The Friedman Brain Institute

Advancing the Understanding New Collaboration Multiplexing of Cognitive Loss and Dementia Collaborative Drives Dementia Alison M. Goate, Immunofluorescence in at Mount Sinai’s Alzheimer’s Programs Science and DPhil, Joins the Neocortex in Severe Disease Research Center Awarded Care Delivery Mount Sinai Alzheimer’s Disease The Friedman

SPRING 2015 Brain Institute www.mountsinai.org/fbi Compassionate Care, Pioneering Research

Alzheimer’s disease and related dementias are among the top 10 causes of recently established Ronald M. Loeb Center for death and debility in the United States, and the number of deaths attributed Alzheimer’s Disease joins Mount Sinai’s long- standing National Institute on Aging-funded to Alzheimer’s disease is expected to triple by 2050, when it is estimated Alzheimer’s Disease Research Center and our that more than 135 million people worldwide will be afflicted. Center for Cognitive Health in driving efforts to better understand dementing illnesses, Without dramatic improvements in our Institutes of Health provides manyfold fewer developing better ways at diagnosing and ability to treat or prevent these illnesses, dollars for dementia. treating them, and working toward ultimate dementia will likely overwhelm health care cures and preventive measures. budgets worldwide. Still, research into the Mount Sinai is leading efforts to study causes and treatment of these dementias Alzheimer’s disease and other dementias, as Eric J. Nestler, MD, PhD does not receive support commensurate with well as chronic traumatic encephalopathies, Nash Family Professor and Chair, Department of Neuroscience; their devastating impact. For example, when which are caused by repeated traumas—even Director, The Friedman Brain Institute compared to the health and economic costs concussions—resulting in similar syndromes [email protected] of cancer and heart disease, the National with shared pathological mechanisms. The neuroscience.mssm.edu/nestler

RESEARCH FRONTIERS

healthy, and recent research has begun to New Loeb Center Targets Alzheimer’s Disease uncover genetic factors in these individuals And Other Degenerative Disorders that appear protective. Identification of such protective genes, and understanding how With the recent launch of the Ronald M. and progressive supranuclear palsy; as well they counteract pathogenic mechanisms, Loeb Center for Alzheimer’s Disease, Mount as Parkinson’s disease and amyotrophic is driving highly novel approaches to Sinai is further expanding its commitment lateral sclerosis (ALS)—are characterized therapeutics aimed at developing drugs that to develop major research and clinical by the accumulation of abnormal protein prevent or delay the onset of disease. breakthroughs for this devastating illness. aggregates in the brain, leading to the death The Loeb Center was established with a of specific types of nerve cells. Some of the The Loeb Center will build upon substantial $15 million gift from Daniel S. and Margaret same proteins may even be involved across existing strengths at Mount Sinai (see Loeb and is named after Mr. Loeb’s father, these syndromes, such as β-amyloid, tau, and related stories on pages 2 and 3), helping who succumbed to Alzheimer’s disease. α-synuclein. Genetic studies in humans with to strengthen collaborative efforts among Alison M. Goate, DPhil, world-renowned for each of these diseases, as well as research innovative scientists and physicians her work on the genetic causes of dementia, on animal models, have demonstrated that with a goal to discover the fundamental was recruited to Mount Sinai to direct the this protein aggregation is causal in disease mechanisms underlying disease and bring new Center (see page 3). The Loeb Center will pathogenesis. These findings suggest there new treatments to the patient. advance basic research and compassionate are common mechanistic principles shared clinical care, and drive the development of across these disorders that may be exploited To learn more, visit transformative new therapeutics. to develop fundamentally new treatments. www.mountsinai.org/loebcenter.

Two scientific themes will guide research A second focus of researchers is to better carried out by the Loeb Center. Many understand nature’s own protective degenerative brain disorders—including mechanisms against these illnesses. It has Alison M. Goate, DPhil Alzheimer’s disease; several types of related long been understood that some people Director, Ronald M. Loeb Center for dementias, such as frontotemporal dementia carrying known genetic risk factors remain Alzheimer’s Disease

Icahn School of Medicine at Mount Sinai | The Friedman Brain Institute | One Gustave L. Levy Place, Box 1107 | New York, NY 10029-6574 | www.icahn.mssm.edu INNOVATIVE CLINICAL AND BASIC RESEARCH Advancing the Understanding of Cognitive Loss and Dementia at Mount Sinai’s Alzheimer’s Disease Research Center

