title: 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.
authors.affiliation: Department of Radiology, Massachusetts General Hospital and Harvard University Medical School, Boston, MA 02114, USA. a.drzezga@lrz.tum.de
authors.forename: Alexander
authors.initials: A
authors.lastname: Drzezga
authors.forename: J Alex
authors.initials: JA
authors.lastname: Becker
authors.forename: Koene R A
authors.initials: KR
authors.lastname: Van Dijk
authors.forename: Aishwarya
authors.initials: A
authors.lastname: Sreenivasan
authors.forename: Tanveer
authors.initials: T
authors.lastname: Talukdar
authors.forename: Caroline
authors.initials: C
authors.lastname: Sullivan
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Schultz
authors.forename: Jorge
authors.initials: J
authors.lastname: Sepulcre
authors.forename: Deepti
authors.initials: D
authors.lastname: Putcha
authors.forename: Doug
authors.initials: D
authors.lastname: Greve
authors.forename: Keith A
authors.initials: KA
authors.lastname: Johnson
authors.forename: Reisa A
authors.initials: RA
authors.lastname: Sperling
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications* / Q000000981:diagnostic imaging / Q000473:pathology; D000682:Amyloid / Q000378:metabolism*; D000814:Aniline Compounds; D052160:Benzothiazoles; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000098:blood supply / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D003072:Cognition Disorders / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000097:blood; D049268:Positron-Emission Tomography / Q000379:methods; D013223:Statistics as Topic; D013844:Thiazoles
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D000682:Amyloid; D000814:Aniline Compounds; D052160:Benzothiazoles; D013844:Thiazoles; D019788:Fluorodeoxyglucose F18; D010100:Oxygen