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To achieve these aims mentioned above, HARC of consists 7 research teams. The research findings obtained by these groups will be integrated, and effectively translated into health promotion and health care of seniors. Research Group are as follows:

  Neurodegenerative Disease Research Team



The program project for Neurodegenerative Disease group focuses on two leading ageing diseases, i.e. Parkinson’s disease (PD) and Alzheimer’s disease. Group projects will adopt various testing platforms that have already been established in Chang-Gung Molecular Medicine Research Center or proposed in Gerontology Research Center and will take advantage of precious clinical resources obtained from Chang-Gung Memorial Hospitals for integrative basic-clinic research. Approached by genomics, proteomics, metabolomics, molecular imaging and bioengineering, we expect to identify useful pre-clinical marker(s) or risk factor(s) in PD/AD and transform successively into translational research. The studies will cover series of experiments at molecular, cellular and systemic levels, assisted with cutting-edge biomedical techniques and advanced analytical instruments. The disease models could also bridge with Chinese Herbal ingredient group for interdisciplinary attempts to advance our current knowledge in PD and AD. The PD projects will focus on genetic mutation decoding, characterization of PD models of PINK1 and LRRK2, cell-based therapy on MPTP-induced PD model and metabolomic analyses of PD animals. The AD projects will focus on molecular mechanism ofb-amyloid (Ab) aggregation in GM1 ganglioside matrix, Ab-induced inflammation and signaling, G-CSF therapy and AV-45 imaging on Ab Tg2576 mice. The outlines of individual project are listed in below:

Project 1. Genetic diagnosis and translational research in Parkinson disease (PI: Dr. Chin-Song Lu; co-PIs: Drs. Yah-Huei Chou Wu and Tzu-Chen Yen).

The development and practical application of genetic diagnostic would be essential in post-genomic era, in particular several mutations in domestic PD patients are quite different from western society. Successively decoding the genetic mutations related to PD would facilitate the understanding of gene regulation and protein-protein interaction in disease progress. The main purpose of this project is to establish gene bank from domestic PD patients and correlate with their behavioral and structural phenotypes, assisted by molecular imaging for diagnostic standardization. To this end, we will (1) systemic screen genetic mutation in sporadic PD patients and (2) explore the unknown genetic causes in familial Parkinsonism (FPM) with the analyses of PCR, SSCP, DHPLC, qPCR, MALDI-TOF and direct sequencing. (3) Those genetic findings will correlate with clinical symptoms and brain imaging (99mTc-TRODAT, 123I-IBZM, AV-133, fMRI) database for translational research.

Project 2. An investigation on the pathogenic mechanisms of autosomal recessive PARK6 and dominant PARK8 using mouse animal models (PI: Dr. Hong-Li Wang; co-PIs: Drs. Tu-Hsueh Yeh and Yi-Hsin Weng).

The recent identification of genes linked to familiar form of Parkinson’s disease led to a better understanding of novel proteins and molecular pathways that may cause the neurodegeneration of substantia nigra (SN) dopaminergic cells and resulting PD syndrome. Clinical features of PD patients with LRRK2 or PINK1 mutation are similar to those of sporadic PD patients, suggesting that common cellular and molecular mechanisms are involved in the pathogenesis of both hereditary and sporadic PD. Therefore, elucidation of the pathogenic mechanism underlying PARK6 or PARK8 is expected to shed a light on the molecular pathogenesis of more common sporadic PD. To this end, we will (1) investigate the molecular pathogenesis of PARK6 and physiological functions of PINK1 in vivo using PINK1 knockout mice; (2) investigate cellular and molecular mechanisms of mutant LRRK2-induced neurotoxicity and degeneration of dopaminergic nigrostriatal system in mutant LRRK2 Tg mice; (3) examine, via proteomic approaches, the possible substrates of PINK1 and LRRK2 in mutant striatal tissues.

Project 3. Explore the impact of subventricular zone progenitor/stem cell proliferation and piggyBac-iPS on MPTP-induced PD animal model (PI: Dr. Jin-Chung Chen; co-PIs: Drs. Chiung-Yuan Wu and Mei-Ling Cheng).

In adult brain, subventricular zone (SVZ) contains a mass of stem/progenitor cells (NPCs), under normal physiological condition, they proliferate and migrate to olfactory bulb through rostral migratory stream. Those NPCs receive dopamine innervation from the substantia nigra and heavily expressed dopamine D3 receptors. Recent findings indicated D3 agonists could induce numbers of BrdU+ cells and offer neural protection in the striatum of MPTP-treated animals, suggests a possible link of D3 DA receptors with SVZ neurogenesis. The purpose of this project is to test if cell-based therapy would rescue DA degeneration in MPTP-induced PD animal model. To this end, we will (1) test if D3 agonist treatment would promote SVZ neurogenesis and its therapeutic potential and cellular mechanism; (2) taking advantage of advanced piggyBac-iPS technique, we will use it as alternative source and also induce specific PD patient iPS for toxicity study. (3) Considering the advanced NMR and LC/MS techniques in modern metabolomic analyses, we will monitor the oxidative and metabolic index in striatum of MPTP-induced PD animals and/or biological samples (CSF, blood or urine) from PD patients.

