Longitudinal Changes of CSF Biomarkers in Alzheimer's Disease

Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 04/2011; 25(4):583-94. DOI: 10.3233/JAD-2011-101911
Source: PubMed


Longitudinal changes of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) have been studied, but there are few consistent conclusions and even less is known about their variation during the different stages of the disease. We hypothesized that changes in CSF biomarker values would correlate with the progression of the cognitive decline in AD. One hundred and thirty-one memory clinic patients [56 AD, 57 mild cognitive impairment (MCI), 10 other neurological disorders, eight unimpaired subjects] underwent a clinical follow-up with repeated Mini-Mental Status Examination (MMSE) tests and two lumbar punctures with a median interval of 3 years. Levels of CSF amyloid-β (Aβ)(42), tau, and p-tau-181 were measured using commercially available ELISA. Twenty-one of the MCI subjects progressed to AD, whereas 26 subjects remained stable and 56 subjects had AD already at the baseline. The subjects displaying the most rapid MMSE decline rate had the lowest baseline Aβ(42), highest tau, and highest p-tau-181 CSF concentrations. An annual decrease of 2.20 pg/ml/year in the CSF p-tau-181 concentration was seen in AD-AD patients (p = 0.001). The difference was significant compared to stable MCI-MCI (increase of 1.24 pg/ml/year, p = 0.001) and cognitively healthy (increase of 0.84 pg/ml/year, p = 0.013) subjects (p for group difference 0.004). The decrease rate of p-tau-181 correlated with the MMSE decrease rate in AD subjects (r = 0.579, p < 0.001). The CSF Aβ(42) level decreased in the AD-AD group (decrease 11.9 pg/ml/year, p < 0.001). Concentrations of hyperphosphorylated tau decline in the late stages of the AD process. The decrease of p-tau-181 appears to correlate with cognitive functioning and probably reflects neuronal loss. More longitudinal studies of CSF biomarker dynamics are needed, especially in patients during the preclinical stage of the disease.

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    • "CSF levels of A␤ and phospho-tau are abnormal in AD, with decreased levels of A␤, and increased phospho-tau compared to cognitively normal controls [26] [27] [28]. In MCI, lower baseline A␤ and higher phospho-tau is associated with more rapid cognitive decline, greater cortical thinning, and increased likelihood of transition to dementia of the Alzheimer's type (DAT) [29] [30] [31] [32] [33]. Critically for the present study, CSF levels of A␤ and phospho-tau from lumbar puncture are significantly correlated with cortical brain biopsy histology, suggesting they are adequate surrogates for ex vivo histopathological measurements [34] [35]. "
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    ABSTRACT: Alzheimer’s disease (AD) is characterized by two primary pathologies: tau-related neurofibrillary tangles and the extracellular accumulation of amyloid-β (Aβ). The development of these pathologies is topologically distinct early in the disease, with Aβ beginning to accumulate as a diffuse, neocortical pathology, while tau-related pathology begins to form in mesial temporal regions. This study investigated the hypothesis that, by virtue of this distinction, there exist preferential associations between the primary pathologies and aspects of the cognitive phenotype. We investigated the relationship between cerebrospinal fluid (CSF) biomarkers for tau and Aβ pathologies with neurocognitive measures in 191 patients with mild cognitive impairment (MCI). Participants completed cognitive tests of new learning, information processing speed, and working memory. Separate regression models were computed and then followed up with mediation analyses to examine the predictive status of CSF biomarkers. The effect of Aβ on learning was mediated by phospho-tau (p = 0.008). In contrast, Aβ had a direct effect on information processing speed that was not mediated by phospho-tau (p = 0.59). No predictors were significant for working memory. This study provided evidence for a differential relationship of Aβ and phospho-tau pathologies on the neurocognitive phenotype of MCI. This supports the proposition that these primary AD pathologies maximally affect different aspects of cognition, and has potential implications for cognitive assessments and the use of biomarkers in disease-modifying therapeutic trials.
    Full-text · Article · May 2015 · Journal of Alzheimer's disease: JAD
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    • "Recent studies have shown CSF biomarkers (Aβ1-42, t-tau, p-tau) to be stable from 6 months up to 2 years of disease progression and suitable for monitoring the CSF changes induced by therapy (69-71). On the other hand, Bouwman et al (72) reported an increase in Aβ1-42 and t-tau (but not p-tau) during AD progression, while two other studies indicated a decrease in Aβ1-42 in AD patients and in p-tau in the late stages of the disease (73,74). In addition, Toledo et al (75) described two distinct groups of participants with normal baseline CSF values: patients with stable and patients with abnormal longitudinal CSF biomarkers (decreasing Aβ1-42 and increasing p-tau181). "
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    ABSTRACT: Alzheimer disease (AD) is a complex neurodegenerative disorder, whose prevalence will dramatically rise by 2050. Despite numerous clinical trials investigating this disease, there is still no effective treatment. Many trials showed negative or inconclusive results, possibly because they recruited only patients with severe disease, who had not undergone disease-modifying therapies in preclinical stages of AD before severe degeneration occurred. Detection of AD in asymptomatic at risk individuals (and a few presymptomatic individuals who carry an autosomal dominant monogenic AD mutation) remains impractical in many of clinical situations and is possible only with reliable biomarkers. In addition to early diagnosis of AD, biomarkers should serve for monitoring disease progression and response to therapy. To date, the most promising biomarkers are cerebrospinal fluid (CSF) and neuroimaging biomarkers. Core CSF biomarkers (amyloid β1-42, total tau, and phosphorylated tau) showed a high diagnostic accuracy but were still unreliable for preclinical detection of AD. Hence, there is an urgent need for detection and validation of novel CSF biomarkers that would enable early diagnosis of AD in asymptomatic individuals. This article reviews recent research advances on biomarkers for AD, focusing mainly on the CSF biomarkers. In addition to core CSF biomarkers, the potential usefulness of novel CSF biomarkers is discussed.
    Full-text · Article · Aug 2014 · Croatian Medical Journal
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    • "Furthermore, when Aβ1-42 and t-tau are used together, p-tau does not appear to have additional value for the purpose of predicting progression from MCI to AD, although p-tau appears to be more specific to AD pathology and t-tau can be elevated in other neurodegenerative conditions [49]. However, a more recent study found that p-tau decreases at a rate of 2.2 pg/ml/year and correlates better with cognitive functioning than either Aβ1-42 or t-tau, possibly reflecting neuronal loss specific to AD [74]. "
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    ABSTRACT: Fluid biomarkers improve the diagnostic accuracy in dementia and provide an objective measure potentially useful as a therapeutic response in clinical trials. The role of fluid biomarkers in patient care is a rapidly evolving field. Here, we provide a review and recommendations regarding the use of fluid biomarkers in clinical practice as discussed at the Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD4) convened in Montreal, 4 to 5 May 2012. At present, there is no consensus regarding the optimal methodology for conducting quantification of plasma amyloid-beta (Aβ) peptides. In addition, since there is insufficient evidence supporting clinical applications for plasma Aβ-peptide measures, the CCCDTD4 does not recommended plasma biomarkers either for primary care or for specialists. Evidence for CSF Aβ1-42, total tau and phosphorylated tau in the diagnosis of Alzheimer pathology is much stronger, and can be considered at the tertiary care level for selected cases to improve diagnostic certainty, particularly in those cases presenting atypical clinical features.
    Full-text · Article · Nov 2013 · Alzheimer's Research and Therapy
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