Serotonergic loss in motor circuitries correlates with severity of action-postural tremor in PD

Abstract

Objective: The underlying pathophysiology of tremor in Parkinson disease (PD) is unclear; however, it is known that tremor does not appear to be as responsive to dopaminergic medication as bradykinesia or rigidity. It is suggested that serotonergic dysfunction could have a role in tremor development.

Methods: Using (11)C-DASB PET, a marker of serotonin transporter binding, and clinical observations, we have investigated function of serotonergic terminals in 12 patients with tremor-predominant and 12 with akinetic-rigid PD. Findings were compared with those of 12 healthy controls.

Results: Reductions of (11)C-DASB in caudate, putamen, and raphe nuclei significantly correlated with tremor severity on posture and action, but not with resting tremor. The tremor-predominant group also showed reductions of (11)C-DASB in other regions involved in motor circuitry, including the thalamus and Brodmann areas 4 and 10.

Conclusions: Our findings support a role for serotonergic dysfunction in motor circuitries in the generation of postural tremor in PD.

Figure 1. ¹¹C-DASB binding in normal controls and patients with tremor-predominant PD and akinetic-rigid PD and correlation of ¹¹C-DASB binding and action-postural tremor in the tremor-predominant PD group

¹¹C-DASB BP_ND values of 12 healthy controls, 12 patients with bradykinetic PD, and 12 patients with tremor-predominant PD in (A) caudate, (B) putamen, and (C) raphe nuclei. Significant correlations between increased AP tremor scores and reduced ¹¹C-DASB BP_ND values in (D) caudate (r = −0.80, p < 0.001), (E) putamen (r = −0.74, p < 0.005), and (F) raphe nuclei (r = −0.78, p < 0.005) in 12 patients with tremor-predominant PD. *p < 0.005. AP = action-postural; BP_ND = nondisplaceable binding potential; ¹¹C-DASB = 11C-labeled 3-amino-4-[2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile; PD = Parkinson disease.

Figure 2. Motor circuitries in the human brain

(A) Diagrammatic representation of the major motor circuitries in the human brain. The regions and interregional circuitry identified in this study to be associated with action-postural tremor in PD are highlighted in red. Summed ¹¹C-DASB PET images in transverse, sagittal, and coronal planes showing regions of 5-HT loss within the motor pathway: (B) rostral raphe nuclei; (C) caudate, putamen, and thalamus; (D) Brodmann area 10; and (E) Brodmann area 4, the primary motor area (PMA). Color bar reflects z scores (BP_ND range: 0–12). BP_ND = nondisplaceable binding potential; ¹¹C-DASB = 11C-labeled 3-amino-4-[2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile;5-HT = serotonin; PD = Parkinson disease.