Vascular dysfunction-The disregarded partner of Alzheimer's disease

Melanie D Sweeney; Axel Montagne; Abhay P Sagare; Daniel A Nation; Lon S Schneider; Helena C Chui; Michael G Harrington; Judy Pa; Meng Law; Danny J J Wang; Russell E Jacobs; Fergus N Doubal; Joel Ramirez; Sandra E Black; Maiken Nedergaard; Helene Benveniste; Martin Dichgans; Costantino Iadecola; Seth Love; Philip M Bath; Hugh S Markus; Rustam Al-Shahi Salman; Stuart M Allan; Terence J Quinn; Rajesh N Kalaria; David J Werring; Roxana O Carare; Rhian M Touyz; Steve C R Williams; Michael A Moskowitz; Zvonimir S Katusic; Sarah E Lutz; Orly Lazarov; Richard D Minshall; Jalees Rehman; Thomas P Davis; Cheryl L Wellington; Hector M González; Chun Yuan; Samuel N Lockhart; Timothy M Hughes; Christopher L H Chen; Perminder Sachdev; John T O'Brien; Ingmar Skoog; Leonardo Pantoni; Deborah R Gustafson; Geert Jan Biessels; Anders Wallin; Eric E Smith; Vincent Mok; Adrian Wong; Peter Passmore; Frederick Barkof; Majon Muller; Monique M B Breteler; Gustavo C Román; Edith Hamel; Sudha Seshadri; Rebecca F Gottesman; Mark A van Buchem; Zoe Arvanitakis; Julie A Schneider; Lester R Drewes; Vladimir Hachinski; Caleb E Finch; Arthur W Toga; Joanna M Wardlaw; Berislav V Zlokovic

doi:10.1016/j.jalz.2018.07.222

Vascular dysfunction-The disregarded partner of Alzheimer's disease

Alzheimers Dement. 2019 Jan;15(1):158-167. doi: 10.1016/j.jalz.2018.07.222.

Authors

Melanie D Sweeney¹, Axel Montagne¹, Abhay P Sagare¹, Daniel A Nation², Lon S Schneider³, Helena C Chui⁴, Michael G Harrington⁵, Judy Pa⁶, Meng Law⁷, Danny J J Wang⁶, Russell E Jacobs¹, Fergus N Doubal⁸, Joel Ramirez⁹, Sandra E Black¹⁰, Maiken Nedergaard¹¹, Helene Benveniste¹², Martin Dichgans¹³, Costantino Iadecola¹⁴, Seth Love¹⁵, Philip M Bath¹⁶, Hugh S Markus¹⁷, Rustam Al-Shahi Salman⁸, Stuart M Allan¹⁸, Terence J Quinn¹⁹, Rajesh N Kalaria²⁰, David J Werring²¹, Roxana O Carare²², Rhian M Touyz²³, Steve C R Williams²⁴, Michael A Moskowitz²⁵, Zvonimir S Katusic²⁶, Sarah E Lutz²⁷, Orly Lazarov²⁷, Richard D Minshall²⁸, Jalees Rehman²⁹, Thomas P Davis³⁰, Cheryl L Wellington³¹, Hector M González³², Chun Yuan³³, Samuel N Lockhart³⁴, Timothy M Hughes³⁴, Christopher L H Chen³⁵, Perminder Sachdev³⁶, John T O'Brien³⁷, Ingmar Skoog³⁸, Leonardo Pantoni³⁹, Deborah R Gustafson⁴⁰, Geert Jan Biessels⁴¹, Anders Wallin⁴², Eric E Smith⁴³, Vincent Mok⁴⁴, Adrian Wong⁴⁵, Peter Passmore⁴⁶, Frederick Barkof⁴⁷, Majon Muller⁴⁸, Monique M B Breteler⁴⁹, Gustavo C Román⁵⁰, Edith Hamel⁵¹, Sudha Seshadri⁵², Rebecca F Gottesman⁵³, Mark A van Buchem⁵⁴, Zoe Arvanitakis⁵⁵, Julie A Schneider⁵⁵, Lester R Drewes⁵⁶, Vladimir Hachinski⁵⁷, Caleb E Finch⁵⁸, Arthur W Toga⁵⁹, Joanna M Wardlaw⁸, Berislav V Zlokovic⁶⁰

