Detection of Amyloid-beta aggregates in body fluids: a suitable method for early diagnosis of Alzheimer's disease?
Today, the most reliable diagnosis for Alzheimer's disease (AD) is the post mortem identification of amyloid plaques, consisting of the Amyloid-beta (Abeta) peptide, (and neurofibrillary tangles) in the brain of the patient. Great efforts are being made to identify reliable biomarkers for AD that are suitable for minimal invasive early diagnosis and prognosis of AD. During the past years, body fluids of AD patients were assayed for their content of total or soluble Abeta(1-40) or Abeta(1-42) concentrations using classical (ELISA) or non-classical (with additional signal amplification) read-out. Cerebrospinal fluid (CSF) concentrations of soluble Abeta(1-42) are reduced by 40 to 50 % in AD patients compared to age-matched healthy controls as confirmed in more than 30 studies, with both sensitivity and specificity exceeding 80 % in most of the studies. Thus, it was suggested that low levels of CSF Abeta(1-42) might be useful for preclinical diagnosis. Because the current average sensitivity of AD biomarker detection in the CSF is approximately 85 %, these assays do not offer a considerable increase in predictive value over existing algorithms based on neuropsychological and imaging modalities. Regarding the amyloid cascade hypothesis, Abeta oligomers and aggregates are directly involved in the pathogenic process. Therefore, presence of Abeta aggregates seem to be the most direct disease biomarker for AD and increasing effort is being made into the development of methods suitable for the detection of different Abeta aggregates in body fluids like CSF and plasma. We therefore give an overview of the current state of Abeta aggregate specific detection.
Available from: Edson Amaro
- "We believe the SVM approach shown here can be used to compare classification performance in different populations and subtypes of the disease in multicentre studies. Another point worth mentioning is that our findings are in the same line as results from recent neuropathological studies , pointing out that a diagnosis of AD is virtually impossible on a routine basis – thus making the search for a biomarker for AD very challenging . At the same time, clinical evaluation is a subjective estimate and prone to errors, not to mention that there is no clear-cut estimate of patient prognosis from a structured diagnostic criterion. "
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ABSTRACT: Here, we examine morphological changes in cortical thickness of patients with Alzheimer's disease (AD) using image analysis algorithms for brain structure segmentation and study automatic classification of AD patients using cortical and volumetric data. Cortical thickness of AD patients (n=14) was measured using MRI cortical surface-based analysis and compared with healthy subjects (n=20). Data was analyzed using an automated algorithm for tissue segmentation and classification. A Support Vector Machine (SVM) was applied over the volumetric measurements of subcortical and cortical structures to separate AD patients from controls. The group analysis showed cortical thickness reduction in the superior temporal lobe, parahippocampal gyrus, and enthorhinal cortex in both hemispheres. We also found cortical thinning in the isthmus of cingulate gyrus and middle temporal gyrus at the right hemisphere, as well as a reduction of the cortical mantle in areas previously shown to be associated with AD. We also confirmed that automatic classification algorithms (SVM) could be helpful to distinguish AD patients from healthy controls. Moreover, the same areas implicated in the pathogenesis of AD were the main parameters driving the classification algorithm. While the patient sample used in this study was relatively small, we expect that using a database of regional volumes derived from MRI scans of a large number of subjects will increase the SVM power of AD patient identification.
Journal of Alzheimer's disease: JAD 01/2010; 19(4):1263-72. DOI:10.3233/JAD-2010-1322 · 4.15 Impact Factor
Available from: James E Galvin
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ABSTRACT: Misfolded proteins are at the core of many neurodegenerative diseases, nearly all of them associated with cognitive impairment. For example Creutzfeldt-Jacob disease is associated with aggregation of prion protein, Lewy body dementia and Parkinson disease with α-synuclein and forms of frontotemporal dementia with tau, TDP 43 and host of other proteins, Alzheimer disease (AD), the most common cause of dementia, and its prodromal syndrome mild cognitive impairment (MCI) are an increasing public health problem and a diagnostic challenge to may clinicians. AD is characterized pathologically by the accumulation of amyloid β protein (Aβ) as senile plaques and in the walls of blood vessels as amyloid angiopathy. Additionally, there are accumulations of tau-protein as neurofibrillary tangles and dystrophic neurites. Biological markers of AD and MCI can serve as in vivo diagnostic indicators of underlying pathology, particularly when clinical symptoms are mild and are likely present years before the onset of clinical symptoms. Research to discover and refine fluid and imaging biomarkers of protein aggregation has undergone a rapid evolution and combined analysis of different modalities may further increase diagnostic sensitivity and specificity. Multi-center trials are now investigating whether imaging and/or cerebrospinal fluid (CSF) biomarker candidates can be used as outcome measures for use in phase III clinical trials for AD.
Prion 01/2011; 5(1):16-21. DOI:10.4161/pri.5.1.14439 · 2.24 Impact Factor
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ABSTRACT: The cellular prion protein (PrP(c)) is a multifunctional, highly conserved and ubiquitously expressed protein. It undergoes a number of modifications during its post-translational processing, resulting in different PrP(c) glycoforms and truncated PrP(c) fragments. Limited data are available in humans on the expression and cleavage of PrP(c). In this study we investigated the PrP(c) isoform composition in the cerebrospinal fluid from patients with different human prion diseases. The first group of patients was affected by sporadic Creutzfeldt-Jakob disease exhibiting different PrP codon 129 genotypes. The second group contained patients with a genetic form of Creutzfeldt-Jakob disease (E200K). The third group consisted of patients with fatal familial insomnia and the last group comprised cases with the Gerstmann-Sträussler-Scheinker syndrome. We examined whether the PrP codon 129 polymorphism in sporadic Creutzfeldt-Jakob disease as well as the type of prion disease in human patients has an impact on the glycosylation and processing of PrP(c). Immunoblotting analyses using different monoclonal PrP(c) antibodies directed against various epitopes of PrP(c) revealed, for all examined groups of patients, a consistent predominance of the glycosylated PrP(c) isoforms as compared with the unglycosylated form. In addition, the antibody SAF70 recognized a variety of PrP(c) fragments with sizes of 21, 18, 13 and 12 kDa. Our findings indicate that the polymorphisms at PrP codon 129, the E200K mutation at codon 200 or the examined types of human transmissible spongiform encephalopathies do not exert a measurable effect on the glycosylation and processing of PrP(c) in human prion diseases.
European Journal of Neuroscience 06/2010; 31(11):2024-31. DOI:10.1111/j.1460-9568.2010.07224.x · 3.18 Impact Factor
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