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.

Relating pessimistic memory predictions to Alzheimer's disease brain structure

“…Of note, despite semantic memory gradually deteriorates with Alzheimer's disease pathological process, in the current task, relatively preserved performance can be supported by relative preservation of the most important regions for semantic memory, namely in superior lateral temporal lobe in early stage of Alzheimer's disease (Buckner et al, 2005;Dalla Barba et al, 1998) and the relatively automatic retrieval promoted by forced-choice recognition in our task.…”

New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation

“…Lower sleep quality was associated with greater Aβ burden in the precuneus (Spira et al, 2013). Importantly, Aβ overlaps DMN regions in which hypometabolism and atrophy were detected in AD patients (Buckner et al, 2005). Aβ deposition in the preclinical stage of AD appears to be associated with worse sleep quality (Ju et al, 2013; Spira and Gottesman, 2017) and was also associated with worse cognitive and memory performance (Molano et al, 2017).…”

Molecular Brain Imaging in the Multimodality Era

“…It may be advantageous and more powerful to pursue an ROI-based approach when testing regionally specific hypotheses (Mitsis et al, 2008), although voxel-based and data-driven approaches are sometimes required (e.g., functional connectivity). Numerous methods have been used to enable the statistical analysis of multimodal and intramodal data sets that include statistical parametric mapping methods and specialized toolboxes with correlative, concordant, or integrative techniques and modeling-based approaches (Buckner et al, 2005;Casanova et al, 2007;Hayasaka et al, 2006;Krishnan et al, 2011;Ye et al, 2009). As an example, concordance-discordance analysis (Hayasaka et al, 2006) can be powerful for the comparison of group difference t-maps within and across imaging modalities.…”

“…At higher levels of metabolism, more Ab is required for conversion from normal (white circles) to MCI (black circles) or from MCI to AD (gray circles) ). (F) Buckner et al (2005) proposed that lifetime cerebral metabolism associated with regionally specific default activity predisposes cortical regions to AD-related changes and these cortical areas may be part of a network with the mesial temporal lobe (MTL), whose disruption contributes to memory impairment. (G) Jack et al (2009) proposed a model that relates disease stage to AD biomarkers in which Ab biomarkers become abnormal first, while neurodegenerative biomarkers become abnormal later and correlate with clinical symptom severity.…”

“…This model has since been revised to include a synaptic dysfunction phase evidenced by abnormal [ 18 F]2-fluoro-2-deoxy-D-glucose (or FDG) positron emission tomography (PET) and fMRI, before tau-mediated neuronal injury and precuneus cortices ) (see Figure 3E). Buckner et al (2005) sought to better understand how cortical patterns of metabolic disruption relate to structural atrophy and MTL neuropathology in AD and to the observed correlation between Ab load, atrophy and hypometabolism in posterior cingulate cortex. The authors integrated results across five neuroimaging data sets (n = 764) that were maps of: (1) [ 15 O]water PET default mode activity; (2) PiB PET Ab load; (3) MRI structural atrophy; (4) FDG PET glucose metabolism; and (5) fMRI retrieval success effect.…”