Zetterberg, H. et al. Intra-individual stability of CSF biomarkers for Alzheimer's disease over two years. J. Alzheimers Dis. 12, 255-260

Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at Göteborg University, Mölndal, Sweden.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 11/2007; 12(3):255-60.
Source: PubMed


This study examines the intra-individual stability of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) over 2 years in 83 patients with mild cognitive impairment (MCI) and 17 cognitively healthy control individuals. All participants underwent clinical and neuropsychological evaluation and lumbar puncture at baseline and after 2 years at a university hospital memory clinic. CSF was analyzed for total tau (T-tau), phospho-tau(181) (P-tau(181)) and amyloid-beta(1-42) (Abeta(1-42)). During the 2-year observational time, 12 MCI patients progressed to AD and 3 progressed to vascular dementia, while 68 remained stable. Baseline T-tau and P-tau(181) levels were elevated in the MCI-AD group as compared to the stable MCI patients and the control group (p<0.01), while baseline Abeta(1-42) levels were lower (p<0.001). Stable MCI patients were biochemically indistinguishable from controls. The biomarker levels at baseline and after 2 years showed Pearson R values between 0.81 and 0.91 (p<0.001) and coefficients of variation of 7.2 to 8.7%. In conclusion, intra-individual biomarker levels are remarkably stable over 2 years. Thus, even minor biochemical changes induced by treatment against AD should be detectable using these biomarkers, which bodes well for their usefulness as surrogate markers for drug efficacy in clinical trials.

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Available from: Eugeen Vanmechelen, Nov 11, 2014
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    • "Several studies have shown that CSF Ab 42 , T-tau, and P-tau show no or minimal change during the clinical phase of AD with dementia [43] [44] [45] or during the progression from MCI to AD dementia [46]. Thus, the change from normal to pathologic levels most likely occurs during the preclinical asymptomatic phase of the disease. "
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    ABSTRACT: Several potential disease-modifying drugs for Alzheimer's disease (AD) have failed to show any effect on disease progression in clinical trials, conceivably because the AD subjects are already too advanced to derive clinical benefit from treatment and because diagnosis based on clinical criteria alone introduces a high misdiagnosis rate. Thus, well-validated biomarkers for early detection and accurate diagnosis are crucial. Low cerebrospinal fluid (CSF) concentrations of the amyloid-β (Aβ1-42) peptide, in combination with high total tau and phosphorylated tau, are sensitive and specific biomarkers highly predictive of progression to AD dementia in patients with mild cognitive impairment. However, interlaboratory variations in the results seen with currently available immunoassays are of concern. Recent worldwide standardization efforts and quality control programs include standard operating procedures for both preanalytical (e.g., lumbar puncture and sample handling) and analytical (e.g., preparation of calibration curve) procedures. Efforts are also ongoing to develop highly reproducible assays on fully automated instruments. These global standardization and harmonization measures will provide the basis for the generalized international application of CSF biomarkers for both clinical trials and routine clinical diagnosis of AD.
    Full-text · Article · May 2014 · Alzheimer's & dementia: the journal of the Alzheimer's Association
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    • "Several studies have indicated an increase in β-site amyloid precursor protein cleaving enzyme (BACE1) protein levels or activity in the CSF of AD (Ewers et al., 2008; Holsinger et al., 2004; Zetterberg et al., 2008) and MCI (Ewers et al., 2008; Zetterberg et al., 2008; Zhong et al., 2007) patients compared to controls. BACE1 activity correlates well with total tau levels in AD indicating that amyloid metabolism may be related to neuronal loss (Zetterberg et al., 2008). "
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    ABSTRACT: Alzheimer's disease (AD) represents an escalating global threat as life expectancy and disease prevalence continue to increase. There is a considerable need for earlier diagnoses to improve clinical outcomes. Fluid biomarkers measured from cerebrospinal fluid (CSF) and blood, or imaging biomarkers have considerable potential to assist in the diagnosis and management of AD. An additional important utility of biomarkers is in novel therapeutic development and clinical trials to assess efficacy and side effects of therapeutic interventions. Because many biomarkers are initially examined in animal models, the extent to which markers translate from animals to humans is an important issue. The current review highlights many existing and pipeline biomarker approaches, focusing on the degree of correspondence between AD patients and animal models. The review also highlights the need for greater translational correspondence between human and animal biomarkers.
    Full-text · Article · Apr 2013 · Neurobiology of Disease
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    • "Kang et al [17] reported that the fluctuations of Ab levels in human CSF were similar to the diurnal fluctuations observed in the brain interstitial fluid of mice, and suggested that the sleep–wake cycle and orexin might play a role in Ab levels. These data apparently conflict with data showing stability in CSF Ab levels measured with isolated lumbar punctures over a 2-year period [18]. The increase in CSF Ab levels over a 24-hour period currently makes it extremely difficult to use CSF Ab as a biomarker to discern a drug effect over a short period. "
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    ABSTRACT: β-amyloid peptide (Aβ) is associated with neurodegeneration in Alzheimer's disease. Emerging evidence indicates that Aβ levels in cerebrospinal fluid (CSF) may serve as an early clinical biomarker for evaluating pharmacological activity of new drug candidates targeting Aβ production or Aβ clearance. Therefore, it is critical to understand whether intrasubject levels of CSF Aβ are consistent between sampling intervals to determine whether Aβ can be used as a pharmacodynamic biomarker for drug candidates. Previous studies have produced seemingly conflicting observations for the intrasubject stability of CSF Aβ levels; we attempt to reconcile these conflicting observations. The current study examined the Aβ levels in CSF collected with various sampling frequencies from three clinical studies conducted in healthy young or elderly subjects at the same investigative site for the purpose of designing future studies. The results suggest that CSF sampling frequency and/or sampling volume contributes to intrasubject variability in CSF Aβ levels, and that lowering the CSF sampling frequency may help minimize this effect. These results will help guide clinical trial design for Alzheimer's disease therapy.
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