22213780
Altered CSF Orexin and α-Synuclein Levels in Dementia Patients.
Source
Molecular Memory Research Unit, The Wallenberg Lab, Lund University, Department of Clinical Sciences Malmö, Sweden.
Abstract
Neurodegenerative dementia, most frequently represented by Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), is often accompanied by altered sleeping patterns and excessive daytime sleepiness. Studies showing an association between the neuropeptide orexin and AD/DLB-related processes such as amyloid-β (Aβ)1-42 plaque formation, α-synuclein accumulation, and inflammation indicate that orexin might play a pathogenic role similar to the situation in narcolepsy. Our study of patients with AD (n = 26), DLB (n = 18), and non-demented controls (n = 24) shows a decrease in cerebrospinal fluid (CSF) orexin concentrations in DLB versus AD patients and controls. The observed differences in orexin levels were found to be specific to female DLB patients. We also show that the female DLB patients exclusively displayed lower levels of α-synuclein compared to AD patients and controls. Orexin was linked to α-synuclein and total-tau in female non-demented controls whereas associations between orexin and Aβ1-42 concentrations were absent in all groups regardless of gender. Thus, the proposed links between orexin, Aβ, and α-synuclein pathology could not be monitored in CSF protein concentrations. Interestingly, α-synuclein was strongly correlated to the CSF levels of total-tau in all groups, suggesting α-synuclein to be an unspecific marker of neurodegeneration. We conclude that lower levels of CSF orexin are specific to DLB versus AD and appear unrelated to Aβ1-42 and α-synuclein levels in AD and DLB. Alterations in CSF orexin and α-synuclein levels may be related to gender which warrants further investigation.
Cerebrospinal fluid amyloid β and tau in LRRK2 mutation carriers.
Source
Correspondence & reprint requests to Dr. Zhang: zhangj@uw.edu.
Abstract
OBJECTIVE:
The goal of the current investigation was to examine a cohort of symptomatic and asymptomatic LRRK2 mutation carriers, in order to address whether the reported alterations in amyloid β (Aβ) and tau species in the CSF of patients with sporadic Parkinson disease (PD) are a part of PD pathogenesis, the aging process, or a comorbid disease in patients with PD, and to explore the possibility of Aβ and tau as markers of early or presymptomatic PD.
METHODS:
CSF Aβ42, total tau, and phosphorylated tau were measured with Luminex assays in 26 LRRK2 mutation carriers, who were either asymptomatic (n = 18) or had a phenotype resembling sporadic PD (n = 8). All patients also underwent PET scans with (18)F-6-fluoro-l-dopa (FD), (11)C-(±)-α-dihydrotetrabenazine (DTBZ), and (11)C-d-threo-methylphenidate (MP) to measure dopaminergic function in the striatum. The levels of CSF markers were then compared to each PET measurement.
RESULTS:
Reduced CSF Aβ42 and tau levels correlated with lower striatal dopaminergic function as determined by all 3 PET tracers, with a significant association between Aβ42 and FD uptake. When cases were restricted to carriers of the G2019S mutation, the most common LRRK2 variant in our cohort, significant correlations were also observed for tau.
CONCLUSIONS:
The disposition of Aβ and tau is likely important in both LRRK2-related and sporadic PD, even during early phases of the disease. A better understanding of their production, aggregation, and degradation, including changes in their CSF levels, may provide insights into the pathogenesis of PD and the potential utility of these proteins as biomarkers.
A Blood-Based Screening Tool for Alzheimer's Disease That Spans Serum and Plasma: Findings from TARC and ADNI.
Source
Department of Neurology, F. Marie Hall Institute for Rural and Community Health, Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, Texas, United States of America.
Abstract
CONTEXT:
There is no rapid and cost effective tool that can be implemented as a front-line screening tool for Alzheimer's disease (AD) at the population level.
OBJECTIVE:
To generate and cross-validate a blood-based screener for AD that yields acceptable accuracy across both serum and plasma.
DESIGN, SETTING, PARTICIPANTS:
Analysis of serum biomarker proteins were conducted on 197 Alzheimer's disease (AD) participants and 199 control participants from the Texas Alzheimer's Research Consortium (TARC) with further analysis conducted on plasma proteins from 112 AD and 52 control participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The full algorithm was derived from a biomarker risk score, clinical lab (glucose, triglycerides, total cholesterol, homocysteine), and demographic (age, gender, education, APOE*E4 status) data.
MAJOR OUTCOME MEASURES:
Alzheimer's disease.
RESULTS:
11 proteins met our criteria and were utilized for the biomarker risk score. The random forest (RF) biomarker risk score from the TARC serum samples (training set) yielded adequate accuracy in the ADNI plasma sample (training set) (AUC = 0.70, sensitivity (SN) = 0.54 and specificity (SP) = 0.78), which was below that obtained from ADNI cerebral spinal fluid (CSF) analyses (t-tau/Aβ ratio AUC = 0.92). However, the full algorithm yielded excellent accuracy (AUC = 0.88, SN = 0.75, and SP = 0.91). The likelihood ratio of having AD based on a positive test finding (LR+) = 7.03 (SE = 1.17; 95% CI = 4.49-14.47), the likelihood ratio of not having AD based on the algorithm (LR-) = 3.55 (SE = 1.15; 2.22-5.71), and the odds ratio of AD were calculated in the ADNI cohort (OR) = 28.70 (1.55; 95% CI = 11.86-69.47).
CONCLUSIONS:
It is possible to create a blood-based screening algorithm that works across both serum and plasma that provides a comparable screening accuracy to that obtained from CSF analyses.
- PMID:
- 22163278
- [PubMed - as supplied by publisher]
- PMCID: PMC3233542
Cerebrospinal Fluid Proteins Predict Longitudinal Hippocampal Degeneration in Early-stage Dementia of the Alzheimer Type.
Source
*Northwestern University Feinberg School of Medicine, Chicago, IL †Washington University School of Medicine, St. Louis, MO ‡Simon Frasier University, Vancouver, BC, Canada.
Abstract
OBJECTIVE:
Biomarkers are needed to improve the sensitivity and accuracy of diagnosis, and also prognosis, in individuals with early Alzheimer disease (AD). Measures of brain structure and disease-related proteins in the cerebrospinal fluid (CSF) have been proposed as biomarkers, yet relatively little is known about the relationships between such measures. The present study was conducted to assess the relationship between CSF Aβ and tau proteinlevels and longitudinal measures of hippocampal structure in individuals with and without very mild dementia of the Alzheimer type.
DESIGN:
A single CSF sample and longitudinal magnetic resonance scans were collected. The CSF samples were assayed for tau, phosphorylated tau181 (p-tau181), Aβ1-42, and Aβ1-40 using an enzyme-linked immunosorbent assay. Large-deformation diffeomorphic metric mapping was used to generate hippocampal surfaces, and a composite hippocampal surface (previously constructed from 86 healthy participants) was used as a structural reference.
PATIENTS OR OTHER PARTICIPANTS:
Thirteen participants with very mild AD (Clinical Dementia Rating, CDR 0.5) and 11 cognitively normal participants (CDR 0).
INTERVENTION:
None.
MAIN OUTCOME MEASURES:
Initial and rate-of-change measures of total hippocampal volume and displacement of the hippocampal surface within zones overlying the CA1, subiculum, and CA2-4+DG cellular subfields, and their correlations with initial CSF measures.
RESULTS:
Lower CSF Αβ1-42 levels and higher tau/Αβ1-42 and p-tau181/Αβ1-42 ratios were strongly correlated with decreases in hippocampal volume and measures of progressive inward deformations of the CA1 subfield in participants with early AD, but not in cognitively normal participants.
CONCLUSIONS:
Despite the small sample size, we found that Αβ1-42 related and tau-related CSF measures were associated with hippocampal degeneration in individuals with clinically diagnosed early AD and may reflect an association with a common underlying disease mechanism.
[Multicenter study on lumbar puncture indication, clinical practice and feasibility.]
Source
CMRR Paris Nord Île-de-France, groupe hospitalier Lariboisière Fernand-Widal Saint-Louis, AP-HP, université Denis-Diderot, 2, rue Ambroise-Paré, 75010 Paris, France; Laboratoire de biologie du vieillissement, groupe hospitalier Lariboisière Fernand-Widal Saint-Louis, AP-HP, université Denis-Diderot, 2, rue Ambroise-Paré, 75010 Paris, France; Inserm U839, institut du Fer-à-Moulin, 17, rue du Fer-à-Moulin, 75005 Paris, France.
