Association of Plasma Biomarkers With Longitudinal Atrophy and Microvascular Burden on MRI Across Neurodegenerative and Cerebrovascular Diseases

Erlan Sanchez¹, Gillian T Coughlan², Tim Wilkinson³, Joel Ramirez⁴, Saira Saeed Mirza¹, Andrée-Ann Baril^{5

6}, Allison A Dilliott^{7

8}, Andrew Frank⁹, Anthony E Lang^{10

11}, Ayman Hassan¹², Bruce G Pollock^{13

14}, Christopher J M Scott⁴, Connie Marras¹⁵, Corinne E Fischer¹⁶, Dallas Seitz¹⁷, Daniela Andriuta¹⁸, Dar Dowlatshahi¹⁹, David A Grimes^{19

20}, David F Tang-Wai^{11

21}, Demetrios J Sahlas²², Ekaterina A Rogaeva²³, Elizabeth Finger²⁴, John F Robinson²⁵, Kubra Tan²⁶, Malcolm A Binns^{27

28}, Maria Carmela Tartaglia^{21

23}, Michael J Borrie^{29

30}, Michael J Strong²⁴, Miracle Ozzoude^{3

31

32}, Nuwan D Nanayakkara²⁵, Rafaella A Goncalves³³, Robert Bartha³⁴, Robert A Hegele^{25

35}, Sali M K Farhan^{7

8

36}, Sandra E Black^{4

11}, Sanjeev Kumar^{37

38}, Sean P Symons^{39

40}, Seyyed M H Haddad⁴¹, Stephen H Pasternak^{24

42}, Stephen R Arnott⁴³, Tarek K Rajji^{13

38}, Thomas Steeves⁴⁴, Walter Swardfager^{4

45}, Nicholas J Ashton^{46

47

48

49}, Hlin Kvartsberg^{46

50}, Henrik Zetterberg^{46

50

51

52

53}, Douglas P Munoz⁵⁴, Mario Masellis^{1

11}; ONDRI Investigators

Collaborators, Affiliations

Collaborators

ONDRI Investigators:
Agessandro Abrahao, Angela Troyer, Angela C Roberts, Athena Theyers, Barry Coe, Brian Levine, Brian Tan, Christen Shoesmith, Christopher J M Hudson, Courtney Berezuk, David Munoz, Dennis Bulman, Derek Beaton, Donald C Brien, Donna Kwan, Edward Margollin, Efrem Mandelcorn, Elena Leontieva, Frederico Peiruccini-Faria, Gustavo Saposnik, J B Orange, Jane Lawrence, Jennifer Mandzia, John Turnbull, John D Robinson, Karen Van Ooteghem, Kelly Sunderland, Leanne K Casaubon, Lorne Zinman, Mahdi Chani, Mandar Jog, Manuel Montero, Melissa Holmes, Morris Freedman, Paula M McLaughlin, Peter W Kleinstiver, Richard H Swartz, Roger A Dixon, Sherif Defrawy, Stephen C Strother, Susan E Bronskill, W E Bill McIlroy, Wendy Lou, Wendy V Hatch

