Attacking Alzheimer ’s disease
16 million. That’s how many Americans may be living with Alzheimer’s disease by the year 2050, according to the Alzheimer’s Association. Not only does this projection indicate the vast number of patients and families who will suffer physically and emotionally in the coming years, it also points to a significant economic burden; in that same year, the disease is expected to cost the U.S. $1.1 trillion.
Researchers across the SUNY campuses hope to reduce the emotional and financial burden that Alzheimer’s disease poses by investigating better techniques to diagnose, treat, and even prevent the disease. Together, they are making meaningful strides toward improving the outcomes of patients with Alzheimer’s.
Scientists and clinicians generally agree that the key to preventing Alzheimer’s disease (AD) is early and accurate diagnosis. To that end, several research groups across the SUNY system are working to predict who is likely to acquire the disease.
Sungeun Kim, assistant professor of electrical and computer engineering at SUNY Oswego, is one of them. He and his colleagues are combining information from massive, disparate datasets to create software that can predict the onset of AD by analyzing a patient’s history, genes, and certain biomarkers. “If we can develop a toolkit to more accurately identify people at risk years earlier, we have more chance to intervene in the progression of the disease,” said Kim.
Meanwhile, at the University at Albany, Professor of Chemistry Igor Lednev and colleagues at Albany Medical Center are using Near Infrared Raman microspectroscopy of blood—which provides a fingerprint of a molecule based on how it interacts with light—along with advanced computer analysis to distinguish people with AD from healthy controls, as well as from people with other forms of dementia. This noninvasive method offers the potential for diagnosing the disease before the onset of symptoms, such as memory loss or confusion.
In addition, Lednev is using the technique to decode amyloid fibrils—extracellular protein deposits found in organs and tissues that, unlike other fibrous proteins, have no supportive role in human health. “Amyloid fibrils are instead found in patients suffering from Alzheimer’s or Type 2 diabetes,” said Lednev. The scientist hopes that unlocking the chemical properties of amyloids may lead to a better understanding of AD and its profoundly devastating impact.
Lednev isn’t the only SUNY researcher investigating Alzheimer’s-related amyloids. Dmitry Goldgaber, professor of psychiatry at Stony Brook University, was the first scientist to identify the location of the gene for amyloid precursor protein (on chromosome 21). Amyloid precursor protein is responsible for making beta-amyloid peptides—which clump together to form plaques. A mutation in amyloid precursor protein causes increases amounts of beta-amyloid and can lead to early-onset AD. This information led to the creation of genetic tests to predict whether or not a patient will develop early-onset AD.
Late-onset AD is harder to predict and diagnose. Complicating the difficulty of achieving a diagnosis is a person’s reading ability, according to Brian Lebowitz, clinical assistant professor of neurology at Stony Brook Medicine. He and his colleagues have found that older adults with a history of reading problems perform similarly on some neuropsychological tests to those who show signs of mild cognitive impairment associated with early AD.
“Identifying the clinical significance of our finding is our next challenge,” said Lebowitz. “It could mean that a reading or learning disorder history may increase the misdiagnosis of neurodegenerative disease, including Alzheimer’s disease. Alternatively, a reading disorder may represent a risk factor for the development of Alzheimer’s disease in later life.” This further justifies the need for specific biochemical or spectroscopic tests for AD and other forms of dementia.
Research conducted by Deborah Gustafson, professor of neurology at Downstate Medical University, suggests that body weight change may aid in the diagnosis and management of Alzheimer’s disease. Her long-term (nearly 40 years) study of women shows a link between specific patterns of body mass index (BMI) change in later life and the development of dementia. In a related study, she is examining the impact of body weight on cognition in women aging with HIV infection, reflecting Downstate’s leadership role in studying and caring for this vulnerable populations. The community Downstate serves has one of the highest levels of HIV infection in New York State.
Gustafson’s research has also considered the role of APOEe4, a relatively common gene variant that is a known risk factor for late onset AD. “Body weight change and BMI are easily measured, noninvasive potential prognostic indicators for dementia,” explains Gustafson. “Better understanding of APOEe4 and how it modifies risk may aid in our understanding of how we can better intervene among those at highest risk for dementia.”
Joining her in these studies is Herman Moreno, associate professor of neurology and physiology & pharmacology and members of his team, along with researchers from Columbia University. They are looking to uncover exactly why APOE4 is associated with increased AD risk. Using complementary imaging techniques, including functional MRI, in vitro and in vivo electrophysiology, and metabolite profiling, they believe that APOE4-driven hyperactivity may be the root cause of the increased risk for AD seen in those who carry this gene allele. “The question,” says Moreno, “is whether APOE4 causes the differences we see, or whether those differences are caused by the interaction of APOE4 with AD pathology.”
