Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to beta-amyloid peptide42

BACKGROUND: The antemortem diagnosis of Alzheimer disease (AD) requires time-consuming and costly procedures. Therefore, biochemical tests that can direct the physician rapidly to the correct diagnosis are highly desirable. Measurement of single biochemical markers in cerebrospinal fluid (CSF), such as total tau protein and beta-amyloid peptide42 (Abeta42), shows robust alterations that highly correlate with the clinical diagnosis of AD but generally lack sufficient diagnostic accuracy. OBJECTIVE: To study the combination of CSF phosphorylated tau protein (phospho-tau) and Abeta42 as biochemical markers for AD. METHODS: We combined CSF measurements of phospho-tau and Abeta42 in 100 consecutive patients who under-went diagnostic workup for dementia and in 31 healthy control subjects. RESULTS: We found that the calculated ratio of phospho-tau to Abeta42 was significantly increased in patients with AD and provided high diagnostic accuracy in distinguishing patients with AD from healthy control subjects (sensitivity, 86%; specificity, 97%), subjects with non-AD dementias (sensitivity, 80%; specificity, 73%), and subjects with other neurological disorders (sensitivity, 80%; specificity, 89%). CONCLUSION: The diagnostic usefulness of the CSF ratio of phospho-tau to Abeta42 is superior to either measure alone and can be recommended as an aid to evaluating individuals suspected of having dementia.     

Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study

BACKGROUND: Abnormal hyperphosphorylation of the microtubule-associated protein tau and its incorporation into neurofibrillary tangles are major hallmarks of the pathogenesis of Alzheimer disease (AD). Different tau phosphoepitopes can be sensitively detected in cerebrospinal fluid (CSF). OBJECTIVE: To compare the diagnostic accuracy of CSF concentrations of tau proteins phosphorylated at 3 pathophysiologically important epitopes (p-tau) to discriminate among patients with AD, nondemented control subjects, and patients with other dementias. DESIGN AND SETTING: Cross-sectional, bicenter, memory clinic-based studies. PARTICIPANTS: One hundred sixty-one patients with a clinical diagnosis of AD, frontotemporal dementia, dementia with Lewy bodies, or vascular dementia and 45 nondemented controls (N = 206). MAIN OUTCOME MEASURES: Levels of tau protein phosphorylated at threonine 231 (p-tau231), threonine 181 (p-tau181), and serine 199 (p-tau199). The CSF p-tau protein levels were measured using 3 different enzyme-linked immunosorbent assays. RESULTS: The mean CSF levels of the studied p-tau proteins were significantly elevated in patients with AD compared with the other groups. Applied as single markers, p-tau231and p-tau181 reached specificity levels greater than 75% between AD and the combined non-AD group when sensitivity was set at 85% or greater. Statistical differences between the assay performances are presented. Particularly, discrimination between AD and dementia with Lewy bodies was maximized using p-tau181at a sensitivity of 94% and a specificity of 64%, and p-tau231 maximized group separation between AD and frontotemporal dementia with a sensitivity of 88% and a specificity of 92%. Combinations of the 3 markers did not add discriminative power compared with the application as single markers. CONCLUSIONS: The p-tau proteins in CSF come closest to fulfilling the criteria of a biological marker of AD. There is a tendency for p-tau proteins to perform differently in the discrimination of primary dementia disorders from AD.     

The measurement of phosphorylated tau in human cerebrospinal fluid as a diagnostic marker for Alzheimer's disease]

We examined total 570 cerebrospinal fluid (CSF) samples from a variety of diseases, including Alzheimer's disease (AD; n = 236), non-AD-demented and nondemented diseases (n = 239), and normal controls (n = 95) to quantitate levels of tau protein phosphorylated at serine 199 (CSF/p-tau199) by a recently established sandwich ELISA. The CSF/p-tau199 levels in the AD group were significantly elevated compared to those in all the other non-AD groups. Receiver operating characteristics curves showed that the diagnostic sensitivity and specificity for the AD group vs all the other non-AD group using the CSF/p-tau199 were 85. 2% and 85.0%, respectively. Although there was a significant positive correlation between CSF/p-tau199 and CSF total tau (CSF/t-tau) levels in the AD group, CSF/p-tau199 classifies patients with AD and other disorders more accurately than the CSF/t-tau. Our study suggests that CSF/p-tau199 testing will help in supporting antemortem diagnosis of AD and in conducting emerging therapies that should be based on an accurate detection of AD while patients are alive.     

