The Mary S. Easton Center for Alzheimer’s Disease Research at UCLA has very active teams working on basic research, drug discovery, biomarkers for early diagnosis and clinical activity including clinical trials, cognitive testing, and patient care. [PDF Version]
2019 Turken Research Award and Symposium
This year’s Turken Research Award and Symposium brought together the UCLA Alzheimer’s research community and celebrated 30 years of continued support from Beth Devermont and the Sam and Ida Turken Charitable Foundation. Alzheimer’s disease (AD) is now recognized as a complex syndrome: Over the course of the disease, multiple contributing genetic and environmental factors interact with vascular and other pathologies (e.g. amyloid and tau proteins) that regulate disease progression and cognitive decline. This year’s event focused on tau protein and diseases caused by tau pathologies, AD-related genes, and how differences in gene expression may affect disease processes.
Before the formal event commenced, Ms. Devermont and guests were able to meet with Dr. Noah Zaitlen, Associate Professor of Neurology and Computational Medicine at UCLA. He presented “Precision Medicine: Using Electronic Medical Records (EMR), Genetic Sources, and Other Information to Understand Disease”. Dr. Zaitlen explained how Alzheimer’s researchers at UCLA could benefit from UCLA Medicine’s massive Precision Medicine initiative that seeks to obtain a genetic workup from blood samples on not only patients in the Neurology Department, but over 100,000 consenting UCLA patients from all sites. While this initiative protects patient’s individual identities, it will allow researchers to understand which genes may act individually or collectively to increase or decrease “polygenic” risk for dementia from different combinations of genetic factors. It will also provide insight into how these factors interact with imaging or blood biomarkers, treatments, lifestyle, sex and ethnicity. Though the symptoms of Alzheimer’s dementia may seem similar across people, the underlying causes may not be exactly the same in all people, and subsequently, there may not be a “one-diagnosis-fits-all” treatment. We can anticipate that the UCLA Precision Medicine initiative will help us to develop new personalized treatments that would be precisely tailored to genetic and other factors causing cognitive decline. Dr. S. Thomas Carmichael, Chair of the UCLA Department of Neurology, recognized the power of Precision Medicine in his opening remarks, citing this as the foundation for an NIH proposal that was submitted to propel research in our Mary S. Easton Center for Alzheimer’s Disease Research at UCLA.
Following Dr. Carmichael, Dr. Mario Mendez, a UCLA/VA behavioral neurologist and international leader on early-onset dementias, discussed the subtypes of early-onset AD. These variants typically do not present with short-term memory difficulties, but instead with visual-spatial, linguistic, or behavioral/problem solving difficulties. They are also distinct from the genetic forms of early-onset AD, of which the latter account for 1% of AD cases and are caused by autosomal dominant genes (APP, PSEN1 and PSEN2). Dr. Mendez’s clinic and research also spans rarer neurodegenerative diseases including some types of frontotemporal dementias (e.g. behavioral variant caused by the gene FTDP-17), degeneration (CBD), and progressive supranuclear palsy (PSP). Similar to AD, these rarer diseases feature symptoms that appear to be caused by tau aggregation. Unlike AD, these related diseases begin with the buildup of tau in different brain circuits than AD, and therefore, give rise to distinct patterns of symptoms, usually with Parkinson-like symptoms and behavioral or language difficulties. Dr. Mendez also specializes in teasing apart the subtle differences between these diseases and traumatic brain injury (TBI), which can look similar. TBI is associated with injured vessels and nerve axons and can serve as an AD risk factor or a cause of the chronic traumatic encephalopathy (CTE) found in athletes and combat veterans.
Dr. Jason Hinman, a UCLA Neurologist and researcher specializing in stroke and vascular causes of cognitive impairment presented new findings from his collaborative work with Drs. Eric Hayden, Lin Jiang and Gal Bitan, and other Easton Center colleagues. For this particular project, the research team focused on the connection between vascular and neurodegenerative disease. Their research showed that stroke-induced loss of blood flow damages axons, the primary transmission lines of the nervous system between neurons. This results in an elevation in an enzyme, Mark4. Mark4 elevation in turn contributes to aggregation of tau, a key contributing factor to cognitive decline. Their work provides a fresh insight into how vascular injury-related axon damage that occurs with aging and hypertension-associated strokes may contribute to tau pathology and disease progression.
