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Original Contribution |

Decreased β-Amyloid1-42 and Increased Tau Levels in Cerebrospinal Fluid of Patients With Alzheimer Disease FREE

Trey Sunderland, MD; Gary Linker, MD; Nadeem Mirza, MD; Karen T. Putnam; David L. Friedman, PhD; Lida H. Kimmel, MS; Judy Bergeson, MA; Guy J. Manetti; Matthew Zimmermann; Brian Tang; John J. Bartko, PhD; Robert M. Cohen, MD, PhD
[+] Author Affiliations

Author Affiliations: Geriatric Psychiatry Branch, National Institute of Mental Health, Bethesda, Md (Drs Sunderland, Linker, Mirza, Mss Putnam, Bergeson, Mssrs Manetti, Zimmermann, Tang, and Dr Cohen); Pharmacogenomics and Clinical Biochemical Measurements Division, Pfizer, Central Research, Groton, Conn (Dr Friedman and Ms Kimmel); Proteomics Group, Vertex Pharmaceuticals, Cambridge, Mass (Dr Friedman); and Consultant Statistician, Bethesda, Md (Dr Bartko).


JAMA. 2003;289(16):2094-2103. doi:10.1001/jama.289.16.2094.
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Published online

Context Alzheimer disease (AD) is characterized by pathological results at autopsy of amyloid plaques and tau-associated neurofibrillary tangles, but the clinical diagnosis of AD is determined on the basis of medical history, cognitive symptoms, and exclusionary criteria. The search for antemortem biomarkers is intense and has focused on cerebrospinal fluid (CSF) β-amyloid1-42 and tau proteins.

Objectives To compare CSF β-amyloid and tau levels in a new population of AD patients and controls. To perform a meta-analysis of studies of CSF β-amyloid and tau levels in AD patients and controls.

Design Cross-sectional study of the comparison of baseline CSF β-amyloid1-42 and tau levels in AD patients and controls. Meta-analysis involved 17 studies of CSF β-amyloid and 34 studies of CSF tau.

Setting Clinical research unit of the National Institute of Mental Health, Bethesda, Md.

Patients The Geriatric Psychiatry Branch evaluated AD patients as inpatients at the National Institutes of Health Clinical Center between May 1985 and January 2001. A total of 203 patients participated in this study (131 with AD and 72 controls). None had other serious illnesses, and 31 of 131 AD cases had AD confirmed at autopsy. Meta-analysis provided an additional 3133 AD patients and 1481 controls.

Main Outcome Measures Levels of CSF β-amyloid1-42 were measured by a sandwich enzyme-linked immunoabsorbent assay with a polyclonal capture antibody and a monoclonal detection antibody. Levels of CSF tau were measured with a standard commercial immunoassay.

Results Levels of CSF β-amyloid1-42 were significantly lower in the AD patients vs controls (mean [SD], 183 [121] pg/mL vs 491 [245] pg/mL; P<.001). Levels of CSF tau were significantly higher in AD patients (mean [SD], 587 [365] pg/mL vs 244 [156] pg/mL; P<.001). The cutpoints of 444 pg/mL for CSF β-amyloid1-42 and 195 pg/mL for CSF tau gave a sensitivity and specificity of 92% and 89%, respectively, to distinguish AD patients from controls, which is comparable with rates with clinical diagnosis. Meta-analyses of studies comparing CSF β-amyloid and tau levels in AD participants and controls confirmed an overall difference between levels in these 2 groups.

Conclusions Alzheimer disease is associated with a significant decrease in CSF β-amyloid1-42 levels along with an increase in CSF tau levels. These findings suggest that the 2 measures are biological markers of AD pathophysiology. While these CSF measures may have a potential clinical utility as biomarkers of disease, the preliminary and retrospective nature of the findings, the absence of assay standardization, and the lack of comparison patient populations must be addressed in future studies testing the usefulness of these CSF measures for predictive, diagnostic, or treatment evaluation purposes.

Figures in this Article

While the exact biological cascade associated with Alzheimer disease (AD) is only partially understood, many potential biomarkers of this disease process are known.1 Two of the most obvious candidates are β-amyloid1-42 and tau proteins, as they are intimately related to the pathognomonic features of amyloid plaques and neurofibrillary tangles in the AD brain.2,3 Multiple previous studies have reported decreases in cerebrospinal fluid (CSF) measures of β-amyloid.47 Similarly, CSF measures of tau have routinely showed considerable elevations of this peptide in AD cases worldwide.712 Some authors have reported that these 2 measures alone can accurately differentiate clinically diagnosed AD cases from controls more than 85% of the time.7,13

Studies of CSF in AD patients have used widely varying methods and nomenclature for assessing and describing CSF β-amyloid1-42.4,6,7,14,15 Furthermore, while the majority of studies report decreases in CSF β-amyloid levels in AD patients, some studies show no significant change or even a slight increase in CSF β-amyloid levels in AD patients when compared with controls.16,17 Finally, the majority of CSF β-amyloid reports include a paucity of participants. We assessed CSF β-amyloid and tau levels in the largest cohort of AD patients and controls evaluated to date, to our knowledge. In addition, we performed a meta-analysis of CSF β-amyloid1-42 and tau to help clarify whether consistent trends emerged.

Participants

A total of 208 participants (136 with AD and 72 controls) were evaluated as part of an ongoing study of AD. (Five patients were excluded after autopsy showed they did not have AD. See "Autopsy" section.) Patients with AD were referred by their primary physician, and controls were self-referred, in response to local advertisements, as unpaid volunteers. Participants signed informed consent documents for this prospective study after approval of the National Institute of Mental Health institutional review board (protocols 82-M-123 and 95-M-96). For AD patients (n = 136), signed informed consent was obtained from the patient and from the individual's durable power of attorney for research decisions, as previously described.18,19 All AD patients were given both written and verbal explanations of the study procedures involved, and repeated assent was required before any individual procedure could proceed. For the control participants, written informed consent was obtained in a routine fashion.

Clinical Evaluation

The Geriatric Psychiatry Branch evaluated AD patients as inpatients at the National Institutes of Health Clinical Center between May 1985 and January 2001. Evaluation included thorough medical screenings, neurocognitive profiling, magnetic resonance imaging scan, lumbar puncture for CSF examination, and behavioral observations for 1 to 2 weeks. Individuals were participating in a longitudinal study of biological changes that occur over time in AD (protocols 82-M-123 and 95-M-96). Medical evaluations for all participants included a physical examination, a routine electrocardiogram, and blood tests (eg, venereal disease research laboratory test for syphilis, complete blood cell count, vitamin B12 levels, and thyroid function tests) to eliminate other known contributors to memory impairment. Routine computed tomography scans or magnetic resonance imaging scans (1.5 tesla) also were performed to exclude the possibility of overt cerebrovascular disease. Controls underwent medical evaluations to exclude serious medical illnesses (eg, type 1 diabetes mellitus, significant hypertension, or cardiovascular disease).

Clinical Assessment

Trained inpatient staff administered to all participants several global clinical rating instruments, including the Clinical Dementia Rating (CDR),20 Global Deterioration Scale (GDS),21 and the Mini-Mental State Examination (MMSE).22 These well-established rating instruments were given within 1 month of the lumbar punctures. Patients with AD were diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and NINCDS-ADRDA criteria.23,24

Lumbar Puncture

Lumbar punctures were performed at the start of the morning. Participants were inpatients at the National Institutes of Health Clinical Center and were kept at bedrest and had nothing by mouth until the procedure was completed. While the patient was in the lateral decubitus or sitting position, lumbar punctures were performed with a 20- or 22-gauge needle after application of local anesthesia with 1% to 2% lidocaine. Headache rates following lumbar punctures were less than 10% (ranging from mild discomfort to severe headaches requiring follow-up care with a blood patch). Approximately 30 mL of CSF was withdrawn during the lumbar puncture; the CSF was aliquoted into individual polypropylene tubes without preservative and frozen at the bedside on dry ice within minutes of withdrawal. Samples were then transferred to −70°C freezers. The low-temperature freezers are monitored daily for temperature control, and they have auxiliary liquid carbon dioxide backup in case of mechanical or electrical failures.

CSF Assays

Assays were performed on the CSF samples from AD patients that had been stored undisturbed at − 70°C for variable lengths of time, ranging from less than 6 months to longer than 15 years. Since the time samples were stored in the freezer before CSF assay (shelf life) differed significantly by diagnostic category (mean [SD] for controls, 3.1 [2.9] years vs for AD patients, 7.1 [3.4] years; P<.001), we tested whether shelf life was associated with CSF β-amyloid1-42 or tau levels. Within the control group, neither CSF β-amyloid1-42 nor tau levels were significantly correlated with duration of shelf life (r = − 0.03, P = .78 and r = 0.02, P = .81, respectively). Similarly, neither CSF β-amyloid1-42 nor tau levels were significantly associated with duration of shelf life in the AD group (r = − 0.07, P = .33 and r = 0.02, P = .79, respectively).

CSF β-Amyloid1-42 Levels. β-Amyloid1-42 was measured with a 1-step sandwich enzyme-linked immunoabsorbent assay (IGEN International Inc, Gaithersburg, Md) using a polyclonal antibody specific for β-amyloid1-42 used as the capture antibody and a monoclonal antibody, 4G8, used as the detection antibody. This assay is designed specifically to measure the human β-amyloid 1-42 peptide in CSF in a 10 × excess background of 1-40. The monoclonal antibody (catalog No. 4G8 240-10; Senetek, Napa, Calif) was supplied in the form of purified IgG at 1 mg/mL and ruthinylated at 7:1 ratio. The β-amyloid polyclonal antisera (catalog No. 44-344; QCB Division of BioSource International, Hopkinton, Mass) was supplied as 0.530 mg/mL and biotinylated at a 20:1 ratio. β-Amyloid peptide (catalog No. 03-111 [1-42] and catalog No. 03-136[1-40]; QCB) was supplied as 1 mg and as trifluoroacetate salt. Solubilization was performed in 1 mg/mL of dimethylsulfoxide and snap frozen on dry ice. Samples of CSF (200 µL) or standards (200 µL) were added to 50 µL of antibody (4 µg/mL of monoclonal antibody 4G8 and 3 µg/mL of polyclonal antibody) and 25 µL of streptavidin M-280 paramagnetic beads (IGEN International Inc) at 600 µg/mL, which was prepared in phosphate buffered saline with 15% bovine serum albumin. This mixture was incubated at room temperature for 3 hours with shaking followed by the addition of 300 µL of phosphate buffered saline at the end of the incubation period.

The immune complexes were quantitated by measurement of electrochemiluminescent signal using an ORIGEN 1.5 Analyzer (IGEN International Inc) with 5 standard concentrations from 125 to 2000 pg/mL. The intra-assay variability was assessed by calculating the percent coefficient variation for replicates of the individual samples on the same assay and then averaging those values for each assay. Using a standard curve, the inter-assay variability was determined by calculating the percent coefficient variation for the quality control samples across all of the assays. Intra-assay and inter-assay variability measures were 3.5% and 5.2%, respectively.

CSF Tau Protein Levels. Tau was measured using a commercial enzyme immunoassay (Innotest Inc, Ghent, Belgium). In this assay, the wells of polystyrene microtiter plates were coated with the solid phase anti–human tau monoclonal antibody (AT120). The test samples were incubated in these wells along with 2 separate biotinylated tau monoclonal antibodies (H57 and BT2) that recognize different tau epitopes. Samples were rinsed with an assay buffer and then incubated with peroxidase-labeled streptavidin. Samples were then incubated with tetramethylbenzidine and 0.006% hydrogen peroxide per manufacturer's instructions. The reaction was stopped with diluted sulfuric acid and optical density measurements read using a Molecular Devices Spectramax Plus plate reader. Intra-assay and inter-assay variability measures were 5.6% and 8.1%, respectively.

Autopsy. The original clinical population consisted of 136 patients with"probable" AD. Of those patients, 36 have since died and undergone autopsy. The diagnosis of AD was confirmed in 31 of 36 patients (86% accuracy) according to standard neuropathologic criteria25,26 without knowledge of CSF data. Autopsy results revealed that 5 cases of clinical AD were found to have other neuropathological diagnoses: 2 with Lewy body dementia, 2 with cerebrovascular dementia, and 1 with thalamic dementia. These cases were excluded from the dataset for the CSF analysis. The final AD group (n = 131) consists of 100 patients with "probable" AD who are still alive and 31 patients with autopsy-proven AD.

Statistical Analysis

Parametric comparisons between the AD and control groups were performed using unpaired t tests. Satterthwaite adjusted t tests and degrees of freedom are reported when the group variances were unequal. Pearson correlation coefficient was used for exploratory correlations within groups. When our key outcome measures (ie, CSF β-amyloid1-42 and tau) were significantly correlated with the baseline variables (P<.05), factorial designs were applied to the data with sex and age as grouping variables.27 Data are expressed as mean (SD) unless otherwise specified. All analyses were performed using the software packages of SAS version 8.02 (SAS Institute, Cary, NC), CART version 3.6 (Salford Systems, San Diego, Calif), and NCSS 2001 (Kaysville, Utah).

A classification and regression tree (CART) is a nonparametric, binary decision tree method of analysis (an "if-then" scenario) similar to the diagnostic decision trees used in differential diagnosis in medicine,28 especially when looking for relationships between a small number of variables.29 The CART approach allows for variables to be tested simultaneously for diagnostic classification without relying on classical statistical assumptions, such as the normality of the data and homogeneity of variance. CART also was used to estimate objective bivariate cutpoints for the CSF variables to determine maximal sensitivity and specificity associated with the clinical diagnosis of AD. In this analysis, the lead variable was CSF β-amyloid1-42 followed by CSF tau.

