Aging & Neurocognitive

The RMATRIX Aging and Neurocognitive Health leverages the considerable strengths of the Department of Geriatric Medicine and the Hawaii Center for AIDS (HiCFA) to address clinical and translational research priorities in neurosciences and aging.

The Department of Geriatric Medicine’s international collaborative research studies are well established and respected, tailored to the uniqueness of Hawaii in location and population diversity. Some its largest epidemiological studies include:

• The Honolulu Heart Program, a long-term study of cardiovascular disease in a cohort of Japanese-American males, which is currently the nation’s largest health follow-up study of a minority group.

• The Honolulu-Asia Aging Study, established in 1991 to study diseases associated with aging, including Alzheimer’s disease, vascular dementia, and Parkinson’s disease.

• The Women’s Health Initiative, a headline-making clinical trial and observational study to address the effects of hormone replacement therapy and other factors on the overall health of post-menopausal women.

• The Hawaii Lifespan Study, which uses innovative approaches for secondary data analyses and novel genetic analyses that focus on functional characteristics of healthy aging, and has allowed for a better characterization of the phenotype of longevity.

• The Genetic Basis for Exceptional Longevity Study has enrolled centurions of Okinawan descent for basic phenotyping and genotyping to better understand gene variants liked to the exceptional longevity phenotype through whole genome analysis.

The strengths of the Hawaii Center for AIDS (HiCFA) include its considerable expertise in the conduct of phase I to IV clinical trials including clinical trials in dementia and neuropathy, and in the Center’s understanding of how to effectively combine clinical and laboratory resources to conduct translational research. In addition, expertise in various specialized tools important for neuroscience research exist within HiCFA and this will be leveraged to meet the goals of the RMATRIX. Similar to the expertise existing in the Department of Geriatric Medicine, HiCFA has familiarity with and has published data that involved neuropsychological testing and consensus panel determination of cognitive status. Standardized neuropathy clinical assessment algorithms patterned after the ACTG neuropathy evaluations are in place and have been used for our published studies of neuropathy. Skin punch biopsy and immunohistologic quantification of distal leg epidermal nerve fiber density (ENFD) obtained from such specimens is a technique now validated in studies of neuropathy. HiCFA has participated in research utilizing this technique and has a R01 study on neuropathy in which this ENFD technique plays a prominent role. HiCFA has been particularly interested in the role of cerebrovascular disease as a co-morbid condition contributing to dementia in HIV-infected individuals as this population ages. Therefore HiCFA has had an interest in novel tools for the assessment of cardiovascular risk and atherosclerosis as well as of advanced neuroimaging modalities to assess changes in brain, all of which can be leveraged for RMATRIX research in neuroscience and aging research for example in the context of vascular dementia or Alzheimer’s Disease. Standard operating procedures for fasting metabolic labs as well as for the conduct of oral glucose tolerance testing are in place. A Lunar DXA machine exists on the HiCFA clinic premises for the determination of alterations in body composition, a recognized risk factor for vascular disease, as part of a recently funded R01 grant looking at cardiovascular risk in the HIV-infected population (PI: C Shikuma). HiCFA now has an established algorithm for and connection to credible national central reading centers for the conduct of 3 recognized assessment tools for subclinical atherosclerosis [FMD and cIMT assessments by ultrasound and coronary artery calcium (CAC) assessment by computerized tomography]. Autonomic testing including microneurography techniques are in place. Also, in the field of NeuroAIDS, HiCFA has devoted considerable energy into developing expertise in various MRI neuroimaging techniques.

The combination of expertise, tools and resources from the Department of Geriatric Medicine and HiCFA can be leveraged within the RMATRIX to conduct research studies focused on neurosciences and aging.

Emerging Investigators and Pilot Projects

Beau Nakamoto (PI) Neuroimaging Correlates of Monocyte/Macrophage Infiltration in HIV-infected Individuals: A Cross-sectional Pilot Study Using IV Furomoxytol

Thomas Wills (PI); J. Keawe’aimoku Kaholokula (Co-PI) Discrimination and Substance Abuse Among Adolescents in Hawaii

Cancer

In partnership with the University of Hawaii Cancer Center (UHCC), RMATRIX is committed to expanding clinical and translational research aimed at reducing the burden of cancer in Hawaii. The ethnic composition of the state of Hawaii leads to a different cancer pattern than seen for the general US population. The rates for several cancer sites are higher in the state than in the general US, such as stomach and liver cancer, while others are lower, such as Non-Hodgkin Lymphoma. Thyroid cancer rates are notable in that Filipinos have twice the risk of other ethnic groups, and this pattern has held for the 30-year period.