Affiliations

¹ Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
² Department of Psychology, University of Southern California, Los Angeles, CA, USA; Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA.
³ Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁴ Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA; Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁵ Huntington Medical Research Institutes, Pasadena, CA, USA.
⁶ Laboratory of Neuro Imaging (LONI), Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷ Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA; Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁸ Neuroimaging Sciences and Brain Research Imaging Center, Division of Neuroimaging Sciences, Center for Clinical Brain Sciences, UK Dementia Research Institute at the University of Edinburgh, UK.
⁹ LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Medicine (Neurology), Hurvitz Brain Sciences Program, Canadian Partnership for Stroke Recovery, and LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto Dementia Research Alliance, University of Toronto, Toronto, Canada.
¹¹ Section for Translational Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Division of Glia Disease and Therapeutics, Center for Translational Neuromedicine, University of Rochester Medical School, Rochester, NY, USA.
¹² Department of Anesthesiology, Yale School of Medicine, New Haven, CT, USA.
¹³ Institute for Stroke and Dementia Research (ISD), Ludwing-Maximilians-University Munich, Munich, Germany.
¹⁴ Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
¹⁵ Institute of Clinical Neurosciences, University of Bristol, School of Medicine, Level 2 Learning and Research, Southmead Hospital, Bristol, UK.
¹⁶ Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, City Hospital Campus, Nottingham, UK; Stroke, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, UK.
¹⁷ Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
¹⁸ Faculty of Biology, Medicine and Health, Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, Manchester, UK.
¹⁹ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
²⁰ Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
²¹ Stroke Research Centre, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, UK.
²² Faculty of Medicine, University of Southampton, Southampton, UK.
²³ British Heart Foundation, Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK.
²⁴ Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
²⁵ Stroke and Neurovascular Regulation Laboratory, Departments of Radiology and Neurology Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
²⁶ Department of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA.
²⁷ Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA.
²⁸ Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, USA; Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA.
²⁹ Department of Pharmacology, The Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, IL, USA; Department of Medicine, The Center for Lung and Vascular Biology, The University of Illinois College of Medicine, Chicago, IL, USA.
³⁰ Department of Pharmacology, University of Arizona, Tucson, AZ, USA.
³¹ Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
³² Department of Neurosciences, University of California, San Diego, CA, USA.
³³ Department of Radiology, University of Washington, Seattle, WA, USA.
³⁴ Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; Alzheimer's Disease Research Center, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³⁵ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Memory Aging and Cognition Centre, National University Health System, Singapore; Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Memory Aging and Cognition Centre, National University Health System, Singapore.
³⁶ Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales Australia, Sydney, Australia.
³⁷ Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, UK.
³⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
³⁹ "L. Sacco" Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
⁴⁰ Department of Neurology, State University of New York-Downstate Medical Center, Brooklyn, NY, USA.
⁴¹ Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
⁴² Institute of Neuroscience and Physiology, University of Gothenburg, Gothenberg, Sweden.
⁴³ Hotchkiss Brain Institute, University of Calgary, Alberta, Canada.
⁴⁴ Department of Medicine and Therapeutics, Therese Pei Fong Chow Research Centre for Prevention of Dementia, The Chinese University of Hong Kong, Hong Kong SAR, China; Gerald Choa Neuroscience Centre, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁴⁵ Department of Medicine and Therapeutics, Therese Pei Fong Chow Research Centre for Prevention of Dementia, The Chinese University of Hong Kong, Hong Kong SAR, China.
⁴⁶ School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
⁴⁷ Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, The Netherlands; Institutes of Neurology and Healthcare Engineering, University College London, London, UK.
⁴⁸ Section of Geriatrics, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.
⁴⁹ Department of Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), Faculty of Medicine, University of Bonn, Bonn, Germany.
⁵⁰ Department of Neurology, Methodist Neurological Institute, Houston, TX, USA.
⁵¹ Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
⁵² The Framingham Heart Study, Framingham, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
⁵³ Departments of Neurology and Epidemiology, Johns Hopkins University, Baltimore, MD, USA.
⁵⁴ Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
⁵⁵ Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁵⁶ Laboratory of Cerebral Vascular Biology, Department of Biomedical Sciences, University of Minnesota Medical School Duluth, Duluth, MN, USA.
⁵⁷ Division of Neurology, Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada.
⁵⁸ Leonard Davis School of Gerontology, Dornsife College, University of Southern California, Los Angeles, CA, USA.
⁵⁹ Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA; Laboratory of Neuro Imaging (LONI), Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶⁰ Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Alzheimer's Disease Research Center, Keck School of Medicine at the University of Southern California, Los Angeles, CA, USA. Electronic address: zlokovic@usc.edu.

Abstract

Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.

Keywords: Alzheimer's disease; Biomarkers; Blood-brain barrier; Cerebral blood flow; MRI; Vascular.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / pathology
Alzheimer Disease / physiopathology*
Amyloid beta-Peptides / metabolism
Biomarkers*
Blood-Brain Barrier / metabolism
Brain / pathology
Cerebrovascular Circulation / physiology
Humans
National Institute on Aging (U.S.)
United States
Vascular Diseases / physiopathology*
White Matter / pathology*

Substances

Amyloid beta-Peptides
Biomarkers

Abstract

Publication types

MeSH terms

Substances

Grants and funding