Journal of Parkinson's Disease - Volume Pre-press, issue Pre-press

Authors: Sung, Chee Boon | Danoudis, Mary | Paul, Eldho | Iansek, Robert

Article Type: Review Article

Abstract: Background: Tablet formulations of Parkinson’s disease (PD) medications may become ineffective at managing motor fluctuations in advanced PD. The liquid formulation, levodopa carbidopa ascorbic acid solution, or LCAS, is an effective and inexpensive treatment for motor fluctuations however it remains underutilized. Objective: We compared the efficacy of LCAS with tablet formulations and Duodopa jejunal infusion through routine inpatient management using hourly functional status measures, the Timed Up and Go Test (TUG). The TUG differentiates between ‘off’ and ‘on’ states and quantifies motor fluctuations. Methods: Experienced nurses used the TUG times and functional observations recorded hourly throughout …the waking day to optimize the LCAS hourly dose and the Duodopa flow rate over several days. When patients were stabilized on each of the interventions, the TUG measures were then recorded to compare the outcomes of the interventions. Results: Twenty-six participants had TUG times recorded while on one or more of the formulations: 19 had TUG times recorded on tablets, 23 on LCAS and 10 on Duodopa. TUG times on LCAS and Duodopa were significantly faster compared to tablets (p  <  0.0001, p  = 0.001 respectively). Severity of dyskinesia was not significantly different between formulations (p  = 0.35). Daily dose for the three formulations and the hourly doses for LCAS and Duodopa did not differ significantly (p  = 0.37, p  = 0.19 respectively). Conclusion: This report demonstrated the efficacy of LCAS for improving motor complications and its equivalency with Duodopa jejunal infusion. Show more

Keywords: Advanced Parkinson’s disease, Duodopa, inpatient management, liquid sinemet, motor fluctuations, Timed Up and Go test

DOI: 10.3233/JPD-225117

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2023

Authors: Meinders, Marjan J. | Marks Jr. , William J. | van Zundert, Sabine B.M. | Kapur, Ritu | Bloem, Bastiaan R.

Article Type: Letter

DOI: 10.3233/JPD-225015

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2023

Authors: Breit, Sorin | Milosevic, Luka | Naros, Georgios | Cebi, Idil | Weiss, Daniel | Gharabaghi, Alireza

Article Type: Research Article

Abstract: Background: Axial symptoms of Parkinson’s disease (PD) can be debilitating and are often refractory to conventional therapies such as dopamine replacement therapy and deep brain stimulation (DBS) of the subthalamic nuclei (STN). Objective: Evaluate the efficacy of bilateral DBS of the pedunculopontine nucleus area (PPNa) and investigate structural and physiological correlates of clinical response. Methods: A randomized, double-blind, cross-over clinical trial was employed to evaluate the efficacy of bilateral PPNa-DBS on axial symptoms. Lead positions and neuronal activity were evaluated with respect to clinical response. Connectomic cortical activation profiles were generated based on the volumes of …tissue activated. Results: PPNa-DBS modestly improved (p  = 0.057) axial symptoms in the medication-off condition, with greatest positive effects on gait symptoms (p  = 0.027). Electrode placements towards the anterior commissure (ρ= 0.912; p  = 0.011) or foramen caecum (ρ= 0.853; p  = 0.031), near the 50% mark of the ponto-mesencephalic junction, yielded better therapeutic responses. Recording trajectories of patients with better therapeutic responses (i.e., more anterior electrode placements) had neurons with lower firing-rates (p  = 0.003) and higher burst indexes (p  = 0.007). Structural connectomic profiles implicated activation of fibers of the posterior parietal lobule which is involved in orienting behavior and locomotion. Conclusion: Bilateral PPNa-DBS influenced gait symptoms in patients with PD. Anatomical and physiological information may aid in localization of a favorable stimulation target. Show more

Keywords: Deep brain stimulation, Parkinson’s disease, pedunculopontine nucleus

DOI: 10.3233/JPD-225031

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023

Authors: Bosch, Taylor J. | Cole, Rachel C. | Bezchlibnyk, Yarema | Flouty, Oliver | Singh, Arun

