White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities

doi:10.1016/j.trci.2019.02.001

Review

. 2019 Apr 9:5:107-117.

doi: 10.1016/j.trci.2019.02.001. eCollection 2019.

White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities

Jessica Alber¹, Suvarna Alladi², Hee-Joon Bae³, David A Barton⁴, Laurel A Beckett⁵, Joanne M Bell⁶, Sara E Berman⁷, Geert Jan Biessels⁸, Sandra E Black⁹, Isabelle Bos¹⁰, Gene L Bowman^{11

12

13}, Emanuele Brai¹⁴, Adam M Brickman¹⁵, Brandy L Callahan¹⁶, Roderick A Corriveau¹⁶, Silvia Fossati¹⁷, Rebecca F Gottesman¹⁸, Deborah R Gustafson¹⁹, Vladimir Hachinski²⁰, Kathleen M Hayden²¹, Alex M Helman²², Timothy M Hughes²³, Jeremy D Isaacs²⁴, Angela L Jefferson²⁵, Sterling C Johnson²⁶, Alifiya Kapasi²⁷, Silke Kern²⁸, Jay C Kwon²⁹, Juraj Kukolja³⁰, Athene Lee³¹, Samuel N Lockhart³², Anne Murray³³, Katie E Osborn²⁵, Melinda C Power³⁴, Brittani R Price³⁵, Hanneke F M Rhodius-Meester³⁶, Jacqueline A Rondeau³⁷, Allyson C Rosen³⁸, Douglas L Rosene³⁹, Julie A Schneider⁴⁰, Henrieta Scholtzova⁴¹, C Elizabeth Shaaban⁴², Narlon C B S Silva⁴³, Heather M Snyder⁴⁴, Walter Swardfager⁴⁵, Aron M Troen⁴⁶, Susanne J van Veluw⁴⁷, Prashanthi Vemuri⁴⁸, Anders Wallin⁴⁹, Cheryl Wellington⁵⁰, Donna M Wilcock⁵¹, Sharon Xiangwen Xie⁵², Atticus H Hainsworth⁵³

Affiliations

¹ Department of Biomedical and Pharmaceutical Sciences, George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, USA.
² Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.
³ Cerebrovascular Disease Center, Seoul National University Bundang Hospital, Seongnam, Korea.
⁴ Department of Psychiatry, University of Melbourne, Melbourne, Australia.
⁵ Department of Public Health Sciences, School of Medicine University of California, Davis, CA, USA.
⁶ Syneos Health, Wilmington, NC, USA.
⁷ Wisconsin Alzheimer's Disease Research Center, Medical Scientist Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
⁸ Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus Institute, University Medical Center Utrecht, Utrecht, The Netherlands.
⁹ Department of Medicine, University of Toronto, Sunnybrook Research Institute, Toronto, ON, Canada.
¹⁰ Department of Psychiatry & Neuropsychology, Alzheimer Centre Limburg, School for Mental Health & Neuroscience, Maastricht University, Maastricht, The Netherlands.
¹¹ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹² Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.
¹³ Department of Neurology, Oregon Health & Science University, Portland, OR, USA.
¹⁴ Neuro-Bio Ltd, Culham Science Centre, Abingdon, UK.
¹⁵ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
¹⁶ Department of Psychology, University of Calgary & Hotchkiss Brain Institute, Calgary, AB, Canada.
¹⁷ Departments of Neurology and Psychiatry, NYU School of Medicine, New York, NY, USA.
¹⁸ Division of Cerebrovascular Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁹ Section for NeuroEpidemiology, State University of New York - Downstate Medical Center, Brooklyn, NY, USA.
²⁰ Western University, London Health Sciences Centre, London, ON, Canada.
²¹ Department of Social Sciences and Health Policy, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
²² University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY, USA.
²³ Department of Internal Medicine - Section of Gerontology and Geriatric Medicine, and Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC, USA.
²⁴ St George's University of London and Department of Neurology, St George's University Hospitals NHS Foundation Trust, London, UK.
²⁵ Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁶ Department of Medicine-Geriatrics, Institute on Aging, University of Wisconsin-Madison, Madison, WI, USA.
²⁷ Department of Pathology (Neuropathology), Rush Alzheimer's Disease Center, Chicago, IL, USA.
²⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
²⁹ Department of Neurology, Changwon Fatima Hospital, Changwon, Korea.
³⁰ Department of Neurology and Clinical Neurophysiology, Helios University Hospital Wuppertal, Wuppertal, Germany.
³¹ Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.
³² Department of Internal Medicine - Section of Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³³ Berman Center for Outcomes and Clinical Research, 20298 Minneapolis Medical Research Foundation, Minneapolis, MN, USA.
³⁴ Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, George Washington University, Washington, DC, USA.
³⁵ Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
³⁶ Alzheimer Center, Department of Neurology, VU University Medical Centre, Amsterdam Neuroscience, Amsterdam, The Netherlands.
³⁷ Montclair Memory Clinic, Montclair, NJ, USA.
³⁸ Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.
³⁹ Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, USA.
⁴⁰ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago IL, USA.
⁴¹ Department of Neurology, NYU School of Medicine, New York, NY, USA.
⁴² Department of Epidemiology, Graduate School of Public Health & Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA, USA.
⁴³ School of Kinesiology, Western Centre for Public Health & Family Medicine, London, ON, Canada.
⁴⁴ Division of Medical and Scientific Relations, Alzheimer's Association, Chicago, IL, USA.
⁴⁵ Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.
⁴⁶ Institute of Biochemistry Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture Food and Environment, The Hebrew University of Jerusalem, Jerusalem, Israel.
⁴⁷ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁴⁸ Department of Radiology, Mayo Clinic Rochester, Rochester, MN, USA.
⁴⁹ Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
⁵⁰ Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.
⁵¹ Sanders-Brown Center on Aging, Department of Physiology, University of Kentucky, Lexington, KY, USA.
⁵² Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, USA.
⁵³ Molecular & Clinical Sciences Research Institute, St George's University of London and Department of Neurology, St George's University Hospitals NHS Foundation Trust, London, UK.