Abstract
INTRODUCTION:
Cerebrospinal fluid (CSF) biomarkers have been extensively studied as diagnostic markers for Alzheimer's disease (AD). However, results are variable probably due to lumbar puncture (LP) procedure, CSF collection and transport. This intercenter variability highlights the need for an efficient standardization of clinical and technical procedures. The aims of this study were firstly to compare the LP procedure and CSF transport process in all French Memory Centers and secondly to evaluate the incidence of LP side effects in 100 patients with cognitive disturbances.
METHODS:
LP practice and side effect prospective questionnaires were sent to all French Memory Centers in May 2010. Memory Centers were asked about their LP procedure. The prospective study over a three-week-period has evaluated the LP feasibility and side effects. All data were collected until the end of July 2010.
RESULTS:
The answers of 18 out of 26 Memory Centers were collected. Although, these centers did not have the same LP procedure and CSF transport, the majority of them proceeded according to Innogenetics's advices concerning the use of polypropylene tubes and transport duration but not sample conditioning. Polypropylene tubes were different from one center to the other. CSF volume, pharmacological premedication and prevention of post-LP syndrome were variable in all responding centers. The prospective study carried out in 100 patients revealed a very good LP acceptability (93/100 patients). LP feasibility was 97 % (90/93) and failed LP were consequently performed with success using radiological scopes. Three minor complications were observed.
DISCUSSION AND CONCLUSION:
All French Centers complied with Innogenetics' recommendations for pretechnicalCSF procedures; however each Center put in place its own procedure that was different one center to the other. It will be very interesting to compare cut-off and result values for Aβ, tau and phosphorylated tau protein on threonine 181 between several centers that used their own procedures. Acceptability and safety were very good in our short but significant prospective study. These results confirm the data of Zetterberg et al., 2010.
Copyright © 2011 Elsevier Masson SAS. All rights reserved.
Evidence for Elevated Cerebrospinal Fluid ERK1/2 Levels in Alzheimer Dementia.
Source
Department of Psychiatry and Psychotherapy, Laboratory for Molecular Neurobiology, LVR-Klinikum Essen, University of Duisburg-Essen, Virchowstraße 174, 45147 Essen, Germany.
Abstract
Cerebrospinal fluid (CSF) samples from 33 patients with Alzheimer dementia (AD), 21 patients with mild cognitive impairment who converted to AD during followup (MCI-AD), 25 patients with stable mild cognitive impairment (MCI-stable), and 16 nondemented subjects (ND) were analyzed with a chemiluminescence immunoassay to assess the levels of the mitogen-activated protein kinase ERK1/2 (extracellular signal-regulated kinase 1/2). The results were evaluated in relation to total Tau (tTau), phosphorylated Tau (pTau), and beta-amyloid 42 peptide (Aβ42). CSF-ERK1/2 was significantly increased in the AD group as compared to stable MCI patients and the ND group. Western blot analysis of a pooled cerebrospinal fluid sample revealed that both isoforms, ERK1 and ERK2, and low amounts of doubly phosphorylated ERK2 were detectable. As a predictive diagnostic AD biomarker, CSF-ERK1/2 was inferior to tTau, pTau, and Aβ42.
Increased intrathecal high-avidity anti-tau antibodies in patients with multiple sclerosis.
Source
Institute of Medical Biochemistry, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
Abstract
BACKGROUND:
Antibodies against tau protein indicate an interaction between the immune system and the neurocytoskeleton and therefore may reflect axonal injury in multiple sclerosis (MS).
METHODOLOGY/PRINCIPAL FINDINGS:
The levels and avidities of anti-tau IgG antibodies were measured using ELISA in paired cerebrospinal fluid (CSF) and serum samples obtained from 49 MS patients and 47 controls. Anti-tauantibodies were significantly elevated intrathecally (p<0.0001) in the MS group. The CSF anti-tau antibody levels were lower in MS patients receiving therapy than those without treatment (p<0.05). The avidities of anti-tau antibodies were higher in the CSF than in the serum (MS group p<0.0001; controls p<0.005). Anti-tau avidities in the CSF were elevated in MS patients in comparison with controls (p<0.05), but not in serum.
