Identification of radiation treatment impact on brain development. Radiation therapy is an integral part of treament for pediatric brain tumours and for high-risk leukemias, but is also associated with the generation of late-appearing side effects including cognitive, behavioural, and psychological impairments. This dramatically impacts quality of life in children who survive cancer. A means of eliminating or treating these “late effects” is urgently needed, but the mechanism by which they appear is not clear. Dr. Nieman’s group has characterized the anatomical phenotypes seen in childhood cancer survivors who were treated with radiation therapy. Their results showed white matter volume deficits, as well as significant changes in gray matter morphology, including increased cortical thickness and decreasing hippocampal volume. Comparison of these observations side-by-side with results from mouse models showed remarkable similarities overall. On this basis, the Nieman group has conducted detailed characterization of the time course, dose dependence, and age dependence in a mouse model. Ongoing work will map sensitivity after focal treatments and in mice with modified radiation response.
Characterization of chemotherapy impact on brain development. Like radiation, chemotherapy impacts brain development and results in late-appearing side effects that impair learning, memory and attention in many childhood acute lymphoblastic leukemia survivors. The Nieman group is working closely with other SickKids investigators to characterize how chemotherapy affects brain growth and to determine how this relates to performance on cognitive and behavioural tests. As modern chemotherapy is very complicated, including ~10 chemotherapy agents administered over as long as 3 years, identifying the key cause of brain impairments is no small undertaking. The Nieman group is using mouse models to understand how each aspect of treatment impacts the brain and its development with the goal of isolating the most damaging components of the chemotherapy treatment with the goal of developing strategies to eliminate late effects.
Imaging of mouse development in utero and postnatally. Mouse MRI historically has been restricted to a small number of anatomical regions, in part because long scan times result in a high likelihood of motion-related artifact over much of the body. Dr. Nieman developed a method combining imaging and registration tools to improve image quality for a number of imaging applications. This has shown benefit in imaging of the mouse brain, the adult mouse heart, the embryonic brain in utero and, ultimately, produced time-lapse movies of the beating embryonic heart in utero. This significantly expands the range of applications for mouse MRI, enabling longitudinal studies of development from embryonic stages through adulthood.
Development of cellular imaging in the mouse brain. Particular cell populations play more prominent roles in homeostasis or disease pathogenesis than others, a fact that motivates development of cell-specific imaging. Dr. Nieman has used iron-oxide particles to label endogenous neuroblasts (NBs) in the subventricular zone (SVZ), which are a particularly important in homeostasis of the olfactory bulb. This allowed quantification of the temporal dynamics of NB migrations, showing that cells en route to the olfactory bulb are able to travel at speeds of ~100 µm/hr. His group has used similar approaches to evaluate heterogeneity in tumour proliferation over time, revealing characteristic differences between mouse models of glioma development. Dr. Nieman’s group is also investigating proteins that may be responsible for sequestering manganese, an important contrast agent in mouse MRI, which may become useful for cell imaging in future.