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Abstract

Objective

To test the hypothesis that multi-shell diffusion models improve the characterization of microstructural alterations in cerebral small vessel disease (SVD), we assessed associations with processing speed performance, longitudinal change, and reproducibility of diffusion metrics.

Methods

We included 50 patients with sporadic and 59 patients with genetically defined SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) with cognitive testing and standardized 3T MRI, including multi-shell diffusion imaging. We applied the simple diffusion tensor imaging (DTI) model and 2 advanced models: diffusion kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI). Linear regression and multivariable random forest regression (including conventional SVD markers) were used to determine associations between diffusion metrics and processing speed performance. The detection of short-term disease progression was assessed by linear mixed models in 49 patients with sporadic SVD with longitudinal high-frequency imaging (in total 459 MRIs). Intersite reproducibility was determined in 10 patients with CADASIL scanned back-to-back on 2 different 3T MRI scanners.

Results

Metrics from DKI showed the strongest associations with processing speed performance (R2 up to 21%) and the largest added benefit on top of conventional SVD imaging markers in patients with sporadic SVD and patients with CADASIL with lower SVD burden. Several metrics from DTI and DKI performed similarly in detecting disease progression. Reproducibility was excellent (intraclass correlation coefficient >0.93) for DTI and DKI metrics. NODDI metrics were less reproducible.

Conclusion

Multi-shell diffusion imaging and DKI improve the detection and characterization of cognitively relevant microstructural white matter alterations in SVD. Excellent reproducibility of diffusion metrics endorses their use as SVD markers in research and clinical care. Our publicly available intersite dataset facilitates future studies.

Classification of evidence

This study provides Class I evidence that in patients with SVD, diffusion MRI metrics are associated with processing speed performance.

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References

1.
Wardlaw JM, Smith C, Dichgans M. Small vessel disease: mechanisms and clinical implications. Lancet Neurol 2019;18:684–696.
2.
Smith EE, Schneider JA, Wardlaw JM, Greenberg SM. Cerebral microinfarcts: the invisible lesions. Lancet Neurol 2012;11:272–282.
3.
Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013;12:822–838.
4.
Baykara E, Gesierich B, Adam R, et al. A novel imaging marker for small vessel disease based on skeletonization of white matter tracts and diffusion histograms. Ann Neurol 2016;80:581–592.
5.
Nitkunan A, Barrick TR, Charlton RA, Clark CA, Markus HS. Multimodal MRI in cerebral small vessel disease: its relationship with cognition and sensitivity to change over time. Stroke 2008;39:1999–2005.
6.
Patel B, Markus HS. Magnetic resonance imaging in cerebral small vessel disease and its use as a surrogate disease marker. Int J Stroke 2011;6:47–59.
7.
Zeestraten EA, Benjamin P, Lambert C, et al. Application of diffusion tensor imaging parameters to detect change in longitudinal studies in cerebral small vessel disease. PLoS One 2016;11:e0147836.
8.
Jensen JH, Helpern JA, Ramani A, Lu H, Kaczynski K. Diffusional kurtosis imaging: the quantification of non-Gaussian water diffusion by means of magnetic resonance imaging. Magn Reson Med 2005;53:1432–1440.
9.
Zhang H, Schneider T, Wheeler-Kingshott CA, Alexander DC. NODDI: practical in vivo neurite orientation dispersion and density imaging of the human brain. Neuroimage 2012;61:1000–1016.
10.
ter Telgte A, Wiegertjes K, Tuladhar AM, et al. Investigating the origin and evolution of cerebral small vessel disease: the RUN DMC-InTENse study. Eur Stroke J 2018;3:369–378.
11.
ter Telgte A, Wiegertjes K, Gesierich B, et al. The contribution of acute infarcts to cerebral small vessel disease progression. Ann Neurol 2019;86:582–592.
12.
Duering M, Zieren N, Herve D, et al. Strategic role of frontal white matter tracts in vascular cognitive impairment: a voxel-based lesion-symptom mapping study in CADASIL. Brain 2011;134:2366–2375.
13.
Charlton RA, Morris RG, Nitkunan A, Markus HS. The cognitive profiles of CADASIL and sporadic small vessel disease. Neurology 2006;66:1523–1526.
14.
Zieren N, Duering M, Peters N, et al. Education modifies the relation of vascular pathology to cognitive function: cognitive reserve in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Neurobiol Aging 2013;34:400–407.
15.
Tombaugh TN. Trail Making Test A and B: normative data stratified by age and education. Arch Clin Neuropsychol 2004;19:203–214.
16.
Tournier JD, Smith R, Raffelt D, et al. MRtrix3: a fast, flexible and open software framework for medical image processing and visualisation. Neuroimage 2019;202:116137.
17.
Smith SM, Jenkinson M, Woolrich MW, et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 2004;23(suppl 1):S208–S219.
18.
Tabesh A, Jensen JH, Ardekani BA, Helpern JA. Estimation of tensors and tensor-derived measures in diffusional kurtosis imaging. Magn Reson Med 2011;65:823–836.
19.
R Core Team. A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing; 2016.
20.
Yeo IK, Johnson RA. A new family of power transformations to improve normality or symmetry. Biometrika 2000;87:954–959.
21.
Strobl C, Malley J, Tutz G. An introduction to recursive partitioning: rationale, application, and characteristics of classification and regression trees, bagging, and random forests. Psychol Methods 2009;14:323–348.
22.
Bates D, Mächler M, Bolker B, Walker S. Fitting linear mixed-effects models using Lme4. arXiv 2014:14065823.
23.
Kuznetsova A, Brockhoff PB, Christensen RHB. lmerTest package: tests in linear mixed effects models. J Stat Softw 2017;82.
24.
Canty A, Ripley B. boot: Bootstrap R (S-Plus) Functions: R Package Version 1.3-11. The R Package for Statistical Reporting: 2014.
25.
Barton K, Barton MK. Package “MuMIn”: Multi-Model Inference Version 1. The R Package for Statistical Reporting: 2019.
26.
Revelle WR. psych: Procedures for Personality and Psychological Research. Evanston, IL: Northwestern University: 2017.
27.
Shrout PE, Fleiss JL. Intraclass correlations: uses in assessing rater reliability. Psychol Bull 1979;86:420–428.
28.
Zhao J, Wang YL, Li XB, et al. Comparative analysis of the diffusion kurtosis imaging and diffusion tensor imaging in grading gliomas, predicting tumour cell proliferation and IDH-1 gene mutation status. J Neurooncol 2019;141:195–203.
29.
Wang Z, Zhang S, Liu C, et al. A study of neurite orientation dispersion and density imaging in ischemic stroke. Magn Reson Imaging 2019;57:28–33.
30.
Bester M, Jensen JH, Babb JS, et al. Non-Gaussian diffusion MRI of gray matter is associated with cognitive impairment in multiple sclerosis. Mult Scler 2015;21:935–944.
31.
Zhong G, Zhang R, Jiaerken Y, et al. Better correlation of cognitive function to white matter integrity than to blood supply in subjects with leukoaraiosis. Front Aging Neurosci 2017;9:185.
32.
Xu S, Ye D, Lian T, et al. Assessment of severity of leukoaraiosis: a diffusional kurtosis imaging study. Clin Imaging 2016;40:732–738.
33.
Grussu F, Schneider T, Tur C, et al. Neurite dispersion: a new marker of multiple sclerosis spinal cord pathology? Ann Clin Transl Neurol 2017;4:663–679.
34.
Duering M, Finsterwalder S, Baykara E, et al. Free water determines diffusion alterations and clinical status in cerebral small vessel disease. Alzheimers Demen 2018;14:764–774.
35.
Setsompop K, Cohen-Adad J, Gagoski B, et al. Improving diffusion MRI using simultaneous multi-slice echo planar imaging. Neuroimage 2012;63:569–580.
36.
Grech-Sollars M, Hales PW, Miyazaki K, et al. Multi-centre reproducibility of diffusion MRI parameters for clinical sequences in the brain. NMR Biomed 2015;28:468–485.
37.
Kuhn T, Gullett J, Nguyen P, et al. Test-retest reliability of high angular resolution diffusion imaging acquisition within medial temporal lobe connections assessed via tract based spatial statistics, probabilistic tractography and a novel graph theory metric. Brain Imaging Behav 2016;10:533–547.
38.
Tariq M, Schneider T, Alexander DC, Wheeler-Kingshot C, Zhang H. Scan-rescan reproducibility of neurite microstructure estimates using NODDI. The British Machine Vision Association and Society for Pattern Recognition; 2012.
39.
Wollenweber FA, Baykara E, Zedde M, et al. Cortical superficial siderosis in different types of cerebral small vessel disease. Stroke 2017;48:1404–1407.
40.
Duering M, Csanadi E, Gesierich B, et al. Incident lacunes preferentially localize to the edge of white matter hyperintensities: insights into the pathophysiology of cerebral small vessel disease. Brain 2013;136:2717–2726.

Information & Authors

Information

Published In

Neurology®
Volume 96Number 5February 2, 2021
Pages: e698-e708
PubMed: 33199431

Publication History

Received: December 19, 2019
Accepted: September 21, 2020
Published online: November 16, 2020
Published in print: February 2, 2021

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Disclosure

A. Kopczak reports travel grants from Pfizer Pharma GmbH, unrelated to this work. M. Duering reports honoraria for lectures from Bayer Vital GmbH and Pfizer Pharma GmbH, unrelated to this work. The other authors report no disclosures. Go to Neurology.org/N for full disclosures.