CONCLUSIONS:
MS patients have higher levels of intrathecal anti-tau antibodies. Anti-tau antibodies have different avidities in different compartments with the highest values in the CSF of MS patients.
Impact of chronic Helicobacter pylori infection on Alzheimer's disease: preliminary results.
Source
Institut National de la Sante et de la Recherche Medicale U853, Bordeaux, France; Univ. Bordeaux, Laboratoire de Bactériologie, F-33000 Bordeaux, France; Pôle de gérontologie clinique, CHU Hôpitaux de Bordeaux, Bordeaux, France.
Abstract
Recent case-control studies reported an association between H. pylori infection and Alzheimer's disease (AD). Our aim was to compare cognitive impairment, neuroinflammation, and cerebrovascular lesion load in a group of AD patients according to their H. pylori status. For the 53 AD patients included, we assessed: clinical data (vascular comorbidities and cognitive assessment), biological data (especially fibrinogen, homocysteine levels, apolipoprotein E4 genotype; cerebrospinal fluid [CSF] total tau protein [Tau], phospho-tau(181) protein [pTau(181)]), and amyloid beta peptide levels, serum/CSF-cytokines (interleukin [IL]-1β, IL-6, IL-8, tumor necrosis factor [TNF]-α) and pepsinogen I/pepsinogen II (PgI/PgII) ratio, and cerebrovascular lesion load (magnetic resonance imaging [MRI] fluid-attenuated inversion recovery [FLAIR] with the Fazekas and Schmidt scale). H. pylori infection was diagnosed by enzyme-linked immunosorbent assay (ELISA) and immunoblot test. H. pylori infection was associated with a decreased Mini Mental State Examination (MMS) (p = 0.024), and higher CSF pTau(181) (p = 0.014) and tau (p = 0.021) levels. A decreased PgI/II ratio (i.e., an increased gastric atrophy) was associated with the infection (p = 0.005). Homocysteine levels were positively correlated to Fazekas score (r = 0.34; p = 0.032) and to H. pylori immunoglobulin (Ig)G levels (r = 0.44; p = 0.001). Higher CSFcytokine levels (IL-8, p = 0.003; TNF-α, p = 0.019) were associated with the infection, but systemic inflammation results were controversial. Finally, in multivariate analysis, a lower MMSE score (odds ratio [OR], 0.83 [0.72-0.97]; p = 0.017), plasma IL-1β level (OR, 0.31 [0.11-0.87]; p = 0.025), an increased gastric atrophy, i.e., a lower PgI/PgII ratio (OR, 0.63 [0.43-0.93]; p = 0.020) were still associated with the infection. AD patients infected by H. pylori tended to be more cognitively impaired. Studies are needed to attest to the impact of H. pylori infection on AD course, especially on cerebrovascular lesions and neuroinflammation.
Copyright © 2011 Elsevier Inc. All rights reserved.
Some markers of neuronal damage in cerebrospinal fluid of multiple sclerosis patients in relapse.
Source
Department of Neurology, Medical University of Lublin, ul. Jaczewskiego 8, 20-954 Lublin, Poland.
Abstract
In this paper the performance of cerebrospinal fluid (CSF) protein biomarkers important for monitoring damage of brain astrocytes and neurons for MS is reviewed. We estimated neurofilament, tau and phospho-tau proteins, β-APP, Aβ, S-100B and neuron-specific enolase in CSF of MS patients during relapse. We noted elevation of neurofilament, tau and phospho-tau proteins, S-100B, neuron-specific enolase and c-terminal epitopes of β-APP; concomitantly decrease of Aβ was observed. These CSF biomarkers for MS relapse should reflect the central pathogenic processes in the brain, i.e., axonal and neuronal degeneration.
CSF levels of oligomeric alpha-synuclein and beta-amyloid as biomarkers for neurodegenerative disease.
Source
Department of Chemical Engineering, Box 876106, Arizona State University, Tempe, AZ 85287. sierks@asu.edu.
