| Volume
8, Number 4, December 2005 - Special Issue "Biomarkers for Alzheimer's Disease" (Guest Editor: Thomas Montine)
Pages 325-326
Elaine R. Peskind, Thomas J. Montine
Foreword: Biomarkers for Alzheimer’s Disease
Pages 327-337
Jeffrey L. Cummings
Clinical Evaluation as a Biomarker for Alzheimer’s Disease
Abstract: Clinical assessment is the gold standard of diagnosis, differential diagnosis, and assessment of the success of therapeutic interventions. Changes in clinical state are the principal indicator of disease presence and progression. Clinical status is a complex estate determined by an interaction of host and disease factors. Host factors manifest as cerebral reserve, determined by genetic and environmental-historical influences. Variability in host factors creates variability in clinical states not attributable to disease burden and compromises the extent to which clinical evaluation and disease activity are directly related. The utility of biomarkers is judged by the degree to which they reflect clinical outcomes. Some biomarkers are more directly related to disease activity, are less influenced by host factors, have smaller standard deviation of measures, and require fewer patients to establish between-group difference than clinical assessment. Biomarkers must closely reflect clinical outcomes to be useful as evaluation of disease progression or as outcomes in clinical trials.
Pages 339-346
Douglas Galasko
Biomarkers for Alzheimer’s Disease – Clinical needs and application
Biomarkers for Alzheimer’s disease have many diagnostic and therapeutic uses. They can be used to facilitate diagnosis, particularly early diagnosis and possibly presymptomatic diagnosis. In evaluating treatment aimed at modifying the course of AD, biomarkers can help to assess whether the drug is hitting a target or influencing disease mechanisms in the brain, and can help with dose-finding. In definitive clinical trails, biomarkers can be used as surrogate outcome measures. Progress has been made in investigating candidate biomarkers in cerebrospinal fluid and plasma. At present, cerebrospinal fluid levels of amyloid-ß, tau and phospho-tau come closest to meeting criteria proposed for useful biomarkers for diagnosis. Other biomarkers can provide insight into processes such as inflammation and oxidative damage. Unbiased and broad-based searches for novel biomarkers using proteomics have much potential. As efforts to diagnose and treat AD move towards earlier intervention and even towards prevention, biomarkers will gain significance as tools to aid research and ultimately clinical practice.
Pages 347-358
Anne M. Fagan, Cynthia A. Csernansky, John C. Morris, David M. Holtzman
The search for antecedent biomarkers of Alzheimer’s disease
Abstract: Alzheimer’s disease (AD) will likely become the greatest public health crisis in the United States within the next 2-3 decades if left unchecked. There are no proven treatments that delay the onset or prevent the progression of AD, although a few promising candidates are under development. Even the earliest clinical symptoms of AD are accompanied by, and likely due to, neuronal/synaptic dysfunction and/or cell death. Thus, it is critical to identify individuals with “preclinical AD,” prior to the development of clinical symptoms and concomitant neuronal loss, so new therapies will have the greatest clinical impact. At present, there are no antecedent biomarkers that will identify individuals with preclinical AD, however ongoing investigations of “at risk” populations, including those with Mild Cognitive Impairment (MCI), presymptomatic individuals harboring known disease-causing familial AD mutations or carriers of the e4 allele of apolipoprotein E are offering insights into possible biomarkers of early disease processes. To discover antecedent biomarkers of AD, a prospective, longitudinal study of middle-aged individuals with positive or negative family history of AD has been initiated at Washington University in St. Louis. The Adult Children Study provides an opportunity to discuss the challenges and goals for investigations of antecedent AD biomarkers.
Pages 359-367
Thomas J. Montine, Joseph F. Quinn, Kathleen S. Montine, Jeffrey A. Kaye, John C.S. Breitner
Quantitative in vivo biomarkers of oxidative damage and their application to the diagnosis and management of Alzheimer’s disease
Dementia from Alzheimer’s disease (AD) represents a significant and growing public health burden and presents a clear therapeutic imperative. Key to success in this undertaking will be biomarkers for the objective assessment of disease progression and response to therapeutics. Oxidative damage is one facet of AD pathogenesis for which there are experimentally validated quantitative in vivo biomarkers, the F2-isoprostanes (IsoPs). While plasma- or urine-based assays are desirable, consistent and reproducible cross-sectional data for increased F2-IsoPs in AD and mild cognitive impairment have been obtained only for CSF. In addition, measurement of CSF F2-IsoPs can increase the accuracy of laboratory-based classification of geriatric dementias, and have been used to assess objectively the response to anti-oxidant interventions in AD.
Pages 369-375
Robert E. Mrak, W. Sue T. Griffin
Inflammatory biomarkers in Alzheimer’s disease
Abstract: The role of the brain’s innate immune system in Alzheimer pathogenesis is now well established. Proinflammatory cytokines elaborated by this system, in particular activated microglia-derived interleukin-1 (IL-1), drive a cascade of neurotoxic changes that are important for the development and progression of both the neuritic plaques and neurofibrillary tangles characteristic of Alzheimer's disease. Cytokine expression may also be modulated by variants of genes. For instance, inheritance of certain IL-1 gene variants is associated with Alzheimer's disease. The potential for using blood levels of proinflammatory cytokines as biomarkers of disease progression, however, remains unrealized. The interpretation of cytokine levels in the blood is complicated by the fact, for example, that the overexpression of IL-1 in Alzheimer brain may act to increase adrenal cortisol production through the hypothalamic-pituitary-adrenal axis, which acts to limit macrophage activation and peripheral cytokine production.
Pages 377-386
Jing Zhang, David R. Goodlett, Thomas J. Montine
Proteomic Biomarker Discovery in Cerebrospinal Fluid for Neurodegenerative Diseases
Abstract: The clinical diagnosis of major neurodegenerative disorders, e.g. Alzheimer's disease, Parkinson’s disease, and dementia with Lewy body, remains unsatisfactory based on current clinical criteria and limited laboratory investigations. The possibility of identifying multiple novel biomarkers for neurodegenerative diseases, those related to disease pathogeneses in particular, has been greatly enhanced with recent advances in genomics, proteomics, and metabolomics. In this chapter, we will be reviewing a few issues related to proteomic identification of proteins in human cerebrospinal fluid (CSF) as well as unique protein markers that could be used for clinical diagnosis of various neurodegenerative diseases or monitoring their progression. Great attention has been directed to practical considerations and limitations of several major aspects of proteomic analysis of human CSF.
Pages 387-392
Transcript: Alzheimer Research Forum Live Discussion
Imaging in Alzheimer's Disease: The Current State of Affairs
Pages 393-399
Transcript: Alzheimer Research Forum Live Discussion
Making a BioMark on Alzheimer Disease
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