Article Type: Research Article

Abstract: Background: Standard high-frequency deep brain stimulation (HF-DBS) at the subthalamic nucleus (STN) is less effective for lower-limb motor dysfunctions in Parkinson’s disease (PD) patients. However, the effects of very low frequency (VLF; 4 Hz)-DBS on lower-limb movement and motor cortical oscillations have not been compared. Objective: To compare the effects of VLF-DBS and HF-DBS at the STN on a lower-limb pedaling motor task and motor cortical oscillations in patients with PD and with and without freezing of gait (FOG). Methods: Thirteen PD patients with bilateral STN-DBS performed a cue-triggered lower-limb pedaling motor task with electroencephalography (EEG) in …OFF-DBS, VLF-DBS (4 Hz), and HF-DBS (120-175 Hz) states. We performed spectral analysis on the preparatory signals and compared GO-cue-triggered theta and movement-related beta oscillations over motor cortical regions across DBS conditions in PD patients and subgroups (PDFOG–and PDFOG+). Results: Both VLF-DBS and HF-DBS decreased the linear speed of the pedaling task in PD, and HF-DBS decreased speed in both PDFOG–and PDFOG+. Preparatory theta and beta activities were increased with both stimulation frequencies. Both DBS frequencies increased motor cortical theta activity during pedaling movement in PD patients, but this increase was only observed in PDFOG + group. Beta activity was not significantly different from OFF-DBS at either frequency regardless of FOG status. Conclusion: Results suggest that VL and HF DBS may induce similar effects on lower-limb kinematics by impairing movement speed and modulating motor cortical oscillations in the lower frequency band. Show more

Keywords: Subthalamic nucleus, deep brain stimulation, EEG, oscillations, pedaling

DOI: 10.3233/JPD-225113

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023

Authors: Williams, Stefan | Wong, David | Alty, Jane E. | Relton, Samuel D.

Article Type: Research Article

Abstract: Background: Bradykinesia is considered the fundamental motor feature of Parkinson’s disease (PD). It is central to diagnosis, monitoring, and research outcomes. However, as a clinical sign determined purely by visual judgement, the reliability of humans to detect and measure bradykinesia remains unclear. Objective: To establish interrater reliability for expert neurologists assessing bradykinesia during the finger tapping test, without cues from additional examination or history. Methods: 21 movement disorder neurologists rated finger tapping bradykinesia, by Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Modified Bradykinesia Rating Scale (MBRS), in 133 videos of hands: 73 from 39 people with …idiopathic PD, 60 from 30 healthy controls. Each neurologist rated 30 randomly-selected videos. 19 neurologists were also asked to judge whether the hand was PD or control. We calculated intraclass correlation coefficients (ICC) for absolute agreement and consistency of MDS-UPDRS ratings, using standard linear and cumulative linked mixed models. Results: There was only moderate agreement for finger tapping MDS-UPDRS between neurologists, ICC 0.53 (standard linear model) and 0.65 (cumulative linked mixed model). Among control videos, 53% were rated >  0 by MDS-UPDRS, and 24% were rated as bradykinesia by MBRS subscore combination. Neurologists correctly identified PD/control status in 70% of videos, without strictly following bradykinesia presence/absence. Conclusion: Even experts show considerable disagreement about the level of bradykinesia on finger tapping, and frequently see bradykinesia in the hands of those without neurological disease. Bradykinesia is to some extent a phenomenon in the eye of the clinician rather than simply the hand of the person with PD. Show more

Keywords: Parkinson’s disease, bradykinesia, finger tapping, interrater reliability, intraclass correlation coefficients, MBRS, MDS-UPDRS

DOI: 10.3233/JPD-223256

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2023

Authors: Kehnemouyi, Yasmine M. | Petrucci, Matthew N. | Wilkins, Kevin B. | Melbourne, Jillian A. | Bronte-Stewart, Helen M.

Article Type: Research Article

Abstract: Background: The sequence effect is the progressive deterioration in speech, limb movement, and gait that leads to an inability to communicate, manipulate objects, or walk without freezing of gait. Many studies have demonstrated a lack of improvement of the sequence effect from dopaminergic medication, however few studies have studied the metric over time or investigated the effect of open-loop deep brain stimulation in people with Parkinson’s disease (PD). Objective: To investigate whether the sequence effect worsens over time and/or is improved on clinical (open-loop) deep brain stimulation (DBS). Methods: Twenty-one people with PD with bilateral subthalamic …nucleus (STN) DBS performed thirty seconds of instrumented repetitive wrist flexion extension and the MDS-UPDRS III off therapy, prior to activation of DBS and every six months for up to three years. A sub-cohort of ten people performed the task during randomized presentations of different intensities of STN DBS. Results: The sequence effect was highly correlated with the overall MDS-UPDRS III score and the bradykinesia sub-score and worsened over three years. Increasing intensities of STN open-loop DBS improved the sequence effect and one subject demonstrated improvement on both open-loop and closed-loop DBS. Conclusion: Sequence effect in limb bradykinesia worsened over time off therapy due to disease progression but improved on open-loop DBS. These results demonstrate that DBS is a useful treatment of the debilitating effects of the sequence effect in limb bradykinesia and upon further investigation closed-loop DBS may offer added improvement. Show more

DOI: 10.3233/JPD-223368

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2023

Authors: Geraedts, Victor J. | van Vugt, Jeroen P.P. | Marinus, Johan | Kuiper, Roy | Middelkoop, Huub A.M. | Zutt, Rodi | van der Gaag, Niels A. | Hoffmann, Carel F.E. | Dorresteijn, Lucille D.A. | van Hilten, Jacobus J. | Contarino, Maria Fiorella

Article Type: Research Article

Abstract: Background: Standardized screening for subthalamic deep brain stimulation (STN DBS) in Parkinson’s disease (PD) patients is crucial to determine eligibility, but its utility to predict postoperative outcomes in eligible patients is inconclusive. It is unknown whether wearable data can contribute to this aim. Objective: To evaluate the utility of universal components incorporated in the DBS screening, complemented by a wearable sensor, to predict motor outcomes and Quality of life (QoL) one year after STN DBS surgery. Methods: Consecutive patients were included in the OPTIMIST cohort study from two DBS centers. Standardized assessments included a preoperative Levodopa …Challenge Test (LCT), and questionnaires on QoL and non-motor symptoms including cognition, psychiatric symptoms, impulsiveness, autonomic symptoms, and sleeping problems. Moreover, an ambulatory wearable sensor (Parkinson Kinetigraph (PKG)) was used. Postoperative assessments were similar and also included a Stimulation Challenge Test to determine DBS effects on motor function. Results: Eighty-three patients were included (median (interquartile range) age 63 (56–68) years, 36% female). Med-OFF (Stim-OFF) motor severity deteriorated indicating disease progression, but patients significantly improved in terms of Med-ON (Stim-ON) motor function, motor fluctuations, QoL, and most non-motor domains. Motor outcomes were not predicted by preoperative tests, including covariates of either LCT or PKG. Postoperative QoL was predicted by better preoperative QoL, lower age, and more preoperative impulsiveness scores in multivariate models. Conclusion: Data from the DBS screening including wearable data do not predict postoperative motor outcome at one year. Post-DBS QoL appears primarily driven by non-motor symptoms, rather than by motor improvement. Show more

Keywords: Deep brain stimulation, subthalamic nucleus, Parkinson’s disease, motor function, quality of life, screening

DOI: 10.3233/JPD-225101

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023

Authors: Zhang, Xuan | Ma, Li | Liang, Danqi | Song, Bingxin | Chen, Jingshan | Huang, Yaqin | Xu, Lin | Zhao, Peng | Wu, Wei | Zhang, Nan | Xue, Rong

Article Type: Research Article

Abstract: Background: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is increasingly recognized as a manifestation preceding the α-synucleinopathies like Parkinson’s disease (PD). Neurofilament light chain (NfL) have been reported to be higher in synucleinopathies as a sign of neurodegeneration. Objective: To evaluate whether plasma NfL is valuable in reflecting cognitive and motor status in iRBD and PD with a premorbid history of RBD (PDRBD), and predicting disease progression in iRBD. Methods: Thirty-one patients with iRBD, 30 with PDRBD, and 18 healthy controls were included in the cross-sectional and prospective study. Another cohort from the Parkinson’s Progression …Markers Initiative (PPMI) dataset was enrolled for verification analysis. All patients received evaluations of cognitive, motor, and autonomic function by a battery of clinical tests at baseline and follow-up. Blood NfL was measured by the Quanterix Simoa HD-1. Results: In our cohort, 26 patients with iRBD completed the follow-up evaluations, among whom eight (30.8%) patients displayed phenoconversion. Baseline plasma NfL cutoff value of 22.93 pg/mL performed best in distinguishing the iRBD converters from non-converters (sensitivity: 75.0%, specificity: 83.3%, area under the curve: 0.84). Cognitive and motor function were significantly correlated with NfL levels in PDRBD (correlation coefficients: –0.379, 0.399; respectively). Higher baseline NfL levels in iRBD were significantly associated with higher risks for cognitive, motor, autonomic function progression, and phenoconversion at follow-up (hazard ratios: 1.069, 1.065, 1.170, 1.065; respectively). The findings were supported by the PPMI dataset. Conclusion: Plasma NfL is valuable in reflecting disease severity of PDRBD and predicting disease progression and phenoconversion in iRBD. Show more

Keywords: Idiopathic REM sleep behavior disorder, Parkinson’s disease, plasma neurofilament light, single molecule array (Simoa) technique, disease progression

DOI: 10.3233/JPD-223519

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023

Authors: Domingos, Josefa | Teixeira Bastos, Maria do Carmo | Couto, Rui | Cameira, Ana Rita | Cardoso, Ana Leal | Reffóios, Alexandre | Magalhães, Susana | Massano, João | Outeiro, Tiago Fleming

Article Type: Article Commentary

Abstract: Patient organizations play an ever-growing role in modern societies by providing organized resources for patients and care partners. Importantly, patient organizations enable patients to define and share their needs and views. In Parkinson’s disease (PD), patient organizations play significant roles in different countries. However, there is limited support and resources tailored for people with early onset Parkinson’s disease (EOPD). These individuals face unique social, professional, and personal challenges that are often not accounted for by general PD organizations, which play very important roles for a significant proportion of individuals with PD. In Portugal, this was the situation until 2022, when …Young Parkies Portugal (YPP) was founded to allow people with EOPD and various stakeholders to join forces to cover their specific needs. In this manuscript, we aim to share our experience in building an association for people with EOPD, reflecting on the reasons for this need, the activities developed thus far, challenges in implementation, and future directions. In summary, we believe that nonprofit organizations like YPP play an essential role in shaping the care and support of people with PD care and should be considered key partners of care alongside the larger multidisciplinary team. We are confident that sharing our experience can inspire and guide the implementation of similar initiatives in other countries. Show more

Keywords: Parkinson’s disease, early-onset, neurodegeneration, parkinsonism, patient association

DOI: 10.3233/JPD-230039

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2023

Authors: Wang, Shu | Zhu, Guanyu | Shi, Lin | Zhang, Chunkui | Wu, Bing | Yang, Anchao | Meng, Fangang | Jiang, Yin | Zhang, Jianguo

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is a neurodegenerative disease with a heavy burden on patients, families, and society. Deep brain stimulation (DBS) can improve the symptoms of PD patients for whom medication is insufficient. However, current open-loop uninterrupted conventional DBS (cDBS) has inherent limitations, such as adverse effects, rapid battery consumption, and a need for frequent parameter adjustment. To overcome these shortcomings, adaptive DBS (aDBS) was proposed to provide responsive optimized stimulation for PD. This topic has attracted scientific interest, and a growing body of preclinical and clinical evidence has shown its benefits. However, both achievements and challenges have emerged in this …novel field. To date, only limited reviews comprehensively analyzed the full framework and procedures for aDBS implementation. Herein, we review current preclinical and clinical data on aDBS for PD to discuss the full procedures for its achievement and to provide future perspectives on this treatment. Show more

Keywords: Deep brain stimulation, neuromodulation, Parkinson’s disease, adaptive, closed-loop

DOI: 10.3233/JPD-225053

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2023

Authors: Martinez-Nunez, Alfonso E. | LeWitt, Peter A.

Article Type: Review Article

Abstract: Patients with Parkinson’s disease often suffer from OFF symptoms disrupting their daily routines and adding to disabilities. Despite polypharmacy and adjustments to medication schedules, they often do not experience consistent relief from their motor symptoms. As the disease progresses, impaired gastric emptying may evolve, making it even more challenging for dopaminergic drugs to provide consistent results. This review focuses on a group of drugs that have the pharmacokinetic advantage of a much earlier onset of action by virtue of their non-oral routes of absorption. We compare the current marketed options: subcutaneous apomorphine, sublingual apomorphine, and inhaled levodopa. Subcutaneous apomorphine is …the speediest to take effect, whereas sublingual apomorphine offers the longest clinical effect. Inhaled levodopa has the most favorable side effect profile among the three options. An inhaled form of apomorphine is currently under development, having passed safety and efficacy studies. Each of these drugs has unique characteristics for the user, including different side effect profiles and onset of action. The best choice for a patient will depend on individual needs and circumstances. In this review, we explore those nuances to allow clinicians to select the best option for their patients. Show more

Keywords: Parkinson’s disease, dopaminergic drugs, apomorphine, levodopa

DOI: 10.3233/JPD-230055

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023

Authors: Mammen, Jennifer R. | Speck, Rebecca M. | Stebbins, Glenn M. | Müller, Martijn L.T.M. | Yang, Phillip T. | Campbell, Michelle | Cosman, Josh | Crawford, John E. | Dam, Tien | Hellsten, Johan | Jensen-Roberts, Stella | Kostrzebski, Melissa | Simuni, Tanya | Barowicz, Kimberly Ward | Cedarbaum, Jesse M. | Dorsey, E. Ray | Stephenson, Diane | Adams, Jamie L.

Article Type: Research Article

Abstract: Background: Adoption of new digital measures for clinical trials and practice has been hindered by lack of actionable qualitative data demonstrating relevance of these metrics to people with Parkinson’s disease. Objective: This study evaluated of relevance of WATCH-PD digital measures to meaningful symptoms and impacts of early Parkinson’s disease from the patient perspective. Methods: Participants with early Parkinson’s disease (N = 40) completed surveys and 1:1 online-interviews. Interviews combined: 1) symptom mapping to delineate meaningful symptoms/impacts of disease, 2) cognitive interviewing to assess content validity of digital measures, and 3) mapping of digital measures back to personal symptoms …to assess relevance from the patient perspective. Content analysis and descriptive techniques were used to analyze data. Results: Participants perceived mapping as deeply engaging, with 39/40 reporting improved ability to communicate important symptoms and relevance of measures. Most measures (9/10) were rated relevant by both cognitive interviewing (70–92.5%) and mapping (80–100%). Two measures related to actively bothersome symptoms for more than 80% of participants (Tremor, Shape rotation). Tasks were generally deemed relevant if they met three participant context criteria: 1) understanding what the task measured, 2) believing it targeted an important symptom of PD (past, present, or future), and 3) believing the task was a good test of that important symptom. Participants did not require that a task relate to active symptoms or “real” life to be relevant. Conclusion: Digital measures of tremor and hand dexterity were rated most relevant in early PD. Use of mapping enabled precise quantification of qualitative data for more rigorous evaluation of new measures. Show more