Abstract
Protein misfolding and aggregation is a critically important feature in many devastating neurodegenerative diseases, therefore characterization of the CSF concentration profiles of selected key forms and morphologies of proteins involved in these diseases, including β-amyloid (Aβ) and α-synuclein (a-syn), can be an effective diagnostic assay for these diseases. CSF levels of tau and Aβ have been shown to have great promise as biomarkers for Alzheimer's disease. However since the onset and progression of many neurodegenerative diseases have been strongly correlated with the presence of soluble oligomeric aggregates of proteins including various Aβ and a-syn aggregate species, specific detection and quantification of levels of each of these different toxic protein species in CSF may provide a simple and accurate means to presymptomatically diagnose and distinguish between these diseases. Here we show that the presence of different protein morphologies in human CSF samples can be readily detected using highly selective morphology specific reagents in conjunction with a sensitive electronic biosensor. We further show that these morphology specific reagents can readily distinguish between post-mortem CSF samples from AD, PD and cognitively normal sources. These studies suggest that detection of specific oligomeric aggregate species holds great promise as sensitive biomarkers for neurodegenerative disease.
CSF biomarkers in different phenotypes of Parkinson disease.
Source
, Wein, Austria, kurt.jellinger@univie.ac.at.
Abstract
CSF biomarker studies were performed in 6 patients each with tremor-dominant (TD) and non-tremor-dominant (NT) Parkinson disease (PD) patients, 27 Alzheimer disease (AD) and 17 age-matched controls. In both NT-PD and AD patients total tau levels and the cortex tau/Aβ-42 were significantly increased compared to both TD-PD patients and controls (p < 0.01). These data in a small cohort confirm previous studies, corroborating the opinion that CSF levels oftau protein and the index total-tau/Aβ-42 may be potential markers of the severity of neurodegeneration in PD.
Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid (CSF) in early Alzheimer's Disease.
Source
University of Massachusetts Lowell, United States;
Abstract
Recent demonstrations that secretion, uptake, and interneuronal transfer of tau in tauopathy models can be modulated by disease-associated tau modifications suggest that secretion may be an element in the pathobiology of tau-induced neurodegeneration. Here we show that much of the tau secreted by M1C cells occurs via exosomal release, a widely characterized mechanism that mediates unconventional secretion of other aggregation-prone proteins (alpha synuclein, prion protein, and beta amyloid) in neurodegenerative disease. Exosome-associated tau is also present in human CSFsamples, and is phosphorylated at Thr 181 (AT270), an established phosphotau biomarker for Alzheimer's Disease, in both M1C cells and CSF samples. A preliminary analysis of the proteins copurified with tau in secreted exosomes identified several that are known to be involved in disease-associated tau misprocessing. Our results therefore suggest that membrane trafficking pathways may play a significant role in the abnormal processing of tau that is not bound to microtubules.
Progression from Mild to Pronounced MCI Is Not Associated with Cerebrospinal Fluid Biomarker Deviations.
Source
Institute of Neuroscience and Physiology, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
Abstract
Background/Aim: Detection of cerebrospinal fluid (CSF) biomarker deviations improve prediction of progression from mild cognitive impairment (MCI) to dementia. However, it is not settled whether the same pattern exists in patients progressing from very mild to more pronounced MCI. Given that neurodegenerative processes occur very early in the disease course, we also expected to find biomarker deviations in these patients. Methods: A total of 246 memory clinic patients with non-progressive (n = 161), progressive (n = 19), or converting (n = 66) MCI, 67 with stable dementia, and 80 controls were followed for 24 months. At baseline, CSF total tau (T-tau), β-amyloid 1-42 (Aβ42) and the light subunit of neurofilament protein (NFL) were determined. Results: Patients with converting MCI and stable dementia had lowerCSF Aβ42 concentrations and higher T-tau concentrations and NFL in comparison with controls and non-progressive/progressive MCI (p < 0.0005). No differences were found between progressive and non-progressive MCI. Conclusion: As expected, biomarker deviations predicted progression from MCI to dementia. Contrary to our hypothesis, progression from very mild MCI to more pronounced MCI was not reflected by biomarker deviations. The results suggest that the measured biomarkers are not early disease markers, or alternatively Alzheimer or vascular pathology is not the underlying cause in this patient group.
Copyright © 2011 S. Karger AG, Basel.
Peptide fingerprinting of Alzheimer's disease in cerebrospinal fluid: identification and prospective evaluation of new synaptic biomarkers.
Source
Department of Psychiatry, University Hospital Hamburg-Eppendorf, Hamburg, Germany. jahn@uke.uni-hamburg.de
Abstract
BACKGROUND:
Today, dementias are diagnosed late in the course of disease. Future treatments have to start earlier in the disease process to avoid disability requiring new diagnostic tools. The objective of this study is to develop a new method for the differential diagnosis and identification of new biomarkers of Alzheimer's disease (AD) using capillary-electrophoresis coupled to mass-spectrometry (CE-MS) and to assess the potential of early diagnosis of AD.
METHODS AND FINDINGS:
Cerebrospinal fluid (CSF) of 159 out-patients of a memory-clinic at a University Hospital suffering from neurodegenerative disorders and 17 cognitively-healthy controls was used to create differential peptide pattern for dementias and prospective blinded-comparison of sensitivity and specificity for AD diagnosis against the Criterion standard in a naturalistic prospective sample of patients. Sensitivity and specificity of the new method compared to standard diagnostic procedures and identification of new putative biomarkers for AD was the main outcome measure. CE-MS was used to reliably detect 1104 low-molecular-weight peptides in CSF. Training-sets of patients with clinically secured sporadic Alzheimer's disease, frontotemporal dementia, and cognitively healthy controls allowed establishing discriminative biomarker pattern for diagnosis of AD. This pattern was already detectable in patients with mild cognitive impairment (MCI). The AD-pattern was tested in a prospective sample of patients (n = 100) and AD was diagnosed with a sensitivity of 87% and a specificity of 83%. Using CSF measurements of beta-amyloid1-42, total-tau, and phospho(181)-tau, AD-diagnosis had a sensitivity of 88% and a specificity of 67% in the same sample. Sequence analysis of the discriminating biomarkers identified fragments of synaptic proteins like proSAAS, apolipoprotein J, neurosecretory protein VGF, phospholemman, and chromogranin A.
CONCLUSIONS:
The method may allow early differential diagnosis of various dementias using specific peptide fingerprints and identification of incipient AD in patients suffering from MCI. Identified biomarkers facilitate face validity for the use in AD diagnosis.
Interrelations between CSF Soluble AβPPβ, Amyloid-β 1-42, SORL1, and TauLevels in Alzheimer's Disease.
Source
Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Abstract
Recently, light has been shed on possible interrelations between the two most important pathological hallmarks of Alzheimer's disease (AD): the amyloid cascade and axonal degeneration. In this study, we investigated associations between sβAPPβ, a product of the cleavage of the amyloid-β protein precursor (AβPP) by β-secretase, amyloid-β 1-42 (Aβ42), soluble SORL1 (also called LR11 or SORLA), a receptor that is involved in AβPP processing, and the marker of axonal degeneration tau in the cerebrospinal fluid (CSF) of 76 patients with mild cognitive impairment (MCI), 61 patients with AD, and 17 patients with frontotemporal dementia, which neuropathologically is not related to the amyloid pathology. In the AD group, significant associations between sAβPPβ, tau (p < 0.001), and soluble SORL1 (p < 0.001) were detected according to linear regression models. In patients with MCI, sAβPPβ correlated significantly with tau (p < 0.001) and soluble SORL1 (p = 0.003). In the FTD group, only SORL1 (p = 0.011) was associated with sAβPPβ and nottau. Aβ42 was found to be significantly related to tau levels in CSF in the MCI group (p < 0.001) and they tended to be associated in the AD group (p = 0.05). Our results provide further evidence for a link between the two facets of AD pathology, which is likely to be mediated by the binding of Aβ oligomers to specifically targeted neurons, resulting in stimulating tau hyperphosphorylation and neurodegeneration.
Stage-dependent agreement between cerebrospinal fluid proteins and FDG-PET findings in Alzheimer's disease.
Source
Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Untere Zahlbacher Str. 855131 Mainz, Germany. igor.yakushev@uni-mainz.de.
