Molecular Imaging of Inflammation in Amyotrophic Lateral Sclerosis (ALS) PI: Nazem Atassi, MD MMSc Candidate: I am a board-certified neurologist at Massachusetts General Hospital (MGH), and Assistant Professor of Neurology at Harvard Medical School (HMS). I was awarded a full scholarship from HMS and received a Masters of Medical Science degree in June 2010. I benefited from protected time for clinical research and was very productive with the grant awards I was fortunate to receive including one year T32 National Institute of Health (NIH) training grant and competitive Research Fellowships from the American Academy of Neurology (AAN) and the Muscular Dystrophy Association (MDA). I have published 6 first- or senior-author papers, 1 book chapter, and co-authored several papers. I currently have 4 submitted manuscripts under review. My goal is to accelerate drug development for people suffering from amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative disorders. My research is focused on developing mechanism-based imaging platforms to uncover pharmacodynamics (PD) biomarkers and improve the efficiency of clinical trials. Building on my previous clinical and research training, I will gain proficiency in the following new research areas through mentored project and structured career development plan:(1) Conduct patient-oriented research in subject recruitment and retention, imaging acquisition, sample collection, and clinical outcome measurements;(2) Design and implement studies to carefully characterize innovative and mechanism-based disease biomarkers;(3) Develop clinically relevant applications of multidisciplinary molecular neuroimaging techniques such positron emission tomography (PET) and magnetic resonance spectroscopy (MRS);(4) Leverage neuroimaging and biomarkers discovery to improve clinical trial design and efficiency. Acquiring these new research skills will enable me to achieve my career goals and transition to an independent researcher. Environment: To achieve the training objectives, I assembled a multidisciplinary advisory committee of mentors, consultants, and senior faculty members with complimentary expertise to guide my research and career development. My advisory committee includes (1) Dr. Merit Cudkowicz (primary mentor), an expert in ALS patient-oriented research and clinical trials study design and conduct;(2) Dr. Bruce Rosen (co- mentor), an expert in molecular neuroimaging;(3) Dr. Georges El-Fakhri (co-mentor), an expert in positron emission tomography (PET) (4) Dr. David Schoenfeld (Advisor), an experts in biostatistics and ALS outcome measures;and (5) Dr. Howard Weiner (advisor), and expert in neuroimmunology and inflammation. This multi-layered mentoring committee is embedded in a highly collaborative environment of high intellectual caliber that is part of Harvard affiliated institutions: MGH Department of Neurology, MGH Neurological Clinical Research Institute (NCRI), MGH Martinos Center for Biomedical Imaging, MGH Biostatistics Center, and the Center of Neurological Diseases at Brigham and Women's Hospital (BWH). In addition to this multi-layered mentor structure, I will participate in structured education through a combination of formal course work, workshops, and seminars. Research: The lack of mechanism-based biomarkers is one of the major challenges facing therapy development for people with neurodegenerative disorders. The main goal of this project is to characterize PD biomarkers of neuroinflammation in people with ALS using a combination of imaging and fluid markers. Specifically, we propose to study the interaction between cytokine levels in the cerebrospinal fluid (CSF) and activated microglia/monocytes in the brain using advanced molecular neuroimaging. We hypothesize that these biomarkers of inflammation contribute to ALS severity and progression and can serve as PD outcomes in future ALS clinical trials. To test these hypotheses we will enroll 30 people with ALS and 30 healthy volunteers to undergo [11C]-PBR28-PETand 3D-MRS scans. ALS participants will also undergo lumbar punctures for cytokines analysis at baseline, PET and 3D-MRS follow up scans at 6 months, and clinical follow up over 12 months. We will then design interventional studies to test the effects of anti- inflammatory treatments on these imaging and fluid pharmacodynamics (PD) biomarkers. Innovation: Our study applies novel approaches to address important and understudied questions: What is the contribution of CNS inflammation to clinical disability and prognosis in people with ALS? And how can we utilize fluid and imaging biomarkers to improve the efficiency of ALS trial designs? The proposed study leverages our center's expertise in molecular neuroimaging (synthesizing [11C]-PBR28, unique simultaneous MR-PET scanning, and 3D-MRS acquisition techniques) and ALS clinical research (impressive track record of designing and conducting ALS trials). This project has the potential to identify new disease outcomes and shift the paradigm of how we evaluate treatments in clinical trials. Identifying new mechanism-based outcome measures capable of efficiently screening potential therapeutics in people at earlier stages of development will potentially de-risk and reduce the costs of neuro-drug development.

Public Health Relevance

The development of therapies for neurological disorders is in real crisis, with less than 8% of neuro-compounds that enter early clinical studies succeeding in showing clinical efficacy. Due to lack of tools that predict early drug response, many therapies fail in later stages of testing, resulting in increased risk and cost of neuro-drug development. The goal of this career development award is to acquire new in-depth expertise in advanced neuroimaging tools that can de-risk and accelerate drug development for people with Amyotrophic Lateral Sclerosis (Lou Gehrig's disease) and other neurodegenerative disorders.

National Institute of Health (NIH)
Mentored Patient-Oriented Research Career Development Award (K23)
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Neurological Sciences Training Initial Review Group (NST)
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Gubitz, Amelie
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Massachusetts General Hospital
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Andrews, J A; Paganoni, Sabrina; Braastad, Corey et al. (2014) Disease burden in upper motor neuron syndromes: a survey of patient perspectives. J Clin Neuromuscul Dis 16:104-5