Project 4. Model studies of molecular mechanisms during amyloid aggregation toward molecular therapeutics for Alzheimer’s disease (PI: Dr. Chien Chou; co-PIs: Drs. Yu-Sun Chang, Jau-Song Yu, Yin Yeh [UC Davis] and Atul Parikh [UC Davis]).

The pathological hallmark in AD is the accumulation of extracellular deposits of b-amyloid (Ab) in senile plaques. Soluble Ab is non-toxic and predominantly in a-helical structure, whiles aggregated Ab fibrils enrich in b-sheet conformation, is generally believed to represent one of the earliest steps during AD progress. However, molecular mechanism by which this conversion is effected remains poorly understood. Recent finding suggests a novel form of Ab, tightly bound to GM1 ganglioside, serves as a precursor to seed the Ab fibril formation. We hypothesize that GM1 recognizing soluble Ab is linked to cholesterol enriched, raft-like micro-environment and successful therapeutics require the exogenous presentation of high affinity GM1 in raft-mimetic environment. To this end, we will (1) compare the Ab binding affinity to GM1 in cholesterol and sphingomyelin enriched and depleted bilayer configurations; (2) determine if Ab binding targets GM1 into raft-like micro-environment or conversely alters the composition of “naïve” rafts and (3) explore if exogenous presentation of liposomes (contain high-affinity GM1) can divert Ab away from the primary supported bilayers and thus provide a basis for novel therapeutic development..

Project 5. Cellular mechanism of pro-inflammatory cytokines and ß-amyloid interplay in Alzheimer’s disease (PI: Dr. Chun-Mao Yang; co-PIs: Drs. Mei-Jie Chou and Wen-Chuin Hsu).

Oxidative stress (ROS) can be sensed by the cells and trigger intracellular signaling cascades potentiating chronic inflammation. Interplay between ROS and inflammatory proteins induced by Aß peptide and cytokines leading to neurodegeneration remains largely unknown. Based on our previous studies, these inflammatory proteins may change the BBB function in various brain injuries and neuroinflammation. Therefore, we hypothesize that the Aß peptide and cytokines- initiated neurodegeneration is mediated by the generation of ROS and the induction of inflammatory proteins (MMPs, COX-2 or cPLA2) in brain cells. To test this hypothesis, this proposal will investigate the molecular mechanisms underlying Aß peptide and cytokines regulated expression of MMPs, cPLA2, or COX-2 in astrocytes, including (1) to evaluate whether the expression of inflammatory proteins induced by Aß peptide and cytokines, (2) to characterize the role of ROS in expression of inflammatory proteins induced by Aß peptide and cytokines, (3) to identify the cellular and nuclear signaling pathways by Aß peptide and cytokines and (4) to evaluate the roles of these up-regulated inflammatory proteins on astrocytic or neuronal physiological and pathological functions in vitro and in vivo studies.

Project 6. Evaluation of F18-AV-45 in neural plaques detection in Aß transgenic mice: PET study and G-CSF therapy (PI: Dr. Ho-Ling Liu; co-PIs: Drs. Shiaw-Pyng Wey, Mei-Ping Kung [U. Penn.] and Che-Kun James Shen [Academia Sinica]).

Detection the A senile plaques with F-18-AV-45 radiotracer has been recently setup as a gold standard in AD diagnostics world-wide. Application of this tracer in AD animal research would provide a sensitive indicator to semi-quantify the plaque formation hence could facilitate the drug screening process for selecting the potential therapeutic agents. In addition, imaging of A plaques in AD animal brain would form a valid and sensitive end-up assay in helping the molecular mechanism approaches. The main purpose of this project is to use molecular imaging techniques for AD transgenic study, in order to establish a testable platform for mechanistic and pharmacological examination. To this end, we will (1) apply the animal micro-PET and MRI (7T MRI in Chang-Gung Memorial Hospital Molecular Imaging Center) in Tg2576 or other AD animal models; (2) apply immunohistochemisty and fluorescence technique for Aß plaques detection for correlation with in vivobrain imaging data; (3) use F-18-AV-45 radiotracer for disease progress study in Tg2576 AD mice and (4) evaluate the effect of G-CSF therapy in Tg2576 AD mice, assisted with micro-PET imaging.

Project 7. Application of non-invasive focused ultra-sound for drug and stem delivery in treatment of PD and AD (PI: Hao-Li Liu; co-PIs: Drs. Jiann-Der Lee and Kun-Ju Lin).

Blood-brain barrier (BBB) plays a protective role in the central nervous system to prevent the movement of many substances into the brain, thus limit over 95 % of therapeutic agents entering into brain for potential neurodegenerative disorder treatment. It has been recently discovered that focused ultrasound can locally and reversibly disrupt BBB, which opens new frontier toward delivering large therapeutic agents, such as growth factors NGF, BDNF and/or GDNF for PD and AD treatment. To monitor the BBB opening process from MRI, we have been implemented contrast-enhanced T1-weighted MR imaging for preclinical animal test and show fruitful research achievement and proof the potential and value of focused ultrasound brain drug delivery approach. Hence, the aim of this project is to (1) develop a novel focused-ultrasound treatment platform for AD or PD treatment; (2) deliver therapeutic stem cells or growth factors that cannot normally penetrate through BBB to control neuronal degeneration in PD animal models and (3) via the similar application, deliver Aß antibody or G-CSF to control neuronal degeneration in AD animal models.