Keywords: Parkinson’s disease, digital health technology, qualitative, meaningfulness, patient experience data

DOI: 10.3233/JPD-225122

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2023

Authors: Mammen, Jennifer R. | Speck, Rebecca M. | Stebbins, Glenn T. | Müller, Martijn L.T.M. | Yang, Phillip T. | Campbell, Michelle | Cosman, Josh | Crawford, John E. | Dam, Tien | Hellsten, Johan | Jensen-Roberts, Stella | Kostrzebski, Melissa | Simuni, Tanya | Barowicz, Kimberly Ward | Cedarbaum, Jesse M. | Dorsey, E. Ray | Stephenson, Diane | Adams, Jamie L.

Article Type: Research Article

Abstract: Background: Patient perspectives on meaningful symptoms and impacts in early Parkinson’s disease (PD) are lacking and are urgently needed to clarify priority areas for monitoring, management, and new therapies. Objective: To examine experiences of people with early-stage PD, systematically describe meaningful symptoms and impacts, and determine which are most bothersome or important. Methods: Forty adults with early PD who participated in a study evaluating smartwatch and smartphone digital measures (WATCH-PD study) completed online interviews with symptom mapping to hierarchically delineate symptoms and impacts of disease from “Most bothersome” to “Not present,” and to identify which of …these were viewed as most important and why. Individual symptom maps were coded for types, frequencies, and bothersomeness of symptoms and their impacts, with thematic analysis of narratives to explore perceptions. Results: The three most bothersome and important symptoms were tremor, fine motor difficulties, and slow movements. Symptoms had the greatest impact on sleep, job functioning, exercise, communication, relationships, and self-concept— commonly expressed as a sense of being limited by PD. Thematically, most bothersome symptoms were those that were personally limiting with broadest negative impact on well-being and activities. However, symptoms could be important to patients even when not present or limiting (e.g., speech, cognition). Conclusion: Meaningful symptoms of early PD can include symptoms that are present or anticipated future symptoms that are important to the individual. Systematic assessment of meaningful symptoms should aim to assess the extent to which symptoms are personally important , present , bothersome, and limiting Show more

Keywords: Parkinson’s disease, digital health technology, qualitative, meaningfulness

DOI: 10.3233/JPD-225068

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023

Authors: Hou, Xiangqing | Wong, Garry

Article Type: Research Article

Abstract: Background: Few efficient and simple models for the early prediction of Parkinson’s disease (PD) exists. Objective: To develop and validate a novel nomogram for early identification of PD by incorporating microRNA (miRNA) expression profiles and clinical indicators. Methods: Expression levels of blood-based miRNAs and clinical variables from 1,284 individuals were downloaded from the Parkinson’s Progression Marker Initiative database on June 1, 2022. Initially, the generalized estimating equation was used to screen candidate biomarkers of PD progression in the discovery phase. Then, the elastic net model was utilized for variable selection and a logistics regression model was …constructed to establish a nomogram. Additionally, the receiver operating characteristic (ROC) curves, decision curve analysis (DCA), and calibration curves were utilized to evaluate the performance of the nomogram. Results: An accurate and externally validated nomogram was constructed for predicting prodromal and early PD. The nomogram is easy to utilize in a clinical setting since it consists of age, gender, education level, and transcriptional score (calculated by 10 miRNA profiles). Compared with the independent clinical model or 10 miRNA panel separately, the nomogram was reliable and satisfactory because the area under the ROC curve achieved 0.72 (95% confidence interval, 0.68-0.77) and obtained a superior clinical net benefit in DCA based on external datasets. Moreover, calibration curves also revealed its excellent prediction power. Conclusion: The constructed nomogram has potential for large-scale early screening of PD based upon its utility and precision. Show more

Keywords: Clinical variables, decision curve analysis, early prediction, microRNA profiles, nomogram, Parkinson’s disease

DOI: 10.3233/JPD-225080

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2023

Authors: Brown, Eric L. | Essigmann, Heather T. | Hoffman, Kristi L. | Alexander, Ashley | Newmark, Michael | Jiang, Zhi-Dong | Ocampo, Jessika S. | Schiess, Mya C. | Hanis, Craig L. | DuPont, Herbert L.

