Background:

Dementia syndromes are neurodegenerative disorders characterized by cognitive impairment that are sufficiently severe to interfere with daily function. Alzheimer’s Disease (AD) is the most common dementia diagnosis. However, AD as a clinical syndrome has mixed pathology and multifactorial etiology. Emerging evidence suggests that most clinical AD cases, especially those in persons over the age of 80, have both classic AD plaques and tangles pathology and vascular pathology. VCID is defined as the aging neurovascular unit being confronted with and failing to cope with biological insults due to systematic and cerebral vascular disease, proteinopathy including Alzheimer’s biology, metabolic disease, and immune affront, resulting in cognitive decline. VCID research overlays multiple clinical diagnoses, including cerebro- and cardio-vascular disease, stroke, AD and other types of dementia, some of which involve neither AD or stroke.

The societal burden of dementia in the US is substantial and growing. Estimates suggest as many as 5.7 million Americans have AD, including one in nine adults age 65 years or older. AD is the sixth leading cause of death in the United States, and the annual costs of direct care for people with AD exceed $200 billion, which is comparable to that of cardiovascular diseases (CVD). Unfortunately, at this time dementia cannot be effectively treated, prevented or slowed down, and the burden of AD/ADRD is expected to grow, in large part as a result of the rising number of people living into older age with cardiometabolic comorbidities. Although recent evidence from Framingham Heart Study suggests a decline in incidence of dementia, a better understanding of overall trends in incidence and prevalence of dementia are needed given the aging of the U.S. population.

Besides the effects of aging, chronic systemic comorbidities are associated with cognitive outcomes and the common dementia-associated pathologies. These AD/ADRD research areas are of interest to both the NHLBI and the NINDS and include, but are not limited to: cardio- and cerebrovascular disease, metabolic disorders of lipid and glucose metabolism including diabetes, and immune dysfunction, as well as obesity and behavioral risks factors for these diseases, such as smoking, dietary behavior, physical inactivity, and stress. The racial/ethnic and socioeconomic health disparities in ADRD have been described yet are not well understood, and often mirror patterns in other age-related comorbidities and ADRD/VCID risk factors. We expect that promoting a fuller and better understanding of the biological mechanisms of VCID across the wide spectrum of pathologies, chronic systemic comorbidities, and other risk factors, may lead to potential prevention and treatment strategies to decrease the burden of dementia.

NHLBI, often in collaboration with NINDS, the National Institute on Aging (NIA), and other NIH institutes, supports several well-characterized, longitudinal, population-based cohort studies and clinical trials in diverse populations to understand key determinants of vascular and cerebrovascular outcomes; clinical and subclinical markers of pathology across the body (including brain vessels); and natural history and pathological mechanisms of, and prevention and treatment of various diseases, including hypertension, atherosclerosis, sleep disorders, and their brain manifestations. These cohorts are a rich source of data and stored biospecimens, that are being leveraged using multi-omic screening methods for targeted and agnostic research. These approaches will promote development of new imaging and blood-based diagnostics/biomarkers for people with symptomatic disease – both AD and ADRD – as well as asymptomatic individuals. These approaches will also help us understand the relative contribution of the potential vascular contributions to AD and ADRD. This working group was convened to evaluate status of VCID basic and epidemiological research, to identify research gaps and barriers, and to recommend future research opportunities.

Workshop Discussion:     

The WG presentations and discussions focused on the following areas:

• Known vascular factors which may lead to dementia
• Optimal methods to study VCID
• Suspected mechanisms relating CVD with VCID

The WG identified several important challenges and barriers to better understanding of the contributions of vascular factors to dementia:

• Lack of experimental models that can recapitulate multi-factorial and progressive changes in human dementia, including pathologies in the vasculature, heart, and other organs that may lead to dementia
• Need to understand regional changes at the molecular and cellular level to define pathological mechanisms underlying different AD, VCID, and small vessel disease in animal models and prospective human cohorts
• Need to understand the difference and interaction between small vessel disease and large vessel disease and their contributions to VCID
• Lack of non-invasive imaging tools for measuring vascular pathologies, including roles of unstable atheroma and functional changes associated with cognitive impairment that can be applied both in animal models and human studies
• Need for a better molecular understanding of the human brain vasculature and the blood- brain barrier during healthy aging, accelerated aging, and VCID, as part of the clinical pathology of AD as well as its absence
• Need to understand the potential effects of medications for cardiovascular and other chronic diseases on cognitive impairment and dementia
• Lack of common data elements that will allow for standardized acquisition and merging of vascular and cognitive function measurements across studies
• Need for designing and conducting clinical trials with sufficient follow-up to test whether prevention and treatment of CVD or its risk factors could reduce the incidence/severity or delay the progression of dementia
• Lack of collaboration among researchers from various disciplines (such as cardiologists, neurologists, pulmonologists, hematologists, and sleep researchers) and across the translational research spectrum, from basic research, epidemiology, clinical trial and clinical care, to implementation research

