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The New York Academy of Sciences (NYAS) symposium, Biomarkers and Brain Imaging of Presymptomatic Alzheimer’s Disease, was held last week Tuesday. About 150 people were in attendance consisting of a mix of academic and industrial researchers. [On a side note, the NYAS symposium office is located on the 40th floor of 7 World Trade Center and the views of New York city are spectacular.]
The biomarker symposium featured five speakers:
- Reisa Sperling, MD, Brigham and Women’s Hospital and Harvard Medical School
- John C. Morris, MD, Washington University School of Medicine
- Brian T. Gold, PhD, University of Kentucky
- John Olichney, MD, University of California, Davis
- Simon Lovestone, PhD, MRCPsych, MRC Centre for Neurodegeneration Research, London
Here are some of the comments and ideas captured from symposium.
First, Jennifer Henry, PhD, NYAS Director, Life Sciences, spoke. She welcomed everyone and talked briefly about NYAS. Robert B. Nelson, PhD, Lundbeck Research, then gave an introduction. The focus of the symposium “Exploring the Silent Years,” he said, was to discuss an integrated view of structural, biochemical & functional events that precede Alzheimer’s Disease. Two other comments caught my attention as he was speaking:
- Neuritic plaques are no longer considered a tombstone marker but a trail marker on the path to Alzheimer’s disease (appears prior to cognitive dysfunction)
- Clusterin is a complement lysis inhibitor whose presence correlates with immune response to AD in blood.
The first speaker of the afternoon was Reisa Sperling, MD, from Brigham and Woman’s Hospital and Harvard. Dr. Sperling is a neurologist specializing in dementia and imaging research, and an Associate Professor in Neurology at Harvard Medical School. Dr. Sperling is the Director of the Center for Alzheimer Research and Treatment at Brigham and Woman’s Hospital and serves as the Director of the Alzheimer’s disease Neuroimaging Program of the Massachusetts Alzheimer’s Disease Research Center at Massachusetts General Hospital. Dr. Sperling’s research is focused on the early diagnosis and treatment of Alzheimer’s disease. Her recent work involves the use of functional MRI and PET amyloid imaging to study alterations in brain function during in aging and early Alzheimer’s disease. The title of Dr. Sperling’s presentation was Molecular and Functional Imaging of Preclinical Alzheimer’s Disease: Defining Cohorts for Secondary Prevention Trials.
- Over the course of AD, there is progressive failure of memory network function.
- There’s a relationship between the rate of amyloid-beta deposition and rate of cognitive decline.
- Imagine if, like cholesterol with drugs that reduced heart disease by 25%, we could lower AD same way with anti-Amyloid treatment.
The next speaker was John C. Morris, MD, from Washington University School of Medicine. Dr. Morris is the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology, Professor of Pathology and Immunology, Professor of Physical Therapy, and Professor of Occupational Therapy at Washington University. He also is the Director and Principal Investigator of the Alzheimer’s Disease Research Center. The focus of Dr. Morris’ research and practice is Alzheimer’s disease and other neurological disorders associated with aging. Specific research interests include detecting preclinical Alzheimer’s disease, improving the diagnosis of early-stage Alzheimer’s disease, evaluating new drugs for the treatment of dementia, and establishing phenotypes for inherited forms of Alzheimer’s disease and other dementias. The title of Dr. Morris’ presentation was New Perspectives on ‘Silent’ Brain Amyloidosis: Relationships to Other Markers of Preclinical AD and Risk for AD Dementia.
- Dr. Morris defines AD as, regardless of clinical status, a continuous process of synaptic & neuronal deterioration.
- Many patients at the time of AD diagnosis have lost a great number of brain cells (some as much as 60%!)
- We can enhance confidence that basis of dementia syndrome is AD using biomarkers.
- AD biomarker tests must be standardized and validated; we have to classify sensitivity/specificity.
- Dr. Morris showed data that a single AD marker in CSF isn’t very specific, as it is also in other neurodegenerative diseases such as FTLD.
- Clinical Amyloid imaging is coming (PIB, Florbetapir).
- Question: what do we do when a cognitively normal person scores positive for AD PIB imaging?
- Dr. Morris then talked about the aims of DIAN, Dominantly Inherited Alzheimer Network.
The third speaker of the afternoon was Brian T. Gold, PhD, an Associate Professor in the Department of Anatomy and Neurobiology at the University of Kentucky (UK) College of Medicine. Dr. Gold is the Director of the Cognitive Neuroscience Laboratory at UK. His research focuses on characterizing cognitive and brain changes associated with normal aging, early Alzheimer’s disease (AD), and preclinical AD. In addition, Dr. Gold is investigating how certain lifestyle variables (e.g. exercise, education) may slow cognitive decline and brain aging. A multimodal imaging approach is employed, making use of functional magnetic resonance imaging and structural imaging methods such as volumetric assessment and diffusion tensor imaging. The title of Dr. Gold’s presentation was White matter microstructural Alterations: Relation to Other Markers of Preclinical Alzheimer’s Disease.
- The average lifespan following diagnosis of AD is 8 years. We need better biomarkers.
- Mild AD is too late for intervention therapies.
- Dr. Gold showed pictures on diffusion tensor imaging (DTI). Different diffusion patterns indicative of different types of damage in the brain.
- Dr. Gold uses DTI to study connections between different areas of the brain, correlate with clinical data.
- Dr. Gold’s presentation is complex; lots of acronyms, a number of regional brain areas. In summary, the data shows changes in connections with amnestic mild cognitive impairment (aMCI).
- Gold’s data shows different changes between various regions of the brain at different times during AD progression. Data dense presentation.
The next speaker was John Olichney, MD, a Professor of Neurology at University of California, Davis and Clinical Core Leader for their NIA-funded Alzheimer’s Disease Center. He is responsible for overseeing a large multi-disciplinary clinical research program in dementia, including their Alzheimer’s disease clinical trials unit. Dr. Olichney also directs the Cognitive Electrophysiology and Neuroimaging (CEaN) Laboratory in the Center for Mind and Brain at Davis, where he is active in translational cognitive neuroscience research. His main research focus is on the physiology of human memory function during normal aging and disease, using the techniques of event-related potentials (ERPs) and functional MRI (fMRI). The title of Dr. Olichney’s presentation was Cognitive ERPs as Biomarkers for Very Early Alzheimer’s Disease.
- First, Dr. Olichney described ERP components, including P600 and N400, and how they can be elicited.
- Dr. Olichney then showed event-related functional MRI data. He talked about an N600 or P400 repetition effect in mild AD.
- Generally speaking, loss of both P600 and N400 supports loss of neural plasticity in AD.
- Cognitive ERPs can provide useful biomarkers for staging AD.
- Dr. Olichney thinks the measure of cognitive function may be more important for AD than Amyloid burden.
The last speaker of the day was Simon Lovestone PhD, MRCPsych, from MRC Centre for Neurodegeneration Research, London. Dr. Lovestone is Director of Research, King’s Health Partners, Professor of Old Age Psychiatry at the Institute of Psychiatry, King’s College London, and director of the NIHR Biomedical Research Centre for Mental Health and Unit for Dementia at the South London and Maudsley NHS Foundation Trust and King’s College London. The title of Dr. Lovestone’s presentation was Plasma and CSF-based Biomarkers for MCI and AD: Relationship to Pathogenesis, Conversion, and Progression Rate.
- Problems in the AD biomarker pipeline include toxicity, efficacy, difficulty monitoring & predicting progression.
- The problem with CSF biomarkers is that they fluctuate day-by-day but don’t reflect disease progression over longer periods.
- Trials where normals show pathology don’t make sense. Lovestone instead searching for endophenotypes of histopath.
- We’re moving to complex biomarkers, multiple modalities.
A networking reception followed and the symposium came to a close.