These neurobiological measures appear to relate closely to pathophysiological, neuropathological, and clinical data, such as hyperphosphorylation of tau, abeta metabolism, lipid peroxidation, pattern and rate of atrophy, loss of neuronal integrity, functional and cognitive decline, as well as risk of future decline. On the neurochemical level, CSF concentration of Aβ42, tau, and Ptau can distinguish subjects with MCI who are likely to progress to AD. They also show Mdm2 high throughput screening preclinical alterations Inhibitors,research,lifescience,medical that predict later development of

early AD symptoms. Studies on plasma Aβ are not entirely consistent, but recent findings suggest that decreased plasma Aβ42 relative to Aβ40 may increase the risk of AD. Increased production of Aβ in aging is suggested by elevation of BACE-1 protein and enzyme activity in the brain and CSF of subjects with MCI. CSF tau and P-tau are increased in MCI as well, and show predictive value, Other biomarkers may indicate components of a Inhibitors,research,lifescience,medical cascade initiated by Aβ, such as oxidative stress

or inflammation. Other interesting Inhibitors,research,lifescience,medical novel marker candidates derived from blood are being currently proposed (phase I). These merit further study in MCI and earlier stages. Manual hippocampal volumetry is currently the bestestablished biomarker for AD in the field of structural imaging, but due to the laborious nature of the procedure it will only be used in clinical studies for risk stratification of study populations and as an end point Inhibitors,research,lifescience,medical for treatment effects in the foreseeable future. Automated data-driven and rater- independent methods are currently being investigated to detect regional changes, namely VBM, DBM, and the measurement of cortical thickness. In the medium term, particularly in combination with multivariate statistical analysis methods, analysis algorithms are likely to be identified that are at least as effective Inhibitors,research,lifescience,medical as hippocampal volumetry in the early detection of AD in MCI subjects

and will therefore be used in pharmacological studies. However, if secondary preventive treatment approaches are approved in the coming years, the use of these kinds of automated methods for the early detection of AD will be of socioeconomic enough importance in routine diagnostic practice as well. Besides structural neuroimaging, pilot studies using other neuroimaging approaches such as PET (FDG and PIB), DTI and MRS yielded promising results and should be prospectively applied to larger samples. Apart from hippocampal volumetry, whole-brain volumetry is currently being investigated as a secondary end point in several clinical studies, and other studies are beginning on whole brain volumetry; however, the validity of this marker is limited. PET has been used as an end point in single-center studies.