Subthalamic nucleus local field potential stability in patients with Parkinson's disease.

BACKGROUND: Despite the large body of work on local field potentials (LFPs), a measure of oscillatory activity in patients with Parkinson's disease (PD), the longitudinal evolution of LFPs is less explored. OBJECTIVE: To determine LFP fluctuations collected in clinical settings in patients with PD and STN deep brain stimulation (DBS). METHODS: Twenty-two STN-DBS patients (age: 67.6 ±â€¯8.3 years; 9 females; disease duration: 10.3 ±â€¯4.5 years) completed bilateral LFP recordings over three visits in the OFF-stimulation setting. Peak and band power measures were calculated from each recording. RESULTS: After bilateral LFP recordings, at least one peak was detected in 18 (81.8%), 20 (90.9%), and 22 (100%) patients at visit 1, 2, and 3, respectively. No significant differences were seen in primary peak amplitude (F = 2.91, p = 0.060) over time. Amplitude of the second largest peak (F = 5.49, p = 0.006) and low-beta (F = 6.89, p = 0.002), high-beta (F = 13.23, p < 0.001), and gamma (F = 12.71, p < 0.001) band power demonstrated a significant effect of time. Post hoc comparisons determined low-beta power (Visit 1-Visit 2: t = 3.59, p = 0.002; Visit 1-Visit 3: t = 2.61, p = 0.031), high-beta (Visit 1-Visit 2: t = 4.64, p < 0.001; Visit 1-Visit 3: t = 4.23, p < 0.001) and gamma band power (Visit 1-Visit 2: t = 4.65, p < 0.001; Visit 1-Visit 3: t = 4.00, p < 0.001) were significantly increased from visit 1 recordings to both follow-up visits. CONCLUSION: Our results provide substantial evidence that LFP can reliably be detected across multiple real-world clinical visits in patients with STN-DBS for PD. Moreover, it provides insights on the evolution of these LFPs.

Long-Read Sequencing Resolves a Complex Structural Variant in PRKN Parkinson's Disease.

BACKGROUND: Parkin RBR E3 ubiquitin-protein ligase (PRKN) mutations are the most common cause of young onset and autosomal recessive Parkinson's disease (PD). PRKN is located in FRA6E, which is one of the common fragile sites in the human genome, making this region prone to structural variants. However, complex structural variants such as inversions of PRKN are seldom reported, suggesting that there are potentially unrevealed complex pathogenic PRKN structural variants. OBJECTIVES: To identify complex structural variants in PRKN using long-read sequencing. METHODS: We investigated the genetic cause of monozygotic twins presenting with a young onset dystonia-parkinsonism using targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long-read sequencing. We assessed the presence and frequency of complex inversions overlapping PRKN using whole-genome sequencing data of Accelerating Medicines Partnership Parkinson's disease (AMP-PD) and United Kingdom (UK)-Biobank datasets. RESULTS: Multiple ligation probe amplification identified a heterozygous exon three deletion in PRKN and long-read sequencing identified a large novel inversion spanning over 7 Mb, including a large part of the coding DNA sequence of PRKN. We could diagnose the affected subjects as compound heterozygous carriers of PRKN. We analyzed whole genome sequencing data of 43,538 participants of the UK-Biobank and 4941 participants of the AMP-PD datasets. Nine inversions in the UK-Biobank and two in AMP PD were identified and were considered potentially damaging and likely to affect PRKN expression. CONCLUSIONS: This is the first report describing a large 7 Mb inversion involving breakpoints outside of PRKN. This study highlights the importance of using long-read sequencing for structural variant analysis in unresolved young-onset PD cases. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

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.

New modalities and directions for dystonia care.

Dystonia is an abnormal involuntary movement or posture owing to sustained or intermittent muscle contraction. Standard treatment for dystonia includes medications, such as levodopa, anticholinergic and antiepileptic drugs, botulinum toxin, and baclofen pump, and surgeries, such as lesioning surgery and deep-brain stimulation. New treatment modalities aimed toward improving dystonia care in the future are under investigation. There are two main axes to improve dystonia care; one is non-invasive neuromodulation, such as transcranial magnetic stimulation, transcranial electrical stimulation, and transcutaneous electrical nerve stimulation. The other is a quantitative evaluation of dystonia using a wearable device and motion-capturing system, which can be empowered by artificial intelligence. In this article, the current status of these axes will be reviewed.

