title: Regional brain hypometabolism is unrelated to regional amyloid plaque burden.
abstract: In its original form, the amyloid cascade hypothesis of Alzheimer's disease holds that fibrillar deposits of amyloid are an early, driving force in pathological events leading ultimately to neuronal death. Early clinicopathological investigations highlighted a number of inconsistencies leading to an updated hypothesis in which amyloid plaques give way to amyloid oligomers as the driving force in pathogenesis. Rather than focusing on the inconsistencies, amyloid imaging studies have tended to highlight the overlap between regions that show early amyloid plaque signal on positron emission tomography and that also happen to be affected early in Alzheimer's disease. Recent imaging studies investigating the regional dependency between metabolism and amyloid plaque deposition have arrived at conflicting results, with some showing regional associations and other not. We extracted multimodal neuroimaging data from the Alzheimer's disease neuroimaging database for 227 healthy controls and 434 subjects with mild cognitive impairment. We analysed regional patterns of amyloid deposition, regional glucose metabolism and regional atrophy using florbetapir ((18)F) positron emission tomography, (18)F-fluordeoxyglucose positron emission tomography and T1-weighted magnetic resonance imaging, respectively. Specifically, we derived grey matter density and standardized uptake value ratios for both positron emission tomography tracers in 404 functionally defined regions of interest. We examined the relation between regional glucose metabolism and amyloid plaques using linear models. For each region of interest, correcting for regional grey matter density, age, education and disease status, we tested the association of regional glucose metabolism with (i) cortex-wide florbetapir uptake; (ii) regional (i.e. in the same region of interest) florbetapir uptake; and (iii) regional florbetapir uptake while correcting in addition for cortex-wide florbetapir uptake. P-values for each setting were Bonferroni corrected for 404 tests. Regions showing significant hypometabolism with increasing cortex-wide amyloid burden were classic Alzheimer's disease-related regions: the medial and lateral parietal cortices. The associations between regional amyloid burden and regional metabolism were more heterogeneous: there were significant hypometabolic effects in posterior cingulate, precuneus, and parietal regions but also significant positive associations in bilateral hippocampus and entorhinal cortex. However, after correcting for global amyloid burden, few of the negative associations remained and the number of positive associations increased. Given the wide-spread distribution of amyloid plaques, if the canonical cascade hypothesis were true, we would expect wide-spread, cortical hypometabolism. Instead, cortical hypometabolism appears to be linked to global amyloid burden. Thus we conclude that regional fibrillar amyloid deposition has little to no association with regional hypometabolism.
authors.affiliation: 1 FIND Lab, Department of Neurology and Neurological Sciences, Stanford University, Stanford California, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Altmann
authors.affiliation: 1 FIND Lab, Department of Neurology and Neurological Sciences, Stanford University, Stanford California, USA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Ng
authors.affiliation: 2 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Landau
authors.affiliation: 2 Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jagust
authors.affiliation: 1 FIND Lab, Department of Neurology and Neurological Sciences, Stanford University, Stanford California, USA greicius@stanford.edu.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Greicius
mesh_terms: D000368:Aged; D000814:Aniline Compounds / Q000378:metabolism; D001284:Atrophy / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D060825:Cognitive Dysfunction / Q000473:pathology*; D005026:Ethylene Glycols / Q000378:metabolism; D005260:Female; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D059906:Neuroimaging; D058225:Plaque, Amyloid / Q000473:pathology*; D049268:Positron-Emission Tomography
chemical_list: D000814:Aniline Compounds; D005026:Ethylene Glycols; D019788:Fluorodeoxyglucose F18; C545186:florbetapir; D005947:Glucose
keywords: Alzheimer’s disease; amyloid imaging; glucose metabolism; positron emission tomography