Affiliations

¹ L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada.
² Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
³ Centre for Clinical Brain Sciences, University of Edinburgh, United Kingdom.
⁴ Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, ON, Canada.
⁵ Center for Advanced Research in Sleep Medicine, Research Center of the CIUSSS-NIM, Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada.
⁶ Department of Medicine, Université de Montreal, QC, Canada.
⁷ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
⁸ Montreal Neurological Institute-Hospital, McGill University, QC, Canada.
⁹ Bruyere Research Institute, University of Ottawa, ON, Canada.
¹⁰ Edmond J Safra Program in Parkinson's Disease and the Rossy PSP Centre, University Health Network, Toronto, ON, Canada.
¹¹ Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, ON, Canada.
¹² Thunder Bay Regional Health Science Centre, Northern Ontario School of Medicine University, ON, Canada.
¹³ Centre for Addiction and Mental Health, Toronto, ON, Canada.
¹⁴ Department of Psychiatry and Department of Pharmacology and Toxicology, University of Toronto, ON, Canada.
¹⁵ Edmond J Safra Program in Parkinson's disease, University Health Network, University of Toronto, ON, Canada.
¹⁶ Keenan Research Centre for Biomedical Research, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.
¹⁷ Department of Psychiatry and Hotchkiss Brain Institute, University of Calgary, AB, Canada.
¹⁸ Department of Neurology, Amiens University Medical Center, France.
¹⁹ Department of Medicine, University of Ottawa and Ottawa Hospital Research Institute, ON, Canada.
²⁰ Brain and Mind Research Institute, Ottawa, ON, Canada.
²¹ Krembil Brain Institute, University Health Network, Toronto, ON, Canada.
²² Division of Neurology, Department of Medicine, McMaster University, Hamilton, ON, Canada.
²³ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, ON, Canada.
²⁴ Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
²⁵ Robarts Research Institute, Western University, London, ON, Canada.
²⁶ Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden.
²⁷ Rotman Research Institute, Baycrest Health Sciences, Toronto, ON, Canada.
²⁸ Department of Public Health Sciences, University of Toronto, ON, Canada.
²⁹ Lawson Health Research Institute, London, ON, Canada.
³⁰ Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.
³¹ Curle Ophthalmology Laboratory, Institute for Regeneration and Repair, University of Edinburgh, United Kingdom.
³² Edinburgh Imaging Facility, University of Edinburgh, United Kingdom.
³³ Gladstone Institutes of Neurological Disease, Gladstone Institutes, San Francisco, CA.
³⁴ Department of Medical Biophysics, Schulich School of Medicine & Dentistry, Robarts Research Institute, Western University, London, ON, Canada.
³⁵ Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
³⁶ Department of Human Genetics, McGill University, Montreal, QC, Canada.
³⁷ Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
³⁸ Department of Psychiatry, University of Toronto, ON, M5T 1R8, Canada.
³⁹ Precision Diagnostics and Therapeutics Program, Sunnybrook Research Institute, Toronto, ON, Canada.
⁴⁰ Departments of Medical Imaging and Otolaryngology-Head and Neck Surgery, University of Toronto, ON, Canada.
⁴¹ Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, ON, Canada.
⁴² Cognitive Neurology, Parkwood Institute, St. Joseph's Health Care Centre, Western University, London, ON, Canada.
⁴³ Indoc Systems, Toronto, ON, Canada.
⁴⁴ Division of Neurology, Nuvance Health Vassar Brothers Medical Center, Poughkeepsie, NY.
⁴⁵ Department of Pharmacology and Toxicology, University of Toronto, ON, Canada.
⁴⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁴⁷ King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, United Kingdom.
⁴⁸ NIHR Maudsley Biomedical Research Centre, London, United Kingdom.
⁴⁹ Centre for Age-Related Medicine, Stavanger University Hospital, Norway.
⁵⁰ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁵¹ Department of Neurodegenerative Disease, Dementia Research Institute, UCL Queen Square Institute of Neurology, London, United Kingdom.
⁵² Hong Kong Center for Neurodegenerative Diseases, HKG, China.
⁵³ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin, Madison; and.
⁵⁴ Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada.

PMID: 40063856
DOI: 10.1212/WNL.0000000000213438

Association of Plasma Biomarkers With Longitudinal Atrophy and Microvascular Burden on MRI Across Neurodegenerative and Cerebrovascular Diseases

Erlan Sanchez et al. Neurology. 2025.

. 2025 Apr 8;104(7):e213438.

doi: 10.1212/WNL.0000000000213438. Epub 2025 Mar 10.