Abstract
Cerebral hypometabolism and abonrmal levels of amyloid beta (Aβ), total (t-tau) and phosphorylated tau (p-tau) proteinsin cerebrospinal fluid (CSF) are established biomarkers of Alzheimer's disease (AD). We examined the agreement between these biomarkers in a single center study of patients with AD of severity extending over a wide range. Forty seven patients (MMSE 21.4±3.6, range 13-28 points) with incipient (n=11) and probable (n=36) AD underwent positron emission tomography with [(18)F]-fluorodeoxyglucose (FDG-PET) and lumbar puncture for CSF assays of Aβ(1-42), p-tau(181), and t-tau. All findings were classified as either positive or negative for AD. Statistical analyses were performed for the whole sample (n=47) and for the subgroups stratified as mild (MMSE >20 points, n=30) and moderate (MMSE <21 points, n=17) AD. In the whole patient sample, the agreement with the FDG-PET finding was 77% (chance-corrected kappa [κ]=0.34, p=0.016) for t-tau, 68% (κ=0.10, n.s.) for p-tau(181), and 68% (κ=0.04, n.s.) for Aβ(1-42). No significant agreement was found in the mild AD subgroup, while there was a strong agreement for t-tau (94%, κ=0.77, p=0.001) and p-tau(181) (88%, κ=0.60, p=0.014) in the moderate AD group. A significant agreement between the FDG-PET and CSF tau findings in patients with AD supports the view that both are markers of neurodegeneration. CSF tau proteins and FDG-PET might substitute each other as supportive diagnostic tools in patients with suspected moderate-to-severe Alzheimer's dementia, while this is not the case in subjects at an earlier disease stage.
- PMID:
- 22044023
- [PubMed - as supplied by publisher]
Diagnostic accuracy of cerebrospinal fluid protein markers for sporadic Creutzfeldt-Jakob disease in Canada: a 6-year prospective study.
Source
Canadian Creutzfeldt-Jakob Disease Surveillance System, Public Health Agency of Canada, Winnipeg, Canada. michael.coulthart@phac-aspc.gc.ca
Abstract
BACKGROUND:
To better characterize the value of cerebrospinal fluid (CSF) proteins as diagnostic markers in a clinical population of subacute encephalopathy patients with relatively low prevalence of sporadic Creutzfeldt-Jakob disease (sCJD), we studied the diagnostic accuracies of several such markers (14-3-3, tau and S100B) in 1000 prospectively and sequentially recruited Canadian patients with clinically suspected sCJD.
METHODS:
The study included 127 patients with autopsy-confirmed sCJD (prevalence = 12.7%) and 873 with probable non-CJD diagnoses. Standard statistical measures of diagnostic accuracy were employed, including sensitivity (Se), specificity (Sp), predictive values (PVs), likelihood ratios (LRs), and Receiver Operating Characteristic (ROC) analysis.
RESULTS:
At optimal cutoff thresholds (empirically selected for 14-3-3, assayed by immunoblot; 976 pg/mL for tau and 2.5 ng/mL for S100B, both assayed by ELISA), Se and Sp respectively were 0.88 (95% CI, 0.81-0.93) and 0.72 (0.69-0.75) for 14-3-3; 0.91 (0.84-0.95) and 0.88 (0.85-0.90) for tau; and 0.87 (0.80-0.92) and 0.87 (0.84-0.89) for S100B. The observed differences in Sp between 14-3-3 and either of the other 2 markers were statistically significant. Positive LRs were 3.1 (2.8-3.6) for 14-3-3; 7.4 (6.9-7.8) for tau; and 6.6 (6.1-7.1) for S100B. Negative LRs were 0.16 (0.10-0.26) for 14-3-3; 0.10 (0.06-0.20) for tau; and 0.15 (0.09-0.20) for S100B. Estimates of areas under ROC curves were 0.947 (0.931-0.961) for tau and 0.908 (0.888-0.926) for S100B. Use of interval LRs (iLRs) significantly enhanced accuracy for patient subsets [e.g., 41/120 (34.2%) of tested sCJD patients displayed tau levels > 10,000 pg/mL, with an iLR of 56.4 (22.8-140.0)], as did combining tau and S100B [e.g., for tau > 976 pg/mL and S100B > 2.5 ng/mL, positive LR = 18.0 (12.9-25.0) and negative LR = 0.02 (0.01-0.09)].
CONCLUSIONS:
CSF 14-3-3, tau and S100B proteins are useful diagnostic markers of sCJD even in a low-prevalence clinical population. CSF tau showed better overall diagnostic accuracy than 14-3-3 or S100B. Reporting of quantitative assay results and combining tau with S100B could enhance case definitions used in diagnosis and surveillance of sCJD.
Cerebrospinal fluid markers in sporadic creutzfeldt-jakob disease.
Source
Section of Neuropathology, Department of Neurological, Neuropsychological, Morphological and Motor Sciences, University of Verona, Policlinico G.B. Rossi, Piazzale L.A. Scuro 10, 37134 Verona, Italy; E-Mails: michele.fiorini@univr.it (M.F.); sergio.ferrari@ospedaleuniverona.it (S.F.).
Abstract
Sporadic Creutzfeldt-Jakob disease (sCJD) is the commonest form of human prion diseases, accounting for about 85% of all cases. Current criteria for intra vitam diagnosis include a distinct phenotype, periodic sharp and slow-wave complexes at electroencephalography (EEG), and a positive 14-3-3-protein assay in the cerebrospinal fluid (CSF). In sCJD, the disease phenotype may vary, depending upon the genotype at codon 129 of the prion protein gene (PRNP), a site of a common methionine/valine polymorphism, and two distinct conformers of the pathological prion protein. Based on the combination of these molecular determinants, six different sCJD subtypes are recognized, each with distinctive clinical and pathologic phenotypes. We analyzed CSF samples from 127 subjects with definite sCJD to assess the diagnostic value of 14-3-3 protein, total tau protein, phosphorylated(181) tau, and amyloid beta (Aβ) peptide 1-42, either alone or in combination. While the 14-3-3 assay and tau protein levels were the most sensitive indicators of sCJD, the highest sensitivity, specificity and positive predictive value were obtained when all the above markers were combined. The latter approach also allowed a reliable differential diagnosis with other neurodegenerative dementias.
Value of Neuropsychological Testing, Imaging, and CSF Biomarkers for the Differential Diagnosis and Prognosis of Clinically Ambiguous Dementia.
Source
CHU Nantes, Centre de Mémoire et de Ressource et Recherche (CM2R), Nantes, France Inserm, Nantes, France.
Abstract
The objective of this study was to examine the diagnostic accuracy of imaging and CSF biomarkers in clinically ambiguous dementia (CAD). 69 patients were prospectively followed. The endpoint was clinical diagnosis at follow-up of 24 months based upon existing criteria. Medial temporal lobe atrophy score on MRI, distinctive patterns on 99 mTc-HMPAO-SPECT, and CSF levels of amyloid-β peptide, total tau protein, and P-tau181P were used together with neuropsychological testing to assess Se (sensitivity) and Sp (specificity) of separate and combined markers. 60 patients reached the endpoint. A definite diagnosis was achieved in 48 patients. CSF biomarkers had a Sp of 71% and a Se of 100% for Alzheimer's disease (AD) diagnosis. Sp increased to 88% and 93% when MRI and MRI + SPECT were combined, at the expense of Se. CSF biomarkers levels also provided clues to frontotemporal (FTD) or vascular dementias (VaD) diagnosis when situated in an intermediate range between normal and pathological values. MRI and SPECT contributed mostly to the diagnosis of VaD (Se 88%, Sp 75%) and FTD (Se 73%, Sp 78%), respectively. Initial neuropsychological testing had a poor diagnostic accuracy, except for a neuropsychiatric inventory score >40 for the diagnosis of FTD (Se 73%, Sp 84%). Independent of the clinical diagnosis, medial temporal lobe atrophy and total-tauwere best correlated with cognitive decline at 2 years. In conclusion, CSF biomarkers efficiently predict evolution toward an AD phenotype in CAD. Imaging biomarkers mostly contribute to the differential diagnosis between non-AD dementias. Initial neuropsychological testing was poorly contributive in CAD diagnosis.
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