title: Structural network alterations and neurological dysfunction in cerebral amyloid angiopathy.
abstract: Cerebral amyloid angiopathy is a common form of small-vessel disease and an important risk factor for cognitive impairment. The mechanisms linking small-vessel disease to cognitive impairment are not well understood. We hypothesized that in patients with cerebral amyloid angiopathy, multiple small spatially distributed lesions affect cognition through disruption of brain connectivity. We therefore compared the structural brain network in patients with cerebral amyloid angiopathy to healthy control subjects and examined the relationship between markers of cerebral amyloid angiopathy-related brain injury, network efficiency, and potential clinical consequences. Structural brain networks were reconstructed from diffusion-weighted magnetic resonance imaging in 38 non-demented patients with probable cerebral amyloid angiopathy (69 ± 10 years) and 29 similar aged control participants. The efficiency of the brain network was characterized using graph theory and brain amyloid deposition was quantified by Pittsburgh compound B retention on positron emission tomography imaging. Global efficiency of the brain network was reduced in patients compared to controls (0.187 ± 0.018 and 0.201 ± 0.015, respectively, P < 0.001). Network disturbances were most pronounced in the occipital, parietal, and posterior temporal lobes. Among patients, lower global network efficiency was related to higher cortical amyloid load (r = -0.52; P = 0.004), and to magnetic resonance imaging markers of small-vessel disease including increased white matter hyperintensity volume (P < 0.001), lower total brain volume (P = 0.02), and number of microbleeds (trend P = 0.06). Lower global network efficiency was also related to worse performance on tests of processing speed (r = 0.58, P < 0.001), executive functioning (r = 0.54, P = 0.001), gait velocity (r = 0.41, P = 0.02), but not memory. Correlations with cognition were independent of age, sex, education level, and other magnetic resonance imaging markers of small-vessel disease. These findings suggest that reduced structural brain network efficiency might mediate the relationship between advanced cerebral amyloid angiopathy and neurologic dysfunction and that such large-scale brain network measures may represent useful outcome markers for tracking disease progression.
authors.affiliation: 1 Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Yael D
authors.initials: YD
authors.lastname: Reijmer
authors.affiliation: 1 Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Fotiadis
authors.affiliation: 1 Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Sergi
authors.initials: S
authors.lastname: Martinez-Ramirez
authors.affiliation: 2 Athinoula A. Martinos Centre for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Salat
authors.affiliation: 2 Athinoula A. Martinos Centre for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Schultz
authors.affiliation: 1 Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Ashkan
authors.initials: A
authors.lastname: Shoamanesh
authors.affiliation: 1 Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Ayres
authors.affiliation: 1 Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Vashkevich
authors.affiliation: 3 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Rosas
authors.affiliation: 1 Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Schwab
authors.affiliation: 4 Image Sciences Institute, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Leemans
authors.affiliation: 5 Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: Biessels
authors.affiliation: 1 Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosand
authors.affiliation: 3 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 6 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Johnson
authors.affiliation: 1 Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Viswanathan
authors.affiliation: 1 Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: M Edip
authors.initials: ME
authors.lastname: Gurol
authors.affiliation: 1 Stroke Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA sgreenberg@mgh.harvard.edu.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Greenberg
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D001921:Brain / Q000473:pathology*; D016657:Cerebral Amyloid Angiopathy / Q000150:complications*; D003072:Cognition Disorders / Q000209:etiology; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D056324:Diffusion Tensor Imaging; D005260:Female; D007839:Functional Laterality; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D009422:Nervous System Diseases / Q000209:etiology* / Q000473:pathology*; D009434:Neural Pathways / Q000473:pathology*
keywords: amyloid imaging; executive function; mild cognitive impairment; small vessel disease; stroke: imaging; tractography