Dr. Moreno is a member of the M2OVE-AD (Molecular Mechanisms of the Vascular Etiology of Alzheimer’s) Consortium, which brings together teams of scientists from diverse fields and universities with the goal of building more nuanced models of Alzheimer’s disease and its causes. Developed jointly by the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, this five-year, $30 million collaboration seeks to leverage the power of new molecular technologies with those of big data analytics.
Dr. Moreno is the principal investigator of the Consortium’s group study9ng the interplay between diabetes, vascular pathology, and AD. His team uses clinical and braining imaging data obtained from 400 middle-aged Hispanic study participants to explore biomarkers in individuals with/without pre-diabetes or diabetes that could potentially predict risk for AD or identify promising therapeutic targets. Moreno is the only SUNY faculty member serving as the PI of a M2OVE-AD group; Frank Barone, professor of neurology and physiology at Downstate, is among the group’s collaborators.
Barone, with Daniel Rosenbaum, chair of neurology at Downstate, is investigating AD from a different perspective – how vascular events such as stroke and conditions such as hypertension contribute to cognitive impairment through injury to the brain’s white matter, the connecting tissue that carries nerve impulses between neurons. Baron and Rosenbaum theorize that inflammatory processes might be driving white matter pathology, resulting in cognitive loss – and that these, in turn, are “important components of the progression to dementia,” says Barone.
Once a diagnosis of AD is made, what happens next? Unfortunately, no cure for the disease exists, but SUNY researchers are working to change that.
Binghamton University mechanical engineers Paul Chairot and Peter Huang, for example, are looking inside arterial walls to find a possible cause of Alzheimer’s disease. “There’s significant evidence that the onset of Alzheimer’s is closely related to the removal failure of protein molecules from the brain,” said Chiarot. “We believe that there may be deficiencies in how these protein molecules are being transported in the brains of patients suffering from Alzheimer’s and hope to use this study as a chance to find out exactly where it goes wrong.”
The research, which is funded by the NIH, aims to find an answer to some seemingly contradictory results. “There have been studies that show protein molecules driven from the walls of arteries to veins where they are drained,” said Huang. “However, there have also been studies that trace the movement of the protein molecules and show them moving inside the walls of the arteries in the opposite direction.
Ultimately, this study will try to find out what’s happening within the arterial walls during that transportation process and solve what appears to be a contradiction.” Solving this mystery could bring researchers one step closer to pinpointing the cause of Alzheimer’s and ultimately finding a cure.
In the Department of Physiology and Biophysics at the University at Buffalo (UB) a team of scientists is studying the genetic and epigenetic factors in Alzheimer’s disease to develop techniques for restoring function to AD patients. According to Zhen Yan, professor of physiology and biophysics, who is leading the research, epigenetic factors are non-DNA-based factors that can change gene expression without altering the underlying DNA sequence—which in turn affects how cells read the genes.
“We hypothesize that Alzheimer’s is produced by a combination of genetic risk factors and environmental factors, such as aging, that induce the dysregulation of specific epigenetic processes that lead to impaired cognition,” said Zhen Yan, professor of physiology and biophysics.
One area Yan and her colleagues are investigating is the loss of glutamate receptors, which are responsible for mediating some of the processes related to short-term memory.
“At the later stages of the disease, we know that there is a loss of glutamate receptors that are crucial for learning and memory,” she said. “When these receptors lose the ability to communicate, there is a loss of cognition. Our research will try to restore gene expression in these glutamate receptors using epigenetic tools, with the ultimate goal of restoring cognitive function.”
Another avenue for improving outcomes is to boost a patient’s positive memories by manipulating one of the brain’s natural signaling mechanisms related to memory, a neurotransmitter called acetylcholine.
According to Lorna Role, co-director of the Neurosciences Institute and Distinguished Professor and Chair of the Department of Neurobiology and Behavior at Stony Brook University, the amygdala is the region of the brain that is most involved in emotional memory. Acetylcholine is delivered to the amygdala by cholinergic neurons that reside in the base of the brain. These cholinergic neurons appear to be affected early in cognitive decline. Previous research has suggested that cholinergic input to the amygdala appears to strengthen emotional memories.
Role and her colleagues are using opto-genetics, a technique that uses light to control cells in living tissue, to stimulate specific populations of cholinergic neurons. In mice, they have found they found that increasing acetylcholine release in the amygdala during the formation of a traumatic memory greatly strengthens memory making. On the other hand, decreasing acetylcholine release in the amygdala during a traumatic experience, actually deleted memories.
