Identification and Utilization of Upper Motor Neuron Biomarkers for ALS
Abstract
ALS is a disease of the upper and lower motor neurons, where upper motor neurons (UMNs) reside in the brain and the lower motor neurons reside in the spinal cord. An ALS diagnosis requires that both types of motor neurons be affected and that they display progressive degeneration. However, the cortical component of ALS has not been studied to the same depth as the spinal cord component. There were valid reasons to avoid the cortex of ALS in the past. It was suggested that brain is too complex, it is hard to visualize and study the UMNs, and that brain neuron degeneration is part of the ongoing overall degeneration observed in ALS. However, a growing volume of scientific evidence has started to reveal that the cortex begins to degenerate very early in ALS patients and that degeneration of UMNs contributes to disease pathology. Even though researchers now realize that the brain plays a critical role in ALS, the impact of potential ALS therapeutics upon the UMNs has not been integrated into clinical trials. One of the limiting factors is the lack of accurate and reliable biomarkers. Currently, there are no measures (e.g., biomarkers, such as blood proteins) that can be used to distinguish ALS patients with prominent UMN loss from other UMN disease patients, such as patients with hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS). Biomarkers are needed to inform clinicians regarding the underlying causes of UMN degeneration, so that patients can be included in specific clinical trial for drugs targeting the cause of their disease. They are also needed to (a) inform neurologists about the timing and the extent of UMN loss in patients; (b) to assess whether compound treatment is effective in patients; and (c) whether UMNs begin to regain their health and stability in response to treatment. Without these biomarkers, it is not feasible to determine the impact of new therapies on UMNs in clinical trials. This is a major limitation in developing long-term, effective treatment strategies for ALS. This proposal is the result of a collaborative effort between (a) a clinical team at Massachusetts General Hospital/Harvard Medical School, who have created the world s largest platform for ALS clinical trials; and (b) a multi-disciplinary team at Northwestern University, composed of scientists who have developed ways to detect proteins in blood with unprecedented precision and clarity, and scientists who have extensive knowledge of the biology of UMNs and their role in ALS. This multi-institutional team will apply its expertise and resources toward the goal of identifying UMN biomarkers in ALS. The team will have access to a broad array of rare patient blood samples: the largest cohort of ALS patients with prominent UMN loss, patients with minimal UMN involvement, HSP, PLS patients, as well as patients who donated their blood at different time points of the disease. In addition, the team brings expertise in the science of protein analysis proteomics, which will enable determination of both the identity and quantity, as well as the potential changes in structure, of proteins with respect to UMN loss in ALS patients. These studies will be used to determine whether specific patterns of protein in blood can be used to diagnose ALS, develop more precise and sensitive clinical trials, and provide a reliable measure of the impact of treatment on the cortical component of ALS more quickly and accurately. The development of biomarkers for UMN degeneration has the potential to substantially improve the diagnosis, treatment, and prognosis of individuals with ALS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210166
Entities
People
- Hande Ozdinler
Organizations
- Northwestern University
- United States Army