Canavan disease is a metabolic disorder of the cen tral nervous system (CNS) caused by mutations in the aspartoacylase (ASPA) gene. This devastating neuro degenerative disease manifests soon after birth and is inevitably fatal before the age of ten.Due to its monogenic nature and a pathology restricted to the CNS Canavan disease was the first neurological disor der ever to be trialled by gene therapy.

The loss of the enzyme ASPA causes toxic accumula tion of its substrate NAA and leads to disruption of the myelin sheath. Elevated NAA levels are thought to lead to a build up of water in the CNS causing se vere brain anomalies. To better understand the un derlying pathomechanisms and optimise a genetic treatment for the disease a UNSW research group lead by A.Prof. Matthias Klugmann has devel oped several mouse models in which genes encoding enzymes involved in the NAA me tabolism were deleted or enhanced.

Magnetic resonance imaging (MRI) and local ised Magnetic resonance spectroscopy (MRS) are ideal modalities to detect, characterise and monitor both anatomical and metabolic changes know to occur in myelin disorders. This makes them well suited tools to gain lon gitudinal and group information about CNS pathology in Canavan mouse mutants and to assess treatment efficacy following gene ther apy.

In a collaborative research effort between the Klugmann group and the Biological Re sources Imaging Laboratory (BRIL) NIF node at UNSW, both MRI and MRS platforms are intensively used to enlighten CNS alterations in these transgenic models. Dr Andre Bongers who manages the research at the NIF flagship equipment the high field pre clinical MRI Bruker BioSpec 94/20USR leads the MRI re search in this collaboration. He brings over 13 years of expertise in MRI method develop ment and applications into the project with physio logical imaging methods (such as quantitative sus ceptibility mapping) that facilitate the quantification of brain structure integrity and metabolism.

As a part of the project anatomical abnormalities due to water accumulation in the brain are investigated in a longitudinal high resolution volumetry study. As an example the unpublished data in Fig. 1 demonstrate the segmentation of pathologically increased brain ventricles in the Canavan mouse faithfully replicating a key pathological feature of the human condition.

Canavan disease patients and mouse models exhibit high levels of NAA. Although NAA is among the most abundant metabolites in the brain its role in the nor mal or diseased brain is still poorly understood. In another effort in the collaborative research project the group currently carries out studies to investigate NAA in mouse models using optimised MR spectros copy methods. Klugmann’s team provides additional mouse models by genetically manipulating key en zymes involved in the NAA metabolism. Dr Bongers will use proton magnetic resonance spectroscopy (1H MRS) in an optimized set up using micro gradi ents and RF cryo coil for longitudinal in vivo quantifi cation of metabolites including NAA.

These experiments will be complemented by ex vivo NMR spectroscopy in col laboration with UNSW NIF Node Director Prof. Lindy Rae (UNSW/NeuRA) to analyse intracellular meta bolic pathways in vitro and in vivo. The project demonstrates the high power of interdis ciplinary research collabo rations facilitated by the National Imaging Facility.

The combination of expertise in transgenic mouse models and MRI method development and appli cation facilitates significant progress in key ques tions of physiological research.
For more information about BRIL and access to the re search facilities, please visit:; Or contact Dr Andre Bongers