  Bio/Functional Markers for Cardiovascular Diseases (CVD) Research Team



Heart failure (HF) is a major and increasingly common cardiovascular syndrome, and is the end result of many cardiovascular disorders. Moreover, the syndrome is one of the most common reasons for new or recurrent hospitalizations among persons over 65 years of age. To fight with this problem, one of the best ways is to identify the high risk group subject to HF by new risk stratification biomarkers far before the happening of diseases. By elucidating the relationship between biomarkers and pathogenesis in HF, the novel strategies that involve suitable medicine and rehabilitation will be developed to prevent early hemodynamic dysfunction and thrombotic events, further retarding the progression of HF.

HF is associated with neurohumoral changes as the body attempts to reverse the effect of reduced cardiac output and organ perfusion. The sympathetic and renin–angiotensin–aldosterone systems are activated in an attempt to increase myocardial contractility, heart rate and vasoconstriction, and expand extracellular fluid volume. Persistent neurohumoral excitation, however, actually results in deterioration of myocardial function with inflammatory response, end-organ damage, and skeletal muscle derangement, which lead to worsened exercise capacity. According to previous investigations, the biomarkers of HF may include various influence factors that involved inflammation, oxidative stress, extracellular matrix remodeling, neurohormones, and mycardiocyte stress/injury. To our knowledge, an integrated strategy for the analytic multimarkers in HF progression has not yet been established. This proposal will integrate the research sources in CGU oxidative stress/damage and metabolomic core laboratories to establish an excellent research platform for analyzing HF multimarkers including oxidative stress profiles, metabolomics, and mycardiocyte stress/injury.

Cardiac dysfunction is generally considered to be a critical influencing factor for the abnormal exercise response observed in HF population. However, clinical investigations have indicated weak correlation between resting ventricular function and exercise tolerance as well as failure of inotropic and vasodilatory agents to improve exercise capacity, implying that cardiac dysfunction is not the only factor contributing to progressive exercise intolerance in patients with HF, impaired pulmonary and skeletal muscle function are also thought to have a role. Recently, abnormal cerebral metabolism has been diagnosed using magnetic resonance spectroscopy in patients with advanced HF, which abnormality is chiefly attributable to cerebral hypo-perfusion. This proposal will be the first to integrate the novel bioreactance-based measurement with near-infrared spectroscopy and automatic gas analysis to identify the roles of ventilatory and cardiac-cerebral-muscle hemodynamic responses to exercise on functional impairments in patients with HF. Additionally, hemorheology, atherothrombosis, and angiogenesis modulated by erythrocyte, monocyte, and endothelial progenitor cells in patients with HF will be also determined in this investigation.

The importance of oxidative stress is increasingly emerging, with respect to a pathophysiological mechanism of the myocardium remodeling responsible for HF progression. However, the molecular mechanisms in HF progression are complex and not fully defined. Therefore, this proposal will focus on the dissection of molecular mechanisms concerning involvement of ROS in HF. Increased understanding of signal transduction mechanisms underlying oxidative stress/inflammation gene regulations will create opportunities for the development of therapeutic strategies beneficial for HF.

In the etiology of HF, coronary artery disease is frequently encountered, associated with severe or end-stage of coronary artery obstruction. In the population of aging, available conduit vessels are often not enough for a complete re-vascularization when bypass surgery is performed. Thus, it is important in the future to bio-engineer an artificial vessel, especially from an autologous source and non-invasively. Vascular progenitor cells contain a few different cell types, at least smooth muscle progenitor cells (SMPCs) and endothelial progenitor cells (EPCs). These progenitor cells have unlimited potentials in both risk stratification and tissue engineering. In this project, we will use updated technologies to find out potential gene targets for separating SMPCs from EPCs. To use these targets to identify SMPCs, development of antibodies appropriate for flow cytometer use is mandatory to positively select SMPCs from other contaminated or mixed cell populations. Finally, combined with the magnet system, we will test whether our work can separate pure SMPCs from other cell populations and specifically head for vascular conduit engineering.

Decreased exercise capacity negatively affects an individual’s ability to adequately perform activities required for normal daily life and, therefore, their independence and quality of life. Physical training can have beneficial effects on neurohumoral, inflammatory, metabolic and central hemodynamic responses, as well as on endothelial, skeletal muscle and cardiovascular function, leading to improvement in functional capacity and quality of life. However, which exercise intensity yields maximal beneficial adaptations is controversial. Aerobic interval training has been shown to rescue impaired cardiomyocyte contractility, attenuate myocardial hypertrophy, and reduce myocardial expression of atrial natriuretic peptide in animal model of post-infarction heart failure. However, underlying mechanisms of the exercise-improved regulations of cardiac hemodynamics and risk factors in patients with HF remain unclear. This proposal will further clarify how various regimens of cardiac rehabilitation affect cardiovascular hemorheological characterics and atherothrombosis/ angiogenesis-related variables in patients with HF.

