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.

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.

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.

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.