Identifying Upper Motor Neuron Pathology and Molecular Signatures in the Amyotrophic Lateral Sclerosis (ALS) Motor Cortex - Abstract Dr. Frank Diaz is a neurologist and neuromuscular medicine specialist interested in identifying and understanding the pathophysiology of the motor cortex and upper motor neurons in patients with amyotrophic lateral sclerosis (ALS). Since ALS is a very heterogeneous disease without ideal animal models, Dr. Diaz’s goal is to develop additional skills to become an independent physician-scientist and develop a translational research program that will combine longitudinal clinical measures, in vivo magnetic resonance imaging measures, and postmortem imaging and transcriptomics to identify underlying pathophysiological mechanisms in ALS. For Aim 1, Dr. Diaz proposes to use advanced iron-sensitive MRI techniques in vivo and postmortem to identify the pathological substrate and clinical significance of “the motor band sign”, a promising marker of motor cortex pathology in ALS patients. The goal is to first determine the correlation of upper motor neuron degeneration, TDP-43 pathology, microgliosis/ astrogliosis, and iron with the MRI motor band sign in the hand knob area of postmortem brains. To do so, Dr. Diaz proposes to develop and use novel 3D-printed custom brain sectioning templates for accurate imaging-pathological correlations. To understand the clinical significance, he proposes to image the motor band sign in vivo and longitudinally in patients with classic ALS, ALS variants with different degrees of clinical upper motor neuron involvement, and controls, and determine the correlation with clinical measures of upper motor neuron involvement, and disease progression. The goal of Aim 2 is to identify motor cortex and upper motor neuron-specific molecular signatures from the hand knob area of patients with ALS. To do so he proposes to first generate a single nucleus RNA sequencing (snRNA-seq) dataset from readily available frozen specimens from patients with classic ALS and controls. However, since the clinical data from available samples is limited, to determine molecular signatures associated with clinical upper motor neuron dysfunction, he proposes to collect the brains from patients in Aim 1, perform snRNA-seq postmortem, and compare the molecular signatures from patients that in vivo had evidence of upper motor neuron dysfunction those without clinical evidence of upper motor neuron dysfunction. These studies will identify novel targets of motor cortex and upper motor neuron dysfunction for drug development. In addition, the motor band sign could develop into a non-invasive imaging biomarker for early identification of upper motor neuron dysfunction and/or for monitoring drug efficacy. Dr. Diaz will be supported by his primary mentor, Dr. Clive Svendsen, a leader in ALS research, as well as his co-mentor Dr. Pascal Sati, an expert on MRI, and a multidisciplinary advisory committee that will provide the expertise and training necessary in advanced MRI applications, imaging-histological correlations, and transcriptomics. The long-term research goals are to address important and complex questions in ALS, such as the temporal and spatial progression and spread of the disease and identify early vs. late pathophysiological markers of disease using a combination of clinical measures, MRI, and transcriptomics in the same patients in vivo and postmortem.
