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Investigating the contribution of white matter hyperintensities and cortical thickness to empathy in neurodegenerative and cerebrovascular diseases

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Abstract

Change in empathy is an increasingly recognised symptom of neurodegenerative diseases and contributes to caregiver burden and patient distress. Empathy impairment has been associated with brain atrophy but its relationship to white matter hyperintensities (WMH) is unknown. We aimed to investigate the relationships amongst WMH, brain atrophy, and empathy deficits in neurodegenerative and cerebrovascular diseases. Five hundred thirteen participants with Alzheimer’s disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), Parkinson’s disease, or cerebrovascular disease (CVD) were included. Empathy was assessed using the Interpersonal Reactivity Index. WMH were measured using a semi-automatic segmentation and FreeSurfer was used to measure cortical thickness. A heterogeneous pattern of cortical thinning was found between groups, with FTD showing thinning in frontotemporal regions and CVD in left superior parietal, left insula, and left postcentral. Results from both univariate and multivariate analyses revealed that several variables were associated with empathy, particularly cortical thickness in the fronto-insulo-temporal and cingulate regions, sex (female), global cognition, and right parietal and occipital WMH. Our results suggest that cortical atrophy and WMH may be associated with empathy deficits in neurodegenerative and cerebrovascular diseases. Future work should consider investigating the longitudinal effects of WMH and atrophy on empathy deficits in neurodegenerative and cerebrovascular diseases.

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Data availability

The datasets presented in this article are not readily available because the ONDRI data will be made publicly available through an application process. For more information on the ONDRI project, please visit http://ondri.ca/. Requests to access the datasets should be directed to http://ondri.ca/.

Abbreviations

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

bvFTD:

Behavioural variant frontotemporal dementia

CVD:

Cerebrovascular disease

CBS:

Corticobasal syndrome

CT:

Computed tomography

dWMH:

Deep white matter hyperintensities

dx:

Diagnostic

EC:

Emotional concern

FTD:

Frontotemporal dementia

IRI:

Interpersonal Reactivity Index

MCI:

Mild cognitive impairment

MRI:

Magnetic resonance imaging

MoCA:

Montreal Cognitive Assessment

MSE:

Mean square error

nfvPPA:

Non-fluent primary progressive aphasia

ONDRI:

Ontario Neurodegenerative Disease Research Initiative

OFC:

Orbitofrontal cortex

PeD:

Personal distress

PLSc:

Partial least square correlation

PT:

Perspective taking

PD:

Parkinson’s disease

PSP:

Progressive supranuclear palsy

pWMH:

Periventricular white matter hyperintensities

svPPA:

Semantic variant primary progressive aphasia

ST-TIV:

Supratentorial total intracranial volume

SVD:

Small vessel disease

WMH:

White matter hyperintensities

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Acknowledgements

We would like to thank the ONDRI participants for the time, consent, and participation in our study. The manuscript has been submitted to bioRxiv preprint.

CONSORTIUM NAME: ONDRI Investigators; Members: Michael Strong1, Peter Kleinstiver2, Jane Lawrence-Dewar3, Natalie Rashkovan4, Susan Bronskil5,6,7, Julia Fraser8, Bill McIlroy8, Ben Cornish8, Karen Van Ooteghem8, Frederico Faria9, Yanina Sarquis-Adamson9, Alanna Black9, Barry Greenberg10, Wendy Hatch11, Chris Hudson11,12, Elena Leontieva12,13, Ed Margolin11, Efrem Mandelcorn11, Faryan Tayyari12, Sherif Defrawy11, Don Brien14, Ying Chen14, Brian Coe14, Doug Munoz14, Alisia Southwell4, Dennis Bulman15,16,17, Allison Ann Dilliott18,19, Mahdi Ghani20, Rob Hegele21, John Robinson1, Ekaterina Rogaeva20, Sali Farhan22, Seyyed Mohammad Hassan Haddad1, Nuwan Nanayakkara1, Courtney Berezuk23, Sabrina Adamo23,24, Malcolm Binns25,26, Wendy Lou26, Athena Theyers25, Abiramy Uthirakumaran25, Guangyong (GY) Zou27, Sujeevini Sujanthan28, Mojdeh Zamyadi25, David Munoz29, Roger A. Dixon30, John Woulfe31, Brian Levine25,32, JB Orange33,34, Alicia Peltsch35, Angela Troyer36,37, Marvin Chum38,39.

Affiliations:

1Robarts Research Institute, Western University, London, ON, Canada

2Schulich School of Medicine & Dentistry, Western University, London, ON, Canada

3Thunder Bay Regional Research Institute, ON, Canada

4Sunnybrook Health Sciences Centre, Toronto, ON, Canada.

