Journal of Parkinson's Disease - Volume 13, issue 4

Authors: McFarthing, Kevin | Buff, Susan | 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. 13, no. 4, pp. 427-439, 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. 13, no. 4, pp. 441-451, 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. 13, no. 4, pp. 453-471, 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. 13, no. 4, pp. 473-484, 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. 13, no. 4, pp. 485-499, 2023

Authors: Brown, Eric L. | Essigmann, Heather T. | Hoffman, Kristi L. | Alexander, Ashley S. | Newmark, Michael | Jiang, Zhi-Dong | Suescun, Jessika | 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 analyses identified a 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. 13, no. 4, pp. 501-513, 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. 13, no. 4, pp. 515-523, 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. 13, no. 4, pp. 525-536, 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. 13, no. 4, pp. 537-548, 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 the 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. 13, no. 4, pp. 549-561, 2023