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Abstract: Nondopaminergic neurotransmitters such as adenosine, norepinephrine, serotonin, glutamate, and acetylcholine are all involved in Parkinson's disease (PD) and promote its symptoms. Therefore, nondopaminergic receptors are key targets for developing novel preparations for the management of motor and non-motor symptoms in PD, without the potential adverse events of dopamine replacement therapy. We reviewed English-written articles and ongoing clinical trials of nondopaminergic treatments for PD patients till 2014 to summarize the recent findings on nondopaminergic preparations for the treatment of PD patients. The most promising research area of nondopaminergic targets is to reduce motor complications caused by traditional dopamine replacement therapy, including motor fluctuations and levodopa-induced dyskinesia. Istradefylline, Safinamide, and Zonisamide were licensed for the management of motor fluctuations in PD patients, while novel serotonergic and glutamatergic agents to improve motor fluctuations are still under research. Sustained- release agents of Amantadine were approved for treating levodopa induced dyskinesia (LID), and serotonin 5HT1B receptor agonist also showed clinical benefits to LID. Nondopaminergic targets were also being explored for the treatment of non-motor symptoms of PD. Pimavanserin was approved globally for the management of hallucinations and delusions related to PD psychosis. Istradefylline revealed beneficial effect on daytime sleepiness, apathy, depression, and lower urinary tract symptoms in PD subjects. Droxidopa may benefit orthostatic hypotension in PD patients. Safinamide and Zonisamide also showed clinical efficacy on certain non-motor symptoms of PD patients. Nondopaminergic drugs are not expected to replace dopaminergic strategies, but further development of these drugs may lead to new approaches with positive clinical implications.

Abstract: Dopamine (DA) agonists, as an excellent dopamine replacement therapy for patients with early and advanced Parkinson's disease (PD), play a vital role in controlling motor and several non-motor symptoms. Besides, the application of DA agonists may delay levodopa therapy and the associated risk of motor complications. Indeed, each DA agonist has unique pharmacokinetic and pharmacodynamic characteristics and therefore has different therapeutic efficacy and safety profile. The comorbidities, significant non-motor manifestations, concomitant medications, and clinical features of PD individuals should guide the selection of a specific DA agonist to provide a more patient-tailored treatment option. Thorough knowledge of DA agonists helps clinicians better balance clinical efficacy and side effects. Therefore, this review refers to recent English-written articles on DA agonist therapy for PD patients and summarizes the latest findings on non-ergot DA agonists as well as the advantages and disadvantages of each compound to help clinicians in the selection of a specific DA agonist. In addition, novel D1/D5 partial agonists and new formulations of DA agonists are also discussed.

BackgroundHistopathological studies in Wilson's disease (WD) have revealed increased copper and iron concentrations in the deep gray matter nuclei. However, the commonly used mean bulk susceptibility only reflects the regional metal concentration rather than the total metal content, and regional atrophy may affect the assessment of mean bulk susceptibility. Our study aimed to quantitatively assess the changes of metal concentration and total metal content in deep gray matter nuclei by quantitative susceptibility mapping to distinguish patients with neurological and hepatic WD from healthy controls.MethodsQuantitative susceptibility maps were obtained from 20 patients with neurological WD, 10 patients with hepatic WD, and 25 healthy controls on a 3T magnetic resonance imaging system. Mean bulk susceptibility, volumes, and total susceptibility of deep gray matter nuclei in different groups were compared using a linear regression model. The area under the curve (AUC) was calculated by receiver characteristic curve to analyze the diagnostic capability of mean bulk susceptibility and total susceptibility.ResultsMean bulk susceptibility and total susceptibility of multiple deep gray matter nuclei in patients with WD were higher than those in healthy controls. Compared with patients with hepatic WD, patients with neurological WD had higher mean bulk susceptibility but similar total susceptibility in the head of the caudate nuclei, globus pallidus, and putamen. Mean bulk susceptibility of putamen demonstrated the best diagnostic capability for patients with neurological WD, the AUC was 1, and the sensitivity and specificity were all equal to 1. Total susceptibility of pontine tegmentum was most significant for the diagnosis of patients with hepatic WD, the AUC was 0.848, and the sensitivity and specificity were 0.7 and 0.96, respectively.ConclusionBrain atrophy may affect the assessment of mean bulk susceptibility in the deep gray matter nuclei of patients with WD, and total susceptibility should be an additional metric for total metal content assessment. Mean bulk susceptibility and total susceptibility of deep gray matter nuclei may be helpful for the early diagnosis of WD.

A 58-year-old man diagnosed with stiff-person syndrome1 presented with increased axial muscle tone (video 1, [links.lww.com/WNL/A42][1]). A successional electromyographic video in the right rectus abdominis demonstrated a large quantity of continuous motor unit potentials at rest. One minute after administration of diazepam, motor unit potentials were extraordinarily attenuated. However, 10 minutes after diazepam administration, the motor unit potentials were gradually restored (video 2, [links.lww.com/WNL/A43][2]). This case gives us a better understanding of the clinical manifestation of stiff-person syndrome and shows more intuitive electrophysiologic hallmarks of this rare disease. [1]: http://links.lww.com/WNL/A42 [2]: http://links.lww.com/WNL/A43