Cerebrospinal Fluid Abeta42 Research Articles

Establishment of updated biomarker cut‐off values for the second‐generation Elecsys β‐amyloid(1–42), pTau and tTau CSF immunoassays

AbstractBackgroundCompared with the first‐generation (Gen1), second‐generation (Gen2) Elecsys® cerebrospinal fluid (CSF) immunoassays (currently under development, Roche Diagnostics International Ltd) for detection of β‐amyloid(1–42) (Abeta42), phospho‐tau(181P) (pTau) and total‐tau (tTau) have higher thresholds for biotin interference. Abeta42 Gen2 is re‐standardized to Abeta42 certified reference materials ERM‐DA480/IFCC, ERM‐DA481/IFCC and ERM‐DA482/IFCC and has an extended measurement range. Additionally, the newly developed pre‐analytical ‘Routine‐Use’ protocol provides more reliable analyte recovery for Abeta42 against comparators (Hansson et al., Alzheimers Dement. 2020;16(S3):e047394). Here, we establish adjusted cut‐off values for concordance of Abeta42, pTau/Abeta42 and tTau/Abeta42 Gen2 results with amyloid‐PET based on those previously established for Gen1, accounting for different pre‐analytical protocols.MethodCSF samples from 26 patients with normal pressure hydrocephalus were collected per the Routine‐Use protocol for fresh CSF (n=3 aliquots/patient) and two clinical trial protocols (BioFINDER and Roche‐Trial) for frozen CSF (<–60°C; n=4 aliquots/patient). Abeta42, pTau and tTau were quantified using Elecsys Gen1/Gen2 immunoassays (cobas e 601 analyzer; Roche Diagnostics International Ltd). Bias at medical decision point was estimated for comparison of Gen1 and Gen2 immunoassays (Roche‐Trial protocol) by weighted‐Deming regression. Original cut‐off values were determined in the BioFINDER cohort using Gen1 immunoassays (Hansson et al.). Adjusted cut‐off values for Gen2 immunoassays with both Routine‐Use and Roche‐Trial protocols were determined. Concentration bias between Routine‐Use and Roche‐Trial protocols was also investigated, measured using Gen2 immunoassays. Mean percentage differences provided estimates of overall bias between protocols and protocol‐assay combinations.ResultNo clinically meaningful differences between assay generations and pre‐analytical protocols were obtained for pTau or tTau. Bias at medical decision point for Abeta42 Gen2 immunoassay versus Gen1 was –20% (95% confidence interval [CI]: –22%, –18%). Bias between concentrations of Abeta42 measured using BioFINDER/Gen1 versus Routine‐Use/Gen2 was –6.3% (95% CI: –8.7%, –3.9%). Cut‐off values for Routine‐Use/Gen2 were adjusted based on this result (). Bias between Routine‐Use versus Roche‐Trial protocols for Abeta42 Gen2 was –22% (95% CI: –24%, –19%). Cut‐off values for Roche‐Trial/Gen2 were adjusted based on this result.ConclusionElecsys CSF Abeta42 results were independently affected by immunoassay generation and pre‐analytical protocol, while tau results were unaffected. Appropriate adjusted cut‐off values have been established.

