexpiprazole in a real-world setting among Medicare beneficiaries with AD in Texas. Our proposal aligns with the research priority associated with dementia care, aiming to evaluate the impact of the advanced treatment option for agitation associated with AD and ensure its safety, particularly among diverse and underrepresented populations in clinical trials. The anticipated outcomes will provide timely and informative insights into antipsychotic drug use for stakeholders in Texas, encompassing state authorities, clinicians, patients, and families.

Impact of FDA approval of brexpiprazole for agitation in Alzheimer's disease

Recipient: Christian LoBue, PhD
Title: Assistant Professor
Department: Psychiatry
University: The University of Texas Southwestern Medical Center (UT Southwestern)

Email: [email protected]
Web: https://profiles.utsouthwestern.edu/profile/127352/christian-lobue.html

Grant Title: An Alzheimer’s Clinical Spectrum Proteome Associated with A History of Mild TBI

Abstract: The Alzheimer’s Clinical Syndrome (ACS) involves a stage preceding dementia, called amnestic mild cognitive impairment (aMCI), and a history of traumatic brain injury (TBI) has been linked to an earlier onset of cognitive symptoms in the context of aMCI and ACS. The mechanistic pathway for TBI being a risk factor for a hastened onset is unknown and it remains unclear if mild TBI (mTBI) can serve as a risk factor for aMCI and ACS. Uncovering the biological processes linking TBI to ACS and the potential influence of mTBI was identified as a national research priority at the National Institutes of Health Alzheimer’s Disease 2022 Summit. Proteomic profiling is a novel, unbiased technique to measure many proteins in biofluids simultaneously with links to biological functions. This is a sophisticated method to study a wide range of biological processes involved in ACS that may be influenced by a history of mTBI to capture if mTBI may serve as a risk factor for ACS as well as identify potential mechanistic pathways. We recently completed enrollment of a pilot project that collected CSF samples and neuropsychological data on aMCI individuals with a history of mTBI (n = 19) and aMCI individuals with no TBI history (n = 17). Furthermore, the Texas Alzheimer’s Research and Care Consortium (TARCC) Database and Biobank contains blood samples along with neuropsychological data and information about mTBI history in a subset of participants with normal cognition, aMCI, and ACS. For this proposal, we will leverage the biofluid samples from our pilot study and TARCC to perform in-depth proteome profiling of two independent cohorts and integrate the results with neuropsychological data in order to accomplish three study aims. Aim 1 will focus on the discovery of CSF-derived proteomic markers in aMCI that are associated with a history of mTBI. Aim 2 will identify if a history of mTBI influences CSF-based proteome associations with cognitive endophenotypes in aMCI pertaining to episodic memory, language, attention, and executive functions. Aim 3 will focus on blood-derived proteomic discovery and evaluation of blood-based protein links to cognitive endophenotypes across the cognitive spectrum. We will also examine the overlap between markers identified in CSF and blood to assess if brain-linked markers can be detected in blood, shared across cognitive stages, and replicated in an independent cohort. This will be the first proteomic study on the link between mTBI and cognitive decline, serving as a timely step in addressing a critical research priority for the National Institutes of Health. This TARCC proposal could provide the groundwork and essential pilot data for an innovative NIH R01 application to identify the biological processes linking the onset of ACS to prior TBI, which could eventually lead to the development of new prognostic markers and interventions to mitigate risk for ACS.

An Alzheimer’s Clinical Spectrum Proteome Associated with A History of Mild TBI

2023 Investigator Initiated Research Grants

Recipient

Grant Title

Recipient: Karienn de Souza, PhD
Title: Research Assistant Professor
Department: Department of Neuroscience & Experimental Therapeutics
University: Texas A&M University Health Science Center

Email: [email protected]
Web: https://medicine.tamu.edu/faculty-listings/de-Souza.html

Grant Title: Impact of pro inflammatory cell expansion on behavioral dysfunction during aging

Abstract: Fragmentation of the sleep-wake cycle and decreases in the amplitude of other circadian rhythms precede cognitive impairment during aging and in Alzheimer’s disease and Related Dementias (AD/ADRDs), suggesting that alterations in circadian rhythmicity may contribute to the age-related decline in learning and memory performance. However, the extent to which, and how, early circadian rhythm dysregulation affects cognitive aging are unknown. Because immune cell activation and inflammation have been commonly implicated in the pathophysiology of dementia and in response to circadian rhythm dysregulation, we propose that expansion of pro-inflammatory cells (CLIP+ B cells) is a key factor in the mechanism by which circadian dysregulation directly contributes to cognitive impairment and synaptic dysfunction during aging. To study how circadian dysregulation, aging and inflammation interact to modulate age-related impairment of cognitive function, we will use an experimental model combining our established paradigm for controlled circadian rhythm desynchronization (CCD) with novel analysis of cognitive aging in C57Bl/6J mice. Our pilot data indicate that following exposure to shifted LD cycles (12hr advance/5d) during early adulthood (˜3mo) and then to a standard LD 12:12 schedule for an additional ˜6mo, all mice exhibited dramatic impairment in the Barnes maze test at middle age (13mo), well before cognitive decline is normally observed. Using this LD cycle shifting paradigm and our cognitive index scoring strategy, we will assess whether altered B cell regulation mediates CCD-induced acceleration of cognitive dysfunction during aging. These studies are innovative in: 1) providing an opportunity to precisely isolate the mechanistic factors by which circadian rhythm dysregulation alone contributes to the progressive decline in cognitive function, and 2) testing novel therapeutic agents and approaches (prevention with CAP, and reversal with B cell depletion) for counteracting the long-term effects of circadian dysregulation on immune cell activation and accelerated decline in cognitive function. Overall, the long-term objectives of this project are to determine if circadian dysregulation provides an early biomarker of age-related decline as observed in AD/ADRDs, and to identify therapeutic targets for modulating long-term outcomes in individuals at risk for circadian rhythm disturbances and accelerated cognitive aging.

Impact of pro inflammatory cell expansion on behavioral dysfunction during aging

Recipient: Tatiana Barichello, PhD
Title: Associate Professor
Department: Psychiatry and Behavioral Science
University: The University of Texas Health Science Center at Houston

Email: [email protected]
Web: https://med.uth.edu/psychiatry/2022/11/11/tatiana-barichello-phd/

Grant Title: Unraveling the Influence of Delirium in Alzheimer's Disease Pathogenesis

Abstract: Delirium is a profound neuropsychiatric syndrome marked by the abrupt onset of attention and cognitive deficits, circadian rhythm and arousal system dysregulation, and alterations in psychomotor functioning. In the context of Alzheimer's disease (AD), delirium has been found to hasten the trajectory of cognitive decline in affected patients. Our hypothesis posits that delirium is a precipitating or exacerbating factor of dementia by driving gut dysbiosis and neuroinflammation that, in turn, favor AD pathology. The primary objective of this project is to elucidate the potential relationship between delirium, induced either by infection or surgery, and AD pathology. Our research question is, Does delirium due to infection or surgery heighten the brain's vulnerability to AD? We selected two distinct animal models; the first involves inducing delirium through cecal ligation and perforation (CLP) surgery to mimic a systemic infection. The second model entails open abdominal surgery to avoid infection intentionally (postoperative delirium model, POD). Aim 1: Investigating the influence of delirium-like states, with or without infection, on AD Pathology. We hypothesize that the induction of delirium through CLP or POD leads to increased brain amyloidosis mediated through gut dysbiosis and neuroinflammation mechanisms. Fifty-day-old male/female mice with an APP/PS1 genotype (with no amyloidosis present in the brain) and wild-type (WT) mice will undergo either CLP (SA1.1) or the POD (SA1.2). A delirium-like state will be confirmed 36 hours post-surgery. Brain tissue will be analyzed using sc-RNA-seq to explore cellular subtypes or states based on gene expression, providing insights into the molecular changes associated with delirium. The gut microbiome will be assessed using 16S rRNA to identify alterations in microbial composition, and microbiome metabolites, particularly short-chain fatty acids (SCFAs), will be quantified to understand the metabolic consequences of gut dysbiosis. Long-Term Assessment: At day 130 post-surgery, six-month-old mice undergo behavioral tasks and various assessments, including microbiome analysis evaluation of glial cells, neurons, and AD markers. Objective 2: Assessing the impact of delirium-like states on established AD pathology. We aim to investigate how a delirium-like state induced by CLP or POD influences the progression of established AD pathology. We postulate that delirium exacerbates the advancement of AD pathology in mice with pre-existing amyloidosis. Specifically, APP/PS1 transgenic mice and WT mice will undergo CLP (SA2.1) or POD (SA2.2) procedures at six months old when amyloidosis has already been established. Mice will be euthanized at nine months, long-term, to assess the impact of delirium on the progression of AD pathology. The presence of the delirium-like state will be meticulously confirmed 36 hours after the procedures, and the same comprehensive assessments outlined in Aim 1 will be conducted.

Unraveling the Influence of Delirium in Alzheimer's Disease Pathogenesis

Sex specific function of ACSL4 in aging and Alzheimer’s disease

Recipient: Laurent Calvier, PhD
Title: Assistant Professor
Department: Molecular Genetics
University: The University of Texas Southwestern Medical Center (UT Southwestern)

Email: [email protected]
Web: https://profiles.utsouthwestern.edu/profile/174706/laurent-calvier.html

Grant Title: New communication axis from the brain to the peripheral immune system during AD

Abstract: Alzheimer’s disease (AD) is histologically defined by the accumulation of ß-amyloid (Aß) plaques and neurofibrillary tau tangles. Consequently, tremendous effort has been invested to directly target those two components with very little success in clinic. Another hallmark of AD has been investigated besides neurotoxic protein accumulation. Sustain inflammation has been established in pre-clinical and clinical AD subjects, initially thought to be reactive to the neuronal loss occurring in the disorder. However, a substantial body of research has now demonstrated that a persistent immune response in the brain also facilitates and exacerbates both Aß and tau pathologies. This chronic neuroinflammation is attributed to activated microglia cells and the release of numerous cytokines and chemokines promoting leukocyte infiltration through the blood–brain barrier (BBB). Under AD, this barrier is compromised by inflammation and leukocytes infiltrate the brain where they promote neurodegeneration in concert with activated microglia. A better understanding of leukocyte recruitment and BBB permeability will offer new accessible targets to dampen neuroinflammation. This study hypothesizes that the AD-affected brain communicates inflammation to the peripheric immune system, which in turn, disturbs the BBB, promoting the infiltration of leukocytes into the CNS. Investigating this communication pathway and its impact on AD progression is critical for identifying novel therapeutic targets. In preliminary experiments, we have identified that a crucial aspect of this communication may involve the activation of the skull bone marrow, which responds to AD by increasing hematopoiesis and secreting proinflammatory markers, such as Reelin. However, how Aß deposition during AD triggers the skull bone marrow activation remains largely unknown and will be studied in Aim 1, while the contribution of activated skull bone marrow in neuroinflammation will be explored in Aim 2. In summary, this research seeks to decipher the inflammatory communication axis from the brain to the periphery, how it influences the peripheral immune system and CNS infiltration by leukocytes, but also to identify and target key mediators in this communication.