In light of the above discussion, this proposal will integrate six research programs that include from bio/functional markers to clinical therapeutics in HF. By elucidating the relationship between biomarkers/physiological markers and HF pathogenesis, this proposal attempts to provide some novel strategies for developing suitable medicine/rehabilitation regimens that prevent early hemodyamic dysfunction and thrombotic events, further retarding the progression of HF. The six research programs in this proposal list as follows:

  1. To establish the research platform of multi-biomarkers for analyzing oxidative stress profiles, metabolomics, and mycardiocyte stress/injury in HF progression.
  2. To establish the research platform of systemic physiological markers for evaluating central/peripheral hemorheological characterics and atherothrombosis/ angiogenesis-related variables in HF progression.
  3. To dissect molecular mechanisms concerning involvement of oxidative stress/inflammation inHF progression for creating opportunities for the development of therapeutic strategies beneficial for HF.
  4. To develop the animal models in HF for employing novel developments of tissue engineering and cardiac rehabilitation.
  5. To develop a novel technology of vascular conduit engineering for constructing an artificial vessel from an autologous source and non-invasively.

To design the “safe and effective” cardiac rehabilitation for promoting aerobic fitness and minimizing the hemodynamic limitations and vascular thrombotic events.

  Diabetes and Metabolic Syndrome Research Team



We will continue to validate portfolios of disease biomarkers, pathogenesis, and diagnostic criteria for metabolic syndrome and type 2 diabetes mellitus. work with animal models to illustrate the correlation and interaction of the multiple risk factors which affect metabolism and cardiovascular function during aging process. translate the research results to clinical applications.

  Cognitive & Behavior Indices Research Team



Cognitive and behavioral indices are important indicators of mental and physical health during the aging process. Cognitive decline and related behavioral changes constitute a severe health problem for the elderly. Not only does it seriously impact their quality of, life, but for many of them it leads to dementia. Studies have shown that the differentiation of changes in cognitive function and behavior caused by diseases resulting from normal aging can help the health care professional to make a more accurate assessment and diagnosis. This then allows the health care professional to arrange for appropriate interventions to delay the onset or progress of dementia and decrease the financial burden on society. The main focus of this group project is the “cognitive and behavioral indices of aging”. Cognitive decline associated with a progressive neurological condition (e.g., Alzheimer’s disease), depression, a surgical procedure (e.g. hip fracture) or cognitive improvement as a result of an intervention (music, Tai-Chi, case management, or cognitive training) are common interests for health care providers.

Research Purposes:
The main focus of this group project is to develop cognitive and behavioral indicators that can then be used to determine the mental and physical condition of the elderly and the intervention required. Therefore, the main purpose of this group project is to:
  1. develop cognitive and behavioral indices for the assessment, detection and diagnosis of cognitive decline in elderly patients;
  2. explore the influence of aging and disease/disability on the cognitive and behavioral indices; and
  3. determine the effects of dementia management and cognitive training on changes in cognitive and behavioral indices (Figure 1).
Description of Subprojects:
Subprojects include: 1) develop a measurement for the cognitive and behavioral indices: anintelligent information system for the behavior of the elderly and a cognition analysis andmagnetic resonance imaging biomarker for geriatric depression ; as well as long-term follow-ups for patients with dementia 2) investigate the influence of age and disease/disability on cognitive and behavioral indices: cognitive, behavioral and functional decline for different living arrangements, and cognitive/behavioral indices for the elderly following a hip fracture; and 3) determine the effects of interventions: Tai Chi Chuan, music therapy, patient-centered case management for patients with mild to moderate dementia, and Intelligent co-community system for community dwelling elders (Table 1).
Table 1. Subprojects


Principal investigators Subprojects
I. Develop a measurement for the cognitive and behavioral indices
1. Chyan-Goei Chung
Chung-Chih Lin
The research and development of intelligent information system for elder’s behavior and cognition analysis
2. Ho-Ling Liu
Shwu-Hua Lee
Magnetic resonance imaging biomarker for geriatric depression
3. Chin-Chang Huang Dementia center: A long term follow-up study in patient with senile dementia
II. Investigate the influences of age and disease/disability on cognitive and behavioral indices
4. Tzu-Ting Huang The risk factors and strategies for cognitive, behavioral and functional decline in different living arrangement elderly adults
5. Yea-Ing Lotus Shyu
Chi-Chuan Wu
Huey-Shinn Cheng
Ching-Yen Chen
Yueh-E Lin
Jersey Liang
Long-term trajectory of cognitive/behavior indices for elders following hip fracture
III. Determine the effects of interventions
6. Shih-Lin Wu
Wann-Yun Shieh
Hsien-Tsung Chang
Yung-Cheng Ma
Intelligent co-community system
7. Yu-Cheng Pei
Alice May-Kuen Wong
Application of complementary and alternative Medicine (CAM) for Alzheimer's dementia--Tai Chi Chuan and music therapy?
8. Yi-Chen Chiu
Wen-Chuin Hsu
Jersey Liang
Development of a patient-centered case management model for early to moderate community-dwelling demented patients


