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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. This edition of our newsletter focuses on our clinical programs. [PDF Version]
”An Interview with Dr. Sarah Kremen About Dementia with Lewy Bodies”
Alzheimer’s Disease (AD) is the most common form of dementia currently affecting an estimated 4.5 million Americans, yet Alzheimer’s disease is not the only cause of dementia. This article will be the first in a 3-part series discussing the other forms of dementia. In this interview, Dr. Sarah Kremen discusses Dementia with Lewy Bodies (DLB second most common form of dementia currently affecting 1.4 million Americans.)
1. What is DLB? How does a neurologist diagnose someone with DLB? Can you please explain the symptoms of DLB?
Fluctuations in levels of alertness refers to waxing and waning levels of attention or cognitive sharpness, that may vary from day to day or throughout the day. It can present as staring or “zoning out” for long periods during the day, episodes of disorganized thoughts or speech, periods of daytime drowsiness, or lethargy.
Up to 80% of patients with DLB experience recurrent visual hallucinations that are well formed images, usually of small people or animals. Patients do not find these images threatening, they are just there. Sometimes a patient will understand that these images are not real, and sometimes they do not.
In DLB, spontaneous parkinsonism will develop in about 85% of patients, though it does not have to be the first feature a patient develops. Parkinsonism means that people have slowed movements, more difficulty initiating movements, postural imbalance, development of a shuffling gait, and sometimes tremor. These features are similar to the parkinsonism seen in patients with Parkinson’s disease (PD). Spontaneous parkinsonism means these changes in motor function are not due to another reason, such as stroke or medications. It can be difficult sometimes to distinguish between DLB and PD but timing of cognitive and motor features are important. In contrast to PD, parkinsonism in DLB occurs at the same time or after the cognitive changes; it does not occur before cognitive changes.
The last core feature of DLB is REM sleep disorder where people will act out their dreams while they are asleep. We often ask partners of patients if they have had to move to a separate bed or room because they are getting beat up while the patient acts out dreams or moves their limbs violently. REM sleep behavior disorder may appear many years before any other core features of DLB appear.
2. Do patients with DLB have trouble with their memory or thinking?
In addition to cognitive changes, patients with DLB sometimes experience delusional thinking, where they may believe someone is stealing from them, or that their lifelong partner has been replaced by someone else. Agitation can occur too.
3. What parts of the brain are affected by DLB?
4. Are MRIs or PET scans used to help with diagnosis?
5. How does DLB affect a person’s activities of daily living?
6. What is the prognosis for someone with DLB?
7. What are some of the biggest challenges caregivers face when caring for someone with DLB?
8. What are the current treatments for DLB?
We may treat a patient with additional medications if other symptoms are negatively impacting their life For example, we may treat REM sleep behavior disorder with various medications if patients are falling out of bed and injuring themselves. We may use medications used in PD to treat tremor and parkinsonism. If a patient is experiencing delusions or visual hallucinations that are so severe that they are interfering with their own safety, or the safety of their loved ones, we might consider using antipsychotic medications, but we have to be careful, as DLB patients are very sensitive to these medications.
If you or a loved one is experiencing any of the symptoms of DLB and have yet to be diagnosed, please call the Easton Center, Memory Disorders Clinic to schedule an appointment with one of our neurologists at (310) 794-6039 or visit www.eastonad.ucla.edu for more information on DLB and the other forms of dementia.
After beginning operations in early 2015 as part of the Mary S. Easton Center for Alzheimer's Disease (AD) Research at UCLA Neurology, the Drug Discovery Lab (DDL) led by Dr. Varghese John, has made significant progress towards development of new treatments for AD. The lab, in collaboration with a corporate partner, plans to file its first Investigational New Drug (IND) application by early 2018 for a new agent that increases production of a protein fragment that is neurotrophic and important for cognitive function – sAPPα. It is decreased in AD, especially in patients carrying the major risk factor apolipoprotein E4 (ApoE4). Our goal, says Dr. John, is to test this New Chemical Entity (NCE) in clinical trials to provide proof-of-concept in patients for restoring sAPPα, as a therapeutic approach in AD. Testing of this agent would be performed, in part, by the Easton Center AD Clinical Trials Program.
The DDL has two additional advanced lead series for AD that target different disease mechanisms. One lead series known as ‘APP-Selective BACE inhibitors’ (ASBI) targets selective inhibition of cleavage of amyloid precursor protein (APP) by the beta-amyloid precursor protein cleaving enzyme (BACE) reducing production of the beta-amyloid peptide. The second series works by altering the effects of chronic stress through the corticotrophin-releasing factor receptor-1 (CRFR1), resulting in decreased phosphorylated-tau (p-tau) and affecting neurofibrillary tangle pathology in AD. These leads are advancing toward selection of preclinical- candidates for IND-enabling studies.
The DDL uses cutting-edge technologies to find new solutions for AD and other neurodegenerative disorders. The lab focuses on translating new leads, both NCEs and repurposed drugs (approved for other indications) from the bench to the clinic. The translational discovery process involves a number of steps as shown in the figure (“Discovery Process”) leading to an IND Application.
The DDL conducts high-throughput screening (HTS) using the ~200,000 compound-library in the UCLA screening core, hit-to-lead optimization using microfluidic flow-chemistry, structure-based design, and iterative testing in AD models using a critical- path approach ordered in a funneling-way, to identify pre-clinical candidates.