New communication axis from the brain to the peripheral immune system during AD

Recipient: Keran Ma, PhD
Title: Assistant Professor
Department: Neurobiology and Anatomy
University: McGovern Medical School at the University of Texas Health Sciences Center (UTHealth)

Email: [email protected]
Web: https://med.uth.edu/nba/2022/11/03/keran-ma-phd/

Grant Title: Dysfunctional Microglia-Neuron Interactions in Alzheimer's Disease

Abstract: Alzheimer’s disease (AD) causes abnormal neuronal network activity including altered brain rhythms (oscillations) and network hyperexcitability (epileptiform discharges and seizures), resulting in cognitive impairment. Genome-wide association studies in AD patients identified disease risk loci corresponding to more genes that are expressed in microglia rather than in neurons. Microglia-expressing triggering receptor expressed on myeloid cells 2 (TREM2) gene corresponds to one of the risk loci and its variants including R47H has been confirmed to significantly increase AD risk. We and others recently showed that microglia are critical modulators of neuronal activity, functioning similar to inhibitory neurons in suppressing neuronal hyperexcitability. We hypothesize that TREM2 risk variant R47H induces cognitive impairment by altering microglial surveillance and modulation of neuronal activity resulting in dysregulation of neuronal synchronization, abnormal brain oscillations, and network hyperexcitability. To address our hypothesis, we will use TREM2 knock-in (KI) mice carrying either the R47H AD disease variant or the common variant (CV) as controls. We will 1) examine microglial neuronal surveillance in mice expressing the hTREM2 R47H AD variant vs. hTREM2 common variant; 2) determine altered neuronal activity at the cellular and network levels in hTREM2 R47H/+ mice compared to hTREM2 CV/+ mice; and 3) investigate cellular basis of memory impairment by mapping microglia process motility and neuronal population dynamics to behavior in TREM2-KI-R47H and TREM2-KI-CV mice. We will employ a combination of state-of-the-art advanced systems neuroscience tools including 2-photon microscopy to image microglia and neuronal subtypes, Neuropixels recordings of single-unit/local field potential, virtual reality and real-life behavioral paradigms, and machine learning analysis of neuronal activity and microglia motility coupled to mouse behavior. This study will provide an unprecedented mechanistic understanding of how microglia modulate neuronal function in health and in AD, offering much-needed insight into the maladaptive microglia–neuron interactions in AD. Targeting microglia to suppress network hyperexcitability and restore brain oscillations is a novel approach that could improve cognitive impairment in AD and offer an alternative therapeutic strategy to complement current AD treatment options.

Dysfunctional Microglia-Neuron Interactions in Alzheimer's Disease

2023 Collaborative Research Grants

Recipient

Grant Title

Recipient: Joachim Herz, MD
Title: Professor
Department: Molecular Genetics
University: The University of Texas Southwestern Medical Center (UT Southwestern)

Email: [email protected]
Web: https://profiles.utsouthwestern.edu/profile/13165/joachim-herz.html

Grant Title: COVID-19 and elevated plasma Reelin are risk factors for Alzheimer's disease

Abstract: The COVID-19 pandemic has revealed intricate interactions between the SARS-CoV-2 virus and the central nervous system (CNS), resulting in diverse neurological symptoms. Despite its initial classification as a respiratory disease, accumulating evidence suggests that SARS-CoV-2 can infiltrate the CNS, potentially by binding to ACE2 receptors in neural tissues, leading to various neurological manifestations. Furthermore, the virus can incite neuroinflammation, prompting concerns about its potential role in neurodegenerative diseases like Alzheimer's disease (AD), characterized by amyloid ß plaques and neurofibrillary tangles. This research endeavors to investigate shared inflammatory pathways between COVID-19 and AD, contributing to blood-brain barrier (BBB) dysfunction and immune cell infiltration into the CNS. The study places particular emphasis on Reelin, a proinflammatory endothelial factor present in plasma, and its role in regulating BBB integrity. Preliminary findings suggest that Reelin correlates with COVID-19 severity and may exacerbate neuroinflammation and cognitive dysfunction in AD models. Therefore, we hypothesize that plasma Reelin expression is increased during COVID-19 and amplifies the BBB dysfunction occurring early in AD, thus promoting leukocyte infiltration into the CNS, neuroinflammation, and neurodegeneration. By unveiling a common inflammatory communication axis between COVID-19 and AD, this research aims to identify potential therapeutic targets, such as Reelin, for regulating BBB permeability. This study challenges conventional AD hypotheses by establishing COVID-19 as a novel risk factor and it prioritizes the restoration of BBB integrity over immune suppression as a novel strategy for managing neuroinflammation. Additionally, it investigates the dual role of Reelin, formerly seen as beneficial in the brain but now recognized as a pro-inflammatory factor in circulation. These findings may have broader implications for the treatment of chronic inflammatory diseases like multiple sclerosis and Parkinson's disease.

COVID-19 and elevated plasma Reelin are risk factors for Alzheimer's disease

Recipient: Jared Benge, PhD, ABPP
Title: Associate Professor
Department: Neurology
University: The University of Texas at Austin

Email: [email protected]
Web: https://dellmed.utexas.edu/directory/jared-benge-ph-d

Grant Title: Refining iADL Assessments for the Modern ADRD Clinical and Research Environment

Abstract: The Lawton instrumental Activities of Daily Living (iADL) scale serves as the primary iADL measure for the TARCC database among many other large and robust clinical cohorts. Despite its ubiquitous use, the Lawton was initially published in 1969 and is necessarily is lacking coverage of daily activities now important to the lives of many seniors, such as ability to use digital technologies for daily tasks. Further, shifts in cultural and societal expectations for iADL performance have occurred in the 50 years since the scale’s inception, calling into question some item content. That being said, as the instrument is broadly adopted in the field, using a new instrument in isolation risks deprecating the utility of existing data. To address these needs, the proposed study focuses on three aims. First, we will use the existing TARCC Lawton data to determine if there are problematic items in need of revision through a method known as differential item functioning. This approach will allow us to determine if the existing instrument systematically over and or under estimates daily abilities on the basis of factors such as age, gender, or particularly given the rich Hispanic cohort data in the TARCC study, ethnic background. Armed with analyses of the existing items, Aim 2 focuses on systematic cognitive interviews of 40 care partners to help understand domains not covered by the existing measure as well as to clarify response options, which will in turn lead to a revised and expanded measure creation. Finally, Aim 3 involves piloting the measure in a multiple TARCC site project, collecting data on 200 clinically referred older adults from diverse backgrounds to evaluate the utility of the new instrument. We will use an Item Response Theory driven linking and equating approach to allow for newly developed and refined items to be linked to the existing TARCC data, demonstrating an approach that will allow for the creation of living iADL instruments that can grow and change as day to day activities change, without abandoning existing data. This project is responsive to core TARCC goals of understanding the impact of demographics such as sex, ethnicity, and technology on patient centered outcomes of ADRD and leverages both existing TARCC data and two TARCC member sites to achieve it’s aims. Ultimately the data generated and validation of the techniques involved will allow our sites to pursue broader projects to help harmonize existing clinical cohorts and increase the sensitivity and applicability of iADL measures to the day to day lives of those impacted by ADRD and as endpoints for clinical trials.

Refining iADL Assessments for the Modern ADRD Clinical and Research Environment

2021 Postdoctoral Fellowship Grants

Recipient

Grant Title

Recipient: Robin C. Hilsabeck, PhD
Title: Associate Professor
Department: Neurology
University: UT Austin Dell Medical School

Email: [email protected]
Web: https://dellmed.utexas.edu/directory/robin-hilsabeck

Grant Title: Continuation of TARCC Neuropsychology Fellowship Program

Abstract: Given the projected growth of the older adult population and need for dementia care services in Texas and beyond, postdoctoral training in neurodegenerative diseases is more important than ever before. The Adult Neuropsychology Postdoctoral Fellowship training program at The University of Texas (UT) at Austin Dell Medical School (DMS) was developed in 2020 with the goal to train clinician-scientists to help fill the large need for neurocognitive disorder specialists in Alzheimer disease and related conditions (ADRD). This 2-year program follows the scientist-practitioner model, which specifies requirements in clinical training, research, and didactic programming, and is intended to be the final neuropsychology training experience that will prepare postdoctoral fellows for independent practice in neuropsychology and eventual board certification in clinical neuropsychology. Fellows in our training program have the opportunity to learn about the full spectrum of dementia care within an integrated practice setting and value-based care model at the Comprehensive Memory Center (CMC) at Mulva Clinic for the Neurosciences at UT Health Austin. Fellows participate in 2-3 neuropsychological evaluations per week and observe the typical practice of all team members which includes exposure to behavioral neurology, geriatric psychiatry, social work, and speech language therapy sessions all geared toward neurodegenerative disease diagnosis and management. Research is part of the daily clinic operations of the CMC, and one thematic area of study for the CMC is examining the effects of our interprofessional collaborative dementia care model on health outcomes of both patients and care partners. For the required TARCC-related research project, the fellow will examine the utility of a novel patient-centered outcome measure currently entitled the Health Needs Assessment (HNA) that assesses the effect of multicomponent dementia care on aspects of health that are valued by patients with ADRD and their families as a means of demonstrating the value of interprofessional care for ADRD. To ensure successful completion of this project within the 2-year training period, the fellow will have 30% protected research time, access to clinical and research personnel needed to collect and enter data, and mentorship from faculty with expertise in developing and validating measures for use in ADRD. Finally, fellows participate in required weekly and monthly didactics and choose from a variety of optional didactics based on individual training needs and goals. They also are provided several opportunities for professional development that will prepare them well for a career as a board-certified clinical neuropsychologist and allow them to network with other neuropsychologists, researchers, and clinicians involved in dementia care in Texas.

Continuation of TARCC Neuropsychology Fellowship Program

Recipient: Laura Lacritz, PhD
Title: Professor
Department: Psychiatry
University: UT Southwestern Medical Center at Dallas

Email: [email protected]
Web: https://profiles.utsouthwestern.edu/profile/14083/laura-lacritz.html

Grant Title: TARCC Neuropsychology of Dementia Postdoctoral Fellowship

Abstract: The primary objective of this post-doctoral neuropsychology fellowship is to train a highly qualified, board-eligible neuropsychologist for practice and research in the care and treatment of patients with cognitive disorders of aging. This is a two-year, graded fellowship with experiences and expectations commensurate with level of training. The Fellow will receive specialized training in the diagnosis and treatment of Alzheimer’s disease and related disorders (ADRD) and actively participate in novel ADRD-related research, making them highly competitive for a job in an academic medical setting focusing on dementia. The neuropsychology fellowship will involve 3 major components: clinical training and teaching, education and knowledge base, and research development. Fellows will spend 50% time in clinical and teaching activities and 50% time in research activities. The primary clinical training site will be the UTSW Neuropsychology Clinic where the Fellow will see a diverse population of older adults with cognitive disorders and will be involved in assessment, differential diagnosis, treatment planning, and conveying results back to patients and their families, as well as referral sources. Other rotations include inpatient neuropsychological and neurobehavioral consultation, behavioral neurology, and pre-surgical cognitive evaluations for a variety of neurosurgical populations. There is also a teaching rotation where the Fellow will engage in supervision, classroom teaching, and specialty lectures. Research time will involve collaboration on existing projects and initiation of independent research and grant writing, focused on how risk factors and individual differences contribute to developing dementia, particularly in minority populations such as the Hispanic cohort within the TARCC dataset. The Fellow will be expected to submit a minimum of 2 manuscripts and 2 poster/paper presentations per year, and write a grant by the end of year one. The Fellow will participate in weekly neuropsychology and dementia related didactics to help prepare them for board certification in clinical neuropsychology. The fellowship also includes professional development opportunities to promote readiness for an academic career in aging and dementia.

TARCC Neuropsychology of Dementia Postdoctoral Fellowship

2021 Junior Investigator Research Grants

Recipient

Grant Title

Recipient: Elena Daoud, MD, PhD
Title: Assistant Professor
Department: Neuropathology
University: UT Southwestern Medical Center at Dallas

Email: [email protected]
Web: https://profiles.utsouthwestern.edu/profile/420118/elena-daoud.html

Grant Title: Digital spatial profiling of hippocampal subregions in tauopathies

Abstract: Numerous neurodegenerative diseases are pathologically defined by the presence of phosphorylated tau (p-tau) protein deposited within neurons with varying distribution patterns in discrete regions of the brain. The most well-known of these, Alzheimer disease (AD) classically has neurofibrillary tangles (NFTs) composed of paired helical 3R/4R-positive p-tau filaments that progress from the entorhinal cortex to the hippocampus and other limbic regions before progressing to the neocortex in well-defined Braak stages that correspond roughly to the progression of cognitive decline. While the neuropathologic diagnosis of AD requires the presence of ß-amyloid plaque deposition in concert with NFT formation, other tauopathies occur in the absence of ß-amyloid. One such disorder, primary age-related tauopathy (PART) is defined by the presence of 3R/4R-positive NFTs affecting hippocampal subregions, although there is no relationship between these NFTs and ß-amyloid plaques. Additionally, there are a number of 4R-only tauopathies that occur without ß-amyloid plaques, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The lack of ß-amyloid plaques is a key difference in these disorders, as the presence and progression of these plaques are thought to be important in the pathogenesis of AD. Previous experiments have shown that the NFTs of AD patients have proteins specifically regulating ß-amyloid processing, and that this is present only in patients with clinical dementia, indicating that the presence of ß-amyloid may be crucial to the pathogenicity of NFTs in AD. In addition, the ß-amyloid-independent tauopathies have different hippocampal distributions of p-tau; compared to AD, all of these disorders have a predilection for NFT formation in the CA2 hippocampal subregion with relative sparing of the CA1 subregion (which is affected earliest in AD) until later in the disease course. Herein, we propose to use Nanostring GeoMx™ Digital Spatial Profiling (DSP) to evaluate the protein composition of individual hippocampal subregions as well as individual tangle and non-tangle bearing neurons and their immediate microenvironments in histopathologically-confirmed AD, PART, PSP, and CBD cases to identify minute and more broad regional protein differences in the CA2 regions between these disorders as well as between the ß-amyloid-independent tauopathies and AD to better understand the role of ß-amyloid and differential subregion involvement in the progression of these disorders. These studies will enhance our current understanding of the role of NFTs at the level of the hippocampus as well as the impact of NFTs in particular hippocampal subregions and will potentially aid in the development of the next generation of biomarkers for these disorders.

Digital spatial profiling of hippocampal subregions in tauopathies

Spatial proteomic analyses of neuropathologic changes in TARCC participants

Recipient: Christian Lobue, PhD
Title: Assistant Professor
Department: Psychiatry
University: UT Southwestern Medical Center at Dallas

Email: [email protected]
Web: https://profiles.utsouthwestern.edu/profile/127352/christian-lobue.html

Grant Title: Modulating brain circuitry to treat word retrieval deficits in amnestic MCI

Abstract: Word retrieval difficulty is often experienced in amnestic mild cognitive impairment (aMCI, often a prodromal stage for Alzheimer’s Clinical Syndrome, ACS) and a major stressor for patients. Targeted treatment is lacking but significantly needed to lessen word retrieval deficits in order to improve the functioning of patients with aMCI. High Definition transcranial Direct Current Stimulation (HD-tDCS) represents a safe and low-cost noninvasive brain stimulation technology to target brain regions and modulate dysfunctional brain circuitry underlying neurocognitive symptoms. We propose to use HD-tDCS to target the pre-Supplementary Motor Area (pre-SMA), a central part of the neural circuit underlying word retrieval functioning, to potentially enhance circuit functioning in aMCI that could mediate improvements in word retrieval deficits. Our pilot data demonstrate that targeting the pre-SMA using HD-tDCS can improve word retrieval deficits in patient populations including aMCI. We propose a two-year prospective, double-blind, randomized, sham-controlled study to examine the potential for HD-tDCS to 1) improve word retrieval deficits in aMCI and 2) modulate underlying neural circuitry that may inform a possible therapeutic mechanism. We will enroll 24 participants with aMCI having word retrieval deficits to complete 10 sessions of active anodal HD-tDCS or sham stimulation across 2 consecutive weeks. All participants will complete neuropsychological and electroencephalography (EEG)-based measures of word retrieval at baseline, immediately following HD-tDCS (last session), and then a 2-month followup. We have two specific aims: we will examine 1) the efficacy of HD-tDCS targeting the pre-SMA to improve word retrieval deficits in adults with aMCI and 2) electrophysiological changes in response to HD-tDCS targeting the pre-SMA in aMCI. We hypothesize that active HD-tDCS (vs sham) will improve word retrieval function on clinical neuropsychological tests both immediately and 2 months after completion of intervention. Also, we hypothesize that active HD-tDCS (vs sham) will enhance evoked/oscillatory frontal EEG activities by reducing the latency and increasing the magnitude during semantic/word retrieval tasks, suggesting modulation of underlying neural circuitry. This will be the first HD-tDCS study to combine neuropsychological and EEG assessments to evaluate the technology’s therapeutic application to aMCI for word retrieval deficits. The study will address a clinically relevant but frequently unanswered need in aMCI, serving as a timely step in developing a new intervention that could readily translate to clinical practice. The study results will help set the groundwork for future research in identifying novel and effective strategies for deploying electromodulation as an intervention in ACS as well as elucidating its potential for mitigating the impact of disease progression.

Modulating brain circuitry to treat word retrieval deficits in amnestic MCI

Recipient: Jose Moruno-Manchon, PhD
Title: Assistant Professor
Department: Neurology
University: UT Health Science Center at Houston

Email: [email protected]
Web: https://med.uth.edu/neurology/faculty/jose-f-moruno-manchon-phd/

Grant Title: Cerebrovascular senescence in vascular dementia

Abstract: Vascular contributions to cognitive impairment and dementia (VCID) includes a number of different disorders identified by cognitive deficits secondary to cerebrovascular pathology. Cerebral hypoperfusion increases the risk for VCID and Alzheimer disease-related dementias (ADRD). The risk of VCID and ADRD is higher in people after the age of 70. With aging, the main component of the blood brain barrier (BBB), cerebral endothelial cells (CEC), enter into a non-proliferative state of senescence, characterized by accumulation of DNA damage and the development of a pro-inflammatory secretory phenotype that negatively affects the cerebral vasculature. The mechanisms underlying endothelial senescence and their contribution to VCID remain poorly understood. E2F transcription factor 1 (E2F1) is a “master regulator” of cell cycle progression and DNA damage repair. Importantly, its deficiency has been associated with cell senescence. We found that E2F1 and several of its gene targets that are related to DNA repair, including Exonuclease I (EXO1), are downregulated in aged (18-months old, mo) mouse brains and in cultured CEC isolated from aged mice, compared with young (4-mo) groups. We found that mice subjected to bilateral carotid artery stenosis (BCAS, used as a VCID model), which is relevant to VCID, had reduced E2F1 transcriptional activity, more severe SA phenotypes, reduced cerebral blood flow, and memory deficits, compared with control mice. Our preliminary data suggest that upregulating E2F1 in the cerebrovasculature also restores memory deficits in aged BCAS mice. Thus, we hypothesize that E2F1 prevents senescence in the cerebral endothelium of aged mice, and that reversing endothelial senescence by upregulating E2F1 will restore cognitive function in a mouse model of VCID. In Aim 1, we will overexpress E2F1 in the cerebrovasculature of BCAS mice to determine if upregulating E2F1 could reverse or prevent endothelial senescence, BBB impairment and cognitive dysfunction in aged mice. In Aim 2, we will identify the role of EXO1 in endothelial senescence and function, and will determine whether the preventive effects of E2F1 in senescence is mediated by the DNA repair factor EXO1 in cultured CEC. If successful, these studies will identify potential therapeutic targets that could protect cerebrovasculature from cerebral hypoperfusion with aging and mitigate the progression of VCID and ADRD.

Cerebrovascular senescence in vascular dementia

Determine how chaperones regulate TDP-43 liquid-liquid phase separation

2021 Investigator Initiated Research Grants

Recipient

Grant Title

Digital spatial profiling of hippocampal subregions in tauopathies

Recipient: Xiaoyong Bao, PhD
Title: Professor
Department: Pediatrics
University: The University of Texas Medical Branch at Galveston

Email: [email protected]
Web: https://scmm.utmb.edu/Researcher-Profiles/bao

Grant Title: Biogenesis of tRNA-derived RNA Fragments in Alzheimer's Disease:Novel Biomarkers

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disorder, with low specificity of clinical tests and many unknowns regarding pathophysiological processes. Accumulating evidence supported that in addition to amyloid plaque and tau tangle as pathology hallmarks of AD, there is still an urgent need for the discovery of other changes in AD to predict disease onset/progression. The recent implication of non-coding RNAs (ncRNAs) in AD development opens such an avenue, with many emerging ncRNAs uninvestigated. Our recent publication demonstrated that tRNA-derived RNA fragments (tRFs), arelatively new ncRNA family, are the most impacted small ncRNA (sncRNA) by AD in the hippocampus. The changes were contributed mainly from five tRFs with one showing the correlation of its expression with AD disease severity. Such a correlation between AD-impacted tRF and AD severity was also observed in serum samples. We also discovered that the expression of a tRNA ribonuclease angiogenin (ANG) and a methyltransferase NSUN2 (NOP2/Sun RNA methyltransferase 2) was significantly changed in AD patients. Combined with the reports from several groups including ours that the tRNA nucleotide(nt) modifications play a critical role in determining tRNA’s accessibility by ribonucleases, the results of AD-impacted ANG and NSUN2 implicate a tRF biogenesis mechanism in AD. Here, we hypothesize that AD-impacted tRFs are products of a tightly regulated biogenesis process, not random tRNA degradation byproducts, and the investigation of molecular mechanisms associated with their biogenesis are clinically instructive to the discovery of novel AD biomarkers and also potentially the development of prophylactic and therapeutic strategies against AD. We will determine tRF signatures associated with the progression of AD (Aim 1). We will then determine and localize nt modifications responsible for tRNA cleavage in AD (Aim 2). We will identify the ribonuclease(s) associated with tRNA cleavage in AD (Aim 3). Our experience in tRF research has provided us with the expertise and tools needed for this project. Our group will collaborate closely with members of the Collaborative Alzheimer's Disease and Memory Disorders (CADMD) Program at UTMB, including its Medical Director Dr. Xiang Fang, Dr. Michael Pappolla, and Dr. Aimee Giammittorio. We will also work with Dr. Shenglong Zhang at the New York Institute of Technology, who pioneers the development of 2-dimensional LC-MS-based direct RNA sequencing to locate and quantify tRNA modifications; Dr. Inhan Lee, CEO of miRcore, an expert in ncRNA bioinformatics; and a seniorBiostatistician, Dr. Heidi Spratt, who will oversee the statistical analysis and patient sample size determinations. These multidisciplinary research collaborative efforts will help us to achieve our long-term goal to develop readily assayable disease biomarkers to understand the AD onset/progression mechanism and develop therapeutic strategies.

Biogenesis of tRNA-derived RNA Fragments in Alzheimer's Disease:Novel Biomarkers

Recipient: Mark Kunik, MD
Title: Professor
Department: Menninger Department of Psychiatry and Behavioral Sciences
University: Baylor College of Medicine

Email: [email protected]
Web: https://www.bcm.edu/people-search/mark-kunik-24868

Grant Title: Precision Recruitment for Precision Medicine

Abstract: Hispanics/Latinos, the largest historically underrepresented ethnic group and one of the fastest growing groups in the United States, are at increased risk for Alzheimer’s disease and related dementias (AD/ADRD) and are projected to have the largest increases in dementia cases by 2060. However, limited representation of H/Ls in AD/ADRD research clearly impacts our ability to characterize clinical phenotypes in these individuals as well as our ability to develop culturally appropriate assessments and treatments. Multi-site collaborations and the development of data repositories, like TARCC, play an important role in our understanding of the factors associated with AD/ADRD risk, onset, diagnosis, and progression. Common variable sets and data that are harmonizable across sites allow for larger scale analyses than what a single site could achieve alone. Questions remain, though, about how generalizable these repository data are to the broader population. Factors that may influence likelihood of study participation have important implications for AD/ADRD research. These selection factors – such as demographic and personal/medical history variables – introduce bias in research results, confounding interpretation. Compared to community-based recruitment, individuals recruited from clinic-based referrals tend to have greater AD/ADRD health literacy as well as greater risk for progression to MCI and dementia during the course of an AD/ADRD study. Nonrepresentative research samples threaten both the internal and external validity of the research. Despite concerns about generalizability and known issues of bias, few studies have directly examined selection factors and their role in key AD/ADRD outcomes. To our knowledge, the proposed research is the first to explore these issues in the context of the TARCC. By applying an inclusion science approach, the proposed study seeks to address recruitment disparities of H/Ls and identify the role of selection factors in both the proposed sample and the larger TARCC sample. Along these lines, the proposed plan aims to (1) Recruit and characterize a community-based sample of 200 H/Ls in the Houston Metro area; (2) Identify selection factors related to recruitment for both the new sample and the existing TARCC H/L sample; and (3) Examine the relationships between selection factors and key AD/ADRD variables (e.g., cognition, biomarkers). Results from the proposed plan would elucidate the impact of selection factors on clinic vs community-based data related to AD/ADRD, contributing to recruitment and inclusion science. Findings will also help better characterize the representativeness of the TARCC data base, informing future research carried out with these data and increasing TARCC’s potential to advance AD/ADRD research and discovery for all Texans.