Interaction among subprojects and with other group projects
The variables that are explored in each subgroup-project can be categorized and understood by using the framework of the WHO’s International Classification Framework (ICF).
The ICF emphasizes that an individual’s function/structure, activities and participation are inter-related and are influenced by health and illness, as well as personal and environmental factors. Thus, this group project develops the measure of both function and activities (cognitive and behavioral indices), explores the influence of normal aging and diseases/disability (dementia, depression and hip fracture) on the cognitive and behavioral indices, and determines the effects of interventions targeting elders under different conditions and settings (hospital, community and long-term care facilities). The same measures can be used in the different sub-projects to compare the differences among the elderly under different conditions, such as living in the community, following surgery for hip fracture, can be referred for further assessment, diagnosis, follow-ups in dementia center or studies of interventions. In addition, a platform for an intelligent information system for the early detection and management of dementia can be developed. This group project can interact with other group projects (Figure 2). For example, the physical indices project can provide a measure for the physical predictors of the cognitive and behavioral functions, the impact of dementia on society as a whole can be explored with the Population Aging and Socioeconomics Research Team and the mechanism developed by the Neurodegenerative Disease Research Team can provide insight for the dementia intervention sub-projects.



Prior accomplishment and resources
The PIs of our sub-projects are all well-established researchers. Dr. Yea-Ing Lotus Shyu has been collaborating with Dr. Liang from University of Michigan to conduct clinical trials on improving recovery for older patients following hip fracture that funded by National Health Research Institute since 1996 until now. She has also been collaborating with Prof. Stewart from Oregon Health Sciences University and Prof. Archbold from John A. Hartford foundation on studies related to family caregiving and management of behavioral problems for older persons with dementia. Dr. Ho-Ling Liu has been conducting studies on functional MRI and collaborating with Chicago University and NIH. Dr. Yu-Cheng Pei has collaboration with Prof. Rothwell at British Neurology Institute and Prof Ugawa at Tokyo University. Dr. Tzu-Ting Huang’s research focus in on promotion health and functional independence for older persons and has worked with Dr. Acton at the Institute of Gerontology of The University of Texas at Austin. Dr.Yi-Chen Chiu established a cognition recovery lab to study behavior problems of older persons with dementia and has collaborations with Dr. Algase and Dr. Liang from University of Michigan. Research team of Dr. Chyan-Goei Chung and Dr. Chung-Chih Lin has had rich experiences in developing health information system for older persons. They have been conducted projects on health care services for older citizen supported by Ministry of Economic Affairs and established remote monitoring and communication technology to facilitate health care services in Chang Gung Health and Culture Village. Dr. Chin-Chang Huang and Dr. Wen-Chuin Hsu establish and in charge of the Chang Gung Dementia Care Center and have been conducting studies on patients with dementia. Currently, they are conducting imaging study and competing clinical guidance related to patients with AD, DLB, and FTD. Their international research projects include studies on g-secretase inhibitor. They established the first Taiwan ADNI and recently published 2 articles on ApoE4, ApoCI, and Lrrk2. These prior accomplishments have built a good foundation for our future studies.
In addition, the Chang Gung Memorial hospital (Linkou and Taoyuan Branch), the Chang Gung Health and Culture Village and its dementia center can serve as the study sites and provide resources for this group project. In addition, the PIs of our projects have a long-term collaborative relationship with an internationally-known gerontological researcher, Dr. Jersey Liang, from the Institute of Gerontology at the University of Michigan.
Expected outcomes and international collaboration
As a result, in addition to achieve the research purposes of this group research project, collaborations with Dr. Liang for comparing population data on the cognitive and behavioral functions of the elderly in the United States and Japan can be carried out. Collaborations with the dementia research group at University of Edinburgh will be explored and conducted.
Students that participate in any of these group projects will learn how to assess and diagnose cognitive function, and how to intervene with elders that suffer from cognitive decline or from dementia. Graduate students will learn how to analyze longitudinal data, use an intelligent information system, and how to conduct a cross-national comparative analysis. Contents for courses to advance the role of health care workers by teaching them how to assess and take care of elderly patients with cognitive impairment can also be developed.
  Population Aging and Socioeconomics Research Team



Research objectives: we propose to research on

  1. substitution of morbidity and mortality in Taiwan;
  2. the epidemiological study of elderly population in Taiwan;
  3. association of psychosocial factors, subjective health status, self-care behaviors, and health care utilization among elderly with diabetes;
  4. cost-effectiveness evaluation of dementia screening strategies;
  5. health inequality among the elderly through exploiting the health/disability indices developed by the center and assessing the impacts of socioeconomic factors on health inequality and medical expenditures;
  6. designing integrated care models for elderly with multiple chronic diseases, devising portfolio of incomes and assets for old age financial security, and developing innovative business models to promote the productivity of the silver-haired industry.

