Assessment if iron deposition and microstructural tissue changes in ALS patients

Amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease, is a devastating, progressive, neurodegenerative disorder that results in the degeneration of lower and upper motor neurones in the brain and the spinal cord. Typically the patient is paralyzed or deceased within 2 to 5 years of the initial diagnosis. The etiopathogenesis of ALS is probably complex, multi-factorial and largely unknown. After a presymptomatic stage of unknown duration, the disaease shows great variation in onset, clinical phenotype and survival. Presently, there is no specific biological marker for ALS and the diagnosis depends upon the recognition of a characteristic clinical constellation that is supported by electrophysiological findings. Conventional MRI has only limited value in the diagnostic workup of ALS because of its low sensitivity in the detection of corticospinal tract (CST) degeneration. However, further progress is expected with more detailed and quantitative measurements of tissue changes which have become possible with high resolution MRI, diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI). In addition, use of higher field strengths has opened the way to estimate the regional content in iron, which is believed to mediate oxidative stress and formation of cytotoxic proteins, and microstructural tissue changes associated to ALS. So far data on this topic are scarce and a combined assessment has not yet been performed. Also longitudinal data is very limited. The current project aims to characterize these microstructural changes in the CST but also extramotor regions with DTI, MTI, high resolution imaging, and by the assessment of iron accumulation. With a longitudinal study design and by using a normal age and sex matched cohort as reference we expect to get more detailed insights into macroscopic and microscopic characteristics of ALS and their relation to functional deficits and disease progression.

Amyotrophic lateral sclerosis (ALS) is an invariably fatal and rapidly progressive disorder of the motor neuron system. The initiation, onset and course of the disease are poorly understood. Although clinical and electrophysiological examinations are mandatory techniques for initial diagnosis, they provide only limited diagnostic certainty at an early stage of the disease and also less information regarding prognosis. Much hope has been put on quantitative magnetic resonance imaging (MRI) techniques which allow to study microscopic tissue changes in the cortico-spinal tract (CST) and in other white matter areas which appear normal on conventional MRI. In a study with 40 ALS patients and 40 age matched healthy controls, we here compared different quantitative MRI techniques with respect to microstructural tissue changes and we found that diffusion tensor imaging (DTI) is the most sensitive technique. DTI probes the mobility of tissue water in the nerves which is usually hindered by cell membranes and lipid-bilayers. We observed an increase of the radial diffusivity in the CST and other white matter tracts which is indicative of a damage to the myelin and which does not reflect axonal damage. In contrast to smaller studies published previously, no elevated levels of iron in brain tissue were observed. Microstructural tissue changes observed by quantitative MRI could not fully explain the clinical condition. However, these changes were highly predictive for disease progression. This study further supports the role of MRI as a potential biomarker for ALS.