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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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Volume of interest based group comparisons (left) and correlation analyses (right). Left: Mean and standard deviation of (A) glucose metabolism as measured by 18F-fluorodeoxyglucose-PET, (B) amyloid burden measured by 11C-PiB-PET and (C) whole-brain connectivity (WBC) (cortical hub integrity) as measured by resting-state functional MRI within the posterior cingulate cortex-volume of interest in PiB-negative healthy controls (HC PiB−), PiB-positive healthy controls (HC PiB+) and PiB-positive patients with mild cognitive impairment (MCI). Error bars refer to the standard deviations. Right: Correlation analyses between: (D) glucose metabolism (posterior cingulate cortex-volume of interest) and amyloid burden (FLR-VOI); (E) whole-brain connectivity (posterior cingulate cortex-volume of interest) and amyloid burden (FLR-VOI) and (F) glucose metabolism and whole-brain connectivity (both posterior cingulate cortex-volume of interest) as measured in the entire sample (including PiB-negative healthy controls, PiB-positive healthy controls and PiB-positive patients with mild cognitive impairment). Number of data points: n = 37. FDG-PET = fluorodeoxyglucose PET; PCC-VOI = independently predefined spherical volume of interest in the posterior cingulate cortex; rCMRglc = regional cerebral metabolic rate of glucose consumption; *Significant as compared with PiB-negative healthy controls (unpaired t-test, significance threshold P < 0.05). +significant as compared with PiB-negative healthy controls and to PiB-positive healthy controls (unpaired t-test, significance threshold P < 0.05).
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Figure 3: Volume of interest based group comparisons (left) and correlation analyses (right). Left: Mean and standard deviation of (A) glucose metabolism as measured by 18F-fluorodeoxyglucose-PET, (B) amyloid burden measured by 11C-PiB-PET and (C) whole-brain connectivity (WBC) (cortical hub integrity) as measured by resting-state functional MRI within the posterior cingulate cortex-volume of interest in PiB-negative healthy controls (HC PiB−), PiB-positive healthy controls (HC PiB+) and PiB-positive patients with mild cognitive impairment (MCI). Error bars refer to the standard deviations. Right: Correlation analyses between: (D) glucose metabolism (posterior cingulate cortex-volume of interest) and amyloid burden (FLR-VOI); (E) whole-brain connectivity (posterior cingulate cortex-volume of interest) and amyloid burden (FLR-VOI) and (F) glucose metabolism and whole-brain connectivity (both posterior cingulate cortex-volume of interest) as measured in the entire sample (including PiB-negative healthy controls, PiB-positive healthy controls and PiB-positive patients with mild cognitive impairment). Number of data points: n = 37. FDG-PET = fluorodeoxyglucose PET; PCC-VOI = independently predefined spherical volume of interest in the posterior cingulate cortex; rCMRglc = regional cerebral metabolic rate of glucose consumption; *Significant as compared with PiB-negative healthy controls (unpaired t-test, significance threshold P < 0.05). +significant as compared with PiB-negative healthy controls and to PiB-positive healthy controls (unpaired t-test, significance threshold P < 0.05).

Mentions: We employed an independently predefined spherical volume in the posterior cingulate cortex, which has been previously established (refer to the ‘Materials and Methods' section and Supplementary Material) (Andrews-Hanna et al., 2007). Within the posterior cingulate cortex volume of interest, statistically significant reductions of cerebral metabolism were observed in patients with mild cognitive impairment but also in PiB-positive healthy controls, as compared to PiB-negative healthy controls (Fig. 3B and Table 2). Furthermore, a significantly reduced degree of whole-brain connectivity was observed within this volume of interest in patients with mild cognitive impairment, as compared with PiB-negative healthy controls. In PiB-positive healthy controls, whole-brain connectivity values were numerically lower as compared with PiB-negative healthy controls and higher as compared with subjects with mild cognitive impairment; however, due to high standard deviation, these differences did not reach significance (Fig. 3C and Table 2). No significant differences in grey matter density between subjects with mild cognitive impairment, PiB-negative healthy controls and PiB-positive healthy controls were found in volume of interest-based analysis. This indicates that differences in fluorodeoxyglucose and whole-brain connectivity were unlikely to be due to structural grey matter differences (Table 2).Figure 3


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)

Volume of interest based group comparisons (left) and correlation analyses (right). Left: Mean and standard deviation of (A) glucose metabolism as measured by 18F-fluorodeoxyglucose-PET, (B) amyloid burden measured by 11C-PiB-PET and (C) whole-brain connectivity (WBC) (cortical hub integrity) as measured by resting-state functional MRI within the posterior cingulate cortex-volume of interest in PiB-negative healthy controls (HC PiB−), PiB-positive healthy controls (HC PiB+) and PiB-positive patients with mild cognitive impairment (MCI). Error bars refer to the standard deviations. Right: Correlation analyses between: (D) glucose metabolism (posterior cingulate cortex-volume of interest) and amyloid burden (FLR-VOI); (E) whole-brain connectivity (posterior cingulate cortex-volume of interest) and amyloid burden (FLR-VOI) and (F) glucose metabolism and whole-brain connectivity (both posterior cingulate cortex-volume of interest) as measured in the entire sample (including PiB-negative healthy controls, PiB-positive healthy controls and PiB-positive patients with mild cognitive impairment). Number of data points: n = 37. FDG-PET = fluorodeoxyglucose PET; PCC-VOI = independently predefined spherical volume of interest in the posterior cingulate cortex; rCMRglc = regional cerebral metabolic rate of glucose consumption; *Significant as compared with PiB-negative healthy controls (unpaired t-test, significance threshold P < 0.05). +significant as compared with PiB-negative healthy controls and to PiB-positive healthy controls (unpaired t-test, significance threshold P < 0.05).
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Figure 3: Volume of interest based group comparisons (left) and correlation analyses (right). Left: Mean and standard deviation of (A) glucose metabolism as measured by 18F-fluorodeoxyglucose-PET, (B) amyloid burden measured by 11C-PiB-PET and (C) whole-brain connectivity (WBC) (cortical hub integrity) as measured by resting-state functional MRI within the posterior cingulate cortex-volume of interest in PiB-negative healthy controls (HC PiB−), PiB-positive healthy controls (HC PiB+) and PiB-positive patients with mild cognitive impairment (MCI). Error bars refer to the standard deviations. Right: Correlation analyses between: (D) glucose metabolism (posterior cingulate cortex-volume of interest) and amyloid burden (FLR-VOI); (E) whole-brain connectivity (posterior cingulate cortex-volume of interest) and amyloid burden (FLR-VOI) and (F) glucose metabolism and whole-brain connectivity (both posterior cingulate cortex-volume of interest) as measured in the entire sample (including PiB-negative healthy controls, PiB-positive healthy controls and PiB-positive patients with mild cognitive impairment). Number of data points: n = 37. FDG-PET = fluorodeoxyglucose PET; PCC-VOI = independently predefined spherical volume of interest in the posterior cingulate cortex; rCMRglc = regional cerebral metabolic rate of glucose consumption; *Significant as compared with PiB-negative healthy controls (unpaired t-test, significance threshold P < 0.05). +significant as compared with PiB-negative healthy controls and to PiB-positive healthy controls (unpaired t-test, significance threshold P < 0.05).
Mentions: We employed an independently predefined spherical volume in the posterior cingulate cortex, which has been previously established (refer to the ‘Materials and Methods' section and Supplementary Material) (Andrews-Hanna et al., 2007). Within the posterior cingulate cortex volume of interest, statistically significant reductions of cerebral metabolism were observed in patients with mild cognitive impairment but also in PiB-positive healthy controls, as compared to PiB-negative healthy controls (Fig. 3B and Table 2). Furthermore, a significantly reduced degree of whole-brain connectivity was observed within this volume of interest in patients with mild cognitive impairment, as compared with PiB-negative healthy controls. In PiB-positive healthy controls, whole-brain connectivity values were numerically lower as compared with PiB-negative healthy controls and higher as compared with subjects with mild cognitive impairment; however, due to high standard deviation, these differences did not reach significance (Fig. 3C and Table 2). No significant differences in grey matter density between subjects with mild cognitive impairment, PiB-negative healthy controls and PiB-positive healthy controls were found in volume of interest-based analysis. This indicates that differences in fluorodeoxyglucose and whole-brain connectivity were unlikely to be due to structural grey matter differences (Table 2).Figure 3

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