This manuscript compares 5 commonly used CSF biomarkers in the prediction of transition between MCI and AD.  The biomarkers studied total tau, pTau231, Ab42/Ab40 ratio, and isoprostanes.  pTau231 and total tau showed comparable accuracy in predicting MCI to AD progression (83%) followed by isoprostanes (74%) and Ab42/Ab40 ratios (69%).  However, if sensitivity was held at 82%, pTau 231 had the best specificity and accuracy (80% and 80%) while the specificity and accuracy of T-tau was 70% and 74%, isoprostane was 61% and 68% and Ab42/Ab40 was 63% and 69% respectively.  Under these requirements only pTau231 exceeds the 80% threshold of sensitivity and specificity as recommended by the consensus report of the NIA Working Group on Biological Measures.

MCI (mild cognitive impairment) is a major risk factor for AD.  Predicting cognitive decline in patients with MCI is important because of upcoming disease-modifying antidementia drugs. This longitudinal study of 77 patients with MCI investigated whether levels of ptau-231 in CSF correlate with the progression of cognitive decline.  Included in the study were 55 AD subjects and 30 healthy controls. For comparative purposes, total tau was also investigated.

Of the 77 MCI patients, 39 cognitively deteriorated over time. Ptau-231 levels were higher in patients with MCI who converted to AD than in the nonconverters.  Furthermore, the higher the baseline levels of ptau 231 were, the more rapidly the patient declined as measured by point loss in the MMSE score. No differences were found for total tau levels in the MCI patients other than their baseline level of total tau was elevated over healthy controls, as were ptau-231 levels.

This study was designed to investigate the ability to use CSF ptau-231 levels to distinguish patients with AD from control subjects and from patients with other dementias.  CSF from 192 patients with a clinical diagnosis of AD, frontotemporal dementia, vascular dementia, Lewy body dementia, other neurological disorders and healthy controls were analyzed in the ptau-231 test.  Overall, the assay had sensitivity level of 90.2% and specificity of 80%.  The same patient samples analyzed for total tau gave an overall sensitivity of 81.3% and a specificity of 68.5%.  Clearly the ptau-231 assay is superior to the total tau assay.  Additionally, the ptau-231 assay results fulfill the core criteria of a useful biomarker of AD as outlined by the consensus report of the Working Group on Molecular and Biochemical Markers of AD.

This study reports on the ability of the CSF assay to distinguish between Alzheimer's disease and major depression.  The patient population consisted of 34 individuals with depression, 64 probable AD, 17 possible AD and 21 healthy control individuals. Sensitivity was calculated at 92% with a specificity of 85%.

A comparison of the ptau-231, ptau-181 and ptau-199 assays in predicting the rate of cognitive decline in MCI subjects.  All three assays were correlated significantly with cognitive decline, with the ptau-231 and ptau-181 assays having superior performance.  This study consisted of 59 patients with MCI and 23 healthy controls.

This study investigated the correlation between the apolipoprotein E e4 allele (apoE  e4) and the levels of ptau-231 in 71 AD patients, 29 healthy controls, and 31 individuals originally diagnosed with MCI that subsequently converted to AD. The presence of 1 or more apoE e4 alleles is a major risk factor for Alzheimer’s disease although by itself, this genetic information is not diagnostic. In MCI, ptau-231 levels were higher in those individuals that had the apoE e4 allele. This indicates that the potential effect of apoE e4 on disease onset also results in higher ptau-231 levels, which is a biomarker for AD.

This study demonstrates that the levels of CSF ptau-231 taken while the patient was living correlates with the neurofibrillary pathology observed in the brain upon autopsy. This study consisted of 26 autopsy confirmed AD patients.

This study examined the potential diagnostic value of the ptau-231 assay to differentiate Creutzfeldt-Jakob disease (CJD), a very rare brain disorder in humans,  from AD (note: CJD is the human form of what is popularly called in cattle, Mad Cow Disease).  When the ptau-231/total tau ratio was used, 95% of the cases were correctly identified, however p-tau-231 alone had less diagnostic value.  The reason for this is that ptau-231 is a specific marker for AD. As reported in this paper and other articles, up to 19% of CJD patients also have underlying AD pathology when examined by autopsy, close to the 23% reported here that have higher levels of ptau-231 and are presumed to have AD pathology. This study involved CSF from 21 patients with CJD, 37 patients with AD, and 10 healthy controls.

This is a short note to the editor that  describes the finding that CSF pTau181 measured using the  Innogenetics assay does not correlated to scores of neurofibrillary tangles (NFTs) and neuritic plaques (NP ) found in brain at autopsy.  Furthermore, CSF pTau181 is not correlated with levels of pTau181 measured in brain homogenates.  This is in contrast to our recent report in Brain that positive correlations were found for CSFpTau231 in the same study group, on the same material, applying the same statistical analyses.  In this report CSF pTau231 concentrations were correlated  with scores of  NFTs, NP’s in the frontal cortex and the amount of pTau 231 measured in brain homogenates from the same autopsy brains.

A one year longitudinal study of 8 MCI patients and 10 controls demonstrates that the ptau-231 levels increase in MCI with time after correcting for change in brain ventricular volumes (which increase in size as the disease progresses) as measured by MRI.

