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| 45. |
- Duits, Flora H., et al.
(författare)
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The cerebrospinal fluid "Alzheimer profile": Easily said, but what does it mean?
- 2014
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Ingår i: Alzheimer's & Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 10:6, s. 713-723
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Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to identify the most useful definition of the "cerebrospinal fluid Alzheimer profile," based on amyloid-beta(1-42) (A beta(42)), total tau, and phosphorylated tau (p-tau), for diagnosis and prognosis of Alzheimers disease (AD). Methods: We constructed eight Alzheimer profiles with previously published combinations, including regression formulas and simple ratios. We compared their diagnostic accuracy and ability to predict dementia due to AD in 1385 patients from the Amsterdam Dementia Cohort. Results were validated in an independent cohort (n = 1442). Results: Combinations outperformed individual biomarkers. Based on the sensitivity of the best performing regression formulas, cutoffs were chosen at 0.52 for the tau/A beta(42) ratio and 0.08 for the p-tau/A beta(42) ratio. Ratios performed similar to formulas (sensitivity, 91%-93%; specificity, 81%-84%). The same combinations best predicted cognitive decline in mild cognitive impairment patients. Validation confirmed these results, especially regarding the tau/A beta(42) ratio. Conclusions: A tau/A beta(42) ratio of greater than0.52 constitutes a robust cerebrospinal fluid Alzheimer profile. We recommend using this ratio to combine biomarkers.
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| 46. |
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| 47. |
- Hampel, H, et al.
(författare)
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Core biological marker candidates of Alzheimer's disease - perspectives for diagnosis, prediction of outcome and reflection of biological activity.
- 2004
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Ingår i: Journal of neural transmission (Vienna, Austria : 1996). - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 111:3, s. 247-72
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Forskningsöversikt (refereegranskat)abstract
- Alzheimer's disease (AD) is a complex neurodegenerative dementing illness. Over the past few years, however, remarkable advances have taken place in understanding both the genetic and molecular biology with the intracellular processing of amyloid and tau and the changes leading to the pathologic formation of extracellular amyloid plaques and the intraneuronal aggregation of hyperphosphorylated tau into neurofibrillary tangles. This progress in our understanding of the molecular pathology has set the stage for clinically meaningful advances in the development of biomarkers. Emerging diagnostic methods that are based on biochemical and imaging biomarkers of disease specific pathology hold the potential to provide effective measures of natural history (marker of disease that is predictive of outcome), biological activity (such as magnitude and frequency of response correlating with drug potency) and markers of surrogate endpoints (single or composite marker that accounts for clinical benefit of the therapy). Markers of biological activity should be also evaluated regarding their value to reflect disease progression, heterogeneity of the clinical population, for early decision making and characterization of new treatments. We focussed on the current status of core analytes which provide reasonable evidence for association with key mechanisms of pathogenesis or neurodegeneration in AD. In addition, feasibility was important, such as availability of a validated assay for the biological measure in question, with properties that included high precision and reliability of measurement, reagents and standards well described. On this basis we reviewed the body of literature that has examined CSF total tau (t-tau) and beta-amyloid 1-42 (Abeta(1-42)), phosphorylated tau (p-tau) and beta-amyloid-antibodies as diagnostic tests for AD versus clinically representative comparison groups. Measurement of t-tau and Abeta(1-42) in the CSF seems useful to discriminate early and incipient AD from age-associated memory-impairment, depression, and some secondary dementias. First studies showed that measurement of p-tau proteins significantly improves early and differential diagnosis, as well as disease prediction in subjects at risk for AD and comes closest to fulfilling proposed criteria of a biological marker for AD. However, the nature of the majority of reported findings are still preliminary and retrospective. General issues for biomarkers have to be adequately addressed, such as sensitivity of the method, frequency of assessments, stability of the method, standardization of methods and dynamic range. There is still a partial lack of comparison patient populations that must be addressed in future studies. International dementia networks have been recently established to advance the establishment of core biomarker candidates of AD as potential surrogate endpoints for clinical trials and their clinical use for predictive and diagnostic purposes.
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| 48. |
- Hampel, H., et al.
(författare)
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State-of-the-art of lumbar puncture and its place in the journey of patients with Alzheimer's disease
- 2022
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:1, s. 159-177
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Tidskriftsartikel (refereegranskat)abstract
- Recent advances in developing disease-modifying therapies (DMT) for Alzheimer's disease (AD), and the recognition that AD pathophysiology emerges decades before clinical symptoms, necessitate a paradigm shift of health-care systems toward biomarker-guided early detection, diagnosis, and therapeutic decision-making. Appropriate incorporation of cerebrospinal fluid biomarker analysis in clinical practice is an essential step toward system readiness for accommodating the demand of AD diagnosis and proper use of DMTs-once they become available. However, the use of lumbar puncture (LP) in individuals with suspected neurodegenerative diseases such as AD is inconsistent, and the perception of its utility and safety differs considerably among medical specialties as well as among regions and countries. This review describes the state-of-the-art evidence concerning the safety profile of LP in older adults, discusses the risk factors for LP-associated adverse events, and provides recommendations and an outlook for optimized use and global implementation of LP in individuals with suspected AD.
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| 49. |
- Hampel, H., et al.
(författare)
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The Amyloid-beta Pathway in Alzheimer's Disease
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26
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Tidskriftsartikel (refereegranskat)abstract
- Breakthroughs in molecular medicine have positioned the amyloid-beta (A beta) pathway at the center of Alzheimer's disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established biochemical alterations of the A beta cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. Here, we systematically review and update the vast state-of-the-art literature of A beta science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of A beta pathway dyshomeostasis in AD pathophysiological dynamics. We discuss the evidence highlighting a differentiated interaction of distinct A beta species with other AD-related biological mechanisms, such as tau-mediated, neuroimmune and inflammatory changes, as well as a neurochemical imbalance. Through the lens of the latest development of multimodal in vivo biomarkers of AD, this cross-disciplinary review examines the compelling hypothesis- and data-driven rationale for A beta-targeting therapeutic strategies in development for the early treatment of AD.
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| 50. |
- Hampel, H., et al.
(författare)
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The amyloid-beta pathway in Alzheimer's disease: a plain language summary
- 2023
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Ingår i: Neurodegenerative Disease Management. - : Future Medicine Ltd. - 1758-2024 .- 1758-2032. ; 13:3, s. 141-9
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Tidskriftsartikel (refereegranskat)abstract
- What is this summary about? This plain language summary of an article published in Molecular Psychiatry, reviews the evidence supporting the role of the amyloid-b (Ab) pathway and its dysregulation in Alzheimer's disease (AD), and highlights the rationale for drugs targeting the A beta pathway in the early stages of the disease. Why is this important? A beta is a protein fragment (or peptide) that exists in several forms distinguished by their size, shape/structure, degree of solubility and disease relevance. The accumulation of A beta plaques is a hallmark of AD. However, smaller, soluble aggregates of A beta - including Ab protofibrils - also play a role in the disease. Because A beta-related disease mechanisms are complex, the diagnosis, treatment and management of AD should be reflective of and guided by up-to-date scientific knowledge and research findings in this area. This article describes the A beta protein and its role in AD, summarizing the evidence showing that altered A beta clearance from the brain may lead to the imbalance, toxic buildup and misfolding of the protein - triggering a cascade of cellular, molecular and systematic events that ultimately lead to AD. What are the key takeaways? The physiological balance of brain A beta levels in the context of AD is complex. Despite many unanswered questions, mounting evidence indicates that A beta has a central role in driving AD progression. A better understanding of the A beta pathway biology will help identify the best therapeutic targets for AD and inform treatment approaches.
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