This year’s Turken event featured 18 poster presentations, each with its own significant and intriguing new findings. Many of the presentations were by researchers in the Neurogenetics group led by Dr. Dan Geschwind. Yonatan Cooper, an M.D./Ph.D. candidate, presented work selected from one of the posters with Drs. Giovanni Coppola and Geschwind: “Systematic Characterization of Tauopathy-Associated Genetic Variation using Multiplexed Reporter Assays”. There are many genetic variants that associate with risk for various diseases caused by underlying tau pathologies. Often these variants may occur in regions of genes that code for proteins that lead to disease. Genome-wide research has led to the discovery that non-coding genes – genes that do not code for proteins, but instead may contribute to gene and protein regulation – are responsible for complex traits and variations in disease. Yonatan’s novel project employs “Massively Parallel Reporter Assays” as a high throughput approach to hunt for functional effects of the non-coding genetic variation seen in diseases associated with tau pathology. Using this method, these researchers identified 14 previously identified genetic sites associated with late-onset AD, three potentially novel AD risk genes, and five genes associated with PSP, a tauopathy which lacks a known genetic cause and which causes progressive ocular, balance, and behavioral disturbances. This work has potentially important implications with regards to a better understanding of the mechanism of tau diseases and perhaps future potential therapeutic targets.
At lunch, we learned about the progress made by our 2018 Turken Research Award recipient, Dr. Paul Seidler, working with his postdoctoral mentor, Dr. David Eisenberg. Dr. Seidler explained that different tau pathologies including AD, CBD, FTDP-17 and PSP use different binding sites to aggregate and that the initial aggregates or “seeds”, assemble into fibrils or filaments with distinct structures or morphologies, “polymorphs”. Dr. Seidler and colleagues have identified the atomic-level structure and precise binding sites of these different polymorphs and their seeds. Using this information, they have designed specific inhibitors that block further aggregate formation and stop the ability to propagate further seeding and aggregate formation. Initial results with intranasal delivery of the aggregate inhibitors into animal models suggest that this approach can lead to potential new and very specific tau-directed therapeutics.
Dr. Jessica Rexach, M.D., Ph.D., a new Neurology faculty member, and this year’s Turken Research Award winner was introduced by her mentor, Dr. Dan Geschwind, and Dr. Varghese John, who nominated her for the Award. In her talk, “A Functional Genomics Quest for Causal and Regulatory Mechanisms of Dementia,” Dr. Rexach described multiple genetics-based approaches that she is applying to understand the causes of dementia. In particular, she described the use of transcriptomics of single brain cells and neurons to study tauopathies in AD, PSP, and FTD and to compare them to healthy controls. Transcriptomics involves studying the complete set of RNA of nuclei or single cells. To better understand transcriptomics, it is important to remember that DNA, which codes for genes, resides in the nuclei of all cells, and gets transcribed into RNA. RNA then leaves the nucleus and goes on to produce proteins or regulate gene expression. Dr. Rexach’s transcriptomics work and sophisticated algorithm-driven quantitative analysis, allow a vision of how individual brain cell types (astrocytes, microglia, different types of neurons, and other cell types) interact and get altered by different types of tau pathologies in various brain regions. She also described a major new result from collaborative work with UCLA colleagues and other academic centers that resulted in a 2019 Nature Medicine paper. In this paper, a similar “functional genomic” and genome-wide association study analysis was carried out to identify a small regulatory RNA (a microRNA) that appears sufficient to activate a progressive cascade of neuronal dysfunction and reactive proliferation of supportive non-neuronal brain cells (e.g., astrocytes, microglia). This ultimately leads to neuronal cell death in tau pathologies. Dr. Rexach used these examples to explain the power of these cutting-edge methods to generate new approaches towards currently untreatable tau-based diseases. We are truly proud to have Dr. Rexach as a new UCLA Neurology faculty member and the 31st Turken Research Awardee.
The Turken event concluded with remarks from Beth Devermont, representing the Sam and Ida Turken Foundation, and Heather Cooper Ortner, CEO of Alzheimer’s Los Angeles. Overall, this was an outstanding event that illustrated the power of teamwork and discovery from the researchers at the Mary S. Easton Center and associated UCLA research teams, and the outstanding young investigators that the Turken Research Award aims to foster.
We would like to thank the following people for helping us make this year’s Turken Symposium a success:
- Ms. Beth Devermont, President and Director, Sam and Ida Turken Charitable Foundation.
- Dr. S. Thomas Carmichael, Chair, Department of Neurology.
- Dr. Greg Cole, Interim Director, Mary S. Easton Center for Alzheimer’s Disease Research at UCLA.
- Easton Center and Kagan Program staff: Nancy Osuch, Monica Moore, Lauren Garcia, Robert Hernandez, Lorena Macias.
Harnessing ‘Old Technology’ to Study the Alzheimer’s Epidemic
By: Harry V. Vinters, M.D., F.R.C.P.C., F.C.A.P.
Distinguished Professor Emeritus, Depts. Of Pathology & Laboratory Medicine & Neurology, David Geffen School of Medicine at UCLA
An article that recently appeared in a high-profile Pathology journal came to an interesting, somewhat surprising conclusion: during heart surgery or placement of catheters to examine the interior of blood vessels in living patients, small fragments of catheter coating polymers or bits of heart valve materials had drifted into the circulation, causing tissue death in various parts of the body. These sorts of particles are described as “emboli” and the resulting problems as being the result of “iatrogenic embolization”, meaning as an (unintended) consequence of physician intervention. A few of the wayward particles found had lodged in the brain to cause strokes, or in the heart to cause heart attacks. In rare cases, these events were fatal. The findings do not negate the overall positive value of the surgical procedures themselves—they simply highlight some of their risks.