Mount Sinai’s Alzheimer’s Disease that capture subtle deficits using home- The ADRC provides critical resources to Research Center (ADRC), a nationally based and audio-recorded testing, and support dementia-related research across renowned program established in 1984, provided normative data for Spanish- the Mount Sinai Health System by offering conducts clinical and basic research speaking populations. Basic laboratory expertise in clinical characterization and dedicated to understanding both normal projects have specifically focused on maintaining cohorts of aging individuals. aging and Alzheimer’s disease (AD). The γ-secretase-related mechanisms and Mount Sinai researchers can share access Center’s goals are to develop techniques to efforts that may point to the development to national datasets of clinical populations detect the progression from normal aging of new vasculotropic drugs. and, in some cases, biological samples. The to the earliest signs of cognitive loss and Mount Sinai ADRC works closely with the dementia, and to develop therapies to stop Over the next five years, the team, NIA Alzheimer’s Disease Neuroimaging this deterioration and to treat cognitive including Sam Gandy, MD, PhD, expects Initiative, as well as the NIA Alzheimer’s loss and other symptoms. Directed by Mary to define the mechanisms that link type 2 Disease Cooperative Study, the main federal Sano, PhD, the Center is one of 14 ADRCs diabetes and insulin resistance to cognitive entity responsible for conducting human supported by the National Institute on impairment and dementia with clinical clinical trials of promising new drugs. Aging (NIA). characterization using both AD- and diabetes-related biomarkers. Investigators To learn more, visit icahn.mssm.edu/adrc. Recent focus has been on clinical and intend to generate human skin fibroblasts molecular endophenotyping. This includes and induced pluripotent stem cells from characterizing the associations among AD individuals—representing a full range of neuropathology, hypertension, diabetes, insulin resistance and cognitive function— Mary Sano, PhD Director, Alzheimer’s Disease renal disease, depression, and cognitive to enable unique tools for understanding Research Center; Associate Dean, decline. The Center has also pioneered the overlap and the biology of these Clinical Research; and Professor of cognitive assessment with technologies interrelated diseases. Psychiatry

New Collaborative Programs Awarded

Thus, well-studied compounds can be The National Institute on Aging (NIA) principal investigators, supported by the repurposed without the need for extensive recently created a new generation of National Institutes of Health and several preclinical testing. To complete the circle, Alzheimer’s disease (AD) centers to pharmaceutical firms aimed at developing the clinical trials unit of the ADRC will be known as NIA Alzheimer’s Disease computational approaches for a number of be tasked with assessing a number of Translational Centers for Predictive Drug common conditions, such as type 2 diabetes these repurposed drugs for the specific Development (ADCPD). and Alzheimer’s disease. treatment and prevention of AD.

Mount Sinai received a planning award The Icahn School of Medicine at Mount Sinai for one of these new Centers under the is one of only five sites across the nation direction of Joel Dudley, PhD, and Sam selected to focus on Alzheimer’s disease, Gandy, MD, PhD, and also involving Eric specifically, the transcriptomic analysis of Joel Dudley, PhD Assistant Professor, Genetics Schadt, PhD, and Alison Goate, DPhil. The brains from early stage AD patients from and Genomic Sciences, and its Alzheimer’s Disease Research Center new ADCPD will partner Mount Sinai with Population Health Science and individuals at General Electric and the (ADRC) Brain Bank. This new approach Policy New York Stem Cell Foundation. will take investigators from Mount Sinai and its collaborators in Japan, New York, Eric Schadt, PhD Director, Icahn Institute for The Mount Sinai ADCPD would also and Boston, beyond the discovery of gene Genomics and Multiscale Biology; network hubs and drivers, and allow them expand the work of the Accelerating Chair, Genetics and Genomic Medicines Partnership (AMP), a new to merge molecular pathway data with the Sciences; and Jean C. and James effort led by Dr. Schadt and seven other universe of knowledge about existing drugs. W. Crystal Professor of Genomics

2 AIMING FOR NEW INSIGHTS Collaboration Drives Dementia Science and Care Delivery

The Center for Cognitive Health (CCH) and the National Football League Neurological Center (NFLNC) are at the crossroads of dementia science and care delivery. Its leadership includes Director Sam Gandy, MD, PhD, who also serves as an Associate Director of the National Institute on Aging- designated Alzheimer’s Disease Research Center (ADRC); Martin Goldstein, MD, who oversees the clinical care division; and Mary Sano, PhD, ADRC Director, who heads the research division.