International collaborations:

With current collaboration with Finnish Cancer Screening Registry Center, our team will adopt valuable experiences from Europe for future policy making in Taiwan. In addition, we also work closely with Prof. Sandra Liu from Purdue University to develop innovative integrated care models for the elderly.

Past research performance:

  1. the etiology of selected diseases based on epidemiological methodology emphasizing on interactive effects of environmental factors and genetic characteristics;
  2. assessment of equity in health care financing, health utilization and health;
  3. the study of etiological mechanism and health care management among DM patients with epidemiological methodology;
  4. the epidemiological studies with community-based screening;
  5. research results have been published in leading journals, such as NEJM, Soc Sci Med, Journal of Health Economics etc.
  Chinese Herbal Medicine Research Team



The diseases about gerontology are becoming an urgent issue following the era of aged society. Among the diseases of gerontology, the diabetes mellitus, neurodegeneration, and cardiovascular illness are mostly concerned. Especially the oldies always have many health problems, hence the drug therapies are complex for these oldies. In fact, there are many limitations for the drug use of the oldies who have got diseases of gerontology. The efficacy of drug therapy is limited and accompanied with adverse reactions, Parkinson’s disease and Alzheimer’s disease for example, as well as is even difficult to target the diseased nidus. The development of new drug or therapy is critical to treat diseases about gerontology. Chinese herbal ingredients may provide an alternative approach for solving such problems. Previous studies have encouraged this strategy. For example, ferulic acid in brans, cerely, and eggplant is approved to treat and prevent Parkinson’s disease. Another example is indirubin from strobilanthes. It can inhibit glycogen synthase kinase-3 beta(GSK-3β) and CDK5/p25 for treating Alzheimer’s disease. There are antioxidant compounds in traditional Chinese herbs which are related to the therapy of neurodegenerative and cardiovascular diseases. Thus Chinese herbal ingredients may be a potential way for the application on diseases ofgerontology. The aim of our study is to develop the lead compound and extract from natural products for preventing or treating diabetes mellitus, neurodegeneration, and cardiovascular diseases. The biomarkers from Group A will be utilized as a target to evaluate the efficacy and safety of these natural products. The final target is to commercialize a new product about gerontology after a series of evaluation, including basic and clinical aspects. The first strategy is to select some ingredients by the clinical experience. Then the crude extracts and pure compounds will be extracted from the plants for in vitro and in vivo evaluations by experimental platforms. The animal study is performed to assess efficacy and possible toxicity of these natural ingredients. We also design and develop the formulations for these ingredients based on the consideration of administration route and drug targeting. The nanoparticle system is an interesting concept to achieve these considerations. The optimized compouds from the herbs will be synthesized for scale-up to assure a sufficient quantity for in vivo and clinical studies. The molecular modeling based on computer assistance is also used to design the chemical structure of the optimized compounds for attaining better performance. Finally, the clinical trial will be carried out to confirm the efficacy and safety of the selected products.

Our previous study has shown that the compounds isolated from Dianthus superbus L. could exhibit cholesterol lowering activity, anti-proliferative effect, and neutrophil superoxide generation inhibition. Among these compounds, DSM-RX78, DSM-RX116, and WHH-34 showed the better pharmacological activities with strong phosphodiesterase inhibition. They may be the candidates for neuroprotective agents. We regard it as the possible medicine candidates to regard these compounds as the first and carry on a series of research and utilize biomarkers of different aging diseases to carry on the assessment via in vitro and in vivo experiments. The formulation of the candidates will be designed for further evaluations, including the physicochemical property of dosage form, the compound release experiments, in vivo pharmacokinetic experiment, the test of toxicity, tolerance test, pharmacologic and stability monitoring. At this time the chemical structures of these candidates are continuously modified and scale up for better performance Finally the compounds or extracts will carry on the clinical trial after validity and security have already been passed and assessed in detail.