UHCC investigators have assembled a number of unique resources to facilitate their research in Hawaii’s population. Chief among them is the Multiethnic Cohort (MEC) study, a large prospective study of 215,000 Hawaii and Los Angeles residents (in collaboration with colleagues at the University of Southern California) who have provided repeat questionnaire information on lifestyle, medical history and family history and are followed for cancer occurrence and cause-specific mortality. A large biorepository was also assembled by collecting blood and urine specimens from 38,000 Japanese American, Native Hawaiian and white MEC members in Hawaii and 35,000 African American and Latino MEC members in Los Angeles. Two cohorts of ~2,000 female and ~700 male young adults were also assembled by collecting repeat data and specimens, every 2-4 months over several years, to study the acquisition and persistence of anogenital HPV infection. The Hawaii site of the NCI-supported Colorectal Cancer Family Registry also contributes important data and samples for colorectal cancer research. A large population-based Residual Tissue Repository was also established within the Hawaii Tumor Registry to provide an unbiased sampling frame for investigating molecular subtypes and prognostic signatures that may be used for etiologic studies and therapeutic decision, respectively.

UHCC members have developed a number of core resources which are unique in Hawaii: the Nutrition Support Shared Resource (SR) which has developed diet assessment instruments adapted to the local diets and maintains a large food composition database; the Genomics SR which supports genome-wide investigations of genetic variation, gene expression, epigenetic patterns and copy number alterations; and the Analytical Laboratory SR which provides measurements of plasma micronutrients, metabolites and hormones using state-of-the-art HPLC LC/MS and GC/MS methodology, and is developing metabolomic assays. Finally, the Biostatistics and Bioinformatics SR provide the support required to manage, analyze and interpret the large, data-intensive studies conducted by UHCC members.

RMATRIX effectively augments the infrastructure of the UHCC by providing capacity to conduct clinical research, such as exam rooms, imaging, research nurses, and sample collection support, an expanded outreach network to help cancer clinical trials accrual, as well as funding support for pilot studies to develop preliminary data for NIH grant applications. RMATRIX provides a needed structured mechanism for facilitating similar clinically relevant collaborations between physicians and cancer researchers, and creates additional links among community partners. Finally, RMATRIX helps in leveraging existing projects in its other HEALTH Initiatives, which complement established research themes at the UHCC (e.g., on nutrition and cancer and lung cancer) and utilize known ethnic/racial differences in cancer rates and risk factors in Hawaii’s multiethnic population to generate new knowledge about cancer etiology, treatment and prevention.

Emerging Investigators and Pilot Projects

Shane Morita (PI) Thyroid Cancer and Ethnic Disparity in Hawaii: Profiling the MAPK and MTOR Signaling Pathways

Thomas Wills (PI); J. Keawe’aimoku Kaholokula (Co-PI) Discrimination and Substance Abuse Among Adolescents in Hawaii

Cardiovascular

Mortality rates for cardiovascular disease in Native Hawaiians and Filipinos are the highest in Hawaii and among the highest nationally, with Native Hawaiians having the highest coronary heart disease and Filipinos having the highest stroke mortality rates. Recognizing differences in diagnosis, management and health outcomes in Hawaii’s population, UH has been at the forefront of research aimed at addressing cardiovascular-related health disparities. In the Cardiovascular HEALTH Initiative, RMATRIX works to complement, augment and support existing programs and centers of excellence engaged in cardiovascular-related health disparities research in Hawaii. Programs include:

• The UH Center for Native and Pacific Health Disparities Research (CNPHDR). A multidisciplinary, university-wide program, the CNPHDR is housed within the JABSOM Department of Native Hawaiian Health and is focused on research to address cardiometabolic health disparities, including heart disease, diabetes, obesity and metabolic syndrome. The CNPHDR has considerable experience in community-based participatory research (CBPR), training, and education, including a CBPR training program for community investigators. The heart of the CNPHDR is the Outreach and Information Dissemination Core and its Ulu Network, a coalition of community groups that includes 22 organizations and over 50 sites throughout the state that links the Center and its partners with the community.

• The NHLBI-funded, Heart Failure Disparities Among Native Hawaiians, a partnership grant between the UH-JABSOM Department of Native Hawaiian Health and The Queen’s Medical Center. The program includes four studies: a randomized trial of the impact of culturally appropriate education on heart failure readmissions, an evaluation of racial differences in the etiology of heart failure, the feasibility of training community health workers to use hand-carried ultrasound to screen for heart failure, and the development of pedigrees of families with heritable cardiomyopathy. This partnership required close collaborations with four community health centers – the Waianae Coast Comprehensive Health Center, Kokua Kalihi Valley, Kalihi Palama Health Center and the Waimanalo Health Center – and had led to planned studies with the COBRE Center for Cardiovascular Research and the UH Magnetic Resonance Research Program.