Study Funding

B. Gesierich and M. Duering were supported by the German Research Foundation (DFG DU1626/1-1). S. Finsterwalder was supported by the Alzheimer Forschung Initiative e.V. (16018CB). A.M. Tuladhar was supported by the Dutch Heart Foundation (grant 2016T044) and by the Netherlands CardioVascular Research Initiative (CVON 2018-28 and 2012-06 Heart Brain Connection). A. Kopczak was supported by the European Union's Horizon 2020 research and innovation programme (grant 666881, SVDs@target). R. Schmidt was supported by the Austrian Science Fund (FWF grant I2889-B31). M. Duering was supported by the Radboud Excellence Initiative (18U.018651). Procurement of the Prisma MRI scanner in Munich was supported by the German Research Foundation (DFG INST 409/193-1 FUGG).

Authors

Affiliations & Disclosures

Marek J. Konieczny, MSc*
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Anna Dewenter, MSc*
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Annemieke ter Telgte, MSc
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Benno Gesierich, PhD
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Kim Wiegertjes, MSc
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Sofia Finsterwalder, MSc
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Anna Kopczak, MD
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Pfizer Pharma GmbH (Commercial entity), travel grant to the German Congress of Neurology (non-commercial national congress)
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
European Union’s Horizon 2020 research and innovation programme (grant agreement number 666881, SVDs@target), study coordinator and study physician, 04/2016 - ongoing
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Mathias Hübner, MSc
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
None
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
None
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
None
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Rainer Malik, PhD
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Anil M. Tuladhar, MD, PhD https://orcid.org/0000-0002-4815-2834
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
AMT is supported by the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation (CVON 2018-28 & 2012-06 Heart Brain Connection), Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences.
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
José P. Marques, PhD
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
None
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
None
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NWO (Dutch Science Foundation) - FOM-N-31/16PR1056 - 2016 - Role PINWO (Dutch Science Foundation) - VIDI 2019 - Role husband of the PI
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
None
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
Editorial board of 2001- BMC Medical Imaging 2003- BMC Medicine 2006- MAGMA 2013- Neuroimage 2015- Tomography
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Siemens medical solutions supports one PhD student in my group working on a completely unrelated topic.
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Alexandra Koch, PhD
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
European Radiology, member of scientific editorial board
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
Österreichische Forschungsförderungsgesellschaft mbH, reviewer of grant proposals
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Michael Ewers, PhD
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Received compensation of expenses for traveling to conferences from the Alzheimer's Association and International College of Geriatric Psychoneuropharmacology.
Editorial Boards:
1.
Senior Editor of Alzheimer's & Dementia.
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Reinhold Schmidt, MD
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
Rivastigmin Patch, 2010, Novartis JSW Life Sciences 2010, Advisory Board for Dementia Trial Axon Neuroscience 2013 2014, 2015- 2019 Neuroscios 2016-2017
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Received travel expenses and/or honoraria for lectures from Pfizer (2004-2010), Novartis (2003-2010), Merz Austria (2005-2010) and Lundbeck Axon Neuroscience 2015 Merz Austria 2016,2017 (2004-2009) and for educational activity from Takeda 2010, Axon Neuroscience Merz, Austria 2018
Editorial Boards:
1.
Editoral board member of Clinical Neurology and Neurosurgery 2004-currently European Journal of Neurology
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
Pfizer 2004-2010,lectures Novartis 2003-2010,2014 lectures Merz Austria 2005-2010, lectures Lundbeck 2004-2009, lectures Takeda, 2010, teaching course Merz Austria 2009-3017
Consultancies:
1.
QPS, Austria Axon Neuroscience Neuroscios, Austria Avraham Pharmaceuticals, Isreal
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
Austrian Science Fund projects P20103 and I904
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Frank-Erik de Leeuw, MD, PhD
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
Associate editor International JOurnal of Stroke (as of MArch first 2020)
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
VIDI innovational grant from The Netherlands Organisation for Health Research and Development (ZonMw grant 016•126•351)
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
supported by a clinical established investigator grant of the Dutch Heart Foundation (grant number 2014 T060)
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
(1) Bayer Vital GmbH, speaker honoraria (2) Pfizer Pharma GmbH, speaker honoraria
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
(1) German Research Foundation (DFG), DU 1626/1-1, PI, 2017-2020 (2) German Research Foundation (DFG), INST 409/193-1 FUGG, 2018
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
(1) Vascular Dementia Research Foundation, (2) Else Kröner-Fresenius- Stiftung, 2014-A200, PI, 2015-2017, (3) Alzheimer Forschung Initiative e.V. (AFI), 16018CB, PI, 2016-2018
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE

Notes

Correspondence Dr. Duering [email protected]
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
*
These authors contributed equally to this work.

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