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Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden.

Drzezga A, Becker JA, Van Dijk KR, Sreenivasan A, Talukdar T, Sullivan C, Schultz AP, Sepulcre J, Putcha D, Greve D, Johnson KA, Sperling RA - Brain (2011)

Bottom Line: Significant disruptions of whole-brain connectivity were found in amyloid-positive patients with mild cognitive impairment in typical cortical hubs (posterior cingulate cortex/precuneus), strongly overlapping with regional hypometabolism.These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer's disease pathology, evolving prior to clinical onset of dementia.The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer's-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Massachusetts General Hospital and Harvard University Medical School, Boston, MA 02114, USA. a.drzezga@lrz.tum.de

ABSTRACT
Disruption of functional connectivity between brain regions may represent an early functional consequence of β-amyloid pathology prior to clinical Alzheimer's disease. We aimed to investigate if non-demented older individuals with increased amyloid burden demonstrate disruptions of functional whole-brain connectivity in cortical hubs (brain regions typically highly connected to multiple other brain areas) and if these disruptions are associated with neuronal dysfunction as measured with fluorodeoxyglucose-positron emission tomography. In healthy subjects without cognitive symptoms and patients with mild cognitive impairment, we used positron emission tomography to assess amyloid burden and cerebral glucose metabolism, structural magnetic resonance imaging to quantify atrophy and novel resting state functional magnetic resonance imaging processing methods to calculate whole-brain connectivity. Significant disruptions of whole-brain connectivity were found in amyloid-positive patients with mild cognitive impairment in typical cortical hubs (posterior cingulate cortex/precuneus), strongly overlapping with regional hypometabolism. Subtle connectivity disruptions and hypometabolism were already present in amyloid-positive asymptomatic subjects. Voxel-based morphometry measures indicate that these findings were not solely a consequence of regional atrophy. Whole-brain connectivity values and metabolism showed a positive correlation with each other and a negative correlation with amyloid burden. These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer's disease pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer's-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.

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(A) Cortical hubs, identified by whole-brain functional connectivity analysis of resting state functional MRI in PiB-negative healthy controls (HC-PiB−), PiB-positive healthy controls (HC-PiB+) and PiB-positive patients with mild cognitive impairment (MCI). Regions affected by loss of cortical hubs in patients with mild cognitive impairment and PiB-positive healthy controls are labelled with circles on (1) lateral (yellow) and (2) medial (blue) aspects of the right hemisphere (contralateral results are comparable). (B) Voxel-based statistical group comparison between mild cognitive impairment and PiB-negative healthy controls. (Left) Hypometabolism in mild cognitive impairment as compared to PiB-negative healthy controls (18F-fluorodeoxyglucose-PET). (Right) Disrupted cortical hubs in mild cognitive impairment as compared to PiB-negative healthy controls. Aspects: 1 = left lateral; 2 = cranial; 3 = right lateral; 4 = dorsal. Significance threshold P < 0.001 (uncorrected).
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Figure 1: (A) Cortical hubs, identified by whole-brain functional connectivity analysis of resting state functional MRI in PiB-negative healthy controls (HC-PiB−), PiB-positive healthy controls (HC-PiB+) and PiB-positive patients with mild cognitive impairment (MCI). Regions affected by loss of cortical hubs in patients with mild cognitive impairment and PiB-positive healthy controls are labelled with circles on (1) lateral (yellow) and (2) medial (blue) aspects of the right hemisphere (contralateral results are comparable). (B) Voxel-based statistical group comparison between mild cognitive impairment and PiB-negative healthy controls. (Left) Hypometabolism in mild cognitive impairment as compared to PiB-negative healthy controls (18F-fluorodeoxyglucose-PET). (Right) Disrupted cortical hubs in mild cognitive impairment as compared to PiB-negative healthy controls. Aspects: 1 = left lateral; 2 = cranial; 3 = right lateral; 4 = dorsal. Significance threshold P < 0.001 (uncorrected).

Mentions: The whole-brain connectivity in the group of PiB-negative healthy controls revealed areas with a high degree of whole-brain connectivity (cortical hubs) distributed in a similar pattern as described in a previous study in healthy younger adults (Buckner et al., 2009), with maxima in medial prefrontal cortex, bilateral parietal/angular cortex, posterior cingulate cortex/precuneus and bilateral lateral temporal cortex (Fig. 1A and Supplementary Table 1). In contrast, the PiB-positive healthy control group demonstrated no significant whole-brain connectivity clusters in right angular and posterior cingulate cortex/precuneus cortical hub regions and whole-brain connectivity clusters were completely absent in bilateral angular and posterior cingulate cortex/precuneus regions in the mild cognitive impairment group. Correspondingly, statistical comparison between the groups revealed a reduced degree of whole-brain connectivity in mild cognitive impairment as compared to PiB-negative healthy controls in posterior cortical hub regions, including angular, lateral temporal and the posterior cingulate cortex/precuneus regions (Fig. 1B and Supplementary Table 2). Whole-brain connectivity disruptions in left lateral temporal cortical regions were also detected in mild cognitive impairment as compared to PiB-positive healthy controls (Supplementary Fig. 1B and Supplementary Table 2). PiB-positive healthy controls revealed decreased whole-brain connectivity compared with PiB-negative healthy controls in right-hemispheric lateral temporal cortex, extending into the posterior cingulate cortex (Supplementary Fig. 1B and Supplementary Table 2).Figure 1


Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden.

