| New Clinical Trial for Those at Risk for AD | Neuropsychology Program |
| Veil of Fog | The Jiang Lab | Reintroducing Dr. Zhefeng Guo | FYN Kinase (Connect) Study |
| New Additions to the Easton Center | Clinical Trials | Upcoming Event |
New Clinical Trial for Those at Risk for Alzheimer's Disease
By: UCLA Department of Neurology, "Partner in Discovery" - Spring 2015 Issue
Kathleen D. Tingus, Ph.D. Director of the Neuropsychology Clinic in the Department of Neurology and Associate Director of Operations of the Mary S. Easton Center for Alzheimer’s Disease Research at UCLA, has been actively involved in clinical services, teaching, and numerous clinical trials investigating Alzheimer’s disease treatments since 1999. “The number of patients with this disease has grown rapidly in recent years. We are hoping to slow the progression of the disease with therapeutic agents,” she explains. “Our goal is to intervene before the onset of significant cognitive losses with early drug intervention.”
Dr. Tingus performs neuropsychological evaluations of patients who present with cognitive complaints, and quantifies the level of cognitive and functional impairment in order to help neurologists refine their differential diagnoses. These evaluations are designed to assess the patient’s cognitive performance in the domains of attention, memory, language, spatial skills, and executive functioning, as well as assess for changes in behavior, mood, and motor functioning. “I am typically seeing these patients at a very vulnerable point in their lives,” Dr. Tingus says. “The testing process can be challenging for patients, as we are tapping into areas of weakness and cognitive decline. It is an honor for me to walk with them through this process and to help provide diagnostic clarification and answers to challenging questions. Sometimes the most difficult phase is not knowing what the patient is facing. We provide clarification and assist families and patients in coping with difficult diagnoses.”
Dr. Tingus is currently involved with the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (the “A4” study), which is testing a new investigational treatment, called an anti-amyloid antibody. The hope is that this can slow memory loss caused by Alzheimer’s disease. Scientists believe that a buildup of amyloid (a protein in the brain that can build up in older people) deposits may play a key role in the eventual development of Alzheimer’s disease- related memory loss. The overall goal of the A4 study is to test whether decreasing amyloid with antibody investigational treatment can help slow this memory loss in some people.
Participants in the study are older individuals (ages 65-85) who have normal thinking and memory function, who may be at risk for memory loss due to Alzheimer’s disease, but have no outward signs of the disease. The study seeks to enroll 1,000 adults who have an elevated level of amyloid plaque in their brains. Positive emission tomography (PET) scans will be used to determine evidence of this plaque buildup in potential participants.
The three-year A4 study is a landmark public- private partnership sponsored by the National Institute on Aging/NIH, Eli Lilly and Company, and several philanthropic organizations. The A4 trial is coordinated by the Alzheimer’s Disease Cooperative Study.
Dr. Tingus also serves as the director of the UCLA Alzheimer’s Disease Research Center (ADRC) Neuropsychology practicum training program and has mentored more than 100 Ph.D. students over the past 18 years.
Dr. Ellen Woo, the Director of Neuropsychology at the Easton Center and Department of Neurology, oversees the wide-ranging research, clinical, and teaching activities of the Neuropsychology Program. The Neuropsychology Program includes neuropsychologists, Drs. Kathleen Tingus and Christopher Nunez; staff research associates, Aurora Rosales, Angie He, Fransia De Leon, and Isabella Hanulik; and numerous research assistants and clinical trainees who volunteer their time to work in the Program each year. We are excited to welcome to the Neuropsychology Program two incoming postdoctoral fellows, Drs. Brandon Roberg and Earl Thorndyke. Dr. Thorndyke was a former graduate student trainee in the Program who returns for his postdoctoral training.
The overarching theme of the research is the identification of the earliest cognitive changes in Mild Cognitive Impairment and dementia. Dr. Woo is an expert on the types of memory and executive difficulties that have real-world relevance and are predictive of changes in everyday functioning. Dr. Nunez is an expert on the multicultural impact of cognitive changes across the lifespan, and he directly supervises the Spanish-speaking research assessments. The Staff Research Associates administer neuropsychological tests to research participants and engage in scholarly activities, co-authoring research presentations and manuscripts.
The clinical activities are focused in the Neuropsychology Clinic, which is directed by Dr. Kathleen Tingus, in the Easton Center & Department of Neurology. Dr. Tingus is an expert on the clinical manifestations of dementia. Psychologists provide neuropsychological assessment services to adults with a broad range of neurological conditions. These assessments provide important diagnostic information that is important for treatment planning and also provides recommendations for physicians, patients and their loved ones.
