I have been an investigator at the Framingham Heart Study (FHS) since 1998, leading the clinical neurology and neurogenetics cores since 2005 and serving as PI on 9 NIH grants, 5 R01 grants, 3 U01s and a UH2. As a board certified neurologist and Professor of Neurology at the Chobanian and Avedisian School of Medicine, I ran a Geriatric Memory Disorders and Dementia clinic, supervised a resident general neurology clinic and covered the in-patient, consult and emergency services for one month in each year. I also served as Co-Director of Medical Education for the Neurology Residency Program between 2005 and 2012. I was Director of the neurology segment of the Biology of Disease/ Disease and Therapy course for 2nd year medical students between 2008-2010 and in 2015-16 and continue to teach the Dementia module. I currently spend 75% of my time on research and mentoring within the context of the Framingham study and have served as primary mentor for over 30 physician and non-physician investigators funded by a wide range of grants, national (K23, AAN, AHA) and international (Fulbright, Bettencourt-Schuller, Sidney-Sax etc.).
In my research capacity, I currently lead the clinical neurology and neurogenetics cores at the FHS, where we explore the cumulated and age-specific impacts of a wide variety of genomic and environmental risk factors underlying stroke, dementia and brain aging across 3 generations of participants. This entails undertaking brain MRI, cognitive tests, brain autopsies, biomarker, candidate gene, genome-wide association, sequencing and expression studies. At FHS, my key contributions have included updating the dementia database with improved tracking, review and new classification systems, studying novel biomarkers such as BDNF, NGF and beta-amyloid, and establishing a brain bank program. In addition I play a major role in consolidating, refining and expanding various aspects of the MRI and stroke databases. Further, as lead neurogenetics investigator I have funded whole exome sequencing on over 1300 Framingham Study participants.
My research focuses on 4 interrelated areas: (a) exploring the correlates of subclinical brain aging including establishing norms for brain MRI and cognitive test performance and relating these measures to novel risk factors (such as visceral fat mass), multiple circulating biomarkers and clinical and subclinical indices of vascular and metabolic disease; (b) the epidemiology of stroke and vascular cognitive impairment including the lifetime risk of stroke, cognitive decline and dementia following stroke, the role of parental stroke and midlife risk factors in determining late-life stroke risk and temporal trends in stroke risk over the past 50 years; (c) the epidemiology of dementia and Alzheimer’s disease (AD) including describing the lifetime risk of AD and relating traditional and novel biomarkers (homocysteine, lipids, diabetes, estrogen, bone mineral density, thyroid function, inflammation) to the risk of dementia and AD. I have been especially interested in exploring the role of reversible lifestyle, vascular and metabolic risk factors in determining dementia risk with a special focus on understanding the putative causal pathways and biomarkers, such as leptin and other adipokines, BDNF and other neurotrophic factors, in mediating this risk, and (d) understanding the genomic and epigenetic variation underlying brain aging, stroke, AD and vascular cognitive impairment.
My most significant research contributions have been (i) developing the concept of lifetime risk as applicable to dementia and other chronic diseases, (ii) helping to establish plasma homocysteine as an important risk marker for dementia and AD (including a first author paper in the NEJM in 2002 that has had over 1400 citations), (iii) relating low plasma leptin levels to the risk of dementia and AD (published in JAMA, 2009 as senior author), (iv) describing a novel gene, NINJ2, associated with ischemic stroke (NEJM, 2009 as corresponding author), (v) describing two genes, BIN1 and EXOCL2, associated with Alzheimer disease in the largest, multi-centric genome-wide association study to date (JAMA, 2010 as first author) and identifying novel genes underlying hippocampal volume in healthy adults (Nature Genetics, 2012 as Senior author).
I have over 280 peer-reviewed publications and reviews. I also established, partially fund and coordinate the neurology phenotype working group within the international Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium started in January 2008. This consortium brings together investigators from several of the leading cohort studies, the FHS, the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health study (CHS), the Rotterdam study, the Age, Gene, Environment Susceptibility- Reykjavik (AGES-Reykjavik) study and the Austrian Study for Prevention of Stroke (ASPS). In my capacity as coordinator of neuroCHARGE, I am also a founding member of the International Genomics of Alzheimer’s Project (IGAP) that brings together 4 major European and US groups who are currently the leaders in AD genomics research, am a PI of the Alzheimer Disease Sequencing Project (ADSP) that assesses rare genetic variation underlying PD in over 11,500 persons, a member of the Steering Committee for the International Stroke Genetics Consortium (ISGC) and Chair of the METASTROKE consortium.
A particular emphasis of mine throughout my career has been and will continue to be mentoring younger colleagues at my own institution and around the world towards academic careers. Collectively, my mentees have over 80 first author papers that I mentored published in leading journals including NEJM, Lancet, Nature Genetics, JAMA, JAMA Internal Medicine, JAMA Neurology, Annals of Neurology, Brain, Stroke and Neurology.
- Investigator, Framingham Heart Study
- Director, Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, UT Health San Antonio
- All India Institute of Medical Science (AIIMS), MD
- Christian Medical College & Hospital, MBBS
- All India Institute of Medical Science (AIIMS), DM
- Published on 9/22/2023
Pase MP, Pinheiro A, Rowsthorn E, Demissie S, Hurmez S, Aparicio H, Rodriguez-Lara F, Gonzales MM, Beiser A, DeCarli C, Seshadri S, Romero JR. MRI Visible Perivascular Spaces and the Risk of Incident Mild Cognitive Impairment in a Community Sample. J Alzheimers Dis. 2023 Sep 22. PMID: 37742645.
- Published on 9/14/2023
Rodriguez Lara F, Toro AR, Pinheiro A, Demissie S, Ekenze O, Martinez O, Parva P, Charidimou A, Ghosh S, DeCarli C, Seshadri S, Habes M, Maillard P, Romero JR. Relation of MRI-Visible Perivascular Spaces and Other MRI Markers of Cerebral Small Vessel Disease. Brain Sci. 2023 Sep 14; 13(9). PMID: 37759924.
- Published on 9/12/2023
Vered S, Beiser AS, Sulimani L, Sznitman S, Gonzales MM, Aparicio HJ, DeCarli C, Scott MR, Ghosh S, Lewitus GM, Meiri D, Seshadri S, Weinstein G. The association of circulating endocannabinoids with neuroimaging and blood biomarkers of neuro-injury. Alzheimers Res Ther. 2023 Sep 12; 15(1):154. PMID: 37700370.
- Published on 9/12/2023
Dubnov S, Yayon N, Yakov O, Bennett DA, Seshadri S, Mufson E, Tzur Y, Bennet ER, Greenberg D, Kuro-O M, Paldor I, Abraham CR, Soreq H. Knockout of the longevity gene Klotho perturbs aging- and Alzheimer's disease-linked brain microRNAs and tRNA fragments. bioRxiv. 2023 Sep 12. PMID: 37745362.
- Published on 9/7/2023
Gonzales MM, Garbarino VR, Kautz TF, Palavicini JP, Lopez-Cruzan M, Dehkordi SK, Mathews JJ, Zare H, Xu P, Zhang B, Franklin C, Habes M, Craft S, Petersen RC, Tchkonia T, Kirkland JL, Salardini A, Seshadri S, Musi N, Orr ME. Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial. Nat Med. 2023 Sep 07. PMID: 37679434.
- Published on 9/2/2023
Lee WP, Choi SH, Shea MG, Cheng PL, Dombroski BA, Pitsillides AN, Heard-Costa NL, Wang H, Bulekova K, Kuzma AB, Leung YY, Farrell JJ, Lin H, Naj A, Blue EE, Nusetor F, Wang D, Boerwinkle E, Bush WS, Zhang X, De Jager PL, Dupuis J, Farrer LA, Fornage M, Martin E, Pericak-Vance M, Seshadri S, Wijsman EM, Wang LS, Schellenberg GD, Destefano AL, Haines JL, Peloso GM. Association of Common and Rare Variants with Alzheimer's Disease in over 13,000 Diverse Individuals with Whole-Genome Sequencing from the Alzheimer's Disease Sequencing Project. medRxiv. 2023 Sep 02. PMID: 37693521.
- Published on 8/29/2023
Wang Y, Sarnowski C, Lin H, Pitsillides AN, Heard-Costa NL, Choi SH, Wang D, Bis JC, Blue EE, Boerwinkle E, De Jager PL, Fornage M, Wijsman EM, Seshadri S, Dupuis J, Peloso GM, DeStefano AL. Key variants via Alzheimer's Disease Sequencing Project whole genome sequence data. medRxiv. 2023 Aug 29. PMID: 37693453.
- Published on 8/28/2023
Weinstein G, O'Donnell A, Frenzel S, Xiao T, Yaqub A, Yilmaz P, de Knegt RJ, Maestre GE, Melo van Lent D, Long M, Gireud-Goss M, Ittermann T, Frost F, Bülow R, Vasan RS, Grabe HJ, Ikram MA, Beiser AS, Seshadri S. Nonalcoholic fatty liver disease, liver fibrosis, and structural brain imaging: The Cross-Cohort Collaboration. Eur J Neurol. 2023 Aug 28. PMID: 37641505.
- Published on 8/22/2023
Melo van Lent D, Mesa HG, Short MI, Gonzales MM, Aparicio HJ, Salinas J, Yuan C, Jacques PF, Beiser A, Seshadri S, Jacob ME, Himali JJ. Association between dietary inflammatory index score and incident dementia: results from the Framingham heart Study offspring cohort. medRxiv. 2023 Aug 22. PMID: 37662354.
- Published on 8/21/2023
Fongang B, Satizabal C, Kautz TF, Wadop YN, Muhammad JAS, Vasquez E, Mathews J, Gireud-Goss M, Saklad AR, Himali J, Beiser A, Cavazos JE, Mahaney MC, Maestre G, DeCarli C, Shipp EL, Vasan RS, Seshadri S. Cerebral small vessel disease burden is associated with decreased abundance of gut Barnesiella intestinihominis bacterium in the Framingham Heart Study. Sci Rep. 2023 Aug 21; 13(1):13622. PMID: 37604954.
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