Journal of Parkinson's Disease - Volume 12, issue 7

Authors: McCarter, Stuart J. | Savica, Rodolfo

Article Type: Review Article

Abstract: Levodopa-induced dyskinesia (LID), a frequent complication of Parkinson’s disease (PD), occurs in ∼30% of patients after five years’ treatment with levodopa. In atypical parkinsonism, LID occurs less frequently than in PD. Lower frequency of LID in atypical parkinsonism has traditionally been attributed to lower amounts of levodopa used by these patients; however, recent studies have shown lower frequency of LID in atypical parkinsonism compared with PD when adjusting for levodopa dose. The mechanism of LID is complex but requires pulsatile levodopa stimulation, progressive presynaptic dopaminergic degeneration, and a relatively intact postsynaptic dopaminergic system. The globus pallidus internus (GPi), the main …inhibitory nucleus of the basal ganglia, may play a major role in the development and treatment of LID. Surgical lesioning of the posteroventral GPi is directly antidyskinetic; animal models showing GPi-associated striatal neurons are directly responsible for the development of LID. However, other cortical areas, particularly the primary sensory and motor cortices may also play a role in LID. In some cases of atypical parkinsonism, particularly progressive supranuclear palsy and corticobasal degeneration, severe degeneration of the GPi, a so-called “autopallidotomy,” may explain the absence of LID in these patients. In other atypical parkinsonisms, such as PD dementia and dementia with Lewy bodies, the lower incidence of LID may partly be attributed to more striatal degeneration but likely also relates to the degeneration of the motor cortex and resultant network dysfunction. Overall, atypical parkinsonism serves as a natural model that may ultimately reveal more effective therapies for LID. Show more

Keywords: Dyskinesia, Parkinson’s disease, parkinsonism, dementia

DOI: 10.3233/JPD-223491

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2009-2013, 2022

Authors: Kauppila, Linda Azevedo | Ten Holter, Susanne E.M. | van de Warrenburg, Bart | Bloem, Bastiaan R.

Article Type: Review Article

Abstract: Multiple system atrophy (MSA) is a sporadic and progressive neurodegenerative disorder with a complex differential diagnosis. A range of disorders— also of nondegenerative etiology— can mimic MSA, expanding its differential diagnosis. Both misdiagnosis and diagnostic delays are relatively common in clinical practice. A correct diagnosis is vital for daily clinical practice, in order to facilitate proper counselling and to timely install therapies in treatable disorders that mimic MSA. A correct diagnosis is also essential for including properly classified individuals into research studies that aim to better understand the pathophysiology of MSA, to develop specific biomarkers or to evaluate novel symptomatic …or disease-modifying therapies. Here, we offer some practical guidance to support the diagnostic process, by highlighting conditions that may be considered as MSA lookalikes, by emphasizing some key clinical aspects of these mimics, and by discussing several useful ancillary diagnostic tests. Show more

Keywords: Differential diagnosis, mimics, multiple system atrophy, neurodegenerative diseases

DOI: 10.3233/JPD-223392

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2015-2027, 2022

Authors: Schütz, Lukas | Sixel-Döring, Friederike | Hermann, Wiebke

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is defined by its motor symptoms rigidity, tremor, and akinesia. However, non-motor symptoms, particularly autonomic disorders and sleep disturbances, occur frequently in PD causing equivalent or even greater discomfort than motor symptoms effectively decreasing quality of life in patients and caregivers. Most common sleep disturbances in PD are insomnia, sleep disordered breathing, excessive daytime sleepiness, REM sleep behavior disorder, and sleep-related movement disorders such as restless legs syndrome. Despite their high prevalence, therapeutic options in the in- and outpatient setting are limited, partly due to lack of scientific evidence. The importance of sleep disturbances in neurodegenerative diseases …has been further emphasized by recent evidence indicating a bidirectional relationship between neurodegeneration and sleep. A more profound insight into the underlying pathophysiological mechanisms intertwining sleep and neurodegeneration might lead to unique and individually tailored disease modifying or even neuroprotective therapeutic options in the long run. Therefore, current evidence concerning the management of sleep disturbances in PD will be discussed with the aim of providing a substantiated scaffolding for clinical decisions in long-term PD therapy. Show more

Keywords: Sleep disturbances, sleep, Parkinson’s disease, insomnia. excessive daytime sleepiness, rapid eye movement sleep behavior disorder, restless legs syndrome, sleep disordered breathing, sleep apnea, non-motor symptoms

DOI: 10.3233/JPD-212749

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2029-2058, 2022

Authors: Vinke, R. Saman | Geerlings, Martin | Selvaraj, Ashok K. | Georgiev, Dejan | Bloem, Bastiaan R. | Esselink, Rianne A.J. | Bartels, Ronald H.M.A.

Article Type: Research Article

Abstract: Background: STN-DBS is a cornerstone in the treatment of advanced Parkinson’s disease (PD). The traditional approach is to use an awake operative technique with microelectrode recording (MER). However, more centers start using an asleep MRI-guided technique without MER. Objective: We systematically reviewed the literature to compare STN-DBS surgery with and without MER for differences in clinical outcome. Methods: We systematically searched PubMed, Embase, MEDLINE, and Web of Science databases for randomized clinical trials and consecutive cohort studies published between 01-01-2000 and 26-08-2021, that included at least 10 PD patients who had received bilateral STN-DBS. …Results: 2,129 articles were identified. After abstract screening and full-text review, 26 studies were included in the final analysis, comprising a total of 34 study groups (29 MER and 5 non-MER). The standardized mean difference (SMD) in change in motor symptoms between baseline (OFF medication) and 6–24 months follow-up (OFF medication and ON stimulation) was 1.64 for the MER group and 1.87 for non-MER group (p  = 0.59). SMD in change in levodopa equivalent daily dose (LEDD) was 1.14 for the MER group and 0.65 for non-MER group (p  < 0.01). Insufficient data were available for comparative analysis of PDQ-39 and complications. Conclusion: The change in motor symptoms from baseline to follow-up did not differ between studies that used MER and those that did not. The postoperative reduction in LEDD from baseline to follow-up was greater in the MER-group. In the absence of high-quality studies comparing both methods, there is a clear need for a well-designed comparative trial. Show more

Keywords: Deep brain stimulation, microelectrode recording, MRI, subthalamic nucleus, Parkinson’s disease

DOI: 10.3233/JPD-223333

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2059-2069, 2022

Authors: Chaudhuri, K. Ray | Antonini, Angelo | Pahwa, Rajesh | Odin, Per | Titova, Nataliya | Thakkar, Sandeep | Snedecor, Sonya J. | Hegde, Saket | Alobaidi, Ali | Parra, Juan Carlos | Zadikoff, Cindy | Bergmann, Lars | Standaert, David G.

Article Type: Research Article

Abstract: Background: In advanced Parkinson’s disease (PD), dyskinesias and non-motor symptoms such as sleep dysfunction can significantly impair quality of life, and high-quality management is an unmet need. Objective: To analyze changes in dyskinesia and non-motor symptoms (including sleep) among studies with levodopa-carbidopa intestinal gel (LCIG) in patients with advanced PD. Methods: A comprehensive literature review identified relevant studies examining LCIG efficacy. Outcomes of interest were dyskinesia (UDysRS, UPDRS IV item 32), overall non-motor symptoms (NMSS), mentation/behavior/mood (UPDRS I), and sleep/daytime sleepiness (PDSS-2, ESS). The pooled mean (95% confidence interval) change from baseline per outcome was estimated …for each 3-month interval with sufficient data (i.e., reported by≥3 studies) up to 24 months using a random-effects model. Results: Seventeen open-label studies evaluating 1243 patients with advanced PD were included. All outcomes of interest with sufficient data for meta-analysis showed statistically significant improvement within 6 months of starting LCIG. There were statistically significant improvements in dyskinesia duration as measured by UPDRS IV item 32 at 6 months (–1.10 [–1.69, –0.51] h/day) and 12 months (–1.35 [–2.07, –0.62] h/day). There were statistically and clinically significant improvements in non-motor symptoms as measured by NMSS scores at 3 months (–28.71 [–40.26, –17.15] points). Significant reduction of NMSS burden was maintained through 24 months (–17.61 [–21.52, –13.70] points). UPDRS I scores significantly improved at 3 months (–0.39 [–0.55, –0.22] points). Clinically significant improvements in PDSS-2 and ESS scores were observed at 6 and 12 months in individual studies. Conclusion: Patients with advanced PD receiving LCIG showed significant sustained improvements in the burden of dyskinesia and non-motor symptoms up to 24 months after initiation. Show more

