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 evaluate 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 thirty age- and sex-matched healthy control subjects were included. Patient’s symptoms characteristics were assessed using the MDS-UPDRS scale. Patients showed reduced neuromelanin signal intensity in the locus coeruleus compared to controls, and diminished [11C]yohimbine binding in widespread cortical regions including the motor cortex as well as in the insula, the thalamus and the 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-ARs 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 findings highlight a multifaceted alteration of the noradrenergic system in Parkinson’s disease since locus coeruleus and α2-ARs degenerations were found to be partly uncoupled. These findings raise important issues about noradrenergic dysfunctions that may encourage the search for new drugs targeting this system, including α2-ARs, for the treatment of Parkinson’s disease.

Imaging Biomarkers in Prodromal and Earliest Phases of Parkinson’s Disease

“…Currently, the integrity of the noradrenergic system is studied either analyzing neuromelanin-dependent MRI signal of the small locus coeruleus-the principal origin of noradrenergic neurons of the brain, or using PET radioligands targeting receptors or transporters of noradrenalin. Interestingly, studies have rather consistently shown a dissociation of locus coeruleus integrity as measured with MRI and integrity of noradrenergic cortical terminals using PET [77,78]. A widespread cortical (motor cortex and insula) and subcortical (thalamus and putamen) reduction of NA receptors has very recently been described [78].…”

“…Interestingly, studies have rather consistently shown a dissociation of locus coeruleus integrity as measured with MRI and integrity of noradrenergic cortical terminals using PET [77,78]. A widespread cortical (motor cortex and insula) and subcortical (thalamus and putamen) reduction of NA receptors has very recently been described [78]. NA transporters do not appear to be dramatically reduced in prodromal PD, with some evidence for moderately reduced availability of NA transporters in the sensorimotor cortex and the thalamus [79].…”

EEG Frequency Correlates with α2-Receptor Density in Parkinson’s Disease

“…We showed previously that the density of α 2 adrenoceptors can be quantified by imaging with [ 11 C]yohimbine positron emission tomography (PET) [11]. Interestingly, a recently published study showed α 2 adrenoceptors, as measured with [ 11 C]yohimbine, are diminished in PD patients, in correlation with both motor and non-motor indices [12]. In the present study, we hypothesize that the degeneration of the LC by the loss of noradrenergic terminals is associated with the pathological slowing of EEG patterns in PD patients.…”