Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort.

OBJECTIVE: To determine how amyloid ß 42 (Aß42), total tau (t-tau), and phosphorylated tau (p-tau) levels in CSF behave in a large cohort of patients with different types of dementia. METHODS: Baseline CSF was collected from 512 patients with Alzheimer disease (AD) and 272 patients with other types of dementia (OD), 135 patients with a psychiatric disorder (PSY), and 275 patients with subjective memory complaints (SMC). Aß42, t-tau, and p-tau (at amino acid 181) were measured in CSF by ELISA. Autopsy was obtained in a subgroup of 17 patients. RESULTS: A correct classification of patients with AD (92%) and patients with OD (66%) was accomplished when CSF Aß42 and p-tau were combined. Patients with progressive supranuclear palsy had normal CSF biomarker values in 90%. Patients with Creutzfeldt-Jakob disease demonstrated an extremely high CSF t-tau at a relatively normal CSF p-tau. CSF AD biomarker profile was seen in 47% of patients with dementia with Lewy bodies (DLB), 38% in corticobasal degeneration (CBD), and almost 30% in frontotemporal lobar degeneration (FTLD) and vascular dementia (VaD). PSY and SMC patients had normal CSF biomarkers in 91% and 88%. Older patients are more likely to have a CSF AD profile. Concordance between clinical and neuropathologic diagnosis was 85%. CSF markers reflected neuropathology in 94%. CONCLUSION: CSF Aß42, t-tau, and p-tau are useful in differential dementia diagnosis. However, in DLB, FTLD, VaD, and CBD, a substantial group exhibit a CSF AD biomarker profile, which requires more autopsy confirmation in the future.

Batch prepared protein standards for cerebrospinal fluid (CSF) biomarkers for neurodegeneration.

Immuno-assays are increasingly used for quantification of protein biomarkers for neurodegeneration. It has been proposed to use such cerebrospinal fluid (CSF) protein biomarkers as diagnostic tests for Alzheimer's disease. In two recent world-wide validation studies we found the analytical accuracy to be poor (inter-laboratory coefficient of variation, CV>10%) for CSF tau protein, CSF phospho-tau protein, CSF amyloid beta protein and the CSF neurofilament light chain protein. Retrospectively we suspected that the lack of preparation of accurate and consistent protein standards may have been one reason for the poor inter-laboratory CV. Here we confirm this hypothesis prospectively under standardised and optimised conditions. The CVs for CSF tau, CSF phospho-tau and CSF amyloid beta of individually prepared standards are 8%, 12% and 12% compared to significantly lower CVs for batch prepared standards (5%, 8%, 7%, respectively, p<0.05). This issue will need to be solved in order to ensure that the attempts to include these CSF protein biomarkers either as a diagnostic tool or a secondary outcome measure for treatment trials will be successful.

New research criteria for the diagnosis of Alzheimer's disease applied in a memory clinic population.

BACKGROUND: In the newly proposed research criteria for Alzheimer's disease (AD), patients are defined as having memory dysfunction in addition to either hippocampal atrophy or an abnormal cerebrospinal fluid (CSF) profile. This study applies the criteria in a memory clinic population, using clinical criteria as the reference criterion. METHODS: 138 AD patients, 145 nondemented subjects, 78 patients with other dementias and 91 patients with mild cognitive impairment (MCI) were included. Dichotomized medial temporal lobe atrophy (MTA) score on MRI and dichotomized CSF profiles (based on beta-amyloid1-42, tau and phosphorylated tau at threonine 181 levels) were used in combination with an episodic memory test to assess sensitivity, specificity and likelihood ratios (LR) of the newly proposed criteria and their components separately. RESULTS: We found specificities of 95 and 49% for comparison with nondemented subjects and other demented patients, respectively, with a sensitivity of 86% for AD. Specificity was highest (100 and 77%, respectively, LR+ = 48) when both MTA score and CSF profile were abnormal in addition to the episodic memory test, at the cost of a low sensitivity (48%). CONCLUSION: The newly proposed research criteria for AD yield a good specificity for comparison with nondemented subjects. When the type of dementia is clinically doubted, however, at least two supportive features should be considered (i.e. abnormal MTA score and CSF profile) in addition to memory impairment as core diagnostic criterion.

