Margaret Flanagan, MD

JAD profile

Affiliation(s): 

UT Health San Antonio

Areas of Interest: 

aging, TDP43, Alzheimer's disease, neuropathology, Epidemiology of dementia

Biography & Research: 

Margaret E. Flanagan, M.D. is an anatomic pathologist and neuropathologist whose research focus is on neurodegenerative diseases including Alzheimer’s disease and frontotemporal dementias. She is an Associate Professor of Pathology and Endowed Baptist Health Foundation of San Antonio's Distinguished Chair in Alzheimer and Neurodegenerative Diseases. She obtained her M.D. from Trinity College Dublin, Ireland in 2013 and completed her Neuropathology fellowship at Stanford University. She directs the Nun Study of Aging and Alzheimer's disease, a longitudinal study launched in 1986 to determine the causes and prevention of Alzheimer’s disease, other brain diseases, and mental and physical disability associated with old age. Additionally she serves as Co-Director for the South Texas ADRC Neuropathology Core and Bigg's Institute Brain Bank. Flanagan specializes in analyzing human brain samples at autopsy. She participates in studies of community-based epidemiologic cohorts such as the ACT (Adult Changes in Thought) Study, a collaboration between the University of Washington and Kaiser Permanente (formerly Group Health). The ACT study is a community-based cohort with the requirement that subjects be community dwelling, 65 years of age or older and not demented at time of entry. Investigators track subject changes, exposures, and lifestyles and analyze various samples and genetic factors, with the data endpoint a brain autopsy. The purpose of the ACT study is to prospectively examine the incidence of Alzheimer’s disease and dementia, as well as risk factors for these conditions. Flanagan and her colleagues have found that ACT participants with higher prescription non-steroidal anti-inflammatory drug (NSAID) exposure had increased concentrations of beta-amyloid, the main component of amyloid plaques found in Alzheimer’s disease, and that ACT participants with higher prescription opioid exposure had increased concentrations of phospho-tau, the main component seen in neurofibrillary degeneration in Alzheimer’s disease. The National Institute on Aging (NIA) and the Alzheimer’s Association (AA) established neuropathologic guidelines in 2012 for diagnosing dementia that include the distribution and density of plaques and distribution of tau protein neurofibrillary tangles. Investigators including Flanagan have developed what they term the “condensed protocol” that meets or exceeds the 2012 NIA-AA guidelines for diagnosing Alzheimer’s Disease, Lewy body dementia, and microvascular lesions while simultaneously reducing time and cost. More recently, she extended and validated her condensed protocol for the diagnoses of FTLD-Tau (Pick's disease, Corticobasal Degeneration, and Progressive Supranuclear Palsy in addition to TDP43 proteinopathy (FTLD TDP and Limbic Predominant Age Related TDP43 Encephalopathy). Because traditional assessments can be subjective, Flanagan is developing newer technologies that can more objectively quantify these abnormal proteins. She has worked with Histelide, a novel antibody capture assay developed at the University of Washington that can be used to obtain quantitative and localization data, and currently is working with the development of disease-specific panels using multiplex ion-beam imaging (MIBI), which allows neuropathologists to analyze expression levels of thirty or more antibodies on a single slide using mass spectrometry. Flanagan and her colleagues are designing and optimizing MIBI panels for studies of healthy aging, Alzheimer’s disease, Lewy body dementia, and other cognitive disorders. She thinks MIBI and other multiplexing technologies will be especially helpful in both identifying and understanding the multiple disease processes that often coexist in individual dementia patients. Co-existing brain neuropathologies suggest that the interaction of amyloid plaques, tau neurofibrillary tangles, inflammatory factors, genetics, and other entities is fundamental to the development of cognitive decline. Understanding such complex interactions is key to understanding the disease pathobiology and identifying new pathways for treatment and prevention. Large datasets from community-based epidemiological cohorts are required to sort out these complex interactions and to find genetic factors associated with different ethnic groups. Flanagan is working with a multi-institutional team that is combining the cohorts of the Nun Study, comprising mainly Caucasian Roman Catholic School Sisters of Notre Dame who were born in the U.S. between 1890 and 1916, with the Honolulu-Asia Aging Study (HAAS), comprising men of Japanese ancestry born on Oahu between 1900 and 1919. Flanagan and fellow investigators have evaluated epidemiologic data and observational neuropathologic findings with the aim of identifying similarities between the cohorts that will help clarify both the pathophysiology of Alzheimer’s disease and cognitive resilience in these two very different groups. She will continue to work with multiplexing and objective quantification platforms studying longitudinal cohorts in an attempt to better understand dementia and aging.