. 2023 Jun 20;15(1):114.

doi: 10.1186/s13195-023-01257-y.

White matter hyperintensities and smaller cortical thickness are associated with neuropsychiatric symptoms in neurodegenerative and cerebrovascular diseases

Miracle Ozzoude^{1

2

3

4}, Brenda Varriano^{1

5}, Derek Beaton⁶, Joel Ramirez^{2

3}, Sabrina Adamo⁷, Melissa F Holmes^{2

3}, Christopher J M Scott^{2

3}, Fuqiang Gao^{2

3}, Kelly M Sunderland⁸, Paula McLaughlin⁹, Maged Goubran^{3

10

11

12}, Donna Kwan^{13

14}, Angela Roberts^{15

16}, Robert Bartha¹⁷, Sean Symons¹², Brian Tan⁸, Richard H Swartz^{12

18

19}, Agessandro Abrahao^{12

18}, Gustavo Saposnik^{20

21}, Mario Masellis^{12

18}, Anthony E Lang^{18

22}, Connie Marras^{18

22}, Lorne Zinman^{12

18}, Christen Shoesmith²³, Michael Borrie^{17

23

24}, Corinne E Fischer^{20

21

25}, Andrew Frank^{26

27}, Morris Freedman^{8

18

28}, Manuel Montero-Odasso^{23

29

30}, Sanjeev Kumar^{31

32}, Stephen Pasternak²⁴, Stephen C Strother^{8

11}, Bruce G Pollock^{31

32}, Tarek K Rajji^{31

32

33}, Dallas Seitz³⁴, David F Tang-Wai^{18

35}, John Turnbull^{36

37}, Dar Dowlatshahi²⁶, Ayman Hassan³⁸, Leanne Casaubon¹⁸, Jennifer Mandzia^{23

24

39}, Demetrios Sahlas^{36

37}, David P Breen^{40

41

42}, David Grimes²⁶, Mandar Jog^{23

24

43}, Thomas D L Steeves²⁰, Stephen R Arnott⁸, Sandra E Black^{2

3

12

18

19

33}, Elizabeth Finger^{23

24}, Jennifer Rabin^{3

10

12

18

44}; ONDRI Investigators; Maria Carmela Tartaglia^{45

46

47

48}

Collaborators, Affiliations

Collaborators

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, 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

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 2S8, Canada.
² L.C. Campbell Cognitive Neurology Unit, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
³ Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.
⁴ Department of Psychology, Faculty of Health, York University, Toronto, ON, Canada.
⁵ Central Michigan University College of Medicine, Mount Pleasant, MI, USA.
⁶ Data Science & Advanced Analytic, St. Michael's Hospital, Toronto, ON, Canada.
⁷ Graduate Department of Psychological Clinical Science, University of Toronto Scarborough, Scarborough, ON, Canada.
⁸ Rotman Research Institute of Baycrest Centre, Toronto, ON, Canada.
⁹ Nova Scotia Health, Halifax, NS, Canada.
¹⁰ Harquail Centre for Neuromodulation, Hurvitz Brain Sciences Program, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
¹¹ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
¹² Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
¹³ Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
¹⁴ Queen's University, Kingston, ON, Canada.
¹⁵ Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL, USA.
¹⁶ School of Communication Sciences and Disorders, Faculty of Health Sciences, Western University, London, ON, Canada.
¹⁷ Robarts Research Institute, Western University, London, ON, Canada.
¹⁸ Department of Medicine, Division of Neurology, University of Toronto, Toronto, ON, Canada.
¹⁹ Heart & Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
²⁰ Division of Neurology, Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
²¹ Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
²² Edmond J Safra Program for Parkinson Disease, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.
²³ Department of Clinical Neurological Sciences, Western University, London, ON, Canada.
²⁴ Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
²⁵ Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada.
²⁶ Department of Medicine (Neurology), University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada.
²⁷ Bruyère Research Institute, Ottawa, ON, Canada.
²⁸ Division of Neurology, Baycrest Health Sciences, Toronto, ON, Canada.
²⁹ Lawsone Health Research Institute, London, ON, Canada.
³⁰ Gait and Brain Lab, Parkwood Institute, London, ON, Canada.
³¹ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
³² Adult Neurodevelopment and Geriatric Psychiatry, Centre for Addiction and Mental Health, Toronto, ON, Canada.
³³ Toronto Dementia Research Alliance, University of Toronto, Toronto, ON, Canada.
³⁴ Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
³⁵ Memory Clinic, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.
³⁶ Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
³⁷ Department of Medicine, McMaster University, Hamilton, ON, Canada.
³⁸ Thunder Bay Regional Health Research Institute, Thunder Bay, ON, Canada.
³⁹ St. Joseph's Healthcare Centre, London, ON, Canada.
⁴⁰ Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
⁴¹ Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, UK.
⁴² Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
⁴³ London Health Sciences Centre, London, ON, Canada.
⁴⁴ Rehabilitation Sciences Institute, University of Toronto, Toronto, ON, Canada.
⁴⁵ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, 6th floor 6KD-407, Toronto, ON, M5T 2S8, Canada. carmela.tartaglia@uhn.ca.
⁴⁶ Department of Medicine, Division of Neurology, University of Toronto, Toronto, ON, Canada. carmela.tartaglia@uhn.ca.
⁴⁷ Toronto Dementia Research Alliance, University of Toronto, Toronto, ON, Canada. carmela.tartaglia@uhn.ca.
⁴⁸ Memory Clinic, Toronto Western Hospital, University Health Network, Toronto, ON, Canada. carmela.tartaglia@uhn.ca.