Neurocognitive and psychiatric disorders-related axonal degeneration in Parkinson's disease.

Neurocognitive and psychiatric disorders have significant consequences for quality of life in patients with Parkinson's disease (PD). In the current study, we evaluated microstructural white matter (WM) alterations associated with neurocognitive and psychiatric disorders in PD using neurite orientation dispersion and density imaging (NODDI) and linked independent component analysis (LICA). The indices of NODDI were compared between 20 and 19 patients with PD with and without neurocognitive and psychiatric disorders, respectively, and 25 healthy controls using tract-based spatial statistics and tract-of-interest analyses. LICA was applied to model inter-subject variability across measures. A widespread reduction in axonal density (indexed by intracellular volume fraction [ICVF]) was demonstrated in PD patients with and without neurocognitive and psychiatric disorders, as compared with healthy controls. Compared with patients without neurocognitive and psychiatric disorders, patients with neurocognitive and psychiatric disorders exhibited more extensive (posterior predominant) decreases in axonal density. Using LICA, ICVF demonstrated the highest contribution (59% weight) to the main effects of diagnosis that reflected widespread decreases in axonal density. These findings suggest that axonal loss is a major factor underlying WM pathology related to neurocognitive and psychiatric disorders in PD, whereas patients with neurocognitive and psychiatric disorders had broader axonal pathology, as compared with those without. LICA suggested that the ICVF can be used as a useful biomarker of microstructural changes in the WM related to neurocognitive and psychiatric disorders in PD.

Clinical characterization of patients with leucine-rich repeat kinase 2 genetic variants in Japan.

Variants of leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of familial Parkinson's disease (PD). We aimed to investigate the genetic and clinical features of patients with PD and LRRK2 variants in Japan by screening for LRRK2 variants in three exons (31, 41, and 48), which include the following pathogenic mutations: p.R1441C, p.R1441G, p.R1441H, p.G2019S, and p.I2020T. Herein, we obtained data containing LRRK2 variants derived from 1402 patients with PD (653 with sporadic PD and 749 with familial PD). As a result, we successfully detected pathogenic variants (four with p.R1441G, five with p.R1441H, seven with p.G2019S, and seven with p.I2020T) and other rare variants (two with p.V1447M, one with p.V1450I, one with p.T1491delT, and one with p.H2391Q). Two risk variants, p.P1446L and p.G2385R, were found in 10 and 146 patients, respectively. Most of the patients presented the symptoms resembling a common type of PD, such as middle-aged onset, tremor, akinesia, rigidity, and gait disturbance. Dysautonomia, cognitive decline, and psychosis were rarely observed. Each known pathogenic variant had a different founder in our cohort proven by haplotype analysis. The generation study revealed that the LRRK2 variants p.G2019S and p.I2020T were derived 3500 and 1300 years ago, respectively. Our findings present overviews of the prevalence and distribution of LRRK2 variants in Japanese cohorts.

Evaluation of white matter microstructure in patients with Parkinson's disease using microscopic fractional anisotropy.

PURPOSE: Micro fractional anisotropy (µFA) is more accurate than conventional fractional anisotropy (FA) for assessing microscopic tissue properties and can overcome limitations related to crossing white matter fibres. We compared µFA and FA for evaluating white matter changes in patients with Parkinson's disease (PD). METHODS: We compared FA and µFA measures between 25 patients with PD and 25 age- and gender-matched healthy controls using tract-based spatial statistics (TBSS) analysis. We also examined potential correlations between changes, revealed by conventional FA or µFA, and disease duration or Unified Parkinson's Disease Rating Scale (UPDRS)-III scores. RESULTS: Compared with healthy controls, patients with PD had significantly reduced µFA values, mainly in the anterior corona radiata (ACR). In the PD group, µFA values (primarily those from the ACR) were significantly negatively correlated with UPDRS-III motor scores. No significant changes or correlations with disease duration or UPDRS-III scores with tissue properties were detected using conventional FA. CONCLUSION: µFA can evaluate microstructural changes that occur during white matter degeneration in patients with PD and may overcome a key limitation of FA.

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.

Convolutional neural network-based segmentation can help in assessing the substantia nigra in neuromelanin MRI.

