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.     

Cerebrospinal fluid phospho-tau,total tau and beta-amyloid(1-42) in the differentiation between Alzheimer's disease and vascular dementia

The two most frequently examined biomarkers in the diagnosis of dementia are cerebrospinal fluid (CSF) tau and beta-amyloid(1-42) (Abeta(1-42)). An assay for tau phosphorylated at threonine 181 (phospho-tau) has recently been developed. We studied these three markers in patients with possible Alzheimer's disease (AD; n = 23), probable AD (n = 50), AD with relevant cerebrovascular disease (AD with CVD; n = 14), possible vascular dementia (VaD; n = 39), probable VaD (n = 36), cognitively impaired (n = 13) and 27 neurologically healthy controls. Compared with the controls, tau levels were significantly increased in possible AD, probable AD, AD with CVD and probable VaD. Abeta(1-42) was decreased in all dementia groups compared with the controls. In contrast, phospho-tau levels were increased only in probable AD compared with the controls. From the results of the present study, it is concluded that neither measurement of phospho-tau, tau nor Abeta(1-42) in CSF can discriminate entirely between dementia and cognitively non-disturbed controls or between dementia of different aetiologies in the clinical diagnostic procedure.     

The neurofilament heavy chain (NfH) in the cerebrospinal fluid diagnosis of Alzheimer's disease

BACKGROUND/AIMS: Attempting to improve the cerebrospinal fluid (CSF) diagnosis of Alzheimer's disease (AD), the neurofilament heavy chain isoform, NfH(SMI35) was compared to other CSF markers [total tau, phospho-tau, amyloid beta 1-42 (Abeta42), the ratio of amyloid beta fragments Abeta42/Abeta40 (Abeta ratio)]. METHODS: CSF levels were determined in patients with AD (n = 109), mild cognitive impairment (MCI, n = 25), frontotemporal dementia (n = 15), vascular dementia (VD, n = 41), and controls (n = 58). RESULTS: CSF NfH(SMI35) was elevated in AD and VD as compared to controls (p < 0.05). Total tau was higher in AD as compared to controls (p < 0.05). CSF phospho-tau was elevated in AD as compared to controls and VD (p < 0.05 each). CSF Abeta42 and Abeta ratios in AD were lower than in MCI and controls (p < 0.05 each). CONCLUSION: The diagnostic potential of NfH(SMI35) is not superior to that of other CSF markers.     

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.     

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.     

Glycosylation of acetylcholinesterase and butyrylcholinesterase changes as a function of the duration of Alzheimer's disease

The identification of biochemical markers of Alzheimer's disease (AD) may help in the diagnosis of the disease. Previous studies have shown that Abeta(1-42) is decreased, and tau and phospho-tau are increased in AD cerebrospinal fluid (CSF). Our own studies have identified glycosylated isoforms of acetylcholinesterase (Glyc-AChE) and butyrylcholinesterase (Glyc-BuChE) that are increased in AD CSF. Glyc-AChE is increased in APP (SW) Tg2576 transgenic mice prior to amyloid plaque deposition, which suggests that Glyc-AChE may be an early marker of AD. The aim of this study was to determine whether Glyc-AChE or Glyc-BuChE is increased in CSF at early stages of AD and to compare the levels of these markers with those of Abeta(1-42), tau and phospho-tau. Lumbar CSF was obtained ante mortem from 106 non-AD patients, including 15 patients with mild cognitive impairment (MCI), and 102 patients with probable AD. Glyc-AChE, tau and phospho-tau were significantly increased in the CSF of AD patients compared to non-neurological disease (NND) controls. Abeta(1-42) was lower in the AD patients than in NND controls. A positive correlation was found between the levels of Glyc-AChE or Glyc-BuChE and disease duration. However, there was no clear correlation between the levels of tau, phospho-tau or Abeta(1-42) and disease duration. The results suggest that Glyc-AChE and Glyc-BuChE are unlikely to be early markers of AD, although they may have value as markers of disease progression.     

CSF markers for Alzheimer's disease: total tau, phospho-tau and Abeta42.

Today we have the first therapeutic compounds for treatment of Alzheimer's disease (AD) e.g. acetylcholine esterase inhibitors and in the near future we may expect new compounds such as gamma- and beta-secretase inhibitors. This has demanded increased accuracy in the diagnosis of AD and thus, among other possible approaches, diagnostic markers in the cerebrospinal fluid (CSF) have become a rapidly growing research field. Especially early in the course of the disease, when correct diagnosis is most difficult, such biomarkers would be especially valuable as one might expect the compounds to have the greatest potential of being effective. Two of the defining lesions in AD brains are senile plaques and neurofibrillary tangles with beta-amyloid (Abeta) and tau proteins as the main components respectively. Abeta and tau proteins are secreted to body fluids including plasma and cerebrospinal fluid (CSF). In this paper we review CSF markers for AD, with focus on their role in the clinical diagnosis. Reduced CSF levels of the 42 amino acid form of Abeta (Abeta42) and increased CSF levels of total tau (T-tau) in AD have been found in numerous studies, with high sensitivity figures. However, the specificity against other dementias is lower. The addition of phospho-tau (P-tau) seems to increase the specificity, since normal levels are found in other dementias and in cerebrovascular disease. An increasing number of studies suggests that these CSF markers perform well enough to have a role in the clinical work-up of patients with dementia if used together. We stress that the CSF markers should be combined with the clinical information and brain-imaging techniques.     

Cerebrospinal fluid tau and beta-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses?

BACKGROUND: Tau and beta-amyloid (Abeta) are proposed diagnostic biomarkers for Alzheimer disease (AD). Previous studies report their relationship to clinical diagnoses of AD and other dementias. To understand their value as predictors of disease-specific pathology, levels determined during life must be correlated with definitive diagnoses in mixed dementia groups and cognitively normal subjects. OBJECTIVES: To correlate antemortem cerebrospinal fluid (CSF) tau and Abeta levels with definitive dementia diagnosis in a diverse group of patients; to calculate statistics for CSF tau and Abeta. DESIGN: Prospective study. SETTING: Ten clinics experienced in the diagnosis of neurodegenerative dementias.Patients One hundred six patients with dementia and 4 cognitively normal subjects with a definitive diagnosis, and 69 clinically diagnosed cognitively normal subjects. MAIN OUTCOME MEASURES: Correlation of CSF tau and Abeta with final diagnosis. RESULTS: Mean tau level was 612 pg/mL for the 74 patients with AD, 272 pg/mL for 10 patients with frontal dementia, 282 pg/mL for 3 patients with dementia with Lewy bodies, and 140 pg/mL for 73 cognitively normal control subjects. Tau was less than 334 pg/mL for 20 patients with AD. Abeta42 was reduced in patients with AD (61 fmol/mL) compared with patients with frontal dementia (133 fmol/mL) and control subjects (109 fmol/mL), but not compared with patients with dementia with Lewy bodies (14 fmol/mL) or prion disease (60 fmol/mL). CONCLUSIONS: Elevated CSF tau levels are associated with AD pathology and can help discriminate AD from other dementing disorders. However, some patients with AD have a level less than the mean +/- 2 SDs of the cognitively normal cohort.     

Measurement of thirteen biological markers in CSF of patients with Alzheimer's disease and other dementias

Cerebrospinal fluid (CSF) biological markers may be of valuable help in the diagnosis of dementia. The aim of the present study was to evaluate CSF levels of 13 potential biomarkers in patients with Alzheimer's disease (AD), frontotemporal lobe dementia, alcohol dementia, major depression and control patients without any neuropsychiatric disease. The study was performed using beta-amyloid 1-42 (Abeta42), total tau and phosphorylated tau-181 (P-tau181) as core markers. The ratio P-tau181/Abeta42 could significantly distinguish AD patients from all other diagnostic subgroups. CSF levels of 5 growth factors (HGF, GDNF, VEGF, BDNF, FGF-2) and 3 cytokines/chemokines (TNF-alpha, TGF-beta1, MIP-1alpha) did not significantly differentiate between the studied groups. However, depending on the degree of neurodegeneration (as expressed by the ratio P-tau181/Abeta42), patients with AD displayed significantly increased CSF levels of nerve growth factor (NGF) as compared to healthy controls. CSF levels of monocyte chemoattractant protein 1 (MCP-1) were found to be significantly increased with age in all groups but did not distinguish AD patients from healthy controls. The results confirmed the suitability of the ratio P-tau181/Abeta42 for the diagnosis of AD, while CSF levels of NGF and MCP-1 are less specific and reliable for AD. It is suggested that the increase in NGF depends on the extent of neurodegeneration of the AD type and the increase in MCP-1 on age.     

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.     

Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans

OBJECTIVES: Amyloid-beta(42) (Abeta(42)) appears central to Alzheimer's disease (AD) pathogenesis and is a major component of amyloid plaques. Mean cerebrospinal fluid (CSF) Abeta(42) is decreased in dementia of the Alzheimer's type. This decrease may reflect plaques acting as an Abeta(42) "sink," hindering transport of soluble Abeta(42) between brain and CSF. We investigated this hypothesis. METHODS: We compared the in vivo brain amyloid load (via positron emission tomography imaging of the amyloid-binding agent, Pittsburgh Compound-B [PIB]) with CSF Abeta(42) and other measures (via enzyme-linked immunosorbent assay) in clinically characterized research subjects. RESULTS: Subjects fell into two nonoverlapping groups: those with positive PIB binding had the lowest CSF Abeta(42) level, and those with negative PIB binding had the highest CSF Abeta(42) level. No relation was observed between PIB binding and CSF Abeta(40), tau, phospho-tau(181), plasma Abeta(40), or plasma Abeta(42). Importantly, PIB binding and CSF Abeta(42) did not consistently correspond with clinical diagnosis; three cognitively normal subjects were PIB-positive with low CSF Abeta(42), suggesting the presence of amyloid in the absence of cognitive impairment (ie, preclinical AD). INTERPRETATION: These observations suggest that brain amyloid deposition results in low CSF Abeta(42), and that amyloid imaging and CSF Abeta(42) may potentially serve as antecedent biomarkers of (preclinical) AD.     

Cerebrospinal fluid levels of total-tau, phospho-tau and Aβ42 predicts development of Alzheimer's disease in patients with mild cognitive impairment

Cerebrospinal fluid (CSF) biochemical diagnostic markers may be valuable to help in the diagnosis early in the course of Alzheimer's disease (AD), especially in the phase before clinically overt dementia, i.e. in patients with mild cognitive impairment (MCI). We studied 44 patients with MCI who, at 1-year follow-up investigation, had progressed to AD with dementia, and 32 controls. Three CSF biomarkers related to the central pathogenic processes in AD were analysed, including CSF total-tau (T-tau) (as a marker for neuronal degeneration), CSF phospho-tau (P-tau) (as a marker for hyperphosphorylation of tau and possibly for the formation of neurofibrillary tangles), and CSF Aβ42 (as a marker for Aβ metabolism, and possibly for the formation of senile plaques). At baseline, 35/44 (79.5%) of the MCI patients had high CSF T-tau, 31/44 (70.4%) high CSF P-tau, while 34/44 (77.3%) had low CSF-Aβ42 levels. The positive likelihood ratio was 8.45 for CSF T-tau, 7.49 for CSF P-tau and 8.20 for CSF Aβ42. These findings suggest that these CSF-markers are abnormal before the onset of clinical dementia, and that they may help to identify MCI patients that will progress to AD. CSF diagnostic markers will be especially important when drugs with potential effects on the progression of AD (e.g. γ-secretase inhibitors) will reach the clinical phase.     

AD with subcortical white matter lesions and vascular dementia: CSF markers for differential diagnosis

We investigated whether the cerebrospinal fluid (CSF) biomarkers beta-amyloid 1-42 (Abeta1-42), total tau (t-tau) protein and tau protein phosphorylated at threonine 181 (p-tau181) could discriminate Alzheimer's disease (AD) from vascular dementia (VD) patients. CSF samples of Abeta1-42, t-tau, and p-tau181 were collected from probable AD (n=35), probable AD with white matter changes (WMC) indicative of concomitant cerebrovascular disorder (CVD, n=31), VD (n=20), and an age-matched subgroup of patients with other neurological disorders (OND) without cognitive impairment (n=24). AD patients showed very low Abeta1-42 levels (median=393 pg/ml). Abeta1-42, but not t-tau, differentiated AD from VD patients. However, the markers did not discriminate AD vs. AD plus WMC. In particular, both subgroups showed similar CSF biomarkers but they were significantly different from VD. ROC analysis showed that Abeta1-42 could discriminate AD from VD (AUC=0.85). The cutoff of 493 pg/ml gave sensitivity and specificity values of 77% and 80%, respectively. Similar results were obtained when Abeta1-42 was employed to discriminate AD with WMC from VD (95% specificity and 60% sensitivity, but with cutoff of 750 pg/ml). T-tau increased aspecifically in all cognitively impaired patients. P-tau181 performed better than t-tau in discriminating AD (with or without WMC) vs. VD. In conclusion, Abeta1-42 proved to be a valuable tool to discriminate AD vs. VD patients and possibly to improve diagnostic accuracy in clinical forms, improperly classified as "mixed dementia" based on radiological vascular lesions.     

