2013 — 2014 |
Hu, William Tzu-Lung |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
African American Alzheimer's Progression Markers - Csf and Neuro-Imaging
DESCRIPTION (provided by applicant): African Americans represent about 10% of the population in the US, but are under-represented in biomarker- related aging studies such as the Alzheimer's Disease Neuro-imaging Initiative (ADNI) and World Wide ADNI. Epidemiologic studies show that, compared to non-Hispanic white (NHW) Americans, African Americans (AA) are more likely to develop mild cognitive impairment (MCI) and Alzheimer's disease (AD), have different genetic risks of developing AD, and experience different rates of cognitive decline after cognitive symptoms develop. All these point to the existence of an MCI/AD endophenotype for AA, although few of these epidemiological studies involve modern chemical or imaging biomarkers associated with AD pathology and progression. Preliminary studies using AA subjects who have undergone CSF analysis (n=36) show that AA MCI subjects are more likely to have normal CSF AD biomarkers than NHW MCI subjects, yet at the same time greater hippocampal atrophy on MRI. We hypothesize that endothelial dysfunction is an alternate mechanism which independently contributes to cognitive impairment in AA subjects with sub-threshold AD pathology in a race-independent fashion, and endothelia dysfunction further enhances the neurotoxicity of AD- associated brain changes in a race-dependent fashion. We propose to build on our success in recruiting AA volunteers into memory and aging studies at the Emory's Registry for Remembrance to recruit a cross- sectional cohort of 75 AA subjects along with 75 NHW subjects with normal cognition, MCI, or mild AD. We will test our hypothesis through two aims. In Aim 1, we will determine whether endothelial dysfunctions independently contribute to cognitive decline in AA and NHW subjects by measuring cerebrospinal fluid (CSF) levels of AD, endothelial, and inflammatory markers. Each subject will also undergo MRI analysis for total area of white matter hyperintensities as an imaging marker of endothelial dysfunction. Based on our hypothesis, we predict that AA MCI/AD subjects are more likely than NHW MCI subjects to have normal CSF AD biomarkers, abnormal CSF endothelial markers, and greater number and area of white matter hyperintensities on MRI. In Aim 2, we will determine if an endothelial marker - intercellular adhesion molecule 1 or ICAM-1 - gene variant unique to AA enhances AD neurotoxicity to explain the greater hippocampal atrophy among AA MCI subjects. The Lys56Met ICAM1 gene variant associated with low ICAM-1 levels is uniquely found in 16-20% of AA, and these subjects may have impaired downstream activation of neprilysin, an Ab-degrading enzyme. If our hypothesis is true, AA subjects with the Lys56Met gene variant will be more likely to have hippocampal atrophy, temporal-parietal cerebral hypoperfusion, and cerebral amyloid deposition than AA subjects and NHW subjects without the gene variant. This may occur in the setting of CSF Ab42 pseudo-normalization if low neprilysin levels lead to increased Ab42 levels.