PMID: 31011621
PMCID: PMC6461571
DOI: 10.1016/j.trci.2019.02.001

Review

White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities

Jessica Alber et al. Alzheimers Dement (N Y). 2019.

. 2019 Apr 9:5:107-117.

doi: 10.1016/j.trci.2019.02.001. eCollection 2019.

Authors

Affiliations

¹ Department of Biomedical and Pharmaceutical Sciences, George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, USA.
² Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India.
³ Cerebrovascular Disease Center, Seoul National University Bundang Hospital, Seongnam, Korea.
⁴ Department of Psychiatry, University of Melbourne, Melbourne, Australia.
⁵ Department of Public Health Sciences, School of Medicine University of California, Davis, CA, USA.
⁶ Syneos Health, Wilmington, NC, USA.
⁷ Wisconsin Alzheimer's Disease Research Center, Medical Scientist Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
⁸ Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus Institute, University Medical Center Utrecht, Utrecht, The Netherlands.
⁹ Department of Medicine, University of Toronto, Sunnybrook Research Institute, Toronto, ON, Canada.
¹⁰ Department of Psychiatry & Neuropsychology, Alzheimer Centre Limburg, School for Mental Health & Neuroscience, Maastricht University, Maastricht, The Netherlands.
¹¹ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹² Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.
¹³ Department of Neurology, Oregon Health & Science University, Portland, OR, USA.
¹⁴ Neuro-Bio Ltd, Culham Science Centre, Abingdon, UK.
¹⁵ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
¹⁶ Department of Psychology, University of Calgary & Hotchkiss Brain Institute, Calgary, AB, Canada.
¹⁷ Departments of Neurology and Psychiatry, NYU School of Medicine, New York, NY, USA.
¹⁸ Division of Cerebrovascular Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁹ Section for NeuroEpidemiology, State University of New York - Downstate Medical Center, Brooklyn, NY, USA.
²⁰ Western University, London Health Sciences Centre, London, ON, Canada.
²¹ Department of Social Sciences and Health Policy, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
²² University of Kentucky, Sanders-Brown Center on Aging, Lexington, KY, USA.
²³ Department of Internal Medicine - Section of Gerontology and Geriatric Medicine, and Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC, USA.
²⁴ St George's University of London and Department of Neurology, St George's University Hospitals NHS Foundation Trust, London, UK.
²⁵ Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁶ Department of Medicine-Geriatrics, Institute on Aging, University of Wisconsin-Madison, Madison, WI, USA.
²⁷ Department of Pathology (Neuropathology), Rush Alzheimer's Disease Center, Chicago, IL, USA.
²⁸ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
²⁹ Department of Neurology, Changwon Fatima Hospital, Changwon, Korea.
³⁰ Department of Neurology and Clinical Neurophysiology, Helios University Hospital Wuppertal, Wuppertal, Germany.
³¹ Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI, USA.
³² Department of Internal Medicine - Section of Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³³ Berman Center for Outcomes and Clinical Research, 20298 Minneapolis Medical Research Foundation, Minneapolis, MN, USA.
³⁴ Department of Epidemiology and Biostatistics, Milken Institute School of Public Health, George Washington University, Washington, DC, USA.
³⁵ Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
³⁶ Alzheimer Center, Department of Neurology, VU University Medical Centre, Amsterdam Neuroscience, Amsterdam, The Netherlands.
³⁷ Montclair Memory Clinic, Montclair, NJ, USA.
³⁸ Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.
³⁹ Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, USA.
⁴⁰ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago IL, USA.
⁴¹ Department of Neurology, NYU School of Medicine, New York, NY, USA.
⁴² Department of Epidemiology, Graduate School of Public Health & Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA, USA.
⁴³ School of Kinesiology, Western Centre for Public Health & Family Medicine, London, ON, Canada.
⁴⁴ Division of Medical and Scientific Relations, Alzheimer's Association, Chicago, IL, USA.
⁴⁵ Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.
⁴⁶ Institute of Biochemistry Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture Food and Environment, The Hebrew University of Jerusalem, Jerusalem, Israel.
⁴⁷ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁴⁸ Department of Radiology, Mayo Clinic Rochester, Rochester, MN, USA.
⁴⁹ Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
⁵⁰ Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.
⁵¹ Sanders-Brown Center on Aging, Department of Physiology, University of Kentucky, Lexington, KY, USA.
⁵² Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, USA.
⁵³ Molecular & Clinical Sciences Research Institute, St George's University of London and Department of Neurology, St George's University Hospitals NHS Foundation Trust, London, UK.