Diagnostic markers for diagnosing dementia with Lewy bodies: CSF and MIBG cardiac scintigraphy study

OBJECTIVE: This study examined the diagnostic value of cerebrospinal fluid (CSF) markers and iodine-123 metaiodobenzylguanidine ((123)I-MIBG) cardiac scintigraphy in distinguishing dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). METHODS: CSF levels of amyloid beta1-42 (Abeta42) and 181-Thr phosphorylated tau (p-tau) were measured using enzyme linked immunosorbent assay (ELISA) kits. (123)I-MIBG cardiac scintigraphy was performed in patients with AD and DLB, and control (CTL) subjects. RESULTS: Increased CSF levels of p-tau in AD were found compared to DLB patients and CTL subjects (P<0.01), but there was no significant difference in CSF levels of Abeta42 between AD and DLB patients. The early and delayed heart to mediastinum (H/M) ratios of (123)I-MIBG cardiac scintigraphy were significantly decreased in patients with DLB compared to AD patients and CTL subjects (P<0.01). The receiver operating characteristic (ROC) analysis revealed that the diagnostic value of (123)I-MIBG cardiac scintigraphy was superior to that of CSF markers. CONCLUSIONS: (123)I-MIBG cardiac scintigraphy may be useful for discriminating between DLB and 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.     

Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults

OBJECTIVES: To investigate the ability of cerebrospinal fluid (CSF) and plasma measures to discriminate early-stage Alzheimer disease (AD) (defined by clinical criteria and presence/absence of brain amyloid) from nondemented aging and to assess whether these biomarkers can predict future dementia in cognitively normal individuals. DESIGN: Evaluation of CSF beta-amyloid(40) (Abeta(40)), Abeta(42), tau, phosphorylated tau(181), and plasma Abeta(40) and Abeta(42) and longitudinal clinical follow-up (from 1 to 8 years). SETTING: Longitudinal studies of healthy aging and dementia through an AD research center. PARTICIPANTS: Community-dwelling volunteers (n = 139) aged 60 to 91 years and clinically judged as cognitively normal (Clinical Dementia Rating [CDR], 0) or having very mild (CDR, 0.5) or mild (CDR, 1) AD dementia. RESULTS: Individuals with very mild or mild AD have reduced mean levels of CSF Abeta(42) and increased levels of CSF tau and phosphorylated tau(181). Cerebrospinal fluid Abeta(42) level completely corresponds with the presence or absence of brain amyloid (imaged with Pittsburgh Compound B) in demented and nondemented individuals. The CSF tau/Abeta(42) ratio (adjusted hazard ratio, 5.21; 95% confidence interval, 1.58-17.22) and phosphorylated tau(181)/Abeta(42) ratio (adjusted hazard ratio, 4.39; 95% confidence interval, 1.62-11.86) predict conversion from a CDR of 0 to a CDR greater than 0. CONCLUSIONS: The very mildest symptomatic stage of AD exhibits the same CSF biomarker phenotype as more advanced AD. In addition, levels of CSF Abeta(42), when combined with amyloid imaging, augment clinical methods for identifying in individuals with brain amyloid deposits whether dementia is present or not. Importantly, CSF tau/Abeta(42) ratios show strong promise as antecedent (preclinical) biomarkers that predict future dementia in cognitively normal older adults.     

CSF phosphorylated tau is a possible marker for discriminating Alzheimer's disease from dementia with Lewy bodies

Tau and β-amyloid (1–42) (Aβ42) are two independent markers for the early diagnosis of Alzheimer's disease (AD). In the present study, biochemical markers were validated as tools for differential diagnosis between AD and dementia with Lewy bodies (DLB). Tau, Aβ42 and phosphotau (181P) were measured in cerebrospinal fluid (CSF) from controls (n=40) and from patients with AD (n=80) or DLB (n=43) using the HT7-AT270 assay (prototype version). In comparison with AD, in DLB no differences were found for Aβ42 and lower phospho-tau. ROC analysis was used to compare the discriminatory power of total tau with that of phospho-tau. The area under the curve (AUC) amounted to 0.782±0.048 (mean ±SE) for tau and to 0.839±0.042 for phospho-tau (p<0.039) for differentiation of AD from DLB. The present results indicate that CSF phospho-tau may be a good marker for differentiation between AD and DLB.     

Improved discrimination of AD patients using beta-amyloid(1-42) and tau levels in CSF.

OBJECTIVE: To evaluate CSF levels of beta-amyloid(1-42) (Abeta42) alone and in combination with CSF tau for distinguishing AD from other conditions. METHODS: At 10 centers in Europe and the United States, 150 CSF samples from AD patients were analyzed and compared with 100 CSF samples from healthy volunteers or patients with disorders not associated with pathologic conditions of the brain (CON), 84 patients with other neurologic disorders (ND), and 79 patients with non-Alzheimer types of dementia (NAD). Sandwich ELISA techniques were used on site for measuring Abeta42 and tau. RESULTS: Median levels of Abeta42 in CSF were significantly lower in AD (487 pg/mL) than in CON (849 pg/mL; p = 0.001), ND (643 pg/mL; p = 0.001), and NAD (603 pg/mL; p = 0.001). Discrimination of AD from CON and ND was significantly improved by the combined assessment of Abeta42 and tau. At 85% sensitivity, specificity of the combined test was 86% (95% CI: 81% to 91%) compared with 55% (95% CI: 47% to 62%) for Abeta42 alone and 65% (95% CI: 58% to 72%) for tau. The combined test at 85% sensitivity was 58% (95% CI: 47% to 69%) specific for NAD. The APOE e4 gene load was negatively correlated with Abeta42 levels not only in AD but also in NAD. CONCLUSIONS: The combined measure of CSF Abeta42 and tau meets the requirements for clinical use in discriminating AD from normal aging and specific neurologic disorders.     

Tau protein, Abeta42 and S-100B protein in cerebrospinal fluid of patients with dementia with Lewy bodies

The intra vitam diagnosis of dementia with Lewy bodies (DLB) is still based on clinical grounds. So far no technical investigations have been available to support this diagnosis. As for tau protein and beta-amyloid(1-42) (Abeta42), promising results for the diagnosis of Alzheimer's disease (AD) have been reported; we evaluated these markers and S-100B protein in cerebrospinal fluid (CSF), using a set of commercially available assays, of 71 patients with DLB, 67 patients with AD and 41 nondemented controls (NDC) for their differential diagnostic relevance. Patients with DLB showed significantly lower tau protein values compared to AD but with a high overlap of values. More prominent differences were observed in the comparison of DLB patients with all three clinical core features and AD patients. Abeta42 levels were decreased in the DLB and AD groups versus NDC, without significant subgroup differences. S-100B levels were not significantly different between the groups. Tau protein levels in CSF may contribute to the clinical distinction between DLB and AD, but the value of the markers is still limited especially due to mixed pathology. We conclude that more specific markers have to be established for the differentiation of these diseases.     

Biomarker profiles and their relation to clinical variables in mild cognitive impairment

The aim of the study was to compare clinical variables between MCI patients at different risk for Alzheimer's disease (AD) according to their biomarker profile. Fifty-four percent out of 39 MCI patients had a low Abeta42 and high tau in cerebrospinal fluid (CSF) (high-risk), 26% either a low CSF Abeta32 or high CSF tau (intermediate-risk) and 20% a normal CSF Abeta42 and tau (low-risk). Both high-and intermediate-risk subjects differed from the low-risk group in episodic memory, executive functions and the preclinical AD scale (PAS),which combines a set of clinical parameters. Subjects at high risk did not differ from subjects with an intermediate risk. Abeta42 levels correlated with the MTA and PAS scores, tau levels with episodic memory. These correlations suggest that the biomarkers are not independent when compared to the other AD markers. Longitudinal studies are necessary to interpret the correlations between biomarkers, imaging, and neuropsychological markers.