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CSF tau and amyloid β42 levels in Alzheimer’s disease—A meta-analysis  [PDF]
Rachna Agarwal, Neelam Chhillar, Vijay Nath Mishra, Chandra Bhushan Tripathi
Advances in Alzheimer's Disease (AAD) , 2012, DOI: 10.4236/aad.2012.13005
Abstract: Alzheimer’s disease International (ADI) estimates that there are currently 30 million people with dementia in the world. The main objective was to perform meta-analysis of studies of CSF tau and Amyloid β42 (Aβ42) levels in Alzheimer’s disease (AD) patients and controls. In the present study MEDLINE was reviewed from 1995 to 2009, supplemented by citation analysis from retrieved articles to select case control studies. Descriptive statistics showed that median effect size (raw mean difference) of CSF tau and Aβ42 levels were 301 pg/ml (Range: 22 to 614 pg/ml) and –352 pg/ml (Range: –969 to 203 pg/ml) respectively. The pooled effect size CSF tau and Aβ42 was 289.14 pg/ml (95% CI 253.278 to 325.013 pg/ml) and –329.02 pg/ml (95% CI –387.740 to –270.445 pg/ml) respectively. Heterogeneity in effect size of selected studies was present for both parameters (CSF tau: Q statistics = 1816.596, DF = 40, P = 0.000 and CSF Aβ42: Q-statistics = 1259.358, DF = 24, p < 0.001). Based on the findings of meta-analysis in the present study, CSF tau and Aβ42 levels in AD and controls may be considered as potential biomarker along with the clinical phenotype to perform them during high quality diagnostic testing in dementia.
Diagnostic Utility of CSF Tau and A in Dementia: A Meta-Analysis  [PDF]
Rachna Agarwal,Chandra Bhushan Tripathi
International Journal of Alzheimer's Disease , 2011, DOI: 10.4061/2011/503293
Abstract: CSF tau and Aβ42 are considered as important markers to diagnose Alzheimer’s disease in early stages. Hence, it is important to assess their status in different types of dementia. The main objective of this study was to assess whether these CSF biomarkers can be used to make the differential diagnosis of AD. In the present study, articles published from 1998 till 2009 were taken and meta-analysis was performed to clarify the consistency in trends of biomarkers- CSF tau and Aβ42 in AD and other dementias and whether the same can be used as diagnostic biomarkers for its early diagnosis. 11 out of 60 for CSF tau and 07 out of 40 for CSF Aβ42, dementia case-control studies were selected for final analysis. Descriptive statistics shows that median effect size (raw mean difference) of CSF tau was 429?pg/mL (range: 32 to 910?pg/mL) in AD whereas in Dementia due to other causes (DOC) studies it was 69?pg/mL (range: ?53 to 518?pg/mL). Similarly the median effect size of CSF Aβ42 levels was ?442?pg/mL (range: ?652 to ?41.200?pg/mL) whereas in DOC studies it was ?193?pg/mL (range: ?356 to ?33?pg/mL). 1. Introduction With the increase in life expectancy, Alzheimer’s disease, considered as disease of aging population, has become a major public health problem adding burden to societal costs each year for chronic care and lost productivity in developed and developing countries [1]. Presently, diagnosis of AD is primarily based on the exclusion of other causes of dementia on clinical trials. However, it is not of much help due to overlapping of clinical features of AD with other dementias in early stages. Attempts have been made in the last 4-5 decades to develop and validate specific biological markers which are able to detect the fundamental neuropathological changes occurring in AD in its early stage with high sensitivity (≥80%) and distinguish it from other dementias [2]. Based on these studies, the combination of total tau and amyloid β42 (Aβ42) was identified as being among the most promising and informative AD markers to be of use in early diagnosis and as surrogate biomarkers in CSF [2–4]. Increased levels of tau in CSF have been suggested to reflect neuronal and axonal degeneration [5] whereas reduced CSF levels of Aβ42 might reflect extracellular accumulation of Aβ42 into insoluble senile plaques in the AD brain [6, 7]. However, high CSF concentration of total tau has also been reported in mild cognitive impairment [8], as well as in vascular dementia (VaD) [2, 9–11]. The comorbidity of AD and other dementias can further generate problems. Though studies have