PMID: 31011621
PMCID: PMC6461571
DOI: 10.1016/j.trci.2019.02.001

Abstract

White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia.

Keywords: Leukoaraiosis; Small vessel disease; Vascular cognitive impairment; Vascular dementia; White matter lesions.

PubMed Disclaimer

Figures

**Fig. 1**
MRI scans showing typical examples of WMHs of presumed vascular origin. (A) Punctate deep subcortical WMH in the left hemisphere and periventricular caps. This scan is Fazekas grade 1, on the Fazekas scale of WMH severity (range: 0-3). In the right thalamus, a lacune can be seen. (B, C) Two examples of severe confluent WMH. Note that borders between periventricular and deep subcortical WMHs become difficult to define. Scans B and C are Fazekas grade 3. Scans A-C are FLAIR sequences. Figure provided by GJ Biessels. Abbreviations: MRI, magnetic resonance imaging; WMHs, white matter hyperintensities; FLAIR, fluid-attenuated inversion recovery.

**Fig. 2**
Conceptual clinical courses leading to vascular dementia. (A) Multi-infarct dementia, stepwise pattern of cognitive decline. (B) Strategic vascular dementia due to a focal lesion in a clinically eloquent site. One-step pattern, with some recovery. (C) WMH-associated subcortical vascular dementia. Slow progression without stepwise pattern. Figure provided by J Kwon. Abbreviation: WMH, white matter hyperintensity.

See this image and copyright information in PMC

Cited by

Research progress on cognitive impairment and the expression of serum inflammatory markers in patients with white matter hyperintensities: a narrative review.
Qiao S, Li H, Guo F, Cai G, Zhang Y. Qiao S, et al. Ann Transl Med. 2022 Apr;10(7):421. doi: 10.21037/atm-22-1016. Ann Transl Med. 2022. PMID: 35530941 Free PMC article. Review.
Cerebral small vessel disease, cardiovascular risk factors, and future walking speed in old age: a population-based cohort study.
Heiland EG, Welmer AK, Kalpouzos G, Laveskog A, Wang R, Qiu C. Heiland EG, et al. BMC Neurol. 2021 Dec 24;21(1):496. doi: 10.1186/s12883-021-02529-6. BMC Neurol. 2021. PMID: 34949170 Free PMC article.
A multiphysics model to predict periventricular white matter hyperintensity growth during healthy brain aging.
Caçoilo A, Dortdivanlioglu B, Rusinek H, Weickenmeier J. Caçoilo A, et al. Brain Multiphys. 2023 Dec;5:100072. doi: 10.1016/j.brain.2023.100072. Epub 2023 May 26. Brain Multiphys. 2023. PMID: 37546181 Free PMC article.
Clinical and cognitive correlates tractography analysis in patients with white matter hyperintensity of vascular origin.
Kuang Q, Huang M, Lei Y, Wu L, Jin C, Dai J, Zhou F. Kuang Q, et al. Front Neurosci. 2023 Jun 16;17:1187979. doi: 10.3389/fnins.2023.1187979. eCollection 2023. Front Neurosci. 2023. PMID: 37397447 Free PMC article.
Distinct patterns of voxel- and connection-based white matter hyperintensity distribution and associated factors in early-onset and late-onset Alzheimer's disease.
Hong H, Chen Y, Liu W, Luo X, Zhang M; Alzheimer's Disease Neuroimaging Initiative (ADNI). Hong H, et al. Alzheimers Dement (Amst). 2024 Apr 22;16(2):e12585. doi: 10.1002/dad2.12585. eCollection 2024 Apr-Jun. Alzheimers Dement (Amst). 2024. PMID: 38651161 Free PMC article.