PURPOSE: This study aimed to evaluate the accuracy and diagnostic test performance of the U-net-based segmentation method in neuromelanin magnetic resonance imaging (NM-MRI) compared to the established manual segmentation method for Parkinson's disease (PD) diagnosis. METHODS: NM-MRI datasets from two different 3T-scanners were used: a "principal dataset" with 122 participants and an "external validation dataset" with 24 participants, including 62 and 12 PD patients, respectively. Two radiologists performed SNpc manual segmentation. Inter-reader precision was determined using Dice coefficients. The U-net was trained with manual segmentation as ground truth and Dice coefficients used to measure accuracy. Training and validation steps were performed on the principal dataset using a 4-fold cross-validation method. We tested the U-net on the external validation dataset. SNpc hyperintense areas were estimated from U-net and manual segmentation masks, replicating a previously validated thresholding method, and their diagnostic test performances for PD determined. RESULTS: For SNpc segmentation, U-net accuracy was comparable to inter-reader precision in the principal dataset (Dice coefficient: U-net, 0.83 ± 0.04; inter-reader, 0.83 ± 0.04), but lower in external validation dataset (Dice coefficient: U-net, 079 ± 0.04; inter-reader, 0.85 ± 0.03). Diagnostic test performances for PD were comparable between U-net and manual segmentation methods in both principal (area under the receiver operating characteristic curve: U-net, 0.950; manual, 0.948) and external (U-net, 0.944; manual, 0.931) datasets. CONCLUSION: U-net segmentation provided relatively high accuracy in the evaluation of the SNpc in NM-MRI and yielded diagnostic performance comparable to that of the established manual method.

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).

Deep brain stimulation may improve quality of life in people with Parkinson's disease without affecting caregiver burden.

OBJECTIVE: This study aims to investigate the influence of deep brain stimulation (DBS) on caregiver burden and quality of life in Parkinson's disease. METHODS: A cross-sectional retrospective study utilizing the National Parkinson Foundation Quality Improvement Initiative clinical study was conducted. A group of 275 patients who had undergone DBS for Parkinson's disease were extracted from 2916 subjects who were included in this data base. The data were compared to an age, sex, and disease severity matched control group. A secondary analysis was then performed on two more control groups that were matched to account for presence or absence of motor fluctuations. The multidimensional caregiver strain index and Parkinson's disease quality-of-life questionnaire 39 summary index were compared. RESULTS: The multidimensional caregiver strain index did not differ between the DBS group (16.9 ± 11.8) and a matched non-DBS group (16.1 ± 17.6, p = 0.618). The quality-of-life index was, however, significantly better in the DBS group (28.9 ± 15.6) than in the non-DBS group (32.3 ± 17.6, p = 0.034). A secondary analysis revealed that the total caregiver strain score was lower in the no motor fluctuation control group than the other two groups (p < 0.05). Regression analysis revealed significant relationships between the quality-of-life index and caregiver strain index total scores (p < 0.001), between caregiver strain index total score and age at surgery (p = 0.027), and also between the interval since surgery (p = 0.048). CONCLUSIONS: Although there were several limitations to this study, DBS seems to improve quality of life without significantly increasing caregiver burden.

A proof of concept: digital diary using 24-hour monitoring using wearable device for patients with Parkinson's disease in nursing homes.

Introduction: In the advanced stages of Parkinson's disease (PD), motor complications such as wearing-off and dyskinesia are problematic and vary daily. These symptoms need to be monitored precisely to provide adequate care for patients with advanced PD. Methods: This study used wearable devices to explore biomarkers for motor complications by measuring multiple biomarkers in patients with PD residing in facilities and combining them with lifestyle and clinical assessments. Data on the pulse rate and activity index (metabolic equivalents) were collected from 12 patients over 30 days. Results: The pulse rate and activity index during the off- and on-periods and dyskinesia were analyzed for two participants; the pulse rate and activity index did not show any particular trend in each participant; however, the pulse rate/activity index was significantly greater in the off-state compared to that in the dyskinesia and on-states, and this index in the dyskinesia state was significantly greater than that in the on-state in both participants. Conclusion: These results suggest the pulse rate and activity index combination would be a useful indicator of wearing-off and dyskinesia and that biometric information from wearable devices may function as a digital diary. Accumulating more cases and collecting additional data are necessary to verify our findings.

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.

Efficacy and Safety of Elobixibat in Parkinson's Disease with Chronic Constipation: CONST-PD Study.

