Quantification of GABA in Children with Neurofibromatosis Type 1 Using Magnetic Resonance Spectroscopy: A Cognitive Biomarker?
Abstract
Rationale and Objective for the Proposed Research: Neurofibromatosis type 1 (NF1) is a genetic disorder that affects 1 in 2,700 individuals. Significant variation in disease severity is typical and all patients are at risk of developing debilitating and potentially life-limiting complications. The most common complication of NF1 in childhood is cognitive and learning deficits such as reduced intelligence, academic underachievement, difficulties with attention and concentration, and social dysfunction. These impairments are a major manifestation of NF1, and the development of treatments are a high priority in the NF community. Understanding the abnormal cell and brain processes underlying these difficulties is essential to advance research of possible treatments. Studies using genetically engineered mouse models of NF1 have revealed that cognitive and behavioral deficits are caused by increased levels of a brain chemical called GABA. Exciting studies have shown that medication can normalize GABA levels in NF1 mice and rescue their cognitive deficits. Early attempts at translating these findings in human trials have unfortunately failed. The reasons for this are unclear, making the results of these large, expensive trials difficult to interpret. Best scientific practices in this area are significantly limited by the lack of an evidence-based measure to assess whether treatments were able to modulate GABA levels in the human brain. In this study, we propose to use magnetic resonance spectroscopy (MRS), a safe, non-invasive brain imaging technique to measure GABA levels in 25 children with NF1 and a comparison group of 25 typically developing peers. The objectives of this study are to (1) determine whether GABA levels in specified regions of the brain are abnormal in children with NF1 and (2) determine whether GABA levels in these regions contribute to cognitive deficits in children with NF1. We hypothesize that GABA levels will be abnormal in these regions and that they will be associated with cognitive and behavioral deficits. Ultimate Applicability of the Research: There is currently no established biomarker of cognitive deficits in children with NF1. The proposed MRS methodology is a safe and an extremely powerful approach to investigate the relationship between GABA levels and cognition in children with NF1. While these links have been established in NF1 mouse models, it is essential to examine this relationship in children with NF1. This study has the potential to provide high-impact findings that, if realized, will be ground-breaking for not only conceptualizing the biology and brain pathology of NF1 in humans, but for advancement in clinical trial design for cognitive deficits in NF1. To this end, our findings are likely to impact the 80% of patients with NF1 that experience cognitive deficits. Positive patient-related outcomes will be immediate. If our hypotheses are confirmed, we would propose that large, expensive clinical trials were preceded by a small pilot study measuring GABA levels before and after treatment to show whether the proposed dose was able to normalize GABA levels in the brain. If GABA levels were normalized, then an accompanying reversal in cognitive deficits would be expected and the clinical trial should proceed. However, if GABA levels were not normalized, then a new pilot study would need to be conducted with either a modified dosing regimen or a different medication. Such an approach will result in better informed research, enabling a refined trial design based on human evidence. Critically, it will also reduce the likelihood of an expensive negative study, which will impact hope and confidence of the NF community and patient participation rates in future studies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610408
Entities
People
- Jonathan M Payne
Organizations
- United States Army