Parkinson's Disease Tremors and Serotonin

Joseph Jankovic MD DISCLOSURES Brain. 2018;141(3):624-626. 
April 3, 2018

Tremor, the most recognizable sign of Parkinson's disease, remains enigmatic in terms of its phenomenology and pathophysiology. While tremor at rest is typical of Parkinson's disease, the most disabling form of tremor in patients with the disease is the so-called 're-emergent tremor' (Jankovic, 2016). This tremor often interferes with important daily tasks such as holding objects. Frequently misinterepreted as 'postural' tremor because it occurs during posture holding, the 're-emergent' tremor can be differentiated from true postural tremor of Parkinson's disease or that of essential tremor by a latency of seconds or even minutes before the tremor appears after assuming the horizontal (holding) position of the arms. Recent studies have confirmed our original observation that 're-emergent tremor' is a variant of rest tremor (Belvisi et al., 2017) and should be differentiated from the postural tremor typically observed in patients with essential tremor. In this issue of Brain, Pasquini et al.(2018) provide evidence that rest (and by implication 're-emergent') tremor is more likely related to serotonin than to dopamine deficiency.

Pasquini and colleagues analysed clinical ratings and imaging of dopamine and serotonin transporters in patients with early Parkinson's disease enrolled over a 2-year observation period in the Parkinson's Progressive Markers Initiative (PPMI), a biomarker study supported mainly by the Michael J. Fox Foundation for Parkinson's Research (Pasquini et al., 2018). Using previously defined criteria (Stebbins et al., 2013), 268 (71%) of the total cohort of 378 patients were classified as tremor dominant, 73 (19%) as postural instability/gait difficulty (PIGD) and 37 as indeterminate (10%). As expected from our prior studies that showed better outcomes in tremor dominant compared to PIGD Parkinson's disease (Thenganatt and Jankovic, 2014), patients presenting with rest tremor had significantly less rigidity and bradykinesia. Suprisingly and most importantly, based on imaging with ¹²³I-FP-CIT single photon emission computed tomography (SPECT), Pasquini and colleagues found that the severity of rest tremor correlated with the loss of serotonin transporter in the brainstem raphe nuclei more than with the loss of dopamine transporter in the striatum. This is consistent with other studies that have shown that striatal dopamine is relatively spared in patients with the tremor dominant form of Parkinson's diseae, and that rest tremor is related more to pallidal than striatal dopamine deficiency, and to involvement of serotonergic raphe nuclei and the noradrenergic locus coeruleus (Politis and Niccolini, 2015). The predominant serotonin deficiency in patients with prominent rest tremor may also explain why such tremors disappear during sleep and why they are often less responsive to levodopa than other cardinal features such as bradykinesia or rigidity. Indeed, in the study by Pasquini and colleagues, more severe degeneration in raphe compared to putaminal nuclei correlated with a poorer response of tremor to dopamine replacement therapy.

Although the findings of Pasquini et al. suggest that degeneration of raphe serotonergic nuclei may play a more important role in the pathophysiology of Parkinson's disease-related rest tremor than degeneration of substantia nigra dopaminergic neurons, such an interpretation requires caution. While a reduction in dopamine transporter density, demonstrated by ¹²³I-FP-CIT SPECT, implies nigral degeneration, a recent imaging-pathological study found no correlation between dopamine transporter density and counts of substantia nigra neurons in the post-mortem brains of patients with Parkinson's disease (Saari et al., 2017). Thus, decreased dopamine transporter density may be more representative of damage to striatal terminals than loss of the neurons of origin in the substantia nigra. On the other hand, binding in the raphe nuclei presumably reflects somatodendritic serotonin transporter availability in this brainstem area (Figure 1).

Figure 1.

Major neurotransmitter pathways. The findings of Pasquini et al. suggest that degeneration of raphe serotonergic nuclei may play a more important role in the pathophysiology of Parkinson's disease-related rest tremor than degeneration of substantia nigra dopaminergic neurons. 5-HT = serotonergic; ACC = anterior cingulate cortex; Amygd = amygdala; Caud = caudate nucleus; DA = dopaminergic; DR = dorsal raphe nucleus; GABA = gamma-aminobutyric acid; Glu = glutamatergic; GP = globus pallidus; MCC = mid cingulate cortex; NAcc = nucleus accumbens; OFC = orbitofrontal cortex; PCC = posterior cingulate cortex; PFC = prefrontal cortex; Put = putamen; RN = raphe nucleus; SMA = supplementary motor area; SN = substantia nigra; Tha = thalamus; VM-PFC = ventromedial prefrontal cortex; VTA = ventral tegmental area. Reproduced from Forde et al. (2016) CC BY.

Pasquini et al. must be congratulated on this comprehensive prospective study designed to correlate the progression of Parkinson's disease tremor with markers of dopaminergic and serotonergic function. There are, however, several limitations to the study, some of which they fully acknowledge. For example, of the 378 patients with baseline assessment, only 263 (70%) had rest tremor (10% had bilateral tremor at baseline but this increased to 24% over the 2 years). Interestingly, 21% of the patients with tremor presented with postural and/or kinetic tremor alone. This raises the possibility of co-existent essential tremor that would confound the interpretation of the findings (Thenganatt and Jankovic, 2016). Although 173 patients had adequate baseline and 2-year scans and were not taking serotonergic drugs that could potentially interfere with ¹²³I-FP-CIT SPECT, correlative analyses between imaging and clinical response were possible in only 98 patients who had both ON and OFF assessments in the same follow-up visit. It is not clear, however, whether the assessments were performed during true ON and OFF states. In the PPMI study, we were instructed to rate the amplitude of postural tremor whether it was re-emergent or not, and therefore the two types of tremors—which presumably have different mechaninsms—were not differentiated by the clinical raters. Another limitation of the study was the subjective determination of the regions of interest, which were traced by hand according to anatomical borders that were not always clearly defined.

While the findings of Pasquini et al. are intriguing, it would be interesting to perform a similar study with different imaging markers, such as VMAT2 density assessed by ¹⁸F-AV-133 PET. Using ¹¹C-DASB PET as a marker of serotonin transporter binding in 12 patients with tremor dominant Parkinson's disease, 12 with akinetic-rigid Parkinson's disease, and 12 healthy controls, serotonergic dysfunction was found to play a significant role in generation of postural rather than rest tremor (Loane et al., 2013). Although the latter was a much smaller study, the findings differ from those of Pasquini et al. and therefore replication using different imaging techniques is needed.

Finally, based on the results of Pasquini et al., drugs that modulate the serotonergic system, such as eltoprazine, pimavanserin, nelotanserin, and SYN-120, should be investigated in the treatment of Parkinson's disease-related tremor (Huot et al., 2017). Most of these drugs, however, have multiple mechanisms of action besides their effects on the serotonergic system and many act as serotonin receptor antagonists or partial agonists and could potentially exacerbate rest tremor. There is therefore a need to develop selective 5-HT type 1 or type 2 agonists that could act on the spared postsynaptic serotonin receptors. Such drugs may provide benefits for patients with Parkinson's patients with troublesome rest or 're-emergent' tremor as well as with some non-motor symptoms, including depression and psychosis.

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Brain. 2018;141(3):624-626. © 2018 Oxford University Press