Regional free-water diffusion is more strongly related to neuroinflammation than neurodegeneration

Vishaal Sumra; Mohsen Hadian; Allison A Dilliott; Sali M K Farhan; Andrew R Frank; Anthony E Lang; Angela C Roberts; Angela Troyer; Stephen R Arnott; Connie Marras; David F Tang-Wai; Elizabeth Finger; Ekaterina Rogaeva; Joseph B Orange; Joel Ramirez; Lorne Zinman; Malcolm Binns; Michael Borrie; Morris Freedman; Miracle Ozzoude; Robert Bartha; Richard H Swartz; David Munoz; Mario Masellis; Sandra E Black; Roger A Dixon; Dar Dowlatshahi; David Grimes; Ayman Hassan; Robert A Hegele; Sanjeev Kumar; Stephen Pasternak; Bruce Pollock; Tarek Rajji; Demetrios Sahlas; Gustavo Saposnik; Maria Carmela Tartaglia; ONDRI Investigators

doi:10.1007/s00415-025-13201-1

Regional free-water diffusion is more strongly related to neuroinflammation than neurodegeneration

J Neurol. 2025 Jun 25;272(7):478. doi: 10.1007/s00415-025-13201-1.

Authors

Vishaal Sumra^{1

2}, Mohsen Hadian^{3

4}, Allison A Dilliott^{5

6}, Sali M K Farhan^{5

6}, Andrew R Frank^{7

8}, Anthony E Lang^{9

3

10

11}, Angela C Roberts^{12

13}, Angela Troyer¹⁴, Stephen R Arnott¹⁵, Connie Marras^{4

10}, David F Tang-Wai^{4

16}, Elizabeth Finger¹⁷, Ekaterina Rogaeva⁹, Joseph B Orange¹⁸, Joel Ramirez^{19

20}, Lorne Zinman^{11

19}, Malcolm Binns²¹, Michael Borrie^{12

22}, Morris Freedman^{14

15}, Miracle Ozzoude^{9

23}, Robert Bartha²⁴, Richard H Swartz²⁰, David Munoz²⁵, Mario Masellis²⁶, Sandra E Black¹⁹, Roger A Dixon^{27

28}, Dar Dowlatshahi⁷, David Grimes²⁹, Ayman Hassan³⁰, Robert A Hegele^{22

31}, Sanjeev Kumar³², Stephen Pasternak²⁴, Bruce Pollock¹⁸, Tarek Rajji³², Demetrios Sahlas³³, Gustavo Saposnik²⁵, Maria Carmela Tartaglia^{34

9

3

11}; ONDRI Investigators

Affiliations

¹ Institute of Medical Science, University of Toronto, Medical Sciences Building, 1 King's College Cir Suite 2374, Toronto, ON, M5S 1A8, Canada. Vishaal.sumra@mail.utoronto.ca.
² Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Medical Sciences Building, 1 King's College Cir Suite 2374, Toronto, ON, M5S 1A8, Canada. Vishaal.sumra@mail.utoronto.ca.
³ Krembil Brain Institute, 135 Nassau St, Toronto, ON, M5T 1M8, Canada.
⁴ University Health Network, 190 Elizabeth St, Toronto, ON, M5G 2C4, Canada.
⁵ Montreal Neurological Institute and Hospital, 3801 Rue University, Montréal, QC, H3A 2B4, Canada.
⁶ Department of Neurology and Neurosurgery, McGill University, 3801 Rue University, Montréal, QC, H3A 2B4, Canada.
⁷ University of Ottawa, 75 Laurier Ave E, Ottawa, ON, K1N 6N5, Canada.
⁸ Bruyere Research Institute, 85 Primrose Ave, Ottawa, ON, K1R 6M1, Canada.
⁹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Medical Sciences Building, 1 King's College Cir Suite 2374, Toronto, ON, M5S 1A8, Canada.
¹⁰ Movement Disorder Clinic, Toronto Western Hospital, University Health Network, 399 Bathurst St, Toronto, ON, M5T 2S8, Canada.
¹¹ Faculty of Medicine, University of Toronto, 27 King's College Cir, Toronto, ON, M5S 1A1, Canada.
¹² Western University, 1151 Richmond St, London, ON, N6A 3K7, Canada.
¹³ Canadian Centre for Activity and Aging, Western University, 1201 Western Rd, London, ON, N6G 1H1, Canada.
¹⁴ Baycrest Health Sciences Centre, 3560 Bathurst St, Toronto, ON, M6A 2E1, Canada.
¹⁵ Baycrest Hospital, 3560 Bathurst St, Toronto, ON, M6A 2E1, Canada.
¹⁶ Temerty Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Cir, Toronto, ON, M5S 1A8, Canada.
¹⁷ Department of Clinical Neurological Sciences, University of Western Ontario, 1151 Richmond St, London, ON, N6A 3K7, Canada.
¹⁸ School of Communication Sciences and Disorders, University of Western Ontario, 1151 Richmond St, London, ON, N6A 3K7, Canada.
¹⁹ Sunnybrook Health Sciences Centre, 2075 Bayview Ave, Toronto, ON, M4N 3M5, Canada.
²⁰ Hurvitz Brain Sciences Program, Sunnybrook Research Institute, 2075 Bayview Ave, Toronto, ON, M4N 3M5, Canada.
²¹ Rotman Research Institute, 3560 Bathurst St, Toronto, ON, M6A 2E1, Canada.
²² Schulich School of Medicine& Dentistry, Division of Geriatric Medicine, Western University, 1151 Richmond St, London, ON, N6A 3K7, Canada.
²³ LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, University of Toronto, 2075 Bayview Ave, Toronto, ON, M4N 3M5, Canada.
²⁴ Robarts Research Institute, Western University, 1151 Richmond St, London, ON, N6A 3K7, Canada.
²⁵ Unity Health Toronto, 61 Queen St E, Toronto, ON, M5C 2T2, Canada.
²⁶ Sunnybrook Research Institute, 2075 Bayview Ave, Toronto, ON, M4N 3M5, Canada.
²⁷ Department of Psychology Science, University of Alberta, 116 St & 85 Ave, Edmonton, AB, T6G 2R3, Canada.
²⁸ Neuroscience and Mental Health Institute, University of Alberta, 116 St & 85 Ave, Edmonton, AB, T6G 2R3, Canada.
²⁹ Ottawa Hospital Research Institute, 1053 Carling Ave, Ottawa, ON, K1Y 4E9, Canada.
³⁰ Northern Ontario School of Medicine, 935 Ramsey Lake Rd, Sudbury, ON, P3E 2C6, Canada.
³¹ Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, ON, N6A 3K7, Canada.
³² Centre for Addiction and Mental Health, 1000 Queen St W, Toronto, ON, M6J 1H4, Canada.
³³ McMaster University, 1280 Main St W, Hamilton, ON, L8S 4L8, Canada.
³⁴ Institute of Medical Science, University of Toronto, Medical Sciences Building, 1 King's College Cir Suite 2374, Toronto, ON, M5S 1A8, Canada.

PMID: 40560468
DOI: 10.1007/s00415-025-13201-1

Abstract

Introduction: Recent research has suggested that neuroinflammation may be important in the pathogenesis of neurodegenerative diseases. Free-water diffusion (FWD) has been proposed as a non-invasive neuroimaging-based biomarker for neuroinflammation.

Methods: Free-water maps were generated using diffusion MRI data in 367 patients from the Ontario Neurodegenerative Disease Research Initiative (108 Alzheimer's Disease/Mild Cognitive Impairment, 42 Frontotemporal Dementia, 37 Amyotrophic Lateral Sclerosis, 123 Parkinson's Disease, and 58 vascular disease-related Cognitive Impairment). The ability of FWD to predict neuroinflammation and neurodegeneration from biofluids was estimated using plasma glial fibrillary-associated protein (GFAP) and neurofilament light chain (NfL), respectively.

Results: Recursive Feature Elimination (RFE) performed the strongest out of all feature selection algorithms used and revealed regional specificity for areas that are the most important features for predicting GFAP over NfL concentration. Deep learning models using selected features and demographic information revealed better prediction of GFAP over NfL.

Discussion: Based on feature selection and deep learning methods, FWD was found to be more strongly related to GFAP concentration (measure of astrogliosis) over NfL (measure of neuro-axonal damage), across neurodegenerative disease groups, in terms of predictive performance. Non-invasive markers of neurodegeneration such as MRI structural imaging that can reveal neurodegeneration already exist, while non-invasive markers of neuroinflammation are not available. Our results support the use of FWD as a non-invasive neuroimaging-based biomarker for neuroinflammation.

Keywords: Biomarkers; Diffusion MRI; Freewater; Neurodegeneration; Neurodegenerative disease; Quantitative MRI.

MeSH terms

Aged
Aged, 80 and over
Biomarkers / blood
Cognitive Dysfunction / diagnostic imaging
Diffusion Magnetic Resonance Imaging* / methods
Female
Glial Fibrillary Acidic Protein / blood
Humans
Male
Middle Aged
Neurodegenerative Diseases* / diagnostic imaging
Neurodegenerative Diseases* / metabolism
Neurofilament Proteins / blood
Neuroinflammatory Diseases* / diagnostic imaging
Neuroinflammatory Diseases* / metabolism

Substances

Neurofilament Proteins
Glial Fibrillary Acidic Protein
Biomarkers
GFAP protein, human
neurofilament protein L