The Group E has divided into six sub plan. These six sub plans will cooperate to each other. In addition, we combine the works with other groups and the core facilities, including diabetes, neurodegenerative disease and cardiovascular vessel disease and biomarkers, leading to the benefit for the healthy aging centre and reach top research and mark. The first plan is " Research and development lead compounds of anti-aging agents from natural source” by assistant professor Pei-Wen Hsieh. This project will plan to set up the base group of drug effect (pharmacophore) related to aging disease with the molecular modeling system. Subsequently it makes use of this to search the possible lead compounds from chemical database, utilize the experimental test to evaluate the activity. This plan will offer Chinese herbal medicines, extracts and pure compounds for other plans for further screening. The results from other labs will feedback the experimental results to this plan for decorating the chemical structure. The second sub plan "Research on anti-inflammatory agents from medicinal herbs" for Professor Tsong-Long Hwang will carry on herbal activity test to neurodegenerative diseases and relevant inflammation, utilizing the biomarkers developed by Group A2 to assess activity and toxicity The animal model developed by Group A2 will be utilized in this plan also, for choosing optimized herbal medicines. The third sub plan "The effect of TCM to oxidative stress/damage markers in cardiovascular disease" by Professor Jiang-Zhong Shen probes into Chinese herbal medicine to cardiovascular oxidization and damage. This sub plan will initially choose several candidates from Chinese herbal medicine based on the clinical experience so as to utilize biomarkers developed by Group A3 for assessing cardiovascular disease. The fourth sub plan is performed by Dr. Tzong-Yan Lee. The topic entitled "Herbal medicine on immunological response and oxidative stress pathways in obesity mice with steatohepatitis". This plan will use Chinese herbal medicine for the therapy of fatty liver and diabetes. The molecular mechanism of the activity is also elucidated. The purpose is to set up the fat mouse model. The biomarkers from Group A1 will be set up to indicate the activity. The fifth sub plan "Design and evaluation of delivery carriers for Chinese herbal ingredients in gerontology” is predominated by Professor Jia-You Fang. This plan will develop various dosage forms for herbal medicines, especially the nanoparticles. We will utilize two to four effective components screened from other sub plans to carry on the prescription to design. The imaging system will be used to monitor the drug targeting efficiency of these delivery systems. This approach will offer the next sub plan for clinical trial consideration. The last sub plan "Clinical trials for Chinese herbal ingredients in gerontology" by Professor Hen-Hong Chang utilizes a series of herbal composition optimized from previous sub plans for clinical trial in Clinical Trial Center for Traditional Chinese Medicine, Chang Gung Health and Culture Village, and Nursing Home of Chang Gung Medical Foundation. We will cooperate with Group C for investigation of patient satisfactory level and compliance after Chinese herbal medicine administration. We also cooperate with group D to estimate to the clinical economic efficiency or cost that uses in the Chinese herbal medicine. The goal of Group E is to develop at least one product for anti-aging aim. Another approach is to publish excellent research articles about herbal compounds for diseases of gerontology.

  Intelligent-based Medical Device for the Care of Elderly and Wellbeing



Taiwan will become a 「super-aged society」 approximately around 2026, ageing population will reach 20 percent of total population. As age increases, health and function will decline, such as physical function, endurance and muscle strength, ambulation ability, and balance ability. Problems with aging may interrupt family’s living style, raise the cost of social care, and waste medical resources. Successful aging enables older adults to continue to enjoy healthy life, maintain better quality of life, and decrease burdens of family and society. For healthy elderly, the first concern is how to maintain existing body condition. “Frailty” was a newly defined syndrome in the elderly, which will make older people highly vulnerable to adverse health outcomes. Early identification of the risk for frailty, provision of prevented interventions in time, and avoidance of health deterioration and function decline are important issues. Cardiovascular disease is one of the most common diseases among older people over 65 years old, and cerebral vascular accident (stroke) is the leading causes of death in the elderly. Hence, how to identify possible physical and physiological index, provide stroke treatment, decrease impairment, suspend disability, and establish the predicting factors of therapeutic effects to maximize the therapeutic effects are also essential issues.

