The role of glutamatergic neurotransmission in the motor and non-motor symptoms in Parkinson's disease: clinical cases and a review of the literature

Glutamate is the major excitatory neurotransmitter in the central nervous system and, as such, many brain regions, including the basal ganglia, are rich in glutamatergic neurons. The importance of the basal ganglia in the control of voluntary movement has long been recognised, with the effect of dysfunction of the region exemplified by the motor symptoms seen in Parkinson's disease (PD). However, the basal ganglia and the associated glutamatergic system also play a role in the modulation of emotion, nociception and cognition, dysregulation of which result in some of the non-motor symptoms of PD (depression/anxiety, pain and cognitive deficits). Thus, while the treatment of PD has traditionally been approached from the perspective of dopaminergic replacement, using agents such as levodopa and dopamine receptor agonists, the glutamatergic system offers a novel treatment target for the disease. Safinamide has been approved in over 20 countries globally for fluctuating PD as add-on therapy to levodopa regimens for the management of 'off' episodes. The drug has both dopaminergic and non-dopaminergic pharmacological effects, the latter including inhibition of abnormal glutamate release. The effect of safinamide on the glutamatergic system might present some advantages over dopamine-based therapies for PD by providing efficacy for motor (levodopa-induced dyskinesia) as well as non-motor (anxiety, mood disorders, pain) symptoms. In this article, we discuss the potential role of glutamatergic inhibition on these symptoms, using illustrative real-world examples of patients we have treated with safinamide

Differentiating drug-induced parkinsonism from Parkinson's disease: An update on non-motor symptoms and investigations

Abstract Drug-induced parkinsonism is the second most common cause of parkinsonism after Parkinson's disease and their distinction has crucial implications in terms of management and prognosis. However, differentiating between these conditions can be challenging on a clinical ground, especially in the early stages. We therefore performed a review to ascertain whether assessment of non-motor symptoms, or use of ancillary investigations, namely dopamine transporter imaging, transcranial sonography of the substantia nigra, and scintigraphy for myocardial sympathetic innervation, can be recommended to distinguish between these conditions. Among non-motor symptoms, there is evidence that hyposmia can differentiate between patients with "pure" drug-induced parkinsonism and those with degenerative parkinsonism unmasked by an anti-dopaminergic drug. However, several issues, including smoking history and cognitive functions, can influence smell function assessment. Higher diagnostic accuracy has been demonstrated for dopamine transporter imaging. Finally, preliminary evidence exists for sympathetic cardiac scintigraphy to predict dopaminergic pathway abnormalities and to differentiate between drug-induced parkinsonism and Parkinson's disease. Imaging of the dopaminergic pathway seems to be the only, reasonably available, technique to aid the differential diagnosis between drug-induced parkinsonism and Parkinson's disease

The impact of recurrent Covid-19 waves on patients with Functional Movement Disorders: A follow-up study

Background: Functional Movement Disorders (FMDs) might exacerbate in stressful conditions. As the global health emergency due to Covid-19 rise and multiple waves hit the Italian population, the recurrent severe restrictions' periods imposed could represent important triggers and worsen the symptoms of FMDs. Through a follow-up study, we compare results on Motor Symptoms (MS), Non-Motor Symptoms (NMS), and Global Health Status (GHS) of two surveys, one referred to the first Covid-19 wave and the other to the third Covid-19 wave. Methods: 60 FMDs patients responded to an online survey after the first and the third Covid-19 waves in Italy. Questions regarding sociodemographic, clinical and Covid-19 information, MS, NMS, and GHS were collected to assess severity of symptoms and changes in comparison to a period with less severe social restrictions. Results: Patients showed minimal to mild motor symptoms' severity, and substantial stability through time in all collected measures, both for severity and changes of MS, NMS, and GHS in comparison at two time points (p > 0.050). The worsening of pain resulted as predictor factor for the worsening of Motor Symptoms (p = 0.042). Conclusions: Patients did not show a vulnerability due to the recurrent restrictions' periods: MS, NMS and GHS did not vary in comparison to the first wave, confirming the previous results and highlighting the role of the social context in those disorders. Further investigations are required to better disentangle the relationship between stressful events, motor symptoms, and pain

Triggers in functional motor disorder: a clinical feature distinct from precipitating factors

Background and objective: People with functional motor disorder (FMD) report triggers-sensory or motor-induced stimuli that exacerbate or initiate paroxysmal occurrences of their movement disorder. These are a distinct phenomenon from precipitating factors occurring at the initial onset of the disorder. We aimed to assess triggers in FMD and understand their relevance to paroxysmal variability often seen in FMD. Methods: We enrolled consecutive outpatients with a definite diagnosis of FMD. Each patient underwent a detailed clinical evaluation also including the presence of trigger factors and video-recordings both during neurological examination and physiotherapy treatment. Patients were classified as having "triggers" (T-FMD) or "not having triggers" (NoT-FMD) as well as "paroxysmal" compared to "persistent with paroxysmal variability". Results: The study sample was 100 patients (82% female) with FMD; the mean age at onset was 41 years. Triggers were observed in 88% of patients and in 65 of these the FMD was pure paroxysmal. The most common triggers were movement or physical exercise, followed by emotional, visual, touch, and auditory stimuli; 39 (44%) were isolated and 49 (56%) were combined triggers. Among the T-FMD patients, FMD were paroxysmal in 74% (n = 65) and persistent with paroxysmal variability in 26% (n = 23). The T-FMD patients were younger (p = 0.016) and had a gait disorder (p = 0.035) more frequently than the NoT-FMD patients. Discussion: Triggers are frequent in FMD and may have diverse overlapping clinical presentations. In this sample, FMD was most often paroxysmal, suggesting the value of noting triggers as clinical clues in the diagnosis and rehabilitation of FMD

Shoulder-touch test to reveal incongruencies in persons with functional motor disorders

Clinical experience suggests that many patients with functional motor disorders (FMD), despite reporting severe balance problems, typically do not fall frequently. This discrepancy may hint towards a functional component. Here, we explored the role of the Shoulder-Touch test, which features a light touch on the patient's shoulders to reveal a possible functional etiology of postural instability

Functional neurological disorders as seen by a cohort of general practitioners in Northern Italy: evidence from an online survey

General practitioners (GPs) provide primary care and advise their patients on which diagnostic and therapeutic pathways they judge most appropriate. For patients with functional neurological disorders (FND), receiving a proper explanation of diagnosis by their GP from the very beginning may drastically improve prognosis. Novel approaches to the diagnosis and treatment of FND have important implications for effective management. The aim of this study was to investigate Italian GP opinion and knowledge about FND in light of new approaches to the illness. To do this, we evaluated the responses to a 13-item web-based survey completed by 133 GPs practicing in northern Italy. Psychological terms to describe FND were more frequently used than functional neurological disorder and mental illness was considered an important predictor of diagnosis. Referral to a neurologist rather than to a psychiatrist was largely preferred, while physiotherapy consultation was seldom recognized as a valuable approach to treating FND. Overall, the survey findings suggest that knowledge about novel approaches to FND is somewhat lacking. Currently, GPs appear to be transitioning from a classical psychological view of the disorder toward a more modern conceptualization, in which neurobiological, psychological, and social factors all play an important role. Professional education during this transition would be an advantageous way to optimize physician management of FND and to enhance diagnosis, explanation, and management across primary and secondary care pathways

Treating patients like athletes: sports science applied to Parkinson's Disease

The evidence demonstrating the benefits of exercise is indisputable for healthy subjects, and more recently, it is growing for Parkinson\u2019s disease (PD) patients. Due to its easy access, low cost, social facilitation and, above all, the symptomatic effect, clinical exercise may have a profound impact on PD management. Especially considering that in recent decades there have been no major advances from the pharmacological point of view. Despite this, clinical exercise use it stills limited by the existent flaws in the available evidence supporting its use and guiding its prescription as a PD therapeutic intervention. We believe that a approach from the most relevant scientific and clinical fields is crucial to establish the use of clinical exercise in PD patients\u2019 routine care. Therefore, in this viewpoint, we aim to highlight the importance of clinical exercise as a therapeutic intervention in PD, and particularly of the benefits of applying sports science principles to potentiate the use of clinical exercise as a therapeutic intervention in PD management

Age-related changes in the sense of body ownership: New insights from the rubber hand illusion

How do age-related changes affect the sense of body ownership? This study tackles this issue by means of the rubber hand illusion (RHI), a widely used experimental tool for investigating the sense of body ownership. There is ample literature on the RHI in young populations, but research on age-related changes in the RHI is still scarce. Here we extend the use of the RHI to examine the changes in the sense of body ownership related to healthy aging. Subjective reports (i.e., questionnaire) and proprioceptive drift were compared among young (n = 22, age range 20-22 years), middle-aged (n = 22, age range 44-55 years), and older adults (n = 22, age range 60-72 years). A stronger subjective experience of illusion was observed in the young and older adults as compared to the middle-aged. No differences in proprioceptive drift were found between the three groups. These findings are discussed in relation to: 1) different stages of development of perceptual and cognitive components of the sense of body ownership, and 2) compensatory mechanisms

Effect of balance training on postural instability in patients with idiopathic Parkinson’s disease

Background. Postural instability (PI) is a disabling sign of Parkinson’s disease (PD) not easily amenable to treatment with medication. Objective. To evaluate the effects of balance training on PI in patients with PD. Methods. A total of 64 patients with PI were randomly assigned to the experimental group (n = 33) for balance training or to the control group (n = 31) for general physical exercises. Each patient received 21 treatment sessions of 50 minutes each. Patients were evaluated by a blinded rater before and after treatment as well as 1 month posttreatment using the Berg Balance Scale (BBS), ActivitiesSpecific Balance Confidence Scale (ABC), postural transfer test, self-destabilization of the center of foot pressure test, number of falls, Unified Parkinson’s Disease Rating Scale (UPDRS), modified Hoehn and Yahr (H&Y) Staging Scale, and Geriatric Depression Scale (GDS). Results. At the end of treatment, the experimental group showed significant improvements in all outcome measures, except for the UPDRS and the H&Y scale. Improvement was maintained at the 1-month follow-up in all outcome measures except for the GDS. No significant changes in performance were observed in the control group. Conclusions. A program of balance training can improve PI in patients with PD