Article

Cerebrospinal Fluid and Plasma Biomarkers in Alzheimer Disease

Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, SE-431 80 Mölndal, Sweden.
Nature Reviews Neurology (Impact Factor: 15.36). 02/2010; 6(3):131-44. DOI: 10.1038/nrneurol.2010.4
Source: PubMed

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.

    • "As to my knowledge, an end-of-life study as performed for amyloid PET tracers has not yet been reported to compare CSFPlease cite this article in press as: D.R. Thal, Symptomatic and preclinical Alzheimer's disease:NeuropathologyBraak, Zetterberg, Del Tredici, & Blennow, 2013) discuss discrepancies between the development of morphologically detectable Ab and t pathology and the respective changes reported for CSF biomarkers. Pathologically , t pathology in the brain stem precedes Ab plaque deposition for many years (Braak et al., 2011) whereas CSF-Ab declines before CSF-t levels rise (Braak et al., 2013;Sjogren et al., 2001;Blennow, Hampel, Weiner, & Zetterberg, 2010) (Fig. 1B). It is not yet clear in which preclinical phases of AD CSF biomarkers become positive. "
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    ABSTRACT: The current gold standard for the diagnosis of Alzheimer’s disease (AD) is the pathological examination at autopsy. Clinical diagnostic procedures are quite well developed for symptomatic AD and permit a reliable and valid identification of AD patients. Today, there is strong interest to diagnose AD already in a preclinical stage to include protective treatment strategies into the treatment regimes for AD. This is important because current therapies for AD mainly focus on symptomatic improvement rather than on delaying disease progression. The current diagnostic criteria for preclinical AD (preAD) rely on biomarker profiles indicative for AD in non-demented individuals. At autopsy, pathological lesions considered to represent AD pathology permit the classification of non-demented cases exhibiting AD pathology as pathologically-defined preAD (p-preAD) cases. Recent studies investigating amyloid imaging as a biomarker and comparing it with the post-mortem findings on AD pathology revealed that preAD cases identified clinically by amyloid imaging already exhibited advanced stages of AD pathology whereas p-preAD cases with initial AD lesions failed clinical detection. In this article I will discuss these findings and its potential impact on clinical studies aimed at stopping or delaying the progression from preAD to symptomatic AD as well as on the interpretation of imaging or biomarker data in relation to the underlying disease progress with a focus on propagation and maturation of Aβ and τ pathology in-p-preAD.
    No preview · Article · Jan 2016 · Neurology Psychiatry and Brain Research
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    • "When phosphorylated, tau detaches from microtubules; abnormal tau phosphorylation in neurons is a hallmark of AD and other neurodegenerative diseases (including frontotemporal dementia, and progressive supranuclear palsy), and is accompanied by aggregation, and progressive intraneuronal tau accumulation. In addition to its buildup within neurons, more recent studies demonstrated that tau is also released in the extracellular space (Gómez-Ramos et al., 2006; Avila, 2010); and that increased levels of tau (total and phosphorylated) in the human's cerebrospinal fluid (CSF) are associated with an increased risk of developing AD (Blennow et al., 2010). Tau protein is traditionally considered to be localized in axons; however, when neurons are exposed to Aβ oligomers, tau relocates to somatodendritic compartments in association with loss of spines and microtubule breakdown (Zempel et al., 2010). "

    Full-text · Dataset · Nov 2015
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    • "When phosphorylated, tau detaches from microtubules; abnormal tau phosphorylation in neurons is a hallmark of AD and other neurodegenerative diseases (including frontotemporal dementia, and progressive supranuclear palsy), and is accompanied by aggregation, and progressive intraneuronal tau accumulation. In addition to its buildup within neurons, more recent studies demonstrated that tau is also released in the extracellular space (Gómez-Ramos et al., 2006; Avila, 2010); and that increased levels of tau (total and phosphorylated) in the human's cerebrospinal fluid (CSF) are associated with an increased risk of developing AD (Blennow et al., 2010). Tau protein is traditionally considered to be localized in axons; however, when neurons are exposed to Aβ oligomers, tau relocates to somatodendritic compartments in association with loss of spines and microtubule breakdown (Zempel et al., 2010). "
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    ABSTRACT: Synapses have been known for many years to be the crucial target of pathology in different forms of dementia, in particular Alzheimer's disease (AD). Synapses and their appropriate activation or inhibition are fundamental for the proper brain function. Alterations in synaptic/neuronal activity and brain metabolism are considered among the earliest symptoms linked to the progression of AD, and lead to a central question in AD research: what is the role played by synaptic activity in AD pathogenesis? Intriguingly, in the last decade, important studies demonstrated that the state of activation of synapses affects the homeostasis of beta-amyloid (Aβ) and tau, both of which aggregate and accumulate during AD, and are involved in neuronal dysfunction. In this review we aim to summarize the up-to-date data linking synaptic/neuronal activity with Aβ and tau; moreover, we also intend to provide a critical overview on brain activity alterations in AD, and their role in the disease's pathophysiology.
    Full-text · Article · Nov 2015 · Frontiers in Neuroscience
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