Article Type: Research Article

Abstract: Background: Parkinson’s disease is a heterogeneous neurodegenerative disorder with distinctive gut microbiome patterns suggesting that interventions targeting the gut microbiota may prevent, slow, or reverse disease progression and severity. Objective: Because secretory IgA (SIgA) plays a key role in shaping the gut microbiota, characterization of the IgA-Biome of individuals classified into either the akinetic rigid (AR) or tremor dominant (TD) Parkinson’s disease clinical subtypes was used to further define taxa unique to these distinct clinical phenotypes. Methods: Flow cytometry was used to separate IgA-coated and -uncoated bacteria from stool samples obtained from AR and TD patients …followed by amplification and sequencing of the V4 region of the 16 S rDNA gene on the MiSeq platform (Illumina). Results: IgA-Biome analyses identified significant alpha and beta diversity differences between the Parkinson’s disease phenotypes and the Firmicutes/Bacteroides ratio was significantly higher in those with TD compared to those with AR. In addition, discriminant taxa analyses identified a more pro-inflammatory bacterial profile in the IgA + fraction of those with the AR clinical subclass compared to IgA-Biome analyses of those with the TD subclass and with the taxa identified in the unsorted control samples. Conclusion: IgA-Biome analyses underscores the importance of the host immune response in shaping the gut microbiome potentially affecting disease progression and presentation. In the present study, IgA-Biome analysis identified unique proinflammatory microbial signature in the IgA + fraction of those with AR that would have otherwise been undetected using conventional microbiome analysis approaches. Show more

Keywords: 16S RNA gene sequencing, IgA-Biome, microbiome, Parkinson’s disease, Parkinson’s disease clinical subtypes, secretory IgA

DOI: 10.3233/JPD-230066

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2023

Authors: Fedorova, Tatyana Dmitrievna | Knudsen, Karoline | Horsager, Jacob | Hansen, Allan K. | Okkels, Niels | Gottrup, Hanne | Vang, Kim | Borghammer, Per

Article Type: Research Article

Abstract: Background: The α -syn Origin site and Connectome model (SOC) proposes that α -synucleinopathies can be divided into two categories: the asymmetrical brain-first, and more symmetrical body-first Lewy body disease. We have hypothesized that most patients with dementia with Lewy bodies (DLB) belong to the body-first subtype, whereas patients with Parkinson’s disease (PD) more often belong to the brain-first subtype. Objective: To compare asymmetry of striatal dopaminergic dysfunction in DLB and PD patients using [18 F]-FE-PE2I positron emission tomography (PET). Methods: We analyzed [18 F]-FE-PE2I PET data from 29 DLB patients and …76 PD patients who were identified retrospectively during a 5-year period at Dept. of Neurology, Aarhus University Hospital. Additionally, imaging data from 34 healthy controls was used for age-correction and visual comparison. Results: PD patients showed significantly more asymmetry in specific binding ratios between the most and least affected putamen (p  < 0.0001) and caudate (p  = 0.003) compared to DLB patients. PD patients also had more severe degeneration in the putamen compared to the caudate in comparison to DLB patients (p  < 0.0001) who had a more universal pattern of striatal degeneration. Conclusion: Patients with DLB show significantly more symmetric striatal degeneration on average compared to PD patients. These results support the hypothesis that DLB patients may be more likely to conform to the body-first subtype characterized by a symmetrical spread of pathology, whereas PD patients may be more likely to conform to the brain-first subtype with more lateralized initial propagation of pathology. Show more

Keywords: Parkinson’s disease, Lewy body disease, lewy body dementia, positron emission tomography computed tomography, dopaminergic imaging

DOI: 10.3233/JPD-230001

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2023

Authors: Li, Hui | Jia, Xuejia | Chen, Min | Jia, Xiuqin | Yang, Qi

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) varies in occurrence, presentation, and severity between males and females. However, the sex effects on the patterns of brain structure, cross-sectionally and longitudinally, are still unclear. Objective: We aimed to compare sex differences in brain features cross-sectionally and longitudinally using grey matter volume (GMV) and cortical thickness in a large sample of newly diagnosed drug-naive PD patients. Methods: Cognitive assessments and structural MR images of 262 PD patients (171 males) and 113 healthy controls (68 males) were selected from the Parkinson Progression Markers Initiative. Of these, 97 PD patients (66 males) completed …12- and 24-month follow-up examinations. After regressing out the expected effects of age and sex, brain maps of GMV and cortical thickness were compared using two-sample t tests cross-sectionally and were compared using repeated measurement analyses of variance longitudinally. Results: At baseline, male PD patients exhibited a greater extent of brain atrophy and cortical thickness reduction than females, which mainly occurred in the cerebellum, frontal lobe, parietal lobe, and temporal lobe. At follow-up, female and male PD patients showed similar dynamics of disease progression, as both groups declined over time while the females maintained the advantage. The cortical thickness of the right precentral gyrus at baseline was negatively associated with the longitudinal changes of motor function in male PD patients. Conclusion: The current findings might demonstrate sex effect in neuroanatomy during the course of PD, provide new insights into the neurodegenerative process, and facilitate the development of more effective sex-specific therapeutic strategies. Show more

Keywords: Parkinson’s disease, sex differences, structural MRI, cross-sectional, longitudinal

DOI: 10.3233/JPD-225125

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023

Authors: Ineichen, Christian | Vogel-Baumann, Heide | Sitzler, Matthias | Deuschl, Günther | Baumann, Christian R.

