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


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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    • "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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    ABSTRACT: The goal of the present study was to determine the earliest patterns of hypometabolism and atrophy in the development of Alzheimer's disease (AD). Stages of AD were defined by positron emission tomography imaging evidence of cortical amyloid pathology in addition to cognitive criteria. Subjects for the study were selected from the Alzheimer's Disease Neuroimaging Initiative database and divided into 4 groups: cognitively normal (CN) amyloid negative (Aβ-) elderly subjects (n = 36), CN amyloid-positive (Aβ+) (n = 21), early mild cognitive impairment Aβ+ (n = 65), and late mild cognitive impairment Aβ+ (n = 23) subjects. Region of interest-based (primary) and voxel-based (secondary) analyses were used to assess gray matter hypometabolism, quantified by [18F]fluorodeoxyglucose-positron emission tomography, and decrease in gray matter volume and cortical thickness was measured by magnetic resonance imaging. Region of interest- and voxel-based analyses showed significant hypometabolism but not atrophy in CN Aβ+ subjects compared with CN Aβ- subjects. The results suggest that hypometabolism exceeds atrophy in preclinical AD, supporting the notion that amyloid load may affect synaptic activity, leading to synaptic loss and subsequent neuronal loss.
    Neurobiology of aging 04/2014; 35(9). DOI:10.1016/j.neurobiolaging.2014.04.006 · 5.01 Impact Factor
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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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    Clinical neuroimaging 03/2014; 4. DOI:10.1016/j.nicl.2014.03.005 · 2.53 Impact Factor
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    • "It should be noted that CBF is often but not always (Fink et al., 1996) coupled to the metabolic activity in the brain measured by fluorodeoxyglucose PET, and some studies have also found positive associations between fluorodeoxyglucose PET and brain amyloid-b load. These increases in perfusion and metabolism may either reflect mechanisms compensating for amyloid-b neurotoxicity, or suggest that amyloid-b accumulation itself is driven by increased neural activity (Cohen et al., 2009; Jagust and Mormino, 2011; Ossenkoppele et al., 2013). However, the fact that amyloid-b load was associated with CBF reductions in regions other than posterior cingulate gyrus may argue against amyloid-b accumulation resulting from increased neural activity. "
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    ABSTRACT: Patients with Alzheimer's disease have reduced cerebral blood flow measured by arterial spin labelling magnetic resonance imaging, but it is unclear how this is related to amyloid-β pathology. Using 182 subjects from the Alzheimer's Disease Neuroimaging Initiative we tested associations of amyloid-β with regional cerebral blood flow in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer's disease with dementia (n = 24). Based on the theory that Alzheimer's disease starts with amyloid-β accumulation and progresses with symptoms and secondary pathologies in different trajectories, we tested if cerebral blood flow differed between amyloid-β-negative controls and -positive subjects in different diagnostic groups, and if amyloid-β had different associations with cerebral blood flow and grey matter volume. Global amyloid-β load was measured by florbetapir positron emission tomography, and regional blood flow and volume were measured in eight a priori defined regions of interest. Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-β load was related to lower cerebral blood flow in several regions, independent of diagnostic group. When comparing amyloid-β-positive subjects with -negative controls, we found reductions of cerebral blood flow in several diagnostic groups, including in precuneus, entorhinal cortex and hippocampus (dementia), inferior parietal cortex (late mild cognitive impairment and dementia), and inferior temporal cortex (early and late mild cognitive impairment and dementia). The associations of amyloid-β with cerebral blood flow and volume differed across the disease spectrum, with high amyloid-β being associated with greater cerebral blood flow reduction in controls and greater volume reduction in late mild cognitive impairment and dementia. In addition to disease stage, amyloid-β pathology affects cerebral blood flow across the span from controls to dementia patients. Amyloid-β pathology has different associations with cerebral blood flow and volume, and may cause more loss of blood flow in early stages, whereas volume loss dominates in late disease stages.
    Brain 03/2014; 137(5). DOI:10.1093/brain/awu043 · 9.20 Impact Factor
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