The DDL collaborates with several labs at UCLA in the departments of Neurology, Chemistry, Dentistry, and Bio-Engineering with support from the Easton Center and grants from NIH and private foundations. The scope of this collaborative research is represented by the ‘Discovery Research Impact Pyramid’ and includes: 1) Identification of candidates targeting the effects of ApoE4 through normalization of levels of the longevity protein Sirtuin1; 2) Synthesis of a novel Positron Emission Tomography (PET) ligand that can provide information on brain neuronal function and enable more precise diagnosis of AD; 3) Isolation and characterization of brain-derived exosomes in plasma and saliva to provide a window into the brain for monitoring disease progression and therapeutic efficacy; 4) Identification of pathway-dependent inhibitors that could prevent spread of pathological protein aggregates in AD; 5) Development of brain-penetrant deformable nanovesicles (DNVs) using microfluidics for delivery of therapeutics; and 6) Models of disease for preclinical testing. Dr. Dale Bredesen, who helped in the establishment of the DDL, is an advisor on several projects.
Clinical Research Opportunities
If you would like to advance Alzheimer's disease research, please consider participating at the Easton Center. Below are the current recruiting trials. For a complete list of enrolling studies, visit our website at www.eastonad.ucla.edu.
The ENGAGE study is a Phase III clinical trial sponsored by Biogen of the investigational drug aducadumab. Individuals aged 50-85 who are diagnosed with mild cognitive impairment may be eligible to participate in this trial. The goal of the study is to assess whether aducanumab, a drug that targets brain amyloid, can reduce brain amyloid levels and slow memory loss associated with amyloid build up. Participants will be randomized to receive active drug or placebo (inactive substance) via monthly infusions. The study lasts approximately 2 years, which includes an 8-week screening period and 4.5 month follow up period once the investigational drug/placebo phase is completed. To learn more, please call (310) 794-6191 or visit www.eastonad.ucla.edu.
Alzheimer’s Disease Neuroimaging Initiative 3 (ADNI3) Protocol:
ADNI3 (Alzheimer’s Disease Neuroimaging Initiative 3) is the fourth wave of a North American multicenter observational study launched in 2004, sponsored by the National Institute on Aging and the National Institutes of Health. The primary goal of this study is to discover, optimize, standardize, and validate clinical biomarkers used in Alzheimer’s disease research and clinical trials. This study seeks to enroll individuals ages 55-90, willing and able to undergo yearly test procedures including cognitive tests, questionnaires, brain imaging, blood draws, and spinal taps. Eligible individuals may have normal cognition with no memory concerns, or have memory concerns and diagnosis of mild cognitive impairment or dementia due to Alzheimer’s disease. Participants will be evaluated on a yearly basis, for 2 to 4 years.
If you are interested in participating, please call (310) 794-6191 or visit www.eastonad.ucla.edu.
NEAT (Nicotinamide as an Early Alzheimer’s Disease Treatment) Study:
The NEAT study is a phase IIb clinical trial sponsored by a University of California Cures for Alzheimer’s Initiative grant, focusing on nicotinamide, a soluble form of vitamin B3. This 12-month study will investigate the safety and tolerability of daily high dose oral nicotinamide, and assess whether nicotinamide is able to reduce levels of phosphorylated tau found in spinal fluid. It will also assess whether nicotinamide is effective in reducing the rate of cognitive and functional decline. This study is for individuals aged 50-85 with a diagnosis of mild cognitive impairment or mild dementia due to Alzheimer’s disease. Participants will have a 50% chance of receiving the study drug vs placebo (an inactive substance).
Curcumin and Yoga Therapy for Those at Risk for Alzheimer's Disease:
Early-onset Alzheimer’s Disease Phenotypes: Neuropsychology and Neural Networks:
The Behavioral Neurology program is conducting an NIH-funded study to try to understand and clarify why some individuals develop Alzheimer’s disease at a young age. By understanding the reasons for early-onset Alzheimer’s disease, the investigators hope to shed light on what happens in Alzheimer’s disease at all ages. Participants will undergo neurological tasks, neuropsychological assessments, and a special MRI of structural and functional brain networks. The study is approximately 1 year long, with 3 visits within the first month and 2 visits at the 1-year follow up. Study participation is open to all patients with Alzheimer’s disease, but especially those diagnosed with early-onset Alzheimer’s disease (diagnosed before age 65). To learn more, please visit https://behavioral.neurology.ucla.edu/research.
For information on other upcoming lectures and events, please visit the Easton Center Community Calendar.
2017 Alzheimer's Association | Walk to End Alzheimer’s® in Santa Monica, CA
Date: Sunday, September 24, 2017
8:30 A.M. - 12:00 P.M.
Location: Tongva Park
1615 Ocean Avenue, Santa Monica, CA 90401
Held annually in more than 600 communities nationwide, the Alzheimer's Association Walk to End Alzheimer’s® is the world’s largest event to raise awareness and funds for Alzheimer’s care, support and research. This inspiring event calls on participants of all ages and abilities to join the fight against the disease! For more information, please visit act.alz.org/westside.
2017 walk4ALZ | Alzheimer's Greater Los Angeles in Century City, CA
Date: Sunday, October 29, 2017
Time: 7:00 A.M. - 12:00 P.M.
Location: Century Park, Century City
10100 Constellation Boulevard, Los Angeles, CA 90067
Walk4ALZ brings together local communities in the fight against Alzheimer’s and other dementias. Whether you are living with dementia, caring for someone with dementia, lost someone to Alzheimer’s disease, or simply want to make a difference in our community, UCLA Easton Center Team for walk4ALZ.
Alzheimer's Greater LA is a local organization whose mission is to provide Greater Los Angeles families with hands-on support, information and resources, while advancing critical local research for a cure.