Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of motor neurons. An accurate quantitative test of upper motor neuron (UMN) integrity would provide an important biomarker for use in early disease detection, monitoring of disease progression, and development of potential treatments. We will assess the use of state-of-the-art magnetic resonance (MR) techniques, including MR spectroscopy (MRS) and diffusion-tensor imaging (DTI), as potential biomarkers of UMN integrity in ALS patients. Many investigators have previously used these tests in patients with widespread ALS. However, more research is needed to assess the use of these tests in patients with a more limited distribution of disease (specifically categorized as "Clinically Possible ALS" by the revised El Escorial diagnostic criteria), allowing for more definitive diagnosis, and supporting entry into clinical trials. Improvements in imaging and processing techniques to be used in our proposal, particularly a novel high-dimensional normalization technique developed at our institution, will further enhance the ability of these MR-based tests to detect UMN damage. In this proposal, we will investigate the use of MRS and DTI to evaluate the UMN in patients with Clinically Possible ALS, and in comparison populations of normal controls, patients with Clinically Probable or Clinically Definite ALS, and patients with ALS-mimicking disorders. We have the following specific aims: Specific aim 1. UMN assessment with quantitative MR spectroscopy. We determine the degree of UMN damage at the motor strip in Clinically Possible ALS, and compare the damage with ALS patients who have more widespread disease. We also investigate the UMN in ALS-mimicking disorders. Several brain metabolites will be measured at the primary motor strip using the LCModel quantitation software. Specific aim 2. UMN assessment with DTI and high-dimensional normalization. We determine the degree and extent of axonal damage in Clinically Possible ALS, and compare the damage with ALS patients who have more widespread disease. Several DTI parameters will be measured at the corticospinal tract (CST), with tract-specific and voxel-wise analyses to be performed after normalizing the individual tensor datasets into a common spatial frame. The CST will also be evaluated in ALS-mimicking disorders. Our long-term objective is to develop and validate an accurate, quantitative, and non-invasive test of UMN disease using MR, to be used as a biomarker in ALS. PUBLIC HEALTH RELEVANCE: In neurodegenerative diseases, an accurate biomarker reflecting the disease process would be invaluable in detecting early stages of disease, monitoring of disease progression, and facilitating development of novel treatments. This research proposal studies the use of magnetic resonance (MR) technology as potential biomarkers of upper motor neuron (UMN) disease in amyotrophic lateral sclerosis, a rare neurodegenerative disease of motor neurons.