Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory

Abstract

Alzheimer's disease (AD) and antecedent factors associated with AD were explored using amyloid imaging and unbiased measures of longitudinal atrophy in combination with reanalysis of previous metabolic and functional studies. In total, data from 764 participants were compared across five in vivo imaging methods. Convergence of effects was seen in posterior cortical regions, including posterior cingulate, retrosplenial, and lateral parietal cortex. These regions were active in default states in young adults and also showed amyloid deposition in older adults with AD. At early stages of AD progression, prominent atrophy and metabolic abnormalities emerged in these posterior cortical regions; atrophy in medial temporal regions was also observed. Event-related functional magnetic resonance imaging studies further revealed that these cortical regions are active during successful memory retrieval in young adults. One possibility is that lifetime cerebral metabolism associated with regionally specific default activity predisposes cortical regions to AD-related changes, including amyloid deposition, metabolic disruption, and atrophy. These cortical regions may be part of a network with the medial temporal lobe whose disruption contributes to memory impairment.

Figure 1.

Default mode activity in young adults measured by [¹⁵O]H₂O PET. Transverse (horizontal) sections through the brain show activity during default states in young adults from a meta-analysis of nine studies (data from Shulman et al., 1997b). The left hemisphere is displayed on the left. Section labels (at bottom) correspond to the approximate transverse level from the Talairach and Tournoux (1988) atlas. Scale is in percentage of PET counts. Notable default mode activity is apparent in medial and lateral posterior parietal regions, extending into precuneus, posterior cingulate, and retrosplenial cortex, as well as in frontal cortex along the midline.

Figure 2.

Amyloid deposition in older adults measured by [¹¹C]PIB. The format is similar to Figure 1. The scale is a percentage of uptake above brainstem activity (see Materials and Methods). The top image shows nondemented older adults (n = 6) who have minimal amyloid deposition (PIB^-). There is nonspecific binding of [¹¹C]PIB in white matter. The middle image shows nondemented older adults (n = 2) who have significant amyloid deposition (PIB⁺), perhaps indicating preclinical AD. The bottom image shows demented older adults (n = 10). Notable amyloid deposition is apparent in medial and lateral posterior parietal regions, extending into precuneus, posterior cingulate, and retrosplenial cortex, as well as in frontal cortex along the midline. Medial temporal amyloid deposition is minimal. This pattern of amyloid deposition in AD is reliable across separate participants groups (supplemental Fig. 1, available at www.jneurosci.org as supplemental material).

Figure 3.

Longitudinal atrophy in older adults measured by structural MRI. The format is similar to Figure 1. The scale is atrophy rate, per year. Top, The top two rows show nondemented (n = 44) and demented (n = 40) individuals. The demented group includes all participants classified as CDR 0.5 or 1 coincident with the first imaging session. Atrophy is clearly apparent in the medial temporal lobe. In the cortex, posterior cortical regions, extending into precuneus, posterior cingulate, and retrosplenial cortex, show prominent atrophy. Bottom, The bottom three rows show atrophy sorted by disease severity. Converters (n = 8) were nondemented (CDR 0) at initial imaging and progressed to very mild dementia (CDR 0.5) during the study. Very mildly demented individuals (n = 31) were all enrolled at CDR 0.5. Mildly demented individuals (n = 9) were enrolled at CDR 1. Although the topography of the atrophy pattern is preserved across levels of dementia severity, clear acceleration of atrophy rate is apparent as disease severity increases. In the converter group, the earliest indications of atrophy are observed in the medial temporal lobe and posterior cortical regions.

Figure 4.

Metabolism reduction in Alzheimer's disease measured by FDG-PET. The format is similar to Figure 1. The scale reflects the slope of the regression between CMRgl and dementia severity as measured by the MMSE. All included participants (n = 395) were demented (data from Herholz et al., 2002). Regions showing metabolism reduction as dementia severity increases include posterior cortical regions near precuneus extending into posterior cingulate and retrosplenial cortex, as well as to lateral temporoparietal regions.

Figure 5.

Retrieval success effects in young adults measured by event-related fMRI. The format is similar to Figure 1. The scale reflects the number of independent conditions/studies that showed significant differences between hits and correct rejections in a meta-analysis of studies (see Materials and Methods). Regions within precuneus extending into posterior cingulate and retrosplenial cortex, as well as lateral parietal cortex and a frontal region near premotor cortex, all showed significant retrieval success effects in 100% (8 of 8) of the included studies.

Figure 6.

Convergence and hypothetical relationships across molecular, structural, and functional measures. Each image represents the projection of data from Figures 1, 2, 3, 4, 5 onto the cortical surface of the left hemisphere (see Results). Three patterns emerge. First, regions showing default activity in young adults are highly similar to those showing amyloid deposition in older adults with AD, including both posterior cortical regions and anterior regions. Second, atrophy and metabolism disruption in AD prominently affect the posterior cortical regions also affected by amyloid deposition and less so the anterior regions (supplemental Fig. 3, available at www.jneurosci.org as supplemental material). Third, the regions affected in AD and those active in default states in young adults overlap memory networks showing retrieval success effects during recognition in young adults.

Figure 7.

A schematic illustration of one possible configuration of lifelong events that lead to AD. Conducive metabolic conditions, associated with default mode activity patterns, may lead to regionally specific amyloid deposition. In turn, atrophy and dementia may then result. This metabolism cascade should be considered a hypothesis.