Analysis of Manganese Enhanced MRI of the Normal and Injured Rat Central Nervous System

Abstract

Injury or disease in the central nervous system (CNS) such as stroke or Alzheimer's disease is often irreversible, thus patients su_ering from such injuries or diseases have poor prognosis. Important factors in CNS injury and disease are absence of axonal regeneration and axonal transport disturbances. Axons in the mammalian CNS do not regenerate after injury but few experimental procedures have shown to promote CNS regeneration. In some neurodegenerative diseases failure in the axonal transport system is the underlying cause of the disease. Studies of these mechanisms in animal models are important before translating any treatments to humans. Magnetic resonance imaging (MRI) is a non-invasive imaging technique which allows in vivo longitudinal CNS studies in contrast to traditional methods which requires sacri_cing the animals before tissue sampling and microscopic analysis of neurons. Manganese (Mn2+) is a paramagnetic ion which reduces the T1-relaxation time, thus increases tissue contrast in T1-weighted MR images. In addition, Mn2+ enters neurons through voltage gated calcium channels and is transported along neural axons which make Mn2+ well suited as a contrast agent in MRI studies of the CNS and neural pathways.

In this PhD-thesis methods for segmentation of axons and brain tissue with Mn2+ accumulation together with methods for quanti_cation of signal- and contrast changes along axons related to Mn2+ accumulation and transport have been established. The rat optic nerve (ON) and brain was chosen as experimental models for the mammalian CNS. A method for semi-automatic segmentation of the manganese enhanced rat ON and calculation of contrast variation along the ON was developed in Paper I. In Paper II, this method was used to in vivo detect ON axon regeneration after injury and axon re-growth stimulation. In Paper III, the transport kinetics of Mn2+ in the healthy rat ON was investigated. The results indicate that input of Mn2+ into axons is restricted and are transported along the ON axons in a wide range of velocities. In Paper IV, a method for comparison of manganese enhanced MRI and corresponding histology of stroke in the perinatal period was developed. The methods have enabled more reliable in vivo studies of axonal damage and repair in parts of the CNS and provided more profound knowledge about axonal manganese transport kinetics, as well as novel insight into the relationship between manganese enhancement and neural death related to ischemic insult in the neonatal brain.