Neuroimaging Abnormalities Predict Immunotherapy Responsiveness in Down Syndrome Regression Disorder
Jonathan Santoro1, Mellad Khoshnood2, Saba Jafarpour3, Lina Nguyen2, Natalie Boyd2, Benjamin Vogel2, Ryan Kammeyer4, Lina Patel5, Melanie Manning6, Robyn Filipink7, Stephanie Santoro8, Catherine Franklin9, Benita Tamrazi2, Gordon Worley10, Joaquin Espinosa11, Michael Rafii12
1Department of Neurology, Children's Hospital Los Angeles, 2Children's Hospital Los Angeles, 3Children’s Hospital of Los Angeles, 4Childrens Hospital Colorado, 5Children's Hospital Colorado, 6Stanford School of Medicine, 7Children'S Hospital of Pittsburgh of UPMC, 8Massachussetts General Hospital, 9The University of Queensland, 10Duke University School of Medicine, 11University of Colorado, 12USC Alzheimer'S Therapeutic Research Institute
Objective:
To determine the prevalence of neuroimaging abnormalities in individuals with Down Syndrome Regression Disorder (DSRD) and evaluate if neuroimaging abnormalities were predictive of therapeutic responses.
Background:
Down Syndrome Regression Disorder (DSRD) is a neuropsychiatric condition of acute or subacute onset. Symptoms include bradykinesia, catatonia, insomnia, mutism, and loss of previously acquired developmental skills. There are multiple, multi-center, studies demonstrating immunotherapy responsiveness but an etiology has not been elucidated. As such, biomarkers are limited.
Design/Methods:
A multi-center, retrospective, case-control study which reviewed neuroimaging studies of individuals with DSRD and compared them to a control cohort of individuals with Down Syndrome (DS) alone was performed. Individuals aged 10-30 years and meeting international consensus criteria for DSRD were included. The presence of T1, T2/FLAIR and SWI signal abnormalities was reviewed. Response rates to various therapies, including immunotherapy, were evaluated in the presence of neuroimaging abnormalities.
Results:
T2/FLAIR signal abnormalities were appreciated more frequently in individuals with DSRD (14%, 30/210) than in the control cohort (9%, 11/119) (p=0.18, OR: 1.63, 95%CI: 0.79-3.40). SWI signal abnormalities were appreciated at a higher frequency in individuals with DSRD (24%, 51/210) compared to the control cohort (4%, 5/119) (p<0.001, OR: 7.31, 95%CI: 2.83-18.90). T2/FLAIR signal abnormalities were frontal (40%, 12/30) and parietal lobes (37%, 11/30). SWI signal abnormalities were predominantly located in the bilateral basal ganglia (94%, 49/52). Individuals with the presence of T2/FLAIR and/or SWI signal abnormalities were much more likely to respond to immunotherapy (p<0.001, OR: 8.98. 95%CI: 4.10-19.69) and less likely to respond to benzodiazepines (p=0.01, OR: 0.49, 95%CI: 0.27-0.90), antipsychotics (p<0.001, OR: 0.28, 95%CI: 0.12-0.59), or electroconvulsive therapy (p<0.001, OR: 0.14; 95%CI: 0.02-0.78).
Conclusions:
This study indicates that in individuals diagnosed with DSRD, T2/FLAIR and SWI signal abnormalities are common and predicts response to immunotherapy.