Clinical profile of an Alzheimer´s disease cohort in the Peruvian population

AbstractBackgroundAmong older Peruvians (over 65‐years) the prevalence of dementia is 7%, with 56% meeting clinical criteria for Alzheimer Disease (AD). Peruvians, are an admixed population with approximately 80% Amerindian ancestral background. We have ascertained a cohort of Alzheimer Disease (AD) cases and cognitively intact controls for genetic studies.MethodAll participants have been recruited since 2019 using community outreach ascertainment strategies and hospital‐based recruitment from Lima, Peru. Cases were assessed by neurologist following NINDS/ADRDA criteria; and completed a comprehensive neurocognitive, neuropsychiatric and functional assessments. Controls were screened using MMSE, Clock drawing test and Pfeffer functional activities questionnaire. IRBs approvals from the participating Peruvian institutions and University of Miami were obtained for this study.ResultA total of 102 AD cases (4 familial cases) and 152 controls were recruited since 2019 to December 2020. For AD cases: age at examination were 76.5±9.09, age at onset were 72.15±8.82, and 63.7% were female, average of 9.9±4.9 year of education. For controls: age at examination were 73.13±6.54, 62.5% were female, average of 11.62±4.41 year of education. Among cases diagnosis was classified as: 62.8% possible AD (two cases screened for Cerebrospinal fluid Abeta42 and tau protein levels) and 37.2% probable AD. Clinical and cognitive assessment profile for cases: MMSE average score was 17.2± 4.9 and Addenbrook’s Cognitive Examination average score was 38.5± 21.7 with memory loss predominance. Based on NPI the most frequent neuropsychiatric symptoms were irritability (51%), delusions (46%) and apathy (45%). Severity of dementia were assessed by CDR (CDR=3 for 33.9%, CDR=2 for 32.3%, CDR=1 for 24.2% and CDR=0.5 for 9.7%). Depressive symptoms were assessed with Geriatric Depression Scale with an average of 4.4±3.5 .ConclusionThe clinical features of the AD cohort in the Peruvian population are consistent with previous reports. There is a tendency of a higher level of education in the control . Among the Peruvian AD cohort, the main neuropsychiatric symptoms are irritability, delusions and apathy consistent with the predominance of moderate to severe dementia. Reference: Marca V. et al. Dissecting the role of Amerindian genetic ancestry and ApoE ε4 allele on Alzheimer disease in an admixed Peruvian population, Neurobiology of Aging, 2020.

Plasma and cerebrospinal fluid ABeta42 for the differential diagnosis of Alzheimer's disease dementia in participants diagnosed with any dementia subtype in a specialist care setting.

Dementia is a syndrome that comprises many differing pathologies, including Alzheimer's disease dementia (ADD), vascular dementia (VaD) and frontotemporal dementia (FTD). People may benefit from knowing the type of dementia they live with, as this could inform prognosis and may allow for tailored treatment. Beta-amyloid (1-42) (ABeta42) is a protein which decreases in both the plasma and cerebrospinal fluid (CSF) of people living with ADD, when compared to people with no dementia. However, it is not clear if changes in ABeta42 are specific to ADD or if they are also seen in other types of dementia. It is possible that ABeta42 could help differentiate ADD from other dementia subtypes. To determine the accuracy of plasma and CSF ABeta42 for distinguishing ADD from other dementia subtypes in people who meet the criteria for a dementia syndrome. We searched MEDLINE, and nine other databases up to 18 February 2020. We checked reference lists of any relevant systematic reviews to identify additional studies. We considered cross-sectional studies that differentiated people with ADD from other dementia subtypes. Eligible studies required measurement of participant plasma or CSF ABeta42 levels and clinical assessment for dementia subtype. Seven review authors working independently screened the titles and abstracts generated by the searches. We collected data on study characteristics and test accuracy. We used the second version of the 'Quality Assessment of Diagnostic Accuracy Studies' (QUADAS-2) tool to assess internal and external validity of results. We extracted data into 2 x 2 tables, cross-tabulating index test results (ABeta42) with the reference standard (diagnostic criteria for each dementia subtype). We performed meta-analyses using bivariate, random-effects models. We calculated pooled estimates of sensitivity, specificity, positive predictive values, positive and negative likelihood ratios, and corresponding 95% confidence intervals (CIs). In the primary analysis, we assessed accuracy of plasma or CSF ABeta42 for distinguishing ADD from other mixed dementia types (non-ADD). We then assessed accuracy of ABeta42 for differentiating ADD from specific dementia types: VaD, FTD, dementia with Lewy bodies (DLB), alcohol-related cognitive disorder (ARCD), Creutzfeldt-Jakob disease (CJD) and normal pressure hydrocephalus (NPH). To determine test-positive cases, we used the ABeta42 thresholds employed in the respective primary studies. We then performed sensitivity analyses restricted to those studies that used common thresholds for ABeta42. We identified 39 studies (5000 participants) that used CSF ABeta42 levels to differentiate ADD from other subtypes of dementia. No studies of plasma ABeta42 met the inclusion criteria. No studies were rated as low risk of bias across all QUADAS-2 domains. High risk of bias was found predominantly in the domains of patient selection (28 studies) and index test (25 studies). The pooled estimates for differentiating ADD from other dementia subtypes were as follows: ADD from non-ADD: sensitivity 79% (95% CI 0.73 to 0.85), specificity 60% (95% CI 0.52 to 0.67), 13 studies, 1704 participants, 880 participants with ADD; ADD from VaD: sensitivity 79% (95% CI 0.75 to 0.83), specificity 69% (95% CI 0.55 to 0.81), 11 studies, 1151 participants, 941 participants with ADD; ADD from FTD: sensitivity 85% (95% CI 0.79 to 0.89), specificity 72% (95% CI 0.55 to 0.84), 17 studies, 1948 participants, 1371 participants with ADD; ADD from DLB: sensitivity 76% (95% CI 0.69 to 0.82), specificity 67% (95% CI 0.52 to 0.79), nine studies, 1929 participants, 1521 participants with ADD. Across all dementia subtypes, sensitivity was greater than specificity, and the balance of sensitivity and specificity was dependent on the threshold used to define test positivity. Our review indicates that measuring ABeta42 levels in CSF may help differentiate ADD from other dementia subtypes, but the test is imperfect and tends to misdiagnose those with non-ADD as having ADD. We would caution against the use of CSF ABeta42 alone for dementia classification. However, ABeta42 may have value as an adjunct to a full clinical assessment, to aid dementia diagnosis.

