Purpose: To establish brain-based, objective measures that reflect severity of cognitive, behavioral, and motor impairments in Neurofibromatosis Type 1 (NF1) as outcome measures for clinical trials.

Background: In Neurofibromatosis Type 1 (NF1), a genetic disorder affecting 1 in 2,000 individuals, approximately 50% of children exhibit impaired executive function, learning, and/or motor function. Currently, assessing severity of these problems involves subjective rating scales. This impedes accurate measurement of responses to potential therapeutics. We hypothesized that objective brain-based techniques such as Transcranial Magnetic Stimulation (TMS) and MRI-based measures would correlate with clinical assessments.

Methods: We assessed behavior, executive function, and motor development using standardized scales and tests. We measured inhibition and excitation in left motor cortex and biochemical (neurotransmitter/metabolite) concentrations in anterior cingulate cortex. We explored associations between clinical assessments and brain measures using Spearman Correlations.

Results: Data from twenty-five youth with NF1 (age mean 12.4, S.D. 3.0; 12 female) were analyzed. TMS measures of reduced inhibition/excitation in the motor cortex showed some associations with worse executive function and motor skills. Impaired motor function was associated with worse executive functioning. No MR spectroscopy measures of neurotransmitters or metabolites within the anterior cingulate correlated with global executive or motor function; however, elevated choline concentrations correlated with several subdomains of impaired motor function, possibly indicating a role for inflammation or myelin turnover.

Conclusion: TMS and MRS measures may provide quantitative, objective brain-based alternatives to clinical rating scales in therapeutic trials for cognitive, behavioral, or motor impairments in NF1.

Funded by U.S. D.O.D Award W81XWH-20-1-0139

Lindsey Aschbacher-Smith
Cincinnati Children's Hospital Medical Center
United States

David Huddleston
Cincinnati Children's Hospital Medical Center
United States

Karlee Migneault
Cincinnati Children's Hospital Medical Center
United States

Kim Cecil
Cincinnati Children's Hospital Medical Center
United States

James Leach
Cincinnati Children's Hospital Medical Center
United States

Mark DiFrancesco
Cincinnati Children's Hospital Medical Center
United States

Nancy Ratner
Cincinnati Children's Hospital Medical Center
United States

Brittany Simpson
Cincinnati Children's Hospital Medical Center
United States

Elizabeth Schorry
Cincinnati Children's Hospital Medical Center
United States

Carlos Prada
Ann & Robert H. Lurie Children’s Hospital of Chicago
United States

Donald Gilbert
Cincinnati Children's Hospital Medical Center
United States