See all "Cited by" articles

References

1. Prins N.D., Scheltens P. White matter hyperintensities, cognitive impairment and dementia: an update. Nat Rev Neurol. 2015;11:157–165. - PubMed
1. Debette S., Markus H.S. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2010;341:c3666. - PMC - PubMed
1. Kloppenborg R.P., Nederkoorn P.J., Geerlings M.I., van den Berg E. Presence and progression of white matter hyperintensities and cognition: a meta-analysis. Neurology. 2014;82:2127–2138. - PubMed
1. De Guio F., Vignaud A., Chabriat H., Jouvent E. Different types of white matter hyperintensities in CADASIL: insights from 7-Tesla MRI. J Cereb Blood Flow Metab. 2017 271678X17690164. - PMC - PubMed
1. Maniega S.M., Valdes Hernandez M.C., Clayden J.D., Royle N.A., Murray C., Morris Z. White matter hyperintensities and normal-appearing white matter integrity in the aging brain. Neurobiol Aging. 2015;36:909–918. - PMC - PubMed

Publication types

Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
Medical
- ClinicalTrials.gov

[1] Prins N.D., Scheltens P. White matter hyperintensities, cognitive impairment and dementia: an update. Nat Rev Neurol. 2015;11:157–165. - PubMed

[2] Prins N.D., Scheltens P. White matter hyperintensities, cognitive impairment and dementia: an update. Nat Rev Neurol. 2015;11:157–165. - PubMed

[3] Debette S., Markus H.S. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2010;341:c3666. - PMC - PubMed

[4] Debette S., Markus H.S. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2010;341:c3666. - PMC - PubMed

[5] Kloppenborg R.P., Nederkoorn P.J., Geerlings M.I., van den Berg E. Presence and progression of white matter hyperintensities and cognition: a meta-analysis. Neurology. 2014;82:2127–2138. - PubMed

[6] Kloppenborg R.P., Nederkoorn P.J., Geerlings M.I., van den Berg E. Presence and progression of white matter hyperintensities and cognition: a meta-analysis. Neurology. 2014;82:2127–2138. - PubMed

[7] De Guio F., Vignaud A., Chabriat H., Jouvent E. Different types of white matter hyperintensities in CADASIL: insights from 7-Tesla MRI. J Cereb Blood Flow Metab. 2017 271678X17690164. - PMC - PubMed

[8] De Guio F., Vignaud A., Chabriat H., Jouvent E. Different types of white matter hyperintensities in CADASIL: insights from 7-Tesla MRI. J Cereb Blood Flow Metab. 2017 271678X17690164. - PMC - PubMed

[9] Maniega S.M., Valdes Hernandez M.C., Clayden J.D., Royle N.A., Murray C., Morris Z. White matter hyperintensities and normal-appearing white matter integrity in the aging brain. Neurobiol Aging. 2015;36:909–918. - PMC - PubMed

[10] Maniega S.M., Valdes Hernandez M.C., Clayden J.D., Royle N.A., Murray C., Morris Z. White matter hyperintensities and normal-appearing white matter integrity in the aging brain. Neurobiol Aging. 2015;36:909–918. - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities

Affiliations

White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities

Authors

Affiliations

Abstract

Figures

Similar articles

Cited by

References

Publication types

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Abstract

Figures

Similar articles

Cited by

References

Publication types

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical