. 2025 Jul 23;15(1):91.

doi: 10.1186/s13550-025-01288-6.

Association of white matter injury and neuroinflammation in the post-acute phase after ischemic stroke using [¹⁸F]FEPPA-PET/MRI

Stefan E Poirier^{1

2}, Rachel Wagner³, Linshan Liu⁴, Pavlo Ohorodnyk⁵, Michael T Jurkiewicz⁵, Alexander Thiel⁶, Jonathan D Thiessen^{4

7

5

8

9}, Alexander V Khaw^#^{4

10}, Udunna C Anazodo^#^{11

12

13

14}

Affiliations

¹ Lawson Health Research Institute, London, ON, Canada. spoirie6@uwo.ca.
² Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. spoirie6@uwo.ca.
³ School of Medicine, Queen's University, Kingston, ON, Canada.
⁴ Lawson Health Research Institute, London, ON, Canada.
⁵ Department of Medical Imaging, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
⁶ Department of Neurology and Neurosurgery, Jewish General Hospital, McGill University, Montréal, QC, Canada.
⁷ Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
⁸ Division of Medical Physics, CancerCare Manitoba, Winnipeg, MB, Canada.
⁹ Department of Radiology, University of Manitoba, Winnipeg, MB, Canada.
¹⁰ Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
¹¹ Lawson Health Research Institute, London, ON, Canada. udunna.anazodo@mcgill.ca.
¹² Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. udunna.anazodo@mcgill.ca.
¹³ Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. udunna.anazodo@mcgill.ca.
¹⁴ Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC, Canada. udunna.anazodo@mcgill.ca.

^# Contributed equally.

PMID: 40699407
PMCID: PMC12287493
DOI: 10.1186/s13550-025-01288-6

Association of white matter injury and neuroinflammation in the post-acute phase after ischemic stroke using [¹⁸F]FEPPA-PET/MRI

Stefan E Poirier et al. EJNMMI Res. 2025.

. 2025 Jul 23;15(1):91.

doi: 10.1186/s13550-025-01288-6.

Authors

Affiliations

¹ Lawson Health Research Institute, London, ON, Canada. spoirie6@uwo.ca.
² Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. spoirie6@uwo.ca.
³ School of Medicine, Queen's University, Kingston, ON, Canada.
⁴ Lawson Health Research Institute, London, ON, Canada.
⁵ Department of Medical Imaging, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
⁶ Department of Neurology and Neurosurgery, Jewish General Hospital, McGill University, Montréal, QC, Canada.
⁷ Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
⁸ Division of Medical Physics, CancerCare Manitoba, Winnipeg, MB, Canada.
⁹ Department of Radiology, University of Manitoba, Winnipeg, MB, Canada.
¹⁰ Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
¹¹ Lawson Health Research Institute, London, ON, Canada. udunna.anazodo@mcgill.ca.
¹² Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. udunna.anazodo@mcgill.ca.
¹³ Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. udunna.anazodo@mcgill.ca.
¹⁴ Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC, Canada. udunna.anazodo@mcgill.ca.

^# Contributed equally.

PMID: 40699407
PMCID: PMC12287493
DOI: 10.1186/s13550-025-01288-6

Abstract

Background: Cerebral white matter (WM) injury after ischemic stroke is associated with post-stroke cognitive impairment (PSCI), however, the interaction between sustained neuroinflammation and post-stroke WM injury is not well understood. Hybrid PET/MRI can provide insight into pathophysiological mechanisms linking chronic neuroinflammation, ischemic WM injury, and PSCI. Using PET/MRI, this study investigated the relationship between [¹⁸F]FEPPA standardized uptake value ratio (SUVr) measurements of glial activation and diffusion tensor imaging (DTI) measurements of microstructure integrity in brain WM regions in the chronic phase at 6-months after acute ischemic stroke.

Results: [¹⁸F]FEPPA-PET, DTI, and T2-weighted FLAIR were acquired at 6-months post-stroke in 19 elderly humans (seven females; mean age = 76 ± 5 years) with confirmed first-ever acute ischemic stroke using hybrid PET/3T-MRI. Index infarcts, chronic (incidental, covert) infarcts, and WM hyperintensities were manually segmented on FLAIR and excluded from the imaging analysis. Pearson correlation was conducted to assess the association between [¹⁸F]FEPPA-SUVr and DTI measurements in WM regions commonly implicated in PSCI. [¹⁸F]FEPPA-SUVr was elevated in brain regions ipsilateral to the index infarct at 6-months post-stroke, and these increases correlated with decreases in fractional anisotropy in several WM pathways linked to PSCI, including right superior longitudinal fasciculus (SLF) III (r = -0.82, p < 0.0001), right anterior thalamic radiation (r = -0.61, p = 0.006), and right arcuate fasciculus (r = -0.56, p = 0.01). Elevated [¹⁸F]FEPPA-SUVr was also associated with increased mean diffusivity (r = 0.69, p < 0.001), axial diffusivity (r = 0.55, p = 0.02), and radial diffusivity (r = 0.74, p < 0.001) in right SLF III.

Conclusions: This study found an association between elevated post-acute glial activation (neuroinflammation) and reduced microstructure integrity in brain WM pathways ipsilateral to ischemic infarcts and remote from WM lesions at 6-months post-stroke. Hybrid PET/MRI is promising to be a valuable tool for probing post-acute neuroinflammation and associated changes in cerebral WM pathways following ischemic stroke.

Keywords: Diffusion tensor imaging; Neuroinflammation; PET/MRI; Stroke; White matter; [18F]FEPPA.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study was approved by the Western University Research Ethics Board and conducted in accordance with the Declaration of Helsinki ethical standards. All patients provided written informed consent to participate. Consent for publication: All patients gave written consent for publication. Competing interests: All authors declare that they have no competing interests.

Figures

**Fig. 1**
Brain PET/3T-MR images from a 78-year-old male stroke patient (patient #1) at 6-months post-stroke: **(A)** white matter tractography using TractSeg shows right and left anterior thalamic radiation bundles (coloured lines) overlaid onto T1-weighted MRI; **(B)** T2-weighted FLAIR shows index infarct (red circle); **(C)** apparent diffusion coefficient (ADC) map shows elevated ADC within index infarct (red circle); and **(D)** [¹⁸F]FEPPA-SUVr map shows elevated [¹⁸F]FEPPA uptake (white rectangle) ipsilateral to index infarct (red circle) and decreased [¹⁸F]FEPPA uptake within index infarct compared to contralateral hemisphere

**Fig. 2**
**(A)** T2-weighted FLAIR MRI image from five representative stroke patients (patient #1: 78-year-old male; patient #3: 69-year-old male; patient #8: 82-year-old male; patient #13: 84-year-old female; patient #16: 74-year-old male) at 6-months following stroke. **(B)** Manual segmentations of WM hyperintensities (yellow), index infarcts (red), and chronic infarcts (magenta) are shown overlaid onto FLAIR image. Index infarcts are identified as the infarct responsible for hospital admission (acute ischemic stroke). In patients #8 and #16, chronic infarcts are detected incidentally on FLAIR as covert or silent brain infarcts

**Fig. 3**
**(A)** T2-weighted FLAIR at 6-months post-stroke and **(B)** visual representation of lesion exclusion approach overlaid onto FLAIR shows index infarcts (red), chronic infarcts (magenta), and WM hyperintensities (yellow) adjacent to normal appearing WM bundle segmentations (blue) for *a priori* WM regions implicated in stroke; left AF in a 70-year-old male stroke patient (patient #2), right ATR in a 76-year-old female stroke patient (patient #6), and right SLF III in a 76-year-old male stroke patient (patient #9). **(C)** Pearson correlational plots show a negative association between [¹⁸F]FEPPA-SUVr and FA in each WM bundle across all nineteen stroke patients at 6-months post-stroke

See this image and copyright information in PMC

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Association of white matter injury and neuroinflammation in the post-acute phase after ischemic stroke using [¹⁸F]FEPPA-PET/MRI

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Association of white matter injury and neuroinflammation in the post-acute phase after ischemic stroke using [¹⁸F]FEPPA-PET/MRI

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