5Institute of Clinical Evaluative Science, Toronto, ON, Canada

6Institute of Health Policy, Management & Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada

7Sunnybrook Research Institute, Toronto, ON, Canada

8Department of Kinesiology, University of Waterloo, Waterloo, ON, Canada

9Gait and Brain Lab, Western University, London, ON, Canada

10Toronto Dementia Research Alliance, University of Toronto, Toronto, ON, Canada

11Department of Ophthalmology and Vision Sciences, University of Toronto, ON, Canada

12School of Optometry and Vision Science, University of Waterloo, Waterloo, ON, Canada

13Kensington Eye Institute, Toronto, ON, Canada

14Centre for Neuroscience Studies, Queen’s University, Kingston, ON, Canada

15University of Ottawa Brain and Mind Research Institute,, Ottawa, ON, Canada

16Department of Pediatrics, Faculty of Medicine, University of Ottawa, ON, Canada

17Regenerative Medicine, Ottawa Health Research Institute, ON, Canada

18Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada

19Robarts Research Institute, Western University, London, ON, Canada

20Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada

21Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada

22Department of Neurology and Neurosurgery, Department of Human Genetics, The Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada

23Department of Psychological Clinical Science, University of Toronto Scarborough, Scarborough, ON, Canada

24Toronto Western Hospital Neuropsychology Research, University Health Network, Toronto, ON, Canada

25Rotman Research Institute of Baycrest Centre, Toronto, ON, Canada

26Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada

27Department of Epidemiology and Biostatistics, Western University, London, ON, Canada

28Department of Ophthalmology and Visual Sciences, Research Institute of the McGill University Health Center, Quebec, Canada

29Department of Laboratory medicine, St Michael's Hospital, Unity Health, Toronto, ON, Canada

30Department of Psychology (Science), Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada

31Ottawa Hospital Research Institute and University of Ottawa, Ottawa, ON, Canada

32Department of Psychology and Medicine (Neurology), University of Toronto, Toronto, ON, Canada

33School of Communication Sciences and Disorders, Faculty of Health Sciences, Western University, London, ON, Canada

34Canadian Centre for Activity and Aging, Western University, London, ON, Canada

35Faculty of Engineering and Applied Science, Queen's University, Kingston, ON, Canada

36Neuropsychology and Cognitive Health Program, Baycrest Health Sciences, Toronto, ON, Canada

37Department of Psychology, University of Toronto, Toronto, ON, Canada

38Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada

39Department of Medicine, McMaster University, Hamilton, ON, Canada

Funding

This research was conducted with the support of the Ontario Brain Institute, an independent non-profit corporation, funded partially by the Ontario government. The opinions, results, and conclusions are those of the authors and no endorsement by the Ontario Brain Institute is intended or should be inferred. Matching funds were provided by participant hospital and research foundations, including the Baycrest Foundation, Bruyere Research Institute, Centre for Addiction and Mental Health Foundation, London Health Sciences Foundation, McMaster University Faculty of Health Sciences, Ottawa Brain and Mind Research Institute, Queen’s University Faculty of Health Sciences, the Thunder Bay Regional Health Sciences Centre, the University of Ottawa Faculty of Medicine, University Health Network, Sunnybrook, and the Windsor/Essex County ALS Association. The Temerty Family Foundation provided the major infrastructure matching funds.

Author information

Authors and Affiliations

  1. Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, 6th floor 6KD-407, Toronto, ON, M5T 0S8, Canada

    Miracle Ozzoude, Brenda Varriano & Maria Carmela Tartaglia

  2. L.C. Campbell Cognitive Neurology Unit, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

    Miracle Ozzoude, Joel Ramirez, Melissa F. Holmes, Christopher J. M. Scott, Fuqiang Gao & Sandra E. Black

  3. Rotman Research Institute of Baycrest Centre, Toronto, ON, Canada

    Derek Beaton, Kelly M. Sunderland, Brian Tan, Morris Freedman, Stephen C. Strother & Stephen R. Arnott

  4. Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, ON, Canada

    Joel Ramirez, Melissa F. Holmes, Christopher J. M. Scott, Fuqiang Gao, Jennifer Rabin, Maged Goubran, Sean Symons, Richard H. Swartz, Agessandro Abrahao, Lorne Zinman & Sandra E. Black

  5. Nova Scotia Health and Dalhousie University, Halifax, NS, Canada

    Paula McLaughlin

  6. Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada

    Jennifer Rabin, Richard H. Swartz, Mario Masellis, Anthony E. Lang, Connie Marras, Lorne Zinman, Morris Freedman, David F. Tang-Wai, Leanne Casaubon & Maria Carmela Tartaglia

  7. Harquail Centre for Neuromodulation, Hurvitz Brain Sciences Program, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

    Jennifer Rabin, Maged Goubran & Agessandro Abrahao

  8. Rehabilitation Sciences Institute, University of Toronto, Toronto, ON, Canada

    Jennifer Rabin

  9. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Maged Goubran & Stephen C. Strother

