Neurovascular coupling assessment in rat brain following targeted Gamma Knife irradiation J. Constanzo1, M. Lepage1, Luc Tremblay1, M. Descoteaux2, K. Kirby3, L. MassonCoté1,4, M. Guillot1,4, P. Sarret3, B. Paquette1 1Dept.
of Nuclear Medicine and Radiobiology, 2Dept. of Computing Sciences, 3Dept. of Physiology and Biophysics, 4Service of Radiation Oncology
Introduction During stereotactic radiosurgery (SRS) for brain cancer, surrounding normal tissue may receive a significant radiation dose. This can frequently lead to blood brain barrier (BBB) disruption, brain swelling, necrosis, and neuronal dysfunction, thus inducing delayed side effects such as cognitive decline and stroke-like symptoms. We propose to use MRI modalities to enhance our understanding of the neurovascular disorders.
Methods • Animals 31 male Fischer rats (protocol # 363-14) • Irradiation Prescription: 100 Gy at 100% isodose (1) Target: Primary somatosensory forelimb Irradiation: Gamma Knife (GK)
Results 1 - Vascular changes
Conclusions
• Before irradiation and 54 days later
• 82 days & 110 days following irradiation
TAKE HOME MESSAGE: VASCULAR • BBB disruption at day 54 + neovascularization • Between 54 days and 110 days post-irradiation -> Edema, necrosis, hemorrhage and CSF obstruction • SWI is an efficient tool to detect angiogenesis, by determining relative vascular density, which allows to understand the continuum of vascular changes following irradiation
2 - Neuronal changes • Before irradiation to 110 days later: preliminary results
M1 M1 Hippocampus
Bregma -2.40
S1FL
• 110 days & 130 days following irradiation Bregma 2.52
• Using advanced MRI modalities, we demonstrated vascular matrix remodeling and changes in behavioral responses. • Using SWI we showed that irradiation strongly modulate cortical vascularization. Also, SWI could be applied in routine follow-up for patients receiving high dose radiation at risk of necrosis. • White matter and hippocampus are more radiosensitive than gray matter and the neocortex • Symptoms seem similar to those observed in stroke
Perspectives • Using dMRI and tractography, we want to demonstrate neuronal matrix remodeling • Neuroplasticity ? • Neurogenesis ? Stroke may induce neurogenesis from periventricular neural progenitor cells that express GFAP (2) => intense post-stroke remodelling
Acknowledgments • MRI sequences T2-weighted: Tissue structure DCE-MRI: BBB integrity assessment (600 µL/min Gd-DTPA injection) SWI: 3D vascular architecture dMRI: Observation of water molecular diffusion in the brain
• Behavioral tests at 110 & 130 days postirradiation
This research program was supported by the Fonds de recherche du Québec Nature et technologies (Grant No 172009), and Sherbrooke University.
References (1) Constanzo et al., Med. Phys., 2015. (2) Ohab et al., J Neurosci., 2006.
Further informations • Behavioral tests Motricity (rotorod), spatial memory (Morris water maze), arterial blood pressure (CODA) • Histology H&E, GFAP, IBA1, Luxol Blue, Cresyl Violet
TAKE HOME MESSAGE: NEURONAL • Behavioral tasks assessing locomotor activities and motor coordination -> brain irradiation did not affect motor performance • Irradiated rats -> decrease learning abilities longer delay to locate the hidden platform (4th day of training)
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