Alzheimer's Disease and Related Disorders PDF

INTRODUCTION

The relationship of neuropathologic changes to the clinical status of people with dementia is of paramount importance in devising appropriate therapeutic interventions. Despite the fact that a central feature of the diagnostic criteria for Alzheimer's disease (AD) includes a history of insidious onset and a progression of cognitive decline, it was not until the mid 1990s, as large-scale memory clinics obtained increased experience with people presenting early with symptoms of mild dementia, that attention was directed at understanding the processes occurring during the prodromal stages of dementia. Subsequently, individuals with mild memory loss, who were clinically followed as their cognition deteriorated through stages of mild, moderate, and severe AD, were neuropathologically confirmed postmortem as AD. These neuropathologic findings, together with retrospective and prospective imaging studies, led to a reexamination of our concepts of the neuropathologic changes underlying the onset of early symptoms of cognitive impairment, as well as the clinical definition of prodromal AD. Because it is believed that AD has an extensive preclinical phase, it is important to identify people in an early stage when brain pathology has been initiated but prior to significant clinical symptoms. During the past few years, the concept of mild cognitive impairment (MCI) has developed as a possible prodromal stage of AD. Although the precise definition of MCI is being debated, recent evidence suggests that MCI falls into several subtypes. Individuals with isolated memory loss, termed amnestic mild cognitive impairment (aMCI), represent the most extensively analyzed form of MCI in specialty clinics. The ‘conversion rate' of aMCI people to AD (the time at which they meet current formal criteria for AD) is 10–15% annually. 1 On the other hand, mild impairment defined by deficits in other cognitive (and functional) domains is termed multiple domain MCI (mdMCI) and may also occur as memory function declines below a defined threshold. In a recent series of studies examining the onset of MCI in the Cardiovascular Health Study (CHS) cohort, the risk factors for developing MCI included apoE4 genotype (for aMCI), depression, racial and constitutional factors, and the presence of cerebrovascular disease.2 In this population-based study, about two-thirds of the MCI cases were mdMCI, and about one-third were aMCI.3 Thus, a MCI is not as common in population-studies, and may be a less frequent manner of progressing to AD. This chapter provides an overview of neurobiologic observations crucial to our understanding of the chemical, pathologic, and molecular changes which occur in brain during the transitional period between normal aging and the clinical diagnosis of all forms of MCI and AD.