  10. Centre for Neuroscience Studies, Queen’s University, Kingston, ON, Canada

    Donna Kwan

  11. Queen’s University, Kingston, ON, Canada

    Donna Kwan

  12. Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL, USA

    Angela Roberts

  13. School of Communication Sciences and Disorders, Faculty of Health Sciences, Western University, London, ON, Canada

    Angela Roberts

  14. Robarts Research Institute, Western University, London, ON, Canada

    Robert Bartha

  15. Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

    Sean Symons, Richard H. Swartz & Mario Masellis

  16. Heart & Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

    Richard H. Swartz & Sandra E. Black

  17. Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada

    Gustavo Saposnik

  18. Edmond J Safra Program for Parkinson Disease, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, Toronto, ON, Canada

    Anthony E. Lang & Connie Marras

  19. Department of Clinical Neurological Sciences, Western University, London, ON, Canada

    Christen Shoesmith, Stephen Pasternak, Jennifer Mandzia, Mandar Jog & Elizabeth Finger

  20. Schulich School of Medicine and Dentistry, Western University, London, ON, Canada

    Michael Borrie, Manuel Montero-Odasso, Jennifer Mandzia, Mandar Jog & Elizabeth Finger

  21. St. Joseph’s Healthcare Centre, London, ON, Canada

    Michael Borrie

  22. Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, ON, Canada

    Corinne E. Fischer

  23. Department of Medicine (Neurology), University of Ottawa Brain and Mind Research Institute and Ottawa Hospital Research Institute, Ottawa, ON, Canada

    Andrew Frank, Dar Dowlatshahi & David Grimes

  24. Bruyère Research Institute, Ottawa, ON, Canada

    Andrew Frank

  25. Division of Neurology, Baycrest Health Sciences, Toronto, ON, Canada

    Morris Freedman

  26. Lawson Health Research Institute, London, ON, Canada

    Manuel Montero-Odasso

  27. Gait and Brain Lab, Parkwood Institute, London, ON, Canada

    Manuel Montero-Odasso

  28. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Sanjeev Kumar, Bruce G. Pollock & Tarek K. Rajji

  29. Adult Neurodevelopment and Geriatric Psychiatry, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Sanjeev Kumar, Bruce G. Pollock & Tarek K. Rajji

  30. Toronto Dementia Research Alliance, University of Toronto, Toronto, ON, Canada

    Tarek K. Rajji & Sandra E. Black

  31. Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Dallas Seitz

  32. Memory Clinic, Toronto Western Hospital, University Health Network, Toronto, ON, Canada

    David F. Tang-Wai & Maria Carmela Tartaglia

  33. Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada

    John Turnbull & Demetrios Sahlas

  34. Department of Medicine, McMaster University, Hamilton, ON, Canada

    John Turnbull & Demetrios Sahlas

  35. Thunder Bay Regional Health Research Institute, Thunder Bay, ON, Canada

    Ayman Hassan

  36. Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK

    David P. Breen

  37. Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, UK

    David P. Breen

  38. Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK

    David P. Breen

  39. London Health Sciences Centre, London, ON, Canada

    Mandar Jog

  40. Division of Neurology, Department of Medicine, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada

    Gustavo Saposnik, Thomas D. L. Steeves & Sandra E. Black

Authors
  1. Miracle Ozzoude
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  2. Brenda Varriano
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  3. Derek Beaton
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  4. Joel Ramirez
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  5. Melissa F. Holmes
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  6. Christopher J. M. Scott
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  7. Fuqiang Gao
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  8. Kelly M. Sunderland
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  9. Paula McLaughlin
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  10. Jennifer Rabin
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  11. Maged Goubran
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  12. Donna Kwan
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  13. Angela Roberts
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  14. Robert Bartha
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  15. Sean Symons
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  16. Brian Tan
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  17. Richard H. Swartz
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  18. Agessandro Abrahao
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  19. Gustavo Saposnik
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  20. Mario Masellis
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  21. Anthony E. Lang
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  22. Connie Marras
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  23. Lorne Zinman
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  24. Christen Shoesmith
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  25. Michael Borrie
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  26. Corinne E. Fischer
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  27. Andrew Frank
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  28. Morris Freedman
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  29. Manuel Montero-Odasso
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  30. Sanjeev Kumar
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  31. Stephen Pasternak
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  32. Stephen C. Strother
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  33. Bruce G. Pollock
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  34. Tarek K. Rajji
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  35. Dallas Seitz
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  36. David F. Tang-Wai
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  37. John Turnbull
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  38. Dar Dowlatshahi
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  39. Ayman Hassan
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  40. Leanne Casaubon
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  41. Jennifer Mandzia
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  42. Demetrios Sahlas
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  43. David P. Breen
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  44. David Grimes
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  45. Mandar Jog
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  46. Thomas D. L. Steeves
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  47. Stephen R. Arnott
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  48. Sandra E. Black
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  49. Elizabeth Finger
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  50. Maria Carmela Tartaglia
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Consortia