“The long-term goal of our research is that we would like to find ways to enhance or diminish the strength of specific memories, enhance the good ones, and diminish the bad ones,” said Role.
Meanwhile, researchers in the Department of Chemical and Biological Engineering at the University at Buffalo aim to reprogram skin cells to act as healthy neural crest cells, which are present in the spinal cord and brain.
According to Stelios Andreadis, professor and chair, stem cells have been derived from adult cells before, but not without adding genes to alter the cells. The new process yields neural crest cells without addition of foreign genetic material. The reprogrammed neural crest cells can become smooth muscle cells, melanocytes, Schwann cells, or neurons.
“This work has the potential to provide a novel source of abundant, easily accessible and autologous cells for treatment of devastating neurodegenerative diseases,” said Andreadis.
The best way to deal with a disease is to never get it at all. At Avanti Biosciences, a Stony Brook-based company affiliated with the university’s Center for Biotechnology, researchers are attempting to prevent AD from developing through the use of catechins—antioxidants found in green tea. In large concentrations, catechins have been shown to inhibit a particular enzyme—DYRK1A—that is a trigger for AD.
The company, founded by Gian Luca Araldi, a BioEntrepreneurs-In-Residence at the Long Island Bioscience Hub, won a $1.93 million Small Business Innovation Research grant from the National Institute on Aging in 2015 to launch its AD research.
While scientists across the SUNY system seek to understand the biological bases of AD, medical professionals at many of the campuses are working directly with patients to give them the best quality of care available today.
The Alzheimer’s Disease and Memory Disorders Center at the University at Buffalo is one such place. The center, which recently expanded its clinics in Buffalo and Williamsville, treats some 700 patients at its downtown clinic.
According to Kinga Szigeti, associate professor of neurology and the center’s director, the center’s physicians emphasize early screening and diagnosis, including assessing patients for signs of memory loss.
“Some of the things we look for are when patients have trouble learning new information and saying it back,” said Szigeti. “That is a sign of Alzheimer’s, the rapid forgetting of new information. With treatment, we can give patients more good years.”
The great work performed at this center led to a five-year, $2.35 million New York State grant to researchers in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo. The purpose of the grant is to significantly improve the screening, diagnosis, and treatment of AD and other dementias by providing state-of-the-art care and educating primary care providers, patients, and their caregivers in Western New York. The grant also will help educate future medical professionals at the Jacobs School about dementia and geriatrics.
On the other side of the state, SUNY Downstate Medical Center also received a $2.35 million award from New York State to expand its care of patients with AD and other dementias. Downstate’s Center of Excellence for Alzheimer’s Disease offers integrated, one-stop care for patients and caregivers that include geriatric psychiatrists, geriatric medicine specialists, a behavioral neurologist, medical assistant, social workers, care managers, and a neuropsychologist. Many of the staff are bi-lingual. The program serves as a training site for students, residents, and fellows in geriatric psychiatry and medicine.
“The new funding will enhance Downstate’s capacity to address health disparities in the treatment and management of Alzheimer’s among Brooklyn’s many diverse minority and ethnic communities,” said Carl Cohen, Distinguished Service Professor and director of the Division of Geriatric Psychiatry at SUNY Downstate.
At Upstate Medical University, an $8 million gift from Sam and Carol Nappi of Jamesville, NY, is supporting the creation or an eight-floor, 360,000 square foot health and wellness complex that will have a special focus on brain health, expanding Upstate's service related to neurosciences, including a focus on Alzheimer's disease. Upstate is currently a state Center of Excellence for Alzheimer's disease.
“The Nappi support, with its focus on Alzheimer’s disease and brain health, is a down payment on creating healthy futures for all of us as we age,” said Sharon Brangman, MD, division chief of geriatric medicine at Upstate, who is a former president of the American Geriatrics Society. “We do much for our physical body to ensure that we maintain mobility as we age, but almost more important is our ability to exercise our brain and enhance and strengthen our cognitive mobility as we grow older.”
Former University of Tennessee women’s basketball coach and AD patient Pat Summitt once compared the disease to walking along a shoreline and having your footprints washed away. Alzheimer’s disease devastates patients and their families. At SUNY, researchers and medical professionals are attacking the disease from every possible angle.
They are searching for better ways to predict, diagnose, treat, prevent, and even cure the disease. With some of the most important minds in the world focused on the task, along with the resources that the SUNY campuses provide to them, these passionate and determined researchers are making advances every day.
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