The CCH reflects a collaborative effort across the departments of Neurology, PET scan with florbetaben reveals accumulation ofβ -amyloid in the brain of a patient with Psychiatry, Rehabilitation Medicine, and Alzheimer’s disease (AD). In contrast, β-amyloid accumulation is not detectable in a normal Geriatrics. Some Center physicians are control subject (HC) or in a patient with frontotemporal dementia (FTD), which is associated with doubly certified in both neurology and accumulation of tau instead. Courtesy of Sam Gandy, MD, PhD psychiatry and are especially skilled at managing patients of all ages with both brain imaging tests to diagnose Alzheimer’s interest in vascular factors that cause cognitive and behavioral symptoms. disease, other forms of dementia, and dementia. The Center’s staff also includes several chronic traumatic encephalopathy (CTE). neuropsychologists to evaluate a patient’s Mount Sinai was the first institution in New To learn more, visit www.mountsinai.org/cch. cognitive function, and social workers York City to offer patients amyloid brain and psychologists to provide counseling scans, which can detect, for the first time, Sam Gandy, MD, PhD and social support. The NFLNC is one of the deposition of β-amyloid in the brains Mount Sinai Professor in five such centers nationwide and provides of living patients. Research is now under Alzheimer’s Research; Professor complete and standardized neurological, way to similarly scan for pathological of Neurology, and Psychiatry; and Associate Director, Alzheimer’s neuropsychological, and neuroradiological forms of tau and for evidence of abnormal Disease Research Center assessment to former National Football inflammatory activity in the brain. This League players approved and referred by work is being performed in collaboration the league. with Lale Kostakoglu, MD, Chief, Division Martin Goldstein, MD of Nuclear Medicine, in the Department of Assistant Professor of Neurology, and Psychiatry; and Medical An area of particular interest within both Radiology. Additionally, in collaboration Director, Center for Cognitive Centers is the development of innovative with Mount Sinai Heart, there is an active Health

APPOINTMENT Alison M. Goate, DPhil, Joins Mount Sinai

Alison M. Goate, DPhil, the Director of Mount Sinai’s new Ronald Syndrome, and later joined Imperial College where she worked on M. Loeb Center for Alzheimer’s Disease, is a world leader in AD as the lead geneticist for the research team headed by John neurogenetics who has studied the genetic causes of Alzheimer’s Hardy, PhD. disease (AD), other dementias, and neuropsychiatric conditions for more than 27 years. In 1991, Drs. Goate and Hardy reported the first genetic mutations causing AD, a groundbreaking discovery that transformed research A native of the United Kingdom, Dr. Goate completed her doctoral by enabling the development of cellular and animal models of AD. degree at the University of Oxford where she studied the cellular Most of the drugs currently in clinical trials for the treatment of pathology of intermediate filaments and came to the United AD are anti-amyloid drugs that trace their genesis to these seminal States for postdoctoral training on somatic cell genetics under discoveries. She continued to be at the forefront of dementia the mentorship of Theodore T. Puck, PhD, the founding director genetics for many years at Washington University, St. Louis, where of the Eleanor Roosevelt Institute in Denver. She returned to the she served as Professor of Psychiatry, Neurology, and Genetics, UK as a postdoc at the Institute of Neurology in London with Louis and Director of the Hope Center for Neurological Disorders, before Lim, PhD, where she studied the molecular mechanisms of Down joining Mount Sinai. 3 Icahn School of Medicine at Mount Sinai The Friedman Brain Institute One Gustave L. Levy Place, Box 1107 New York, NY 10029-6574

PHOTO ESSAY

Multiplexing Immunofluorescence in the Neocortex in Severe Alzheimer’s Disease

The six imaging channels shown here reveal neuronal, glial, immunity, and pathological markers of the disease.

Courtesy of Dan Meyer, PhD, Senior Scientist, GE Global Research, Niskayuna, N.Y.; and Patrick R. Hof, MD, Irving and Dorothy Regenstreif Research Professor of Neuroscience and Vice Chair of the Department of Neuroscience, and Dara L. Dickstein, PhD, Assistant Professor of Neuroscience, and Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai