Table III. Trade-off between strictness of mild cognitive selleck products impairment (MCI) criterion (based on New York University [NYU] delayed paragraph recall) and decliners missed. GDS, Global Deterioration Score. Recalculated from data in Kluger et al.48 Pathological basis of MCI Most MCI patients identified in research clinics who decline to dementia can be retrospectively diagnosed with probable early stage Inhibitors,research,lifescience,medical AD. Such patients may therefore already harbor neuritic plaques and neurofibrillary tangles (NFTs), the classically recognized histolopathological hallmarks of

AD. In a large study of 109 community-dwelling older adults without dementia,63 33% were found at autopsy to have neocortical neuritic plaques and NFTs suggesting a pathological diagnosis of AD. Methodological considerations preclude knowing how many of these cases actually had MCI, but the findings prompt speculation that gradations of AD-related pathology could explain the milder degrees of intellectual dysfunction prevalent in nondemented Inhibitors,research,lifescience,medical populations. The nature Inhibitors,research,lifescience,medical of the brain changes that distinguish pathological from normal aging and constitute the basis for MCI are

now becoming less obscure. On the basis of a large autopsy series of 2661 cases, Braak and Braak64 identified six age-associated stages of neurofibrillary change where early NFT formation is restricted to the entorhinal and transentorhinal regions of the medial temporal lobe and occurs in the absence of amyloid plaques. In autopsy studies of normal subjects without any cognitive impairment (CDR=0), investigators have found NFTs to be ubiquitous, but generally confined to the entorhinal cortex Inhibitors,research,lifescience,medical and hippocampus65 with densities, particularly for the CA1 region, that increase exponentially with advancing age.66 While most of these cognitively normal cases had either no amyloid deposition or only diffuse nonfibrillar plaques, between 18% and 45% may also exhibit neuritic plaques that are predominately concentrated in the limbic regions of the medial temporal lobe.65-67 It is therefore

apparent that some cognitively normal subjects harbor Inhibitors,research,lifescience,medical “preclinical” brain changes consistent with a pathological diagnosis of early AD; presumably, such individuals will eventually develop MCI and dementia upon longitudinal observation. Virtually all CDR=0.5 (MCI) subjects studied by Price and Morris were found to have neuritic plaques others distributed more diffusely, involving neocortical as well as limbic regions.21,66 These data indicate that MCI, defined as CDR=0.5, may represent early AD more often than previously believed. Such observations, however, must be reconciled with the widely disparate rates of longitudinal decline exhibited by MCI subjects. As discussed previously, the etiological heterogeneity of MCI is most likely influenced by clinical diagnostic criteria as well as the characteristics of the population sampled.