PMID: 37340319
PMCID: PMC10280981
DOI: 10.1186/s13195-023-01257-y

White matter hyperintensities and smaller cortical thickness are associated with neuropsychiatric symptoms in neurodegenerative and cerebrovascular diseases

Miracle Ozzoude et al. Alzheimers Res Ther. 2023.

. 2023 Jun 20;15(1):114.

doi: 10.1186/s13195-023-01257-y.

Authors

Collaborators

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, 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

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 2S8, Canada.
² L.C. Campbell Cognitive Neurology Unit, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
³ Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.
⁴ Department of Psychology, Faculty of Health, York University, Toronto, ON, Canada.
⁵ Central Michigan University College of Medicine, Mount Pleasant, MI, USA.
⁶ Data Science & Advanced Analytic, St. Michael's Hospital, Toronto, ON, Canada.
⁷ Graduate Department of Psychological Clinical Science, University of Toronto Scarborough, Scarborough, ON, Canada.
⁸ Rotman Research Institute of Baycrest Centre, Toronto, ON, Canada.
⁹ Nova Scotia Health, Halifax, NS, Canada.
¹⁰ Harquail Centre for Neuromodulation, Hurvitz Brain Sciences Program, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
¹¹ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
¹² Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
¹³ Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada.
¹⁴ Queen's University, Kingston, ON, Canada.
¹⁵ Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL, USA.
¹⁶ School of Communication Sciences and Disorders, Faculty of Health Sciences, Western University, London, ON, Canada.
¹⁷ Robarts Research Institute, Western University, London, ON, Canada.
¹⁸ Department of Medicine, Division of Neurology, University of Toronto, Toronto, ON, Canada.
¹⁹ Heart & Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
²⁰ Division of Neurology, Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
²¹ Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
²² Edmond J Safra Program for Parkinson Disease, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.
²³ Department of Clinical Neurological Sciences, Western University, London, ON, Canada.
²⁴ Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
²⁵ Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada.
²⁶ Department of Medicine (Neurology), University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada.
²⁷ Bruyère Research Institute, Ottawa, ON, Canada.
²⁸ Division of Neurology, Baycrest Health Sciences, Toronto, ON, Canada.
²⁹ Lawsone Health Research Institute, London, ON, Canada.
³⁰ Gait and Brain Lab, Parkwood Institute, London, ON, Canada.
³¹ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
³² Adult Neurodevelopment and Geriatric Psychiatry, Centre for Addiction and Mental Health, Toronto, ON, Canada.
³³ Toronto Dementia Research Alliance, University of Toronto, Toronto, ON, Canada.
³⁴ Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
³⁵ Memory Clinic, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.
³⁶ Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
³⁷ Department of Medicine, McMaster University, Hamilton, ON, Canada.
³⁸ Thunder Bay Regional Health Research Institute, Thunder Bay, ON, Canada.
³⁹ St. Joseph's Healthcare Centre, London, ON, Canada.
⁴⁰ Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
⁴¹ Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Edinburgh, UK.
⁴² Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
⁴³ London Health Sciences Centre, London, ON, Canada.
⁴⁴ Rehabilitation Sciences Institute, University of Toronto, Toronto, ON, Canada.
⁴⁵ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Tower, 60 Leonard Avenue, 6th floor 6KD-407, Toronto, ON, M5T 2S8, Canada. carmela.tartaglia@uhn.ca.
⁴⁶ Department of Medicine, Division of Neurology, University of Toronto, Toronto, ON, Canada. carmela.tartaglia@uhn.ca.
⁴⁷ Toronto Dementia Research Alliance, University of Toronto, Toronto, ON, Canada. carmela.tartaglia@uhn.ca.
⁴⁸ Memory Clinic, Toronto Western Hospital, University Health Network, Toronto, ON, Canada. carmela.tartaglia@uhn.ca.