Standardization of Assay Procedures for Analysis of the CSF Biomarkers Amyloid , Tau, and Phosphorylated Tau in Alzheimer's Disease: Report of an International Workshop  [PDF]
Charlotte E. Teunissen,Niek A. Verwey,Maartje I. Kester,Kees van Uffelen,Marinus A. Blankenstein
International Journal of Alzheimer's Disease , 2010, DOI: 10.4061/2010/635053
Abstract: Large variation in assay performance and outcomes of CSF A 1-42, total Tau (Tau), and phosphorylated Tau (pTau) (at amino acid 181) levels is observed between laboratories. The aim of this study was to assess the differences in assay procedures between several experienced international laboratories, as potential sources of error. 14 groups performed the A 42, Tau, and pTau assays according to the guidelines of the manufacturer. Differences in analytical procedures between the laboratories were monitored. At least 23 items in assay procedures were identified that varied between the laboratories, including procedures for washing, pipetting, incubation, finishing, and sample handing. In general, the inter- and intra-assay variation between the groups was generally below 10% for all three assays. We concluded that 17 international centers that use the same assays for A 42, Tau and pTau on a regular basis do not uniformly adhere to the procedures recommended by the manufacturer. For harmonization of intercenter results of these biomarkers standardization of protocols is highly needed. 1. Background In the aging population the number of Alzheimer Disease (AD) patients is expected to increase [1]. However, the diagnostic accuracy of the clinical criteria is relatively low (sensitivity 80% and specificity of 70%) [2]). With this in mind, biological markers in body fluids are urgently needed to sustain diagnosis, as they are an objective tool and reflect ongoing processes. Biomarkers can aid not only in early diagnosis or in differential diagnosis but also in estimation of prognosis and, ideally, monitoring progression of this disease. The concentrations of Amyloid-bet (A 42), total Tau (Tau), and Tau phosphorylated at position 181 (pTau) in cerebrospinal fluid (CSF) of AD patients can be used as biomarkers [3]. Several laboratories measure these three biomarkers in CSF, and a major challenge is to translate the technology from the lab to clinical practice. To reach this goal, the technique should be robust and laboratories should be adequately experienced [4]. In addition, results obtained in different centres should be comparable to the highest possible degree [5]. The comparability of results between different centres is crucially dependent on the performance of the biomarker tests in the various institutions, and this can be assessed with an external quality assessment scheme. No such scheme was available and that is why we took the initiative in 2004 to send samples to a number of laboratories with previous experience in performing these CSF biomarker
Amyloid and tau cerebrospinal fluid biomarkers in HIV infection
Magnus Gisslén, Jan Krut, Ulf Andreasson, Kaj Blennow, Paola Cinque, Bruce J Brew, Serena Spudich, Lars Hagberg, Lars Rosengren, Richard W Price, Henrik Zetterberg
BMC Neurology , 2009, DOI: 10.1186/1471-2377-9-63