A meta-analysis of CSF β-amyloid1-42 comparisons in AD and control participants was performed by calculating and combining the effect sizes and t test scores across 17 CSF studies.30 These studies were chosen from 188 articles that resulted from PubMed and MEDLINE literature searches from August 1989 to March 2003 using key words Alzheimer's and CSF and beta-amyloid, or amyloid beta in titles and abstracts. Studies were sorted according to relevance and were excluded if they were not in the English language, did not provide data for controls, did not provide diagnostic criteria, or failed to distinguish total CSF β-amyloid from its components (40 and 42 residue chains). Studies with fewer than 25 total participants or those that did not report the SD of the mean CSF β-amyloid level also were excluded. If identical or overlapping population samples were used in 2 separate articles, a judgment was made to include the more complete article in the meta-analysis. After application of these criteria, a total of 17 studies were included in the meta-analysis. In this meta-analysis, studies were weighted according to sample size.27 Effect size was calculated by dividing the difference of the means for the outcome variable by the pooled SD.31

A meta-analysis using the same procedures also was performed for articles reporting CSF tau levels across the same time period as CSF β-amyloid1-42 levels. Again, articles were excluded from further consideration if they included previously reported data, did not include control participants, had poorly described methods, included mixed diagnostic populations, had missing SDs for mean CSF tau levels, or had fewer than 25 participants. The initial list of 200 articles was reduced to a final count of 34 relevant studies for the meta-analysis focusing on CSF tau levels.

Because the underlying units of measurement varied from study to study, all units were converted to picograms per milliliter using a commonly available calculator program (http://molbiol.ru/eng/scripts/01_04.html). The overall effect size and t test with the associated P value were calculated for this meta-analysis.32 The t tests were calculated with unequal variances using the Satterthwaite adjusted degrees of freedom rounded to the nearest integer.

Baseline and Global Measures

The 131 AD participants (mean [SD] age, 68.1 [9.1] years; range, 44-88 years) had a mean (SD) age of dementia onset of 64.4 (9.4) years and duration of illness of 3.6 (2.4) years. The AD participants were mildly to moderately impaired with mean (SD) MMSE scores of 19.7 (6.7). The control participants (n = 72; mean [SD] age, 59.4 [8.5] years; range, 45-86 years) were significantly younger and more educated than the AD patients (Table 1).

Table Graphic Jump LocationTable 1. Demographic Characteristics and Baseline Measures for Controls and Patients With Alzheimer Disease (AD)
CSF Measures of β-Amyloid

Mean (SD) CSF β-amyloid1-42 were significantly lower in the AD patients compared with the controls (183 [121] pg/mL vs 491 [245] pg/mL; P<.001). Despite the statistically significant differences between groups, the data showed considerable variance, resulting in significant overlap between groups (Figure 1). Marked differences in mean CSF tau levels between AD patients and controls also were observed (587 [365] pg/mL vs 224 [156] pg/mL; P<.001). For CSF tau, tau concentration was significantly associated with age of controls (r = 0.43, P<.001) but not age of AD patients (r = 0.012, P = .90). Conversely, there was a significant sex effect with mean (SD) CSF tau in the AD patients (men, 506 [258] pg/mL vs women, 652 [424] pg/mL; t120 = 2.43 [unequal variance]; P = .02) but not in the controls (t70 = 0.21, P = .84). Because of these exploratory findings, we performed a more definitive 3-way factorial analysis of variance (ANOVA) (diagnosis × sex × age) with age stratified into 3 levels (40-60 years, 60-70 years, and older than 70 years). As expected, the results of the ANOVA revealed a significant difference by diagnosis of AD (F1,191 = 40.9, P<.001) but no main level or interaction effects for the sex or age group variables (3-way ANOVA, F2,191 = 0.30, P = .74). A similar 3-way ANOVA for CSF β-amyloid1-42 also revealed a strong overall effect of AD diagnosis (F1,191 = 106.36, P<.001) but no main level or interaction effects for the sex or age group variables (3-way ANOVA, F2,191 = 0.57, P = .57).

Figure 1. Scattergraphs of β-Amyloid1-42 and Tau Levels in Cerebrospinal Fluid (CSF) for Controls and Patients With Alzheimer Disease
Graphic Jump Location
Boxes represent 25th, 50th, and 75th percentiles of the data. The length of the box is the interquartile range. The lower and upper whiskers represent the 25th and 75th percentile plus or minus 1.5 times the interquartile range, respectively.

Neither CSF biomarker differed significantly by whether AD was confirmed by autopsy or clinically diagnosed (for mean [SD] CSF β-amyloid1-42, 170 [115] pg/mL vs 187 [123] pg/mL, t129 = 0.68, P = .50, respectively, and for mean [SD] CSF tau, 677 [250] pg/mL vs 559 [391] pg/mL, t79 = −1.99, P = .06, respectively). Therefore, the results of the 2 groups were combined.

Across all AD patients and controls, the CSF β-amyloid1-42 and tau levels were significantly negatively correlated (r = − 0.30, P<.001), perhaps a function of the number of AD patients with high CSF tau and low CSF β-amyloid1-42 levels combined with the number of controls showing the opposite pattern. However, for the controls alone, the correlation between these 2 measures was positively correlated (r = 0.29, P = .02), while for AD cases, the 2 measures were not correlated (r = − 0.08, P = .35).

To determine whether changes in CSF β-amyloid1-42 and CSF tau levels occur early in the onset of the disease, we tested for correlation between CSF β-amyloid1-42 and tau measures and severity and duration of illness. Measures of CSF tau were significantly correlated with the CDR rating (r = 0.19, P = .03) and MMSE score (r = − 0.20, P = .03) and revealed a trend with the GDS score (r = 0.17, P = .053), while CSF β-amyloid1-42 levels showed a trend relationship with MMSE only (r = 0.16, P = .09). Interestingly, years of education were associated with lower CSF tau levels in the overall AD group (r = − 0.19, P = .03). Within the AD group, CSF β-amyloid1-42 levels were not associated with age, age of onset, or duration of illness (r = − 0.14, P = .11; r = 0.12, P = .18; and r = 0.08, P = .35, respectively). Similarly, CSF tau levels were not associated with age, age of onset, or duration of illness in the AD group (r = − 0.01, P = .90; r = 0.01, P = .87; and r = − 0.01, P = .90, respectively). When patients with moderate and severe AD (CDR score of 2 or 3; n = 56) were compared with controls, for both mean (SD) CSF β-amyloid1-42 (175 [99] pg/mL vs 491 [245] pg/mL, t99 = 9.94 [unequal variance], P<.001) and tau levels (660 [396] pg/mL vs 224 [156] pg/mL; t68 = 7.79 [unequal variance], P<.001) were significantly different. When only patients with mild AD (CDR score of 0.5 or 1; n = 75) were included, both mean (SD) CSF β-amyloid1-42 (189 [135] pg/mL vs 491 [245] pg/mL; t100 = 9.21 [unequal variance], P<.001) and tau levels (532 [333] pg/mL vs 224 [156] pg/mL; t106 = 7.22 [unequal variance], P<.001) remained significantly different. While this analysis was exploratory, it suggests that changes in CSF β-amyloid1-42 tau levels may be present early in the disease process.

CART Analysis

A CART analysis was performed to evaluate the combined contributions of CSF β-amyloid1-42 and CSF tau to differentiate AD patients from controls. Cutpoints of 444 pg/mL for CSF β-amyloid1-42 and 195 pg/mL for CSF tau maximized sensitivity to 92% and specificity to 82% in this analysis (Figure 2). These CART-defined cutpoints maximize the specificity and sensitivity for this particular group of participants, and would be lower in a new population.