Precision Recruitment for Precision Medicine

Targeting Microglia for Alzheimer's Disease

Effect of COVID-19 in AD, PD and associated protein misfolding

Recipient: Jose del R. Millan, PhD
Title: Professor
Department: Neurology
University: UT Austin Dell Medical School

Email: [email protected]
Web: https://dellmed.utexas.edu/directory/jose-millan

Grant Title: Closed-Loop Brain Stimulation as a Potential Intervention for Cognitive Decline

Abstract: Cognitive decline in conditions such as Alzheimer disease and related disorders, affects a significant and increasing proportion of our society as a consequence of natural longevity and pathological neurodegenerative processes. Since the prevailing paradigm has viewed cognitive decline as inevitable and irreversible, current interventions are focused on slowing the rate of decline and have been met with limited success. Thus, there is a critical need for disruptive approaches in the quest for effective prevention and treatment of cognitive decline. We propose to develop a novel intervention based on brain-computer interface (BCI) technology and closed-loop brain stimulation, which is safe and non-invasive. Based on previous literature and our own work, our overarching hypothesis is that non-invasive, BCI-driven closed-loop theta-burst stimulation (TBS, a particular modality of transcranial magnetic stimulation) targeting cognitive control areas in the brain will be an effective strategy for improving daily-task performance in older adults (primary outcome), which may also yield sustainable memory enhancement (secondary outcome). This goal will be achieved through three specific aims: 1) Design a principle for the BCI to trigger TBS over the dorsolateral prefrontal cortex, an area associated with cognitive control. The BCI decodes in real time the presence or absence of contingent negative variation (CNV) in subjects’ electroencephalogram (EEG) while they play a videogame requiring cognitive control abilities (attending and responding to some events while ignoring others). Our working hypothesis is that contingent TBS upon false outputs of the BCI will enhance CNV modulation. We will validate our approach (videogame, BCI and TBS) in young adults (N=20). 2) Assess the feasibility, acceptability, and potential therapeutic benefit of our BCI-driven closed-loop TBS intervention in cognitively normal older adults (N=30). Our working hypothesis is that the closed-loop TBS condition will yield the greatest CNV modulation and exhibit a trend in improvements in cognitive control as compared to standard TBS and sham TBS. We also postulate that (i) improvements induced by closed-loop TBS will sustain, and (ii) ~90% of participants will complete all 12 sessions and ~85% will rate the intervention as acceptable. Subjects (10 per group: closed-loop TBS, standard TBS and sham TBS), will undergo neuropsychological tests before and after completion of 12 BCI-TBS sessions (3 days/week), and 2 months post-intervention. 3) Evaluate the therapeutical benefit of the BCI-driven closed-loop TBS intervention to enhance cognitive control in older adults with mild cognitive impairment (N=40). Patients will be randomly assigned to one of 2 groups, closed-loop TBS and the best of either standard or sham TBS in aim 2. Intervention will be similar to aim 2. Our working hypothesis is that the closedloop TBS condition will foster sustained improvements in cognitive control.

Closed-Loop Brain Stimulation as a Potential Intervention for Cognitive Decline

2020 Postdoctoral Fellowship Grants

Recipient

Grant Title

Postdoctoral Associate
Department of Molecular and Human Genetics
Baylor College of Medicine

Email: [email protected]
Web: https://www.bcm.edu/people-search/jennifer-johnson-23850

Title: The role of a lipid metabolism pathway in regulating APP levels and processing

Alzheimer's disease (AD), the most common form of dementia, is a complex disease, the mechanisms of which are poorly understood. To date, the only known fully penetrant factors leading to the development of AD are the presence of mutations in one of three genes - amyloid precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2). Individuals carrying an extra copy of APP (e.g., those with Trisomy 21 or APP locus duplication) also develop familial early-onset AD (fAD).Converging pathological mechanisms leading to elevated levels of Aβ in both fAD and sporadic AD suggests that the brain is sensitive to the steady-state levels of APP protein and its processed fragments.

In addition to the known causal genetic factors, a remarkable heterogeneity of risk factors, etiologies, and neuropathologic processes are associated with AD. Notably, dysregulation of lipid pathways have been implicated in a growing number of neurodegenerative disorders, including AD. Although much attention has been given to the link between cholesterol and AD pathogenesis, growing evidence suggests that many, if not all, classes of lipids play a role in AD. Levels of fatty acids, the building blocks of membrane phospholipids, are altered in the AD brain and additional genes involved in the transport of phospholipids such as ABCA1, and ABCA7 have been genetically linked to AD. Nevertheless, the mechanism by which aberrant lipid metabolism could be involved in AD pathology is still unclear.

Using unbiased genetics screens in human cells and fruit flies designed to identify regulators of APP levels, I made a discovery that might help me understand the lipid/APP connection. I identified two genes involved in fatty acid metabolism that, when inhibited, lowered APP levels in a transgenic cell line expressing fluorescently- labeled APP and mitigated toxicity in fruit flies overexpressing APP. Fatty acids are associated with AD through their involvement in membrane fluidity, APP trafficking and metabolism, Aβ aggregation and toxicity, and endosomal function. Thus, my finding is exciting because it affords me the opportunity to investigate the link between two axes of dysfunction in AD: aberrant APP metabolism and dysregulated lipid metabolism. I hypothesize that these two genes regulate the levels and processing of APP and in turn contribute to AD pathogenesis. In this proposal I will test this hypothesis in a human cellular model of sporadic AD (Aim 1) and in an APP AD mouse model (Aim 2) to determine whether these two genes provide mechanistic insight into the link between lipid metabolism and APP. The proposed studies will improve our current understanding of APP biology, including how lipid pathways regulate the composition and structure of the neuronal membrane leading to altered APP steady-state levels and processing. Further mechanistic and translational studies may identify potential therapeutic targets acting through these pathways to offer new and effective options for the treatment of AD.

The role of a lipid metabolism pathway in regulating APP levels and processing

2020 Junior Investigator Research Grants

Recipient

Grant Title

Assistant Professor of Molecular Biology
UT Southwestern Medical Center at Dallas

Email: [email protected]
Web: https://www.utsouthwestern.edu/labs/sun-lu/about/meet-pi.html

Title: Characterization of a New Risk Cell Type in Alzheimer's Disease

The long-term objective of this proposal is to address cell complexity of Alzheimer’s disease (AD), with a focus on a newly identified risk cell type. In the United States, more than 5 million patients have been diagnosed with Alzheimer’s disease. In Texas alone, nearly 500,000 people are projected to have AD by 2025. Despite decades of research, the cellular and molecular complexity for this devastating neurogenerative disease still remains poorly understood. Previous studies primarily focused on the pathology of neurons and synapses. Recent work from many laboratories, however, demonstrated that the dysfunctions of glial cells, the supporter cells in the brain, play critical roles in the occurrence and progression of AD and other forms of brain dementia. In particular, several recent studies suggest that the myelinating glial cells in the central nervous system, called oligodendrocytes, are mysteriously linked with AD. Nevertheless, whether there are inheritable genetic variations in this newly identified risk cell type, and how oligodendrocyte and myelination deficiencies contribute to AD remain unanswered. Based on previous findings, we hypothesize that oligodendrocyte genetic alterations are linked with AD etiology, and that oligodendrocyte-axon decoupling drives AD pathology. In this proposal, we will utilize bioinformatic approach to systematically analyze genomic variations in AD oligodendrocytes, and further employ glial cell biology and genetic methods to determine the roles of this newly identified risk cell type in AD etiology. Specifically, we will utilize the TARCC Genetic I and Genetic II datasets to determine single nucleotide polymorphism (SNP) features and copy number variations among oligodendrocyte specific genes (Aim 1). We will perform comprehensive analysis on oligodendrocyte lineage cells and myelination in several AD mouse models across entire disease progression (Aim 2). Finally, we will address the autonomous function of oligodendrocytes and oligodendrocyte-axon coupling at the onset of AD (Aim 3). The proposed work will characterize a new risk cell type in Alzheimer’s disease, and will provide better understanding about how individual brain cell types communicate with each other and contribute to this complex neurodegenerative disease.

Characterization of a New Risk Cell Type in Alzheimer's Disease

Assistant Professor
Department of Psychiatry
UT Southwestern Medical Center at Dallas

Email: [email protected]
Web: https://profiles.utsouthwestern.edu/profile/146339/annelizabeth-carlew.html

Title: Utility of Neuropsychological Methods to Improve Diagnostic Accuracy of Mild Cognitive Impairment

Mild cognitive impairment (MCI) as a concept was proposed to capture individuals in the earliest stages of dementia (e.g., Alzheimer’s disease [AD]) and thus represents the “gray zone” between normal aging and frank dementia. Conventional diagnostic criteria for MCI in many large-scale studies may require only 1 impaired neuropsychological test score combined with subjective complaint and/or clinical judgment (e.g., Alzheimer’s Disease Neuroimaging Initiative [ADNI]), which can lead to a high rate of false positive diagnoses (>30% in some cases). These false positive diagnoses can dilute results of clinical drug trials, overestimate the prevalence of MCI, and decrease the stability of MCI diagnoses over time, which obscures research on disease course and may result in unneeded treatment. In a series of studies, Jak and Bondi developed a neuropsychological actuarial method of MCI diagnosis that when retrospectively applied to large Alzheimer’s datasets identified subjects who were less likely to revert to normal and who were more likely to have AD biomarkers. However, this method has only been applied to datasets composed of mostly White, highly educated subjects, which may limit generalizability to a rapidly growing elderly minority population in the U.S., 20% of which will be of Hispanic origin by 2050. The Texas Alzheimer’s Research and Care Consortium (TARCC) is one of the few comprehensive longitudinal studies with a large sample of aging Hispanic Mexican Americans, creating a unique opportunity to investigate diagnostic strategies in this rapidly growing population.

This study will analyze existing TARCC data using the actuarial neuropsychological method (developed by Jak and Bondi to optimize sensitivity and reliability) to reclassify MCI participants compared to conventional diagnostic methods in both Hispanic and non-Hispanic subjects. MCI subjects identified by conventional and actuarial methods will be separately submitted to cluster analysis to identify latent groups based on cognitive phenotype. A second step will analyze participants diagnosed with MCI at subsequent visits to investigate which method is most likely to capture true underlying neurodegenerative disease at the first visit, and which is more likely to produce false positive diagnoses (individuals who later revert to normal). Results of this study have the potential to inform and improve the diagnostic method used by TARCC and other research and clinical settings to minimize misdiagnosis, which is of particular concern in Hispanics who are more likely to be clinically misdiagnosed. Furthermore, secondary analyses will seek to identify cognitive risk factors for progression to dementia in Hispanics.