Abstract: In this cross-sectional study we measured soluble amyloid precursor proteins alpha and beta (sAPPα and sAPPβ), amyloid beta fragment 1-42 (Aβ1-42), and total and hyperphosphorylated tau (t-tau and p-tau) in CSF of 86 HIV-infected (HIV+) subjects, including 21 with AIDS dementia complex (ADC), 25 with central nervous system (CNS) opportunistic infections and 40 without neurological symptoms and signs. We also measured these CSF biomarkers in 64 uninfected (HIV-) subjects, including 21 with Alzheimer's disease, and both younger and older controls without neurological disease.CSF sAPPα and sAPPβ concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups. The opportunistic infection group but not the ADC patients had lower CSF Aβ1-42 in comparison to the other HIV+ subjects. CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups. Together, CSF amyloid and tau markers segregated the ADC patients from both HIV+ and HIV- neuroasymptomatics and from Alzheimer's disease patients, but not from those with opportunistic infections.Parallel reductions of CSF sAPPα and sAPPβ in ADC and CNS opportunistic infections suggest an effect of CNS immune activation or inflammation on neuronal amyloid synthesis or processing. Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease. These biomarker changes define pathogenetic pathways to brain injury in ADC that differ from those of Alzheimer's disease.Central nervous system (CNS) infection is a nearly uniform feature of untreated human immunodeficiency virus type 1 (henceforth, HIV) infection. Thus, from initial viremia until death, HIV is detected in the cerebrospinal fluid (CSF) of most
Cerebrospinal fluid amyloid beta and tau protein: Biomarkers for Alzheimer's disease  [PDF]
Mandi? Gorana,Markovi? Ivanka,Ostoji? Marija,Stojkovi? Tanja
Vojnosanitetski Pregled , 2008, DOI: 10.2298/vsp0812901m
Abstract: Background/Aim. Introduction of acetylcholine esterase inhibitors as a symptomatic treatment of Alzheimer's disease (AD) has additionally highlighted the importance of diagnostic markers in cerebrospinal fluid (CSF) for early AD diagnosis: low level of 42 amino acid form of amyloid-β peptide (Aβ42), and levels of tau protein (T-tau) and phosphorylated tau protein (P-tau). The aim of this study was to diagnostic potential of CSF biomarkers T-tau, P-tau and Aβ42 as biochemical markers for AD. Methods. Lumbar puncture was performed in 63 patients with AD and 26 control subjects who passed orthopedic surgery. The Innotest, ELISA sandwich test (Innogenetics - Belgium) was used for measuring the levels of T-tau, P-tau and Aβ42. Results. The patients and the control group did not differ in age, education and sex. Mean levels of CSF T-tau and P-tau were significantly higher in the patients with AD (p < 0.001) compared to the control group, in contrast to significantely lower CSF Aβ42 in AD group (p < 0.001). A significant progressive decrease of Aβ42, as well as significant progressive increase of T-tau and P-tau was found among AD subgroups (according to MMSE staging) and controls. Conclusion. The obtained results suggest that these biomarkers may be supportive in the diagnosis of AD, especially in the early course of the disease and could be used in the routine clinical practice considering the approaching target therapeutics.
Neuroinflammation in Lyme neuroborreliosis affects amyloid metabolism
Niklas Mattsson, Daniel Bremell, Rolf Anckars?ter, Kaj Blennow, Henrik Anckars?ter, Henrik Zetterberg, Lars Hagberg
BMC Neurology , 2010, DOI: 10.1186/1471-2377-10-51
Abstract: The first part of the study was a cross-sectional cohort study in 61 patients with acute facial palsy (19 with LNB and 42 with idiopathic facial paresis, Bell's palsy) and 22 healthy controls. CSF was analysed for the β-amyloid peptides Aβ38, Aβ40 and Aβ42, and the amyloid precursor protein (APP) isoforms α-sAPP and β-sAPP. CSF total-tau (T-tau), phosphorylated tau (P-tau) and neurofilament protein (NFL) were measured to monitor neural cell damage. The second part of the study was a prospective cohort-study in 26 LNB patients undergoing consecutive lumbar punctures before and after antibiotic treatment to study time-dependent dynamics of the biomarkers.In the cross-sectional study, LNB patients had lower levels of CSF α-sAPP, β-sAPP and P-tau, and higher levels of CSF NFL than healthy controls and patients with Bell's palsy. In the prospective study, LNB patients had low levels of CSF α-sAPP, β-sAPP and P-tau at baseline, which all increased towards normal at follow-up.Amyloid metabolism is altered in LNB. CSF levels of α-sAPP, β-sAPP and P-tau are decreased in acute infection and increase after treatment. In combination with earlier findings in multiple sclerosis, cerebral SLE and HIV with cerebral engagement, this points to an influence of neuroinflammation on amyloid metabolism.The trans-membranous protein amyloid precursor protein (APP) has been intensely studied in Alzheimer's disease (AD), since it is the source of β-amyloid (Aβ) peptides, recognized as key-components in AD pathophysiology [1]. Although ubiquitously expressed, the physiological role of APP in the adult organism remains largely unknown. APP may undergo non-amyloidogenic cleavage at the α-site, which inhibits formation of Aβ and releases an extracellular soluble α-sAPP fragment. Alternatively, APP is processed by combined cleavages by β-secretase and γ-secretase, releasing Aβ and β-sAPP. Aβ peptides vary in length due to variability in the γ-secretase cleavage site. Although CSF levels of α-sAPP
Chemokines in CSF of Alzheimer's disease patients
Corrêa, J?ice Dias;Starling, Daniela;Teixeira, Ant?nio Lúcio;Caramelli, Paulo;Silva, Tarcília Aparecida;
Arquivos de Neuro-Psiquiatria , 2011, DOI: 10.1590/S0004-282X2011000400009
Abstract: some studies have linked the presence of chemokines to the early stages of alzheimer's disease (ad). then, the identification of these mediators may contribute to diagnosis. our objective was to evaluate the levels of beta-amyloid (ba), tau, phospho-tau (p-tau) and chemokines (ccl2, cxcl8 and cxcl10) in the cerebrospinal fluid (csf) of patients with ad and healthy controls. the correlation of these markers with clinical parameters was also evaluated. the levels of p-tau were higher in ad compared to controls, while the tau/p-tau ratio was decreased. the expression of ccl2 was increased in ad. a positive correlation was observed between ba levels and all chemokines studied, and between ccl2 and p-tau levels. our results suggest that levels of ccl2 in csf are involved in the pathogenesis of ad and it may be an additional useful biomarker for monitoring disease progression.
Hyperphosphorylated tau protein in the cerebrospinal fluid of patients with Alzheimer's disease and other dementias: preliminary findings
Hartmann, Ana Paula Barbosa Jeronimo;Almeida, Sérgio Monteiro de;Livramento, José Antonio;Nitrini, Ricardo;Takahashi, Daniel;Caramelli, Paulo;
Arquivos de Neuro-Psiquiatria , 2004, DOI: 10.1590/S0004-282X2004000500001
Abstract: alzheimer's disease (ad) is pathologically characterized by the accumulation of amyloid plaques and tau-associated neurofibrillary tangles in the cerebral tissue. the search for antemortem biomarkers is intense including analysis of cerebrospinal fluid (csf) b-amyloid and tau proteins concentrations seeking for an accurate and early diagnosis. levels of hyperphosphorylated tau at threonine 181 were measured in the csf of 34 patients with ad (19 with senile ad - sad and eight with presenile ad - psad) and seven with other dementias (od). the levels of csf phosphotau were significantly higher in the ad patients compared to od (auc 0.812), with no association with severity of dementia, age of onset, duration of the disease or scores in the mini-mental state examination. there were no differences of phosphotau levels between sad and psad patients. these findings corroborate some previous studies and indicate that csf phosphotau may help to differentiate ad from other dementias.
