Article

Basal Cerebral Metabolism May Modulate the Cognitive Effects of A in Mild Cognitive Impairment: An Example of Brain Reserve

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2009; 29(47):14770-8. DOI: 10.1523/JNEUROSCI.3669-09.2009
Source: PubMed

ABSTRACT

Inverse correlations between amyloid-beta (Abeta) load measured by Pittsburgh Compound-B (PiB) positron emission tomography (PET) and cerebral metabolism using [(18)F]fluoro-2-deoxy-d-glucose (FDG) in Alzheimer's disease (AD) patients, suggest local Abeta-induced metabolic insults. However, this relationship has not been well studied in mild cognitive impairment (MCI) or amyloid-positive controls. Here, we explored associations of Abeta deposition with metabolism via both region-of-interest-based and voxel-based analyses in amyloid-positive control subjects and patients with MCI or AD. Metabolism in parietal and precuneus cortices of AD patients was negatively correlated with PiB retention locally, and more distantly with PiB retention in frontal cortex. In amyloid-positive controls, no clear patterns in correlations were observed. In MCI patients, there were essentially no significant, negative correlations, but there were frequent significant positive correlations between metabolism and PiB retention. Metabolism in anterior cingulate showed positive correlations with PiB in most brain areas in MCI, and metabolism and PiB retention were positively correlated locally in precuneus/parietal cortex. However, there was no significant increase in metabolism in MCI compared to age-matched controls, negating the possibility that Abeta deposition directly caused reactive hypermetabolism. This suggests that, in MCI, higher basal metabolism could either be exacerbating Abeta deposition or increasing the level of Abeta necessary for cognitive impairment sufficient for the clinical diagnosis of AD. Only after extensive Abeta deposition has been present for longer periods of time does Abeta become the driving force for decreased metabolism in clinical AD and, only in more vulnerable brain regions such as parietal and precuneus cortices.

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    • "These findings have raised questions whether there is a compensatory metabolic upregulation at the early phases of the AD process or whether the higher metabolism hastens the amyloid accumulation in the brain. Moreover, another explanation is based on the brain reserve theory, as higher basal metabolism has been speculated to mask the clinical manifestations of the disease and, thus, subjects with high amyloid load but relatively spared metabolism would have mild symptoms and still be classified as having MCI instead of AD [9]. The aim of this study was to evaluate the associations between brain metabolism ([ 18 F]FDG uptake) and amyloid accumulation ([ 11 C]PIB uptake) in MCI and to further analyze the long-term changes in these biomarkers and their relationship during a 5-year period. "
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    ABSTRACT: The aim of this longitudinal positron emission tomography (PET) study was to evaluate the interrelationship between brain metabolism and amyloid accumulation during the disease process from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Nine MCI patients, who converted to AD between two and five years, and nine healthy subjects underwent [11C]PIB and [18F]FDG PET scans at baseline and at 5 years. [11C]PIB uptake was clearly higher in MCI patients at baseline compared to controls and spread extensively to the cerebral cortex during the conversion to AD. [18F]FDG uptake was reduced especially in the temporal-parietal regions in MCI compared to controls at baseline, and widely over the cortex at the 5-year follow-up. The reduction in metabolism during the follow-up was significant in the posterior brain regions. In addition, brain amyloid load was positively associated with metabolism in posterior brain regions in MCI, but not after conversion to AD. The results suggest that there are interactions between brain amyloid accumulation and metabolism during the AD process, including a possible compensatory upregulation of posterior brain metabolism in the early phase.
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    • "Only a small number of studies assessed hypometabolic and atrophic patterns in asymptomatic sporadic AD as defined by cognitively normal (CN) subjects with increased PET-measured amyloid load (amyloid-positive, Abþ) (Sperling et al., 2011). One study reported no significant metabolic differences between CN Abþ and CN amyloid-negative (AbÀ) control subjects, and atrophic patterns were not assessed (Cohen et al., 2009). By contrast, another study reported significant posterior cingulate cortex hypometabolism in CN Abþ subjects compared with CN AbÀ subjects , but no significant GM reductions in AD susceptible areas (Drzezga et al., 2011). "
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    • "Notably, hypometabolism in the prefrontal and occipital cortex typically occurs in advanced clinical stages of AD ( Kim et al., 2005 ), whereas medial prefrontal amyloid aggregation may be an early event in the AD cascade ( Sepulcre et al., 2013 ), further underscoring the relative resilience of the prefrontal cortex to AD pathology ( Furst et al., 2012 ). While the reliability and significance of this observation will require further (and ideally longitudinal) study, our observation underscores the complexity of the relationship between amyloid and metabolism, which appears to vary by brain region and disease state ( Cohen et al., 2009 ; La Joie et al., 2012 ). Future studies with larger sample sizes should also attempt to explore whether joint spatial relationships between PiB and FDG correlate with specific clinical features or neuropsychological profiles. "
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