BACKGROUND: Chronic constipation is a common digestive complication of Parkinson's disease (PD). OBJECTIVES: To verify the usefulness of elobixibat, an ileal bile acid transporter inhibitor, for chronic constipation in PD. METHODS: This double-blind, placebo-controlled study consisted of a 2-week observation/washout period and a 4-week treatment period. All patients received a Bowel Movement Diary at Week -2 and were allocated to elobixibat (10 mg) or placebo at Week 0. Patients visited at Weeks 2 and 4 to report daily spontaneous bowel movements (SBM), stool form, drug use, quality of life (QOL), and safety. Changes in these parameters were assessed. RESULTS: The study included 38 patients in the elobixibat group and 39 in the placebo group, and 37 each completed the study. SBM frequency/week (mean ± standard deviation) increased significantly from 4.2 ± 2.6 at baseline to 5.9 ± 3.2 at Week 4 in the elobixibat group (P = 0.0079), but not in the placebo group (4.5 ± 2.7 to 5.3 ± 3.5; P = 0.0889). On analysis of covariance, the between-group difference in frequency changes at Week 4 (primary endpoint) was not significant after adjustment by baseline and sex (point estimate = 0.8; 95% confidence interval = -0.57 to 2.09, P = 0.2601), although a significant difference (P = 0.0011) was evidenced at Week 1 by a similar analysis. Stool form and scores of satisfaction and stigma were improved by elobixibat. Adverse events were as previously reported. CONCLUSIONS: Elobixibat improved the SBM frequency, though the defined primary endpoint was not evidenced. QOL parameters (stool consistency and treatment satisfaction) were also improved. Elobixibat may have therapeutic benefits in PD patients suffering from chronic constipation. TRIAL REGISTRATION INFORMATION: Trial Registration Number: JPRN-jRCTs031200172 (submitted: October 26, 2020; first patient enrolment: December 23, 2020; https://jrct.niph.go.jp/en-latest-detail/jRCTs031200172).

Differential and better response to deep brain stimulation of chorea compared to dystonia in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant and progressive neurodegenerative syndrome characterized by motor, cognitive and psychiatric manifestations. Chorea and dystonia are features that may be troublesome to some patients and may potentially prove unresponsive to pharmacological treatments. There are several reports on the results of globus pallidus internus deep brain stimulation (DBS) surgery for HD. In these published cases, DBS was utilized mainly to treat disabling chorea. We report our experience with 2 HD cases treated with DBS. The cases illustrate a differential response with a better outcome in the choreic presentation compared to the dystonic presentation. Additionally, DBS worsened gait features in both cases.

Taking a better history for behavioral issues pre- and post-deep brain stimulation: issues missed by standardized scales.

OBJECTIVES: To screen for potentially underreported behavioral changes in patients with idiopathic Parkinson's disease (PD) pre- and post-deep brain stimulation (DBS), a retrospective data base review was performed. METHODS: In total, 113 patients who underwent unilateral or bilateral DBS at the University of Florida in either subthalamic nucleus or globus pallidus internus for PD were screened for behavioral issues by asking about the presence or absence of seven neuropsychiatric symptoms (panic, fear, paranoia, anger, suicidal flashes, crying, and laughing). RESULTS: There was a high prevalence of fear (16.3%), panic (14.0%), and anger (11.6%) at baseline in this cohort. In the first six months following DBS implantation, anger (32.6%), fear (26.7%), and uncontrollable crying (26.7%) were the most frequent symptoms reported. Those symptoms also were present following six months of DBS surgery (30.2%, 29.1%, and 19.8%, respectively). New uncontrollable crying occurred more in the acute postoperative stage (less than or equal to six months) (p = 0.033), while new anger occurred more in the chronic postoperative stage (greater than six months) (p = 0.017). The frequency of uncontrollable laughing significantly increased with bilateral DBS (p = 0.033). CONCLUSIONS: Many of the neuropsychiatric issues were identified at preoperative baseline and their overall occurrence was more than expected. There was a potential for worsening of these issues post-DBS. There were subtle differences in time course, and in unilateral vs. bilateral implantations. Clinicians should be aware of these potential behavioral issues that may emerge following DBS therapy, and should consider including screening questions in preoperative and postoperative interviews. Standardized scales may miss the presence or absence of these clinically relevant issues.