Anna E. Leeuwis, MSc; Nick A. Weaver, MD; J. Matthijs Biesbroek, MD, PhD; Lieza G. Exalto, MD, PhD; Hugo J. Kuijf, PhD; Astrid M. Hooghiemstra, PhD; Niels D. Prins, MD, PhD; Philip Scheltens, MD, PhD; Frederik Barkhof, MD, PhD; Wiesje M. van der Flier, PhD; Geert Jan Biessels, MD, PhD; on behalf of the TRACE-VCI study group
Background: We investigated the association between white matter hyperintensity location and depressive symptoms in a memoryclinic population using lesion–symptom mapping.
Methods: We included 680 patients with vascular brain injury from the TRACE-VCI cohort (mean age ± standard deviation: 67 ± 8 years; 52% female): 168 patients with subjective cognitive decline, 164 with mild cognitive impairment and 348 with dementia. We assessed depressive symptoms using the Geriatric Depression Scale. We applied assumption-free voxel-based lesion–symptom mapping, adjusted for age, sex, total white matter hyperintensity volume and multiple testing. Next, we applied exploratory region-of-interest linear regression analyses of major white matter tracts, with additional adjustment for diagnosis.
Results: Voxel-based lesion–symptom mapping identified voxel clusters related to the Geriatric Depression Scale in the left corticospinal tract. Region-of-interest analyses showed no relation between white matter hyperintensity volume and the Geriatric Depression Scale, but revealed an interaction with diagnosis in the forceps minor, where larger regional white matter hyperintensity volume was associated with more depressive symptoms in subjective cognitive decline (β = 0.26, p < 0.05), but not in mild cognitive impairment or dementia.
Limitations: We observed a lack of convergence of findings between voxel-based lesion–symptom mapping and region-of-interest analyses, which may have been due to small effect sizes and limited lesion coverage despite the large sample size. This warrants replication of our findings and further investigation in other cohorts.
Conclusion: This lesion–symptom mapping study in depressive symptoms indicates the corticospinal tract and forceps minor as strategic tracts in which white matter hyperintensity is associated with depressive symptoms in memory-clinic patients with vascular brain injury. The impact of white matter hyperintensity on depressive symptoms is modest, but it appears to depend on the location of white matter hyperintensity and disease severity.
Submitted Aug. 8, 2018; Revised Dec. 6, 2018; Accepted Jan. 9, 2019; Published online Apr. 25, 2019
Acknowledgements: The TRACE-VCI study is supported by Vidi grant 91711384 and Vici Grant 918.16.616 from ZonMw, the Netherlands, Organisation for Health Research and Development, and grant 2010T073 from the Dutch Heart Association to G. Biessels. Research of the VUmc Alzheimer Centre is part of the neurodegeneration research program of Amsterdam Neuroscience. The VUmc Alzheimer Centre is supported by Alzheimer Nederland and Stichting VUmc Fonds. The clinical database structure was developed with funding from Stichting Dioraphte. A. Leeuwis and A. Hooghiemstra are appointed on a grant from The Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation (CVON 2012-06 Heart Brain Connection). F. Barkhof is supported by the NIHR Biomedical Research Centre at University College London Hospital.
Affiliations: From the Alzheimer Centre Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands (Leeuwis, Hooghiemstra, Prins, Scheltens, van der Flier); the Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht, the Netherlands (Weaver, Biesbroek, Exalto, Biessels); the Image Sciences Institute, University Medical Centre Utrecht, Utrecht, the Netherlands (Kuijf); the Department of Medical Humanities, Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands (Hooghiemstra); the Institutes of Neurology and Healthcare Engineering, UCL, London, United Kingdom (Barkhof); the Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands (Barkhof); and the Department of Epidemiology & Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands (Flier).
Competing interests: N. Prins serves on the advisory board of Boehringer Ingelheim and Probiodrug, and on Abbvie’s DSMB M15-566 trial; has provided consultancy services for Sanofi, Takeda and Kyowa Kirin Pharmaceutical Development; receives research support from Alzheimer Nederland (project number WE.03-2012-02); and is the CEO and co-owner of Brain Research Centre, Amsterdam, the Netherlands. P. Scheltens has acquired grant support (for the institution) from GE Healthcare and Piramal; and in the past 2 years he has received consultancy/speaker fees (paid to the institution) from Medavante, Novartis, Probiodrug, Biogen, Roche, Toyama and EIP Pharma. F. Barkhof serves as a consultant for Biogen-Idec, Janssen Alzheimer Immunotherapy, Bayer-Schering, Merck-Serono, Roche, Novartis, Genzyme and Sanofi-aventis; has received sponsoring from EU-H2020, NWO, SMSR, TEVA, Novartis, Toshiba and Imi; and serves on the editorial boards of Radiology, Brain, Neuroradiology, MSJ and Neurology. Research programs of W.M. van der Flier have been funded by ZonMW, NWO, EU-FP7, Alzheimer Nederland, Cardiovasculair Onderzoek Nederland, Stichting Dioraphte, Gieskes-Strijbis fonds, Pasman Stichting, Boehringer Ingelheim, Piramal Imaging, Roche BV, Janssen Stellar, Biogen and Combinostics; all funding is paid to her institution. G. Biessels has been funded by the Dutch Heart Association, ZonMW, the Netherlands Organisation for Health Research and Development and European Union Horizon 2020. No other competing interests declared.
Contributors: A. Leeuwis, N. Weaver, H. Kuijf, W. van der Flier and G. Biessels designed the study. A. Leeuwis, N. Weaver, L. Exalto, H. Kuijf, N. Prins, P. Scheltens, F. Barkhof and G. Biessels acquired the data, which A. Leeuwis, N. Weaver, J.M. Biesbroek, A. Hooghiemstra, N. Prins, P. Scheltens, F. Barkhof, W. van der Flier and G. Biessels analyzed. A. Leeuwis and N. Weaver wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.
Members of the TRACE-VCI study group: M.R. Benedictus, J. Bremer, W.M. van der Flier, A.E. Leeuwis, J. Leijenaar, N.D. Prins, P. Scheltens, B.M. Tijms (Alzheimer Centre and Department of Neurology, Amsterdam UMC, location VU University Medical Centre, Amsterdam, The Netherlands); F. Barkhof, M.P. Wattjes (Department of Radiology and Nuclear Medicine, Amsterdam UMC, location VU University Medical Centre, Amsterdam, The Netherlands); C.E. Teunissen (Department of Clinical Chemistry, Amsterdam UMC, location VU University Medical Centre, Amsterdam, The Netherlands); T. Koene (Department of Medical Psychology, Amsterdam UMC, location VU University Medical Centre, Amsterdam, The Netherlands); E. van den Berg, H. van den Brink, G.J. Biessels, J.M.F. Boomsma, L.G. Exalto, D.A. Ferro, C.J.M. Frijns, O. Groeneveld, R. Heinen, S.M. Heringa, L.J. Kappelle, Y.D. Reijmer, J. Verwer, N.A. Weaver (Department of Neurology, University Medical Centre Utrecht, Utrecht, The Netherlands); J. de Bresser, H.J. Kuijf (Department of Radiology/Image Sciences Institute, University Medical Centre Utrecht, Utrecht, The Netherlands); H.L. Koek (Department of Geriatrics, University Medical Centre Utrecht, Utrecht, The Netherlands); J.M.F. Boomsma, H.M. Boss, H.C. Weinstein (Department of Neurology, Onze Lieve Vrouwe Gasthuis (OLVG) West, Amsterdam, The Netherlands); and F. Barkhof (Department of Radiology, National Institute for Health Research (NIHR) and University College London Hospitals NHS Foundation Trust (UCLH) Biomedical research center, London, United Kingdom).
Correspondence to: A.E. Leeuwis, Alzheimer Amsterdam and Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands; firstname.lastname@example.org