Figure 2. Specificity and Sensitivity Cutpoints for Measures of β-Amyloid1-42 and Tau Levels in Cerebrospinal Fluid (CSF) Classifying Controls (n = 72) and Patients With Alzheimer Disease (AD) (n = 131)
Graphic Jump Location
Cutpoints are chosen for maximum separation of participant groups: upper left quadrant includes 120 participants with AD and 8 controls; upper right quadrant includes 3 participants with AD and 20 controls; lower left quadrant includes 7 participants with AD and 24 controls; and lower right quadrant includes 1 participant with AD and 20 controls. The cutpoints of 444 pg/mL for CSF β-amyloid1-42 and 195 pg/mL for CSF tau generate a sensitivity of 92% and a specificity of 89%.
Meta-Analysis

The meta-analysis of the literature on CSF β-amyloid1-42 involved 17 studies that met criteria for inclusion (Table 2).47,13,14,16,3342 Other studies were reviewed17,4348 but they did not meet our criteria for the meta-analysis. Fourteen47,13,14,16,3339 of the 17 studies in the meta-analysis showed clear reductions in CSF β-amyloid1-42 levels in AD vs control participants while 2 studies were equivocal and another reported changes in the opposite direction (Table 2 and Figure 3). The overall effect size (CSF β-amyloid1-42 level difference between AD and control participants) of the meta-analysis with the previously published studies was 1.53 (95% confidence interval [CI], 1.39-1.69) (Figure 3). In the current study, the effect size was 1.76 (95% CI, 1.42-2.10). When the data from the current study are added to the meta-analysis (for a total of 18 studies), the effect size is 1.56 (95% CI, 1.43-1.69).

Table Graphic Jump LocationTable 2. Meta-analysis of 17 Studies With Participants With Alzheimer Disease (AD) and Controls Compared With the Current Study for Cerebrospinal Fluid (CSF) Measures of β-Amyloid1-42 Levels
Figure 3. Effect Sizes of Results from 17 Studies of Meta-analysis of Measures of β-Amyloid1-42 in Cerebrospinal Fluid (CSF) for Controls and Participants With Alzheimer Disease (AD)
Graphic Jump Location
CI indicates confidence interval. Effect size is the difference in means between AD patients and controls divided by the pooled SD.

A similar meta-analysis was performed for 34 studies on CSF tau in the literature search (Table 3 and Figure 4).4,5,7,10,11,14,36,40 All the studies report a significant difference in CSF tau levels between AD participants and controls. For the combined series of previously published studies, the overall effect size was 1.31 (95% CI, 1.23-1.39). The overall effect size of the current study was 1.18 (95% CI, 0.87-1.49). When all 35 studies are included in the meta-analysis (ie, 34 studies and the current study), the effect size remains 1.31 (95% CI, 1.23-1.39).

Table Graphic Jump LocationTable 3. Meta-analysis of 34 Studies With Participants With Alzheimer Disease (AD) and Controls Compared With the Current Study for Cerebrospinal Fluid (CSF) Measures of Tau Protein Levels
Figure 4. Effect Sizes of Results from 34 Studies of Meta-analysis of Measures of Tau Protein in Cerebrospinal Fluid for Controls and Participants With Alzheimer Disease (AD)
Graphic Jump Location
CI indicates confidence interval. Effect size is the difference in means between AD patients and controls divided by the pooled SD.

The idea that CSF β-amyloid1-42 and tau levels could be useful in diagnosing AD is not new. Numerous authors have documented the changes of these biomarkers in AD patients vs controls,46,13,33 but not without controversy, especially with respect to CSF β-amyloid1-42 levels. While most studies show a decrease of CSF β-amyloid1-42 levels in AD patients vs controls, a small number of studies have shown no changes or even elevations of the protein levels.16,17,43,73 Given the range of methods used and the variable sample sizes of the studies, this result is perhaps not surprising, but it has left open the question of whether and when changes in CSF β-amyloid1-42 levels are manifest in AD. To our knowledge, our study is the largest to confirm the decrease of CSF β-amyloid1-42 and an increase in tau levels in AD participants. In addition, these differences appear to be found in patients with mild AD as well in patients with moderate to severe AD.

Two possible confounding factors within the current study deserve further explanation. First, the age of the controls is significantly lower than that of the AD patients. While this factor was not significantly associated with CSF β-amyloid1-42 levels for either AD patients or controls, an age effect was found within the controls for CSF tau. However, after controlling for age, CSF tau levels remained significantly higher in the AD group vs controls. Second, freezer shelf life might be a factor in the assay values, as the CSF samples from AD patients had been frozen longer than the samples from controls. However, no relationship was found between CSF β-amyloid1-42 or tau levels and shelf life for either the AD patients or controls.

CSF Tau and β-Amyloid

Some authors have found a modest correlation between CSF tau and baseline clinical measures,55,74,75 while others, including our own group, have reported no significant relationship.4,12,57 The lack of correlation may have been due in part to the relatively restricted range of dementia severity in some of these studies. In our current study, with a much larger sample population of AD patients, we found a small but statistically significant correlation between CSF tau levels and several of the global severity measures, including the CDR, GDS, and MMSE ratings. Also of interest, CSF tau levels were inversely correlated with education level, suggesting a possible protective factor. Conversely, analysis of CSF β-amyloid1-42 levels revealed only a modest trend for a correlation with MMSE score in the AD patients, and no significant relationship was found with age, other severity measures of dementia, or CSF tau levels. While a significant correlation exists between CSF β-amyloid1-42 and tau levels across all participants tested, this correlation did not persist within the AD population alone, perhaps reflecting the restricted range of the CSF values in the AD patients in this study.

Meta-analysis

A meta-analysis was performed with published studies of CSF β-amyloid1-42 in AD to elucidate the overall trends in the data and to determine the effect size of group differences. Not all the available studies were amenable to the meta-analysis method, but we did find 17 studies that met the criteria (Table 2 and Figure 3). The considerable variability in mean values among the studies highlights the lack of standardization of assay methods among centers and is of some concern. However, with 14 of the 17 studies showing significant reductions in CSF β-amyloid1-42 levels in the AD vs control participants, the result of the meta-analysis was unequivocal and the effect size quite large, with AD participants showing a lower CSF β-amyloid1-42 level. The direction and effect size of our current study was consistent with the meta-analysis, indicating a similar trend. For the meta-analysis of studies on CSF tau, the data are even more unequivocal (Table 3 and Figure 4). Despite differences in baseline levels across studies, the pattern of change is uniform; all previous studies report AD patients having higher CSF tau levels than that found with controls.

With the general consistency in the literature for CSF β-amyloid1-42 and tau, it is not surprising that several companies have initiated commercial tests of these measures for clinical use with individual patients (Athena Diagnostics, Worcester, Mass; Innogenetics, Ghent, Belgium; and ABETA GmbH, Heidelberg, Germany). However, the claims regarding sensitivity and specificity from the commercial concerns and our own CART analysis are derived from clinically diagnosed AD cases in which the diagnostic accuracy already approximates 85% when validated by the standard pathologic diagnosis at autopsy.25,76,77 Furthermore, the cutpoints for most sensitivity and specificity assessments are chosen to maximize the specificity and sensitivity results with those measures. Our data are fairly representative of the literature and clearly show considerable variance in the data that provides room for misclassification by an individual biomarker, whether the marker is CSF β-amyloid1-42 or CSF tau (Figure 1).

Approach to Clinical Application

Given the overlap between AD and control groups, it is evident that the diagnostic sensitivity and specificity of these individual CSF β-amyloid1-42 and tau assays is simply not sufficient to warrant general clinical use of these biomarkers for individual use. Nonetheless, when the CSF β-amyloid1-42 and tau data are combined into 1 statistical analysis, the overlap with clinical diagnoses generally improves.4,5,7 While the differences in CSF levels between AD populations and controls are indeed impressive, the interpretations of this data are limited because they result from contrasts of starkly different populations (ie, AD vs healthy, self-selected controls). This type of artificial contrast is not representative of realistic clinical comparisons and is considered phase 1 diagnostic testing.78 A truer test of any suggested diagnostic marker would include comparisons among populations with different types of dementia, including vascular, Lewy body dementia, and other neurological disorders, or cases with very early cognitive impairment. It is likely that this phase 2 testing with populations with mixed diagnoses will show poorer sensitivity and specificity results, and this approach has previously been attempted with only modest success.7 Thus, while it can be said that these research diagnostic techniques are indeed improving, a great deal of developmental testing is still in order at the interface of clinical medicine and research methodology.78

Perhaps the biggest future challenge to the research in AD will be to standardize these CSF measures across numerous centers and then apply them as part of a prospective clinical evaluation of participants who are at risk for developing AD. Currently, a clinical criterion standard is not available to help with the early diagnosis of AD. As a result, analysis of CSF β-amyloid1-42 and tau levels are likely to be most useful diagnostically when they are used in conjunction with other biomarkers, including structural magnetic resonance imaging, genetic markers, and positron-emission tomography scans when a tracer for β-amyloid burden is more readily available. This approach is the focus of an ongoing longitudinal, prospective study at the National Institute of Mental Health with a cohort of older controls (protocol 95-M-96).

Conclusion

The study of CSF biomarkers, such as β-amyloid1-42 and tau, in AD participants is emerging as an important but still nascent field.8 The cross-sectional data clearly show group differences between AD participants and controls, both in this large study and in a meta-analysis of the literature. However, these studies represent the early development of diagnostic measures. Additional studies are required to establish methodologic standardization in the CSF assays across centers and to see if a specificity for AD exists over other forms of dementia, which have substantial overlap with AD at postmortem (ie, Lewy body dementia or cerebrovascular dementia). Furthermore, the mixed findings in the literature relating these CSF biomarkers to clinical severity measures of dementia suggest the need for larger sample sizes to establish statistical significance. The reason for the varying data may be because single biomarkers may not be able to provide an accurate reflection of the pathologic process across the entire span of the illness. Rather, individual biomarkers may be correlated to the prominent pathophysiology of a particular stage of the illness but not to the pathophysiology of earlier or later stages.

Perhaps the most important future use for such biomarkers is in the prospective study of participants at risk for developing AD. However, much work is needed with the standardization of assay methods before prognostic significance can be attributed to these biomarkers. Once an individual's normal levels of the biomarkers are well established, it is possible that gradual changes in these levels (eg, CSF levels of β-amyloid1-42 or tau) could eventually be interpreted as suggestive evidence of incipient AD. To test this hypothesis, longitudinal prospective studies of controls and early AD participants are necessary and are currently ongoing.

 Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the NIA working group: consensus report of the working group on: "molecular and biochemical markers of Alzheimer's disease."  Neurobiol Aging.1998;19:109-116.
Selkoe DJ. The origins of Alzheimer disease.  JAMA.2000;283:1615-1617.
Knopman DS, DeKosky ST, Cummings JL.  et al.  Practice parameter: diagnosis of dementia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.  Neurology.2001;56:1143-1153.
Motter R, Vigo-Pelfrey C, Kholodenko D.  et al.  Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease.  Ann Neurol.1995;38:643-648.
Galasko D, Chang L, Motter R.  et al.  High cerebrospinal fluid tau and low amyloid beta42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype.  Arch Neurol.1998;55:937-945.
Mehta PD, Pirttila T, Mehta SP, Sersen EA, Aisen PS, Wisniewski HM. Plasma and cerebrospinal fluid levels of amyloid beta proteins 1-40 and 1-42 in Alzheimer disease.  Arch Neurol.2000;57:100-105.
Andreasen N, Minthon L, Davidsson P.  et al.  Evaluation of CSF-tau and CSF-Abeta42 as diagnostic markers for Alzheimer disease in clinical practice.  Arch Neurol.2001;58:373-379.
Blennow K, Vanmechelen E, Hampel H. CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer's disease.  Mol Neurobiol.2001;24:87-97.
Ishiguro K, Ohno H, Arai H.  et al.  Phosphorylated tau in human cerebrospinal fluid is a diagnostic marker for Alzheimer's disease.  Neurosci Lett.1999;270:91-94.
Itoh N, Arai H, Urakami K.  et al.  Large-scale, multicenter study of cerebrospinal fluid tau protein phosphorylated at serine 199 for the antemortem diagnosis of Alzheimer's disease.  Ann Neurol.2001;50:150-156.
Shoji M, Matsubara E, Murakami T.  et al.  Cerebrospinal fluid tau in dementia disorders.  Neurobiol Aging.2002;23:363-370.
Sunderland T, Wolozin B, Galasko D.  et al.  Longitudinal stability of CSF tau levels in Alzheimer patients.  Biol Psychiatry.1999;46:750-755.
Hulstaert F, Blennow K, Ivanoiu A.  et al.  Improved discrimination of AD patients using beta-amyloid(1-42) and tau levels in CSF.  Neurology.1999;52:1555-1562.
Kanai M, Matsubara E, Isoe K.  et al.  Longitudinal study of cerebrospinal fluid levels of tau, A beta1-40, and A beta1-42(43) in Alzheimer's disease.  Ann Neurol.1998;44:17-26.
Sjogren M, Vanderstichele H, Agren H.  et al.  Tau and Abeta42 in cerebrospinal fluid from healthy adults 21-93 years of age.  Clin Chem.2001;47:1776-1781.
Jensen M, Schroder J, Blomberg M.  et al.  Cerebrospinal fluid A beta42 is increased early in sporadic Alzheimer's disease and declines with disease progression.  Ann Neurol.1999;45:504-511.
Nakamura T, Shoji M, Harigaya Y.  et al.  Amyloid beta protein levels in cerebrospinal fluid are elevated in early-onset Alzheimer's disease.  Ann Neurol.1994;36:903-911.
Dukoff R, Sunderland T. Durable power of attorney and informed consent with Alzheimer's disease patients.  Am J Psychiatry.1997;154:1070-1075.
Sunderland T, Dukoff R. Surrogate decision-making and advanced directives with cognitively-impaired research subjects. In: Pincus HA, ed. Informed Consent: A Resource Manual for Investigators. Washington, DC: American Psychiatric Press; 1999.
Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia.  Br J Psychiatry.1982;140:566-572.
Reisberg B, Ferris SH, de Leon MJ, Crook T. The Global Deterioration Scale for assessment of primary degenerative dementia.  Am J Psychiatry.1982;139:1136-1139.
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state:" a practical method for grading the cognitive state of patients for the clinician.  J Psychiatr Res.1975;12:189-198.
American Psychiatric Association.  Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.  Neurology.1984;34:939-944.
Mirra SS, Heyman A, McKeel D.  et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD).  Neurology.1991;41:479-486.
 The National Institute on Aging and Reagan Institute Work Groups on diagnostic criteria for the neuropathological assessment of Alzheimer's disease "consensus recommendations for the post-mortem diagnosis of Alzheimer's disease."  Neurobiol Aging.1997;18(suppl 4):S1-S2.
Winer BJ. Statistical Principles in Experimental Design3rd ed. New York, NY: McGraw-Hill, Inc; 1991.
Breiman L, Friedman JH, Olshen RA, Stone CJ. Classification and Regression TreesNew York, NY: Chapman & Hall (Wadsworth Inc); 1984.
Lewis RJ. An Introduction to Classification and Regression Tree (CART) Analysis. August 27, 2002. Available at: http://www.saem.org/meetings/00grid2.htm. 2002.
Hedges L. Statistical Methods for Meta-analysisOrlando, Fla: Academic Press; 1985.
Cohen J. Statistical Power Analysis for the Behavioral Sciences2nd ed. New York, NY: Lawrence Erlbaum Associates; 1988.
Rosenthal R. Judgment Studies: Design, Analysis and Meta-analysisCambridge, England: Cambridge University Press; 1978:179-207.
Andreasen N, Hesse C, Davidsson P.  et al.  Cerebrospinal fluid beta-amyloid(1-42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease.  Arch Neurol.1999;56:673-680.
Tamaoka A, Sawamura N, Fukushima T.  et al.  Amyloid beta protein 42(43) in cerebrospinal fluid of patients with Alzheimer's disease.  J Neurol Sci.1997;148:41-45.
Fukuyama R, Mizuno T, Mori S, Nakajima K, Fushiki S, Yanagisawa K. Age-dependent change in the levels of Abeta40 and Abeta42 in cerebrospinal fluid from control subjects, and a decrease in the ratio of Abeta42 to Abeta40 level in cerebrospinal fluid from Alzheimer's disease patients.  Eur Neurol.2000;43:155-160.
Kanemaru K, Kameda N, Yamanouchi H. Decreased CSF amyloid beta42 and normal tau levels in dementia with Lewy bodies.  Neurology.2000;54:1875-1876.
Otto M, Esselmann H, Schulz-Shaeffer W.  et al.  Decreased beta-amyloid1-42 in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease.  Neurology.2000;54:1099-1102.
Riemenschneider M, Schmolke M, Lautenschlager N.  et al.  Cerebrospinal beta-amyloid (1-42) in early Alzheimer's disease: association with apolipoprotein E genotype and cognitive decline.  Neurosci Lett.2000;284:85-88.
Sjogren M, Minthon L, Davidsson P.  et al.  CSF levels of tau, beta-amyloid(1-42) and GAP-43 in frontotemporal dementia, other types of dementia and normal aging.  J Neural Transm.2000;107:563-579.
Csernansky JG, Miller JP, McKeel D, Morris JC. Relationships among cerebrospinal fluid biomarkers in dementia of the Alzheimer type.  Alzheimer Dis Assoc Disord.2002;16:144-149.
Sjogren M, Davidsson P, Wallin A.  et al.  Decreased CSF-beta-amyloid 42 in Alzheimer's disease and amyotrophic lateral sclerosis may reflect mismetabolism of beta-amyloid induced by disparate mechanisms.  Dement Geriatr Cogn Disord.2002;13:112-118.
Skoog I, Davidsson P, Aevarsson O, Vanderstichele H, Vanmechelen E, Blennow K. Cerebrospinal fluid beta-amyloid 42 is reduced before the onset of sporadic dementia.  Dement Geriatr Cogn Disord.2003;15:169-176.
Nitsch RM, Rebeck GW, Deng M.  et al.  Cerebrospinal fluid levels of amyloid beta-protein in Alzheimer's disease.  Ann Neurol.1995;37:512-518.
Pirttila T, Mehta PD, Soininen H.  et al.  Cerebrospinal fluid concentrations of soluble amyloid beta-protein and apolipoprotein E in patients with Alzheimer's disease.  Arch Neurol.1996;53:189-193.
Hock C, Golombowski S, Muller-Spahn F.  et al.  Cerebrospinal fluid levels of amyloid precursor protein and amyloid beta-peptide in Alzheimer's disease and major depression-Inverse correlation with dementia severity.  Eur Neurol.1998;39:111-118.
Vanderstichele H, Van Kerschaver E, Hesse C.  et al.  Standardization of measurement of beta-amyloid(1-42) in cerebrospinal fluid and plasma.  Amyloid.2000;7:245-258.
Tapiola T, Pirttila T, Mehta PD, Alafuzofff I, Lehtovirta M, Soininen H. Relationship between apoE genotype and CSF beta-amyloid (1-42) and tau in patients with probable and definite Alzheimer's disease.  Neurobiol Aging.2000;21:735-740.
Kapaki E, Paraskevas GP, Zalonis I, Zournas C. CSF tau protein and beta-amyloid (1-42) in Alzheimer's disease diagnosis.  Eur J Neurol.2003;10:119-128.
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Arai H, Terajima M, Miura M.  et al.  Tau in cerebrospinal fluid.  Ann Neurol.1995;38:649-652.
Blennow K, Wallin A, Agren H, Spenger C, Siegfried J, Vanmechelen E. Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease?  Mol Chem Neuropathol.1995;26:231-245.
Mori H, Hosoda K, Matsubara E.  et al.  Tau in cerebrospinal fluids.  Neurosci Lett.1995;186:181-183.
Munroe WA, Southwick PC, Chang L.  et al.  Tau protein in cerebrospinal fluid as an aid in the diagnosis of Alzheimer's disease.  Ann Clin Lab Sci.1995;25:207-217.
Skoog I, Vanmechelen E, Andreasson LA.  et al.  A population-based study of tau protein and ubiquitin in cerebrospinal fluid in 85-year-olds.  Neurodegeneration.1995;4:433-442.
Tato RE, Frank A, Hernanz A. Tau protein concentrations in cerebrospinal fluid of patients with dementia of the Alzheimer type.  J Neurol Neurosurg Psychiatry.1995;59:280-283.
Vigo-Pelfrey C, Seubert P, Barbour R.  et al.  Elevation of microtubule-associated protein tau in the cerebrospinal fluid of patients with Alzheimer's disease.  Neurology.1995;45:788-793.
Arai H, Terajima M, Miura M.  et al.  Effect of genetic risk factors and disease progression on the cerebrospinal fluid tau levels in Alzheimer's disease.  J Am Geriatr Soc.1997;45:1228-1231.
Golombowski S, Muller-Spahn F, Romig H, Mendla K, Hock C. Dependence of cerebrospinal fluid Tau protein levels on apolipoprotein E4 allele frequency in patients with Alzheimer's disease.  Neurosci Lett.1997;225:213-215.
Andreasen N, Vanmechelen E, Van de Voorde A.  et al.  Cerebrospinal fluid tau protein as a biochemical marker for Alzheimer's disease.  J Neurol Neurosurg Psychiatry.1998;64:298-305.
Arai H, Satoh-Nakagawa T, Higuchi M.  et al.  No increase in cerebrospinal fluid tau protein levels in patients with vascular dementia.  Neurosci Lett.1998;256:174-176.
Kurz A, Riemenschneider M, Buch K.  et al.  Tau protein in cerebrospinal fluid is significantly increased at the earliest clinical stage of Alzheimer disease.  Alzheimer Dis Assoc Disord.1998;12:372-377.
Mecocci P, Cherubini A, Bregnocchi M.  et al.  Tau protein in cerebrospinal fluid.  Alzheimer Dis Assoc Disord.1998;12:211-214.
Nishimura T, Takeda M, Nakamura Y.  et al.  Basic and clinical studies on the measurement of tau protein in cerebrospinal fluid as a biological marker for Alzheimer's disease and related disorders.  Methods Find Exp Clin Pharmacol.1998;20:227-235.
Shoji M, Matsubara E, Kanai M.  et al.  Combination assay of CSF tau, A beta 1-40 and A beta 1-42(43) as a biochemical marker of Alzheimer's disease.  J Neurol Sci.1998;158:134-140.
Andreasen N, Minthon L, Clarberg A.  et al.  Sensitivity, specificity, and stability of CSF-tau in AD in a community-based patient sample.  Neurology.1999;53:1488-1494.
Burger nee Buch K, Padberg F.  et al.  Cerebrospinal fluid tau protein shows a better discrimination in young old (<70 years) than in old patients with Alzheimer's disease compared with controls.  Neurosci Lett.1999;277:21-24.
Green AJ, Harvey RJ, Thompson EJ, Rossor MN. Increased tau in the cerebrospinal fluid of patients with frontotemporal dementia and Alzheimer's disease.  Neurosci Lett.1999;259:133-135.
Hampel H, Teipel SJ, Padberg F.  et al.  Discriminant power of combined cerebrospinal fluid tau protein and of the soluble interleukin-6 receptor complex in the diagnosis of Alzheimer's disease.  Brain Res.1999;823:104-112.
Molina L, Touchon J, Herpe M.  et al.  Tau and apo E in CSF: potential aid for discriminating Alzheimer's disease from other dementias.  Neuroreport.1999;10:3491-3495.
Kahle PJ, Jakowec M, Teipel SJ.  et al.  Combined assessment of tau and neuronal thread protein in Alzheimer's disease CSF.  Neurology.2000;54:1498-1504.
Hampel H, Buerger K, Kohnken R.  et al.  Tracking of Alzheimer's disease progression with cerebrospinal fluid tau protein phosphorylated at threonine 231.  Ann Neurol.2001;49:545-546.
Rosler N, Wichart I, Jellinger KA. Clinical significance of neurobiochemical profiles in the lumbar cerebrospinal fluid of Alzheimer's disease patients.  J Neural Transm.2001;108:231-246.
van Gool WA, Kuiper MA, Walstra GJ, Wolters EC, Bolhuis PA. Concentrations of amyloid beta protein in cerebrospinal fluid of patients with Alzheimer's disease.  Ann Neurol.1995;37:277-279.
Hock C, Golombowski S, Naser W, Muller-Spahn F. Increased levels of tau protein in cerebrospinal fluid of patients with Alzheimer's disease—correlation with degree of cognitive impairment.  Ann Neurol.1995;37:414-415.
Skoog I, Vanmechelen E, Andreasson LA.  et al.  A population-based study of tau protein and ubiquitin in cerebrospinal fluid in 85-year-olds.  Neurosci Lett.1996;214:163-166.
Mendez MF, Mastri AR, Sung JH, Frey 2nd WH. Clinically diagnosed Alzheimer disease.  Alzheimer Dis Assoc Disord.1992;6:35-43.
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Figures

