PhD defence: Louise Møller Jørgensen

On Friday March 9th at 3 pm in Auditorium 93 at Rigshospitalet, Louise Møller Jørgensen, MD, will defend her PhD thesis entitled "Pharmacological and DBS-induced changes in cerebral serotonin release".


Evaluation committee:
Chair: Professor Tiit Mathiesen, Department of Clinical Medicine, University of Copenhagen, Denmark
Professor David J Brooks, PET Center, Aarhus University, Denmark
Professor Kendall H Lee, Department of Neurosurgery, The Mayo Clinic, Rochester, MN, USA

Academic Advisors:
Professor Gitte Moos Knudsen, MD, DMSc, Neurobiology Research Unit, Copenhagen, Denmark
Professor Jens Christian Hedemann Sørensen, Department of Neurosurgery, Aarhus University Hospital, Denmark
Professor Olaf Paulson, Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Denmark
Senior scientist Pia Weikop, The Laboratory of Neuropsychiatry, Department of Neuroscience and Pharmacology, University of Copenhagen, Denmark.

Summary:
Parkinson’s Disease (PD) is one of the most common movement disorders in the world affecting 1% of the population above 60 years of age causing both motor and non-motor symptoms. Although focus has initially been on dopaminergic dysfunction, there are vast amount of research supporting the involvement of other brain monoamine systems in PD, such as serotonin (5-HT).

Deep Brain Stimulation (DBS) is a potential reversible surgical treatment used to alleviate motor symptoms in a selected group of patients with PD, but DBS also has the potential to treat other neuropsychiatric disorders, such as depression, of which serotonergic modulation at the synaptic level constitute an established treatment. Even though the therapeutic effect of DBS in movement disorders is well established, the mechanism underlying its effect is still unclear. Brain imaging of the 5-HT system and its functions is important to characterize neuropsychiatric disorders and to identify treatment options. Understanding the DBS-induced mechanisms may contribute to improve medical therapy of such brain disorders and support the transition of DBS-treatment to new applications.

The aim of this thesis is to characterize the association between microdialysis and Positron Emission Tomography (PET) measures of changes in cerebral 5-HT level, which will serve as a tool for translating the outcome from future PET imaging studies, as subsequently conducted here in a PET study of patients treated with DBS.

The thesis is based on three studies. In the first two studies in pigs, the association between microdialysis and PET measures of changes in 5-HT level is characterized upon various pharmacological interventions with the aim to raise the extracellular cerebral 5-HT level differently. In the last study, we used the PET radioligand first evaluated in the preclinical study to investigate the presynaptic serotonergic function in patients with PD treated with DBS and the association to mood and clinical measures of PD.

We demonstrate that both PET radioligands, the 5-HT2A receptor agonist [11C]Cimbi-36 and the 5-HT1B partial agonist [11C]AZ10419369, are sensitive to 5-HT, but only when the release is sufficiently high. While the sensitivity of [11C]AZ10419369 to detect 5-HT is comparable to that of [11C]raclopride to detect dopamine (DA), [11C]Cimbi-36 is three times more sensitive than [11C]AZ10419369, but an advantage of [11C]AZ10419369 is that it can be used in a within-scan design.

With [11C]AZ10419369, we show that patients with PD treated with DBS exhibit a region specific loss of serotonergic presynaptic terminals associated with an incapacity to elicit a serotonergic response when DBS was turned off. The serotonergic dysfunction is to some extent correlated with motor symptom severity.

The thesis confirms that data from PET imaging comply with the competition model and diagrams of the association between cerebral 5-HT level and PET measures allow to translate outcome from new PET 5-HT studies as changes in interstitial 5-HT. With this novel technology we observed a presynaptic serotonergic deficit in patients with PD treated with DBS. The observed serotonergic deficits may play an important role in both motor and non-motor symptoms in patients with PD. The outcome from this thesis expand the existing knowledge of serotonergic involvement in PD and the underlying mechanism of DBS. Moreover, it provides an important tool to translate PET images to cerebral 5-HT release in future studies.