Cognitive decline is a common feature of Parkinson’s disease, and many of these cognitive deficits fail to respond to dopaminergic therapy. Therefore, targeting other neuromodulatory systems represents an important therapeutic strategy. Among these, the locus coeruleus-noradrenaline system has been extensively implicated in response inhibition deficits. Restoring noradrenaline levels using the noradrenergic reuptake inhibitor atomoxetine can improve response inhibition in some patients with Parkinson’s disease, but there is considerable heterogeneity in treatment response. Accurately predicting the patients who would benefit from therapies targeting this neurotransmitter system remains a critical goal, in order to design the necessary clinical trials with stratified patient selection to establish the therapeutic potential of atomoxetine. Here, we test the hypothesis that integrity of the noradrenergic locus coeruleus explains the variation in improvement of response inhibition following atomoxetine. In a double-blind placebo-controlled randomised crossover design, 19 people with Parkinson’s disease completed an acute psychopharmacological challenge with 40 mg of oral atomoxetine or placebo. A stop-signal task was used to measure response inhibition, with stop-signal reaction times obtained through hierarchical Bayesian estimation of an ex-Gaussian race model. Twenty-six control subjects completed the same task without undergoing the drug manipulation. In a separate session, patients and controls underwent ultra-high field 7 T imaging of the locus coeruleus using a neuromelanin-sensitive magnetisation transfer sequence. The principal result was that atomoxetine improved stop-signal reaction times in those patients with lower locus coeruleus integrity. This was in the context of a general impairment in response inhibition, as patients on placebo had longer stop-signal reaction times compared to controls. We also found that the caudal portion of the locus coeruleus showed the largest neuromelanin signal decrease in the patients compared to controls. Our results highlight a link between the integrity of the noradrenergic locus coeruleus and response inhibition in Parkinson’s disease patients. Furthermore, they demonstrate the importance of baseline noradrenergic state in determining the response to atomoxetine. We suggest that locus coeruleus neuromelanin imaging offers a marker of noradrenergic capacity that could be used to stratify patients in trials of noradrenergic therapy and to ultimately inform personalised treatment approaches.

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Hemiparkinsonism duration in patients with Parkinson's disease (PD) is a key time window to study early pathology of PD. We aimed to comprehensively explore the alterations of deformation and structural network in PD patients with hemiparkinsonism, which could potentially disclose the early biomarker for PD. Thirty-one PD patients with hemiparkinsonism and 37 age- and gender- matched normal controls were included in the present study. First of all, we normalized the left hemisphere of structural images as the contralateral side to the affected limbs. Deformation-based morphometry (DBM) was conducted to evaluate the brain atrophy and/or enlargement. structural networks were constructed by thresholding gray matter volume correlation matrices of 116 regions and analyzed using graph theoretical approaches (e.g., small-worldness, global, and nodal measures). Significantly decreased deformation values were observed in the temporoparietal regions like bilateral middle temporal gyri, ipsilateral precuneus and contralateral Rolandic operculum extending to supramarginal and postcentral gyri. Lower deformation values in contralateral middle temporal gyrus were negatively correlated with higher motor impairment which was dominated by akinesia/rigidity. Moreover, nodal reorganization of structural network mainly located in frontal, temporal, subcortex and cerebellum was bilaterally explored in PD patients with hemiparkinsonism. Increased nodal properties could be commonly observed in frontal lobes. Disruption of subcortex including basal ganglia and amygdala was detected by nodal local efficiency and nodal clustering coefficient. Twelve hubs, mainly from paralimbic-limbic and heteromodal networks, were disrupted and, alternatively, 14 hubs, most of which were located in frontal lobes, were additionally detected in PD patients with hemiparkinsonism. In conclusion, during hemiparkinsonism period, mild brain atrophy in the temporoparietal regions and widespread reorganization of structural network, e.g., enhanced frontal function and disruption of basal ganglia nodes, occurred in both hemispheres. With our data, we can also argue that MTG contralateral to the affected limbs (expressing clinically verified brain atrophy) might be a potential living biomarker to monitor disease progression. Therefore, the combination of DBM and structural network analyses can provide a comprehensive and sensitive evaluation for potential pathogenesis of early PD patients with hemiparkinsonism.