Large-scale, multicenter study of cerebrospinal fluid tau protein phosphorylated at serine 199 for the antemortem diagnosis of Alzheimer's disease

We surveyed a total of 570 cerebrospinal fluid (CSF) samples from a variety of diseases, including Alzheimer's disease (AD; n = 236), non-AD-demented and nondemented diseases (n = 239), and normal controls (n = 95) to quantitate levels of tau protein phosphorylated at serine 199 (CSF/phospho-tau199) by a recently established sandwich ELISA. The CSF/phospho-tau199 levels in the AD group were significantly elevated compared to those in all the other non-AD groups. Receiver operating characteristics curves showed that the diagnostic sensitivity and specificity for the AD group vs all the other non-AD groups using the CSF/phospho-tau199 were 85.2% and 85.0%, respectively. Furthermore, there was a significant positive correlation between CSF/phospho-tau199 and CSF/total-tau levels in the AD group. Elevated CSF/phospho-tau199 in the AD group was noted irrespective of age, gender, dementia severity, and number of apolipoprotein E4 alleles. Thus, we suggest that CSF/phospho-tau199 may be a novel and logical biomarker in supporting antemortem diagnosis of AD.     

Novel CSF biomarkers for Alzheimer’s disease and mild cognitive impairment

Altered levels of cerebrospinal fluid (CSF) peptides related to Alzheimer’s disease (AD) are associated with pathologic AD diagnosis, although cognitively normal subjects can also have abnormal levels of these AD biomarkers. To identify novel CSF biomarkers that distinguish pathologically confirmed AD from cognitively normal subjects and patients with other neurodegenerative disorders, we collected antemortem CSF samples from 66 AD patients and 25 patients with other neurodegenerative dementias followed longitudinally to neuropathologic confirmation, plus CSF from 33 cognitively normal subjects. We measured levels of 151 novel analytes via a targeted multiplex panel enriched in cytokines, chemokines and growth factors, as well as established AD CSF biomarkers (levels of Aβ42, tau and p-tau₁₈₁). Two categories of biomarkers were identified: (1) analytes that specifically distinguished AD (especially CSF Aβ42 levels) from cognitively normal subjects and other disorders; and (2) analytes altered in multiple diseases (NrCAM, PDGF, C3, IL-1α), but not in cognitively normal subjects. A multi-prong analytical approach showed AD patients were best distinguished from non-AD cases (including cognitively normal subjects and patients with other neurodegenerative disorders) by a combination of traditional AD biomarkers and novel multiplex biomarkers. Six novel biomarkers (C3, CgA, IL-1α, I-309, NrCAM and VEGF) were correlated with the severity of cognitive impairment at CSF collection, and altered levels of IL-1α and TECK associated with subsequent cognitive decline in 38 longitudinally followed subjects with mild cognitive impairment. In summary, our targeted proteomic screen revealed novel CSF biomarkers that can improve the distinction between AD and non-AD cases by established biomarkers alone.     

CSF tau protein and β-amyloid (1–42) in Alzheimer''s disease diagnosis: discrimination from normal ageing and other dementias in the Greek population

