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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.

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.

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 A 2A 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 A 2A 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 (mGluR 5 ) antagonists are being evaluated in phase II randomized controlled trials. Serotonergic agents acting as 5-HT 2A/2C antagonists, such as the atypical antipsychotic clozapine, may also reduce dyskinesia. 5-HT 1A agonists theoretically can reduce dyskinesia, but in practice, may also worsen PD motor symptoms, and so clinical applicability has not yet been shown. Noradrenergic α 2A 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 M 4 cholinergic antagonists (anticholinergics), but tolerability is often poor. Alternatives include β-adrenergic antagonists such as propranolol. Other options include 5-HT 2A 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.

Background 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. Methods 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. Results 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. Conclusion 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.

Glutamatergic, noradrenergic, serotonergic, and cholinergic systems play a critical role in the basal ganglia circuitry. Targeting these non-dopaminergic receptors remains a focus of ongoing research to improve Parkinson’s disease (PD) motor symptoms, without the potential side effects of dopamine replacement therapy. This review updates advancements in non-dopaminergic treatments for motor control in PD since 2013. To date, no non-dopaminergic selective drug has shown significant long-term efficacy as monotherapy in PD. The largest area of development in non-dopaminergic targets has been for motor complications of dopamine replacement therapy (motor fluctuations and dyskinesia). For treatment of motor fluctuations, safinamide, zonisamide, and istradefylline are currently approved, and novel glutamatergic and serotonergic drugs are in development. Long-acting formulations of amantadine are approved for treating dyskinesia. Several non-dopaminergic drugs have failed to show anti-dyskinetic efficacy, while some are still in development. Non-dopaminergic targets are also being pursued to treat specific motor symptoms of PD. For example, CX-8998 (a calcium channel modulator) is being evaluated for PD tremor and rivastigmine may improve gait dysfunction in PD. Drug repurposing continues to be a key strategy for non-dopaminergic targets in PD, but the field needs to increase discovery and availability of such drugs.

The understanding of Parkinson’s disease (PD) classically revolves around dopamine depletion within the striatum. However, PD is a multi-systemic disease in which extra-dopaminergic systems are affected. The serotonergic (5-HT) system is one of these and has been extensively studied in PD. Although the 5-HT system uses one transporter (SERT) and 14 receptor sub-types, most of the studies in PD have focussed on SERT and serotonergic type 1A and 2A receptors (5-HT 1A and 5-HT 2A ). Post-mortem autoradiographic binding studies and in vivo imaging studies have suggested an involvement of the 5-HT system in PD-related anxiety, depression, psychosis and L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. Pre-clinical and clinical pharmacological studies have shown that SERT blockade might effectively alleviate depression and dyskinesia and, more recently, might exert disease-modifying effects. Enhancing the physiological activity of 5-HT 1A receptors with 5-HT 1A agonists might alleviate anxiety, dyskinesia and tremor, although a deleterious effect on the anti-parkinsonian efficacy of L-DOPA may ultimately limit the use of this class of compounds. Enhanced 5-HT 2A -mediated neurotransmission has been associated with depression, dyskinesia, psychosis and tremor. The current article critically reviews studies assessing the SERT, as well as 5-HT 1A and 5-HT 2A receptors in idiopathic PD and animal models of PD, and discusses unmet challenges to effectively treat manifestations of PD using SERT antagonists, 5-HT 1A agonists and 5-HT 2A antagonists.

Motor symptoms are a core feature of Parkinson's disease (PD) and cause a significant burden on patients' quality of life. Oral levodopa is still the most effective treatment, however, the motor benefits are countered by inherent pharmacologic limitations of the drug. Additionally, with disease progression, chronic levodopa leads to the appearance of motor complications including motor fluctuations and dyskinesia. Furthermore, several motor abnormalities of posture, balance, and gait may become less responsive to levodopa. With these unmet needs and our evolving understanding of the neuroanatomic and pathophysiologic underpinnings of PD, several advances have been made in defining new therapies for motor symptoms. These include newer levodopa formulations and drug delivery systems, refinements in adjunctive medications, and non-dopaminergic treatment strategies. Although some are in early stages of development, these novel treatments potentially widen the available options for the management of motor symptoms allowing clinicians to provide an individually tailored care for PD patients. Here, we review the existing and emerging interventions for PD with focus on newly approved and investigational drugs for motor symptoms, motor fluctuations, dyskinesia, and balance and gait dysfunction.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by abnormal accumulation of the protein tau in the brain, leading to motor and cognitive symptoms that vary between individuals. The reasons for this clinical heterogeneity are unknown. Here we show that distinct molecular forms of tau, particularly high molecular weight (HMW) assemblies, differ in abundance and biological activity across PSP brains. By combining biochemical examination, seed amplification assays, proteomic profiling, and spatial transcriptomics, we identify that HMW tau species drive the strongest aggregation activity in the primary motor cortex. Cases with high tau seeding activity display molecular signatures of altered immune and metabolic pathways. These findings reveal that tau seeding activity reflects underlying molecular heterogeneity in PSP and suggest that measuring 4R-tau seeding capacity could help stratify patients and guide the development of targeted therapeutic approaches. This study shows that high-molecular weight tau has enhanced seeding capacity, and seeding differences can define molecular subtypes of progressive supranuclear palsy, underpinning the disease’s heterogeneity.

Non-dopaminergic treatments are increasingly being recognised as part of the therapeutic armamentarium for Parkinson's disease (PD). Clinical and pathological studies have shown that the disease extends beyond the substantia nigra pars compacta and involves various non-dopaminergic neurotransmitter systems that mediate both motor and non-motor symptoms that characterise PD. To date, several therapeutic strategies have been proposed to treat such symptoms. However, despite the significant morbidity associated with these symptoms, particularly non-motor symptoms, research into and drug development for problems such as mood and autonomic dysfunction remain scarce. Here, we review novel non-dopaminergic approaches that are in at least phase II clinical development for the treatment of PD.