Imaging Dyskinesias in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a neurodegenerative movement disorder characterised by the motor features of tremor, rigidity and bradykinesia. These features are associated with the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta and a subsequent deficiency in striatal DA, which is required for the effective control of movements. However, there is evidence of a more diffuse pathology in PD (Braak et al., 2004) with other, non-DA neutotransmitter systems possibly playing a role (Kish et al., 2003, 2008; Remy et al., 2005; Albin et al., 2008; Politis et al., 2010a). To date, regular administration of the direct metabolic precursor for DA, L-3, 4-dihydroxyphenylalanine (L-DOPA) remains the most effective treatment of PD symptomatology. L-DOPA therapy is most optimally effective in the early stages of the disease and long term use leads to the appearance of motor complications such as involuntary movements, so-called L-DOPA-induced dyskinesia (LID). LID represents a debilitating complication of L-DOPA therapy in PD and is experienced by the vast majority of patients (estimates range between 40-90% between 4 and 10 years after initiation of LDOPA therapy) (Racol et al, 2000; Ahlskog and Muenter, 2001). The mechanisms underlying LID remain obscure. It is known that LID is observed following DA therapy and that there is a time-lag between the initiation of DA therapy and the emergence of LID. Risk factors commonly associated with the development of LID include PD severity, L-DOPA dose and duration of L-DOPA therapy. Positron emission tomography (PET) neuroimaging provides a useful tool for assessing in vivo functionality of basal ganglia in the PD brain. As such, the use of specific radiotracers permits insight into the integrity of both preand postsynaptic DA function, which could help elucidate some of the pathophysiological mechanisms underlying LID. Furthermore, over the last decade or so, PET studies have provided evidence that non-DA neurotransmitter systems may be involved in the development of LID. For example, PET has been used to investigate the role of different neuropeptides in LID, such as opioids and NK1, preliminary findings implicating the role of adenosine A2A receptors and more recently promising results have emerged suggesting that the serotonergic system may possess a valuable role in the emergence of LID in PD. Taken together, the in vivo findings to date have provided valuable information regarding the function of various neurotransmitter systems in the occurrence of LID and support the use of PET brain imaging to further explore these investigations. Considering the promising evidence suggesting that non-DA neurotransmitter systems may have a role in the pathogenesis of LID, further manipulation of these systems may offer an alternative