ReviewSerotonin in Parkinson's disease
Introduction
Parkinson's disease (PD) is the second most common neurodegenerative disorder of the elderly and is clinically characterized by the motor symptoms of tremor, bradykinesia, and rigidity [1]. Non-motor features including cognitive and neuropsychiatric disturbances also commonly manifest, dispelling previous beliefs that PD is solely a disorder of movement [2], [3]. The main pathological characteristic of PD is the progressive loss of dopamine neurons in the substantia nigra pars compacta [4], [5], [6], but the pathological processes in PD are not only confined within the dopaminergic system as there is a more diffuse pathology involving other, non-dopaminergic systems, such as the serotonergic [7], [8], [9].
In the brain, serotonin cell bodies are located in the raphe nuclei of the brainstem, where they can be subdivided on the basis of their distribution and main projections into two groups: the rostral group with major projections to the forebrain innervating the hypothalamus, the basal ganglia, amygdala, cingulum, the medial cerebral cortex and part of the hippocampus [10], [11], [12], [13], and the caudal group with major projections to the caudal brainstem and to the spinal cord [14]. Several functions have been attributed to the serotonergic system including cognition, emotion and motor behaviour; thus altered serotonergic neurotransmission may contribute to the motor and non-motor features commonly associated with PD [9], [15], [16]. Evidence from animal and human studies has suggested that striatal serotonergic terminals may contribute in the development of levodopa-induced dyskinesias (LIDs) by promoting a non-physiological release of dopamine [17], [18].
Positron emission tomography (PET) molecular imaging is a powerful analytical method to detect in vivo changes in the brain [19], [20]. PET measures the distribution of a radioligand that is introduced into the body, with the potential to give both structural and kinetic information [21]. PET used together with specific serotonin radioligands has played a major role in elucidating the pathophysiology of serotonergic system in PD. Over the last decade, we have seen the development of several PET radioligands tagging serotonin targets in the human brain. 18F-MPPF for 5-HT1A, 18F-setoperone for 5-HT2A and 11C-AZ10419369 for 5-HT1B receptors are few examples of PET techniques for studying the serotonin system in the human brain [22], [23], [24], [25]. The first PET radioligand successfully developed to image the 5-HT transporter (SERT) density in humans was 11C-McN 5652 [26], [27], [28], [29]. However, its highly nonspecific binding precluded the reliable quantification of SERT in regions of moderate-to-low SERT density and long imaging sessions were required for acquiring accurate SERT measures [30]. More recently, Wilson and colleagues introduced 11C-DASB as another PET radioligand suitable to image SERT [31]. Compared to other radiotracers, 11C-DASB is three orders of magnitude more selective for SERT than for other monoamine transporters (such as those for dopamine and noradrenaline) [31], [32], [33] and has higher specific-to-non specific binding ratios [30].
In this review, we are primarily revising in vivo human studies from research with PET molecular imaging in PD.
Section snippets
Serotonergic dysfunction in Parkinson's disease
Evidence from animal, biochemical, post-mortem and human in vivo studies have demonstrated loss of striatal and extra-striatal serotonin markers in the course of PD indicating that the serotonergic system is affected from PD pathology [8], [34], [35], [36], [37], [38], [39]. According to Braak's staging, the pathological process in PD occurs in a gradual ascending fashion, starting from the olfactory nucleus and the medulla in presymptomatic stages and spreading to the pons and midbrain later
Tremor
Tremor is one of the most challenging symptoms to manage in clinic, as it has a poorer and more unpredictable response to DRT compared to bradykinesia and rigidity [45]. Previous imaging studies utilizing PET with 18F-dopa [46], 11C-raclopride [47] and 123I-β-CIT SPECT [48], have consistently shown that neither dopamine terminal capacity nor dopamine D2 receptor availability correlates with tremor scores, suggesting that PD tremor could be associated with non-dopaminergic mechanisms.
Using PET
Non-motor symptoms
Non-motor symptoms including mood changes, pain, cognitive decline, autonomic dysfunctions and sleep disturbances are common in PD affecting patients’ and caregiver's quality of life [15], [93]. Non-motor symptoms are often poorly recognized and inadequately treated in clinic. From a patient's perspective, pain, mood changes and sleep problems are the most troublesome non-motor symptoms throughout the disease [3]. The pathophysiology of non-motor symptoms remains unclear. There is evidence of
Conclusions
PET molecular imaging has provided strong evidence for the involvement of serotonergic system in the pathophysiology underlying the development of motor and non-motor symptoms and complications in PD. We have now a number of studies suggesting that the non-linear progressive degeneration of 5-HT terminals contributes to the development of symptoms spanning from tremor and LIDs to depression, fatigue, weight loss and visual hallucinations. It is anticipated that the explosion of this research
Acknowledgments
Flavia Niccolini is supported from Parkinson's UK. Marios Politis research is supported by Parkinson's UK, Edmond J. Safra Foundation, Michael J Fox Foundation (MJFF), and NIHR BRC.
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