Working Group Recommendations:

The WG identified the following research opportunities:

• Basic Mechanisms and Experimental Models
  • Understand the contribution of endothelial dysfunction in dementia
  • Comprehensively assess vascular pathologies in the brain and elsewhere that are associated with dementia
  • Develop and validate clinically relevant blood-based biomarkers for vascular dementia that can offer opportunities for early detection and risk stratification, as well as monitoring disease progression and individual response to intervention
  • Understand the impact of atrial fibrillation and heart failure on cognitive impairment and dementia
  • Understand the effects of vascular inflammation on cognitive impairment and dementia, develop tools to measure vascular inflammation, and understand the potential therapeutic value of immunotherapy for VCID


• Human-based studies
  • Develop and validate non-invasive imaging techniques to monitor subtle cerebrovascular and blood flow deficits and other sub-clinical pathologies that can be used as surrogate markers for dementia in humans
  • Understand the effects of the timing of onset and duration of vascular risk factors on cognitive impairment and dementia
  • Develop and validate risk stratification strategies during optimal time-points over the life-course (e.g., mid-life) in longitudinal cohort studies
  • Understand the variations in dementia risk at the population and individual level: biological, psychological and socioeconomic factors that account for differences in incidence and trajectory of cognitive function decline in different racial and ethnic groups, and gender differences
  • Add CVD risk measurements in dementia cohort studies and add cognitive function, brain imaging (MRI, functional MRI, PET), mood and behavioral function measurements in cardiovascular cohorts/trials when feasible
  • Understand the influence of sleep on vascular dysfunctions and cognitive function, or the effect of sleep disorders on cognitive impairment and dementia


• Develop methodologies, workforce, and shared resources
  • Support the development and validation of novel imaging techniques in animals and humans that permit monitoring of cerebral and peripheral vascular function and detecting vascular changes prior to the onset of dementia
  • Develop and validate mammalian animal models of VCID that recapitulate human disease progression and brain pathologies
  • Support the establishment of standard protocols to measure vascular changes and cognitive function that can be applied to multiple population
  • Facilitate cross-cohort and cross-institutional collaboration to consolidate effort and merge available data on VCID
  • Support training and workforce development and encourage collaboration in neurology, cardiovascular research, social and behavioral science, clinical trials, and implementation research

Publication Plans:

The working group plans to prepare a manuscript for publication in a peer-reviewed journal.

NIH Workshop Organizing Committee:

• Jue Chen, PhD, NHLBI
• Roderick A. Corriveau, PhD, NINDS
• Lawrence Fine, MD, DrPH, NHLBI
• Zorina Galis, PhD, NHLBI
• Jared Reis, PhD, NHLBI
• Jacqueline D. Wright, DrPH, NHLBI

NHLBI Contact:

Division of Cardiovascular Sciences
National Heart, Lung, and Blood Institute
National Institutes of Health

Phone: 301-435-0550
Email: jue.chen@nih.gov

Working Group Participants:

Co-chairs:

• Berislav V. Zlokovic, MD, PhD, University of Southern California
• Rebecca Gottesman, MD, PhD, Johns Hopkins University

Members:

• Kenneth E. Bernstein, MD, Cedars-Sinai Medical Center
• Sudha Seshadri, MD, University of Texas, San Antonio and Boston University
• Ann McKee, MD, VA Boston Healthcare System and Boston University
• Heather Snyder, PhD, Alzheimer’s Association
• Steven M. Greenberg, MD, PhD, Massachusetts General Hospital and Harvard Medical School
• Kristin Yaffe, MD, University of California, San Francisco
• Chris B. Schaffer, PhD, Cornell University
• Chun Yuan, PhD, University of Washington
• Timothy M. Hughes, PhD, Wake Forest School of Medicine
• M.J.A.P. (Mat) Daemen, MD, Academic Medical Center in Amsterdam
• Jeff D. Williamson, MD, MHS, Wake Forest School of Medicine
• Hector M. González, PhD, University of California, San Diego
• Julie Schneider, MD, MS, Rush University
• Cheryl Wellington, PhD, University of British Columbia
• Zvonimir S. Katusic, MD, PhD, Mayo Clinic
• Gary H. Gibbons, MD, NHLBI
• Walter, J. Koroshetz, MD, NINDS
• Marie A. Bernard, MD, NIA
• Dallas Anderson, PhD, MPH, NIA
• Nina Silverberg, PhD, NIA
• Luke Stoeckel, PhD, NIDDK
• Jim Koenig, PhD, NINDS
• Jue Chen, PhD, NHLBI
• Roderick A. Corriveau, PhD, NINDS
• Lawrence Fine, MD, DrPH, NHLBI
• Zorina Galis, PhD, NHLBI
• Jared Reis, PhD, NHLBI
• Jacqueline D. Wright, DrPH, NHLBI