ONDRI Investigators

  • Michael Strong
  • , Peter Kleinstiver
  • , Jane Lawrence-Dewar
  • , Natalie Rashkovan
  • , Susan Bronskil
  • , Julia Fraser
  • , Bill McIlroy
  • , Ben Cornish
  • , Karen Van Ooteghem
  • , Frederico Faria
  • , Yanina Sarquis-Adamson
  • , Alanna Black
  • , Barry Greenberg
  • , Wendy Hatch
  • , Chris Hudson
  • , Elena Leontieva
  • , Ed Margolin
  • , Efrem Mandelcorn
  • , Faryan Tayyari
  • , Sherif Defrawy
  • , Don Brien
  • , Ying Chen
  • , Brian Coe
  • , Doug Munoz
  • , Alisia Southwell
  • , Dennis Bulman
  • , Allison Ann Dilliott
  • , Mahdi Ghani
  • , Rob Hegele
  • , John Robinson
  • , Ekaterina Rogaeva
  • , Sali Farhan
  • , Seyyed Mohammad Hassan Haddad
  • , Nuwan Nanayakkara
  • , Courtney Berezuk
  • , Sabrina Adamo
  • , Malcolm Binns
  • , Wendy Lou
  • , Athena Theyers
  • , Abiramy Uthirakumaran
  • , Guangyong GY Zou
  • , Sujeevini Sujanthan
  • , Mojdeh Zamyadi
  • , David Munoz
  • , Roger A. Dixon
  • , John Woulfe
  • , Brian Levine
  • , J. B. Orange
  • , Alicia Peltsch
  • , Angela Troyer
  •  & Marvin Chum

Contributions

MO: conceptualisation, data curation, formal analysis, investigation, methodology, project administration, software, visualisation, and writing (draft, review, and editing). BV: conceptualisation, investigation, methodology, project administration, writing (review and editing). DB: data curation, formal analysis, supervision, methodology, software, visualisation, and writing (draft, review, and editing). JR: data curation, supervision, and writing (review and editing). MFH, PM, AR, CJMS, and BT: data curation and writing (review and editing). KS: data curation, software, writing (review and editing). JR, SA, and MG: writing (review and editing). DK: data curation, project administration, writing (review and editing). FG: data curation, validation, resources, writing (review and editing). RB: data curation, resources, funding acquisition, writing (review and editing). AR, SS, RHS, AA, GS, MM, AEL, CM, SEB, LZ, CS, MM, CF, AF, MF, MMO, SK, SP, BP, TKR, DS, DT, MC, JT, DD, AH, LC, JM, DS, DPB, DG, MJ, TS, and EF: resources, funding acquisition, writing (review and editing). MCT: conceptualisation, investigation, methodology, supervision, resources, funding acquisition, writing (review and editing). All authors contributed to the article and approved the submitted version.

Corresponding author

Correspondence to Maria Carmela Tartaglia.

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Ethics approval and consent to participate

The studies involving human participants were reviewed and approved by ONDRI. Study participants were recruited at various health centres across Ontario, Canada: London Health Science Centre and Parkwood Institute in London; Hamilton General Hospital and McMaster Medical Centre in Hamilton; The Ottawa Civic Hospital in Ottawa; Thunder Bay Regional Health Sciences Centre in Thunder Bay; and St. Michael’s Hospital, Sunnybrook Health Sciences Centre, Baycrest Health Sciences, Centre for Addiction and Mental Health, and Toronto Western Hospital (University Health Network) in Toronto. Ethics approval was obtained from all participating institutions and performed in accordance with the Declaration of Helsinki. All participants and study partners provided informed consent. The patients/participants provided their written informed consent to participate in this study.

Conflict of interest

TKR has received research support from Brain Canada, Brain and Behavior Research Foundation, BrightFocus Foundation, Canada Foundation for Innovation, Canada Research Chair, Canadian Institutes of Health Research, Centre for Aging and Brain Health Innovation, National Institutes of Health, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, and the Weston Brain Institute. TKR also received in-kind equipment support for an investigator-initiated study from Magstim, and in-kind research accounts from Scientific Brain Training Pro. DPB is supported by a Wellcome Clinical Research Career Development Fellowship (214571/Z/18/Z). Other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Ozzoude, M., Varriano, B., Beaton, D. et al. Investigating the contribution of white matter hyperintensities and cortical thickness to empathy in neurodegenerative and cerebrovascular diseases. GeroScience 44, 1575–1598 (2022). https://doi.org/10.1007/s11357-022-00539-x

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  • DOI: https://doi.org/10.1007/s11357-022-00539-x

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