Analysis of the Cognitive-behavioral Dysfunctions Profile and the Potential of Neuroplasticity in Patients With Brain Tumors Subjected to Selected Radiotherapy Techniques and the Possibility of Their Compensation by Psycho-physical Training

Every year, thousands of patients worldwide undergo radiotherapy (RT) for primary brain tumors (BT) and brain metastases originating from extracranial tumors. Radiation injury is multifactorial and is characterized by e.g. vascular abnormalities, inflammation, gliosis, demyelination, and often at high doses, white matter necrosis. Standard treatment of BT includes high dose megavoltage radiation to the cranial vault, but 50-90% of overall survivors exhibit impaired cognition and functional dysfunction. The radiation cognitive syndrome is still poorly understood, and there is no effective prevention or long-term treatment. Therefore, the investigators will analyze specific molecular markers which may have a relationship with morfological changes in the brain, its secretive and imunological role as well as cognitive function and postulate that previously undetected and comparatively subtle early manifestations of irradiation damage to CNS may synergize over time to form macro- and microstructural abnormalities. The investigators plan to corroborate a hypothesis that impairment of cognitive and motor functions in patients undergoing RT can be limited. In study, the investigators will quantitatively and objectively evaluate the effects of exercise on brain activity during cognitive and physical training in BT patients treated with RT. Therefore, specific objectives include: 1. Analysis of the molecular mechanism in BBB disruption. 2. Multidimensional analysis of specific neuroplasticity markers, onconeural-antibodies etc. 3. Assessment of the volume of the brain structures and their morphology. 4. Analysis of the results of neurocognitive and functional tests.

Significance of the project The Response Assessment in Neuro-Oncology working group recommended that neurocognitive outcome should be considered one of the primary endpoints in BT clinical trials. Despite the importance and clear concern about radiation-induced cognitive decline, the pathophysiology driving the progression of this syndrome remains poorly understood, and there are no effective preventative measures or long-term treatments. To date, there has been no study comparing different techniques of irradiation, namely intensity-modulated photon RT (IMRT), whole brain RT (WBRT), and stereotactic radiosurgery (CyberKnife), in BT patients in the aspect of pathophysiology of BBB or immunological aspects, as well as neurogenesis, neuroplasticity. These methods will be rely on a detailed understanding of radiation dose-volume effects, which link the incidence and severity of neurocognitive and functional impairment to specific volumes and morphology of normal brain. Possible explanations for the preservation of cognition and behavior include the resiliency of the cerebellum, frontal and tempo-parietal lobes, the hippocampus-mammillary complex and other supratentorial regions. Radiation is now known to suppress the proliferation of progenitor cells and their differentiation into neurons. The relatively recent discovery of neural stem cells in discrete areas of the brain is the impetus behind the most recent potential target for radiation. Early changes below the gross anatomical level, including a decline in neurogenesis, microvascular damage, subtle loss of white matter integrity, and disturbances of neuronal morphophysiology, may interact and progressively alter neuronal stem cell niches to impede neuronal function, viability, and progenitor cell differentiation. Therefore, the investigators will thoroughly observe the mechanism of neurogenesis and the possible improvement of neuroprotection and neuroregeneration in BT patients undergoing various forms of RT. Previous research has shown that physical exercise in healthy people is associated with increased structural and functional integrity in regions that overlap with brain functions, including the frontal, motor cortex, and the cerebellum. The precise neurobiological mechanism for cognitive effects of rehabilitation remains unknown, however a vast rodent literature supports a central role of protective neurotrophins, which have been shown to facilitate production of new neurons in the hippocampus, promote synaptic plasticity in cerebral cortex, and enhance growth and protection of neurovasculature and suggests exercise may promote formation and strengthening of connections between the hippocampus and its widespread cortical connections, which improve cognitive and behaviour functioning. However, the specific brain structure and function regions activated during rehabilitation exercise in patients with BT during oncological treatment still remain largely undefined. The study results obtained in this project will provide new knowledge about metabolic and structural pathways of the CNS in the context of RT and will also provide the basis for the development of regenerative medicine in oncology.

Work plan The investigators will conduct study in the Greater Poland Cancer Centre. The participants will be enrolled in this study according study criteria from the Department of Radiotherapy after medical assessment by an oncologist (physician). Evaluation of the all subjects will be carried out: at baseline (T0), one month after RT (T1), and control (T2) - 3 months after RT and final (T3) - 6 months after RT (unless there is a deterioration of health making the assessment impossible, or death). The investigators will monitor the patients by:

A. Analysis of the patient's blood serum: 1/ markers of BBB disruption: S-100β and circulating tight junction-related proteins (occludin, claudin-5, zonula occludens-1); 2/ factors with potential effect on neuroplasticity - immune-cell production of neurotrophins e.g. brain-derived neurotrophic factor, beta-nerve growth factor, neurotrophin-3, neurotrophin-4/5; 3/ activity of carnosinase and its isoenzymes; 4/ onconeural antibodies (anti-Hu, anti-Ri, anti-Yo, anti-Ma/Ta, anti-Cv2, and anti-amphiphysin as well as anti-myelin, anti-MAG, anti-GAD) and anti-surface neuronal antigens (anti-NMDA, anti-AMPA, anti-GABA, anti-DPPX, anti-LGI1, anti-CASPR) to investigate correlations with types of BT, RT, and possible paraneoplastic syndromes or cognitive impairment.

B. Assessment of brain structures and volume testing of selected brain structures.