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

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.

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).

Figure 2

(A) 3D surface projection of the overlap between hypometabolic deficits (yellow) and regional disruption of whole-brain connectivity (WBC) (red) in PiB-positive patients with mild cognitive impairment (MCI) as compared to PiB-negative healthy controls at a threshold of P < 0.001 (uncorrected). Aspects: 1 = left lateral; 2 = cranial; 3 = right lateral; 4 = sagittal left medial; 5 = dorsal; 6 = axial caudal. (B) 3D volumetric illustration of the overlap between the abnormalities (in blue). Aspects: 1 = sagittal left lateral; 2 = dorsal; 3 = sagittal right lateral.

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).