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2013 — 2017 |
Hu, William Tzu-Lung |
K23Activity Code Description: To provide support for the career development of investigators who have made a commitment of focus their research endeavors on patient-oriented research. This mechanism provides support for a 3 year minimum up to 5 year period of supervised study and research for clinically trained professionals who have the potential to develop into productive, clinical investigators. |
Early Csf Detection of Ftld
DESCRIPTION (provided by applicant): Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia among subjects under the age of 65. There are two main FTLD subtypes: FTLD associated with lesions immunoreactive to TDP-43 (FTLD-TDP), and FTLD associated with Tau-immunoreactive lesions (FTLD-Tau). Currently, the exact FTLD pathology cannot be confidently defined until autopsy, and there is an urgent need for ante- mortem biomarker which reliably predict FTLD pathology. Over the past 30 months, I have identified and validated a panel of cerebrospinal fluid (CSF) FTLD-TDP biomarkers that identified FTLD-TDP patients with 85% accuracy, including Tau phosphorylation, tripeptidyl peptidase 1 (TPP1) levels, and inflammatory protein levels (FAS, eotaxin-3, IL-23), with 85% accuracy in distinguishing between the two main FTLD subtypes. The identification and validation of these CSF alterations will serve as the basis of the current proposal to translate these markers towards clinical application through multi-site technical validation and advanced classification through machine-based learning, and to better characterize altered biochemical pathways in FTLD-TDP. First, I hypothesize that we can reduce the coefficient of variation for each FTLD-TDP biomarker to under 15% through a multi-site technical validation using 60 banked CSF samples. I will test this hypothesis in Aim 1 by determining technical factors (freeze-thawing, blood contamination, detergent use, protease inhibitor use, buffer condition) which reduce assay precision, and validating the assay at Penn. Second, I hypothesize that machine-based learning/support vector machine approach will better diagnose FTLD-TDP by taking into account non-linear effects of age, gender, and disease duration. I will test this hypothesis in Aim 2 by comparing the classification performance between more established algorithms and the support vector machine algorithm. Lastly, I hypothesize that these biomarker changes reflect altered biochemical pathways in FTLD-TDP. I will test this hypothesis by measuring brain and CSF levels of proteins involved in Tau phosphorylation, TPP1 maturation, and inflammation. As an exploratory Sub-aim 3a, I will determine if any of the changes from Aims 1 & 3 are detectable in asymptomatic subjects carrying familial FTLD-TDP mutations, to power an R01 application on longitudinal CSF biomarker changes in prodromal FTLD-TDP subjects. I will carry out this proposal with guidance from my mentoring team including Allan Levey, MD, PhD (Emory), John Trojanowski, MD, PhD (Penn), James Lah, MD, PhD (Emory), Jonathan Glass, MD (Emory), Leslie Shaw, PhD (Penn), and Eva Lee, PhD (Georgia Tech). I will also obtain formal training in biostatistics, bioinformatics, analytical chemistry, quality control, clinical trial design, geriatrics, and responsible conduct of research. Successful completion of the aims in the current proposal will establish the standard procedures to clinically translate promising FTLD-TDP biomarkers, determine the best algorithm to diagnose FTLD-TDP using these biomarkers, and identify altered CSF and brain pathways related to these biomarker alterations.
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2015 — 2019 |
Hu, William Tzu-Lung |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Ad Biomarkers and Endothelial Dysfunction in Caucasians and African Americans
African Americans represent about 10% of the population in the US, but are under-represented in biomarker- related aging studies such as the Alzheimer's Disease Neuro-imaging Initiative (ADNI) and World Wide ADNI. Epidemiologic studies show that, compared to non-Hispanic white (NHW) Americans, African Americans are more likely to develop mild cognitive impairment (MCI) and Alzheimer's disease (AD), but may have slower rates of cognitive and functional decline. These point to the existence of an MCI/AD endophenotype for African Americans, but epidemiological studies without modern chemical or imaging biomarkers cannot differentiate between potential explanations for these observations, including vascular co-pathology, AD endophenotype, and neuroprotective anti-inflammatory mechanisms. Through a NIA-funded R21 (AG043885, PI: Hu), we have begun a cross-sectional study on race-dependent and race-independent factors associated with differences in AD biomarker profile between African Americans and NHW. In Project 1, we propose a longitudinal, multi-modal biomarker study to examine whether AD progression rates differ between the two races because of endothelial dysfunction, neuro-inflammation, or a true AD endophenotype. We will recruit the cross sectional cohort of 150 to undergo longitudinal biomarker analysis, and expand the cohort by 100 new subjects to account for more factors which may influence rates of AD progression. We will directly examine if 1) rates of cognitive decline in biomarker-confirmed cases of AD differ between African Americans and NHW, 2) endothelial dysfunction undergoes longitudinal change in African Americans and NHW, and 3) the interaction between AD and endothelial dysfunction is mediated through neuro-inflammation. In Aim 1, we will determine if African Americans subjects with AD biomarker profiles (CSF, MRI) experience slower cognitive decline than NHW subjects with the same AD biomarker profiles. In Aim 2, we will determine if African Americans subjects undergo greater longitudinal change in endothelial dysfunction than NHW subjects, using CSF levels of novel endothelial markers and MRI analysis of cerebral blood flow, axonal integrity, and cerebral microbleeds. In Aim 3, we will model the interaction between longitudinal AD and endothelial marker profiles, and test the hypothesis that African Americans subjects with AD biomarker profiles are more likely to have an anti-inflammatory CSF profile than NHW subjects with the same AD biomarker profiles. Successful completion of these aims will create a modern biomarker-rich dataset consisting of equal proportions of African Americans and NHW seniors, construct the first progression profiles of modern AD and endothelial markers in African Americans seniors, identify whether longitudinal changes in CSF and MRI AD biomarkers differ between African Americans and NHW, and set the stage for a multi-center, multi-modal biomarker study involving African Americans and NHW seniors.
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2016 — 2020 |
Hu, William Tzu-Lung |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Csf, Mri, and Pet Biomarkers of Neuroinflammation in Alzheimer's Disease
ABSTRACT Alzheimer?s disease (AD) is the most common form of neurodegenerative disorder. Inflammatory changes in the brain are thought to represent key processes in the onset and progression of AD, but it remains unclear whether neuroinflammation confers neuroprotection, accelerated degeneration, or possibly both. Such an understanding in living humans is critical if we are to begin clinical trials using the array of FDA-approved immunomodulatory drugs in the future. We propose that complement- mediated neuroinflammation is protective in the early AD stages, while suppression of complement activities is accompanied by the development of greater cognitive deficits and faster cognitive decline. Our preliminary data from multiple cohorts support this hypothesis by showing 1) reduced levels of cerebrospinal fluid (CSF) complement-related markers occur in the dementia stage but not mild cognitive impairment (MCI) stage of AD; 2) reduced CSF complement-related markers and elevated CSF interleukin-10 (IL-10) levels are associated with faster decline in AD; and 3) CSF inflammatory protein alterations reveal networks of cellular and protein regulations. In the In the current application, we will build on the association between complement related proteins and rates of cognitive decline in AD to identify associated changes in soluble CSF cytokines and chemokines, differential inflammatory cell type regulation, and imaging correlates of neuroinflammation. This application takes advantage of our group?s strengths in performing CSF cytokine measurements, CSF immunophenotyping, molecular imaging of neuroinflammation through positron emission tomography (PET) and iron-enhanced MRI, and network analysis through a novel biochemical-bioinformatics pipeline. We will directly identify individual and networks of soluble CSF cytokines that accompany the transition from the MCI to the dementia stage of AD, correlate the complement and other altered pathways with microglial activation through two modern PET tracers (11C-PBR28 and 18F-FEPPA), and measure changes in individual T helper cell (type 1, 2, 17) and non-T cell populations. This application represents the first attempt to correlate, at the individual level and at the group level, CSF and imaging measures of neuroinflammation. If successful, this application will advance the understanding of neuroinflammation in AD through parallel approaches, form the basis of a new biomarker panel (and algorithm) to diagnose AD through a combination of degenerative and inflammatory markers, and accelerate the target identification of future therapeutics aimed at modulating the immune system in AD.