Cerebrospinal fluid (CSF) levels of tau protein and amyloid beta(1-42) peptide (Abeta42) have been suggested as possible diagnostic markers of Alzheimer's disease (AD). In order to evaluate their diagnostic potential in clinical practice, we measured tau and Abeta42 levels in the CSF of 49 AD patients, 15 patients with non-AD neurodegenerative dementias (NAND), six patients with vascular dementia (VD) and 49 elderly controls. All the subjects were of Greek origin. A marked increase in tau, a decrease in Abeta42 and a marked increase in the tau/Abeta42 ratio was noted in AD. Abeta42 alone had a specificity of 80% and a sensitivity of 82% in differentiating AD from normal ageing, whilst the corresponding values for differentiating AD from NAND or VD were 80 and 71, or 67 and 82%, respectively. Tau was better in differentiating AD, from normal ageing (specificity 96%, sensitivity 88%), NAND (specificity 93%, sensitivity 71%) and VD (specificity 83%, sensitivity 94%). The tau/Abeta42 ratio achieved values comparable or even better than tau for differentiating AD from normal ageing (specificity 86%, sensitivity 96%) and VD (specificity 83%, sensitivity 90%) and definitely better than any of the candidate markers alone, for differentiating AD from NAND (specificity 100%, sensitivity 71%). Thus, the combined use of CSF tau and Abeta42 in the form of the tau/Abeta42 ratio is a simple, safe and useful adjuvant to clinical criteria for dementia diagnosis.     

Combined assessment of tau and neuronal thread protein in Alzheimer's disease CSF

OBJECTIVE: Comparative study of CSF levels of tau and AD7C-neuronal thread protein (NTP) in patients with AD and control subjects. BACKGROUND: AD is characterized by neurofibrillary tangles composed of the abnormally hyperphosphorylated microtubule-associated protein tau. AD7C-NTP is a proposed AD marker expressed at early stages of neurofibrillary degeneration. METHODS: Enzyme-linked immunosorbent assays specific for tau and AD7C-NTP. CSF samples were obtained from 35 demented patients (25 with antemortem clinical diagnosis of probable AD, 5 with neuropathologic diagnosis of definite AD, 5 with Lewy body pathology), 29 nondemented patients with PD, and 16 elderly healthy control subjects. Receiver operating characteristics (ROC) and multivariate discriminant analysis for AD versus controls. Correlational analysis of CSF tau and AD7C-NTP and of each marker with Mini-Mental State Examination (MMSE) scores was performed. RESULTS: Levels of both tau and AD7C-NTP were significantly elevated in the AD patients compared with control subjects. ROC analysis showed that CSF tau distinguished between patients with AD and nondemented control subjects with 63% sensitivity and 89% specificity, AD7C-NTP with 70% sensitivity and 87% specificity. Combined evaluation of both markers with discriminant analysis raised the specificity to 93% at a 63% sensitivity level. Both markers positively correlated with each other within the AD group, but not among control subjects. CSF levels of AD7C-NTP, but not of tau, showed a small but significant inverse correlation (r = -0.43) with MMSE scores of AD patients. CONCLUSIONS: CSF levels of tau and AD7C-NTP may be useful biomarkers for AD.     

Review and meta-analysis of biomarkers and diagnostic imaging in Alzheimer's disease

Mild Alzheimer's disease (AD) is often difficult to differentiate from mild cognitive impairment (MCI) or non-AD dementias. A multitude of diagnostic biomarkers and advanced imaging strategies have been developed to aid in the diagnosis and management of AD. We sought to review and analyze the published evidence on key test characteristics of major diagnostic strategies to formulate best estimates of sensitivity (SN) and specificity (SP). A systematic review was undertaken to locate and abstract all studies of biomarkers or diagnostic imaging for AD published in English from January 1990 to March 2010 that provided estimates of SN and SP. Meta-analysis was performed using a bivariate mixed-effects binary regression model. We calculated -SN, SP, and area under the receiver operating curves (AUROC), with confidence and prediction contours. Of 1,840 unique studies identified, 119 presented primary data sufficient for analysis. SN and SP were calculated against non-demented controls, non-AD dementias with and without MCI, if available. Compared to non-demented controls, FDG-PET demonstrated the highest AUROC (0.96), with 90% SN (95%CI 84% to 94%), and 89% SP (95% CI 81% to 94%). FDG-PET also was most accurate in discriminating AD from demented controls (including MCI) with AUROC 0.91, and 92% SN (95%CI 84% to 96%) and 78% SP (95% CI 69% to 85%). For discrimination of AD from non-AD dementias (excluding MCI), CSF Ptau, and SPECT produced identical AUROC (0.86). Diagnostic strategies for AD show wide variation in test characteristics and some show promise for use in clinical practice.     