An unbiased, staged, multicentre, validation strategy for Alzheimer's disease CSF tau levels.

Newly proposed diagnostic criteria for Alzheimer's disease include cerebrospinal fluid (CSF) tau levels as one core supportive criterion. The published high sensitivity and specificity figures for CSF tau levels in Alzheimer's disease are offset by the large range of proposed cutoff values (9.6 pg/mL to 1140 pg/mL). This study aimed to provide guidance on how to establish, validate and audit CSF tau cutoff values using an unbiased, two-stage multicentre strategy. Both receiver operator characteristics (ROC) optimised and population-based cutoff values were calculated on a pilot dataset (n=99), validated in a large dataset (n=560) and then compared to the literature. The data suggest using an ROC optimised cutoff level of 323+/-51.7 pg/mL allowing for the published inter-laboratory coefficient of variation of 16%. This cutoff level was confirmed in a prospective audit (n=100). As demand for CSF tau levels will increase globally, the accuracy of local CSF hTau cutoff levels can be compared against this benchmark.

Baseline CSF p-tau levels independently predict progression of hippocampal atrophy in Alzheimer disease.

OBJECTIVE: To investigate whether baseline CSF biomarkers are associated with hippocampal atrophy rate as a measure of disease progression in patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI), and controls, controlling for baseline neuropsychological and MRI findings. METHODS: We assessed data from 31 patients with AD, 25 patients with MCI, and 19 controls (mean age 68 +/- 8 years; 39 [52%] female) who visited our memory clinic and had received serial MRI scanning (scan interval 1.7 +/- 0.7 years). At baseline, CSF biomarkers (amyloid beta 1-42, tau, and tau phosphorylated at threonine 181 [p-tau]) were obtained, as well as neuropsychological data. Baseline MRI scans were assessed using visual rating scales for medial temporal lobe atrophy (MTA), global cortical atrophy, and white matter hyperintensities. Hippocampal atrophy rates were estimated using regional nonlinear "fluid" registration of follow-up scan to baseline scan. RESULTS: Stepwise multiple linear regression, adjusted for age and sex, showed that increased CSF p-tau levels (beta [standard error]: -0.79 [0.35]) at baseline was independently associated with higher subsequent hippocampal atrophy rates (p < 0.05), together with poorer memory performance (0.09 [0.04]) and more severe MTA (-0.60 [0.21]). The association of memory function with hippocampal atrophy rate was explained by the link with diagnosis, because it disappeared from the model after we additionally corrected for diagnosis. CONCLUSIONS: Baseline CSF levels of tau phosphorylated at threonine 181 are independently associated with subsequent disease progression, as reflected by hippocampal atrophy rate. This effect is independent of baseline neuropsychological and MRI predictors. Our results imply that predicting disease progression can best be achieved by combining information from different modalities.

A worldwide multicentre comparison of assays for cerebrospinal fluid biomarkers in Alzheimer's disease.

BACKGROUND: Different cerebrospinal fluid (CSF) amyloid-beta 1-42 (Abeta(1-42)), total Tau (Tau) and Tau phosphorylated at threonine 181 (P-Tau) levels are reported, but currently there is a lack of quality control programmes. The aim of this study was to compare the measurements of these CSF biomarkers, between and within centres. METHODS: Three CSF-pool samples were distributed to 13 laboratories in 2004 and the same samples were again distributed to 18 laboratories in 2008. In 2004 six laboratories measured Abeta(1-42), Tau and P-Tau and seven laboratories measured one or two of these marker(s) by enzyme-linked immunosorbent assays (ELISAs). In 2008, 12 laboratories measured all three markers, three laboratories measured one or two marker(s) by ELISAs and three laboratories measured the markers by Luminex. RESULTS: In 2004, the ELISA intercentre coefficients of variance (interCV) were 31%, 21% and 13% for Abeta(1-42), Tau and P-Tau, respectively. These were 37%, 16% and 15%, respectively, in 2008. When we restricted the analysis to the Innotest (N = 13) for Abeta(1-42), lower interCV were calculated (22%). The centres that participated in both years (N = 9) showed interCVs of 21%, 15% and 9% and intra-centre coefficients (intraCV) of variance of 25%,18% and 7% in 2008. CONCLUSIONS: The highest variability was found for Abeta(1-42). The variabilities for Tau and P-Tau were lower in both years. The centres that participated in both years showed a high intraCV comparable to their interCV, indicating that there is not only a high variation between but also within centres. Besides a uniform standardization of (pre)analytical procedures, the same assay should be used to decrease the inter/intracentre variation.

CSF biomarkers in relationship to cognitive profiles in Alzheimer disease.

OBJECTIVE: To investigate the relationship between CSF biomarkers and cognitive profiles in Alzheimer disease (AD). METHODS: We included 177 patients with AD. Digit Span, Visual Association Test (VAT), VAT object naming, Trail Making Test (TMT), and category fluency were used to assess cognitive functions. Disease severity was assessed using Mini-Mental State Examination; functional impairment was rated by Clinical Dementia Rating. In CSF, levels of amyloid-beta 1-42 (Abeta(1-42)), tau, and tau phosphorylated at threonine 181 (p-tau) were measured. K-means cluster analysis was performed with the three biomarkers to obtain three clusters. Multivariate analysis of variance for repeated measures was performed with CSF cluster as between-subjects factor, neuropsychological z scores as within-subjects variable, and age, sex, and education as covariates. RESULTS: Cluster 1 consisted of 88 patients (49%) with relatively high levels of Abeta(1-42) and low levels of tau and p-tau. Cluster 2 contained 72 patients (41%) with relatively low levels of Abeta(1-42) and high levels of tau and p-tau. Cluster 3 was made up of 17 patients (10%) with low levels of Abeta(1-42) and very high levels of tau and p-tau. No differences between clusters on age, sex, education, APOE genotype, disease duration, functional impairment, or disease severity were found. Patients in cluster 3 performed worse on VAT, TMT-A and -B, and fluency. CONCLUSIONS: Clusters of CSF biomarker levels are related to cognitive profiles in Alzheimer disease. A subgroup of patients with extremely high CSF levels of tau and tau phosphorylated at threonine 181 shows a distinct cognitive profile with more severe impairment of memory, mental speed, and executive functions, which cannot be explained by disease severity.

Assessment of cognition in Parkinson's disease.

OBJECTIVE: To develop a short, practical instrument that is sensitive to the specific cognitive deficits in Parkinson's disease (PD) for comparing groups in research situations and for assessing change in cognitive functioning over time. METHODS: A literature search was conducted to identify the most frequently affected cognitive domains in PD and to select candidate items for the initial scale. This scale was tested in 85 patients and 75 age-, education-, and sex-matched control subjects. Items that met predefined criteria for data quality, reproducibility, and discriminative properties were included in the final scale. RESULTS: The final scale, the SCOPA-COG (SCales for Outcomes of PArkinson's disease-cognition), consists of 10 items with a maximum score of 43, with higher scores reflecting better performance. The test-retest reliability of the total score was 0.78 (intraclass correlation coefficient) and ranged from 0.40 to 0.75 for individual items (weighted kappa). Cronbach's alpha was 0.83. Construct validity of the scale was supported by the expected correlations with the CAMCOG (Cambridge Cognitive Examination) and the Mini-Mental State Examination (MMSE) and by differences found between groups of participants classified by dementia status and between patients grouped by disease severity. The scale showed a clear trend toward lower cognition scores for patients with more advanced PD. The coefficient of variation of the SCOPA-COG was higher than that of the CAMCOG or the MMSE, indicating a better ability to detect differences between individuals. CONCLUSION: The SCOPA-COG is a short, reliable, and valid instrument that is sensitive to the specific cognitive deficits in PD.