• The UH COBRE Center for Cardiovascular Research (CCR) is a focal point for cardiovascular research in Hawaii. The laboratory of Dr. Ralph Shohet (CCR PI) has focused on the role of endothelin (ET-1) signaling and cardiac myocyte survival, an evaluation of hypoxia inducible factor (HIF-1) expression and its ability to ameliorate tissue due following myocardial infarction, the endothelial response to cardiovascular stress, and the development of ultrasound-targeted microbubble delivery of biologically active molecules. RMATRIX emerging scientists, in collaboration with the UH’s COBRE Center for Cardiovascular Research are currently investigating the phenomenon of heart failure associated with crystal methamphetamine use, which appears to affect Native Hawaiians at a much younger age than their Caucasian counterparts.

Emerging Investigators and Pilot Projects

Nisha Parikh (PI) Metabolite Profile As A Postpartum Predictor Of Endothelial Dysfunction Following Preeclampsia

Suwit Jack Somponpun (PI) Morphogenetic Mechanism of Embryonic six2 in Establishing Nephron Endowment

Alexander Stokes (PI) Protection from Cardiac Hypertrophy via Pharmacological Inhibition of the Ion Channel TRPV1

Angel Yanagihara (PI) Identification and Characterization of Cryptic Fleming Bay Marine Stingers

Nutrition & Metabolic

The Center for Native and Pacific Health Disparities Research houses several NIH-funded research projects related to nutrition and metabolic health. In regards to obesity and obesity-related health disparities, the PILI ’Ohana Project: Partnerships to Overcome Obesity in Hawaii (R24MD001660) are testing an 18-month weight loss maintenance lifestyle intervention (PILI Lifestyle Program) and a 3-month diabetes self-management program (Partners in Care) via Randomized Controlled Trials (RCTs). Both interventions are community-engaged and community-located.

In addition, a telemedicine study, entitled Pulama Pau’ole I Ka Mimiko, is a non-randomized clinical trial testing the effectiveness of telemedicine technology in improving HbA1c among diabetics living in two rural communities (P20 MD 000173-07S).

The Comparative Effectiveness Research (CER) program to Eliminate Cardiometabolic Disparities (ECD) is another independently funded study (P20 MD 000173-08S) within the Center that has 4 major activities. 1) Conduct a RCT on the effectiveness of financial incentives and education on patient-provider relationships to improve HbA1c in Medicaid patients with diabetes. 2) Develop and establish a database registry to encourage future CER studies in the Center’s priority populations. 3) Implement education and training programs on CER and cost analysis. 4) Translate the Malama Pu’uwai Program for reducing heart failure hospitalizations in Native Hawaiians and Other Pacific island Peoples (NHOPI) to our target communities.

The Hawaii Youth Metabolic Study (HYMS) is a 5-year project, based in 2 communities in Hawaii, to examine the development of metabolic syndrome in Native Hawaiian and Samoan Adolescents. Metabolic syndrome (MetS) is a well recognized, but poorly understood condition involving lipid, glucose and hormonal abnormalities and is associated with increased risk for cardiovascular disease. The project is supported by the NIH NCMHHD Grant No:P20MD000173 and Research Centers in Minority Institutions award, P20 RR11.

The Westside Wellness Alliance for Youth (Westside Project) is a 3-year project to implement and evaluate processes to support the prevention and management of childhood obesity at two healthcare centers serving a low-income, rural community in Hawaii. The study is funded by Kaiser Permanente (20611160) and supported by Research Centers in Minority Institutions award, P20 RR11.

Emerging Investigators and Pilot Projects

J. Keawe’aimoku Kaholokula (PI) PILI ’Aina Project: Partnerships to Overcome Obesity Disparities in Hawaii

Johann Urschitz (PI); Janet Burlingame (Co-PI) Correlation of genetic risk factors with gestational diabetes and preeclampsia in women from Hawaii

Perinatal, Growth & Development

Lynnae Sauvage (Chair of Obstetrics and Gynecology in the John A. Burns School of Medicine and Dr. Charles Neal, a neonatologist and Medical Director of the NICU and who also directs the Cleft and Craniofacial Center at the Kapiolani Medical Center for Women and Children, are co-leaders of the RMATRIX Perinatal Health and Developmental Growth health initiative. Primary research opportunities are being created through the ongoing biospecimen repository being maintained by Dr. Sauvage and the data repository on cleft and cranial facial children by Dr. Neal.

The biospecimen repository, established at Kapiolani four years ago as part of a Clinical Center for Research Excellent grant to the University of Hawaii, has more than 7,500 obstetrical and fetal samples that have been collected and paired with clinical data. From these samples DNA has also been extracted and is available for study. Data from these samples are actively being used for research projects focusing on various aspects of growth and development in the fetus. The plan is to expand the biospecimen repository to service other core disciplines so they can bank tissues needed for their research, she said.

There is abundant research opportunity pending with respect to improving outcomes of critically ill newborns and in measuring cleft and craniofacial outcomes and quality of life of babies born with facial clefts. In the NICU at Kapiolani, two multicenter clinical trials are under review by the NIH. Kapiolani will be a major site for each. One is a study on caffeine use in preterm infants for apnea and effects on neurodevelopment outcomes. The other is a multicenter study to determine the associate of the NICU Network Neurobehavioral Scale (NNNS) in preterm infants <30 weeks gestation and long-term neurodevelopmental outcomes. Ongoing clinical studies within the NICU include study of Heliox use in nasal CPAP and comparison of IV fluids for arterial lines in critically ill newborns. Finally, ongoing quality improvement studies on line infections, necrotizing enterocolitis and retinopathy of prematurity provide several opportunities for research.

Fixing a cleft surgically is a small component of a child’s recovery from such a disorder. Much more work is needed to help these children with larger issues of speech, language and hearing, helping them fit in and feel better about themselves. About one in 750 infants or 13.3 per 10,000 live births is born each year in the U.S. with a cleft lip or palate. In Hawaii the rate is higher, between 17 and 19 of every 10,000 births. The incidence is higher in the Asian population in general and in Native Hawaiians. We have developed a multidisciplinary clinic at Kapiolani Medical Center for Women and Children and they have created a database to monitor treatment outcomes. Ongoing studies include database inquiries to study patient population demographics and outcomes. In addition, there are many opportunities for studies of patient satisfaction and analysis of infant, child and adolescent quality of life. Ongoing quality of life studies are taking full advantage of our database.

One research opportunity would be to expand the cleft database by collecting biospecimen samples from patients for epidemiology investigations, an example of the cleft center interfacing its database with that of the biospecimen repository.

Researchers are presently looking at some disorders that disproportionately affect the Hawaiian population, including adult and pediatric substance abuse, cardiac disease, diabetes and facial clefting. Diabetes highly prevalent in Native Hawaiian and Pacific Isle populations and we have a high rate of cardiac disease in pregnant women. There definitely are health disparities. The biospecimen repository at JABSOM and the Oregon Health Sciences University are collaborating on a project this summer to determine if certain genetic markers in the Japanese population may be predictive for preterm births. Another study planned is looking at fish intake in pregnant women and studying how mercury and selenium in fish affect child development.

Going forward, we are looking for new projects working with someone in the community. The goal is to expand and continue to answer important scientific questions in our community population as well.

Emerging Investigators and Pilot Projects

Johann Urschitz (PI); Janet Burlingame (Co-PI) Correlation of genetic risk factors with gestational diabetes and preeclampsia in women from Hawaii

Charles Neal (Co-PI) Effect of Corticosteroids on Pulmonary Surfactant of Premature Newborns

Respiratory

In the Respiratory HEALTH Initiative, RMATRIX works to complement, augment and support existing studies on respiratory health disparities unique to Hawaii’s ethnically diverse population. Recognizing that Hawaii has the highest asthma mortality rate in the United States, Respiratory HEALTH Initiative Leader, Dr. Elizabeth Tam, has focused her research on asthma exacerbation and environmental triggers, examining the effects of vog, tobacco, allergens, as well as gene-environment interactions. Examples of Dr. Tam’s research includes The Hawaii Island Children’s Lung Assessment Scientific Study (HICLASS) and The Impact of Vog on Respiratory Health, where the ongoing eruption of Kilauea Volcano on the island of Hawaii has raised significant community concerns about exposure to vog and the effects on health. Dr. Tam has partnered with the Department of Education, Hawaii Island Rural Health Association, the Ka’u Rural Health Community Association, and local health providers to conduct community and school-based studies to assess the effects of vog on Hawaii Island residents. These vog studies embrace a community-based participatory research approach, involving community members as co-equal partners who have an active role in planning and conducting the research. The study also involves members from within the community who have been trained to collect and analyze data, thereby building research capacity on Hawaii Island. In addition, Dr. Tam’s UH laboratory has examined the basic mechanisms in asthma as a focus of the Immunogenetic Diseases – Allergic Inflammation to Airway Remodeling in Asthma study.

Additional studies have been proposed to expand these cohorts in order to fully characterize susceptibilities to vog and other environmental pollutants, as well as to examine in utero determinants of asthma or tobacco addiction.

Vog eruptions have been associated with respiratory complaints
in Hawai’i and are one area of active study by RMATRIX investigators.

Researchers collect vog samples.

Emerging Investigators and Pilot Projects

Yi Zuo (PI) Effect of Corticosteroids on Pulmonary Surfactant of Premature Newborns