Evaluation of the noradrenergic system in Parkinson’s disease: an 11C-MeNER PET and neuromelanin MRI study

Abstract

Pathological involvement of the noradrenergic locus coeruleus occurs early in Parkinson's disease, and widespread noradrenaline reductions are found at post-mortem. Rapid eye movement sleep behaviour disorder (RBD) accompanies Parkinson's disease and its presence predicts an unfavourable disease course with a higher propensity to cognitive impairment and orthostatic hypotension. MRI can detect neuromelanin in the locus coeruleus while 11C-MeNER PET is a marker of noradrenaline transporter availability. Here, we use both imaging modalities to study the association of RBD, cognition and autonomic dysfunction in Parkinson's disease with loss of noradrenergic function. Thirty non-demented Parkinson's disease patients [16 patients with RBD and 14 without RBD, comparable across age (66.6 ± 6.7 years), sex (22 males), and disease stage (Hoehn and Yahr, 2.3 ± 0.5)], had imaging of the locus coeruleus with neuromelanin sensitive MRI and brain noradrenaline transporter availability with 11C-MeNER PET. RBD was confirmed with polysomnography; cognitive function was assessed with a neuropsychological test battery, and blood pressure changes on tilting were documented; results were compared to 12 matched control subjects. We found that Parkinson's disease patients with RBD showed decreased locus coeruleus neuromelanin signal on MRI (P < 0.001) and widespread reduced binding of 11C-MeNER (P < 0.001), which correlated with amount of REM sleep without atonia. Parkinson's disease with RBD was also associated with a higher incidence of cognitive impairment, slowed EEG activity, and orthostatic hypotension. Reduced 11C-MeNER binding correlated with EEG slowing, cognitive performance, and orthostatic hypotension. In conclusion, reduced noradrenergic function in Parkinson's disease was linked to the presence of RBD and associated with cognitive deterioration and orthostatic hypotension. Noradrenergic impairment may contribute to the high prevalence of these non-motor symptoms in Parkinson's disease, and may be of relevance when treating these conditions in Parkinson's disease.

Imaging Markers of Progression in Parkinson's Disease

“…Thus, these observations demonstrated some regional changes in CB1 availability in PD, but did not reveal a role of CB1 in the pathogenesis of LIDs . Noradrenergic impairment may also play an important role in PD complications . Using a noradrenaline transporter, 11 C‐MeNER, PD patients had a reduced binding, which correlated with amount of REM sleep behavioral disorders (RBDs), cognitive performance, and orthostatic hypotension.…”

“…53 Noradrenergic impairment may also play an important role in PD complications. 54,55 Using a noradrenaline transporter, 11 C-MeNER, PD patients had a reduced binding, which correlated with amount of REM sleep behavioral disorders (RBDs), cognitive performance, and orthostatic hypotension. Thus, impaired noradrenergic function in PD may contribute to a number of nonmotor symptoms.…”

“…Thus, impaired noradrenergic function in PD may contribute to a number of nonmotor symptoms. 54,55 The…”

The Noradrenergic System in Parkinson’s Disease

“…The orthostatic hypotension affects 30-58% of PD patients (Goldstein, 2006) and has been linked to peripheral sympathetic cardiovascular denervation and also in a certain degree to central autonomic involvement. PD patients with defined symptomatic orthostatic hypotension exhibit decreased LC neuromelanin signal on magnetic resonance studies (Sommerauer et al, 2018a) and low plasma levels of NA, which is associated with both supersensitivity of vascular adrenergic receptors and an up-regulation of platelet a 2 -adrenoceptors (Senard et al, 1990). As a consequence of a reduced capacity to adapt the peripheral vasculature and cerebral perfusion pressure PD patients can often manifest postural light-headedness and syncope (Sharabi et al, 2008).…”

“…In fact, post mortem examinations of patients with REM sleep behavior disorder without motor symptoms revealed neuronal loss and Lewy bodies in the LC (Uchiyama et al, 1995). A recent magnetic resonance study further linked LC neuromelanin levels with amount of REM sleep without atonia in PD patients (Sommerauer et al, 2018a). Clinical management of sleep disorders in PD is complex because most of the antiparkinsonian drugs can alter sleep architecture and induce sleepiness as a side effect.…”