Authors

Collaborators

ONDRI Investigators:
Agessandro Abrahao, Angela Troyer, Angela C Roberts, Athena Theyers, Barry Coe, Brian Levine, Brian Tan, Christen Shoesmith, Christopher J M Hudson, Courtney Berezuk, David Munoz, Dennis Bulman, Derek Beaton, Donald C Brien, Donna Kwan, Edward Margollin, Efrem Mandelcorn, Elena Leontieva, Frederico Peiruccini-Faria, Gustavo Saposnik, J B Orange, Jane Lawrence, Jennifer Mandzia, John Turnbull, John D Robinson, Karen Van Ooteghem, Kelly Sunderland, Leanne K Casaubon, Lorne Zinman, Mahdi Chani, Mandar Jog, Manuel Montero, Melissa Holmes, Morris Freedman, Paula M McLaughlin, Peter W Kleinstiver, Richard H Swartz, Roger A Dixon, Sherif Defrawy, Stephen C Strother, Susan E Bronskill, W E Bill McIlroy, Wendy Lou, Wendy V Hatch

Affiliations

¹ L.C. Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada.
² Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
³ Centre for Clinical Brain Sciences, University of Edinburgh, United Kingdom.
⁴ Dr. Sandra Black Centre for Brain Resilience and Recovery, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Toronto, ON, Canada.
⁵ Center for Advanced Research in Sleep Medicine, Research Center of the CIUSSS-NIM, Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada.
⁶ Department of Medicine, Université de Montreal, QC, Canada.
⁷ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
⁸ Montreal Neurological Institute-Hospital, McGill University, QC, Canada.
⁹ Bruyere Research Institute, University of Ottawa, ON, Canada.
¹⁰ Edmond J Safra Program in Parkinson's Disease and the Rossy PSP Centre, University Health Network, Toronto, ON, Canada.
¹¹ Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, ON, Canada.
¹² Thunder Bay Regional Health Science Centre, Northern Ontario School of Medicine University, ON, Canada.
¹³ Centre for Addiction and Mental Health, Toronto, ON, Canada.
¹⁴ Department of Psychiatry and Department of Pharmacology and Toxicology, University of Toronto, ON, Canada.
¹⁵ Edmond J Safra Program in Parkinson's disease, University Health Network, University of Toronto, ON, Canada.
¹⁶ Keenan Research Centre for Biomedical Research, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.
¹⁷ Department of Psychiatry and Hotchkiss Brain Institute, University of Calgary, AB, Canada.
¹⁸ Department of Neurology, Amiens University Medical Center, France.
¹⁹ Department of Medicine, University of Ottawa and Ottawa Hospital Research Institute, ON, Canada.
²⁰ Brain and Mind Research Institute, Ottawa, ON, Canada.
²¹ Krembil Brain Institute, University Health Network, Toronto, ON, Canada.
²² Division of Neurology, Department of Medicine, McMaster University, Hamilton, ON, Canada.
²³ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, ON, Canada.
²⁴ Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
²⁵ Robarts Research Institute, Western University, London, ON, Canada.
²⁶ Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden.
²⁷ Rotman Research Institute, Baycrest Health Sciences, Toronto, ON, Canada.
²⁸ Department of Public Health Sciences, University of Toronto, ON, Canada.
²⁹ Lawson Health Research Institute, London, ON, Canada.
³⁰ Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.
³¹ Curle Ophthalmology Laboratory, Institute for Regeneration and Repair, University of Edinburgh, United Kingdom.
³² Edinburgh Imaging Facility, University of Edinburgh, United Kingdom.
³³ Gladstone Institutes of Neurological Disease, Gladstone Institutes, San Francisco, CA.
³⁴ Department of Medical Biophysics, Schulich School of Medicine & Dentistry, Robarts Research Institute, Western University, London, ON, Canada.
³⁵ Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
³⁶ Department of Human Genetics, McGill University, Montreal, QC, Canada.
³⁷ Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
³⁸ Department of Psychiatry, University of Toronto, ON, M5T 1R8, Canada.
³⁹ Precision Diagnostics and Therapeutics Program, Sunnybrook Research Institute, Toronto, ON, Canada.
⁴⁰ Departments of Medical Imaging and Otolaryngology-Head and Neck Surgery, University of Toronto, ON, Canada.
⁴¹ Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, ON, Canada.
⁴² Cognitive Neurology, Parkwood Institute, St. Joseph's Health Care Centre, Western University, London, ON, Canada.
⁴³ Indoc Systems, Toronto, ON, Canada.
⁴⁴ Division of Neurology, Nuvance Health Vassar Brothers Medical Center, Poughkeepsie, NY.
⁴⁵ Department of Pharmacology and Toxicology, University of Toronto, ON, Canada.
⁴⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁴⁷ King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, United Kingdom.
⁴⁸ NIHR Maudsley Biomedical Research Centre, London, United Kingdom.
⁴⁹ Centre for Age-Related Medicine, Stavanger University Hospital, Norway.
⁵⁰ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁵¹ Department of Neurodegenerative Disease, Dementia Research Institute, UCL Queen Square Institute of Neurology, London, United Kingdom.
⁵² Hong Kong Center for Neurodegenerative Diseases, HKG, China.
⁵³ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin, Madison; and.
⁵⁴ Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada.