Figure 1. Scattergraphs of β-Amyloid1-42 and Tau Levels in Cerebrospinal Fluid (CSF) for Controls and Patients With Alzheimer Disease
Graphic Jump Location
Boxes represent 25th, 50th, and 75th percentiles of the data. The length of the box is the interquartile range. The lower and upper whiskers represent the 25th and 75th percentile plus or minus 1.5 times the interquartile range, respectively.
Figure 2. Specificity and Sensitivity Cutpoints for Measures of β-Amyloid1-42 and Tau Levels in Cerebrospinal Fluid (CSF) Classifying Controls (n = 72) and Patients With Alzheimer Disease (AD) (n = 131)
Graphic Jump Location
Cutpoints are chosen for maximum separation of participant groups: upper left quadrant includes 120 participants with AD and 8 controls; upper right quadrant includes 3 participants with AD and 20 controls; lower left quadrant includes 7 participants with AD and 24 controls; and lower right quadrant includes 1 participant with AD and 20 controls. The cutpoints of 444 pg/mL for CSF β-amyloid1-42 and 195 pg/mL for CSF tau generate a sensitivity of 92% and a specificity of 89%.
Figure 3. Effect Sizes of Results from 17 Studies of Meta-analysis of Measures of β-Amyloid1-42 in Cerebrospinal Fluid (CSF) for Controls and Participants With Alzheimer Disease (AD)
Graphic Jump Location
CI indicates confidence interval. Effect size is the difference in means between AD patients and controls divided by the pooled SD.
Figure 4. Effect Sizes of Results from 34 Studies of Meta-analysis of Measures of Tau Protein in Cerebrospinal Fluid for Controls and Participants With Alzheimer Disease (AD)
Graphic Jump Location
CI indicates confidence interval. Effect size is the difference in means between AD patients and controls divided by the pooled SD.

Tables

Table Graphic Jump LocationTable 1. Demographic Characteristics and Baseline Measures for Controls and Patients With Alzheimer Disease (AD)
Table Graphic Jump LocationTable 2. Meta-analysis of 17 Studies With Participants With Alzheimer Disease (AD) and Controls Compared With the Current Study for Cerebrospinal Fluid (CSF) Measures of β-Amyloid1-42 Levels
Table Graphic Jump LocationTable 3. Meta-analysis of 34 Studies With Participants With Alzheimer Disease (AD) and Controls Compared With the Current Study for Cerebrospinal Fluid (CSF) Measures of Tau Protein Levels

