Featured Article Small vessel disease is linked to disrupted structural network covariance in Alzheimer’s disease Q15 Sean M. Nestor a,b,c,d,e, *, Bratislav Mi  si  c f , Joel Ramirez a,b,c , Jiali Zhao a,b , Simon J. Graham b,c,g , Nicolaas P. L. G. Verhoeff h , Donald T. Stuss c,i,j,k , Mario Masellis a,b,c,d,l , Sandra E. Black a,b,c,d,g,k,l,m a LC Campbell Cognitive Neurology Research Unit, Ontario, Canada Q2 b Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Ontario, Canada c Hurvitz Brain Sciences ResearchProgram, Sunnybrook Research Institute, University of Toronto, Ontario, Canada d Institute of Medical Science, University of Toronto, Ontario, Canada e Faculty of Medicine, University of Toronto, Ontario, Canada f Department of Psychological and Brain Sciences, Indiana University, IN, USA g Department of Medical Biophysics, University of Toronto, Ontario, Canada h Department of Psychiatry, Baycrest Health Sciences Centre and University of Toronto, Ontario, Canada i Department of Medicine, University of Toronto, Ontario, Canada j Department of Psychology, University of Toronto, Ontario, Canada k Rotman Research Institute, Baycrest Health Sciences Centre, Ontario, Canada l Department of Medicine, Neurology, Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada m Ontario Brain Institute, Ontario, Canada Abstract Introduction: Cerebral small vessel disease (SVD) is thought to contribute to Alzheimer’s disease (AD) through abnormalities in white matter networks. Gray matter (GM) hub covariance networks share only partial overlap with white matter connectivity, and their relationship with SVD has not been examined in AD. Methods: We developed a multivariate analytical pipeline to elucidate the cortical GM thickness systems that covary with major network hubs and assessed whether SVD and neurodegenerative path- ologic markers were associated with attenuated covariance network integrity in mild AD and normal elderly control subjects. Results: SVD burden was associated with reduced posterior cingulate corticocortical GM network integrity and subneocorticocortical hub network integrity in AD. Discussion: These findings provide evidence that SVD is linked to the selective disruption of cortical hub GM networks in AD brains and point to the need to consider GM hub covariance networks when assessing network disruption in mixed disease. Ó 2016 Published by Elsevier Inc. on behalf of the Alzheimer’s Association. Keywords: Alzheimer’s disease; Small vessel disease; White matter hyperintensity; Hippocampal volume; Magnetic reso- nance imaging; Structural covariance networks; Cortical thickness; Rich-Club network; Shape analysis; Partial least squares 1. Background Alzheimer’s disease (AD) is increasingly conceptualized as the degradation of select cortical hub networks integrated by white matter pathways [1–5]. Adequate perfusion is critical for maintaining stable brain hub energetics and *Corresponding author. Tel.: 4163470257; Fax: ---. Q3 E-mail address: sean.nestor@mail.utoronto.ca http://dx.doi.org/10.1016/j.jalz.2016.12.007 1552-5260/Ó 2016 Published by Elsevier Inc. on behalf of the Alzheimer’s Association. FLA 5.4.0 DTD  JALZ2328_proof  27 January 2017  2:40 pm  ce Alzheimer’s & Dementia - (2017) 1-12 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117