Differential role of CSF alpha-synuclein species, tau, and Aβ42 in Parkinson's Disease  [PDF]
Lucilla Parnetti,Lucia Farotti,Paolo Eusebi,Davide Chiasserini,David Giannandrea,Nicola Salvadori,Viviana Lisetti,Nicola Tambasco,Omar El-Agnaf,Paolo Calabresi
Frontiers in Aging Neuroscience , 2014, DOI: 10.3389/fnagi.2014.00053
Abstract: There is a great interest in developing cerebrospinal fluid (CSF) biomarkers for diagnosis and prognosis of Parkinson's disease (PD). CSF alpha synuclein (α-syn) species, namely total and oligomeric α-syn (t-α-syn and o-α-syn), have shown to be of help for PD diagnosis. Preliminary evidences show that the combination of CSF t-α-syn and classical Alzheimer's disease (AD) biomarkers—β-amyloid 1–42 (Aβ42), total tau (t-tau), phosphorylated tau (p-tau)—differentiate PD patients from controls, and that reduced levels of Aβ42 represent a predictive factor for development of cognitive deterioration in PD. In this prospective study carried out in 44 PD patients and 25 neurological controls we wanted to verify whether the combination of CSF α-synuclein species—t-α-syn and o-α-syn—and classical AD biomarkers may help in differentiating PD from neurological controls, and if these biomarkers may predict cognitive decline. The median of follow-up duration was 3 years (range: 2–6 years). Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used for monitoring cognitive changes along time, being administered once a year. Oligo/total α-syn ratio (o/t-α-syn ratio) confirmed its diagnostic value, significantly contributing to the discrimination of PD from neurological controls. A greater diagnostic accuracy was reached when combining o/t-α-syn and Aβ42/tau ratios (Sens = 0.70, Spec = 0.84, AUC = 0.82; PPV = 0.89, NPV = 0.62, LR+ = 4.40, DOR = 12.52). Low CSF Aβ42 level was associated with a higher rate of MMSE and MoCA decline, confirming its role as independent predictive factor for cognitive decline in PD. None of the other biomarkers assessed (t-tau, p-tau, t-α-syn and o-α-syn) showed to have prognostic value. We conclude that combination of CSF o/t-α-syn and Aβ42/tau ratios improve the diagnostic accuracy of PD. PD patients showing low CSF Aβ42 levels at baseline are more prone to develop cognitive decline.
Variability of CSF Alzheimer’s Disease Biomarkers: Implications for Clinical Practice  [PDF]
Stephanie J. B. Vos, Pieter Jelle Visser, Frans Verhey, Pauline Aalten, Dirk Knol, Inez Ramakers, Philip Scheltens, Marcel G. M. Olde. Rikkert, Marcel M. Verbeek, Charlotte E. Teunissen
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0100784
Abstract: Background Cerebrospinal fluid (CSF) biomarkers are increasingly being used for diagnosis of Alzheimer’s disease (AD). Objective We investigated the influence of CSF intralaboratory and interlaboratory variability on diagnostic CSF-based AD classification of subjects and identified causes of this variation. Methods We measured CSF amyloid-β (Aβ) 1-42, total tau (t-tau), and phosphorylated tau (p-tau) by INNOTEST enzyme-linked-immunosorbent assays (ELISA) in a memory clinic population (n = 126). Samples were measured twice in a single or two laboratories that served as reference labs for CSF analyses in the Netherlands. Predefined cut-offs were used to classify CSF biomarkers as normal or abnormal/AD pattern. Results CSF intralaboratory variability was higher for Aβ1-42 than for t-tau and p-tau. Reanalysis led to a change in biomarker classification (normal vs. abnormal) of 26% of the subjects based on Aβ1-42, 10% based on t-tau, and 29% based on p-tau. The changes in absolute biomarker concentrations were paralleled by a similar change in levels of internal control samples between different assay lots. CSF interlaboratory variability was higher for p-tau than for Aβ1-42 and t-tau, and reanalysis led to a change in biomarker classification of 12% of the subjects based on Aβ1-42, 1% based on t-tau, and 22% based on p-tau. Conclusions Intralaboratory and interlaboratory CSF variability frequently led to change in diagnostic CSF-based AD classification for Aβ1-42 and p-tau. Lot-to-lot variation was a major cause of intralaboratory variability. This will have implications for the use of these biomarkers in clinical practice.
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