Article Type: Article Commentary

Abstract: In a retrospective analysis, we recently reported findings on the detrimental motor effects of interrupted physiotherapy following the COVID-19 pandemic in parkinsonian patients. Using an extended follow-up period, we investigated the beneficial effect of reinstated physiotherapy on patients’ disease severity and reversal of interruption-induced motor deterioration. Compared to before the COVID-19 outbreak, we observed persistence of motor disease worsening despite full resumption of state-of-the-art physical therapy suggesting that motor deterioration after discontinuation of physical therapy could not be compensated for. Therefore, and considering possible future crises, establishing means to safeguard continuation of physical therapy and to foster remote provision of …care should be major goals. Show more

Keywords: Parkinson’s disease, COVID-19, confinement, motor disease severity, MDS-UPDRS part III

DOI: 10.3233/JPD-230061

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2023

Authors: Albano, Luigi | Agosta, Federica | Basaia, Silvia | Cividini, Camilla | Stojkovic, Tanja | Sarasso, Elisabetta | Stankovic, Iva | Tomic, Aleksandra | Markovic, Vladana | Canu, Elisa | Stefanova, Elka | Mortini, Pietro | Kostic, Vladimir S. | Filippi, Massimo

Article Type: Research Article

Abstract: Background: The hypothesis that the effectiveness of deep brain stimulation (DBS) in Parkinson’s disease (PD) would be related to connectivity dysfunctions between the site of stimulation and other brain regions is growing. Objective: To investigate how the subthalamic nucleus (STN), the most frequently used DBS target for PD, is functionally linked to other brain regions in PD patients according to DBS eligibility. Methods: Clinical data and resting-state functional MRI were acquired from 60 PD patients and 60 age- and sex-matched healthy subjects within an ongoing longitudinal project. PD patients were divided into 19 patients eligible for …DBS and 41 not candidates. Bilateral STN were selected as regions of interest and a seed-based functional MRI connectivity analysis was performed. Results: A decreased functional connectivity between STN and sensorimotor cortex in both PD patient groups compared to controls was found. Whereas an increased functional connectivity between STN and thalamus was found in PD patient groups relative to controls. Candidates for DBS showed a decreased functional connectivity between bilateral STN and bilateral sensorimotor areas relative to non-candidates. In patients eligible for DBS, a weaker STN functional connectivity with left supramarginal and angular gyri was related with a more severe rigidity and bradykinesia whereas a higher connectivity between STN and cerebellum/pons was related to poorer tremor score. Conclusion: Our results suggest that functional connectivity of STN varies among PD patients eligible or not for DBS. Future studies would confirm whether DBS modulates and restores functional connectivity between STN and sensorimotor areas in treated patients. Show more

Keywords: Parkinson’s disease, functional connectivity, deep brain stimulation, subthalamic nucleus

DOI: 10.3233/JPD-230005

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2023

Authors: Gelain, Daniel Pens | Bittencourt, Reykla Ramon | Bastos Mendes, Luiz Felipe | Moreira, José Claudio Fonseca | Outeiro, Tiago Fleming

Article Type: Review Article

Abstract: Oligomerization and aggregation of misfolded forms of α -synuclein are believed to be key molecular mechanisms in Parkinson’s disease (PD) and other synucleinopathies, so extensive research has attempted to understand these processes. Among diverse post-translational modifications that impact α -synuclein aggregation, glycation may take place at several lysine sites and modify α -synuclein oligomerization, toxicity, and clearance. The receptor for advanced glycation end products (RAGE) is considered a key regulator of chronic neuroinflammation through microglial activation in response to advanced glycation end-products, such as carboxy-ethyl-lysine, or carboxy-methyl-lysine. The presence of RAGE in the midbrain of PD patients has been reported …in the last decades and this receptor was proposed to have a role in sustaining PD neuroinflammation. However, different PD animal models demonstrated that RAGE is preferentially expressed in neurons and astrocytes, while recent evidence demonstrated that fibrillar, non-glycated α -synuclein binds to RAGE. Here, we summarize the available data on α -synuclein glycation and RAGE in the context of PD, and discuss about the questions yet to be answered that may increase our understanding of the molecular bases of PD and synucleinopathies. Show more

Keywords: α-synuclein, glycation, Parkinson’s disease, RAGE, synucleinopathies

DOI: 10.3233/JPD-230070

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2023

Authors: McFarthing, Kevin | Buff, Sue | Rafaloff, Gary | Fiske, Brian | Mursaleen, Leah | Fuest, Rosie | Wyse, Richard K. | Stott, Simon R.W.