Two Alzheimer's Immunotherapy Drugs Fail in Four Studies

Two Alzheimer's Immunotherapy Drugs Fail in Four Studies

Plasma and Cerebrospinal fluid (CSF) Abeta42 for the differential diagnosis of Alzheimer's disease dementia in participants diagnosed with any dementia subtype in a specialist care setting

Background Dementia is a syndrome that comprises many differing pathologies, including Alzheimer's disease dementia (ADD), vascular dementia (VaD) and frontotemporal dementia (FTD). People may benefit from knowing the type of dementia they live with, as this could inform prognosis and may allow for tailored treatment. Beta-amyloid (1-42) (ABeta42) is a protein which decreases in both the plasma and cerebrospinal fluid (CSF) of people living with ADD, when compared to people with no dementia. However, it is not clear if changes in ABeta42 are specific to ADD or if they are also seen in other types of dementia. It is possible that ABeta42 could help differentiate ADD from other dementia subtypes. Objectives To determine the accuracy of plasma and CSF ABeta42 for distinguishing ADD from other dementia subtypes in people who meet the criteria for a dementia syndrome. Search methods We searched MEDLINE, and nine other databases up to 18 February 2020. We checked reference lists of any relevant systematic reviews to identify additional studies. Selection criteria We considered cross-sectional studies that differentiated people with ADD from other dementia subtypes. Eligible studies required measurement of participant plasma or CSF ABeta42 levels and clinical assessment for dementia subtype. Data collection and analysis Seven review authors working independently screened the titles and abstracts generated by the searches. We collected data on study characteristics and test accuracy. We used the second version of the 'Quality Assessment of Diagnostic Accuracy Studies' (QUADAS-2) tool to assess internal and external validity of results. We extracted data into 2 x 2 tables, cross-tabulating index test results (ABeta42) with the reference standard (diagnostic criteria for each dementia subtype). We performed meta-analyses using bivariate, random-effects models. We calculated pooled estimates of sensitivity, specificity, positive predictive values, positive and negative likelihood ratios, and corresponding 95% confidence intervals (CIs). In the primary analysis, we assessed accuracy of plasma or CSF ABeta42 for distinguishing ADD from other mixed dementia types (non-ADD). We then assessed accuracy of ABeta42 for differentiating ADD from specific dementia types: VaD, FTD, dementia with Lewy bodies (DLB), alcohol-related cognitive disorder (ARCD), Creutzfeldt-Jakob disease (CJD) and normal pressure hydrocephalus (NPH). To determine test-positive cases, we used the ABeta42 thresholds employed in the respective primary studies. We then performed sensitivity analyses restricted to those studies that used common thresholds for ABeta42. Main results We identified 39 studies (5000 participants) that used CSF ABeta42 levels to differentiate ADD from other subtypes of dementia. No studies of plasma ABeta42 met the inclusion criteria. No studies were rated as low risk of bias across all QUADAS-2 domains. High risk of bias was found predominantly in the domains of patient selection (28 studies) and index test (25 studies). The pooled estimates for differentiating ADD from other dementia subtypes were as follows: ADD from non-ADD: sensitivity 79% (95% CI 0.73 to 0.85), specificity 60% (95% CI 0.52 to 0.67), 13 studies, 1704 participants, 880 participants with ADD; ADD from VaD: sensitivity 79% (95% CI 0.75 to 0.83), specificity 69% (95% CI 0.55 to 0.81), 11 studies, 1151 participants, 941 participants with ADD; ADD from FTD: sensitivity 85% (95% CI 0.79 to 0.89), specificity 72% (95% CI 0.55 to 0.84), 17 studies, 1948 participants, 1371 participants with ADD; ADD from DLB: sensitivity 76% (95% CI 0.69 to 0.82), specificity 67% (95% CI 0.52 to 0.79), nine studies, 1929 participants, 1521 participants with ADD. Across all dementia subtypes, sensitivity was greater than specificity, and the balance of sensitivity and specificity was dependent on the threshold used to define test positivity. Authors' conclusions Our review indicates that measuring ABeta42 levels in CSF may help differentiate ADD from other dementia subtypes, but the test is imperfect and tends to misdiagnose those with non-ADD as having ADD. We would caution against the use of CSF ABeta42 alone for dementia classification. However, ABeta42 may have value as an adjunct to a full clinical assessment, to aid dementia diagnosis.

Use of cerebrospinal fluid biomarker analysis for improving Alzheimer's disease diagnosis in a non-specialized setting.

Low levels of amyloid-beta42 (Abeta42) and high total-tau (t-tau) or phosphorylated-tau (p181-tau) levels in cerebrospinal fluid (CSF) were shown to be characteristic for Alzheimer's disease (AD) patients and for mildly cognitively impaired (MCI) or non-demented individuals who will progress to AD. The goal of this study was to evaluate the benefit of CSF biomarker testing in a setting with no specialized dementia centers, in order to improve the accuracy of AD diagnosis and to identify individuals with incipient AD. Using ELISA assay we analyzed CSF Abeta42, t-tau and p181-tau levels among clinically diagnosed non-demented individuals, AD patients and individuals with uncertain dementia (n=36). CSF cut-off values of low Abeta42 (less than or equal to 530 pg/mL) and high t-tau (less than or equal to 350 pg/mL) or p181-tau (less than or equal to 52 pg/mL) were used to identify individuals with AD/MCI-CSF profile, regardless of clinical diagnosis. APOE genotyping was performed using PCR-RFLP method. In accord with previous studies we detected significantly decreased levels of CSF Abeta42 and increased tau and p181-tau levels in clinically diagnosed AD group vs. non-demented controls. CSF profiling identified individuals with a typical AD/MCI-CSF pattern in clinically referred non-demented group (9 percent) and among patients with uncertain dementia (41.7 percent). APOE epsilon4-allele was associated with the CSF biomarker changes typical for AD. This study shows that in a non-specialized setting CSF biomarker testing may be used as a screening tool for improving the accuracy of AD diagnosis and for predicting individuals with incipient Alzheimer's disease who need to receive further clinical follow-up.