This paper documents efforts to use MRI and CSF biomarkers to detect clinically the earliest changes in the brain due to AD. Since changes in brain size (atrophy or the decreasing size of brain areas) detected by MRI are not specific for AD, the use of CSF biomarkers in combination with brain imaging is utilized to improve the diagnostic specificity.  In this ongoing study, the results show that CSF ptau-231 levels are highly correlated with atrophy in the brain as observed by MRI.  This  combination of methods leads to an early and more specific diagnosis of AD and also validates the ptau-231 as a biomarker that is indicative of changes in the brain. This study involved longitudinal analysis of 45 aged cognitively normal individuals at risk for developing AD.  During the study, 13 of the individuals showed cognitive decline and progressed to MCI.

The study reported here is a 2-year longitudinal study of MCI patients and normal controls examining MRI in conjunction with CSF biomarkers. The study consisted of 9 normal elderly volunteers and seven MCI patients.   Patients were given MRI scans and CSF taps for biomarkers at the beginning of the study and during follow-up. ptau-231 levels were elevated in the MCI group relative to the normal group, and it what demonstrated that there was a relationship between hippocampal volume loss and elevated CSF ptau-231 indicating that ptau-231 in the CSF is a measure of loss of neurons involved in AD.   It was also demonstrated that when using a common memory examination test called the “delayed paragraph recall task” to track memory deficit in combination with ptau-231 the overall diagnostic accuracy of using the “delayed recall” test alone (63%) was increased to 88% with the addition of ptau-231.

This is a review article that summarizes the use of MRI, FDG-PET, and CSF markers in the diagnosis of AD and in identifying subjects with mild cognitive impairment.  The conclusion of the paper is that the combined use of conventional imaging (MRI or FDG-PET) with CSF biomarkers, such as ptau-231, contributes to the early and specific diagnosis of AD.

This paper reports the results of an international multicenter study to assess the accuracy of pTau-231 for the prediction of conversion from MCI to AD during a short-term observation interval. Levels of pTau-231 were a significant predictor of conversion to AD within a clinically useful time period of 1.5 years.  An accuracy of 81% was achieved during the short time interval examined in this study and meets the consensus criterion of an ideal biomarker for AD.  The results of this validation study demonstrate the feasibility of using pTau-231 for the early detection of AD in patients with mild cognitive impairment.

This manuscript describes CSF pTau231, isoprostane and Ab42/Ab40 levels in normal individuals and how the levels change with age and the presence of the ApoE4 allele.

This is an abstract of a poster presented at the European CSF symposium in 2000 by Harald Hampel.  The small study presented compares CSF biomarkers total tau, soluble gp130, neuronal thread protein, and ptau-231 in AD patients vs. healthy controls.  Of the biomarkers reported here, ptau-231 showed the best performance (100% sensitivity, 91.7% specificity).  Furthermore, levels of ptau-231 were correlated with AD progression and MCI individuals had elevated levels of ptau-231 indicative of AD.  It was concluded that ptau-231 might serve as a biomarker in the early detection of AD and in following disease progression in subjects at risk and in AD patients.

This paper documents a small study to determine if CSF ptau-231 can be used as a marker of AD progression.  Up to 7 longitudinal spinal taps were performed on 17 patients with probable AD that were not being treated with acetylcholinesterase inhibitors.  For baseline comparisons, 12 age and gender matched healthy controls were included.  At baseline, both total tau and ptau-231 were significantly elevated in AD patients over healthy controls.  Longitudinally, ptau-231 levels decreased linearly with time in AD patients, however the level of total tau did not change.  Furthermore, the rate of change of ptau-231 was correlated with the MMSE score at baseline, with a more pronounced rate of decline with advanced cognitive impairment.  This did not occur for total tau.  Collectively, the data indicates that ptau-231 can be used to monitor AD progression.  Such a marker would be particularly useful to evaluate therapeutic interventions in disease modifying drug trials.

This study compares the performance of the ptau-231 assay with Innogenetics ptau-181 assay and Mitsubishi’s ptau-199 assay. The patient population consisted of 166 patients with a clinical diagnosis of AD, frontotemporal dementia (FTD), Lewy body dementia or vascular dementia and 45 nondemented controls.  To enable comparisons between the three assays sensitivity was set at 85% and the specificity of each assay was assessed.  When comparing AD samples to non-AD samples as a group, the APNS assay had a specificity of 85%, the Innogenetics assay had a specificity of 81% and the Mitsubishi assay had specificity between 61-72%.  When broken down by disease state (i.e. AD versus a specific type of dementia) the APNS assay demonstrated higher levels of sensitivity, especially when the AD vs. FTD catagory was analyzed, with the APNS assay having a sensitivity of 92%, while the sensitivities of the Innogenetics assay and the Mitsubishi assay were 79% and 42-54% respectively.

Levels of the p-tau231 biomarker in CSF were shown do correlate with the reduction of hippocampal volumes as measured by MRI.  These findings demonstrate that levels of ptau-231 may be used to predict progression of brain atrophy in patients with Alzheimer’s disease and further validates the use of ptau 231 as a biochemical marker of pathologic changes that
occur in AD.  This study involved MRI and CSF analysis on 22 patients with AD.

This is the first publication on the APNS CSF assay.  The first part of the paper describes the specificity of the antibodies (Tau-1, CP27, and CP9) as well as describing in detail the laboratory method and reagents used in the assay.  The second part of the paper documents a study which examined the ability of the assay to discriminate between AD and non-AD patients. CSF from 27 AD and 31 non-AD patients were analyzed with a resulting sensitivity of 85% and a specificity of 97%.

The results of this study suggest that the combination of FDG-PET and CSF measures may be sensitive for detection of a preclinical AD state in individuals at risk for future cognitive impairment.