Utility of Neuropsychological Methods to Improve Diagnostic Accuracy of Mild Cognitive Impairment

Sexual Dimorphism in Cerebral Amyloid Angiopathy and Vascular Dementia: Investigating the Role of Fibrinolytic System

Investigation of Retinal Vascular Changes in Tauopathy

A Novel MRI Biomarker for Brain Tau Deposition

2020 Investigator Initiated Research Grants

Recipient

Grant Title

Professor
Department of Neurology and Neurotherapeutics
Peter O’Donnell Jr. Brain Institute
UT Southwestern Medical Center at Dallas

Email: [email protected]
Web: https://profiles.utsouthwestern.edu/profile/80056/john-hart.html

Title: Longitudinal Continuation of TARCC Hispanic Cohort (Neurological, Neuropsychological, Cerebrospinal, MRI Morphometrics, and Resting-state fMRI Measures)

Project involves:
John Hart, Jr, MD (UT Southwestern)
Donald Royall, MD (UT Health San Antonio)
Parunyou Julayanont, MD (Texas Tech University Health Science Center)
Robin Hilsabeck, PhD, ABPP (UT Austin Dell Medical School)
Gladys Maestre, MD, PhD (UT Health Rio Grande Valley)

The cohort of Hispanic participants in TARCC represent one of the largest cohorts of Non-Caribbean Hispanic aging subjects and presently this cohort is being continued at three of the original sites (UT Health San Antonio, Texas Tech University Health Science Center, and UT Dell). These sites are following the previously studied Hispanic subjects as well as recruiting new Hispanic subjects into the cohort. This renewal will also add an additional site, UT Health Rio Grande Valley, to the study to increase the number of participants in the cohort, broaden its demographics, expand the representation of individuals with various socioeconomic status and education in the cohort, expand the expertise of investigators in studies of Hispanic participants, and increase the representation of participating sites throughout the state. These subjects will receive yearly (the same neurological and neuropsychological testing that was previously administered in TARCC), with the addition now that every subject will receive a yearly structural MRI scan and we will recruit each subject to have a lumbar puncture to measure a-beta-42, total tau, and phosphorylated tau. These evaluations will be performed yearly for two years to obtain longitudinal measures to address the following aims: Aim 1. Assess the effectiveness of the CDR in the diagnosis of MCI and AD in the Hispanic population. Aim 2. In the subset of individuals who converted from normal to MCI and MCI to AD during their enrollment in TARCC, determine factors (demographical, neuropsychological, behavioral) that predict progression in diagnoses. Aim 3. Verify via repeat testing of the Hispanic cohort whether factors derived from our pilot statistical analyses are still significant in this repeat testing sample. Aims 4. & 5. Use CSF amyloid-β1-42 and tau measures, and MRI hippocampal volume, global cortical thickness, and resting state functional connectivity to define clinical phenotypes of normal and dementia and to use these measures to better inform diagnostic accuracy and differentiate between Hispanic diagnostic subgroups.

Longitudinal Continuation of TARCC Hispanic Cohort (Neurological, Neuropsychological, Cerebrospinal, MRI Morphometrics, and Resting-state fMRI Measures)

Texas Statewide Brain Bank Initiative

Assistant Professor
Department of Physical Medicine and Rehabilitation
UT Southwestern Medical Center at Dallas

Email: [email protected]
Web: https://profiles.utsouthwestern.edu/profile/171396/shannon-juengst.html

Title: Problem solving training (PST) for English- and Spanish-speaking care partners of adults with Alzheimer's and Alzheimer's-related dementia

Project involves:
Shannon Juengst, PhD (UT Southwestern)
Gladys Maestre, MD, PhD (UT Health Rio Grande Valley)
Matthew Lee Smith, PhD, MPH (Texas A&M University Health Science Center)

Caregivers of individuals with Alzheimer’s disease and related dementia (AD/ADRD) rarely get the preparation or training they need to manage their caregiving responsibilities and to successfully balance their own self-care and their caregiving roles. As a result, caregivers often experience caregiver burden, emotional distress, and substance abuse. Therefore, there is a critical need to support the emotional and social functioning of caregivers to improve their health and well-being and to prevent caregiver burden and poor coping. Problem solving training (PST) can reduce caregivers’ depressive symptoms and improving coping skills. However, critical gaps in knowledge and care remain regarding the necessary components of training (e.g. “active ingredients”): we still do not know how many sessions are necessary or whether caregivers need “booster” sessions to maintain the benefits of PST. We also do not understand how personal factors, like age, gender, etc., affect how effective PST is for individual caregivers. Finally, caregiver interventions have almost exclusively been tested in English-speaking caregivers, contributing to existing health disparities. To address these critical gaps, we will deliver PST to caregivers of adults with AD/ADRD, comparing 3 session versus 6 sessions, both with and without monthly boosters, to see which combination is optimal for improving emotional symptoms and caregiver burden, enabling them to navigate the adjustment and challenges they experience as caregivers.

Design: We will conduct a randomized controlled trial of PST for caregivers of adults with AD/ADRD to assess the effects of number of sessions (3 vs 6) and monthly boosters (boosters vs no boosters) on caregivers’ emotional symptoms and caregiver burden. The specific aims of this project are to: 1) Determine the optimal number of PST sessions and boosters to improve emotional symptoms and caregiver burden among English- and Spanish-speaking caregivers of adults with AD/ADRD; and 2) Identify factors associated with response to treatment (e.g. gender, race, ethnicity, relationship to the care recipient). Our collaborative team has access to and experience working with English- and Spanish-speaking caregivers of adults with AD/ADRD. Our expertise and strong clinical and research environments ensure the rigor, clinical relevance, and feasibility of our proposed research. Conclusions: This project will establish the necessary guidelines for an evidence-based, implementable problem-solving intervention for caregivers to improve their health and well-being. Providing problem-solving skills training to both English- and Spanish-speaking caregivers and identifying potential mechanisms of action for such training directly addresses the mission of TARCC to increase participation of diverse and underserved population, promote collaboration across TARCC institutions (three represented in this project), and contribute to advancement in therapeutic interventions to improve the lives of individual with AD/ADRD.

Problem solving training (PST) for English- and Spanish-speaking care partners of adults with Alzheimer's and Alzheimer's-related dementia

Assistant Professor
Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases
UT Health San Antonio

Email: [email protected]
Web: https://biggsinstitute.org/team-member/claudia-l-satizabal-phd/

Title: Characterization of Microbial Composition in Alzheimer's Disease

Project involves:
Claudia Satizabal, PhD (UT Health San Antonio)
Joseph Petrosino, PhD (Baylor College of Medicine)

Despite tremendous efforts to understand the process underlying Alzheimer’s Disease, the exact mechanisms remain uncertain and there are currently no curative therapeutic strategies. Thanks to recent technological advances, new evidence suggests the set of microorganisms we host have an active role in health and disease. The collective genome of our microbial companions (known as the microbiome) is 150-fold more numerous than human genes. This “extended” pool of genes has the potential to influence several aspects of our physiology, including energy extraction and biosynthesis of vitamins from diet, protection against pathogen overgrowth, and education of the immune system. Recent studies suggest that the microbiome may have a role in neurological disorders, including Alzheimer’s Disease. Studies in mouse models suggest gut microbiome alterations may play a role in the deposition of β-amyloid, a hallmark of the disease. Further small human studies suggest Alzheimer’s patients show decreased microbial richness and diversity, and a distinct composition that correlates to Alzheimer’s CSF biomarkers and pathology. Intriguingly, a study administering probiotics found associations with improved cognitive function in Alzheimer’s patients. This grant aims to expand upon these promising preliminary results in the large, well-characterized, and diverse TARCC cohort. We propose to re-establish contact with TARCC participants to invite them to participate in the study. Consenting participants will receive two kits for easy stool sample collection, a dietary questionnaire, a brief survey to assess current health, and instructions. In parallel, we will perform the Test of Every Day Cognition to assess current cognitive status over the phone. Samples will be shipped to the lead site at Biggs Institute for Alzheimer’s and Neurodegenerative Disorders at UT Health San Antonio until processing. Our first Aim is to identify the microbial signature of Alzheimer’s Disease in the full cohort. For this, we will ship one set of stool samples to our collaborators at the Alkek Center for Metagenomics and Microbiome Research at Baylor College of Medicine, where samples will be processed for DNA extraction and whole-metagenome shotgun sequencing. This characterization will allow us to look deeply into the microbial composition differences between Alzheimer’s and normal cognition. Our second Aim is to collect stool samples for later metabolomics profiling at Metabolon. Assessing stool metabolites is a powerful complementary tool to characterize the interplay between the microbiome and host health. In our third Aim, we will explore the set of environmental factors assessed at previous TARCC visits that contribute to identified microbial signatures, as these factors largely shape the community of host microbiota. This proposal will allow us to improve our understanding of the interrelationships of the gut microbiota and their metabolic yields in Alzheimer’s disease, and has the potential to identify individuals at risk with the prospect of developing personalized treatment strategies for the disease.

Characterization of Microbial Composition in Alzheimer's Disease

Departments of Neuroscience, Molecular and Cellular Biology, Neurology, and Neurosurgery
Associate Director Graduate Program in Neuroscience
Baylor College of Medicine

Email: [email protected]
Web: https://www.bcm.edu/people-search/joanna-jankowsky-23828

Title: Gene therapy for Alzheimer's disease using virally delivered A-beta variants

The recent reversal of fortune for anti-Ab antibody aducanumab has breathed new life into the therapeutic potential for Ab-lowering strategies to treat Alzheimer's disease (AD). Because cost and access may limit utility of antibody-based treatments, other means of chronically and safely reducing Ab load must be identified. Past work had shown that small peptide inhibitors can be readily tailored to prevent Ab aggregation, but in vivo delivery of peptide-based drugs was limited by short half-life and poor brain penetration. We have identified two Ab sequence variants that meet criteria for potential therapeutic use, as they 1) prevent aggregation of WT Ab in vitro, 2) promote disassembly of Ab existing fibrils, 3) mitigate toxicity of Ab oligomers, and importantly, 4) do not self-aggregate. To deliver these peptides in vivo, we have developed a novel mini-gene to express our variant peptides at the plasma membrane where they are released into the extracellular space by g-secretase cleavage. By packaging this minigene into an AAV vector that is injected into APP/PS1 mice, our pilot data show that viral expression of variant Ab lowers Ab load and delays plaque formation. The current proposal will build on these results to determine how dosage, timing, and route of variant Aβ administration influence efficacy in vivo. We will use viral strategies to compare interventional treatment after amyloid onset with preventative treatment starting at birth, determine the lowest effective ratio of variant:wild-type Ab needed to modify plaque formation, and test whether delivery through the CSF can match the effect of neuronal transduction. These pre-clinical studies will tell us how our variants perform in the mammalian brain, both before and after disease onset, and whether we can find a clinically-relevant route of administration in mice that might be considered for future use in humans. If successful, this strategy for self-inhibition may also be applicable to other protein misfolding diseases where peptide treatments have been eschewed for technical reasons that can now be overcome through expression engineering and viral technology.

Gene therapy for Alzheimer's disease using virally delivered A-beta variants

Therapeutic Targets for Alzheimer's Disease in Aging-relevant Human Neurons

Home-based tDCS for apathy in Alzheimer's Disease

Assistant Professor
Lyda Hill Department of Bioinformatics
Department of Pathology
Center for Alzheimer’s and Neurodegenerative Diseases
UT Southwestern Medical Center at Dallas

Email: [email protected]
Web: https://profiles.utsouthwestern.edu/profile/113606/satwik-rajaram.html

Title: Characterization of White Matter Pathology In Tauopathies Using Machine Learning

Neurodegenerative disorders are characterized by the accumulation of aggregated proteins within different cell types and cell compartments in the central nervous system (CNS). As most of these disorders are associated with cognitive impairment, most neuropathological investigations to date have focused on neurons, and by extension, gray matter, where neuronal cell bodies reside. In contrast, despite significant alterations on both neuroimaging and neuropathological evaluations, white matter changes in neurodegeneration have been less well characterized. In this proposal, we will investigate the role of white matter lesions in tauopathies, a large and heterogeneous group of neurodegenerative disorders that include Alzheimer disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). White matter abnormalities in these diseases are variable and complex, making it impractical to manually quantify these changes and integrate them over slides that may contains tens of thousands of cells. Here, we aim to leverage recent computer-based machine learning approaches that have been shown to outperform human recognition for such large-scale tasks involving subtle, complex visual patterns. Specifically, we first will build a computational framework to measure the location, shape, and other properties of aggregates and cell types in the white matter using virtual slides prepared from differentially stained microscope slides of human autopsy brain cases. Next, through a series of controlled comparisons, we will quantify which aspects of white matter neuropathology are most impacted by specific diseases. This work builds on our recently developed machine learning approaches to identify gray matter tau pathology in AD and PSP, but shifts to the less well characterized white matter pathology in AD, PSP, and CBD. At the conclusion of this study, we aim to have a better understanding of several aspects of white matter pathology including the cellular compartments where tau pathology is occurring, the structural impact of the individual diseases (possibly tau independent) on cellular morphology and the relationship between disease in the gray and white matter.

Characterization of White Matter Pathology In Tauopathies Using Machine Learning

Assistant Professor
Mitchell Center for Alzheimer’s Disease & Brain Disorders
UT Health Houston

Web: https://med.uth.edu/neurology/faculty/mohammad-shahnawaz-phd/

Title: Detection of Misfolded Tau Oligometers in Biological Fluid for the Diagnosis of Alzheimer's Disease and Disease Monitoring

Alzheimer’s disease (AD) is the most common type of senile dementia and one of the leading causes of death in the developed world which has no cure or disease-modifying therapy until now. One of the major hurdles in Alzheimer’s disease (AD) is the lack of definitive, sensitive and predictive laboratory test that can identify individuals well before they show clinical signs. The availability of such a test would be of utmost importance for the development of disease-modifying or preventive therapies before irreversible brain damage occurs. One of the pathological hallmarks of AD is the intraneuronal accumulation of protein aggregate in the form of neurofibrillary tangles (NFTs). NFTs are mainly composed of hyper-phosphorylated microtubule associated protein tau. Compelling evidence suggests that tau misfolding, aggregation and accumulation in NFTs is the central event, which involves the formation of several intermediate species including soluble tau oligomers (two or more monomers). The accumulation of tau oligomers precedes NFTs formation and correlates better with neuronal loss and behavioral deficits in a transgenic mouse model expressing wild-type human tau. Increased levels of tau oligomers were detected in the transgenic mouse model and the human brain. Interestingly, tau proteins are actively secreted by cells and circulate in biological fluids such as cerebrospinal fluids (CSF) and blood plasma. Thus, we hypothesize that the detection of tau oligomers in biological fluids holds promise for diagnosis for AD and disease monitoring. The main goal of this project is to develop the technology to detect minute amounts of tau oligomers in biological fluids. To detect very low amounts of tau oligomers in biological fluids, we have developed a highly sensitive protein misfolding cyclic amplification assay (PMCA) that exploits the functional properties of oligomers to catalyze the misfolding of monomeric protein in vitro. PMCA has been widely used for the detection of prion protein (PrPSC) implicated in prion disease. Recently, we adapted PMCA technology for the detection of amyloid-beta (Aβ) oligomers, as well as alpha-synuclein (α-Syn) in CSF implicated in AD and Parkinson’s disease, respectively. To achieve our goal, we will optimize the assay conditions for sensitive and specific detection of tau oligomers in biological fluids (CSF and blood plasma). Then, we will use a well-characterized CSF and plasma samples from individuals affected with AD, other tauopathies and healthy controls. Next, the sensitivity and specificity of Tau-PMCA for AD will be evaluated using a large number of samples. Finally, we will attempt to correlate the kinetic parameters of Tau-PMCA with clinical data at different stages of AD. We expect that our finding will lay the foundation for the development of sensitive and specific detection of tau oligomers in biological fluids of individuals at risk of developing AD. Our findings will not only help to understand the mechanisms implicated in AD progression but also will help in disease monitoring.

Detection of Misfolded Tau Oligometers in Biological Fluid for the Diagnosis of Alzheimer's Disease and Disease Monitoring

Assistant Professor
Departments of Microbiology, Immunology, and Genetics
UNT Health Science Center

Email: [email protected]
Web: https://experts.unthsc.edu/en/persons/nicole-phillips

Title: Longitudinal Mitochondrial DNA and microRNA Profiling of Neuron-enriched Exosomes Associated with Cognitive Decline in Mexican Americans

Mexican Americans experience earlier onset of disease than their Non-Hispanic White counterparts, and the origins of this disparity are not understood. This project aims to study molecules that originate from neurons and travel throughout the body in biological packets called neuronal enriched exosomes (NEEs). The exosomal profiles will shed light on potential mechanisms by which cognitive changes manifest in Mexican Americans as part of Alzheimer’s disease pathogenesis. We are particularly interested in molecules called microRNAs (miRNAs) and mitochondrial DNA (mtDNA) which are released within exosomes by neurons for communication both within the brain and to the peripheral body. MiRNAs and mtDNA have been shown to act in a coordinated fashion to influence expression profiles of target cells/tissues. In neurons, mitochondria—the primary engines of our cells—are critically important for neuronal health and are greatly influenced by environment/lifestyle. Metabolic diseases, such as type 2 diabetes (T2D), increase risk for Alzheimer’s disease (AD), and interestingly, both T2D and AD feature mitochondrial dysfunction as a prominent, early event in disease progression. This fact indicates that neuronal mitochondrial dysfunction may be critical for understanding the AD health disparity in the Mexican American population who (1) have earlier onset of symptoms compared to non-Hispanic whites, and (2) have an over-representation of metabolic diseases such as T2D. The biological basis of the health disparity in Mexican Americans is poorly understood and represents a significant and meaningful gap in our understanding of disease pathogenesis and progression. Our long-term goal is to identify epigenetic-based risk factors and longitudinal modulators of mitochondrial function that originate in the brain and are detectable in the peripheral blood of Mexican Americans. Using TARCC biorepository samples, we propose the following specific aims. Specific Aim 1: To detect and quantify damaged mitochondrial DNA (mtDNA) in plasma NEEs which correlate with disease progression (e.g., by testing plasma samples at two time points, 5 years apart) in Mexican Americans and Non-Hispanic Whites. We will use (1) a novel sequencing approach to specifically identify DNA molecules damaged by oxidation, which are known to accumulate cell-free as a result of mitochondrial dysfunction, and (2) a qPCR method for absolute mtDNA quantification (developed by Phillips et al., 2014). Specific Aim 2: To identify the aberrant miRNAs profiles that correlate with disease progression (e.g., by testing plasma samples at two time points, 5 years apart) in NEEs from Mexican Americans and Non-Hispanic Whites that correlate with disease progression and are associated with oxidation status of mtDNA. Using next generation sequencing of small RNAs, we will obtain miRNA profiles for association with disease-related outcomes as well as mtDNA features. We hypothesize that altered NEE profiles will be characteristic of disease progression in Mexican Americans with type 2 diabetes comorbidity. This will potentially inform future ethnic-specific therapeutic design and disease risk prediction.

Longitudinal Mitochondrial DNA and microRNA Profiling of Neuron-enriched Exosomes Associated with Cognitive Decline in Mexican Americans

2019 Fellowship Grants

Recipient

Grant Title

Training Fellowship in Aging and AD Research and Care

Neuropsychology Fellowship Program

Neuropsychology of Dementia Fellowship

2018 Investigator Initiated Grants

Recipient

Grant Title

Professor
Department of Neurology and Neurotherapeutics
Peter O’Donnell Jr. Brain Institute
UT Southwestern

Email: [email protected]
Web: https://profiles.utsouthwestern.edu/profile/80056/john-hart.html

Title: Longitudinal Continuation of TARCC Hispanic Cohort

Longitudinal Continuation of TARCC Hispanic Cohort (Collaborative Multi-Site Award)

Professor
School of Public Health
Center for Population Health & Aging
Texas A&M University Health Science Center

Email: [email protected]
Web: https://sph.tamhsc.edu/eoh/faculty/ory-bio.html

Title: Assessing the utility and effectiveness of monitoring technology for reducing caregiver burden for Alzheimer’s Disease

Project involves:
Marcia Ory, PhD (Texas A&M University Health Science Center)
David Paydarfar, MD (UT Austin Dell Medical School)
Janice Knebl DO, MBA (University of North Texas Health Science Center)

Persons living with dementia (PWD) who wander due to disorientation and underlying agitation are at increased risk for harm due to being in an unsupervised environment, which can increase the burden of care for family caregivers (CG). In collaboration with three TARCC sites (Texas A&M, University of North Texas, and University of Texas at Austin), this project aims to reduce the risk associated with PWD wandering and prepare family CGs to respond effectively in situations where their loved ones are at safety risks due to wandering. This will be accomplished through a two-phase study including preliminary pilot work (Aim 1) and a randomized controlled trial (RCT) to test the impact of a multi-component intervention that integrates a technology-based approach to increasing PWD safety with evidence-informed skills training for CGs (Aim 2). The proposed intervention is innovative because it is one of the first systematic investigations of the use of a GPS-based wearable technology with call capability. The wearable device has a state-of-the art gyroscope, triple access accelerometer, and GPS capacity that, when paired with a smartphone, functions both as an attractive wristwatch and a communications device to provide a real-time link between PWD and one or more family CGs. When worn by PWD, the technology tracks the wearers’ location, monitors physical activity, and provides a means of communication between the caregiver/care recipient (CG/CR) dyads. The intervention to be tested also includes evidence-informed education/skill building support to family CGs. Integration of the use of technology and skills training is achieved with in-person and telephone-based support. In Aim 1, we will examine the usability (e.g., amount of time worn by PWD, features used by CGs) and user satisfaction (e.g., whether it meets user expectations and needs, ease of use, what, if any changes the users would recommend) of the wearable technology in a sample of 30 CG/CR dyads during the pilot study. In Aim 2, we will employ a RCT to test the relative impact of the multi-component wearable technology and caregiver skills training intervention compared to an education based comparison condition on the safety risks of wandering on PWD (e.g., fewer adverse events, faster reaction times to adverse events, less concern about wandering) and the overall burden of dementia care on family CGs (e.g., burden, depression, leisure activities) with 200 CG/CR dyads. Achieving these two primary study aims will yield evidence about the efficacy of an intervention that represents a new generation in dementia care in which the current knowledge base is enhanced with state-of-technology combined with evidence-informed skill training to increase the safety of PWD and reduce the burden of family caregiving.

NOTE: REVIEW COMMITTEE RECOMMENDED FUNDING AIM 1

Assessing the utility and effectiveness of monitoring technology for reducing caregiver burden for Alzheimer’s Disease (Collaborative Multi-Site Award)

Associate Professor
Departments of Pharmacology and Neuroscience
University of North Texas Health Science Center

Email: [email protected]
Web: https://experts.unthsc.edu/en/persons/robert-barber

Title: Epigenetic risk factors for age at onset of Alzheimer’s & MCI and metabolic dysfunction among non-Caribbean Hispanics and non-Hispanic whites

Mexican Americans are diagnosed with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) at younger ages than non-Hispanic whites. In addition, Mexican Americans who are diagnosed with AD are 1) less likely to carry the ApoEε4 genotype, 2) suffer a greater burden of type 2 diabetes, 3) experience greater metabolic-related cognitive decline and 4) display a proteomic signature of AD that is heavily metabolic in nature, compared to non-Hispanic whites, whose proteomic signature for AD is dominated by inflammatory proteins. The source of the DNA and data for the proposed studies, the Texas Alzheimer’s Research and Care Consortium (TARCC) was designed to identify risk factors and biomarkers for MCI and AD. TARCC is also interested in how dementia etiology may differ between non-Hispanic whites and non-Caribbean Hispanics (represented primarily by Mexican Americans in TARCC). Here we propose to add to that work by conducting an Epigenome-Wide Association Study (EWAS) of associations between differentially methylated regions of DNA (DMRs) and age at onset (AAO) of cognitive decline (defined as MCI/AD) and metabolic dysfunction (defined as metabolic syndrome/type 2 diabetes) among Mexican Americans and non-Hispanic whites.

We propose to measure genomic DNA methylation and perform RNASeq analysis of 600 leukocyte DNA samples from the TARCC biobank. The 600 samples will be comprised of four groups: 1) controls, without metabolic dysfunction or cognitive decline (n=200); 2) cognitive decline (n=150); 3) metabolic dysfunction (n=150); 4) cognitive decline and metabolic dysfunction (n=100). Each group will be split evenly between Mexican Americans and non-Hispanic whites and matched on age and sex. Cellular heterogeneity is a potential confounder in EWAS analysis of intact tissues. We will adjust for potential confounding by the mixed cell population of leukocytes with a validated statistical modeling approach. DMRs will be also confirmed by changes in expression of nearby genes using RNASeq data. We acknowledge that DNA methylation is tissue specific and that leukocytes appear to be on the wrong side of the blood-brain barrier to be useful in studies of neurodegeneration. However, leukocytes are known to traffic across the blood-brain barrier and numerous links have been reliably reported between DNA methylation in leukocytes and common diseases, including diabetes and AD.

We hypothesize that DNA methylation is of key importance to an earlier AAO of MCI/AD and increased rate of metabolic dysfunction among Mexican Americans. We will leverage the TARCC study to address two Specific Aims:

Aim 1. Perform an EWAS and RNASeq to identify differentially methylated regions of DNA in leukocytes that are associated with age at onset of cognitive decline (MCI/AD) in Mexican Americans and non-Hispanic whites.

Aim 2. Use genomic DNA methylation and RNASeq data (Aim 1) to identify DMRs that are associated with risk for metabolic dysfunction (metabolic syndrome/type 2 diabetes) in Mexican Americans and non-Hispanic whites.

Our long-term goal is to understand the relationship between cognitive decline and metabolic dysfunction and how it may differ in Mexican Americans and non-Hispanic whites. This knowledge is critical for development of ethnicity-focused AD treatment options. The data generated in this proposal will be critical to follow up applications for federal funding.

Epigenetic risk factors for age at onset of Alzheimer’s & MCI and metabolic dysfunction among non-Caribbean Hispanics and non-Hispanic whites

Professor
Departments of Molecular and Human Genetics, and Neuroscience
Howard Hughes Medical Institute
Baylor College of Medicine

Email: [email protected]
Web: http://flypush.imgen.bcm.tmc.edu/lab/index.html

Title: Probing the role of glial endocytic genes and ROS on AB42-induced neurotoxicity

Numerous molecules have been identified to be associated with Alzheimer’s disease (AD) or are known to be risk factors for AD based on human genetics studies. These include enzymes involved in the production of the neurotoxic protein Aβ42, genes that affect the accumulation of Aβ42 outside the cells of the brain, and genes that play a role in how cells take up proteins (endocytosis). Endocytosis, particularly by supporting glial cells, can aid in the uptake of toxic proteins from the environment to degrade them.

The role of glia, the support cells of the brain, is of increasing interest to AD researchers. The genes implicated in AD, including the most potent risk factors (APOE and TREM2) and multiple associated risk alleles are highly expressed in glia. Current studies are poised to determine how variation within these genes may lead to AD pathogenesis through their potential role in Aβ42 or tau protein aggregation. Work by us and others has revealed a significant contribution of oxidative damage by reactive oxygen species (ROS) in conjunction with genetic risk to cause robust neurodegeneration. Preceding neuronal loss, we have found that lipid droplets (LDs) accumulate within the glia surrounding the neurons that will eventually die. We have shown that ROS induces lipid peroxidation in neurons which leads to neurotoxicity. Thus, neurons shuttle peroxidated lipids to glia where they are sequestered in LDs and guard against neuron loss. However, prolonged LD accumulation in glia results in the death of both the glia and surrounding neuron. We have shown that APOE is involved in this process of lipid transfer and is protective in response to elevated ROS. On the contrary, the ApoE4 isoform is unable to form glial LDs in response to neuronal ROS and leads to enhanced neuronal death. It is know that ApoE and the neurotoxic protein Aβ42 can bind to the same glial receptors. Therefore we surmise that LD accumulation and the uptake of Aβ42, a highly lipophilic molecule, must be endocytosed by glia as part of the LD pathway for downstream sequestration and degradation.

Intriguingly, many of the AD associated risk genes are enriched in glia in humans and play a key role in endocytosis. We have already established that our lipid droplet model in the retina of the fruit fly is conserved in mammals. Therefore we will use fly to rapidly determine which of the glial-endocytic genes functions in both LD accumulation and Aβ42 sequestration. We will then generated mice that have conditionally deleted endocytic genes in glia to determine if this can exacerbate AD phenotypes. Secondly, we will attempt to create a simpler mouse model of AD by combining increased Aβ42 expression with chronic ROS exposure. These mice will serve as a more physiologically relevant platform for pre-clinical modelling.

Probing the role of glial endocytic genes and ROS on AB42-induced neurotoxicity

Professor
Department of Psychiatry
Peter O’Donnell Jr. Brain Institute
UT Southwestern

Email: [email protected]
Web: https://profiles.utsouthwestern.edu/profile/12533/dwight-german.html

Title: Blood biomarker for Alzheimer’s Disease & disease progression: Phospholipids

Alzheimer’s disease (AD) is the most common neurodegenerative dementia, affecting over 5 million Americans. This disease is the fifth leading cause of death for those over the age of 65 (Alz. Assoc., 2012). There are currently no rapid and cost-effective means for detecting the disease and tracking disease progression, which is critical in order to move research and clinical efforts forward.

Ray et al (2007) were the first to identify a panel of blood-based proteins that accurately distinguished AD patients from healthy controls as well as accurately identifying mild cognitive impairment patients who progressed to AD within a 2 to 6-year follow-up period. However, these findings could not be replicated in another laboratory and using a different measurement platform (Soares et al., 2009). Despite this initial setback, others have continued to search for signals in peripheral blood suggesting that a blood-based AD screen is on the horizon (Booij et al., 2011; Buerger et al., 2009; Laske et al., 2013; O’Bryant et al., 2011, 2014; Nagele et al., 2011; Reddy et al., 2011; Fiandaca et al., 2014). One recent approach identified a panel of 10 lipids in the blood that could diagnose AD, and conversion to AD within a 2-3 year timeframe with >90% accuracy (Mapstone et al., 2014). This latter study opened the door to looking at lipids in the blood as a source of biomarkers for AD.

The premise of the current grant is that we can identify a blood biomarker for AD using a new advanced lipidomic approach with brain-derived blood exosomes.

In our grant we will develop a brain-related lipid biomarker panel: (1) for the identification of AD using blood samples from AD and age-matched normal controls. Here we can determine whether any of the lipids identified in the blood by Mapstone et al., are coming from the brain, and/or if a different brain-related lipid panel proves to be more diagnostic or biologically informative; (2) that can discriminate AD from the second most common neurodegenerative disease – Parkinson’s disease; and (3) that can track AD progression. Here we will use blood samples from AD patients at baseline and again 3-years later.

Blood biomarker for Alzheimer’s Disease & disease progression: Phospholipids

Multi target combinatory therapy for Alzheimer’s Disease

Assistant Professor
Department of Neurology
Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases
UT Health Science Center San Antonio

Email: [email protected]
Web: https://www.uthscsa.edu/patient-care/physicians/providers/1104188648/Alicia-Parker

Title: Diastolic dysfunction and the development of dementia

Cardiovascular health, including that of the heart and blood vessels, is important to brain health. Research has shown that having poor cardiovascular function, such as having positional changes in blood pressure, stiffness of the blood vessel through which blood flows out of the heart, and decreased pumping ability of the heart, can damage the brain’s ability to think. Currently, the diastolic function of the heart, or the ability of the heart to fill with blood, has not been well studied. This project will look at the connection between diastolic heart problems as assessed by echocardiogram and brain structure and function. This clinical study will help determine how often difficulty with cognition occurs when there is poor diastolic functioning of the heart and what brain changes explain this connection. Specific aims for this study include the following:

To study the relationship between diastolic dysfunction and the development of structural changes visualized by brain imaging.
To evaluate the effect of diastolic dysfunction on the pattern of cognitive impairment as determined by neuropsychological testing.
To investigate the relationship between diastolic dysfunction and the development of new mild cognitive impairment and dementia.

This pilot clinical study will examine data from participants with normal cognition and either normal or decreased diastolic function. Participants will be recruited from the TARCC cohort and from the Neurology, Geriatrics and Cardiology clinics at UTHSCSA. Participants will include individuals more than 55 years old with a Clinical Dementia Rating Scale of 0, indicating normal cognition. Structural brain imaging will be obtained at enrollment and at one year to visualize changes in brain structure over time. Comprehensive neuropsychological testing will be performed at enrollment and at one year to determine changes in brain function over time. This study will help describe the pattern and frequency of cognitive impairment that occurs with poor diastolic function. The recognition and treatment of diastolic cardiac problems could help decrease the frequency or severity of cognitive impairment.

Diastolic dysfunction and the development of dementia

2018 Junior Investigator Grants

Recipient

Grant Title

Assistant Professor
Department of Neurology
Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases
UT Health Science Center San Antonio

Email: [email protected]
Web: https://biggsinstitute.org/team-member/mitzi-m-gonzales-ph-d/

Title: Establishing novel blood-based biomarkers for Alzheimer’s Disease in the Texas Alzheimer’s Research and Care Consortium

At present, over 24 million people suffer from dementia and the global prevalence is predicted to nearly double over the next twenty years. Within the United States, Texas has an elevated dementia burden and will bear catastrophically high associated healthcare costs. Enhanced early detection, monitoring, and treatment will be crucial for managing this growing epidemic. The current gold-standard diagnostic assessments for dementia, namely magnetic resonance and positron emission tomography imaging, are costly and burdensome. Establishment of blood-based biomarkers for neurodegenerative disorders has significant potential to aid timely identification of affected individuals, predict disease progression, and monitor efficacy of newly emerging treatments. Alzheimer’s disease (AD) is a genetically and biologically multifactorial disease. Thus, our ability to develop new innovative treatments hinges upon a more complete understanding of underlying biological and cellular processes. Recent genetic studies have implicated heterogeneous pathophysiological processes in AD including abnormal protein folding, neuronal/gilal injury, and inflammation. Leveraging upon these findings, we propose to assess serum biomarkers of abnormal protein accumulation (tau), neuronal injury (NFL), altered protein folding (UCHL1), microglial inflammation (sCD-14, YKL-40), and astrogilal injury (GFAP) in over 3,000 ethnically diverse participants within TARCC. First, we will investigate whether concentrations of novel serum biomarkers for neurodegeneration (tau, NFL, UCHL1, GFAP, sCD-14, YKL-40) individually and collectively have diagnostic accuracy for detection of AD using the area under the receiver operating characteristic curve (AUROC) and machine learning based models (Aim 1). We will also explore the associations between serum biomarkers and cognitive outcomes with data already collected within TARCC (Aim 2). Finally, we will investigate whether the association of serum biomarkers with diagnostic group and cognition is modified by the well-established AD risk factor, APOE genotype (Aim 3). In summary, we propose to utilize the extensive clinical, cognitive, and laboratory data in the ethnically diverse TARCC cohort to establish a novel serum biomarker panel to improve timely diagnosis of AD. The development of this panel has tremendous potential to improve early disease diagnosis and monitor treatment progression. Additionally, findings hold promise to facilitate clinical trials aimed to slow the acceleration of cognitive decline and prevent dementia.

Establishing novel blood-based biomarkers for Alzheimer’s Disease in the Texas Alzheimer’s Research and Care Consortium

Assistant Professor
Department of Surgery
Peter O’Donnell Jr. Brain Institute
UT Southwestern

Email: [email protected]
Web: https://profiles.utsouthwestern.edu/profile/103801/ryan-huebinger.html

Title: Immune profile investigations of Alzheimer’s Disease

The hallmark features of AD include amyloid beta deposition, neurofibrillary tangles and neuronal degeneration, and are the most likely sources of inflammation associated with AD. The hallmark features of AD are readily distinguishable from those of patients with the neuro-inflammatory disease, Multiple Sclerosis (MS). We compared the immune profile of cerebrospinal fluid (CSF) cells between patients with AD and MS. In this preliminary cohort of AD patients, a more robust expansion of innate cell populations in the CSF than MS patients was observed (35.0% vs 2.6%, AD:MS). Furthermore, AD patients display a decreased frequency of CD4+ T cells in the CSF than MS patients (37.8% vs 61.5%, AD:MS).

To determine if systemic immune dysregulation was also present, we performed flow cytometry on blood samples of the pilot AD cohort and observed an expansion of innate cells and contraction of CD4+ T cells in the circulation. This shift in innate immune cell and CD4+ T cell frequency may impact antibody production since a healthy balance of innate immune cells and CD4+ T cells is critical for optimal B cell activation leading to antibody production.

