Donders Institute for Brain, Cognition and Behaviour
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Thesis defense Bart van Nuenen (Donders Series 97)

November 22, 2012

Promotors: Prof. Dr. B.R. Bloem, Prof. Dr. I. Toni, Prof. Dr. H.R. Siebner Co-promotor: Dr. B.P.C van de Warrenbrug

Cerebral reorganization in premotor parkinsonism

The first part of this thesis describes how structural and functional neuroimaging of individuals carrying a mutation in one of the Parkinson disease (PD) genes (Parkin, PINK1 and LRRK2) offers a unique new avenue to obtain insights into the pathophysiology of PD and how fMRI can be used to identify compensatory mechanisms that help to prevent development of overt disease or delay clinical manifestation. Therefore, a combined neurogenetic-neuroimaging approach was used to examine the functional consequences of premotor dopaminergic nigrostriatal dysfunction in the human motor system. The second part of this thesis is focused on Transcranial Magnetic Stimulation (TMS) to induce cerebral reorganization in healthy controls and patients with clinically overt PD.

This thesis has given the first insights in the cerebral structures that are involved in premotor compensation strategies of the human brain in order to overcome the latent nigrostriatal dopaminergic dysfunction. The premotor regions seem to play a key role in these compensatory processes, which are more likely task-dependent rather than gene-dependent. An intriguing question is whether these increases in task-related activity in premotor areas persist, increase or attenuate in mutation carriers who are on the brink of developing clinical (motor) signs of parkinsonism. There are at least two competing explanations for the extra recruitment of premotor areas in these non-manifesting mutation carriers. It may be that among the mutation carriers, who have an increased risk for developing PD, the observed premotor changes reflect early premotor cortical alterations, i.e. an early manifestation of subtle alterations within the motor network. This intriguing possibility can only be confirmed through long-term follow-up of these subjects. Another possibility is that the motor network in these mutation carriers is simply different and as such unrelated to future development of PD. The cortical changes observed in these mutation carriers might therefore reflect, at least in part, an endophenotypic marker and not an early biomarker of PD. Longitudinal studies with repeated functional imaging are now needed to assess whether the observed cortical changes are predictive of PD during the premotor phase and if they are, whether these increase or attenuate when subjects develop clinical signs of PD.