Neuropsychological contributions to the early identification of Alzheimer's disease

Abstract

A wealth of evidence demonstrates that a prodromal period of Alzheimer's disease (AD) exists for some years prior to the appearance of significant cognitive and functional declines required for the clinical diagnosis. This prodromal period of decline is characterized by a number of different neuropsychological and brain changes, and reliable identification of individuals prior to the development of significant clinical symptoms remains a top priority of research. In this review we provide an overview of those neuropsychological changes. In particular, we examine specific domains of cognition that appear to be negatively affected during the prodromal period of AD, and we review newer analytic strategies designed to examine cognitive asymmetries or discrepancies between higher-order cognitive functions versus fundamental skills. Finally, we provide a critical examination of the clinical concept of Mild Cognitive Impairment and offer suggestions for an increased focus on the impact of cerebrovascular disease (CVD) and CVD risk during the prodromal period of AD.

Fig. 1

Evolution of neurofibrillary tangle pathology as originally conceived by Braak and Braak (1991). Prior to the appearance of significant clinical symptoms, neurofibrillary changes begin to accumulate in entorhinal and transentorhinal cortex (stages I and II) and may appear surprisingly early in life (e.g., in one’s thirties or forties). Increasing involvement of the medial temporal lobe and surrounding association cortices are then thought to coincide with the appearance of mild clinical symptoms (stages III and IV), followed by clinically apparent Alzheimer’s disease and correspondingly severe involvement of medial temporal and cortical association areas (stages V and VI; adapted from Braak and Braak 1991, 1995; Braak et al. 1998)

Fig. 2

Linear versus plateau trajectories of episodic memory decline prior to a diagnosis of Alzheimer’s disease. The solid line (—) represents a linear trajectory of cognitive decline, whereas the dashed line (– –) represents individuals with an initial mild decline, then a period of stabilization, followed by a more abrupt decline in the year or two preceding an AD diagnosis. Evidence suggests that episodic memory may reflect a plateau model of decline, whereas other cognitive functions may not (adapted from Smith et al. 2007 and Twamley et al. 2006)

Fig. 3

Control-referenced standard scores for prodromal AD patients on tests of episodic memory, semantic memory, and executive functions. Their neuropsychological profiles were examined 1 year (−1) and 2 years (−2) prior to the first year of their non-normal diagnosis (adapted from Mickes et al. 2007)

Fig. 4

Distribution of standard score differences between naming and visuospatial skills for each participant. Note that 50% of the prodromal AD patients demonstrated an asymmetry score greater than 1 SD, whereas only 25% of the normal control participants demonstrated an asymmetry 1 SD or more. (Adapted from Jacobson et al. 2002)

Fig. 5

Six consecutive years of scores of an individual who progressed to a clinical diagnosis of AD at year 7. The graph depicts the discrepancy between verbal and visual recall measures (solid line), and the discrepancy between tests of naming and visuospatial skills (dashed line). Note the general increase in discrepancies between measures over time (adapted from Jacobson et al. 2002)