RF1NS144268

Investigating the causal role of particulate matter components on Lewy body dementia: Integrating epidemiologic and mechanistic evidence - Project summary

As the United States population ages, the number of individuals affected by Lewy body dementia (LBD), characterized by hallmark α-synuclein (AS) pathology, is expected to rise.

LBD, which profoundly impairs cognition, behavior, and mobility, currently affects 1.4 million individuals and their families in the United States.

It is also the costliest dementia subtype to Medicare, with costs nearly double those of Alzheimer's disease.

The growing health burden of LBD highlights the urgent need to identify and modify environmental factors that may contribute to its development.

Increasing scientific evidence suggests that air pollution, particularly fine particulate matter (PM2.5), plays a significant role in the development and progression of AS-related dementia.

Mechanistically, AS-related dementia may begin when foreign agents, such as PM2.5, enter the body via the nose or gut, triggering AS propagation in the brain and ultimately leading to dementia.

Despite this, critical gaps remain in understanding the interaction between PM2.5 and LBD.

Specifically, it is unknown which specific components of PM2.5 contribute to LBD via AS pathology.

To address these gaps, we propose utilizing large-scale epidemiological data, advanced statistical methods, and mechanistic animal studies to identify which PM2.5 components are associated with LBD diagnoses in human populations and investigate how they promote AS aggregation and prion-like spreading in vivo.

We have assembled a multidisciplinary team of experts, including an atmospheric scientist, biostatistician, environmental epidemiologist, neurologist, and neuropathologist.

The biostatistical and epidemiological experts will have access to 100% of the Medicare chronic condition data—including inpatient, outpatient, and prescriber claims data—from approximately 27 million Medicare enrollees in the United States from 2017 to 2022, where many LBD diagnoses are recorded.

In parallel, the atmospheric chemistry and neuropathology experts will have access to laboratory resources for aerosol generation, atmospheric particle characterization, and a whole-body exposure (WBE) inhalation system to mimic ambient PM2.5 exposure to mice.

The complementary expertise will enable us to examine the role of PM2.5 and its specific components in contributing to LBD.

(1) We will evaluate the long-term effects of total PM2.5 exposure on LBD risk and establish an exposure-response relationship among Medicare enrollees.

(2) We will quantify the effects of individual PM2.5 components and their mixtures on LBD risk using novel causal modeling approaches.

(3) We will conduct in vivo studies using a WBE system in wildtype and AS-deficient mice to explore the causal mechanisms through which specific PM2.5 components, such as black carbon and nickel, induce AS pathology and neurodegeneration.

By identifying the specific PM2.5 components most responsible for LBD risk and elucidating the biological pathways involved, our research will provide critical evidence to inform targeted air pollution policies and therapeutic strategies aimed at reducing the health burden of LBD in older populations.

The Trustees Of Columbia University In The City Of New York

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

New York United States

State-Wide

Interaction Between Environmental Factors and Lewy Body Dementia (R01 - Clinical Trial Not Allowed) (PAR-24-249)