Diagnostic value of CSF biomarker profile in frontotemporal lobar degeneration

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers have been increasingly studied in dementia clinical and differential diagnosis. METHODS: We assessed levels of total tau protein (tauT), tau phosphorylated at threonine 181 (tau P-181), and beta-amyloid1-42 (A beta 42) in 34 patients with frontotemporal lobar degeneration (FTLD), 76 Alzheimer disease (AD) cases, and 93 controls (CTRL). Double sandwich enzyme-linked immunosorbent assays (Innogenetics) were used for measurements. RESULTS: Total tau was significantly increased and A beta 42 decreased in FTLD and AD patients as compared with CTRL. CSF tau P-181 levels were significantly increased only in AD. The tauT/A beta 42 ratio successfully discriminated FTLD from CTRL with a 86.7% specificity and 80.6% sensitivity, whereas the tauT alone was more specific (95.7%) but less sensitive (64.75%). For the discrimination of FTLD from AD, tauT/A beta 42 ratio was better (90.3% sensitivity and 64.5% specificity) compared with the other biomarkers alone or in combination, whereas tau P-181 was less sensitive but more specific (68.4% and 85.7%, respectively). Subtype analysis revealed that the most AD-like profile of biomarkers were observed in FTLD with motor neuron signs, whereas the most non-AD profile were observed in patients with primary progressive aphasia. CONCLUSIONS: Combined analysis of CSF biomarkers may be useful for the best possible antemortem discrimination of FTLD from AD.     

Differential diagnosis of Alzheimer disease with cerebrospinal fluid levels of tau protein phosphorylated at threonine 231

BACKGROUND: Phosphorylation of tau protein at threonine 231 (using full-length tau, 441 amino acids, for the numbering scheme) (p-tau(231)) occurs specifically in postmortem brain tissue of patients with Alzheimer disease (AD) and can be sensitively detected in cerebrospinal fluid (CSF). OBJECTIVES: To determine to what extent CSF levels of p-tau(231) distinguish patients with AD from control subjects and from patients with other dementias, and to investigate whether p-tau(231) levels are a better diagnostic marker than levels of total tau protein (t-tau) in CSF. DESIGN AND SETTING: Cross-sectional, multicenter, memory clinic-based studies. PARTICIPANTS: One hundred ninety-two patients with a clinical diagnosis of AD, frontotemporal dementia (FTD), vascular dementia, Lewy body dementia, or other neurological disorder and healthy controls. MAIN OUTCOME MEASURES: Levels of CSF tau proteins as measured with enzyme-linked immunosorbent assays. RESULTS: Mean CSF levels of p-tau(231) were significantly elevated in the AD group compared with all other groups. Levels of p-tau(231) did not correlate with dementia severity in AD, and discriminated with a sensitivity of 90.2% and a specificity of 80.0% between AD and all non-AD disorders. Moreover, p-tau(231) levels improved diagnostic accuracy compared with t-tau levels when patients with AD were compared with healthy controls (P =.03) and demented subjects (P<.001), particularly those with FTD (P<.001), but not those with vascular and Lewy body dementias. Sensitivity levels between AD and FTD were raised by p-tau(231) compared with t-tau levels from 57.7% to 90.2% at a specificity level of 92.3% for both markers. CONCLUSION: Increased levels of CSF p-tau(231) may be a useful, clinically applicable biological marker for the differential diagnosis of AD, particularly for distinguishing AD from FTD.     