Keywords: Parkinson’s disease, carbidopa/levodopa, quality of life, motor symptoms, meta-analysis

DOI: 10.3233/JPD-223295

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2071-2083, 2022

Authors: Hu, Hao | Xiao, Dongsheng | Rhodin, Helge | Murphy, Timothy H.

Article Type: Research Article

Abstract: Human motion analysis has been a common thread across modern and early medicine. While medicine evolves, analysis of movement disorders is mostly based on clinical presentation and trained observers making subjective assessments using clinical rating scales. Currently, the field of computer vision has seen exponential growth and successful medical applications. While this has been the case, neurology, for the most part, has not embraced digital movement analysis. There are many reasons for this including: the limited size of labeled datasets, accuracy and nontransparent nature of neural networks, and potential legal and ethical concerns. We hypothesize that a number of opportunities …are made available by advancements in computer vision that will enable digitization of human form, movements, and will represent them synthetically in 3D. Representing human movements within synthetic body models will potentially pave the way towards objective standardized digital movement disorder diagnosis and building sharable open-source datasets from such processed videos. We provide a hypothesis of this emerging field and describe how clinicians and computer scientists can navigate this new space. Such digital movement capturing methods will be important for both machine learning-based diagnosis and computer vision-aided clinical assessment. It would also supplement face-to-face clinical visits and be used for longitudinal monitoring and remote diagnosis. Show more

Keywords: Artificial intelligence, computer-assisted diagnosis, computer-assisted image processing, neural networks (computer), movement disorders, Parkinson’s disease

DOI: 10.3233/JPD-223351

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2085-2096, 2022

Authors: Wang, Jialing | Yang, Xiaoman | Zeng, Weiqi | Zhang, Xiaoqian | Yang, Xiaomei | Xu, Yu | Liu, Ke | Zhang, Zhaoyuan | Xu, Yan | Cao, Xuebing

Article Type: Research Article

Abstract: Background: Pathological changes in the brain can affect the gastrointestinal tract, whereas there is less evidence regarding the brain-gut axis. Objective: To identify whether cerebral endogenous phosphorylated α -synuclein induces gastrointestinal dysfunction via the brain-gut axis, mediated by the vagus nerve. Methods: α -syn N103/tau N368 preformed fibrils were injected into the dorsal lateral striatum of rodents, and the cerebral and colonic synucleinopathies and changes in the enteric nervous system were analyzed. Moreover, subdiaphragmatic vagotomy was conducted to confirm the role of the vagus nerve in brain-gut propagation. Results: An anterograde propagation of …phosphorylated α -synuclein from the brain to the proximal colon mainly via the vagus nerve was observed at one month. The accumulation of phosphorylated α -synuclein was detected in the proximal colon over time, accompanied by infiltration of macrophages and eosinophils in the mucosa and submucosa. Upon injection with lower doses of preformed fibrils, the accumulation of phosphorylated α -synuclein and dopaminergic neuron loss was reduced to levels consistent with control at six months, while the expression levels of GFAP, Iba-1, and IL-6 increased. Under high preformed fibrils dose conditions, fecal traits and gastrointestinal motility were significantly reduced at six months, and aggregations of phosphorylated α -synuclein and an increasing level of IL-1β appeared. Conclusion: Induced endogenous α -synuclein can quickly propagate into the proximal colon mainly via the vagus nerve. Injections of low doses of preformed fibrils can elicit recovery of the enteric nervous system and degradation of α -synuclein aggregates whereas high doses cause accumulation of pathological α -synuclein, enteric inflammation, and prominent gastrointestinal dysfunction. Show more