This project expects to translate the basic sciences of physiology and biomedical engineering into aging index exploration and clinical evaluation/intervention.This subproject has three major aims.
The first aim focuses mainly on healthy aging. The purpose is to establish eSMetSHPP (electronic Self Metabolic Syndrome Health Promotion Platform) to decrease the occurrence of chronic diseases, and to developbody motor and balance sensor networks (includes balance function, pulmonary function,activity behavior and physiological function assessment). Furthermore, we will develop wearable healthy aging evaluation system to be used as a verification tool for clinical research. Finally, we will investigate the efficacy of neck exercises training on balance function of middle-aged and old-aged people. The subprojects include: 「A1C Health Exam Application Study and e-Self Metabolic Syndrome Health Promotion Platform Development」、「Development of Wearable Body Sensor Network (WBSNs) in Healthy Aging Assessment for Elderly」、「Effects of neck fitness muscle training on balance function in healthy aging」
The second aim focuses mainly on frail aging. The purpose is to build physiological models for kinetic, kinematic, and metabolic mechanism during specific motor missions and develop a wearable assessment device. Further purpose is to identify risk factors for aging and frailty, and provide rehabilitative exercises and activities to frail and healthy elderly. The subprojects include: 「Kinetic, kinematic and metabolic analysis and wearable device for physical activity and rehabilitation」、「Identification and exercise intervention for the frailty syndrome of the older adults」、「Activity redesign and ageing prevention」
The third aim focuses mainly on ill aging. The purpose is to explore the physical, perceptual, and physiological indexes for stroke patients, establish an integrated assessment technology including electroencephalogram, electromyography, motion, and metabolism, and investigate the therapeutic effects of different interventions on stroke survivors and establish the predicting factors of therapeutic effects. The subprojects include: 「Physical index and robot-assisted arm training for stroke patients: Integration of advanced technology and neurorehabilitation」、「Physical index for stroke patients with perceptual deficits and task-oriented programs for motor and perceptual deficits in stroke patients」、「The therapeutic effects of modified repetitive transcranial magnetic stimulation (rTMS), theta burst stimulation, for patients with cerebral vascular accident」
Preliminary Results
For the first aim, the preliminary results included developed prototype system of e-health lifestyle system for metabolic syndrome (MetS), and established prototype system of balance and postural stability assessment. The neck fitness and balance function in middle-aged and old-aged people with non-specific cervical spine degeneration was significantly worse than young people. For the second aim, we’ve already had kinetic, kinematic, and metabolic instruments. Future research will integrate the instruments as wearable devices. Initial step for assessing the frailty syndrome and related physiological/physical reactions of older adults was conducted. Activity redesign was developed preliminarily. For the third aim, the preliminary results of robot-assisted exercise showed that combined therapy with high intensity showed better effects than combined therapy with low intensity. Task-oriented training indicated the superiority of combined therapy to a single therapy in reducing trunk compensation, improving upper extremity control, enlarging the range of the eye saccade movement, reducing the syndrome of neglect and promoting the function of daily living. For rTMS, we’ve applied new models that could account for the mechanisms affecting neuroplasticity.
Methods and Research Design
This is a 5-year project, the research methods and design for each aim are as follows.
Aim one (healthy aging): The first part is to enhance the applicability of the MetS prototype system, and develop the wireless body sensor networks (WBSNs) with multi-function in tele-home care applications. Part two is to conduct wearable healthy aging assessment research (including balance function, pulmonary function,activity behavior and physiological function assessment) and clinical trials, and test and promote the health exam center. Neck fitness muscle training study will include two groups of therapy (neck exercise training and control intervention). Neck exercise training group will receive neck exercise combined with aerobic exercise training by 3 days per week and 1 hour per day, a total of 18 days. The evaluation will be performed prior to and after the training. 
Aim two (frail aging): The first part will recruit healthy subjects for exercise training so that the physical activity-related multimodal analysis upon kinetic, kinematic, and metabolic data can be performed to build physiological models and indexes, and lend an infrastructure for the development of wearable devices. Furthermore, longitudinal cohort follow-up study will be performed to investigate the differences among 3 groups of frailty (non-, pre-, and frail), and to look at the effects of exercises combined with health and nutrition education on physiological indexes and patient-reported acceptance for such a program. Finally, we will establish the sound exercise criterion and activity prescriptions based on integrated evaluation platform evaluating stand and reach flexibility test, grip test, balance test, reaction test, strength and endurance test, and mobility test. We then experimentally investigate the effect of activity redesign program in the healthy, frailty tendency, and frailty aged, and the evaluations will be performed before, immediately after, 1 year after activity redesign program.
Aim three (ill aging):The first part is to search for the appropriate motor and physiological indexes for stroke and neglect patients by means of integrating electroencephalogram, electromyography, motion, and metabolism into an integrated technological tool. The second part will employ the robot-assisted exercise (higher intensity robot-assisted training, lower intensity robot-assisted training, and regular rehabilitative intervention) and task-oriented training (constraint-induced therapy with eye-patching, constraint-induced therapy, and traditional intervention) for stroke patients. Both robot-assisted exercise and task-oriented training are randomized controlled trials with pretest and posttest assessments. Each patient will receive interventions 1.5 hours per day, 5 days a week in 4 consecutive weeks. For the therapeutic effects of rTMS, we design pilot trials in the first two years to characterize the therapeutic effects and physiological mechanisms underlying several novel stimulation techniques. For the rest of the years, we will choose the experimental design and stimulation model according to results obtained in the first two years and perform a long-term experiment with a large sample size.
Expected Results or Findings
The expected results or findings for each aims are as follows.
Aim one: 1. To support the use of A1C (glycated hemoglobin) test as a screening tool for cardiovascular disease and diabetes. 2. To develop the WBSNs system and four assessment platforms for healthy aging (includes balance function, pulmonary function,activity behavior and physiological function assessment). 3. To employ neck exercise training for enhancing neck fitness, directly decreasing the index of neck pain, and indirectly improving balance function.
Aim two: 1. To establish simple, scientific index for screening elderly frailty, and to provide physiological indexes for motor functions based on kinetic, kinematic and metabolic data and to integrate related technologies to develop wearable assessment device. 2. To understand & compare changes in functional tests and biomarkers among the frail, pre-frail, non-frail groups using longitudinal follow-up experimental design. 3. To reverse the frailty tendency aged into healthy elderly and reduce function decline of frailty elderly through muscle strength training or health and nutrition education programs. To find the (or a battery of ) physical function tests or biomarkers that could possibly be the screening indexes for the elderly frailty syndrome.
Aim three: 1. To obtain the individual motor and physiological indexes in stroke patients with and without neglect and integrate the indexes of electroencephalogram, electromyography, motion, and metabolism. 2. To comprehensively provide robot-assisted therapy for stroke patients and confirm the relationship between the effect and dose. 3. To improve the neglect syndrome and trunk compensation by combining trunk restraint with eye-patching techniques and underscore the underlying mechanism and predictive factors and employ repetitive Transcranial Magnetic Stimulation (rTMS) to improve motor function of stroke patients.

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