Reviewing reasons for the decreased CSF Abeta42 concentration in Alzheimer

Cerebrospinal fluid (CSF) amyloid beta42 (Abeta42) concentrations are decreased in patients with Alzheimer disease (AD). Consequently, low Abeta42 is considered a positive biomarker for AD. Surprisingly, the mechanisms that underlie the decrease in CSF Abeta42 remain speculative. Better understanding of this biomarker is an essential step to unravel AD pathophysiology and to develop and evaluate treatment. Therefore, we systematically examined the possible reasons for the decreased CSF Abeta42 concentration in AD. Under normal conditions, Abeta42 can be degraded by proteases, taken up by microglia, or cleared from the brain interstitial fluid across the blood brain barrier. Alternatively, it can be transported to the CSF and be cleared from there. Aggregation of Abeta42 appears the most likely cause for the decreased CSF Abeta42 concentration in AD: the aggregated state inhibits Abeta42 from being transported from the ISF to the CSF. Evidence for other possibilities such as a decreased production of Abeta42, an increased proteolytic breakdown or microglial uptake of Abeta42, or an increased clearance of Abeta42 to the blood, is - at best - scarce or even absent.

P4‐453: Genome‐wide association analysis using cerebrospinal fluid Abeta42 levels as an endophenotype for Alzheimer's disease

P4‐453: Genome‐wide association analysis using cerebrospinal fluid Abeta42 levels as an endophenotype for Alzheimer's disease

Regional cerebral glucose metabolism provides a sensitive and specific marker of Alzheimer's disease, frontotemporal dementia and mild cognitive impairment, and correlates with cerebrospinal fluid Abeta42 level decline in cognitively normal subjects

Regional cerebral glucose metabolism provides a sensitive and specific marker of Alzheimer's disease, frontotemporal dementia and mild cognitive impairment, and correlates with cerebrospinal fluid Abeta42 level decline in cognitively normal subjects

Additional Value of CSF Amyloid-β40 Levels in the Differentiation between FTLD and Control Subjects

To determine the additional value of cerebrospinal fluid (CSF)amyloid-beta1-40 (Abeta40) next to amyloid-beta1-42 (beta42), total tau (Tau), and tau phosphorylated at threonine-181 (pTau) to distinguish patients with frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), and controls, we measured CSF levels of Abeta40, Abeta42, pTau, and Tau in 55 patients with FTLD, 60 with AD, and 40 control subjects. Logistic regression was used to identify biomarkers that best distinguished the groups. Additionally, a decision tree (cost=test method; Matlab 7.7) was used to predict diagnosis selecting the best set of biomarkers with the optimal cut-off. Logistic regression showed that Abeta42 and pTau CSF levels provided optimal distinction between AD and FTLD. A combination of Abeta42, Tau, and Abeta40 optimally discriminated FTLD from controls and AD from controls. The decision tree used Abeta42 (cut-off 578 pg/ml) to identify AD (positive predictive value (PPV) 97%), followed by Tau(cut-off 336 pg/ml) to identify FTLD (PPV 67%), and in the last step,Abeta40 (cut-off 10 ng/ml) was used to differentiate controls (PPV68%). Applying CSF Abeta40 levels in the model, the PPV of diagnosis increased to 75% as opposed to 70% when only Abeta42 and Tau were used. CSF Abeta40 levels added to the conventional CSF biomarkers increases the potential to discriminate subjects with dementia from controls. Our findings favor the implementation of CSF Abeta40 in differential diagnosis between FTLD, AD, and control subjects.

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 Abeta42, tau and p-tau(181)). Two categories of biomarkers were identified: (1) analytes that specifically distinguished AD (especially CSF Abeta42 levels) from cognitively normal subjects and other disorders; and (2) analytes altered in multiple diseases (NrCAM, PDGF, C3, IL-1alpha), 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-1alpha, I-309, NrCAM and VEGF) were correlated with the severity of cognitive impairment at CSF collection, and altered levels of IL-1alpha 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.