PMID: 37340319
PMCID: PMC10280981
DOI: 10.1186/s13195-023-01257-y

Abstract

Background: Neuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to investigate the relative contribution of white matter hyperintensities and cortical thickness to NPS in participants across neurodegenerative and cerebrovascular diseases.

Methods: Five hundred thirteen participants with one of these conditions, i.e. Alzheimer's Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson's Disease, or Cerebrovascular Disease, were included in the study. NPS were assessed using the Neuropsychiatric Inventory - Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter loss.

Results: Although NPS were frequent across the five disease groups, participants with frontotemporal dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both frontotemporal dementia and Parkinson's disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities.

Conclusions: In participants with neurodegenerative and cerebrovascular diseases, our results suggest that smaller cortical thickness and white matter hyperintensity burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed.

Keywords: Cerebrovascular disease; Cortical thickness; Neurodegenerative disease; Neuropsychiatric symptoms; White matter hyperintensities.

PubMed Disclaimer

Conflict of interest statement

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. SK has recieved research support from Brain and Behavior Foundation, National institute on Ageing, BrightFocus Foundation, Brain Canada, Canadian Institute of Health Research, Canadian Consortium on Neurodegeneration in Aging, Centre for Ageing and Brain Health Innovation, Centre for Addiction and Mental Health, and an Academic Scholars Award from the Department of Psychiatry, University of Toronto. He has also received equipment support from Soterix Medical. 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.

Figures

**Fig. 1**
Frequency of neuropsychiatric symptoms (NPS) in various neurodegenerative and cerebrovascular diseases. *Notes*: AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; CVD, cerebrovascular disease; FTD, frontotemporal disease; MCI, mild cognitive impairment; PD, Parkinson’s disease

**Fig. 2**
Cluster bar graph showing group differences on neuropsychiatric subsyndromes. *Notes*: AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; CVD, cerebrovascular disease; FTD, frontotemporal disease; MCI, mild cognitive impairment; PD, Parkinson’s disease

**Fig. 3**
Frequency of neuropsychiatric symptoms (NPS) by sex across the entire sample

**Fig. 4**
Partial least square correlation diagram for neuropsychiatric subsyndromes component scores. *Notes*: the values for all subsyndromes appear in the same direction where apathy shows the highest amount of variance on Component 1

**Fig. 5**
Partial least square correlation diagram for stable contributors component scores. *Notes*: the stable contributors go in the opposite direction as the neuropsychiatric subsyndromes scores, indicating a negative correlation between them. LH, left hemisphere; MoCA, Montreal Cognitive Assessment; RH, right hemisphere

**Fig. 6**
Relationship between diagnosis, neuropsychiatric subsyndromes, and contributors. *Notes*: FS, FreeSurfer cortical thickness (68 regions); WMH, lobar white matter hyperintensities (10 regions); MoCA = Montreal Cognitive Assessment; AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; CVD, cerebrovascular disease; FTD, frontotemporal disease; MCI, mild cognitive impairment; PD, Parkinson’s disease

See this image and copyright information in PMC

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White matter hyperintensities and smaller cortical thickness are associated with neuropsychiatric symptoms in neurodegenerative and cerebrovascular diseases

Collaborators

Affiliations

White matter hyperintensities and smaller cortical thickness are associated with neuropsychiatric symptoms in neurodegenerative and cerebrovascular diseases

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources

Medical