Based on this preliminary data, we hypothesize that expansion of innate immune cells and contraction of CD4+ T cells as observed in the CSF and periphery contributes to AD development by impacting antibody production against Amyloid beta and Tau. To test this hypothesis, we will collect cerebrospinal fluid and peripheral blood from AD patients and age-matched healthy controls to analyze cellular and molecular aspects of the humoral immune compartment. This hypothesis will be addressed in two specific aims: Aim1: Determine the impact of innate cell expansion and CD4+ T cell contraction on antibody genetics. Aim 2: Determine the impact of innate cell expansion and CD4+ T cell contraction on anti-Abeta and anti-Tau antibody production. The key impact of this project is to map the impact of innate cell expansion and CD4+ T cell contraction on AD progression, particularly as it relates to humoral immunity. The results of this study may support the expanded use of immune-stimulating therapies at an earlier stage of disease when they are most likely to be effective.

Immune profile investigations of Alzheimer’s Disease

Assistant Professor
Department of Neurology
Mitchell Center for Alzheimer’s Disease & Brain Disorders
UT Health Science Center at Houston

Email: [email protected]
Web: https://med.uth.edu/neurology/faculty/ines-moreno-gonzalez-phd/

Title: Stem cell-derived anti-inflammatory treatment for Alzheimer’s disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by memory impairment and cognitive decline. The most prominent pathological hallmarks of the disease are the extracellular accumulation of amyloid β (Aβ) peptides in the form of plaques, the intracellular accumulation of hyper-phosphorylated tau (ptau) proteins as neurofibrillary tangles, and a neuroinflammatory process. Current treatments for AD only ameliorate the symptoms, but none of them delay or halt disease progression. As the disease continues to be a serious global health problem, novel therapies aimed at recovering brain tissue and functionality need to be developed. In recent years, stem cells have received growing attention as a potential therapy for brain disorders, such as AD. Particularly, an emerging and promising cellular approach to treat human disease is the use of stem cells. For the past 20 years, investigators have tried injecting stem cells into the brain in an attempt to get them to replace the cells lost in neurodegenerative diseases but there have been great technical challenges. Patients’ self-derive stem cells offer the possibility to avoid rejection and a more personalized treatment. Preliminary results from our lab indicate that peripheral treatment using neural precursors (NPs) obtained from stem cells ameliorates clinical symptoms and slow down the progression of different neurodegenerative diseases by reducing the inflammation in the brain. Our working hypothesis is that intravenous inoculation of NPs and their released factors can be used as a novel therapeutic treatment for AD. The main goal of this project is to develop a new approach for treating AD using a stem cell based non-invasive therapy. To achieve this goal, we plan to study the efficacy of peripheral administration of stem cells in animal models of AD. In addition, we plan to evaluate the efficacy of factors derived from stem cells in AD mouse models and analyze the profile of factors present in the conditioned media with a disease-modifying effect. The significance of the proposed experiments is that, if our hypothesis is correct, it may lead to a more personalized therapy for AD patients, since the cells can be obtained from the patient’s skin providing an effective, low risk, personalized treatment that will reduce the neuropathological and clinical manifestations of the disease.

Stem cell-derived anti-inflammatory treatment for Alzheimer’s disease

Assistant Professor
Department of Neurology and Neurotherapeutics
Peter O’Donnell Jr. Brain Institute
UT Southwestern

Email: [email protected]
Web: https://profiles.utsouthwestern.edu/profile/157574/trung-nguyen.html

Title: Tau seeding and strain identification across the spectrum of Alzheimer’s Disease and Lewy Body pathology

Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the leading causes of dementia. They have different clinical features and different types of brain pathology. AD pathology includes neurofibrillary tangles that consist of abnormal tau proteins. DLB and other Lewy body diseases are characterized by the presence of Lewy bodies (LB) consisting of abnormal α-synuclein accumulation. Patients often have mixed pathology as well. It is difficult to predict the presence of mixed pathology, but it can lead to more impairment and decline. We must understand how tau and α-synuclein interact to improve our abilities in diagnosing and treating neurodegenerative disorders. One overarching concept is that abnormal proteins like tau and α-synuclein spread throughout the brain like prions, where an abnormal type, or “strain,” of a protein that is more prone to accumulation can spread from cell to cell to convert normal native proteins to abnormal proteins. This then “seeds” further accumulation and spread of abnormal proteins. It is unclear if one type of protein seed (α-synuclein) can convert a different protein (tau). This may depend on the specific protein strain, for which tau has great diversity. We hypothesize that tau and α-synuclein interact to increased tau seeding in a tau strain dependent manner. We aim to test this hypothesis by studying autopsy specimens from subjects seen at UT Southwestern (UTSW) through the Texas Alzheimer’s Research and Care Consortium and the Alzheimer’s Disease Center. Of the 4171 subjects we have evaluated over the past 30 years, 578 autopsy cases have been obtained for the UTSW Neuropathology Laboratory Brain Bank. Many cases are from decades ago, so we will assure that each case is evaluated using contemporary protocols. We will select cases based on extent of AD and LB pathology: 1) AD-only pathology; 2) AD/low LB mixed pathology; 3) AD/high LB mixed pathology; 4) LB/low or no AD pathology. Cases will also be defined by clinical syndrome (AD or DLB) and whether it matched pathology (e.g. clinical AD with AD pathology), had mixed pathology, or had a mismatch with pathology (e.g. DLB with AD-only pathology). We will select up to 10 cases per group. We will collaborate with Dr. Diamond’s lab, who has published techniques for identifying different tau strains and measuring seeding activity. By applying prepared tissue samples to a biosensor cell line, tau seeding activity can be measured and tau strains can be identified by morphometry and biochemical studies. We will compare tau seeding activities and strain identities for each case to the tau and α-synuclein pathology seen on adjacent sections as well as between groups based on pathology and clinical diagnoses. We expect evidence showing that α-synuclein interacts and increases seeding of distinct tau strains that are more associated with LB pathology and a DLB syndrome. Our results will advance the understanding of disease mechanisms of AD and DLB and what happens in cases with mixed pathology, which is becoming even more important as we develop diagnostic agents and therapies designed to target specific proteins like tau or α-synuclein.

Tau seeding and strain identification across the spectrum of Alzheimer’s Disease and Lewy Body pathology

Development of a blood test for Alzheimer’s disease diagnosis

Brain targeted RNAi therapy for Alzheimer’s Disease

2014 Pilot Grants

Recipient

Grant Title

Associate Professor
Center for Neuroscience Discovery
University of North Texas Health Science Center

Email: [email protected]
Web: https://profile.hsc.unt.edu/profilesystem/viewprofile.php?pid=100227

Title: Neuroprotection of nonfeminizing estrogens against cognitive deficits of Alzheimer’s Disease.

Abstract: Memory loss is a common problem in normal aging and is earliest and most recognized symptom in age-associated neurodegenerative diseases including Alzheimer’s (AD) and Parkinson’s disease. Accumulating evidence from clinical and basic studies supports the notion that the effects of estrogen on learning and memory are beneficial. Estrogens have been shown to be useful for the improvement of learning and memory, treatment and prevention or delay of the onset of AD. In addition to these neuroprotective effects of estrogens, estrogens produce female phenotype in both females and males. Moreover, estrogens also increase the risk of female hormone-sensitive cancers such as breast and endometrial cancer. These detrimental effects of estrogen are likely mediated via activation of classical estrogen receptors (ERs) and limit their potential therapeutic for widespread clinical application. Synthetic estrogen analogues, which lack genomic hormonal properties (so-called “nonfeminizing”) may be promising alternatives to natural estrogens to prevent AD- related cognitive decline not only in women but also in men. The ability of estrogen to positively influence cognitive function is likely due at least in part to the fact that it enhances hippocampal long-term potentiation (LTP), the cellular mechanism of long-term memory storage in the brain. Moreover, estrogen modulation of LTP appears to involve a nongenomic mechanism. We have discovered and synthesized over 70 novel nonfeminizing estrogenic compounds. In neuroprotection cell assays, many of these compounds are 10 to 100-time more potent as neuroprotectants than estrogen itself. While the neuroprotection of the nonfeminizing estrogens have been described in vitro and in vivo studies, the cognitive outcomes of such neuroprotection have not been studied. The overall goal of the project is to test the hypothesis that nonfeminizing estrogen analogues have potential utility in improving cognitive function in normal male and female and AD animals. The Specific Aims of the proposal are to: 1) determine whether modulation of hippocampal LTP by nonfeminizing estrogen is dependent on gender, 2) determine whether nonfeminizing estrogen modulates LTP in the brain of AD animal model, 3) determine whether nonfeminizing estrogen attenuates cognitive disorders in a transgenic AD animal model. The proposed experiments will be conducted utilizing in vitro electrophysiological techniques and in vivo behavioral assay. The results of the studies will provide critical evidence needed to demonstrate that nonfeminizing estrogen analogues may provide the cognitive benefits of estrogen without the detrimental side effects, which is the important step towards development of new therapeutics to treat AD. The pilot grant will provide needed resources for accumulating preliminary data essential for submission larger grants to NIH/NIA, state and private foundations.

Neuroprotection of nonfeminizing estrogens against cognitive deficits of Alzheimer’s Disease.

Computational tools for molecular proteotyping: A unique approach to Alzheimer’s disease biomarker discovery.

Does HSF1 over-expression enhance the proteostasis of TDP-43?

Identification of Aß-ABAD Interaction Inhibitors for Evaluation as Small Molecule.

Effect of Youthful Systemic Milieu on Alzheimer’s Disease Patholog

2014 Established Investigator Grants

Recipient

Grant Title

Intermittent Hypoxia – novel intervention for treatment of mild cognitive impairment.

A cross-species genetic screen to identify targets that regulate the steady state levels of tau.

Investigator Grants

John Hart, Jr., MD

2023 Postdoctoral Fellowship Grants

Salvatore Saieva, PhD

Vijay Kumar Marumulla Jagadeshwar Rao, PhD

Elizabeth Ochoa, PhD

Sithara Thomas, PhD

Jared Benge, PhD, ABPP

2023 Junior Investigator Research Grants

Ayde Mendoza Oliva, PhD

Natalia Rocha, PhD, MSc

Rodney Ritzel, PhD

Vijayasree V Giridharan, PhD

Huihui Fan, PhD

Kristin Wilmoth, PhD

Murali Vijayan, PhD

Youngran Kim, PhD

Christian LoBue, PhD

2023 Investigator Initiated Research Grants

Karienn de Souza, PhD

Tatiana Barichello, PhD

Andrey Tsvetkov, PhD

Laurent Calvier, PhD

Keran Ma, PhD

2023 Collaborative Research Grants

Joachim Herz, MD

Jared Benge, PhD, ABPP

2021 Postdoctoral Fellowship Grants

Robin C. Hilsabeck, PhD

Laura Lacritz, PhD

2021 Junior Investigator Research Grants

Elena Daoud, MD, PhD

Tiffany Kautz, MD, PhD

Christian Lobue, PhD

Jose Moruno-Manchon, PhD

Haiyang Yu, PhD

2021 Investigator Initiated Research Grants

Bhavya Shah, MD

Xiaoyong Bao, PhD

Mark Kunik, MD

Chun-Li Zhang, PhD

Rodrigo Morales, PhD and Tatiana Barichello, PhD

Jose del R. Millan, PhD

2020 Postdoctoral Fellowship Grants

Jennifer Johnson, PhD

2020 Junior Investigator Research Grants

Lu Sun, PhD

Anne Carlew, PhD

Bharti Manwani, PhD

Hua Liu, PhD

Fang Yu, MD

2020 Investigator Initiated Research Grants

John Hart, Jr, MD

Charles L. White, III, MD

Shannon Juengst, PhD

Claudia Satizabal, PhD

Joann Jankowsky, PhD

Chun-Li Zhang, PhD

Antonio Lucio Teixeira, Jr, MD, PhD

Satwik Rajaram, PhD

Mohammad Shahnawaz, PhD

Nicole Phillips, PhD

2019 Fellowship Grants

Kelly Dineley, PhD

Robin Hilsabeck, PhD

Laura Lacritz, PhD

2018 Investigator Initiated Grants

John Hart, Jr, MD

Marcia Ory, PhD

Robert Barber, PhD

Hugo Bellen, DVM, PhD

Dwight German, PhD

Rakez Kayed, PhD

Alicia Parker, MD

2018 Junior Investigator Grants

Mitzi Gonzales, PhD

Ryan Huebinger, PhD

Ines Moreno-Gonzalez, PhD

Trung Nguyen, MD, PhD

Sandra Pritzkow, PhD