Article Type: Other

Abstract: Background: Since 2020, annual reports on the clinical development of new drug-based therapies for the neurodegenerative condition of Parkinson’s disease (PD) have been generated. These reviews have followed the progress of both “symptomatic treatments” (ST – improves/reduces symptoms of the condition) and “disease modifying treatments” (DMT - attempts to delay/slow progression by addressing the underlying biology of PD). Additional efforts have been made to further categorize these experimental treatments based on their mechanisms of action and class of drug. Methods: A dataset of clinical trials for drug therapies in PD was obtained using trial data downloaded from the …ClinicalTrials.gov online registry. A breakdown analysis of all the studies that were active as of January 31st, 2023, was conducted. Results: There was a total of 139 clinical trials registered on the ClinicalTrials.gov website as active (with 35 trials newly registered since our last report). Of these trials, 76 (55%) were considered ST and 63 (45%) were designated DMT. Similar to previous years, approximately a third of the studies were in Phase 1 (n  = 47; 34%), half (n  = 72, 52%) were in Phase 2 and there were 20 (14%) studies in Phase 3. Novel therapies again represented the most dominant group of experimental treatments in this year’s report with 58 (42%) trials testing new agents. Repurposed drugs are present in a third (n  = 49, 35%) of trials, with reformulations and new claims representing 19% and 4% of studies, respectively. Conclusions: Our fourth annual review of active clinical trials evaluating ST and DMT therapeutics for PD demonstrates that the drug development pipeline is dynamic and evolving. The slow progress and lack of agents transitioning from Phase 2 to Phase 3 is concerning, but collective efforts by various stakeholders are being made to accelerate the clinical trial process, with the aim of bringing new therapies to the PD community sooner. Show more

Keywords: Clinical trials, studies, Parkinson’s, disease modification, neuroprotection, immunotherapy, inflammation, gene therapy

DOI: 10.3233/JPD-239901

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2023

Authors: Chaudhuri, K. Ray | Kovács, Norbert | Pontieri, Francesco E. | Aldred, Jason | Bourgeois, Paul | Davis, Thomas L. | Cubo, Esther | Anca-Herschkovitsch, Marieta | Iansek, Robert | Siddiqui, Mustafa S. | Simu, Mihaela | Bergmann, Lars | Ballina, Mayra | Kukreja, Pavnit | Ladhani, Omar | Jia, Jia | Standaert, David G.

Article Type: Research Article

Abstract: Background: Levodopa-carbidopa intestinal gel (LCIG) improves motor and non-motor symptoms in patients with advanced Parkinson’s disease (aPD). Objective: To present the final 36-month efficacy and safety results from DUOGLOBE (DUOdopa/Duopa in Patients with Advanced Parkinson’s Disease – a GLobal OBservational Study Evaluating Long-Term Effectiveness; NCT02611713). Methods: DUOGLOBE was an international, prospective, long-term, real-world, observational study of patients with aPD initiating LCIG in routine clinical care. The primary endpoint was change in patient-reported “Off” time to Month 36. Safety was assessed by monitoring serious adverse events (SAEs). Results: Significant improvements in “Off” time were maintained …over 3 years (mean [SD]: –3.3 hours [3.7]; p  < 0.001). There were significant improvements to Month 36 in total scores of the Unified Dyskinesia Rating Scale (–5.9 [23.7]; p  = 0.044), Non-Motor Symptoms Scale (–14.3 [40.5]; p  = 0.002), Parkinson’s Disease Sleep Scale-2 (–5.8 [12.9]; p  < 0.001), and Epworth Sleepiness Scale (–1.8 [6.0]; p  = 0.008). Health-related quality of life and caregiver burden significantly improved through Months 24 and 30, respectively (Month 24, 8-item Parkinson’s Disease Questionnaire Summary Index, –6.0 [22.5]; p  = 0.006; Month 30 Modified Caregiver Strain Index, –2.3 [7.6]; p  = 0.026). Safety was consistent with the well-established LCIG profile (SAEs: 54.9% of patients; discontinuations: 54.4%; discontinuations due to an adverse event: 27.2%). Of 106 study discontinuations, 32 patients (30.2%) continued LCIG outside the study. Conclusion: DUOGLOBE demonstrates real-world, long-term, reductions in motor and non-motor symptoms in patients with aPD treated with LCIG. Show more

Keywords: DUOGLOBE, Parkinson’s disease, levodopa-carbidopa intestinal gel, dyskinesia, real-world data

DOI: 10.3233/JPD-225105

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2023