Drzezga A, Becker JA, Van Dijk KR, Sreenivasan A, Talukdar T, Sullivan C, Schultz AP, Sepulcre J, Putcha D, Greve D, Johnson KA, Sperling RA - Brain (2011)

(A) Cortical hubs, identified by whole-brain functional connectivity analysis of resting state functional MRI in PiB-negative healthy controls (HC-PiB−), PiB-positive healthy controls (HC-PiB+) and PiB-positive patients with mild cognitive impairment (MCI). Regions affected by loss of cortical hubs in patients with mild cognitive impairment and PiB-positive healthy controls are labelled with circles on (1) lateral (yellow) and (2) medial (blue) aspects of the right hemisphere (contralateral results are comparable). (B) Voxel-based statistical group comparison between mild cognitive impairment and PiB-negative healthy controls. (Left) Hypometabolism in mild cognitive impairment as compared to PiB-negative healthy controls (18F-fluorodeoxyglucose-PET). (Right) Disrupted cortical hubs in mild cognitive impairment as compared to PiB-negative healthy controls. Aspects: 1 = left lateral; 2 = cranial; 3 = right lateral; 4 = dorsal. Significance threshold P < 0.001 (uncorrected).
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Figure 1: (A) Cortical hubs, identified by whole-brain functional connectivity analysis of resting state functional MRI in PiB-negative healthy controls (HC-PiB−), PiB-positive healthy controls (HC-PiB+) and PiB-positive patients with mild cognitive impairment (MCI). Regions affected by loss of cortical hubs in patients with mild cognitive impairment and PiB-positive healthy controls are labelled with circles on (1) lateral (yellow) and (2) medial (blue) aspects of the right hemisphere (contralateral results are comparable). (B) Voxel-based statistical group comparison between mild cognitive impairment and PiB-negative healthy controls. (Left) Hypometabolism in mild cognitive impairment as compared to PiB-negative healthy controls (18F-fluorodeoxyglucose-PET). (Right) Disrupted cortical hubs in mild cognitive impairment as compared to PiB-negative healthy controls. Aspects: 1 = left lateral; 2 = cranial; 3 = right lateral; 4 = dorsal. Significance threshold P < 0.001 (uncorrected).
Mentions: The whole-brain connectivity in the group of PiB-negative healthy controls revealed areas with a high degree of whole-brain connectivity (cortical hubs) distributed in a similar pattern as described in a previous study in healthy younger adults (Buckner et al., 2009), with maxima in medial prefrontal cortex, bilateral parietal/angular cortex, posterior cingulate cortex/precuneus and bilateral lateral temporal cortex (Fig. 1A and Supplementary Table 1). In contrast, the PiB-positive healthy control group demonstrated no significant whole-brain connectivity clusters in right angular and posterior cingulate cortex/precuneus cortical hub regions and whole-brain connectivity clusters were completely absent in bilateral angular and posterior cingulate cortex/precuneus regions in the mild cognitive impairment group. Correspondingly, statistical comparison between the groups revealed a reduced degree of whole-brain connectivity in mild cognitive impairment as compared to PiB-negative healthy controls in posterior cortical hub regions, including angular, lateral temporal and the posterior cingulate cortex/precuneus regions (Fig. 1B and Supplementary Table 2). Whole-brain connectivity disruptions in left lateral temporal cortical regions were also detected in mild cognitive impairment as compared to PiB-positive healthy controls (Supplementary Fig. 1B and Supplementary Table 2). PiB-positive healthy controls revealed decreased whole-brain connectivity compared with PiB-negative healthy controls in right-hemispheric lateral temporal cortex, extending into the posterior cingulate cortex (Supplementary Fig. 1B and Supplementary Table 2).Figure 1

Bottom Line: Significant disruptions of whole-brain connectivity were found in amyloid-positive patients with mild cognitive impairment in typical cortical hubs (posterior cingulate cortex/precuneus), strongly overlapping with regional hypometabolism.These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer's disease pathology, evolving prior to clinical onset of dementia.The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer's-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, Massachusetts General Hospital and Harvard University Medical School, Boston, MA 02114, USA. a.drzezga@lrz.tum.de

ABSTRACT
Disruption of functional connectivity between brain regions may represent an early functional consequence of β-amyloid pathology prior to clinical Alzheimer's disease. We aimed to investigate if non-demented older individuals with increased amyloid burden demonstrate disruptions of functional whole-brain connectivity in cortical hubs (brain regions typically highly connected to multiple other brain areas) and if these disruptions are associated with neuronal dysfunction as measured with fluorodeoxyglucose-positron emission tomography. In healthy subjects without cognitive symptoms and patients with mild cognitive impairment, we used positron emission tomography to assess amyloid burden and cerebral glucose metabolism, structural magnetic resonance imaging to quantify atrophy and novel resting state functional magnetic resonance imaging processing methods to calculate whole-brain connectivity. Significant disruptions of whole-brain connectivity were found in amyloid-positive patients with mild cognitive impairment in typical cortical hubs (posterior cingulate cortex/precuneus), strongly overlapping with regional hypometabolism. Subtle connectivity disruptions and hypometabolism were already present in amyloid-positive asymptomatic subjects. Voxel-based morphometry measures indicate that these findings were not solely a consequence of regional atrophy. Whole-brain connectivity values and metabolism showed a positive correlation with each other and a negative correlation with amyloid burden. These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer's disease pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer's-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.

Show MeSH
Related in: MedlinePlus