PMID: 40063856
DOI: 10.1212/WNL.0000000000213438

Abstract

Background and objectives: Plasma biomarkers of Alzheimer disease (AD), neuroinflammation, and neurodegeneration are increasingly being used in clinical trials for diagnosis and monitoring of dementia. However, their association with longitudinal structural brain MRI changes, an important outcome measure across neurodegenerative and cerebrovascular diseases, is less known. We investigated how baseline plasma biomarkers reflect MRI markers of progression over time in patients with neurodegenerative and cerebrovascular diseases.

Methods: This longitudinal cohort study included patients from the Ontario Neurodegenerative Disease Research Initiative diagnosed with AD or mild cognitive impairment (AD/MCI), Parkinson disease (PD), frontotemporal dementia spectrum disorders (FTD), or cerebrovascular disease (CVD), followed annually for 2 years. Recruitment took place at specialized university-based dementia, movement disorders, and/or stroke clinics in the province of ON, Canada. MRI outcomes included markers of cerebral atrophy (ventricular CSF and regional gray matter volumes) and of small vessel disease pathology (white matter hyperintensity [WMH], perivascular spaces, and lacunar volumes). Hemorrhagic markers at baseline were also included. Plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau181 and tau217 (p-tau181, p-tau217), and β-amyloid (Aβ_42/40) were quantified from blood samples collected at baseline using Simoa and used as predictors in linear mixed models adjusted for time (months), age, sex, apolipoprotein E (APOE)-ε4 carrier status, kidney function, vascular risk factors, microtubule-associated protein tau (MAPT) diplotypes, waist-hip circumference ratio, and disease duration.

Results: We analyzed 1,240 MRIs from 473 patients (age: 69.2 ± 7.4 [range: 49-87]; 32.8% women). Elevated baseline levels of GFAP, NfL, p-tau181, and p-tau217, and to a lesser extent decreased levels of Aβ_42/40, were significantly associated with more cerebral atrophy and WMH burden at baseline (|B| = 0.02 to 1.69, p = 0.044 to <0.001) and with progression over time (|B| = 0.001 to 0.028, p = 0.049 to <0.001) in the pooled disease-agnostic group. Within disease-specific cohorts, GFAP and NfL were associated with cerebral atrophy and/or small vessel disease copathology in AD/MCI, PD, FTD, or CVD. P-tau181 and p-tau217 were associated with cerebral atrophy and/or small vessel disease copathology in AD/MCI, CVD, PD-MCI, or PD-dementia.

Discussion: Selected plasma biomarkers seem useful as prognosis and monitoring tools of longitudinal imaging changes within real-world populations of neurodegenerative and/or cerebrovascular diseases, and provide insight into overlap across diseases in shared pathologic burden.

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Association of Plasma Biomarkers With Longitudinal Atrophy and Microvascular Burden on MRI Across Neurodegenerative and Cerebrovascular Diseases

Collaborators

Affiliations

Association of Plasma Biomarkers With Longitudinal Atrophy and Microvascular Burden on MRI Across Neurodegenerative and Cerebrovascular Diseases

Authors

Collaborators

Affiliations

Abstract

References

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous