By Claire Henchcliffe, MD, PhD
Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College
Dr. Henchcliffe reports she is a consultant and on the speakers bureau for Acadia, Impax, and Allergan, and is a consultant for US WorldMeds and Gerson Lehrman Group.
SYNOPSIS: In a small cross-sectional study, increased serotonin transporter was detected using 11C-DASB PET in striatum, hypothalamus, and brainstem in LRRK2 carriers who did not have clinical Parkinson’s disease. This contrasts with later decreases previously described and implies a likely early compensatory mechanism.
SOURCE: Wile DJ, Agarwal PA, Schulzer M, et al. Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: Cross-sectional studies. Lancet Neurol 2017;16:351-359.
A battery of positron emission tomography (PET) ligands were applied to two independent patient groups to investigate the dopaminergic and serotonergic systems in genetic and sporadic Parkinson’s disease (PD) and in an at-risk cohort with leucine-rich repeat kinase 2 (LRRK2) gene mutations but without PD, assumed to have premotor PD. Multiple ligands for dopamine and serotonin investigations were grouped into two studies. The first study quantitated dopamine transporter (11C-d-threo-methylphenidate) and dopamine synthesis/storage (18F-6-fluoro-L-DOPA:18F-FDOPA) in 138 participants, of whom 15 had LRRK2 mutations leading to PD (LRRK2-PD), 25 had LRRK2 mutations without PD (LRRK2-premotor), 63 had sporadic PD, and 35 were healthy volunteers. Those with PD were mean age 65 ± 11 years (LRRK2-PD) and 63 ± 11 years (sporadic PD), with mean age of PD onset of 58 ± 11 years (LRRK2-PD) and 57 ± 9 years (sporadic PD). LRRK2-premotor participants had a mean age of 50 ± 14 years. As expected, LRRK2-PD subjects had reduced striatal dopamine transporter and 18F-FDOPA uptake, similar to those with sporadic PD. However, LRRK2-premotor participants had comparable 18F-FDOPA uptake to controls, but lower dopamine transporter binding.
In the second study, subjects underwent PET with ligands for serotonin transporter (SERT) (11C-3-amino-4-(2-dimethylaminomethylphenylsulfaryl)-benzonitrile: 11C-DASB), vesicular monoamine transporter (11C-dihydro tetrabenazine), and 18F-FDOPA PET. In this smaller group, seven of the 38 participants had LRRK2-PD, nine were classified as LRRK2-premotor, 13 had sporadic PD, and nine were healthy controls. SERT binding was increased in LRRK2-premotor subjects in the hypothalamus (compared with all other groups), striatum (compared with sporadic PD), and brainstem (compared with LRRK2-PD). As predicted, VMAT density was reduced in the striatum for those with sporadic and LRRK2-PD vs. controls, and was asymmetrically decreased in a single subject classified as LRRK2 premotor.
COMMENTARY
The serotonergic system is garnering increasing attention in PD, with evidence drawn from biochemical, postmortem, and in vivo PET imaging studies. However, it remains difficult to piece together how the cellular and neurochemical changes that occur relate over time to clinical symptoms and medication responses. Loss of the dorsal raphe nuclei, with projections to basal ganglia, cortex, and limbic system, has been demonstrated in early PD. However, striatal hyperinnervation has been observed at postmortem, suggested to be a compensatory change. Improving understanding of how serotonin function changes in PD is critical, as it is involved in mood, psychosis, sleep, and other important non-motor symptoms. Moreover, a key role for serotonin neurons has been proposed in levodopa-associated dyskinesia.
Multiple previous studies have demonstrated increased SERT density in various stages of PD, with a single study describing preserved levels in very early PD. Therefore, the strength of the present study is its focus on LRRK2 mutation carriers who do not have PD but are at high risk of developing the disorder. It can be assumed that the majority of the individuals studied by Wile and colleagues actually are in the premotor phase of PD, despite lack of supporting longitudinal data. The finding of serotonergic changes in multiple brain regions in presumed premotor PD is not only novel but has important implications. The authors suggested it occurs as a compensatory change (that also has been suggested to explain decreased dopamine transporter in the context of depleted dopamine in early PD). Confirmation and longitudinal data will be critical.
However, there are some limitations of the study. Numbers of participants who underwent the 11C-DASB scans are very small, thus limiting interpretation. Clinical data are incomplete; for example, the Beck Depression Inventory and Montreal Cognitive Assessment were performed only in the second study, and then only for 5/9 and 4/9 LRRK2 carriers without PD, respectively. Age ranges are quite broad (for example, 35-68 years at onset in sporadic PD). Two participants in the first study with LRRK2 without PD had significant motor dysfunction, although judged not to be PD (one had a history of poliomyelitis). There is little detail on medications or patient status at the time of clinical motor measurements and limited assessment of motor complications. Given the importance of studies on LRRK2 carriers without PD, it also would be interesting to have more data on other potential premotor manifestations.
For now, it is too early to say what this “premotor” SERT increase means and how its measurement might be applied. However, at a time when the importance of premotor and non-motor features in PD are increasingly appreciated, the study is a superb example of how neuroimaging focused on multiple neurochemical systems can help tease apart the complexity of this neurodegenerative disorder. Longitudinal follow-up is now a critical need.
In a small cross-sectional study, increased serotonin transporter was detected using 11C-DASB PET in striatum, hypothalamus, and brainstem in LRRK2 carriers who did not have clinical Parkinson’s disease. This contrasts with later decreases previously described and implies a likely early compensatory mechanism.
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