Dataset Information

Spatially Distributed Amyloid-? Reduces Glucose Metabolism in Mild Cognitive Impairment.

ABSTRACT:

Background

Several positron emission tomography (PET) studies have explored the relationship between amyloid-? (A?), glucose metabolism, and the APOE?4 genotype. It has been reported that APOE?4, and not aggregated A?, contributes to glucose hypometabolism in pre-clinical stages of Alzheimer's disease (AD) pathology.

Objective

We hypothesize that typical measurements of A? taken either from composite regions-of-interest with relatively high burden actually cover significant patterns of the relationship with glucose metabolism. In contrast, spatially weighted measures of A? are more related to glucose metabolism in cognitively normal (CN) aging and mild cognitive impairment (MCI).

Methods

We have generated a score of amyloid burden based on a joint singular value decomposition (SVD) of the cross-correlation structure between glucose metabolism, as measured by [18F]2-fluoro-2-deoxyglucose (FDG) PET, and A?, as measured by [18F]florbetapir PET, from the Alzheimer's Disease Neuroimaging Initiative study. This SVD-based score reveals cortical regions where a reduced glucose metabolism is maximally correlated with distributed patterns of A?.

Results

From an older population of CN and MCI subjects, we found that the SVD-based A? score was significantly correlated with glucose metabolism in several cortical regions. Additionally, the corresponding A? network has hubs that contribute to distributed glucose hypometabolism, which, in turn, are not necessarily foci of A? deposition.

Conclusions

Our approach uncovered hidden patterns of the glucose metabolism-A? relationship. We showed that the SVD-based A? score produces a stronger relationship with decreasing glucose metabolism than either APOE?4 genotype or global measures of A? burden.

SUBMITTER: Carbonell F

PROVIDER: S-EPMC7029335 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Background:Previous publications indicate that Alzheimer's Disease (AD) related cortical atrophy may develop in asymmetric patterns, with accentuation of the left hemisphere. Since fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the regional cerebral metabolic rate of glucose (rCMRgl) provide a sensitive and specific marker of neurodegenerative disease progression, we sought to investigate the longitudinal pattern of rCMRgl in amyloid-positive persons with mild cognitive impairment (MCI) and dementia, hypothesizing asymmetric declines of cerebral glucose metabolism. Methods:Using florbetapir PET and cerebrospinal fluid (CSF) measures to define amyloid-? (A?) positivity, 40 A? negative (A?-) cognitively unimpaired controls (CU; 76?±?5y), 76 A? positive (A?+) persons with MCI (76?±?7y) and 51 A??+?persons with probable AD dementia (75?±?7y) from the AD Neuroimaging Initiative (ADNI) were included in this study with baseline and 2-year follow-up FDG PET scans. The degree of lateralization of longitudinal rCMRgl declines in subjects with A??+?MCI and AD in comparison with A?- CU were statistically quantified via bootstrapped lateralization indices [(LI); range?-?1 (right) to 1 (left)]. Results:Compared to A?- CU, A??+?MCI patients showed marked left hemispheric lateralization (LI: 0.78). In contrast, modest right hemispheric lateralization (LI: -0.33) of rCMRgl declines was found in A??+?persons with probable AD dementia. Additional comparisons of A??+?groups (i.e. MCI and probable AD dementia) consequently indicated right hemispheric lateralization (LI: -0.79) of stronger rCMRgl declines in dementia stages of AD. For all comparisons, voxel-based analyses confirmed significant (pFWE<0.05) declines of rCMRgl within AD-typical brain regions. Analyses of cognitive data yielded predominant decline of memory functions in both MCI and dementia stages of AD. Conclusions:These data indicate that in early stages, AD may be characterized by a more lateralized pattern of left hemispheric rCMRgl declines. However, metabolic differences between hemispheres appear to diminish with further progression of the disease.

Project description:Introduction: The disconnection hypothesis of Alzheimer's disease (AD) is supported by growing neuroimaging and neurophysiological evidence of altered brain functional connectivity in cognitively impaired individuals. Brain functional modalities such as [18F]fluorodeoxyglucose positron-emission tomography ([18F]FDG-PET) and electroencephalography (EEG) measure different aspects of synaptic functioning, and can contribute to understanding brain connectivity disruptions in AD. Aim: This study investigated the relationship between cortical glucose metabolism and topographical EEG measures of brain functional connectivity in subjects along AD continuum. Methods: Patients diagnosed with mild cognitive impairment (MCI) and AD (n = 67), and stratified into amyloid-positive (n = 32) and negative (n = 10) groups according to cerebrospinal fluid Aβ42/40 ratio, were assessed with [18F]FDG-PET and resting-state EEG recordings. EEG-based neuroimaging analysis involved standardized low-resolution electromagnetic tomography (sLORETA), which estimates functional connectivity from cortical sources of electrical activity in a 3D head model. Results: Glucose hypometabolism in temporoparietal lobes was significantly associated with altered EEG functional connectivity of the same regions of interest in clinically diagnosed MCI and AD patients and in patients with biomarker-verified AD pathology. The correlative pattern of disrupted connectivity in temporoparietal lobes, as detected by EEG sLORETA analysis, included decreased instantaneous linear connectivity in fast frequencies and increased lagged linear connectivity in slow frequencies in relation to the activity of remaining cortex. Conclusions: Topographical EEG measures of functional connectivity detect regional dysfunction of AD-vulnerable brain areas as evidenced by association and spatial overlap with the cortical glucose hypometabolism in MCI and AD patients. Impact statement The association between glucose hypometabolism, as evidenced by [18F]FDG-PET ([18F]fluorodeoxyglucose positron-emission tomography), and altered electroencephalography (EEG) functional connectivity metrics within temporoparietal lobes provides link between synaptic, neurophysiological, and metabolic impairment in mild cognitive impairment and Alzheimer's disease patients. This study reported alterations in EEG measures of both instantaneous and lagged linear connectivity across distinct frequency bands, both of which were shown to be important for inter- and intrahemispheric communication and function of memory systems in general. EEG-based imaging of brain functional connectivity has a potential to serve as a noninvasive, low-cost, and widely available alternative in assessing synaptic and network dysfunction in cognitively impaired patients.