9,10 Amnestic and nonamnestic MCI can be further subdivided to include single or multiple cognitive domains (see refs 11,12 for an MCI algorithm). As in the diagnosis of AD and dementia, the criteria for cognitive impairment in any domain are applicable to a change in cognition, memory or otherwise, from a prior level

of functioning. Other classification schemes have also been used to define the cognitive space between healthy cognition and dementia.9,13 One example is the use of Inhibitors,research,lifescience,medical the clinical dementia rating (CDR)14 scale and definition of MCI as questionable dementia (CDR score of 0.5). Notably, as indicated below, many studies of the neuropathological features of MCI have used the CDR=0.5 metric to define MCI. It must be emphasized, however, that despite the fact that MCI is often used as a global framework to define the space Inhibitors,research,lifescience,medical between no cognitive impairment and frank dementia, different Roxadustat conceptualizations and definitions vary considerably and influence how individuals are classified. One recent study15 that explored the usage of four commonly used definitions and criteria found considerable variation between them (from 5.9% to 32.4% of studied individuals classified

Inhibitors,research,lifescience,medical as MCI depending on the metric used). Of the 34 people studied, no subject was classified as MCI by all four definitions. The neuroimaging literature of pathological changes associated with MCI is more extensive than the postmortem literature. This is in part to due Inhibitors,research,lifescience,medical to the progression of persons with MCI to more severe forms of

dementia before they die and come to autopsy. The neuroimaging literature16-23 implicates pathological changes, such as atrophy and sclerosis, in the hippocampus and entorhinal cortex, and the likely development of amyloid plaques based on molecular neuroimaging, by positron Inhibitors,research,lifescience,medical emission tomography (PET) using an amyloid-β-peptide (Aβ) ligand known as Pittsburgh Compound B (PiB).24,25 The validity of PET studies with PiB has been bolstered by a limited number of in vivo imaging and postmortem neuropathology studies,26,27 and one recent study that combined PiB-PET most with neuropathological study of brain biopsy specimens.28,29 The neuroimaging literature in MCI has been reviewed recently.11,30 An issue that influences how we interpret postmortem neurobiological studies of MCI and dementia is the way that neuropathological criteria are applied and the way that experiments are designed. It is important to recognize that neuropathological criteria such as the CERAD31 or NIA/Reagan32 criteria are probabilistic constructs designed to distinguish between persons with significant AD neuropathology and those without.