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Research at Mass General
In 2017, more than 5 million Americans are living with Alzheimer’s Disease. As we continue to lead longer and healthier lives, the numbers of people living with Alzheimer’s and related neurological disorders will continue to increase. These disorders carry a large financial and emotional toll to society, and currently there is no cure and little symptomatic relief available. Alzheimer’s Disease is a complex disorder with strong relationships to other chronic disorders such as diabetes, agitation and anxiety, and stroke. In the Interdisciplinary Brain Centre, our mission is to break down conceptual silos in Alzheimer’s research, and bring together physicians and scientists from diverse backgrounds to design patient-oriented experimental and clinical trials, paving the way for discovery of novel treatments.
Our specific scientific interests include defining biomarkers for clinical trials in aging and dementias, metabolic and vascular risk factors for dementia, and protective factors that account for cognitive resilience in aging. Our integrated translational approach includes the design of experimental and clinical trials that use advanced neuroimaging techniques, biofluid collection procedures, and medical/psychiatric/neurocognitive assessment. These clinical measures are combined with ultra-sensitive biomarker detection technologies, high throughput proteomic and lipidomic assessment of tissue and biofluids, and molecular biochemistry. This fully integrated approach will lead to a more comprehensive understanding of the pathology of Alzheimer’s Disease, the contributions from concomitant conditions, and highlight novel routes for treating the disorder.
Becky C. Carlyle, PhD Dr Carlyle is a Senior Research Fellow. She manages the “wet lab” side of the Arnold Lab, using her skills in molecular biochemistry to oversee projects on biofluid biomarker discovery, tissue proteomics, and lipid composition.
Before joining MGH in the summer of 2017, Dr Carlyle completed a Post Doc in the lab of Professor Angus Nairn at Yale University, producing a peptide level survey of the adult human brain, and designing novel assays for protein translation. She received her PhD in Molecular Medicine from the University of Edinburgh in 2010, and her bachelors from the University of Oxford in 2005.
Victoria J. Williams, PhD
Dr. Williams is a Research Fellow who oversees patient-oriented clinical research projects within the Arnold Lab. Her work broadly employs neuropsychological assessment and advanced neuroimaging techniques to explore brain-behavior relations in aging and neurodegenerative disease. Whereas her graduate work focused on neurostructural correlates of developmental disorders (e.g., spina bifida, dyslexia), her more current line of research examines the role of modifiable risk factors (such as cerebrovascular health, physical fitness) in typical aging as well as in dementia onset and progression.
Dr. Williams received a B.S. in Psychology from the University of Texas at Austin (2008), and subsequently worked as a research assistant at the Martinos Center for Biomedical Imaging. She received a doctorate degree in Clinical Psychology (Neuropsychology emphasis) from the University of Houston under the guidance of Dr. Jack M. Fletcher (2015), and completed internship within the UCSD/San Diego VA Clinical Internship Training Program. Before joining the Arnold lab in the summer of 2017, Dr. Williams completed a clinical-research postdoctoral fellowship at the Boston VA Hospital investigating how cardiorespiratory fitness attenuates neural and cognitive decline in aging.
Holly Duddy RN, BSN
Holly is our clinical research nurse. She is responsible for IV infusion for our clinical trial; physical assessment of patients across all research studies; administering some cognitive testing measures across our studies; monitoring laboratory values, vital signs, and EKGs across all studies and intervening/ consulting with patients as needed; creating appropriate medical documentation forms and educational tools for patients; ordering and organizing necessary nursing supplies for our studies. In summary, Holly’s goal is to ensure optimal safety and quality care of our patients.
Before joining MGH in May 2017, Holly worked as a telemetry nurse at a hospital in Cape Cod, MA. Here she took care of patients that were ill with a variety of cardiac conditions in addition to several other comorbidities. Holly moved to Boston upon acceptance into Boston College’s Family Nurse Practitioner program. She works during the day and attends classes at night with an intended graduation as an FNP in May 2020.
Bianca A. Trombetta
Bianca joined the Arnold Lab as a Research Technician II in November 2015. She works on several research projects investigating the molecular mechanisms of Alzheimer's disease, including biofluid biomarker discovery, assay development, the regulation of sterol life cycles in neurons, and the relationship between brain insulin resistance and cognitive function.
