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


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.

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Available from: Harald J Hampel, May 24, 2014
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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). "

    • "As expected, given our PET amyloid imaging is primarily directed against A and not tau species, our study found CSF A 1-42 as the most sensitive single analyte for detection of AD (85% sensitivity and 91% specificity) [7] [8] [11] [23] [24] [37] [38], and the three analytes together offered a 92% sensitivity and 77% specificity for detecting symptomatic subjects with PET evidence of in vivo A pathology (the MCI/AD PET+ group) from those HC with A PET– scans. Previous studies have demonstrated the clinical utility of the combination of decreased CSF A 1-42 , and increased CSF T-tau and P-tau 181P , for supporting a clinical diagnosis of AD, with the diagnostic accuracy of this profile greater than 80% [39]. In the AD neuroimaging initiative (ADNI) study, an AD CSF biomarker profile was present in >80% of AD patients, including those with amnestic MCI who progressed to AD [7] [8]. "
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    ABSTRACT: Background: The cerebrospinal fluid (CSF) amyloid-β (Aβ)1-42, total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD). Objective: The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands. Methods: Aβ pathology was determined by PET imaging, utilizing 11C-Pittsburgh Compound B, 18F-flutemetamol, or 18F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aβ1-42 >544 ng/L, T-tau <407 ng/L, and P-tau181P <78 ng/L) employing a rank based method to define a "positive" CSF in the sub-cohort of amyloid-PET negative healthy participants (n = 97), and compared with the presence of PET demonstrated AD pathology. Results: CSF Aβ1-42 was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aβ1-42 provided greater accuracy, predicting MCI/AD with Aβ pathology with ≥92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aβ1-42 to predict MCI/AD, reached ≥92% sensitivity and specificity. Conclusions: CSF Aβ1-42 levels and analyte combination ratios demonstrated very high correlation with PET Aβ imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage.
    Journal of Alzheimer's disease: JAD 09/2015; 48(1):175-187. DOI:10.3233/JAD-150247 · 4.15 Impact Factor
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    • "Multiple studies have investigated the diagnostic accuracy and predictive power of combined CSF tests for total tau (T-tau, a marker of axonal degeneration ), hyperphosphorylated tau (P-tau, a marker of AD-type tau phosphorylation), and the 42 amino acidlong form of the amyloid-(A) peptide (A 1-42 , a marker of amyloid plaque pathology) during different stages of AD [36]. These studies collectively point to sensitivities and specificities of 85–95% in cross-sectional AD-control studies, as well as in longitudinal studies of patients fulfilling MCI criteria [36]. Longitudinal studies have correlated baseline levels of the core biomarkers in cognitively normal individuals "
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    ABSTRACT: There is evolving evidence that individuals categorized with subjective cognitive decline (SCD) are potentially at higher risk for developing objective and progressive cognitive impairment compared to cognitively healthy individuals without apparent subjective complaints. Interestingly, SCD, during advancing preclinical Alzheimer's disease (AD), may denote very early, subtle cognitive decline that cannot be identified using established standardized tests of cognitive performance. The substantial heterogeneity of existing SCD-related research data has led the Subjective Cognitive Decline Initiative (SCD-I) to accomplish an international consensus on the definition of a conceptual research framework on SCD in preclinical AD. In the area of biological markers, the cerebrospinal fluid signature of AD has been reported to be more prevalent in subjects with SCD compared to healthy controls; moreover, there is a pronounced atrophy, as demonstrated by magnetic resonance imaging, and an increased hypometabolism, as revealed by positron emission tomography, in characteristic brain regions affected by AD. In addition, SCD individuals carrying an apolipoprotein ɛ4 allele are more likely to display AD-phenotypic alterations. The urgent requirement to detect and diagnose AD as early as possible has led to the critical examination of the diagnostic power of biological markers, neurophysiology, and neuroimaging methods for AD-related risk and clinical progression in individuals defined with SCD. Observational studies on the predictive value of SCD for developing AD may potentially be of practical value, and an evidence-based, validated, qualified, and fully operationalized concept may inform clinical diagnostic practice and guide earlier designs in future therapy trials.
    Journal of Alzheimer's disease: JAD 09/2015; 48(s1). DOI:10.3233/JAD-150202 · 4.15 Impact Factor
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