Noradrenergic alterations in Parkinson's disease: a combined 11C-yohimbine PET/neuromelanin MRI study

Abstract

Degeneration of the noradrenergic system is now considered a pathological hallmark of Parkinson's disease, but little is known about its consequences in terms of parkinsonian manifestations. Here, we evaluated two aspects of the noradrenergic system using multimodal in vivo imaging in patients with Parkinson's disease and healthy controls: the pigmented cell bodies of the locus coeruleus with neuromelanin sensitive MRI; and the density of α2-adrenergic receptors (ARs) with PET using 11C-yohimbine. Thirty patients with Parkinson's disease and 30 age- and sex-matched healthy control subjects were included. The characteristics of the patients' symptoms were assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Patients showed reduced neuromelanin signal intensity in the locus coeruleus compared with controls and diminished 11C-yohimbine binding in widespread cortical regions, including the motor cortex, as well as in the insula, thalamus and putamen. Clinically, locus coeruleus neuronal loss was correlated with motor (bradykinesia, motor fluctuations, tremor) and non-motor (fatigue, apathy, constipation) symptoms. A reduction of α2-AR availability in the thalamus was associated with tremor, while a reduction in the putamen, the insula and the superior temporal gyrus was associated with anxiety. These results highlight a multifaceted alteration of the noradrenergic system in Parkinson's disease since locus coeruleus and α2-AR degeneration were found to be partly uncoupled. These findings raise important issues about noradrenergic dysfunction that may encourage the search for new drugs targeting this system, including α2-ARs, for the treatment of Parkinson's disease.

Keywords: PET/MRI; Parkinson’s disease; locus coeruleus; noradrenaline; α2-adrenergic receptors.

Figure 1

Data pipeline. ¹¹C-yohimbine and locus coeruleus (LC) neuromelanin data were acquired simultaneously from hybrid PET/MRI. Left: ¹¹C-yohimbine non-displaceable binding potential (BP_ND) parametric maps were used for contrasting the healthy control and Parkinson’s disease groups. The outcome of the voxel-based analysis allowed the identification of four significant clusters that provided the region of interest (ROI) for analysing the links between ¹¹C-yohimbine BP_ND and clinical scores in patients. Right: LC identification was performed for each individual from neuromelanin-sensitive T1 images with a three-step procedure. First, the ROIs were drawn manually as large 3D bounding boxes in Montreal Neurological Institute (MNI) space, then wrapped and resampled onto the subject’s native space. Finally, the clusters of connected voxels with the highest signal intensity were selected to define LC areas. The contrast-to-noise ratio (CNR) between the LC and the reference region was calculated to estimate LC signal intensity, and these values were referred to the clinical scores of the PD patients.

Figure 2

Statistical parametric maps comparing Parkinson’s disease patients to control subjects. A decrease in ¹¹C-yohimbine binding was observed in patients with Parkinson’s disease compared with healthy control subjects. M1 = primary motor cortex; PCC = posterior cingulate cortex; SMA = supplementary motor area; STG = superior temporal gyrus.