Cortical Binding of Pittsburgh Compound B, an Endophenotype for Genetic Studies of Alzheimer's Disease

To date, all known Alzheimer's disease genes influence amyloid beta (Abeta). Imaging of Abeta deposition in the human brain using Pittsburgh Compound B (PIB) offers the possibility of using cortical PIB binding as a quantitative endophenotype for genetic studies of late-onset Alzheimer's disease (LOAD). Heritability of Abeta deposition was determined using 82 elderly siblings from 35 families. Correlation with other Abeta related traits was determined using an unrelated sample of 112 individuals. For both samples, apolipoprotein E (APOE) epsilon4 was genotyped and positron emission tomography imaging was performed using the PIB ligand. Mean cortical binding potential (MCBP) was computed from several regions of interest. MCBP has a high heritability (.61, p = .043). Furthermore, 74% of the heritable component cannot be explained by APOE epsilon4 genotype. The unrelated sample reveals that a third of the variance of MCBP cannot be predicted by other biological traits, including cerebrospinal fluid (CSF) amyloid beta 42 (Abeta42) levels. These findings demonstrate that MCBP is a genetic trait and that other more easily measured Abeta related traits such as CSF Abeta42 do not fully explain the variance in MCBP. Thus, MCBP is a useful trait for large-scale genetic studies of LOAD.

Validity of Cerebrospinal Fluid Biomarkers as Endpoints in Early-Phase Clinical Trials for Alzheimer's Disease

A systematic literature review was performed to assess the suitability of cerebrospinal fluid (CSF) levels of protein amyloid-beta42 (Abeta42) and tau as markers to detect the disease-modifying effects of drugs in clinical trials of AD treatments. All databases were searched for observational studies, single-arm clinical trials, and randomized controlled trials involving patients with AD in which CSF Abeta42 and tau were measured. A meta-analytic random-effects model was used to evaluate the mean absolute change in protein concentration over time. Spearman correlation was used to assess the association between change in CSF protein concentration and change in cognitive function. The mean changes per month in observational studies were -0.4 pg/ml/month (95% CI: -1.9 to 1.1) for 8 CSF Abeta42 and 1.5 pg/ml/month (95% CI: 0.1 to 3.0) for 12 CSF tau studies. The correlation coefficients for the relationship between CSF protein concentration and cognition were 0.43 (p = 0.068) for all 18 Abeta42 studies and -0.05 (p = 0.857) for all 18 tau studies. A trend in which CSF Abeta42 decreases and tau protein increases over time was identified in AD patients. CSF Abeta42 and tau concentrations should be used with caution as surrogate endpoints in early-phase clinical trials for AD.

CSF Biomarkers and Incipient Alzheimer Disease in Patients With Mild Cognitive Impairment

Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted. To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (Abeta42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia. Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Abeta42, T-tau, and P-tau for identifying incipient AD. During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Abeta42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Abeta42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Abeta42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for Abeta42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%. This multicenter study found that CSF Abeta42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.

A surrogate marker for Aβ42 production in the CNS

Alzheimer's disease (AD) is the most common cause of dementia. There are currently no effective treatments that may delay the onset, slow the progression or prevent the disease. Unless such treatments are developed, the number of AD cases is expected to double in the next 30 years. There is overwhelming genetic and biochemical evidence that the aggregation and buildup of the amyloid-β (Aβ) peptide plays a critical role in AD pathogenesis.

