The pathological processes underlying Parkinson's disease (PD) involve more than dopamine cell loss within the midbrain. These non-dopaminergic neurotransmitters include noradrenergic, serotonergic, ...glutamatergic, and cholinergic systems within cortical, brainstem and basal ganglia regions. Several non-dopaminergic treatments are now in clinical use to treat motor symptoms of PD, or are being evaluated as potential therapies. Agents for symptomatic monotherapy and as adjunct to dopaminergic therapies for motor symptoms include adenosine A2A antagonists and the mixed monoamine-B inhibitor (MAO-BI) and glutamate release agent safinamide. The largest area of potential use for non-dopaminergic drugs is as add-on therapy for motor fluctuations. Thus adenosine A2A antagonists, safinamide, and the antiepileptic agent zonisamide can extend the duration of action of levodopa. To reduce levodopa-induced dyskinesia, drugs that target overactive glutamatergic neurotransmission can be used, and include the non-selective N-methyl D-aspartate antagonist amantadine. More recently, selective metabotropic glutamate receptor (mGluR₅) antagonists are being evaluated in phase II randomized controlled trials. Serotonergic agents acting as 5-HT2A/2C antagonists, such as the atypical antipsychotic clozapine, may also reduce dyskinesia. 5-HT1A agonists theoretically can reduce dyskinesia, but in practice, may also worsen PD motor symptoms, and so clinical applicability has not yet been shown. Noradrenergic α2A antagonism using fipamezole can potentially reduce dyskinesia. Several non-dopaminergic agents have also been investigated to reduce non-levodopa-responsive motor symptoms such as gait and tremor. Thus the cholinesterase inhibitor donepezil showed mild benefit in gait, while the predominantly noradrenergic re-uptake inhibitor methylphenidate had conflicting results in advanced PD subjects. Tremor in PD may respond to muscarinic M4 cholinergic antagonists (anticholinergics), but tolerability is often poor. Alternatives include β-adrenergic antagonists such as propranolol. Other options include 5-HT2A antagonists, and drugs that have mixed binding properties involving serotonin and acetylcholine, such as clozapine and the antidepressant mirtazapine, can be effective in reducing PD tremor. Many other non-dopaminergic agents are in preclinical and phase I/II early stages of study, and the reader is directed to recent reviews. While levodopa remains the most effective agent to treat motor symptoms in PD, the overall approach to using non-dopaminergic drugs in PD is to reduce reliance on levodopa and to target non-levodopa-responsive symptoms.
Up to 70% of individuals receiving subcutaneous apomorphine can develop skin nodules,8 although this adverse event does not usually lead to discontinuation.9 Practical options can reduce the risk of ...nodules, including good skin hygiene and rotation of needles, and ultrasound can reduce pain. Grants and contract support to SHF include funding from the Michael J Fox Foundation for Parkinson Research and the Edmond J Safra Foundation, the National Institutes of Health (US; Dystonia Coalition), Parkinson Canada, and the Parkinson Foundation (US). SHF reports honoraria for lectures paid to the institution from the International Parkinson and Movement Disorder Society, BIAL pharmaceutical company, and Lundbeck, consulting fees from Ipsen Pharmaceutical and Sunovion Pharmaceuticals; and SHF received royalties from Oxford University Press.
Levodopa‐induced dyskinesia is a common complication in Parkinson disease. Pathogenic mechanisms include phasic stimulation of dopamine receptors, nonphysiological levodopa‐to‐dopamine conversion in ...serotonergic neurons, hyperactivity of corticostriatal glutamatergic transmission, and overstimulation of nicotinic acetylcholine receptors on dopamine‐releasing axons. Delay in initiating levodopa is no longer recommended, as dyskinesia development is a function of disease duration rather than cumulative levodopa exposure. We review current and in‐development treatments for peak‐dose dyskinesia but suggest that improvements in levodopa delivery alone may reduce its future prevalence. Ann Neurol 2018;84:797–811
Despite the effectiveness of levodopa for treatment of Parkinson's disease (PD), prolonged usage leads to development of motor complications, most notably levodopa-induced dyskinesia (LID). Persons ...with PD and their physicians must regularly modify treatment regimens and timing for optimal relief of symptoms. While standardized clinical rating scales exist for assessing the severity of PD symptoms, they must be administered by a trained medical professional and are inherently subjective. Computer vision is an attractive, non-contact, potential solution for automated assessment of PD, made possible by recent advances in computational power and deep learning algorithms. The objective of this paper was to evaluate the feasibility of vision-based assessment of parkinsonism and LID using pose estimation.
Nine participants with PD and LID completed a levodopa infusion protocol, where symptoms were assessed at regular intervals using the Unified Dyskinesia Rating Scale (UDysRS) and Unified Parkinson's Disease Rating Scale (UPDRS). Movement trajectories of individual joints were extracted from videos of PD assessment using Convolutional Pose Machines, a pose estimation algorithm built with deep learning. Features of the movement trajectories (e.g. kinematic, frequency) were used to train random forests to detect and estimate the severity of parkinsonism and LID. Communication and drinking tasks were used to assess LID, while leg agility and toe tapping tasks were used to assess parkinsonism. Feature sets from tasks were also combined to predict total UDysRS and UPDRS Part III scores.
For LID, the communication task yielded the best results (detection: AUC = 0.930, severity estimation: r = 0.661). For parkinsonism, leg agility had better results for severity estimation (r = 0.618), while toe tapping was better for detection (AUC = 0.773). UDysRS and UPDRS Part III scores were predicted with r = 0.741 and 0.530, respectively.
The proposed system provides insight into the potential of computer vision and deep learning for clinical application in PD and demonstrates promising performance for the future translation of deep learning to PD clinical practices. Convenient and objective assessment of PD symptoms will facilitate more frequent touchpoints between patients and clinicians, leading to better tailoring of treatment and quality of care.
Psychotic symptoms are common in Parkinson's disease (PD) and are associated with poorer quality of life and increased caregiver burden. PD psychosis is correlated with several factors, such as more ...advanced disease, cognitive impairment, depression, and sleep disorders. The underlying causes of psychosis in PD thus involve a complex interplay between exogenous (e.g., drugs, intercurrent illnesses) and endogenous (e.g., PD disease pathology) factors. Current theories of the pathophysiology of PD psychosis have come from several neuropathological and neuroimaging studies that implicate pathways involving visual processing and executive function, including temporo-limbic structures and neocortical gray matter with altered neurotransmitter functioning (e.g., dopamine, serotonin, and acetylcholine). Treatment of PD psychosis requires a step-wise process, including initial careful investigation of treatable triggering conditions and a comprehensive evaluation with adjustment of PD medications and/or initiation of specific antipsychotic therapies. Clozapine remains the only recommended drug for the treatment of PD psychosis; however, because of regular blood monitoring, quetiapine is usually first-line therapy, although less efficacious. Emerging studies have focused on agents involving other neurotransmitters, including the serotonin 5-HT2A receptor inverse agonist pimavanserin, cholinesterase inhibitors, and antidepressants and anxiolytics.
L-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective symptomatic treatment of Parkinson's disease (PD). However, long-term administration of L-DOPA is marred by the emergence of abnormal ...involuntary movements, i.e., L-DOPA-induced dyskinesia (LID). Years of intensive research have yielded significant progress in the quest to elucidate the mechanisms leading to the development and expression of dyskinesia and maintenance of the dyskinetic state, but the search for a complete understanding is still ongoing. Herein, we summarize the current knowledge of the pharmacology of LID in PD. Specifically, we review evidence gathered from postmortem and pharmacological studies, both preclinical and clinical, and discuss the involvement of dopaminergic and nondopaminergic systems, including glutamatergic, opioid, serotonergic, γ-aminobutyric acid (GABA)-ergic, adenosine, cannabinoid, adrenergic, histaminergic, and cholinergic systems. Moreover, we discuss changes occurring in transcription factors, intracellular signaling, and gene expression in the dyskinetic phenotype. Inasmuch as a multitude of neurotransmitters and receptors play a role in the etiology of dyskinesia, we propose that to optimally alleviate this motor complication, it may be necessary to develop combined treatment approaches that will target simultaneously more than one neurotransmitter system. This could be achieved via three ways as follows: 1) by developing compounds that will interact simultaneously to a multitude of receptors with the required agonist/antagonist effect at each target, 2) by targeting intracellular signaling cascades where the signals mediated by multiple receptors converge, and/or 3) to regulate gene expression in a manner that has effects on signaling by multiple pathways.
Debate is ongoing regarding when, why, and how to initiate pharmacotherapy for Parkinson's disease. Early initiation of dopaminergic therapies does not convey disease-modifying effects but does ...reduce disability. Concerns about the development of motor complications arising from the early initiation of levodopa, which led to misconceived levodopa-sparing strategies, have been largely mitigated by the outcomes of the PD MED and Levodopa in Early Parkinson's Disease (LEAP) studies. The LEAP study also showed the potential for early improvement in quality of life, even when disability is negligible. Until more effective methods of providing stable dopamine concentrations are developed, current evidence supports the use of levodopa as initial symptomatic treatment in most patients with Parkinson's disease, starting with low doses and titrating to therapeutic threshold. Monoamine oxidase-B inhibitors and dopamine agonists can be reserved as potential adjunct treatments later in the disease course. Future research will need to establish effective disease-modifying treatments, address whether patients’ quality of life is substantially improved with early initiation of treatment rather than a wait and watch strategy, and establish whether new levodopa formulations will delay onset of dyskinesia.
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