Bianca graduated from Harvard University with a B.A. in Linguistics and a related field in Psychology in May 2015. During her undergraduate career she worked as a research assistant in Dr. Gigi Luk's Brain Experience Education Lab at HGSE on behavioral studies examining the underlying neural networks of bilingualism and learning. She also has prior experience as a research technician in the Harris Orthopedics Laboratory at MGH, where she analyzed the physical properties of biomaterials used in total joint replacements.
Chloe K. Nobuhara
Chloe is a Research Technician I in the Arnold lab. She coordinates the MassGeneral Institute for Neurodegenerative Disease (MIND) Tissue Bank, which collects and distributes CSF, plasma and associated clinical information from participants receiving routine care at MGH Neurology.
Before joining the Arnold Lab in the summer of 2017, Chloe conducted research in the Hyman Lab at MGH for two years. Her research interests include tau propagation and tau immunotherapy for Alzheimer’s disease. Chloe graduated from Northeastern University with a B.S. in Behavioral Neuroscience in May 2017 and will be attending medical school in the fall.
Emma Hanlon is a Clinical Research Coordinator I in the Arnold Lab. She coordinates the AbbVie study—an industry sponsored phase 2 clinical trial evaluating the safety and efficacy of a novel therapeutic for Alzheimer’s disease.
Emma joined the Arnold Lab in May 2017 after graduating from Boston College with a Bachelor’s of Science degree in Biology. While a student at Boston College she worked in Michael McDannald’s behavioral neuroscience lab on projects related to fear regulation. Emma plans to attend medical school in the fall of 2018.
Chase is a clinical research coordinator for the Arnold Lab. He manages multiple projects investigating Alzheimer’s disease and coordinates a study working to establish biomarkers for human prion diseases. Data for these studies is collected from a variety of sources such as MRI, EEG, blood, and spinal fluid.
Chase received his Bachelor of Science in Psychology and minor in Human-Computer Interaction from Carnegie Mellon University in 2015. Before joining the Arnold Lab in the summer of 2016, Chase had previous experience working in a language learning lab, a relationships lab, and an HCI research lab.
Lili Ge is a recent graduate of Boston University's Masters in Bioinformatics program. Her previous research experience was focused on cytokine analysis and predictive modeling of the gut micro-biome. She is working on immuno-histochemistry for project tissue sections and automated downstream quantification.
Resilience The classical features of Alzheimer’s Disease are the presence of amyloid-beta plaques and neurofibrillary tau tangles in the brain. There are a subset of individuals whose brains contain these classical signs of Alzheimer’s, but who don’t show signs of cognitive impairment. In this project we look at tissue from these individuals, to try to discern what happens on a molecular level to protect them from cognitive decline.
Biofluid Biomarker Discovery Despite significant progress in developing biomarkers for Alzheimer’s, definitive diagnosis is still established by autopsy, and current markers do not perform well at staging or predicting disease emergence and progression. In this project we are validating a series of novel biomarkers for their potential use in AD diagnosis and clinical trials.
Insulin Resistance Alzheimer’s Disease shares many of the age-related problems that occur with type 2 diabetes, including insulin resistance, disrupted glucose metabolism and oxidative and inflammatory stress. Having type 2 diabetes greatly increases the risk of developing Alzheimer’s. In this project, we look at the key proteins involved in the regulation of insulin signaling in the brain, their activity, and how they may work together to result in Alzheimer’s Disease.
Lipid homeostasis Abnormal regulation of cholesterol and lipids in the brain have been proposed to play a pivotal role in the development of Alzheimer’s Disease. In this project, we are using biochemical methods to assess changes to lipid regulation in the brain, and trying to discover which proteins are responsible for regulating these changes.
Clinical Trials We are currently involved in a number of clinical trials:
Effects of the Insulin Sensitizer Metformin in Alzheimer Disease: Pilot Data From a Randomized Placebo-controlled Crossover StudyKoenig AM, Mechanic-Hamilton D, Xie SX, Combs MF, Cappola AR, Xie L, Detre JA, Wolk DA, Arnold SE.Alzheimer Dis Assoc Disord. 2017 Apr-Jun;31(2):107-113. doi: 10.1097/WAD.0000000000000202.
Neuronal Activity-Induced Sterol Regulatory Element Binding Protein-1 (SREBP1) is Disrupted in Dysbindin-Null Mice-Potential Link to Cognitive Impairment in Schizophrenia.Chen Y, Bang S, McMullen MF, Kazi H, Talbot K, Ho MX, Carlson G, Arnold SE, Ong WY, Kim SF.Mol Neurobiol. 2017 Apr;54(3):1699-1709. doi: 10.1007/s12035-016-9773-x. Epub 2016 Feb 12.
Agitation and Irritability in Alzheimer's Disease: Evidenced-Based Treatments and the Black-Box WarningKoenig AM, Arnold SE, Streim JE.Curr Psychiatry Rep. 2016 Jan;18(1):3. doi: 10.1007/s11920-015-0640-7. Review.
Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer's disease and tauopathies.Yarchoan M, Toledo JB, Lee EB, Arvanitakis Z, Kazi H, Han LY, Louneva N, Lee VM, Kim SF, Trojanowski JQ, Arnold SE.Acta Neuropathol. 2014 Nov;128(5):679-89. doi: 10.1007/s00401-014-1328-5. Epub 2014 Aug 9.
Repurposing diabetes drugs for brain insulin resistance in Alzheimer diseaseYarchoan M, Arnold SE.Diabetes. 2014 Jul;63(7):2253-61. doi: 10.2337/db14-0287. Epub 2014 Jun 15. Review.
High fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behavior in miceArnold SE, Lucki I, Brookshire BR, Carlson GC, Browne CA, Kazi H, Bang S, Choi BR, Chen Y, McMullen MF, Kim SF.Neurobiol Dis. 2014 Jul;67:79-87. doi: 10.1016/j.nbd.2014.03.011. Epub 2014 Mar 29.
Comparing metabolomic and pathologic biomarkers alone and in combination for discriminating Alzheimer's disease from normal cognitive aging.Motsinger-Reif AA, Zhu H, Kling MA, Matson W, Sharma S, Fiehn O, Reif DM, Appleby DH, Doraiswamy PM, Trojanowski JQ, Kaddurah-Daouk R, Arnold SE.
Resilient brain aging: characterization of discordance between Alzheimer's disease pathology and cognitionNegash S, Wilson RS, Leurgans SE, Wolk DA, Schneider JA, Buchman AS, Bennett DA, Arnold SE.Curr Alzheimer Res. 2013 Oct;10(8):844-51.
Alterations in metabolic pathways and networks in Alzheimer's diseaseKaddurah-Daouk R, Zhu H, Sharma S, Bogdanov M, Rozen SG, Matson W, Oki NO, Motsinger-Reif AA, Churchill E, Lei Z, Appleby D, Kling MA, Trojanowski JQ, Doraiswamy PM, Arnold SE; Pharmacometabolomics Research Network.Transl Psychiatry. 2013 Apr 9;3:e244. doi: 10.1038/tp.2013.18.
Cognitive and functional resilience despite molecular evidence of Alzheimer's disease pathologyNegash S, Xie S, Davatzikos C, Clark CM, Trojanowski JQ, Shaw LM, Wolk DA, Arnold SE.Alzheimers Dement. 2013 May;9(3):e89-95. doi: 10.1016/j.jalz.2012.01.009. Epub 2012 Nov 2.
Cellular, synaptic, and biochemical features of resilient cognition in Alzheimer's diseaseArnold SE, Louneva N, Cao K, Wang LS, Han LY, Wolk DA, Negash S, Leurgans SE, Schneider JA, Buchman AS, Wilson RS, Bennett DA.Neurobiol Aging. 2013 Jan;34(1):157-68. doi: 10.1016/j.neurobiolaging.2012.03.004. Epub 2012 May 2.
Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive declineTalbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, Fuino RL, Kawaguchi KR, Samoyedny AJ, Wilson RS, Arvanitakis Z, Schneider JA, Wolf BA, Bennett DA, Trojanowski JQ, Arnold SE.J Clin Invest. 2012 Apr;122(4):1316-38. doi: 10.1172/JCI59903.
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