Medial temporal lobe atrophy increases the specificity of cerebrospinal fluid biomarkers in alzheimer disease with minor cerebrovascular changes

Although cerebrospinal fluid (CSF) biomarkers and medial temporal lobe atrophy (MTA) contribute to the diagnosis of Alzheimer disease (AD), they may not be specific. Relatively little is known about how they correlate with each other. To identify the validity of the radiological linear measurements of brain atrophy in AD diagnosis by examining the correlation with CSF biomarkers and by examining if specificity could be improved in classification of AD from controls, when the linear measurements are combined with the CSF biomarkers. 59 controls (20 male/39 female, age 73+/-8 years), 162 pure AD patients (49/113, 74+/-7 years), and 86 AD patients with minor cerebrovascular changes (CVC) (31/55, 77+/-5 years), aged between 52 and 94 years, were recruited from the Malmo Alzheimer Study. AD patients were subgrouped into "pure AD" and "AD + CVC" in order to clarify the possible influence of CVC on atrophy or CSF biomarkers in AD patients. Abeta42, T-tau, and P-tau in CSF were examined. Computed tomography (CT) linear measurements were performed, which included temporal horn ratio and suprasellar cistern ratio that reflect MTA. Compared with the 14 significant correlations between the CT measurements and three CSF biomarkers in the pure AD group, there was only one significant correlation in the AD + CVC group and one in the control group. In particular, P-tau correlates with temporal horn ratio only in pure AD. When the CT measurements were added with CSF biomarkers as independent variables in discriminant analysis, the percentage of correct classification of AD + CVC from controls increased from 79.5% (only CSF biomarkers) to 84.6% (combined CT measurements with CSF biomarkers). However, little was changed in the pure AD group. P-tau correlates with the linear CT measure of MTA only in pure AD without CVC. Combined with the measure of MTA, the specificity of CSF biomarkers can be increased, but only in AD + CVC. The linear measurements of MTA are of value in AD diagnosis.

Cerebrospinal Fluid β-Amyloid 42 and Tau Proteins as Biomarkers of Alzheimer-Type Pathologic Changes in the Brain

There is a clear need to develop an objective diagnostic test for Alzheimer disease (AD). Changes in the levels of cerebrospinal fluid (CSF) tau protein and beta-amyloid 42 (Abeta42) peptide in patients with AD have been well documented, but the relationship between these biomarkers and neuropathologic changes in the brain is not established. To study the relationship between antemortem CSF biomarker levels and Alzheimer-type neuropathologic changes in the brain. Cross-sectional study to correlate levels of CSF Abeta42, total tau, and phosphorylated tau protein with neuropathologic changes in the brain. Academic research. Patients The study included 123 patients (79 with clinically diagnosed AD, 29 with other dementia, and 15 with other neurologic disease). All underwent clinical evaluation and provided antemortem lumbar CSF samples, and neuropathologic data were collected from September 11, 1990, to March 13, 2003, in the Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland. Levels of CSF Abeta42, total tau, and phosphorylated tau protein were measured using standard commercial immunoassays. Neuropathologic evaluations included the classic silver impregnation method and immunohistochemistry for Abeta, hyperphosphorylated tau, and alpha-synuclein. Cerebrospinal fluid Abeta42 and tau protein levels were related to amyloid load and the presence of neurofibrillary pathologic abnormalities in the brain. Cerebrospinal fluid Abeta42 level correlated inversely with total Abeta load in the brain, and CSF tau level correlated with results of immunohistochemistry for hyperphosphorylated tau and with the presence of neocortical neurofibrillary tangles. In multivariate logistic regression analysis, the number of neuritic plaques in the brain remained a significant predictor of decreased CSF Abeta42 level and of increased CSF tau level. Based on the ratio of phosphorylated tau level to Abeta42 level, sensitivity was 91.6%, and specificity was 85.7%, with an overall accuracy of 90.2% for the presence of pathologic neuritic plaque in the brain. Cerebrospinal fluid Abeta42 and tau proteins are biomarkers of AD-associated pathologic changes in the brain. The combination of abnormally low CSF Abeta42 level and abnormally high CSF tau level predicted the presence of AD pathologic features with high accuracy. This combination assay may be helpful in diagnosing the presence of AD pathologic changes in the brain.