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2019 |
Hu, William Tzu-Lung |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Beyond Haploinsufficiency - Differential Effects From Distinct Nonsense Progranulin Mutations
ABSTRACT Mutations in progranulin (GRN) represent one of the most common causes of familial frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). Progranulin is involved in inflammatory cascades, but the exact pathogenic link between GRN mutations and FTLD-TDP is unknown. Most mutations result in premature termination codons (PTC) in one GRN allele and 50% reduction on peripheral progranulin protein levels. However, this progranulin haploinsufficiency alone may not account for brain pathology as 1) progranulin deficiency precedes neurological symptom onset by decades, and 2) genetically reducing progranulin levels to 50% in mice does not produce significant pathologic or behavioral changes. During our investigation for inflammatory alterations in cerebrospinal fluid (CSF) from symptomatic GRN mutation carriers, we found different mutation groups to each lead to a cytokine profile. This led us to hypothesize that truncated mutant granulin peptides promote FTLD-TDP pathogenesis. Using sensitive RNA-Seq analysis, we confirmed that mutant GRN transcripts are detectable in brains at levels up to 20% of wildtype transcripts. We then used molecular modeling to design polyclonal antibodies targeting truncated R493X mutant progranulin peptide, and identified mutant progranulin dimers in brains and cultured fibroblasts of subjects carrying the same mutation. In the current application, we propose to extend our innovative findings in three aims by: 1) defining inflammatory phenotypes for GRN mutations predicted to result in short, intermediate, and long truncated mutant progranulin peptides; 2) confirming and characterizing mutant R493X peptides as dimers in carriers of this and other GRN mutations; and 3) directly testing whether mutant progranulin peptides derived from patient samples or plasmids can enhance the formation of TDP-43 oligomers. We will leverage the neurological, biochemical, neuropathological, and genetic expertise of the investigative team from Emory University and University of Pennsylvania, and resources from these two institutions as well as University of Brescia and the multi-centered Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). As an exploratory aim, we will also develop novel antibodies targeting two mutations predicted to result in intermediate-length progranulin peptides significantly shorter than R493X to generalize our findings. Upon completion of these aims, we will have performed clinical, pathological, and mechanistic analysis of the relationship between GRN mutations and FTLD-TDP to inform future therapeutic development and personalized diagnostics.
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2019 — 2021 |
Hu, William Tzu-Lung Wharton, Whitney Lee [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Estradiol and Related Hormones On Inflammation, Sleep, and Risks For Alzheimer's Disease
Women are more likely than men to develop Alzheimer's disease (AD), and available research suggests this is not only because they have a longer life expectancy than men. This increased risk is likely due, in part, to fluctuating sex hormones across the lifespan. Sex hormones likely have direct actions on AD brain biomarkers (A? and tau levels), as well as indirect actions via inflammation, sleep disruptions, and reduced brain blood flow and volume, all of which are independent risk factors for AD. African Americans ?men and women? are also at increased risk for AD vs. Caucasians. As such, mechanistic studies and interventions need to be thoroughly examined and tested in both African American and Caucasian participants. The purpose of the proposed project is to determine the relationship between brain and systemic sex hormones on known AD biomarkers in individuals most at risk for AD. 150 middle age, African American (n=75) and Caucasian (n=75) women will be enrolled in this observational, two year study. The main objectives are to test whether brain and serum sex hormones (estradiol, estrone, progesterone, testosterone) differentially influence AD risk factors (inflammation, sleep and cerebral blood flow,), and if sex hormone levels moderate the relationship between these risk factors and AD biomarkers (cognition, CSF, neuro-imaging). We will leverage existing NIH funded, well characterized cohorts (n=291; followed by MPIs Wharton & Hu), including middle- age women at high risk for AD (through family history or APOE e4 allele) who already have baseline and longitudinal blood, CSF, and MRI analysis for at least 2 years. We will also test our hypotheses in a unique cohort enriched for African Americans based on our extensive track record in recruiting and analyzing aging and AD biomarkers in a diverse cohort. Participants will complete 3 study visits annually. At each year, we will collect medical and medication history, subjective sleep, cognitive testing and questionnaires (stress, sleep, exercise, nutrition) Participants also undergo blood draw for sex hormone and inflammatory markers. At Baseline and Year 2, participants will undergo the aforementioned protocol, AND take part in: lumbar puncture for spinal fluid collection, neuroimaging and will take home a non-invasive monitor for collection of objective sleep data to wear for 1 night. We have assembled a multidisciplinary team with complementary expertise in sex hormones and aging, AD biomarkers, inflammation, neuroimaging, sleep, and biostatistics. Data inform larger NIH funded studies and, to our knowledge, provide the largest and most comprehensive, biomarker driven, characterization of brain and sex hormone levels in a racially diverse sample of middle-age women.
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