Antagonism of metabotropic glutamate receptor type 5 prevents levodopa-induced dyskinesia development in a male rat model of Parkinson's disease: Electrophysiological evidence.

Levodopa-induced dyskinesia (LID) is a common complication in patients with advanced Parkinson's disease (PD) undergoing treatment with levodopa. Glutamate receptor antagonists can suppress LID; however, the underlying mechanisms remain unclear. Here, we aimed to evaluate the effect of 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP), a metabotropic glutamate receptor 5 (mGluR5) antagonist, on dyskinesia. We recorded the neuronal activity of the entopeduncular nucleus and examined responses to cortical electric stimulation in the control group (n = 6) and three groups of rats (male PD model). Saline was intraperitoneally administered to dopamine lesioned (DL) rats (n = 6), levodopa/benserazide (L/B) was administered to LID rats (n = 8), and L/B combined with MTEP was administered to MTEP rats (n = 6) twice daily for 14 days. We administered L/B to LID and MTEP rats 48 h after the final administration of MTEP to examine the chronic effect of MTEP. The control and DL groups did not have LID. The MTEP group had less LID than the LID group (p < .01) on day 1 and day 18. The control group had a typical triphasic pattern consisting of early excitation (early-Ex), inhibition, and late excitation (late-Ex). However, the inhibition phase disappeared, was partially observed, and was fully suppressed in the DL, LID, and MTEP groups, respectively. The cortico-striato-entopeduncular pathway is important in the pathophysiology of LID. mGluR5 antagonism suppresses LID progression by preventing physiological changes in the cortico-striato-entopeduncular pathway. Future studies are required to validate these results.

Intrajejunal Infusion of Levodopa/Carbidopa for Advanced Parkinson's Disease: A Systematic Review.

Advanced Parkinson's disease is inconsistently defined, and evidence is lacking in relation to device-aided therapies. To update existing reviews of intrajejunal infusion of levodopa/carbidopa (LCIG), we performed a literature search for relevant articles (to November 3, 2020) using PubMed supplemented by hand searching. Retrieved articles were categorized by relevance to identified research questions, including motor complications and symptoms; nonmotor symptoms; functioning, quality of life, and caregiver burden; optimal timing of treatment initiation and administration duration; discontinuation; and complications. Most eligible studies (n = 56) were open-label, observational studies including relatively small patient numbers. LCIG consistently reduces OFF time and increased ON time without troublesome dyskinesia with varying effects regarding ON time with troublesome dyskinesia and the possibility of diphasic dyskinesia. More recent evidence provides some increased support for the benefits of LCIG in relation to nonmotor symptoms, quality of life, activities of daily living, and reduced caregiver burden. Patient age does not appear to significantly impact the effectiveness of LCIG. Discontinuation rates with LCIG (~17%-26%) commonly relate to device-related issues, although the ability to easily discontinue LCIG may represent a potential benefit. LCIG may be a favorable option for patients with advanced Parkinson's disease who show predominant nonmotor symptoms and vulnerability to complications of other advanced therapy modalities. Larger, well-controlled studies, including precise investigation of cost effectiveness, would further assist treatment selection. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

An Essential Role of the Intraparietal Sulcus in Response Inhibition Predicted by Parcellation-Based Network.

The posterior parietal cortex (PPC) features close anatomical and functional relationships with the prefrontal cortex. However, the necessity of the PPC in executive functions has been questioned. The present study used the stop-signal task to examine response inhibition, an executive function that inhibits prepotent response tendency. The brain activity and resting-state functional connectivity were measured to analyze a parcellation-based network that was aimed at identifying a candidate PPC region essential for response inhibition in humans. The intraparietal sulcus (IPS) was activated during response inhibition and connected with the inferior frontal cortex and the presupplementary motor area, the two frontal regions known to be necessary for response inhibition. Next, transcranial magnetic stimulation (TMS) was used to test the essential role of the IPS region for response inhibition. TMS over the IPS region prolonged the stop-signal reaction time (SSRT), the standard behavioral index used to evaluate stopping performance, when stimulation was applied 30-0 ms before stopping. On the contrary, stimulation over the temporoparietal junction region, an area activated during response inhibition but lacking connectivity with the two frontal regions, did not show changes in SSRT. These results indicate that the IPS identified using the parcellation-based network plays an essential role in executive functions.SIGNIFICANCE STATEMENT Based on the previous neuropsychological studies reporting no impairment in executive functions after lesions in the posterior parietal cortex (PPC), the necessity of PPC in executive functions has been questioned. Here, contrary to the long-lasting view, by using recently developed analysis in functional MRI ("parcellation-based network analysis"), we identified the intraparietal sulcus (IPS) region in the PPC as essential for response inhibition: one executive function to stop actions that are inaccurate in a given context. The necessity of IPS for response inhibition was further tested by an interventional technique of transcranial magnetic stimulation. Stimulation to the IPS disrupted the performance of stopping. Our findings suggest that the IPS plays essential roles in executive functions.

Technique and outcome of percutaneous endoscopic transgastric jejunostomy for continuous infusion of levodopa-carbidopa intestinal gel for treatment of Parkinson's disease.

Objective: A new method of drug delivery via the small bowel, continuous infusion of levodopa-carbidopa intestinal gel (LCIG), for patients with advanced Parkinson's disease (PD) has been developed and shown to improve patients' quality of life. Levodopa is infused directly and continuously into the proximal jejunum via a percutaneous endoscopic transgastric jejunostomy (PEG-J) tube that is connected to a portable infusion pump. The aim of this study was to evaluate the safety and outcomes of our PEG-J technique performed in advance of LCIG therapy in patients with advanced PD. Material and methods: We reviewed the cases of 37 patients who underwent PEG-J for LCIG therapy at our hospital between November 2016 and May 2018. Pull-through percutaneous endoscopic gastrostomy (PEG) and gastropexy were performed in all patients. The J-tube was inserted through the PEG tube and placed beyond the ligament of Treitz endoscopically under fluoroscopic guidance. After two weeks, the gastropexy sutures were removed. Results: PEG-J with placement of the tube beyond the ligament of Treitz was successful in all 37 patients. Median procedure time was 26.4 min. Median hospital stay after the procedure was 16 days. Median follow-up with the PEG-J tube in place was 11 months. There were five procedure-related complications (13.5%) and 13 device-related complications (35.1%). There was no death related to the procedure. Conclusions: Our PEG-J technique can be performed safely in patients with advanced PD, and favorable outcomes have been achieved to date.

Pembrolizumab-related systemic myositis involving ocular and hindneck muscles resembling myasthenic gravis: a case report.

BACKGROUND: Pembrolizumab is an immune-checkpoints inhibitor that enhances the immune response against cancer cells and therefore is useful for the treatment of several carcinomas. However, pembrolizumab sometimes perturbs the immune system resulting in various autoimmune neurological complications. In this situation, autoimmune myositis due to pembrolizumab is a rare but not-negligible complication. Here, we report two cases of autoimmune myositis due to pembrolizumab, with systemic myositis involving levator palpebrae superioris, extraocular and hindneck muscles. CASE PRESENTATION: Case 1 was a 78-year-old man with advanced urinary cancer referred to the neurological ward presenting with bilateral ptosis, restriction of eye movements, dropped head and weakness in the lower extremities after pembrolizumab administration. His blood examination showed elevated serum levels of creatine kinase with positive anti-PM-Scl 75 and anti-signal recognition particle antibodies. Needle electromyography and MRI suggested systemic inflammatory myopathy. There were no findings to indicate myocardial involvement on electrocardiogram or echocardiogram. Administration of intravenous methylprednisolone following plasma exchange ameliorated creatine kinase levels and inhibited the progression of clinical symptoms. Case 2 was a 72-year-old female with lung cancer and multiple metastasis, including lymph nodes and brain. She presented with back pain, right-sided ptosis, weakness of her neck extensors and flexors and elevated serum creatine kinase after receiving pembrolizumab. Although myositis specific autoantibodies were negative, needle electromyography and MRI suggested systemic inflammatory myopathy and muscle biopsy indicated necrotizing myopathy. There were no signs indicating heart dysfunction and her electrocardiogram was normal. Clinical symptoms and serum creatine kinase levels were ameliorated after the administration of intravenous methylprednisolone. CONCLUSIONS: Both cases showed atypical extensive inflammatory myositis including levator palpebrae superioris, extraocular and hindneck muscles, resembling myasthenia gravis (MG), but they did not have MG-related antibodies. Edrophonium test was negative and showed no daily fluctuation. Two previously reported cases also presented with systemic necrotizing systemic myositis involving extraocular and facial muscles caused by pembrolizumab. Idiopathic inflammatory myositis evolving levator palpebrae superioris and ocular muscles is quite rare; however, myositis due to immune-checkpoint inhibitors may preferentially involve these muscles. This case report will alert physicians to the possibility of systemic inflammatory myopathy evolving levator palpebrae superioris, extraocular and hindneck muscles mimicking MG due to pembrolizumab.

The prevalence, course and clinical correlates of migraine in Parkinson's disease: A multicentre case-controlled study.

Background Previous studies have reported a lower migraine prevalence in Parkinson's disease (PD) patients and improvements in migraine headaches after PD onset, but the clinical association of migraines with PD is unclear. Methods We analysed headache and migraine prevalence and clinical correlates in 436 PD patients (mean age, 69.3 ± 7.8 years) and 401 age- and sex-matched controls (mean age, 69.2 ± 8.6 years) in a case-controlled, multicentre study. Migraines were diagnosed by a questionnaire developed according to the International Classification of Headache Disorders, second edition. We evaluated changes in headache intensity, frequency and severity over several years around the onset of PD among PD patients with headaches or migraines, and over the past several years among control subjects with headaches or migraines. Results PD patients had lower lifetime (9.6% vs. 18.0%) and 1-year (6.7% vs. 11.0%) migraine prevalences than controls. However, lifetime (38.5% vs. 38.9%) and 1-year (26.1% vs. 26.2%) headache prevalence did not differ between PD patients and controls. After adjusting for gender, timing of the evaluation of headache changes, and recall period, PD patients with headaches or migraines exhibited a pronounced reduction in the intensity, frequency and overall severity of their headaches and migraines after the onset of PD compared with controls with headaches or migraines. PD patients with migraines exhibited a higher rate of depression and higher Pittsburgh Sleep Quality Index and PD sleep scale-2 scores than those without headaches. Conclusion While overall headache and migraine severity reduced after PD onset, the presence of migraines was associated with sleep disturbances and depression in PD patients.

Myalgia caused by chronic myositis associated with plasmacytosis: a case report.

BACKGROUND: Cutaneous and systemic plasmacytosis are skin disorders characterized by cutaneous polyclonal plasma cell infiltration accompanied by polyclonal hypergammaglobulinemia. Cutaneous plasmacytosis involvement is limited to the skin, mainly on the face and trunk, while systemic plasmacytosis also involves 2 or more organ systems. However, there have been no reports of inflammatory myositis due to plasmacytosis. Here, we report a patient with plasmacytosis who developed myalgia and easy fatigability due to inflammatory myositis. CASE PRESENTATION: A 54-year-old man with cutaneous plasmacytosis on the face, chest, and back complained of a history of atypical facial and lower leg pain and easy fatigability since the age of 45 years. Muscle-strength tests revealed bilateral trivial gastrocnemius weakness with myalgia. The results of routine blood analysis, including creatine kinase and thyroid function, were normal, but levels of several inflammation markers and autoantibodies were elevated. Additionally, lower leg magnetic resonance imaging and gastrocnemius muscle biopsy revealed inflammatory myositis mimicking polymyositis. His plasmacytosis, myalgia, and lower leg weakness were ameliorated by prednisolone. CONCLUSION: The patient was diagnosed with inflammatory myositis due to plasmacytosis. Given that plasmacytosis has previously been reported to disrupt the immune status, myositis in this patient might have been associated with abnormal autoimmune inflammation. Neurologists and physicians should thus be aware that plasmacytosis might be associated with inflammatory myositis accompanied by myalgia.

Conjugate Eye Deviation Caused by Upper Medial Medullary Infarction: A Case Report.

Conjugate eye deviation (CED) is defined as a sustained shift in horizontal gaze toward 1 side, together with gaze failure to the other side, caused by lesions in the brainstem, basal ganglia, or cortical frontal eye fields. To date, very few reports have described CED in patients with medullary infarction. A 76-year-old woman presented with sudden onset of vertigo and right hemiparesis, accompanied by CED to the right with gaze palsy to the left. Her brain magnetic resonance imaging showed left upper medial medullary infarction involving the left nucleus prepositus hypoglossi (NPH) and adjacent to the left inferior olivary nucleus (ION). After treatments with 200 mg of aspirin and 60 mg of edaravone daily, symptoms gradually improved. The NPH and ION constitute NPH-ION-floccus-vestibular nucleus loop and contribute to the inhibitory mechanisms for horizontal eye movements. In addition, NPH projects excitatory neurons to the contralateral vestibular nucleus. In our case, disorders of the NPH and ION might have dysregulated inhibitory and excitatory projections, and thereby cause CED to the right with gaze palsy to the left. This represents a rare case showing CED to the contralesional side in upper medial medullary infarction.

Subthalamic nucleus and globus pallidus interna influence firing of tonically active neurons in the primate striatum through different mechanisms.

Both the subthalamic nucleus (STN) and the globus pallidus pars interna (GPi) are major targets for neuromodulation therapy for movement disorders. An example of such a therapy is deep brain stimulation (DBS). The striatum is the primary target for pharmacological treatment of these disorders. To further our understanding of both the functional relationships among motor nuclei and the mechanisms of therapies for movement disorders, it is important to clarify how changing the neuronal activity of one target, either by medication or by artificial electrical stimulation, affects the other connected nuclei. To investigate this point, we recorded single-unit activity from tonically active neurons (TANs), which are putative cholinergic interneurons in the striatum, of healthy monkeys (Macaca fuscata) during electrical stimulation of the STN or GPi. Both STN stimulation and GPi stimulation reduced the TAN spike rate. Local infusion of a D2 receptor antagonist in the striatum blocked the reduction in spike rate induced by STN stimulation but not that induced by GPi stimulation. Further, STN stimulation induced phasic dopamine release in the striatum as revealed by in vivo fast-scan cyclic voltammetry. These results suggest the presence of multiple, strong functional relationships among the STN, GPi, and striatum that have different pathways and imply distinct therapeutic mechanisms for STN- and GPi-DBS.

Impact of sleep-related symptoms on clinical motor subtypes and disability in Parkinson's disease: a multicentre cross-sectional study.

OBJECTIVES: To investigate the impact of sleep disturbances on Parkinson's disease (PD) clinical motor subtypes and disease-related disability in a multicentre setting. METHODS: We report a cross-sectional relationship between sleep-related symptoms and clinical motor subtypes (tremor dominant (TD); intermediate; postural instability and gait disturbances (PIGDs)) identified in a multicentre study, including 436 patients with PD and 401 age-matched controls. PD-related sleep problems (PD-SP), excessive daytime sleepiness (EDS) and probable REM sleep behaviour disorder (pRBD) were evaluated using the PD sleep scale (PDSS)-2, Epworth Sleepiness Scale (ESS) and RBD screening questionnaire-Japanese version (RBDSQ-J), respectively. RESULTS: PD-SP (PDSS-2 ≥18; 35.1% vs 7.0%), EDS (ESS ≥10; 37.8% vs 15.5%) and pRBD (RBDSQ-J ≥5; 35.1% vs 7.7%) were more common in patients with PD than in controls. The prevalence of restless legs syndrome did not differ between patients with PD and controls (3.4% vs 2.7%). After adjusting for age, sex, disease duration and Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) part III score, the PIGD group had higher PDSS-2 and ESS scores than the TD group. The RBDSQ-J scores did not differ among the TD, intermediate and PIGD groups. A stepwise regression model predicting the MDS-UPDRS part II score identified the Hoehn and Yahr stage, followed by the number of sleep-related symptoms (PD-SP, EDS and pRBD), disease duration, MDS-UPDRS part III score, PIGD subtype, depression and MDS-UPDRS part IV score as significant predictors. CONCLUSION: Our study found a significant relationship between sleep disturbances and clinical motor subtypes. An increased number of sleep-related symptoms had an impact on disease-related disability.

Deep brain stimulation for Parkinson's disease.

There is a long history of surgical treatment for Parkinson's disease (PD). After pioneering trials and errors, the current primary surgical treatment for PD is deep brain stimulation (DBS). DBS is a promising treatment option for patients with medically refractory PD. In this review, we summarize accumulated findings concerning patient selection, clinical outcomes, complications, target selection, long-term outcomes, manage- ment of axial symptoms, and timing of surgery in DBS for PD. We also describe new technologies of DBS device.

A randomized double-blind multi-center trial of hydrogen water for Parkinson's disease: protocol and baseline characteristics.

BACKGROUND: Our previous randomized double-blind study showed that drinking hydrogen (H2) water for 48 weeks significantly improved the total Unified Parkinson's Disease Rating Scale (UPDRS) score of Parkinson's disease (PD) patients treated with levodopa. We aim to confirm this result using a randomized double-blind placebo-controlled multi-center trial. METHODS: Changes in the total UPDRS scores from baseline to the 8(th), 24(th), 48(th), and 72(nd) weeks, and after the 8(th) week, will be evaluated. The primary endpoint of the efficacy of this treatment in PD is the change in the total UPDRS score from baseline to the 72(nd) week. The changes in UPDRS part II, UPDRS part III, each UPDRS score, PD Questionnaire-39 (PDQ-39), and the modified Hoehn and Yahr stage at these same time-points, as well as the duration until the protocol is finished because additional levodopa is required or until the disease progresses, will also be analyzed. Adverse events and screening laboratory studies will also be examined. Participants in the hydrogen water group will drink 1000 mL/day of H2 water, and those in the placebo water group will drink normal water. One-hundred-and-seventy-eight participants with PD (88 women, 90 men; mean age: 64.2 [SD 9.2] years, total UPDRS: 23.7 [11.8], with levodopa medication: 154 participants, without levodopa medication: 24 participants; daily levodopa dose: 344.1 [202.8] mg, total levodopa equivalent dose: 592.0 [317.6] mg) were enrolled in 14 hospitals and were randomized. DISCUSSION: This study will confirm whether H2 water can improve PD symptoms. TRIAL REGISTRATION: UMIN000010014 (February, 13, 2013).

Spinal Dural Arteriovenous Fistulas in a Patient with Cowden Syndrome and a Phosphatase and Tensin Homolog Mutation.

Cowden syndrome (CS) is an autosomal dominant syndrome characterized by the development of hamartomas and an increased cancer risk. Most CS patients harbor mutations in the phosphatase and tensin homolog (PTEN) gene. We herein report a 70-year-old patient with CS who presented with lower extremity weakness caused by multiple thoracic dural arteriovenous fistulas. Genetic testing revealed a truncated PTEN mutation (c.485_487delACAinsCC and p.D162Afs*5). Vascular malformations are common in CS, particularly in the extremities. However, spinal dural arteriovenous fistulas (AVFs) are extremely rare. Furthermore, in our case, the number of AVFs increased, and both lower limbs became flaccid four months after embolization. Therefore, we suggest that physicians carefully observe the changes in symptoms for prolonged periods after embolization.

Dynamic aphasia as an early sign of corticobasal degeneration: Clinico-radio-pathological correlation.

A 72-year-old man presented with a 6-month history of decreased voluntary speech. Sparse speech and decreased word fluency were observed. Articulation, naming, comprehension, and repetition were preserved. Agrammatism and paraphasia were not observed. These characteristics matched those reported as dynamic aphasia. Other findings were mild behavioral symptoms, recent memory impairment, and right hemiparkinsonism. The patient's voluntary speech continued to reduce and behavioral symptoms progressed. Brain MRI including voxel-based morphometric analysis showed left-dominant white matter volume reduction in the frontal lobe including those between the left supplementary motor area (SMA)/preSMA and the frontal operculum, likely involving the frontal aslant tract (FAT). The patient became completely mute after two years from disease onset and died of aspiration pneumonia. The neuropathological diagnosis was corticobasal degeneration (CBD). This case suggests that dynamic aphasia may be the initial sign of CBD and that early involvement of left FAT may be responsible for this feature.

Prescription trends in Japanese advanced Parkinson's disease patients with non-motor symptoms: J-FIRST.

BACKGROUND: Non-motor symptoms (NMS) are important factors when selecting treatments for patients with advanced Parkinson's disease (PD). We sought to elucidate the prescribing practices for advanced PD patients with NMS in Japanese clinical practice. METHODS: We examined the prescription rates and doses of anti-PD drugs, and the use of non-steroidal anti-inflammatory drugs (NSAIDs) in post hoc analyses of a 52-week observational study of 996 PD patients with wearing-off on levodopa-containing therapy and ≥1 NMS. RESULTS: Dopamine agonists were the most frequently prescribed drugs combined with levodopa-containing drugs, followed by entacapone, zonisamide, istradefylline, selegiline, and amantadine. The daily dose of levodopa-containing drugs, rotigotine, entacapone, istradefylline, and droxidopa, and the levodopa-equivalent dose increased during the observation period. In a subgroup analysis of patients stratified by NMS status (improved/unchanged/deteriorated), the deteriorated group had higher prescription rates of entacapone and istradefylline, whereas the improved group had higher prescription rates of NSAIDs and zonisamide at Week 52. Prescriptions varied by geographical region for anti-PD drugs and by NMS status for NSAIDs. CONCLUSIONS: There were significant changes in the prescriptions and dosing of selected anti-PD drugs, especially newer drugs. Anti-PD drug and NSAID prescriptions also varied by changes in NMS status and geographic region.

Free-water diffusion magnetic resonance imaging under selegiline treatment in Parkinson's disease.

INTRODUCTION: Monoamine oxidase type B inhibitors, including selegiline, are established as anti-Parkinsonian Drugs. Inhibition of monoamine oxidase type B enzymes might suppress the inflammation because of inhibition to generate reactive oxygen species. However, its effect on brain microstructure remains unclear. The aim of this study is to elucidate white matter and substantia nigra (SN) microstructural differences between Patients with Parkinson's disease with and without selegiline treatment by two independently recruited cohorts. METHODS: Diffusion tensor imaging and free water imaging indices of WM and SN were compared among 22/15 Patients with Parkinson's disease with selegiline (PDselegiline(+)), 33/23 Patients with Parkinson's disease without selegiline (PDselegiline(-)), and 25/20 controls, in the first/second cohorts. Two cohorts were analyzed with different MRI protocols. RESULTS: Diffusion tensor imaging and free-water indices of major white matter tracts were significantly differed between the PDselegiline(-) and controls in both cohorts, although not between the PDselegiline(+) and controls except for restricted areas. Compared with the PDselegiline(+), free-water was significantly higher in the PDselegiline(-) in the inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and superior and posterior corona radiata (first cohort) and the forceps major and splenium of the corpus callosum (second cohort). There were no significant differences in free-water of anterior or posterior substantia nigra between PDselegiline(+) and PDselegiline(-). CONCLUSIONS: Selegiline treatment might reduce the white matter microstructural abnormalities detected by free-water imaging in Parkinson's disease.

Safinamide as adjunctive therapy to levodopa monotherapy for patients with Parkinson's disease with wearing-off: The Japanese observational J-SILVER study.

BACKGROUND: Safinamide is an effective adjunctive therapy for wearing-off in Parkinson's disease (PD); however, evidence is lacking in older patients and those in the early stages of wearing-off. This study evaluated the efficacy and safety of safinamide as adjunctive therapy in patients with PD treated with levodopa monotherapy in clinical practice. METHODS: This multicentre, open-label observational study was conducted at five sites in Japan. Patients diagnosed with PD and wearing-off initiated safinamide as adjunctive therapy with levodopa monotherapy. Efficacy endpoints were mean changes in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I, III, and IV scores; daily ON-time without dyskinesia using 24-h patient symptom diaries; and 39-item Parkinson's Disease Questionnaire (PDQ-39) scores at 18 weeks of treatment. RESULTS: In total, 24 patients initiated safinamide (66.7% were aged ≥75 years); the mean duration of wearing-off was 1.2 years. MDS-UPDRS Part III total score, Part IV total score, and PDQ-39 summary index decreased significantly from baseline (mean change -7.0 [p = 0.012], -2.4 [p = 0.007] and - 5.3 [p = 0.012], respectively). There was a non-statistically significant increase of 1.55 h in mean daily ON-time without dyskinesia. Numerical Rating Scale total score for pain (p = 0.015), and scores for OFF-period pain (p = 0.012) and nocturnal pain (p = 0.021) subdomains were significantly improved in the subgroup with pain. Most reported adverse events were classified as mild. CONCLUSION: Safinamide improved motor and non-motor symptoms and quality of life-related measures in older patients with PD in the early stages of wearing-off without new safety concerns. STUDY REGISTRATION: University Hospital Medical Information Network in Japan; study ID: UMIN000044341.