Amyloid-targeted therapeutics in Alzheimer's disease: Use of human albumin in plasma exchange as a novel approach for abeta mobilization

A clinical investigation program was carried out to replace endogenous albumin of patients with mild to moderate Alzheimer's disease (AD) with 5% Human Albumin Grifols(R) through a plasma exchange (PE) schedule, in order to alter the dynamic equilibrium between albumin-bound Abeta in plasma and Abeta in cerebrospinal fluid. In a pilot proof-of-concept study, 7 patients underwent 6 PE in 3 weeks and 1 year of follow-up. Plasma Abeta determinations demonstrated a variation pattern in levels in relation with the PEs. Cognitive status scores (MMSE and ADAS-Cog) were more stable than expected. In a phase II clinical trial, 29 patients were randomized into PEtreated and control groups with 1 year follow-up. Interim results point toward the occurrence of Abeta40 mobilization in the PE-treated patients, who scored better in cognitive tests (differences at 9 months: 2.5 in MMSE and 5.5 in ADAS-cog). These results suggest that a PE program with 5% Human Albumin Grifols may have a promising role in the treatment of mild to moderate AD.

A Technique for Serial Collection of Cerebrospinal Fluid from the Cisterna Magna in Mouse

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is pathologically characterized by extracellular deposition of β-amyloid peptide (Aβ) and intraneuronal accumulation of hyperphosphorylated tau protein. Because cerebrospinal fluid (CSF) is in direct contact with the extracellular space of the brain, it provides a reflection of the biochemical changes in the brain in response to pathological processes. CSF from AD patients shows a decrease in the 42 amino-acid form of Aβ (Aβ42), and increases in total tau and hyperphosphorylated tau, though the mechanisms responsible for these changes are still not fully understood. Transgenic (Tg) mouse models of AD provide an excellent opportunity to investigate how and why Aβ or tau levels in CSF change as the disease progresses. Here, we demonstrate a refined cisterna magna puncture technique for CSF sampling from the mouse. This extremely gentle sampling technique allows serial CSF samples to be obtained from the same mouse at 2-3 month intervals which greatly minimizes the confounding effect of between-mouse variability in Aβ or tau levels, making it possible to detect subtle alterations over time. In combination with Aβ and tau ELISA, this technique will be useful for studies designed to investigate the relationship between the levels of CSF Aβ42 and tau, and their metabolism in the brain in AD mouse models. Studies in Tg mice could provide important validation as to the potential of CSF Aβ or tau levels to be used as biological markers for monitoring disease progression, and to monitor the effect of therapeutic interventions. As the mice can be sacrificed and the brains can be examined for biochemical or histological changes, the mechanisms underlying the CSF changes can be better assessed. These data are likely to be informative for interpretation of human AD CSF changes.

CSF levels of β‐amyloid 1‐42, tau and phosphorylated tau protein in CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can be considered a useful model of pure subcortical vascular dementia (SVD) because it occurs in young adults, unlikely to have concomitant age- and Alzheimer's disease (AD)-related pathology. In patients with CADASIL we evaluated the cerebrospinal fluid (CSF) levels of beta-amyloid 1-42 (Abeta42), total tau protein (t-tau) and phosphorylated tau protein (p-tau), which are well-accepted biomarkers of AD. The CSF Abeta42, t-tau and p-tau levels were determined with Innotest beta-amyloid 1-42, Innotest hTAU-Ag and Innotest Phospho-tau 181p sandwich enzyme-linked immunoassay, in 10 CADASIL patients and 17 healthy age-matched subjects. A case-control statistical analysis was carried out. CSF Abeta42 levels were significantly lower in CADASIL patients than in controls, whereas CSF t-tau and p-tau levels did not differ between the two groups. The pattern found in CADASIL patients is similar to that reported in those with sporadic SVD, suggesting that decreased CSF Abeta42 might be related to the subcortical vascular lesions in the white matter.