References

 Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the NIA working group: consensus report of the working group on: "molecular and biochemical markers of Alzheimer's disease."  Neurobiol Aging.1998;19:109-116.
Selkoe DJ. The origins of Alzheimer disease.  JAMA.2000;283:1615-1617.
Knopman DS, DeKosky ST, Cummings JL.  et al.  Practice parameter: diagnosis of dementia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.  Neurology.2001;56:1143-1153.
Motter R, Vigo-Pelfrey C, Kholodenko D.  et al.  Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease.  Ann Neurol.1995;38:643-648.
Galasko D, Chang L, Motter R.  et al.  High cerebrospinal fluid tau and low amyloid beta42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype.  Arch Neurol.1998;55:937-945.
Mehta PD, Pirttila T, Mehta SP, Sersen EA, Aisen PS, Wisniewski HM. Plasma and cerebrospinal fluid levels of amyloid beta proteins 1-40 and 1-42 in Alzheimer disease.  Arch Neurol.2000;57:100-105.
Andreasen N, Minthon L, Davidsson P.  et al.  Evaluation of CSF-tau and CSF-Abeta42 as diagnostic markers for Alzheimer disease in clinical practice.  Arch Neurol.2001;58:373-379.
Blennow K, Vanmechelen E, Hampel H. CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer's disease.  Mol Neurobiol.2001;24:87-97.
Ishiguro K, Ohno H, Arai H.  et al.  Phosphorylated tau in human cerebrospinal fluid is a diagnostic marker for Alzheimer's disease.  Neurosci Lett.1999;270:91-94.
Itoh N, Arai H, Urakami K.  et al.  Large-scale, multicenter study of cerebrospinal fluid tau protein phosphorylated at serine 199 for the antemortem diagnosis of Alzheimer's disease.  Ann Neurol.2001;50:150-156.
Shoji M, Matsubara E, Murakami T.  et al.  Cerebrospinal fluid tau in dementia disorders.  Neurobiol Aging.2002;23:363-370.
Sunderland T, Wolozin B, Galasko D.  et al.  Longitudinal stability of CSF tau levels in Alzheimer patients.  Biol Psychiatry.1999;46:750-755.
Hulstaert F, Blennow K, Ivanoiu A.  et al.  Improved discrimination of AD patients using beta-amyloid(1-42) and tau levels in CSF.  Neurology.1999;52:1555-1562.
Kanai M, Matsubara E, Isoe K.  et al.  Longitudinal study of cerebrospinal fluid levels of tau, A beta1-40, and A beta1-42(43) in Alzheimer's disease.  Ann Neurol.1998;44:17-26.
Sjogren M, Vanderstichele H, Agren H.  et al.  Tau and Abeta42 in cerebrospinal fluid from healthy adults 21-93 years of age.  Clin Chem.2001;47:1776-1781.
Jensen M, Schroder J, Blomberg M.  et al.  Cerebrospinal fluid A beta42 is increased early in sporadic Alzheimer's disease and declines with disease progression.  Ann Neurol.1999;45:504-511.
Nakamura T, Shoji M, Harigaya Y.  et al.  Amyloid beta protein levels in cerebrospinal fluid are elevated in early-onset Alzheimer's disease.  Ann Neurol.1994;36:903-911.
Dukoff R, Sunderland T. Durable power of attorney and informed consent with Alzheimer's disease patients.  Am J Psychiatry.1997;154:1070-1075.
Sunderland T, Dukoff R. Surrogate decision-making and advanced directives with cognitively-impaired research subjects. In: Pincus HA, ed. Informed Consent: A Resource Manual for Investigators. Washington, DC: American Psychiatric Press; 1999.
Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia.  Br J Psychiatry.1982;140:566-572.
Reisberg B, Ferris SH, de Leon MJ, Crook T. The Global Deterioration Scale for assessment of primary degenerative dementia.  Am J Psychiatry.1982;139:1136-1139.
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state:" a practical method for grading the cognitive state of patients for the clinician.  J Psychiatr Res.1975;12:189-198.
American Psychiatric Association.  Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.  Neurology.1984;34:939-944.
Mirra SS, Heyman A, McKeel D.  et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD).  Neurology.1991;41:479-486.
 The National Institute on Aging and Reagan Institute Work Groups on diagnostic criteria for the neuropathological assessment of Alzheimer's disease "consensus recommendations for the post-mortem diagnosis of Alzheimer's disease."  Neurobiol Aging.1997;18(suppl 4):S1-S2.
Winer BJ. Statistical Principles in Experimental Design3rd ed. New York, NY: McGraw-Hill, Inc; 1991.
Breiman L, Friedman JH, Olshen RA, Stone CJ. Classification and Regression TreesNew York, NY: Chapman & Hall (Wadsworth Inc); 1984.
Lewis RJ. An Introduction to Classification and Regression Tree (CART) Analysis. August 27, 2002. Available at: http://www.saem.org/meetings/00grid2.htm. 2002.
Hedges L. Statistical Methods for Meta-analysisOrlando, Fla: Academic Press; 1985.
Cohen J. Statistical Power Analysis for the Behavioral Sciences2nd ed. New York, NY: Lawrence Erlbaum Associates; 1988.
Rosenthal R. Judgment Studies: Design, Analysis and Meta-analysisCambridge, England: Cambridge University Press; 1978:179-207.
Andreasen N, Hesse C, Davidsson P.  et al.  Cerebrospinal fluid beta-amyloid(1-42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease.  Arch Neurol.1999;56:673-680.
Tamaoka A, Sawamura N, Fukushima T.  et al.  Amyloid beta protein 42(43) in cerebrospinal fluid of patients with Alzheimer's disease.  J Neurol Sci.1997;148:41-45.
Fukuyama R, Mizuno T, Mori S, Nakajima K, Fushiki S, Yanagisawa K. Age-dependent change in the levels of Abeta40 and Abeta42 in cerebrospinal fluid from control subjects, and a decrease in the ratio of Abeta42 to Abeta40 level in cerebrospinal fluid from Alzheimer's disease patients.  Eur Neurol.2000;43:155-160.
Kanemaru K, Kameda N, Yamanouchi H. Decreased CSF amyloid beta42 and normal tau levels in dementia with Lewy bodies.  Neurology.2000;54:1875-1876.
Otto M, Esselmann H, Schulz-Shaeffer W.  et al.  Decreased beta-amyloid1-42 in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease.  Neurology.2000;54:1099-1102.
Riemenschneider M, Schmolke M, Lautenschlager N.  et al.  Cerebrospinal beta-amyloid (1-42) in early Alzheimer's disease: association with apolipoprotein E genotype and cognitive decline.  Neurosci Lett.2000;284:85-88.
Sjogren M, Minthon L, Davidsson P.  et al.  CSF levels of tau, beta-amyloid(1-42) and GAP-43 in frontotemporal dementia, other types of dementia and normal aging.  J Neural Transm.2000;107:563-579.
Csernansky JG, Miller JP, McKeel D, Morris JC. Relationships among cerebrospinal fluid biomarkers in dementia of the Alzheimer type.  Alzheimer Dis Assoc Disord.2002;16:144-149.
Sjogren M, Davidsson P, Wallin A.  et al.  Decreased CSF-beta-amyloid 42 in Alzheimer's disease and amyotrophic lateral sclerosis may reflect mismetabolism of beta-amyloid induced by disparate mechanisms.  Dement Geriatr Cogn Disord.2002;13:112-118.
Skoog I, Davidsson P, Aevarsson O, Vanderstichele H, Vanmechelen E, Blennow K. Cerebrospinal fluid beta-amyloid 42 is reduced before the onset of sporadic dementia.  Dement Geriatr Cogn Disord.2003;15:169-176.
Nitsch RM, Rebeck GW, Deng M.  et al.  Cerebrospinal fluid levels of amyloid beta-protein in Alzheimer's disease.  Ann Neurol.1995;37:512-518.
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