Application of Advanced Neuroimaging Techniques in Prader-Willi Syndrome

Funding Summary

This research will use state of the art neuroimaging techniques to advance our understanding of the neurobiology of two of the most challenging and difficult to manage aspects of PWS: hyperphagia and psychosis. The investigators will determine if imaging can detect changes in hypothalamic function in relation to eating behavior in PWS as well as how brain structure and neurotransmitter metabolism are altered in those with PWS who experience mental illness.  Dr. Brown’s group proposes that altered expression of several genes at or near the PWS region may disrupt key neurotransmitter systems cause a cascade of effects, ultimately altering the inhibitory/excitatory balance in the brain and causing dysfunction of the predictive processing system of the brain.

Lay Abstract

The proposed research aims to address two of the most difficult to manage and treat behavioural aspects of Prader-Willi syndrome (PWS): hyperphagia (over-eating) and psychosis. Overeating in PWS accounts for a significant increase in morbidity and mortality in this population, and as the underlying neurobiology remains largely unknown and difficult to study in the clinical population, it poses a substantial challenge for syndrome management. Similarly, while psychotic symptoms are frequently observed in PWS, the presentation of these symptoms is atypical, making it difficult to classify within currently described psychotic disorders. Importantly, further research is needed to establish treatments to help manage these symptoms and to improve quality of life.
Neuroimaging and the application of MRI technology is a quickly developing field, and with advances in this area, the opportunity arises to shed substantial light on the brain changes that underly the aforementioned behavioural difficulties in PWS. Our research group has taken a community-led approach to successfully scan 32 PWS young adults to date, and the planned research aims to fully utilise the wealth of data collected and expand analyses to include new and innovative approaches to solving behavioural challenges in PWS. These approaches include mapping the brain structurally, examining hypothalamic function (a key regulator of appetite) and looking at brain chemicals (a known causation of psychosis).
Overall, this research plans to significantly develop our knowledge of the underlying neurobiology of two of the most challenging and difficult to manage behavioural aspects of PWS: over-eating and psychosis. To address these research aims, we propose to utilise advanced neuroimaging techniques, for which our research team has both the unique technical expertise and clinical experience.
Next Steps & Therapeutic Development:
We predict that a) function of the hypothalamus will be altered in relation to eating behaviour in PWS and b) that brain structure and neurotransmitter metabolism will reflect the increased presence of psychosis in there mUPD genetic subtype. Identification of metabolite imbalance and the upstream pathways involved will be key in allowing psychosis treatments to be effectively and thoughtfully targeted in PWS.
In the efforts to develop treatments for hyperphagia in PWS, Aardvark Therapeutics have recently developed an agent called ARD101, an agonist for bitter taste receptors which is in clinical trial as an appetite suppressant. ARD101 shows significant promise in the management of appetite in PWS, and our research group is planning a proof-of-concept study with Aardvark, to translate our findings into the development of therapeutics directly. One mechanism ARD101 acts by is through hypothalamic function. Once the present proposed hyperphagia research evidences hypothalamic functional abnormality relating to eating behaviour in PWS, we plan to establish in patients taking ARD101 how this agent may return hypothalamic function to a control baseline level, thus providing valuable neurobiological evidence of the efficacy of the agent.