New York Academy of Sciences and the Global Medical Excellence Cluster
Biomarkers in Brain Disease: Biological and Regulatory Challenges
Posted March 24, 2009
Neurological and psychiatric conditions need good biomarkers—simple, accessible indices of complex biological phenomena. The inaccessibility of the brain, the lack of knowledge about pathophysiology, and the chronic degenerative course of many of these diseases make it difficult to judge who has the disease, how best to treat, and whether or not experimental treatments are successful. The need for clinical biomarkers may soon become acute: the most promising candidate treatments for conditions such as Alzheimer's disease are likely to be most effective for patients in the earliest stages of disease—possibly even before the onset of symptoms.
How to move forward collectively with identifying and validating brain-based biomarkers was the focus of Biomarkers in Brain Disease, a conference sponsored by the New York Academy of Sciences and the Global Medical Excellence Cluster of South East England and held from January 26–28, 2009, at Oxford University.
Use the tabs above to find a meeting report and multimedia from this event.
Image: A blood vessel affected with cerebrovascular amyloid angiopathy in a mouse model of amyloid deposits found in Alzheimer’s disease. The image was obtained with multiphoton microscopy. Claudia Prada, 2007.
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- 00:011. Introduction
- 04:422. AddNeuroMed intro
- 09:143. Phase I: 2DGE and AD plasma
- 12:534. CFH and A2M replication
- 14:285. Biological validation of CFH
- 16:296. Candidate-based biomarker discovery
- 17:407. Phase II: correlation with neuroimaging
- 19:038. De novo 2DGE with volumetry
- 21:199. Phase III: markers of progression
- 25:3510. Summary and conclusion
- 00:011. Challenges facing CNS drugs
- 02:562. Early development biomarkers
- 04:513. Outcome biomarkers
- 06:314. Alzheimer's disease overview
- 07:365. AD biomarkers: target space
- 10:176. AD biomarkers: current status
- 11:577. AD Dx scenarios
- 13:088. CSF Abeta/Tau/pTau231
- 16:519. Search for plasma-based marker
- 00:011. Collection of CSF
- 02:392. Different uses of CSF biomarkers
- 07:063. Diagnostic markers for AD
- 11:124. Can CSF markers predict development of AD?
- 16:405. Can plasma replace CSF for Abeta measurements?
- 19:306. Other potential Abeta markers
- 23:587. Evidence for a new metabolic pathway for APP?
- 25:038. Is there elevated BACE1 activity in CSF?
- 26:589. Conclusion
- 00:011. Introduction
- 01:342. Cycle of human genetics research
- 02:553. Biomarkers in clinical medicine
- 04:014. Genetic variants in Alzheimer's
- 06:375. PS1 genetic screening for early-onset AD?
- 09:046. APOE genetic biomarkers for risk and diagnosis
- 13:387. SORL1 is associated with late-onset AD
- 17:338. Other candidate genes
- 18:419. LOAD Study - Phase 3
- 22:0010. Next steps
- 24:2911. Sample stratification
- 26:2512. Summar
- 00:011. Introduction
- 01:352. Concepts and operational definitions
- 04:123. Value and utility of nonsurrogate biomarkers
- 06:044. Determining monetary value of a biomarker
- 13:395. Generalizations
- 16:236. Biomarkers needs in Phase 2 trials
- 19:047. How much drug to give and how often?
- 21:498. Which patients will respond?
- 24:239. Is the drug altering pathophysiology?
- 26:3510. Is the drug likely to be harmful?
- 28:3811. Validation and surrogate
- 00:011. Introduction
- 03:162. History of CNS biomarkers
- 05:333. Biomarkers for hypothesis testing
- 07:024. Biomarkers and drug development
- 08:545. What percent of mechanisms are tested?
- 10:286. Potential targets for depression
- 11:517. Testing hypotheses for depression
- 18:358. Targets in other CNS diseases
- 24:189. Application to decision making
- 28:4310. CNS biomarker discovery
- 32:5011. Genetics applied to biomarkers
- 36:3912. Behavior as a biomarker
- 40:4313. Working together for the futur
- 00:011. Introduction
- 01:332. Why neuroimaging in AD?
- 02:533. Use of biomarkers in clinical practice
- 04:034. Assessing disease modification
- 05:415. Aspects of imaging
- 07:246. Challenges for research biomarkers
- 09:077. Challenges for clinical practice
- 12:058. Atrophy on CT/MRI
- 13:379. Metabolic patterns on functional imaging
- 13:5310. Trials: define study population
- 17:3111. Imaging markers: examples
- 24:5112. Safety
- 26:4913. Problems and concerns
- 29:3314. Summar
The U.S. Alzheimer's Association Web site offers information for researchers about grant opportunities, its research membership society, and access to the journal Alzheimer's and Dementia.
The Alzheimer's Society provides general information about Alzheimer's disease in the UK, descriptions of research programs and grant opportunities and access to the Dementia Catalogue of the Alzheimer's Society library.
Cambridge Centre for Neuropsychiatric Research
The Cambridge Centre for Neuropsychiatric Research describes research in the Bahn and Lowe laboratories in biomarkers for diseases such as schizophrenia and bipolar disorder, including recent publications and an overview of research.
European Alzheimer's Disease Consortium
The EADC is a fully functional network of European centres of excellence working in the field of Alzheimer's disease. It provides a setting in which to increase the basic scientific understanding of and to develop ways to prevent, slow, or ameliorate the primary and secondary symptoms of Alzheimer's disease. This is done by facilitating large Europe wide research studies. The EADC is funded by the European Commission and as such enjoys the privilege of complete independence and autonomy from the pharmaceutical industry while maintaining close working links with it.
Global Medical Excellence Cluster, UK (GMEC)
GMEC, the largest Global Medical Excellence Cluster in Europe, brings together in a collaborative effort, leading universities, pharmaceutical and medical device companies, and hospitals in the UK. The goal is to improve innovation, product development, and leading-edge research activity; create employment opportunities; and enhance patient outcomes.
Innovative Medicines Initiative
The Innovative Medicines Initiative, a partnership between the European Community and the European Federation of Pharmaceutical Industries and Associations, supports AddNeuroMed, a collaborative effort to identify diagnostic and predictive biomarkers for Alzheimer's disease.
Keynote Address: William Potter
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Giovannoni, G. 2004. The yin and yang of inflammation in multiple sclerosis. In G. Comi, ed., Early indicators, early treatment and neuroprotection in multiple sclerosis. Springer, Rome.
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Sampaio C. 2007. Clinical relevance on Alzheimer's disease endpoints. J. Nutr. Health Aging 11: 316-317.
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Gordon Wilcock and Bruno Vellas
Andrieu S, Coley N, Aisen P, et al. 2009. Methodological issues in primary prevention trials for neurodegenerative dementia. Alzheimers Dis. 16: 235-270.
Sabine Bahn, MD, PhD
Sabine Bahn is the director of the Cambridge Centre for Neuropsychiatric Research at the University of Cambridge's Institute of Biotechnology. Her main research interest is in understanding the molecular basis of neuropsychiatric / neurodevelopmental disorders. Her main focus is on the major psychotic disorders schizophrenia and bipolar disorder.
Karima Boubekeur, PhD
F. Hoffman-LaRoche Ltd.
Karima Boubekeur is head of external R&D at F. Hoffman-LaRoche. She manages the Innovative Medicines Initiative for the Research Directors' Group of the European Federation of Pharmaceutical Industries and Associations (EFPIA).
Maria Carrillo, PhD
Maria Carrillo is the director of medical & scientific relations for the Alzheimer's Association National Office in Chicago. She has a wide range of responsibilities, including oversight of the association's granting process and communication of scientific findings within and outside of the organization. Carrillo also manages several initiatives. One of these is the management of the World-Wide Alzheimer's Disease Neuroimaging Initiative (WW-ADNI) which is a multi-country initiative aimed at finding biomarkers for early detection of Alzheimer's and the Working Group on Technology (WGT), which promotes the use of technologies available today for the support of individuals affected by Alzheimer's disease to retain their independence as long as possible.
Kathy Granger, PhD
Kathy Granger manages the life sciences conferences at the New York Academy of Sciences. She received her PhD from the Department of Medicine at Monash University in Australia. She worked as a postdoctoral associate at Weill Cornell Medical College in New York City before joining the Academy as program manager for life sciences.
David Hawkes, PhD
David Hawkes is professor of medical imaging science and director of the Centre for Medical Image Computing (CMIC) at University College, London and co-founder of the imaging company IXICO Ltd. His current research interests encompass image matching, data fusion, visualization, shape representation, surface geometry, and modeling tissue deformation, promoting medical imaging as an accurate measurement tool and image-guided interventions.
Andrew Lockhart, PhD
Andrew Lockhart is a manager in the Neurosciences Centre of Excellence for DNA Discovery and is based at the New Frontiers Science Park, Harlow. His research interests are in the evaluation and development of soluble and imaging biomarkers to support drug development across a range of neurological diseases.
Simon Lovestone, PhD
Simon Lovestone is 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 at the South London and Maudsley NHS Trust and the Institute of Psychiatry. His research interests concentrate on understanding the molecular and cellular events that take place in the brain and especially the role of tau, in Alzheimer's disease, together with the genetics and proteomics of late onset Alzheimer's disease.
Richard Mayeux, MD
Richard Mayeux is the Gertrude H. Sergievsky Professor of Neurology, Psychiatry and Epidemiology at Columbia University. He is the director of the Gertrude H. Sergievsky Center and the co-director of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain. Mayeux directs several studies on Alzheimer's disease such as the ongoing, 20-year old epidemiological study on Alzheimer's disease and related conditions, a genetic linkage study in Caribbean Hispanic Families, and a study of over 1000 families to examine late onset Alzheimer's disease. In 2007, he won the Potamkin Prize from the American Academy of Neurology.
Jeremy Nicholson, PhD
Jeremy Nicholson is chair in Biological Chemistry, Imperial College London. His research interests include molecular physiochemical processes in metabolism and medicine; nuclear magnetic resonance spectroscopy (NMR), mass spectroscopy, and hyphenated methods for studying drug metabolism and toxicity; pattern recognition and computational chemistry in drug design and diagnostics; and molecular systems biology of disease processes.
Ian Pike, PhD
Ian Pike has a strong career focus on biomarkers and in vitro diagnostics. His experience includes serving as a non-executive director on the boards of biotechnology start-ups Spirogen and Proacta Therapeutics and is currently a director of the South East Healthcare Technologies Alliance. As chief business officer at Proteome Sciences, Pike is responsible for the commercial development of its ProteoSHOP toolkit delivering fast, efficient, and cost-effective solutions for biomarker discovery, validation, and assay development. He is also responsible for general biomarker licensing activities and management of the company's intellectual property portfolio.
William Potter, MD, PhD
William Potter joined Merck Research Laboratories in 2006 as the vice president of translational neuroscience. Prior to joining Merck he was an executive director and research fellow at Lilly Research Labs, specializing in the neuroscience therapeutic area. Potter also spent 25 years at the NIH focusing on translational neuroscience. Potter has become a widely recognized champion for the position that more disciplined hypothesis testing of targets in humans is the best near-term approach to moving central nervous system drug development forward.
Barbara Sahakian, PhD
Barbara Sahakian is a professor of clinical neuropsychology at the University of Cambridge School of Clinical Medicine and Addenbrooke's Hospital, Cambridge. She is best known for her research work on cognition and depression, cognitive enhancement using pharmacological treatments, neuroethics, and early detection of Alzheimer's disease. Barbara is a member of the Science Co-ordination Team for the Foresight Project on Mental Capital and Wellbeing.
Gordon Wilcock, PhD
Gordon Wilcock is a professor of geratology at the University of Oxford, where he leads the Oxford Biomedical Research Centre Dementia programme. He is also the clinical director of the Oxford Project to Investigate Memory and Aging (OPTIMA). Wilcock's area of expertise is in the dementias, especially Alzheimer's disease, the most common cause of dementia in the elderly.
Roger Barker, PhD
Roger Barker's work concentrates on the neurodegenerative disorders of Huntington's and Parkinson's diseases. His experimental focus is on xenotransplantation and stem cells. He has several large Medical Research Council-funded clinical trials in progress.
Carol Brayne, PhD
Carol Brayne has a public health role in training physicians and specialists, and leads the training of postgraduates in epidemiology at Cambridge. Her research interests include longitudinal studies into the aging population, public health and autism spectrum disorders, psychosocial determinants of onset and outcome of chronic disease in the Elderly Pharmaceutical Insurance Coverage Program (EPIC), and a case control study of the genetic aspects of Alzheimer's disease.
David Brooks, MD
David Brooks is Hartnett Professor of Neurology, Imperial College, London and head of Neurology Group, Hammersmith Hospital, UK. Brook's research involves the use of positron emission tomography (PET) and magnetic resonance imaging (MRI) to diagnose and study the progression of Alzheimer's and Parkinson's disease and their validation of biomarkers in therapeutic trials.
Wayne Drevets, MD
Wayne Drevets is chief of neuroimaging in the Mood and Anxiety Disorders Section of the National Institute of Mental Health at the National Institutes of Health. Drevet's research is focused on applying PET and MRI technologies to characterize the neurophysiological, receptor pharmacological, and neuroanatomical correlates of mood and anxiety disorders.
Nick Fox, MD
Nick Fox is professor of clinical neurology at the Institute of Neurology, University College London. Fox's research has focused on MRI in Alzheimer's disease and related disorders. Using techniques that he developed for registration-based atrophy measurements from serial MRI, he has shown that rates of cerebral atrophy predict conversion to AD from mild cognitive impairment and that the rates of atrophy correlate with clinical decline.
Gavin Giovannoni, PhD
Gavin Giovannoni is professor of neurology in the neuroimmunology unit at the Institute of Cell and Molecular Science Neuroscience Center, Barts; and The London School of Medicine and Dentistry, UK. Giovannoni's current research is focused on Epstein Barr virus as a possible cause of multiple sclerosis (MS), MS-related neurodegeneration, MS biomarker discovery, MS clinical outcome measures, MS clinical trials, and immune tolerance strategy.
Orest Hurko, MD
Orest Hurko is assistant vice president of translational research at Wyeth. He is on the Discovery Executive Committee, the Development Council, the Translational Medicine Review Board and the Neuroscience Leadership Team. He is helping build one of the most innovative discovery processes for biomarkers in use today.
Juan Carlos López, PhD
Juan Carlos López started his scientific career at the Universidad Nacional Autónoma de México studying neurochemical correlates of memory formation. He obtained his PhD from Columbia University under the supervision of Eric Kandel, and carried out postdoctoral work at the Instituto Cajal in Madrid. He is the author of two scientific books and was editor of Nature Reviews Neuroscience before joining Nature Medicine as chief editor.
Thomas Metcalfe, PhD
F. Hoffman-LaRoche, Ltd., USA
Thomas Metcalfe is the head of the Roche Biomarker Program where he is responsible for increasing potential synergies between the pharmaceuticals and diagnostics divisions.
Cristina Sampaio, MD, PhD
Cristina Sampaio is professor of clinical pharmacology and therapeutics at the University of Lisbon. Sampaio's main research interests are design and methodology of clinical studies, pharmacoepidemiology, and evidence-based medicine.
Leslie Shaw, PhD
Leslie Shaw is director of the Clinical Toxicology Laboratory and professor of pathology and laboratory medicine at the University of Pennsylvania Medical Center. Shaw's work includes research into biomarkers of oxidant stress as well as therapeutic drug monitoring and clinical toxicology.
Peter Schulz-Knappe, MD, PhD
Peter Schulz-Knappe is research and development director and chief scientific officer of Proteome Sciences plc, UK. Prior to joining Proteome Sciences, Schulz-Knappe was the founder and CSO of the biomarker-discovery firm BioVision, and head of the Department of Preparative Peptide Chemistry at the Lower Saxony Institute of Peptide Research.
Holly Soares, PhD
Holly Soares is director of translational medicine and serves as the translational medicine clinician for Pfizer's CNS programs. She employs translational biomarkers in clinical programs to ensure experimental compounds have centrally mediated pharmacodynamics activity relevant to target under investigation. She also oversees validation of biomarkers that may prove to be predictive of early efficacy in Alzheimer's disease, attention deficit hyperactivity disorder, schizophrenia, depression, and anxiety.
Sheila Taube, PhD
Sheila Taube served with the National Cancer Institute of the NIH for 25 years. During this time she helped to advance personalized medicine approaches and technologies for detecting molecular markers for cancer.
Jochen G.W. Theis, MD
Jochen Theis is the owner and principle consultant for InHeCon (Integrated Healthcare Consulting). Prior to starting this company he was global head of biomarkers and experimental medicine at F. Hoffmann LaRoche.
Arthur Toga, PhD
Arthur Toga is professor of neurology, director of the Laboratory of Neuro Imaging and associate director of the Division of Brain Mapping, University of California, Los Angeles School of Medicine. Toga's interests are in brain mapping and neuroimaging, utilizing mathematical and modeling strategies to measure brain structure and function in health and disease. He has pioneered population-based feature analysis and developed large subject databases of image data for a variety of cohorts.
Bruno Vellas, MD, PhD
Bruno Vellas is currently a professor in the Department of Geriatric Medicine at the University of Toulouse. He is also a hospital practitioner in the university hospital center as well as a research associate professor in the Clinical Nutrition Laboratory (Aging Process Study) in the School of Medicine of the University of New Mexico, USA. He has been involved in numerous studies investigating links between health, and in particular, nutrition and Alzheimer's disease.
Vellas is a member of a number of editorial boards and numerous scientific societies, such as the French Society of Nutrition and the American Geriatric Society.
Henrik Zetterberg, MD, PhD
Henrik Zetterberg is at the Institute of Neuroscience & Physiology in the Department of Psychiatry & Neurochemistry at the Sahlgrenska Academy, University of Gothenburg, Sweden. Zetterberg studies γ-secretase substrates in models of Alzheimer's disease. He also studies how brain injury affects levels of cerebrospinal fluid (CSF) and examines how chemicals present in CSF indicate damage to neurons.
Kathleen McGowan is a freelance magazine writer specializing in science and medicine.
- Imperial College
- Johnson & Johnson
- King's College London
- Oxford University
- The Ellison Medical Foundation
- University College London
- Wellcome Trust
- Alzheimer's Association
- BIOBASE GmbH
- Foresight Programme, Government Office for Science
- Rules-Based Medicine, Inc.
- Schering-Plough Research Institute
- Scout Diagnostics
- The Alzheimer's Research Trust
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Until relatively recently, biomarkers were not a popular area of investigation. By the 1980s, many believed that by individualizing treatment, subdividing disease, and explicating pathophysiology, genetics would make biomarkers unnecessary. The essential role of biomarkers as tools to understanding how drugs work and disease progresses was eclipsed by the rising star of the human genome.
Yet the need for biomarkers—simple, accessible indices of complex biological phenomena—only grew. Now their absence is crippling pharmaceutical research; drug development pipelines are drying up. Meanwhile, record numbers of experimental compounds are failing in increasingly expensive late-stage clinical trials.
Neurological and psychiatric conditions, in particular, need good biomarkers. The inaccessibility of the brain, the lack of knowledge about pathophysiology, and the chronic degenerative course of many of these diseases make it difficult to judge who has the disease, how best to treat, and whether or not experimental treatments are successful. The need for clinical biomarkers may soon become acute: the most promising candidate treatments for conditions such as Alzheimer's disease (AD) are likely to be most effective for patients in the earliest stages of disease—possibly even before the onset of symptoms.
How to move forward collectively with identifying and validating such brain-based biomarkers was the focus of Biomarkers in Brain Disease, a conference sponsored by the New York Academy of Sciences and the Global Medical Excellence Cluster of South East England and held from January 26–28, 2009, at Oxford University. In general, the meeting focused on biomarkers as used in drug development and clinical trials.
In the last few decades, researchers have proposed increasingly sophisticated hypotheses of disease for conditions ranging from depression to Parkinson's, but their ability to test them has not kept up, pointed out keynote speaker William Potter of Merck Research Laboratories. Drug development for depression is a good example: Of the more than 75 potential targets in depression, the mechanisms by which they might affect the condition have been established for only a handful. "That's the reality, and that's a field that we thought was way ahead," he cautioned.
Biomarkers are shining a light on the brain processes involved in these diseases.
But there are signs of progress. Disease-related profiles in cerebrospinal fluid (CSF) have been established for Alzheimer's disease, and much attention is focused on doing the same in plasma. Imaging techniques such as positron emission tomography (PET), magnetic resonance imaging (MRI), and, more recently, diffusion tensor imaging (DTI) are becoming useful adjuncts for the diagnosis and monitoring of neurodegenerative disease and for the testing of antidepressant candidate drugs. Proteomics and metabolomics will no doubt identify characteristic biochemical signatures of physiological processes. None of these techniques are yet ready to answer the biggest questions, said Potter, but we're getting closer. "It's not too strong to say that biomarkers are shining a light on the brain processes involved in these diseases," he said. After years of neglect, we can now look forward to an era in which the biomarker finally comes of age.
Biomarkers: a typology
Most broadly, a biomarker is a quantifiable measure correlated with or predictive of a physiological process involved in health or disease. "Biomarker" means different things in different contexts, so one of the most important challenges in biomarker development is conceptual rather than scientific: researchers must be absolutely clear about what they're looking for and what they plan to do with the information.
Even at this conference, speakers did not agree upon one typology to categorize biomarkers, but rather proposed different categories based on different criteria. Potter distinguished two types of biomarkers. For neurologists, a biomarker is a quantifiable difference in brain tissue or CSF associated with the course or severity of symptoms, he said. But for a drug developer, a biomarker could be any measure of drug action that is proximal to its clinical effect.
Cristina Sampaio of the University of Lisbon proposed three categories:
- Disease-associated biomarkers of risk, diagnosis, and progression
- drug-related biomarkers that relate to pharmacogenomics and drug response
- patient-associated biomarkers that reflect compliance or relate to adverse events
Focusing solely on biomarkers as used in drug development, Orest Hurko of Wyeth Research identified four subtypes:
- Biomarkers reflecting dosing and receptor occupancy
- those identifying patients most likely to suffer toxic effects from the drug
- those predicting which patients will have the most robust response
- those offering an early indicator of efficacy
"It is meaningless to speak of a biomarker unless you specify which of these four questions it is to address," said Hurko.
Biomarker development should be considered an "extremely high-risk undertaking."
The time and expense of identifying and validating a biomarker can be just as burdensome as developing a drug, so biomarker development should be considered an "extremely high-risk undertaking," cautioned Hurko. And the Holy Grail—a biomarker that can serve as a surrogate measure of disease for regulatory purposes—is vanishingly rare. A few have held up in other fields of medicine, such as cholesterol levels for risk of heart disease or T-cell count for AIDS progression. But so far, none stand alone in neurological or psychiatric disease.
Expensive as they are, however, biomarkers can be useful in clinical trials by improving power, rationalizing dosing, and saving money by preventing even costlier research. Candidate drugs for CNS diseases have one of the highest attrition rates in the pharmaceutical industry. "We fail late, which is not a good place to fail," said Holly Soares of Pfizer. A biomarker can tell you when it's time to call it quits. A biomarker can also convert a failure into a learning opportunity, by testing the hypothesis that engaging the new target has an effect. Without being able to monitor what's going on inside the brain, drug development is just a shot in the dark.
As Carol Brayne of the University of Cambridge pointed out, if biomarkers can be developed for risk, diagnosis, and progression, it is also important to keep a public health perspective when deciding whether they should be used in clinical practice. In the case of biomarkers for predicting risk, for example, there is the potential for misdiagnosis and expensive overtreatment of disease, particularly for brain diseases like dementia, which is actually a spectrum of disorders. She advocated for a system that would operate in parallel with biomarker development to assess the public health, ethical, social, and legal implications of potential biomarker-based interventions.
Alzheimer's: The state of the art
Biomarkers are sorely needed for Alzheimer's disease: As many as 150 targets have been suggested to be relevant to AD, Potter pointed out, but few have been validated; that is, proven to influence the pathophysiology of the disease. In terms of treatment, because the disease is slow to progress, assessing whether or not a therapy is effective is a challenge. Clinical trials for potential AD drugs will by necessity be very large and very long, and a biomarker that reflects pathophysiology could give an early signal of success or failure.
The best AD treatments may be neuroprotective agents that must be given before clinical symptoms become evident; thus a biomarker would be required to identify who is likely to benefit. Some of the most promising potential treatments are disease-modifying agents such as β-secretase inhibitors, anti-inflammatories, or immunotherapy, but a disease-modifying effect can't be proven on clinical outcomes alone; physiological changes in the brain must be documented.
A few good AD biomarkers have been established, although none have yet been fully validated. Three peptides, amyloid-beta 42 (Aβ-42), total tau, and phosphorylated tau (phosphotau), have been most thoroughly studied, with the confirmed finding that tau levels increase and Aβ-42 levels decrease in the CSF of people with AD. By monitoring all three, Henrik Zetterberg's group at the Sahlgrenska Academy at the University of Gothenburg can predict conversion to AD in a heterogeneous population. However, peptide levels have no relationship to individual disease state and cannot be used to track progression. Zetterberg mentioned another promising approach: analyzing the pattern of Aβ fragments in CSF with mass spectrometry. He noted that Aβ-42 levels in plasma have no relationship to those in CSF and cannot be used to diagnose disease.
Some types of neuroimaging are coming into their own, such as volumetric structural images that capture hippocampal atrophy, which can diagnose AD at specificity and sensitivity above 90%. Pittsburgh-B is a relatively new ligand that can be paired with PET to image overall amyloid in the brain. It has low specificity: many people have a significant amyloid load and normal cognition.
Alzheimer's: Where we must go
So far, the many efforts to identify plasma biomarkers have not succeeded, but there is good evidence that they ultimately will be found, said Simon Lovestone of King's College London. Lovestone has used 2-D gel electrophoresis and mass spectrometry-based proteomics to identify two plasma-based candidates, complement factor H and α-2 macroglobulin, that correlate with disease activity in the brain. An "in silico" search of existing literature also pointed to C-reactive protein as a potential predictor of disease progression.
Holly Soares described Pfizer's project with the biomarker-testing firm Rules-Based Medicine to develop a panel of up to 151 analytes in blood that could identify presymptomatic patients. She and Lovestone were two of the many speakers who emphasized that multiple biomarkers across several modalities will ultimately be necessary. "I don't think we're in the game of any one protein or gene or anything else being the answer," Lovestone said.
Imaging, although expensive, could reduce the number of people needed for a successful clinical trial, argued Nick Fox of University College London. In one recent study, an estimated 320 human volunteers were needed to show a 50% effect on progression in one year, using a standard behavioral measure. With MRI structural imaging of hippocampal volume, the number could have been as low as 21. Structural imaging can also be used to monitor disease onset or progression in individual patients: Fox's group has pioneered a technique that allows sequential structural images of the brain in people at risk of AD to be precisely compared. Other imaging technologies that are more preliminary include diffusion tensor imaging, which visualizes white matter, functional MRI, which might profitably be combined with vMRI, and FDG-PET, which can distinguish between AD and other dementias by pinpointing activity changes.
Multiple biomarkers across several modalities will ultimately be necessary.
Genetic biomarkers may be most practical in AD to identify who is at high risk for the disease or to predict prognosis, suggested Richard Mayeux of Columbia University. The unique power of genetic biomarkers is that they are present at birth, long before disease onset. His group has focused on variants of SORL1 in a population in the Dominican Republic; other risk variants include the well-known ApoE4 allele, and possibly LRP6 and GAB2.
Cognitive biomarkers may not be as flashy, but refinements in these could yield cheap and widely applicable tools. Barbara Sahakian of the University of Cambridge described success with CANTAB, a cognitive battery that probes the function of the hippocampus, a brain region experiencing early decline in AD. This test, particularly when paired with tests of semantic memory, can distinguish elderly adults with AD from those with other cognitive problems and predict decline in a nonclinical sample of healthy older adults.
Other diseases: lessons learned
Alzheimer's is the 800-pound gorilla of neurodegenerative disease, but biomarkers are being pursued for many other brain diseases. Schizophrenia offers a very different challenge: Effective therapies are available for this disease, but the major difficulty is in timely diagnosis. The hope is that because the disorder appears to have a long prodromal phase, early intervention could alleviate or even prevent psychotic episodes.
Beginning with postmortem brain samples and moving to CSF and serum, Sabine Bahn at the University of Cambridge has found evidence of dysregulation in the periphery as well—which hints of an accessible schizophrenia biomarker. Working with Rules-Based Medicine, her group has identified a panel of 54 biomarkers that predicts schizophrenia with more than 90% specificity and sensitivity, and differentiates from depression, MS, and bipolar disorder.
Making the argument for systems thinking and the power of metabolomics, Jeremy Nicholson of Imperial College London presented provocative data linking autism to variation in gut enzymes and gut microbial flora. Metabolomics can explicate disease even where gene-association studies fail, he argued, by identifying biomarker clusters that reflect both environmental and genetic variation. At the individual level, metabolomic profiling can predict therapeutic outcomes. At the population level, the approach can be used for biomarker discovery to generate hypotheses that are mechanism-based and physiologically testable. The 1.5 kg of gut bacteria make a highly significant contribution to human physiology, Nicholson pointed out: collectively, the human microbiome may have 20 times as many druggable targets as does the human genome.
In Parkinson's, one of the simplest biomarkers is measuring a patient's ability to tap his or her hand.
In Huntington's disease, the D-2 dopamine receptor antagonist raclopride can be used as a ligand in combination with PET imaging to visualize the loss of brain tissue, a powerful but expensive technique. One of the simplest biomarkers turns out to be surprisingly effective, Roger Barker of the University of Cambridge explained: measuring the patient's ability to tap his or her hand, which deteriorates as the disease progresses. Barker also described a slightly more sophisticated version of this movement-measuring technique: a "saccadometer" built of head-mounted lasers to track eye movements. The patient's ability to follow a moving laser light is a sensitive and accurate index of disease progression. For Huntington's disease, an autosomal-dominant genetic disorder with highly variable disease onset, the central questions are whether a patient is beginning to suffer symptoms, and whether treatment is working. A major European study, Track-HD, is now evaluating biomarkers in a large population of pre-manifest carriers.
In multiple sclerosis, a demyelinating disorder, visualization of brain lesions via MRI is now accepted as part of the clinical criteria for diagnosis by the European drug-regulatory agency. Gavin Giovannoni showed a striking example of the neurological damage that occurs in MS patients, highlighting the need for early diagnosis and treatment. MRI data helped get Avonex approved for patients who had had a single demyelinating episode and were at a very high risk of developing definitive MS, "the only real approval based on biomarkers" so far in neurological disease, said Cristina Sampaio.
In MS, autoimmune antibodies attack axons and demyelinate them, but the hope is that sodium-channel blockers and anti-inflammatory agents such as lamotrigine or riluzole may protect axons from death. Clinical trials suggest that if used early on, treatments such as alemtuzumab (CAMPATH), a monoclonal antibody approved for B-cell chronic lymphocytic leukemia, may prevent relapses and disability over the long term. These drugs are promising, but because they are neuroprotective agents, studies are difficult to power. Giovannoni described using heavy-chain neurofilament (NF), a nonspecific marker of axonal damage, as a biomarker. In the CSF, baseline levels of hypophosphorylated neurofilament predict disability in three years' time. "We think this is a prognostic marker for disease progression, or degree of damage due to MS attack," he said. NF could "enrich" clinical trials by identifying the patients who are most likely to benefit.
A collective future
Relying on surrogate biomarker is risky, cautioned Sampaio, telling the story of glycemia in diabetes: For a long time, the FDA accepted glycemic control as a valid surrogate biomarker of disease improvement. In 2007, rosiglitazone, which reduces blood glucose, was shown to increase raise cardiac risk. Some diabetes researchers have suggested that it should be abandoned as a primary endpoint surrogate; at the end of 2008, the FDA concluded that while this biomarker is still an "acceptable" surrogate for new drug approval, developers must now also prove that the candidate drug does not raise cardiovascular risk, a substantial additional burden.
Even validation of "non-surrogate" or "presurrogate" biomarkers will require unprecedented collaboration, cooperation, and standardization, because the process will likely demand large studies that can prove a putative biomarker is robust and reliable among a heterogeneous population. Many talks focused on how best to carry that out. Issues that seem trivial, such as which samples to collect, what readouts to measure, and how these should be curated and documented, are in fact major hurdles to overcome. "Something as seemingly innocuous as file formats can have a profound impact on how effectively we share things," said Arthur Toga of the University of California, Los Angeles School of Medicine.
Validating biomarker will require unprecedented collaboration and standardization.
Successful large-scale collaborations will likely require public-private partnerships, free data sharing, and extensive involvement of regulatory agencies. One such model is the Alzheimer's Disease Neuroimaging Initiative, a $60 million project funded by the National Institute on Aging, private foundations, and the pharmaceutical industry and led by Michael Weiner at University of California, San Francisco. European and Japanese projects have been incorporated into this study, which now includes 25 centers and more than 800 volunteers, and all the data is freely available. "This is an example of how a small amount of money can make a difference, expand collaboration and open up dialog," said Maria Carrillo of the Alzheimer's Association USA, which has taken on the job of maintaining international information flow.
AddNeuroMed, a cross-European effort that links clinical and preclinical research, is another such example of collaboration. Here, the effort is focused on identifying a key target of progression that can substitute for clinical measures in trials of disease-modifying agents. Richard Mayeux also described his data-sharing successes with the NIA-LOAD study, which has made available data from 3698 people either with AD or in an AD family. "My personal experience is that making data and samples available to everyone from the beginning actually works," he said. "You find you have more collaborators than you would have dreamed of."
Despite the obvious challenges, Alzheimer's disease may present a unique opportunity for massive international collaboration in biomarker development to succeed. All the ingredients are there: A disease with a major impact, plenty of funding, a strong public mandate for new treatments, and hundreds of labs around the world focused on the problem. These collaborations could set the pace for biomarker development in other diseases.
Bruno Vellas, head of the European Task Force on Disease-Modifying Alzheimer's Trials reminded the audience of the critical need for better research and clinical tools as he reviewed a number of failed clinical trials for drugs to treat Alzheimer's disease. In the hope of improving future outcomes, the task force has focused its third meeting on the use of biomarkers.