In the modern era, many advances in biomedicine are the result of sophisticated molecular, biochemical and genetic analyses. This study of particles or ‘emboli’ clogging blood vessels, by contrast, utilized one of the oldest techniques in Medicine: careful autopsy examination of deceased individuals who had undergone complex procedures on their hearts or blood vessels, while alive. Indeed, this meticulous study could not have been performed in any other way.
Autopsy—the postmortem examination of organs in the body after a patient dies—is one of the oldest medical procedures in existence. It has been on the decline for several decades, even in first rate academic medical centers, for several reasons: one is the assumption by many doctors that imaging and laboratory data will provide all reasonable information about a patient’s disease, so why bother with an autopsy when an individual passes? In fact, many studies show that the ‘shadows’ seen on high quality CT and MRI scans underestimate the extent, severity or even type of disease eventually found during an autopsy. Even so, requesting an autopsy (and this procedure is only done in academic medical centers with the consent of the family) has, unfortunately, fallen off the radar screens of medical students and clinical trainees.
However, much of what we know about diseases now of epidemic proportions (e.g. Alzheimer disease, AIDS) began with careful autopsy studies of affected patients: in the case of AIDS, at the beginning of the epidemic in the 1980s, with Alzheimer disease many decades ago, in the early 1900s. With AIDS, unique strains of HIV have been isolated from autopsy investigations. In the case of Alzheimer disease, the abnormal proteins that appear to clog up the brain circuitry and lead to its dysfunction, were first found and characterized in postmortem brain specimens. We are in an era when clinical trials are designed to remove these proteins in order to improve a given subject’s memory and thinking. Sadly, many of these trials have failed, but examining the brains of individuals who have been given the drugs are almost certain to provide clues as to why and how they didn’t work.
Examination of autopsy brains has also shown the underlying abnormalities in much less common forms of dementia—e.g. chronic traumatic encephalopathy, where such studies have totally re-focused our thinking about important neurologic disease mechanisms and how to prevent them. Carefully performed autopsies, it turns out, have major public health implications.
So, try this as a (somewhat morbid!) ice breaker at the next cocktail party you attend: “Now Madge, when you die will your family consent to an autopsy? It may well provide important information useful in the care and treatment of living individuals.” To put it differently, there is still much ‘life left in the autopsy’.
Clinical Research Opportunities
If you would like to advance Alzheimer's disease research, please consider being a study participant. Below are the current recruiting trials. For a complete list of enrolling studies, visit our website at www.eastonad.ucla.edu.
EASTON CENTER KAGAN CLINICAL TRIALS PROGRAM
- Alzheimer's Disease Neuroimaging Initiative 3 (ADNI3) Protocol
- NEAT (Nicotinamide as an Early Alzheimer's Disease Treatment) Study
BEHAVIORAL NEUROLOGY PROGRAM
- Curcumin and Yoga Therapy for Those at Risk for Alzheimer's Disease
- Effect of Grapes Dietary Supplement on Brain Metabolism and Cognition
- The UCLA Caregiver Sleep (CARES) Study
For information on other upcoming lectures and events, please visit the Easton Center Community Calendar.
South Bay Dementia Education Consortium Presents:
TURNING POINT | The Quest for a Cure
Date: Rescheduled (TBD)
Where will the future of Alzheimer’s research take us? The South Bay Dementia Education Consortium, in partnership with BrightFocus® Foundation, presents an exclusive screening and panel discussion of the new documentary, Turning Point. Acclaimed filmmaker and director James Keach (Walk the Line, Glen Campbell…I’ll Be Me) follows a team of researchers on the front lines of Alzheimer’s research and captures the perseverance and renewed hope of those working to find a cure for this incurable disease affecting nearly 5.7 million Americans.
For more information: (310) 794-3914
Update on Alzheimer’s Disease Research
Date: Rescheduled (TBD)
Faith and Health Luncheon
Date: Thursday, May 14, 2020
Time: 11:00 A.M. – 1:30 P.M.
Location: Center of Hope
9559 Crenshaw Boulevard
Inglewood, CA 90305
Learn how organizations are working together to inform African American churches about specific diseases and available community resources. Event made possible by Alzheimer’s Los Angeles and Mary S. Easton Center for Alzheimer’s Disease Research at UCLA. [Flyer]
RSVP required (844) 435-7289 by April 14, 2020.
Mary S. Easton Center for Alzheimer's Disease Research at UCLA
710 Westwood Plaza, Room C-224
Los Angeles, CA 90095-1769
| http://www.eastonad.ucla.edu | Phone Number: (310) 794-3665 / Clinic Appointments: (310) 794-1195 |
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