. 2020 Nov;16(11):1504-1514.

doi: 10.1002/alz.12150. Epub 2020 Aug 18.

Small vessel disease more than Alzheimer's disease determines diffusion MRI alterations in memory clinic patients

Sofia Finsterwalder¹, Naomi Vlegels², Benno Gesierich¹, Miguel Á Araque Caballero^{1

3}, Nick A Weaver², Nicolai Franzmeier¹, Marios K Georgakis¹, Marek J Konieczny¹, Huiberdina L Koek⁴; Dominantly Inherited Alzheimer Network (DIAN); Celeste M Karch⁵, Neill R Graff-Radford⁶, Stephen Salloway⁷, Hwamee Oh⁸, Ricardo F Allegri⁹, Jasmeer P Chhatwal¹⁰; DELCODE study group; Frank Jessen^{11

12}, Emrah Düzel^{13

14}, Laura Dobisch^{13

14}, Coraline Metzger^{13

14

15}, Oliver Peters^{16

17}, Enise I Incesoy¹⁷, Josef Priller^{16

17}, Eike J Spruth^{16

17}, Anja Schneider^{11

18}, Klaus Fließbach^{11

18}, Katharina Buerger^{1

3}, Daniel Janowitz¹, Stefan J Teipel^{19

20}, Ingo Kilimann^{19

20}, Christoph Laske^{21

22}, Martina Buchmann^{21

22}, Michael T Heneka^{11

18}, Frederic Brosseron^{11

18}, Annika Spottke^{11

23}, Nina Roy¹¹, Birgit Ertl-Wagner^{24

25}, Klaus Scheffler²⁶; Alzheimer's Disease Neuroimaging Initiative (ADNI); Utrecht VCI study group; Sang Won Seo^{27

28

29

30

31}, Yeshin Kim^{27

28

32}, Duk L Na^{27

28

31

33}, Hee Jin Kim^{27

28

31}, Hyemin Jang^{27

28

31}, Michael Ewers¹, Johannes Levin^{3

34

35}, Reinhold Schmidt³⁶, Ofer Pasternak³⁷, Martin Dichgans^{1

35}, Geert Jan Biessels², Marco Duering^{1

35}

Affiliations

¹ Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany.
² Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
³ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
⁴ Department of Geriatrics, University Medical Center Utrecht, Utrecht, the Netherlands.
⁵ Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri, USA.
⁶ Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, Florida, USA.
⁷ Butler Hospital, Providence, Rhode Island, USA.
⁸ Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
⁹ Department of Cognitive Neurology, FLENI Institute for Neurological Research, Buenos Aires, Argentina.
¹⁰ Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹¹ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
¹² Department of Psychiatry, University of Cologne, Medical Faculty, Cologne, Germany.
¹³ German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
¹⁴ Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany.
¹⁵ Department of Psychiatry and Psychotherapy, Otto-von-Guericke University, Magdeburg, Germany.
¹⁶ German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
¹⁷ Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Psychiatry and Psychotherapy, Berlin, Germany.
¹⁸ Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany.
¹⁹ German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany.
²⁰ Department of Psychosomatic Medicine, Rostock University Medical Center, Rostock, Germany.
²¹ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
²² Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany.
²³ Department of Neurology, University of Bonn, Bonn, Germany.
²⁴ Institute of Clinical Radiology, University Hospital, LMU Munich, Munich, Germany.
²⁵ Department of Medical Imaging, University of Toronto, Toronto, Canada.
²⁶ Department for Biomedical Magnetic Resonance, University of Tübingen, Tübingen, Germany.
²⁷ Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
²⁸ Neuroscience Center, Samsung Medical Center, Seoul, South Korea.
²⁹ Department of Clinical Research Design and Evaluation, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea.
³⁰ Center for Imaging of Neurodegenerative Diseases, University of California, San Francisco, California, USA.
³¹ Samsung Alzheimer Research Center, Samsung Medical Center, Seoul, South Korea.
³² Department of Neurology, Kangwon National University Hospital, Kangwon National University College of Medicine, Chuncheon, South Korea.
³³ Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea.
³⁴ Department of Neurology, University Hospital, LMU Munich, Munich, Germany.
³⁵ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
³⁶ Department of Neurology, Medical University of Graz, Graz, Austria.
³⁷ Department of Psychiatry and Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

PMID: 32808747
PMCID: PMC8102202
DOI: 10.1002/alz.12150

Small vessel disease more than Alzheimer's disease determines diffusion MRI alterations in memory clinic patients

Sofia Finsterwalder et al. Alzheimers Dement. 2020 Nov.

. 2020 Nov;16(11):1504-1514.

doi: 10.1002/alz.12150. Epub 2020 Aug 18.

Authors

Affiliations

¹ Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany.
² Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
³ German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
⁴ Department of Geriatrics, University Medical Center Utrecht, Utrecht, the Netherlands.
⁵ Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri, USA.
⁶ Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, Florida, USA.
⁷ Butler Hospital, Providence, Rhode Island, USA.
⁸ Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
⁹ Department of Cognitive Neurology, FLENI Institute for Neurological Research, Buenos Aires, Argentina.
¹⁰ Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹¹ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
¹² Department of Psychiatry, University of Cologne, Medical Faculty, Cologne, Germany.
¹³ German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
¹⁴ Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany.
¹⁵ Department of Psychiatry and Psychotherapy, Otto-von-Guericke University, Magdeburg, Germany.
¹⁶ German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
¹⁷ Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Psychiatry and Psychotherapy, Berlin, Germany.
¹⁸ Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany.
¹⁹ German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany.
²⁰ Department of Psychosomatic Medicine, Rostock University Medical Center, Rostock, Germany.
²¹ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
²² Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany.
²³ Department of Neurology, University of Bonn, Bonn, Germany.
²⁴ Institute of Clinical Radiology, University Hospital, LMU Munich, Munich, Germany.
²⁵ Department of Medical Imaging, University of Toronto, Toronto, Canada.
²⁶ Department for Biomedical Magnetic Resonance, University of Tübingen, Tübingen, Germany.
²⁷ Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
²⁸ Neuroscience Center, Samsung Medical Center, Seoul, South Korea.
²⁹ Department of Clinical Research Design and Evaluation, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea.
³⁰ Center for Imaging of Neurodegenerative Diseases, University of California, San Francisco, California, USA.
³¹ Samsung Alzheimer Research Center, Samsung Medical Center, Seoul, South Korea.
³² Department of Neurology, Kangwon National University Hospital, Kangwon National University College of Medicine, Chuncheon, South Korea.
³³ Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea.
³⁴ Department of Neurology, University Hospital, LMU Munich, Munich, Germany.
³⁵ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
³⁶ Department of Neurology, Medical University of Graz, Graz, Austria.
³⁷ Department of Psychiatry and Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

PMID: 32808747
PMCID: PMC8102202
DOI: 10.1002/alz.12150

Abstract

Introduction: Microstructural alterations as assessed by diffusion tensor imaging (DTI) are key findings in both Alzheimer's disease (AD) and small vessel disease (SVD). We determined the contribution of each of these conditions to diffusion alterations.

Methods: We studied six samples (N = 365 participants) covering the spectrum of AD and SVD, including genetically defined samples. We calculated diffusion measures from DTI and free water imaging. Simple linear, multivariable random forest, and voxel-based regressions were used to evaluate associations between AD biomarkers (amyloid beta, tau), SVD imaging markers, and diffusion measures.

Results: SVD markers were strongly associated with diffusion measures and showed a higher contribution than AD biomarkers in multivariable analysis across all memory clinic samples. Voxel-wise analyses between tau and diffusion measures were not significant.

Discussion: In memory clinic patients, the effect of SVD on diffusion alterations largely exceeds the effect of AD, supporting the value of diffusion measures as markers of SVD.

Keywords: Alzheimer's disease; biomarker; cerebral small vessel disease; diffusion tensor imaging; free water imaging; white matter.

PubMed Disclaimer

Conflict of interest statement

Declarations of Interest

None.

Figures

**Figure 1.. Study concept and participant selection flowchart.**
Samples cover the entire spectrum of AD, mixed disease, and SVD. AD, Alzheimer’s disease; DTI, diffusion tensor imaging; EYO, estimated years from symptom onset; FLAIR, fluid-attenuated inversion recovery; p-tau, phosphorylated-tau₁₈₁; SVD, small vessel disease; t-tau, total tau.

**Figure 2.. Simple regression analyses.**
Simple linear regression analyses between diffusion measures and AD biomarkers or SVD markers. Standardized β is represented by color. AD, Alzheimer’s disease; β_s, standardized beta; FAu, uncorrected fractional anisotropy; FAt, free water corrected tissue compartment of fractional anisotropy; FW, free water content; MDu, uncorrected mean diffusivity; MDt, free water corrected tissue compartment of mean diffusivity; np, not possible (all patients had the maximum score); ns, not significant; p-tau, phosphorylated- tau₁₈₁; SVD, small vessel disease; SVD score, total small vessel disease score; t-tau, total tau; WMHvol, white matter hyperintensity volume.

**Figure 3.. Multivariable analyses.**
Random forest regression analyses for estimating the relative variable importance of AD biomarkers (grey bars), SVD markers (black bars), age and sex (white bars) with regard to conventional DTI measures (FAu, MDu) while accounting for all other variables (conditional importance). Lines indicate the 95% confidence interval for the conditional variable importance. AD, Alzheimer’s disease; FAu, uncorrected fractional anisotropy; MDu, uncorrected mean diffusivity; p-tau, phosphorylated-tau₁₈₁; SVD, small vessel disease; SVD score, total small vessel disease score; T-tau, total tau; WMHvol, white matter hyperintensity volume.

See this image and copyright information in PMC

References

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1. Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. The Lancet Neurology. 2013;12(8):822–838. - PMC - PubMed
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Small vessel disease more than Alzheimer's disease determines diffusion MRI alterations in memory clinic patients

Affiliations

Small vessel disease more than Alzheimer's disease determines diffusion MRI alterations in memory clinic patients

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical