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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., Competing Interests: Declaration of competing interest N.N., S.S. and W.S. report honoraria and consultation fees from Eisai Co., Ltd. during the conduct of the study. T.H., K.N., R.N., A.Y., Y.S. and H.S. report honoraria from Eisai Co., Ltd. during the conduct of the study. S.-I.U., T.O. and Y.F. have no competing interests to declare. T.K. and T.I. are employees of Eisai Co. Ltd. N.H. reports honoraria, consultation fees and grants from Eisai Co., Ltd. during the conduct of the study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

Background: Dyskinesia frequently occurs during long-term treatment with levodopa in patients with Parkinson's disease (PD) and impacts quality of life. Few studies have examined risk factors for developing dyskinesia in PD patients exhibiting wearing-off. Therefore, we investigated the risk factors and impact of dyskinesia in PD patients exhibiting wearing-off., Methods: We investigated the risk factors and impact of dyskinesia in a 1-year observational study of Japanese PD patients exhibiting wearing-off (J-FIRST). Risk factors were assessed by logistic regression analyses in patients without dyskinesia at study entry. Mixed-effect models were used to evaluate the impact of dyskinesia on changes in Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) Part I and PD Questionnaire (PDQ)-8 scores from one timepoint before dyskinesia was observed., Results: Of 996 patients analyzed, 450 had dyskinesia at baseline, 133 developed dyskinesia within 1 year, and 413 did not develop dyskinesia. Female sex (odds ratio [95% confidence interval]: 2.636 [1.645-4.223]) and administration of a dopamine agonist (1.840 [1.083-3.126]), a catechol-O-methyltransferase inhibitor (2.044 [1.285-3.250]), or zonisamide (1.869 [1.184-2.950]) were independent risk factors for dyskinesia onset. MDS-UPDRS Part I and PDQ-8 scores increased significantly after the onset of dyskinesia (least-squares mean change [standard error] at 52 weeks: 1.11 [0.52], P = 0.0336; 1.53 [0.48], P = 0.0014; respectively)., Conclusion: Female sex and administration of a dopamine agonist, a catechol-O-methyltransferase inhibitor, or zonisamide were risk factors for dyskinesia onset within 1 year in PD patients exhibiting wearing-off. Nonmotor symptoms and quality of life deteriorated after dyskinesia onset., Competing Interests: Declaration of Competing Interest T. Mishima reports research funds from Kyowa Kirin in relation to this work. S.-W.C. reports research funds from Kyowa Kirin in relation to this work. H.S. reports research funds from Kyowa Kirin in relation to this work; research grants from Otsuka Pharmaceutical and Eisai; and honoraria from Kyowa Kirin, Eisai, Takeda Pharmaceutical, Dainippon Sumitomo Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Novartis, Boston Scientific Japan, AbbVie, Medtronic Japan, and Teijin Pharma. T.Y. reports payments made to the institution from Kyowa Kirin in relation to this work; research grants from AC Medical, A2 Healthcare Corporation, EP Croit, ClinChoice, Japan Tobacco, Japan Media Corporation, Medidata Solutions, Ono Pharmaceutical, Asahi Intecc, 3H Clinical Trial, Medrio, Nipro Corporation, Intellim Corporation, Welby, 3H Medi Solution, Baseconnect, Nobori, Puravida Technologies, and Hemp Kitchen; research grants/payments to the institution from Kyowa Kirin, Tsumura & Co, Daiichi Sankyo, Otsuka Pharmaceutical, and Eisai; consulting fees from EP Croit, Japan Tobacco, Medidata Solutions, Ono Pharmaceutical, Kowa Company, Chugai Pharmaceutical, Tsumura & Co., Daiichi Sankyo, Eisai, Asahi Intecc, Asahi Kasei Pharma Corporation, 3H Clinical Trial, Intellim Corporation, Takeda, AstraZeneca, Sonire Therapeutics, and Seikagaku Corporation; payments or honoraria from Nipro Corporation; and participation on a data safety monitoring board or advisory board for Incyte Biosciences Japan. Y.S. reports research funds from Kyowa Kirin in relation to this work. T. Maeda reports research funds from Kyowa Kirin in relation to this work; lecture fees and scholarship donations from Daiichi Sankyo; lecture fees from Nihon Mediphysics, Biogen, Chugai Pharmaceutical, Kyowa Kirin, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, Ono Pharmaceutical, Eisai, and Japan Medtronic; scholarship donations from Bayer Yakuhin, Teijin, and CSL Behring; and consulting fees from Kyowa Kirin and Ono Pharmaceutical. H.W. reports research funds from Kyowa Kirin in relation to this work; and honoraria from Takeda Pharmaceutical, AbbVie, Kyowa Kirin, Sumitomo Dainippon Pharma, Novartis, Otsuka Pharmaceutical, and FP Corporation. K.K. reports research funds from Kyowa Kirin in relation to this work; lecture fees and consulting fees from Kyowa Kirin; and lecture fees from Takeda Pharmaceutical and Ono Pharmaceutical. M.N. reports research funds from Kyowa Kirin in relation to this work; research funds from Kyowa Kirin, Kissei Pharmaceutical, and Hisamitsu Pharmaceutical; and lecture fees from Ehime University School of Medicine, Eisai, and Kyowa Kirin. N.H. reports grants to the Collaborative Research Department of Drug Discovery Research for Synucleopathies, lecture fees, and support for attending advisory boards from Kyowa Kirin in relation to this work; research contracts with Dainippon Sumitomo Pharma, Biogen Japan, and CellSource; consultancy fees from Hisamitsu Pharma and PARKINSON Laboratories; honoraria from Dainippon Sumitomo Pharma, Takeda Pharmaceutical, AbbVie, Nippon Boehringer Ingelheim, Otsuka Pharmaceutical, Novartis, Bristol-Myers Squibb, Ono Pharmaceutical, FP Pharmaceutical, Eisai, Kissei Pharmaceutical, Nihon Mediphysics, and Daiichi Sankyo; support for attending advisory boards from Dainippon Sumitomo Pharma, Takeda Pharmaceutical, Teijin Pharma, Novartis, Ono Pharmaceutical, Biogen Idec Japan, Kissei Pharmaceutical, and Mitsubishi Tanabe Pharma; Japanese (2021–0001888; Differential Diagnosis of Parkinson's Disease and Multiple System Atrophy, Patent Applicants: Juntendo University, Nagasaki University, January 4, 2021) and international (International filing date: 2021/09/22; priority date: 2020/10/29; applicant name: Juntendo Educational Foundation) patents; honoraria for team leader role at RIKEN: Center for Brain Science; and holds stock in PARKINSON Laboratories. Y.T. reports research funds from Kyowa Kirin; lecture fees from Sumitomo Dainippon Pharma, Takeda Pharmaceutical Company, Novartis, AbbVie, Otsuka Pharmaceutical, Ono Pharmaceutical, and Eisai; and contributes to courses run by Sunwels and Nipro Corporation., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Depression is the most common psychiatric complication in patients with Parkinson's disease (PD). Istradefylline, a new anti-parkinsonian agent with completely different mechanism, improves depression-like symptoms in an experimental disease model; however, there is no report of its effects in PD patients. In this study, the effectiveness of istradefylline for treatment of mood disorders in patients with PD was examined in an open-label trial. Thirty PD patients were enrolled. All patients had scores of higher than cut-off level in at least one of the following batteries: Snaith-Hamilton Pleasure Scale Japanese version (SHAPS-J), Apathy scale, or Beck Depression Inventory-2nd edition (BDI). Following study enrollment, all patients received 20 mg of istradefylline, and the dose was increased to 40 mg after 4 weeks. Results from these 3 batteries and the Unified Parkinson's Disease Rating Scale (UPDRS) score were assessed every 2-4 weeks until 12 weeks and the changes in these scores were analyzed. Following administration of istradefylline, the scores of SHAPS-J, Apathy scale, and BDI were significantly improved over time. Significant improvement was also found in the UPDRS score; however, no significant correlation was observed between the score change in these 3 batteries and UPDRS motor function. This is the first study to show the effectiveness of istradefylline for treatment of mood disorders in PD independent of improvement of parkinsonian motor symptoms. In the future, this should be confirmed in a double-blind placebo-controlled trial., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Cerebral microbleeds (CMBs) are often observed in Parkinson's disease (PD); however, their association with cognitive decline has been unclear. We performed a retrospective analysis of 124 cases of clinically diagnosed PD to determine the association between the presence of CMBs and cognitive decline., Results: Of the 124 participants, 21 (16.9%) was diagnosed as PDD in this cohort. CMBs were observed significantly more frequently in the PDD than in the PD (47.6% vs 7.8%, P < .001). The presence of both deep/infratentorial (40% vs 14.9%, P < .05) and strictly lobar (75% vs 12.9%, P < .001) CMBs were associated with PDD. The values of cognitive scales such as Mini-Mental State Examination and the Hasegawa Dementia Scale-revised, were also significantly lower in the presence of each type of CMB. A multivariable logistic regression analysis showed the presence of strictly lobar CMBs as well as a male gender, orthostatic hypotension, periventricular hyperintensity on magnetic resonance imaging were significantly associated with PDD in this cohort., Conclusions: This study showed the presence of CMBs, especially strictly lobar type, was strongly associated with PDD. We suspect that the burden of small vessel disease and cerebral amyloid angiopathy may be related to the development of cognitive decline in PD, and a prospective study enrolling more cases is warranted., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Imaging studies are necessary prior to subthalamic deep brain stimulation (STN-DBS). Dopamine transporter (DAT) imaging is a powerful tool for visualizing dopamine terminals in the striatum, but its usefulness in STN-DBS is unclear. Here, we retrospectively investigated the relationship between motor symptoms and the specific binding ratio (SBR) on DAT imaging in patients with Parkinson's disease (PD). We included 23 consecutive patients (9 female; 14 male) who were evaluated for DBS eligibility between October 2013 and October 2014 and subsequently received bilateral STN-DBS. Correlation and simple regression analyses were performed on SBR values and clinical parameters before and after surgery. SBR value was negatively correlated with Unified Parkinson's Disease Rating Scale (UPDRS) motor score in the "ON" state before surgery (r s =-0.637, p=0.001) and positively correlated with the reduction of the levodopa equivalent daily dose by surgery (r=0.422, p=0.045). A simple regression analysis revealed that SBR value was positively correlated with UPDRS motor score improvement after levodopa challenge before surgery (p=0.001, R 2 =0.423). DAT imaging may be useful in STN-DBS candidate selection and the identification of the therapeutic mechanism of STN-DBS in patients with advanced PD and motor symptom fluctuations., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)