Tau and Abeta42 protein in CSF of patients with frontotemporal degeneration

BACKGROUND: CSF concentrations of tau and beta-amyloid protein-42 (Abeta42) have been extensively studied in AD. Few data are available concerning CSF levels of both proteins in patients with frontotemporal degeneration (FTD). METHODS: The authors investigated CSF tau and Abeta42 concentrations in 34 patients with FTD, 74 patients with AD, and 40 cognitively healthy control subjects. CSF levels of tau and Abeta42 were measured by ELISA. With use of receiver operating characteristic-derived cutoff points and linear discrimination lines, the diagnostic sensitivity and specificity of both markers were determined. RESULTS: CSF tau concentrations were significantly higher in FTD than in control subjects but were significantly lower than in AD. CSF Abeta42 levels were significantly lower in FTD than in control subjects but were significantly higher than in AD. In subjects with FTD, neither tau nor Abeta42 levels correlated with the severity of dementia. The best discrimination between the diagnostic groups was obtained by simultaneous measurement of tau and Abeta42, yielding a sensitivity of 90% at a specificity of 77% (FTD vs controls) and a sensitivity of 85% at a specificity of 85% (FTD vs AD). CONCLUSIONS: In FTD, CSF levels of tau are elevated and Abeta42 levels are decreased. With use of these markers, subjects with FTD can be distinguished from control subjects and from patients with AD with reasonable accuracy.     

Heart-type fatty acid binding protein and vascular endothelial growth factor: cerebrospinal fluid biomarker candidates for Alzheimer’s disease

The main objective of the study was to validate the findings of previous cerebrospinal fluid (CSF) proteomic studies for the differentiation between Alzheimer’s disease (AD) dementia and physiological ageing. The most consistently significant proteins in the separation between AD dementia versus normal controls using CSF proteomics were identified in the literature. The classification performance of the four pre-selected proteins was explored in 92 controls, 149 patients with mild cognitive impairment (MCI), and 69 patients with AD dementia. Heart-type fatty acid binding protein (hFABP) and vascular endothelial growth factor (VEGF) CSF concentrations distinguished between healthy controls and patients with AD dementia with a sensitivity and specificity of 57 and 35 %, and 76 and 84 %, respectively. The optimal classification was achieved by a combination of the two additional CSF biomarker candidates in conjunction with the three established markers Amyloid-β (Aβ)_1–42, total-Tau (tTau), and phosphorylated-Tau (pTau)₁₈₁, which resulted in a sensitivity of 83 % and a specificity of 86 %. hFABP also predicted the progression from MCI to AD dementia. The present study provides evidence in support of hFABP and VEGF in CSF as AD biomarker candidates to be used in combination with the established markers Aβ_1–42, tTau, and pTau₁₈₁.     

Biomarkers in non-Alzheimer dementias

Biomarkers for Alzheimer's Disease (AD) and non-AD dementias could serve as aids to diagnosis and treatment. Biochemical markers have been sought in cerebrospinal fluid (CSF), blood and urine, and are best developed for AD. Ideally, a biomarker should be unique to a dementing disorder and should have high sensitivity. The most widely studied markers for AD, CSF tau and Aβ42, also can show alterations in other disorders. Some non-AD dementias, such as Lewy Body dementia and vascular dementia may be accompanied by AD pathology, making the search for unique markers of these common disorders difficult. However, markers of general pathological processes in neurodegeneration could be used to follow change over time. Prion disorders come closest to having unique biomarkers, although it is difficult to detect the pathogenic Prion proteins (PrPsc) in body fluids. Other protein signatures, such as increased CSF levels of 14-3-3 protein and markedly increased tau have sufficiently high sensitivity and specificity to be used as aids to diagnosis. The development of markers for prion disease stands as a model to drive future research in other dementias.     

Identification of SPARC-like 1 protein as part of a biomarker panel for Alzheimer's disease in cerebrospinal fluid

We have used proteomic fingerprinting to investigate diagnosis of Alzheimer's disease (AD). Samples of lumbar cerebrospinal fluid (CSF) from clinically-diagnosed AD cases (n = 33), age-matched controls (n = 20), and mild cognitive impairment (MCI) patients (n = 10) were used to obtain proteomic profiles, followed by bioinformatic analysis that generated a set of potential biomarkers in CSF samples that could discriminate AD cases from controls. The identity of the biomarker ions was determined using mass spectroscopy. The panel of seven peptide biomarker ions was able to discriminate AD patients from controls with a median accuracy of 95% (sensitivity 85%, specificity 97%). When this model was applied to an independent blind dataset from MCI patients, the intensity of signals was intermediate between the control and AD patients implying that these markers could potentially predict patients with early neurodegenerative disease. The panel were identified, in order of predictive ability, as SPARC-like 1 protein, fibrinogen alpha chain precursor, amyloid-β, apolipoprotein E precursor, serum albumin precursor, keratin type I cytoskeletal 9, and tetranectin. The 7 ion ANN model was further validated using an independent cohort of samples, where the model was able to classify AD cases from controls with median accuracy of 84.5% (sensitivity 93.3%, specificity 75.7%). Validation by immunoassay was performed on the top three identified markers using the discovery samples and an independent sample cohort which was from postmortem confirmed AD patients (n = 17).     

Value of CSF beta-amyloid1-42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment

Subjects with mild cognitive impairment (MCI) are at a high risk of developing clinical Alzheimer's disease (AD). We asked to what extent the core biomarker candidates cerebro-spinal fluid (CSF) beta-amyloid(1-42) (Abeta(1-42)) and CSF tau protein concentrations predict conversion from MCI to AD. We studied 52 patients with MCI, 93 AD patients, and 10 healthy controls (HC). The MCI group was composed of 29 patients who had converted to AD during follow-up, and of 23 patients who showed no cognitive decline. CSF Abeta(1-42) and tau protein levels were assessed at baseline in all subjects, using enzyme-linked immunosorbent assays. For assessment of sensitivity and specificity, we used independently established reference values for CSF Abeta(1-42) and CSF tau. The levels of CSF tau were increased, whereas levels of Abeta(1-42) were decreased in MCI subjects. Abeta(1-42) predicted AD in converted MCI with a sensitivity of 59% and a specificity of 100% compared to HC. Tau yielded a greater sensitivity of 83% and a specificity of 90%. In a multiple Cox regression analysis within the MCI group, low baseline levels of Abeta(1-42), but not other predictor variables (tau protein, gender, age, apolipoprotein E epsilon4 carrier status, Mini Mental Status Examination score, observation time, antidementia therapy), correlated with conversion status (P<0.05). Our findings support the notion that CSF tau and Abeta(1-42) may be useful biomarkers in the early identification of AD in MCI subjects.     

Proteomic analysis of the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease

So far, only the detection of 14-3-3 proteins in cerebrospinal fluid (CSF) has been accepted as diagnostic criterion for Creutzfeldt-Jakob disease (CJD). However, this assay cannot be used for screening because of the high rate of false-positive results, whereas patients with variant CJD are often negative for 14-3-3 proteins. The aim of this study was to compare the spot patterns of CSF by 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) to search for a CJD-specific spot pattern. We analyzed the CSF of 28 patients [11 CJD, 9 Alzheimer's disease (AD), 8 nondemented controls (NDC)] employing 2D-PAGE which was optimized for minimal volumes of CSF (0.1 ml; 7-cm strips). All samples were run at least three times, gels were silver stained and analyzed by an analysis software and manually revised. We could consistently match 268 spots which were then compared between all groups. By the use of 5 spots, we were able to differentiate CJD from AD or NDC with a sensitivity of 100%. CJD could also be distinguished from both groups by using a heuristic clustering algorithm of 2 spots. We conclude that this proteomic approach can differentiate CJD from other diseases and may serve as a model for other neurodegenerative diseases.     

The diagnostic value of tau protein, beta-amyloid (1-42) and their ratio for the discrimination of alcohol-related cognitive disorders from Alzheimer's disease in the early stages

BACKGROUND: Chronic and heavy alcohol abuse or dependence may result in impaired cognition and dementia. The increased risk of Alzheimer's disease (AD) in older individuals interferes with the differential diagnosis, especially when dealing with elderly patients with a long history of alcohol abuse. The aim of the present study was to evaluate the diagnostic value of the putative cerebrospinal fluid (CSF) biomarkers tau, beta-amyloid 1-42 (Abeta42) and their ratio in differentiating alcohol related cognitive disorder (ARCD) from AD. METHODS: Double-sandwich ELISA (Innotest htau antigen and beta-Amyloid (1-42), Innogenetics) were used to quantify the above markers in a total of 20 patients with ARCD, 33 AD patients with mild to moderate dementia and 50 mentally intact subjects. RESULTS: Tau protein successfully differentiated AD from normal ageing with 96% specificity and 93.9% sensitivity and from ARCD with 95% specificity, and 87.9% sensitivity. Abeta42 alone had a specificity of 88% and a sensitivity of 69.7% in differentiating AD from normal ageing, while the corresponding values for differentiating AD from ARCD were 80% and 84.8% respectively. The tau/Abeta42 ratio was better than tau alone for differentiating AD from normal ageing (specificity 94%, sensitivity 97%) and better than any of the candidate markers alone, for differentiating AD from ARCD (specificity 100%, sensitivity 97%). CONCLUSIONS: The combined use of CSF tau and Abeta42 may be a useful tool in the differential diagnosis of ARCD from AD, especially in the early stages, where diagnostic uncertainty is greater.     

Longitudinal study of cerebrospinal fluid levels of tau,Aβ1–40, and Aβ1–42(43) in Alzheimer's disease: A study in Japan

To clarify the alterations of tau, amyloid β protein (Aβ) 1–40 and Aβ1–42(43) in the cerebrospinal fluid (CSF) that accompany normal aging and the progression of Alzheimer's disease (AD), CSF samples of 93 AD patients, 32 longitudinal subjects among these 93 AD patients, 33 patients with non-AD dementia, 56 with other neurological diseases, and 54 normal control subjects from three independent institutes were analyzed by sensitive enzyme-linked immunosorbent assays. Although the tau levels increased with aging, a significant elevation of tau and a correlation between the tau levels and the clinical progression were observed in the AD patients. A significant decrease of the Aβ1–42(43) levels and a significant increase of the ratio of Aβ1–40 to Aβ1–42(43) were observed in the AD patients. The longitudinal AD study showed continuous low Aβ1–42(43) levels and an increase of the ratio of Aβ1–40 to Aβ1–42(43) before the onset of AD. These findings suggest that CSF tau may increase with the clinical progression of dementia and that the alteration of the CSF level of Aβ1–42(43) and the ratio of Aβ1–40 to Aβ1–42(43) may start at early stages in AD. The assays of CSF tau, Aβ1–40, and Aβ1–42(43) provided efficient diagnostic sensitivity (71%) and specificity (83%) by using the production of tau levels and the ratio of Aβ1–40 to Aβ1–42(43), and an improvement in sensitivity (to 91%) was obtained in the longitudinal evaluation.     

Prediction of S-glutathionylated proteins progression in Alzheimer's transgenic mouse model using principle component analysis

To date, prediction of Alzheimer's disease (AD) is mainly based on clinical criteria because no well-established biochemical biomarkers for routine clinical diagnosis of AD currently exist. We developed an approach to aid in the early diagnosis of AD by using principal component analysis (PCA)-based spectral analysis of oxidized protein electrophoretic profiling. We found that the combination of capillary electrophoresis and PCA analysis of S-glutathionylation distribution characterization can be used in the sample classification and molecular weight (Mw) prediction. The comparison of leave-one-out AD versus non-AD gives the sensitivity of 100% and 93.33% in brain tissues and blood samples, respectively, while the specificity of 100% in brain and 90.0% in blood samples. Our findings demonstrate that PCA of S-glutathionylation electrophoretic profiling detects AD pathology features, and that the molecular weight based electrophoretic profiling of blood and brain S-glutathionylated proteins are sensitive to change, even at the early stage of the disease. Our results offer a previously unexplored diagnostic approach by using electrophoretic characteristics of oxidized proteins to serve as a predictor of AD progression and early stage screening.