title: Perforin- and granulysin-mediated cytotoxicity and interleukin 15 play roles in neurocognitive impairment in patients with acute lymphoblastic leukaemia.
abstract: Acute lymphoblastic leukaemia (ALL) is an aggressive disease. The course of disease is regulated by pro-inflammatory agents, and malignant cell infiltration of tissues plays a deleterious role in disease progression, greatly impacting quality of life, especially in the cognitive domains. Our hypothesis is that significant serum concentrations of interleukin 15 (IL-15) are responsible for higher expression of adhesion molecules on endothelial cells of blood-brain barrier (BBB) which allow leukaemia cells and/or normal lymphocytes the infiltration into the brain. In brain tissue these cells could be stimulated to release perforin and granulysin causing induction of apoptosis in brain cells that are involved in complex neural signalling mediated by neurotransmitters, and consequent fine cognitive impairment. Such changes could be detected early, even before notable clinical psycho-neurological or radiological changes in patients with ALL. To evaluate this hypothesis we propose measuring cognitive function using Complex Reactiometer Drenovac (CRD) scores in patients with ALL. The expression of different adhesion molecules on BBB as well as presence and distribution of different lymphocytes in brain tissue will be analyzed. We will then correlate CRD scores with levels of IL-15 and the percentages of T cells, natural killer T cells, and natural killer cells expressing perforin and/or granulysin proteins. CRD is a scientifically recognised and highly sensitive psychometric laboratory test based on the complex chronometric mathematical measuring of speed of reaction to various stimuli. It provides an objective assessment of cognitive functions from the most complex mental activities to the simplest reaction reflexes. Early recognition of cognitive dysfunction might be important when selecting the most appropriate chemotherapy and/or radiotherapy regimens, and could allow for the implementation of preventive measures against further deterioration in cognitive function and quality of life in patients with ALL.
authors.affiliation: Department of Internal Medicine, Hematology, Clinical Hospital Center Rijeka, Faculty of Medicine, University of Rijeka, 51000 Rijeka, B. Branchetta 20, Croatia.
authors.forename: Duska
authors.initials: D
authors.lastname: Petranovic
authors.affiliation: Department of Internal Medicine, Hematology, Clinical Hospital Center Rijeka, Faculty of Medicine, University of Rijeka, 51000 Rijeka, B. Branchetta 20, Croatia.
authors.forename: Gorazd
authors.initials: G
authors.lastname: Pilcic
authors.affiliation: Department of Internal Medicine, Hematology, Clinical Hospital Center Rijeka, Faculty of Medicine, University of Rijeka, 51000 Rijeka, B. Branchetta 20, Croatia.
authors.forename: Toni
authors.initials: T
authors.lastname: Valkovic
authors.affiliation: Department of Physiology and Immunology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, B. Branchetta 20, Croatia; Department of Anesthesiology, Reanimatology and Intensive Care, Faculty of Medicine, University of Rijeka, 51000 Rijeka, B. Branchetta 20, Croatia.
authors.forename: Vlatka
authors.initials: V
authors.lastname: Sotosek Tokmadzic
authors.affiliation: Department of Physiology and Immunology, Faculty of Medicine, University of Rijeka, 51000 Rijeka, B. Branchetta 20, Croatia; Division of Cardiology, Hospital for Medical Rehabilitation of the Hearth and Lung Diseases and Rheumatism "Thalassotherapia-Opatija", 51410 Opatija, M. Tita 188, Croatia. Electronic address: gordana.laskarin@medri.uniri.hr.
authors.forename: Gordana
authors.initials: G
authors.lastname: Laskarin
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000097:blood / Q000502:physiology*; D003072:Cognition Disorders / Q000503:physiopathology*; D006801:Humans; D019409:Interleukin-15 / Q000097:blood / Q000502:physiology*; D054353:Perforin / Q000097:blood / Q000502:physiology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000503:physiopathology* / Q000523:psychology
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; C075005:GNLY protein, human; D019409:Interleukin-15; D054353:Perforin