| 1. |
- Blennow, Kaj, 1958, et al.
(author)
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Cerebrospinal fluid and plasma biomarkers in Alzheimer disease
- 2010
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In: Nature reviews. Neurology. - : Springer Science and Business Media LLC. - 1759-4766 .- 1759-4758. ; 6:3, s. 131-44
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Research review (peer-reviewed)abstract
- Intense multidisciplinary research has provided detailed knowledge of the molecular pathogenesis of Alzheimer disease (AD). This knowledge has been translated into new therapeutic strategies with putative disease-modifying effects. Several of the most promising approaches, such as amyloid-beta immunotherapy and secretase inhibition, are now being tested in clinical trials. Disease-modifying treatments might be at their most effective when initiated very early in the course of AD, before amyloid plaques and neurodegeneration become too widespread. Thus, biomarkers are needed that can detect AD in the predementia phase or, ideally, in presymptomatic individuals. In this Review, we present the rationales behind and the diagnostic performances of the core cerebrospinal fluid (CSF) biomarkers for AD, namely total tau, phosphorylated tau and the 42 amino acid form of amyloid-beta. These biomarkers reflect AD pathology, and are candidate markers for predicting future cognitive decline in healthy individuals and the progression to dementia in patients who are cognitively impaired. We also discuss emerging plasma and CSF biomarkers, and explore new proteomics-based strategies for identifying additional CSF markers. Furthermore, we outline the roles of CSF biomarkers in drug discovery and clinical trials, and provide perspectives on AD biomarker discovery and the validation of such markers for use in the clinic.
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| 2. |
- Blennow, Kaj, 1958, et al.
(author)
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Is it time for biomarker-based diagnostic criteria for prodromal Alzheimer's disease?
- 2010
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In: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 2:2
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Research review (peer-reviewed)abstract
- ABSTRACT: Drug candidates targeting amyloid-beta (Abeta) pathology in Alzheimer's disease are in different phases of clinical trials. These treatments will probably be most effective in the earlier stages of the disease, before neurodegeneration is too severe, but at the same time symptoms are vague and the clinical diagnosis is difficult. Recent research advances have resulted in promising biomarkers, including cerebrospinal fluid analyses for tau and Abeta, magnetic resonance imaging measurement of atrophy, and positron emission tomography imaging of glucose metabolism and Abeta pathology, which allow identification of prodromal Alzheimer's disease. More details are needed, however, on how these biomarkers can be standardized, to allow a general implementation in the clinical routine diagnostic work-up of patients with cognitive disturbances.
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| 3. |
- Hampel, Harald, et al.
(author)
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Biological markers of amyloid beta-related mechanisms in Alzheimer's disease.
- 2010
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In: Experimental neurology. - : Elsevier BV. - 1090-2430 .- 0014-4886. ; 223:2, s. 334-46
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Research review (peer-reviewed)abstract
- Recent research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer's disease (AD), which has been translated into an intense, ongoing development of disease-modifying treatments. Most new drug candidates are targeted on inhibiting amyloid beta (Abeta) production and aggregation. In drug development, it is important to co-develop biomarkers for Abeta-related mechanisms to enable early diagnosis and patient stratification in clinical trials, and to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Biomarkers are also requested by regulatory authorities to serve as safety measurements. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include Abeta isoforms (Abeta40/Abeta42), soluble APP isoforms, Abeta oligomers and beta-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on core candidate CSF and plasma Abeta-related biomarkers, and gives a conceptual review on how to implement biomarkers in clinical trials in AD.
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| 4. |
- Hampel, Harald, et al.
(author)
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Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives.
- 2010
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In: Nature reviews. Drug discovery. - : Springer Science and Business Media LLC. - 1474-1784 .- 1474-1776. ; 9:7, s. 560-74
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Research review (peer-reviewed)abstract
- Advances in therapeutic strategies for Alzheimer's disease that lead to even small delays in onset and progression of the condition would significantly reduce the global burden of the disease. To effectively test compounds for Alzheimer's disease and bring therapy to individuals as early as possible there is an urgent need for collaboration between academic institutions, industry and regulatory organizations for the establishment of standards and networks for the identification and qualification of biological marker candidates. Biomarkers are needed to monitor drug safety, to identify individuals who are most likely to respond to specific treatments, to stratify presymptomatic patients and to quantify the benefits of treatments. Biomarkers that achieve these characteristics should enable objective business decisions in portfolio management and facilitate regulatory approval of new therapies.
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| 5. |
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| 6. |
- Mattsson, Niklas, 1979, et al.
(author)
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Inter-laboratory variation in cerebrospinal fluid biomarkers for Alzheimer's disease: united we stand, divided we fall.
- 2010
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In: Clinical chemistry and laboratory medicine : CCLM / FESCC. - 1434-6621. ; 48:5, s. 603-7
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Research review (peer-reviewed)abstract
- Abstract Several drug candidates for Alzheimer's disease are being evaluated in clinical trials, with the goal of finding a drug with disease-modifying effects. When such a drug finally reaches the market, there will be a demand for accurate diagnostic tools useful for early detection of disease and for monitoring biochemical effects. The core cerebrospinal fluid (CSF) biomarkers amyloid peptides (Abeta42), total-tau and phospo-tau are promising in this respect. However, inter-center variation (caused by pre-analytical, analytical and post-analytical factors), and inter-laboratory variation (caused by analytical factors), particularly for CSF Abeta42, lowers their utility in multicenter studies. Here, we discuss the causes of these variations, and present a global quality control program to overcome them.
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| 7. |
- Mattsson, Niklas, 1979, et al.
(author)
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Lessons from Multicenter Studies on CSF Biomarkers for Alzheimer's Disease.
- 2010
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In: International journal of Alzheimer's disease. - : Hindawi Limited. - 2090-0252. ; 2010
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Research review (peer-reviewed)abstract
- Several single-center studies have confirmed the usability of cerebrospinal fluid (CSF) biomarkers for the diagnosis of Alzheimer's disease (AD), even in early disease stages. Large scale multicenter studies have principally confirmed this, although such studies have also indicated the presence of significant intercenter and interlaboratory variations in biomarker measurements. Such variations may hamper the development of biomarkers and their introduction into clinical routine practice. Recently a quality control program run by the Alzheimer's Association was started in order to harmonize procedures of laboratories world-wide. This program provides both standardized guide lines and external control CSF samples, and will allow longitudinal evaluation of laboratory performance.
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| 8. |
- Mattsson, Niklas, 1979, et al.
(author)
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To know or not to know: ethical issues related to early diagnosis of Alzheimer's disease.
- 2010
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In: International journal of Alzheimer's disease. - : Hindawi Limited. - 2090-0252. ; 2010
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Research review (peer-reviewed)abstract
- In Alzheimer's disease (AD), pathological processes start in the brain long before clinical dementia. Biomarkers reflecting brain alterations may therefore indicate disease at an early stage, enabling early diagnosis. This raises several ethical questions and the potential benefits of early diagnosis must be weighted against possible disadvantages. Currently, there are few strong arguments favouring early diagnosis, due to the lack of disease modifying therapy. Also, available diagnostic methods risk erroneous classifications, with potentially grave consequences. However, a possible benefit of early diagnosis even without disease modifying therapy is that it may enable early decision making when patients still have full decision competence, avoiding problems of hypothetical consents. It may also help identifying patients with cognitive dysfunction secondary to other diseases that may be responsive to treatment already today.
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| 9. |
- Nyhlén, Jakob, et al.
(author)
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Problems associated with fluid biomarkers for Parkinson's disease.
- 2010
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In: Biomarkers in medicine. - : Future Medicine Ltd. - 1752-0371 .- 1752-0363. ; 4:5, s. 671-81
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Research review (peer-reviewed)abstract
- This article focuses on biochemical markers that may be used in the diagnostics of Parkinson's disease and associated disorders, and to identify early cases and stratify patients into subgroups. We present an updated account of some currently available candidate fluid biomarkers, and discuss their diagnostic performance and limitations. We also discuss some of the general problems with Parkinson's disease biomarkers and possible ways of moving forward. It may be concluded that a diagnostically useful fluid biomarker for Parkinson's disease is yet to be identified. However, some interesting candidates exist and may prove useful in the future, alone or when analyzed together in patterns.
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| 10. |
- Olsson, Bob, 1969, et al.
(author)
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Biomarker-based dissection of neurodegenerative diseases.
- 2011
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In: Progress in neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 95:4
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Research review (peer-reviewed)abstract
- The diagnosis of neurodegenerative diseases within neurology and psychiatry are hampered by the difficulty in getting biopsies and thereby validating the diagnosis by pathological findings. Biomarkers for other types of disease have been readily adopted into the clinical practice where for instance troponins are standard tests when myocardial infarction is suspected. However, the use of biomarkers for neurodegeneration has not been fully incorporated into the clinical routine. With the development of cerebrospinal fluid (CSF) biomarkers that reflect pathological events within the central nervous system (CNS), important clinical diagnostic tools are becoming available. This review summarizes the most promising biomarker candidates that may be used to monitor different types of neurodegeneration and protein inclusions, as well as different types of metabolic changes, in living patients in relation to the clinical phenotype and disease progression over time. Our aim is to provide the reader with an updated lexicon on currently available biomarker candidates, how far they have come in development and how well they reflect pathogenic processes in different neurodegenerative diseases. Biomarkers for specific pathogenetic processes would also be valuable tools both to study disease pathogenesis directly in patients and to identify and monitor the effect of novel treatment strategies.
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