Photo: (left to right) Isabella Hanulik, Angie He, Aurora Rosales, and Fransia Deleon.The teaching activities include clinical and research mentoring of trainees from the undergraduate to the postdoctoral levels. Trainees at all levels are mentored in the research lab and instructed in hypothesis generation, data collection and analysis, and dissemination of results. Graduate students and postdoctoral fellows are instructed in these skills, along with clinical psychology training. Trainees in the Neuropsychology Program have moved on to exciting careers in the discipline.
The Neuropsychology Program is an integral part of the Easton Center and Department of Neurology and will continue to conduct innovative research, provide important clinical services to the community, and train the next generation of neuropsychologists.
"Veil of Fog"
On June 19, 2015, Ellen Woo, Ph.D., Director of Neuropsychology and Co-Associate Director of the Mary S. Easton Center for Alzheimer’s Disease Research at UCLA, was invited to speak at TAG Gallery for a special event, “Veil of Fog”, which included art, poetry reading, discussion, and a live auction of artist, Elyse Wyman’s work. This special event was co-chaired by the artist and a donor and supporter of the Easton Center, Beth Devermont, president and director of the Sam and Ida Turken Charitable Foundation. The purpose of the “Veil of Fog” evening was to raise awareness and support for the Alzheimer’s Association as part of its annual event, “The Longest Day.”
Ms. Wyman is an accomplished artist and the daughter of a dancer, actress, and artist who had Alzheimer’s disease. While Elyse’s mother grappled with Alzheimer’s, she transcribed her mother’s communications as poetry. For this exhibit, Elyse also produced unfiltered encaustic paintings that were inspired by a direct dialogue with her mother’s “Poems”. “Veil of Fog” is a series of encaustic paintings that provide some insights into her mother’s struggle to communicate her thoughts and feelings to others.
Previous Turken Research Award recipients were also in attendance to support the “Veil of Fog” event. Drs. Gal Bitan, Edmond Teng, and Sophie Sokolow, who are indebted to the Sam And Ida Turken Charitable Foundation for providing support to their research programs, were there. Dr. Harry Vinters from UCLA was also present to support the event.
Ms. Devermont, the daughter of Phyllis Turken Shamberg who began donating money to Alzheimer’s research on behalf of the Sam and Ida Turken Charitable Foundation in the 1980’s, continues her mother’s legacy by providing an annual gift to support early career researchers at UCLA who are interested in studying Alzheimer’s disease.
The Easton Center was delighted to be part of this important evening. We applaud Ms. Devermont and Ms. Wyman on their successful and remarkable philanthropic event.
The Jiang Computational Structural Biology Laboratory
Dr. Lin Jiang joined the UCLA-Easton Center in 2015. He aims to develop a “translational” research program that can bring basic science to clinical applications and explores new routes for therapeutic intervention in Alzheimer's, Parkinson's, Lou Gehrig's disease and other degenerative disorders.
These neurodegenerative diseases all share a common feature, which is the abnormal accumulation of proteins in the brains of patients. These proteins form harmful structures known as amyloid aggregates. Much effort has focused on screening compounds that delay, prevent or disrupt the formation of amyloid aggregates. However, progress has been hampered by a lack of precise knowledge of their structures. An integrated approach, combining computational methods and structural biology, aims to ease this major bottleneck in drug discovery for neurodegenerative diseases. Dr. Jiang’s approach tightly couples computational methods with experimental studies of amyloid structures, and derives high-resolution three dimensional models of amyloid structures from multiple experimental techniques, e.g. Crystallography, Nuclear magnetic resonance (NMR) and Cryo-electron microscopy (EM). These structural models will be used to guide the design of new agents for Alzheimer's and other degenerative diseases.
The Jiang Lab is also interested in the molecular mechanism of propagation and prion-like transmission of amyloid aggregates in neurodegenerative diseases. The team focused on prion diseases, a group of lethal neurodegenerative diseases that affect humans and a large variety of animals. The diseases are primarily caused by the prion, misfolded and aggregated protein that propagates itself by imposing its conformation onto the cellular prion protein of the host. A structure-based computational approach was applied to the transmission of Chronic Wasting Disease (CWD), a prion disease that affects North American elks and deers. The structural model of a key region of prion recapitulated the human resistance to CWD (Kurt et al, Journal of Clinical Investigation 2015). Dr. Jiang has established a complete structural model of prion propagation and transmission, and is validating this model experimentally. If successful, these experiments could lead to the development of new drugs that block prion propagation and transmission.
All of these are some small steps towards identifying new drug targets for preventing amyloid propagation and toxicity in neurodegenerative diseases. The Jiang lab, working in close collaboration with Easton Center research teams, integrates basic biomedical research of amyloid aggregation to elucidate molecular mechanism of how aggregation lead to disease. By doing so, they hope to open new research directions, to explore new therapeutic strategies, and to design new therapeutic compounds or peptides for the treatment of neurodegenerative diseases.
More detailed information for further reading is to be found in the following publications and news reports:
Dr. Zhefeng Guo Receives a Major Promotion
Dr. Zhefeng Guo is a basic research scientist whose laboratory has one goal in mind: to understand the mechanism of Alzheimer's disease at molecular level. Dr. Guo was recently promoted to the rank of Associate Professor with tenure. He joined the faculty of the UCLA Easton Center and Neurology Department in 2008, after earning a PhD degree in Biochemistry and Molecular Biology.
Like Dr. Jiang’s, Dr. Guo's research group is interested in protein aggregation, a process in which individual protein molecules come together and form big clumps. There are two unwanted consequences of this aggregation process. First, the aggregated proteins lose their natural function. Second, the protein clumps are toxic. Both consequences can lead to diseases. In Alzheimer's disease, the aggregated protein is called Amyloid beta (Aβ or Abeta), and the protein clumps are known as plaques. Plaque formation is a pathological hallmark of Alzheimer's disease. Dr. Guo’s group is determined to understand how Aβ comes together to form plaques and what these plaques look like at molecular level in order to solve the mystery of Alzheimer's disease.
Dr. Guo is also interested in the early prediction and prevention of Alzheimer’s disease. To this end, he is developing a theoretical framework that rationalizes what triggers Aβ aggregation and how Aβ aggregation leads to Alzheimer’s disease. According to Dr. Guo, one of the challenges the Alzheimer’s research community faces is the lack of a cohesive theory that can “glue” together various research findings from different investigators. This has caused some confusion about some seemingly conflicting findings. For example, Dr. Guo said, it is found that brain Aβ levels are lower in Alzheimer’s disease patients than in cognitively normal individuals. At the same time, higher Aβ levels are correlated with earlier onset of symptoms in familial forms of Alzheimer’s disease. Dr. Guo is developing a theory based on a phenomenon called “supersaturation”, which can serve as a new theoretical framework to guide future research. Dr. Guo is hopeful that a new strategy of early prediction and prevention of Alzheimer’s disease will emerge from his research. Complementary work in the Jiang and Guo laboratories ensure that the Center explores multiple avenues to understand the key processes that lead to Alzheimer’s disease and maximize the chances to find effective treatments.
Connect - FYN Kinase Study
Photo: Edmond Teng, M.D., Ph.D.
The Katherine and Benjamin Kagan Alzheimer's Disease Treatment Development Program is continuing to participate in multi-center clinical trials that focus on developing new therapeutic interventions for Alzheimer’s disease. One of the exciting new trials that we are currently recruiting subjects for is the Connect study, which is examining the effects of the experimental drug AZD0530 (also known as saracatinib) in patients with mild Alzheimer’s disease. This study is co-sponsored by Yale University and the National Institute on Aging, and is being conducted at 22 research centers across the United States and Canada.
Saracatinib is a drug that reduces the activity of a protein called Fyn kinase, which appears to play a key role in how the accumulation of β-amyloid peptide in the brain (one of the primary features of Alzheimer’s disease) results in damage to neurons and other brain cells. Studies from animal models of Alzheimer’s disease suggest that treatment with this medication results in significant improvement in memory function.
Saracatinib is an oral medication that was originally developed as an anti-cancer drug (since Fyn kinase also appears to be important for the rapid growth seen with cancer cells), so there is already a substantial amount of information regarding side effects of this medication from over 600 human research participants. In the cancer studies, saracatnib appeared to be well tolerated by cancer patients at the doses that will be used in the current study. The goal of the Connect study is to determine whether saracatinib is similarly safe in patients with mild Alzheimer’s disease, and whether it is effective in slowing declines in brain activity, memory and everyday function.
You may be eligible to join the Connect study if you:
Potential study participants will undergo brain imaging with both MRI scans (which provide information about the structure of the brain) and florbetapir PET scans (which provide information about how much amyloid protein is in the brain). Only individuals with elevated brain amyloid levels will be enrolled in the study, and those participants will receive daily doses of either saracatinib or placebo for a 1-year period. They will also undergo periodic memory testing and FDG PET scans (which provide information about brain activity).
We are very excited to be participating in this trial, which focuses on a very different strategy than the other interventions that we are currently studying. If you think you might be interested in volunteering for this study, please contact us at (310) 794-6191 or visit our website: www.eastonad.ucla.edu.
Clinical Research Opportunities
If you would like to advance Alzheimer's disease research, please consider participating at the Easton Center. Below are two current trials. For a complete list of enrolling studies, visit our website at www.eastonad.ucla.edu.