Keywords: Parkinson’s disease, enteric nervous system, synucleinopathies, propagation, inflammation

DOI: 10.3233/JPD-223294

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2097-2116, 2022

Authors: Nguyen, Linh Thi Nhat | Nguyen, Huu Dat | Kim, Yun Joong | Nguyen, Tinh Thi | Lai, Thuy Thi | Lee, Yoon Kyoung | Ma, Hyeo-il | Kim, Young Eun

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disease, with two main pathological features: misfolded α-synuclein protein accumulation and neurodegeneration. Inflammation has recently been identified as a contributor to a cascade of events that may aggravate PD pathology. Inflammasomes, a group of intracellular protein complexes, play an important role in innate immune responses to various diseases, including infection. In PD research, accumulating evidence suggests that α-synuclein aggregations may activate inflammasomes, particularly the nucleotide-binding oligomerization domain-leucine-rich repeat-pyrin domain-containing 3 (NLRP3) type, which exacerbates inflammation in the central nervous system by secreting proinflammatory cytokines like interleukin (IL)-18 and IL-1β. Afterward, activated …NLRP3 triggers local microglia and astrocytes to release additional IL-1β. In turn, the activated inflammatory process may contribute to additional α-synuclein aggregation and cell loss. This review summarizes current research evidence on how the NLRP3 inflammasome contributes to PD pathogenesis, as well as potential therapeutic strategies targeting the NLRP3 inflammasome in PD. Show more

Keywords: Parkinson’s disease, inflammasome, NLRP3, α-synuclein, treatment

DOI: 10.3233/JPD-223290

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2117-2133, 2022

Authors: Welton, Thomas | Tan, Yi Jayne | Saffari, Seyed Ehsan | Ng, Samuel Y.E. | Chia, Nicole S.Y. | Yong, Alisa C.W. | Choi, Xinyi | Heng, Dede Liana | Shih, Yao-Chia | Hartono, Septian | Lee, Weiling | Xu, Zheyu | Tay, Kay Yaw | Au, Wing Lok | Tan, Eng-King | Chan, Ling Ling | Ng, Adeline S.L. | Tan, Louis C.S.

Article Type: Research Article

Abstract: Background: Neurofilament light is a marker of axonal degeneration, whose measurement from peripheral blood was recently made possible by new assays. Objective: We aimed to determine whether plasma neurofilament light chain (NfL) concentration reflects brain white matter integrity in patients with early Parkinson’s disease (PD). Methods: 137 early PD patients and 51 healthy controls were included. Plasma NfL levels were measured using ultrasensitive single molecule array. 3T MRI including diffusion tensor imaging was acquired for voxelwise analysis of association between NfL and both fractional anisotropy (FA) and mean diffusivity (MD) in white matter tracts and subcortical …nuclei. Results: A pattern of brain microstructural changes consistent with neurodegeneration was associated with increased plasma NfL in most of the frontal lobe and right internal capsule, with decreased FA and increased MD. The same clusters were also associated with poorer global cognition. A significant cluster in the left putamen was associated with increased NfL, with a significantly greater effect in PD than controls. Conclusion: Plasma NfL may be associated with brain microstructure, as measured using diffusion tensor imaging, in patients with early PD. Higher plasma NfL was associated with a frontal pattern of neurodegeneration that also correlates with cognitive performance in our cohort. This may support a future role for plasma NfL as an accessible biomarker for neurodegeneration and cognitive dysfunction in PD. Show more

Keywords: diffusion MRI, neurodegeneration, neurofilament, Parkinson’s disease, single molecule array, TBSS

DOI: 10.3233/JPD-223414

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2135-2146, 2022

Authors: Dumican, Matthew | Watts, Christopher

Article Type: Research Article

Abstract: Background: Cerebrovascular accident (CVA) and Parkinson’s disease (PD) are well established etiologies of dysphagia. However, differing physiological mechanisms underlying dysphagia may exist between these two causes. There have been limited investigations specifically comparing dysphagia between these two groups. Comparing dysphagia presentation in two different populations may improve clinical expectations, guide treatment approaches, and inform future research. Objective: This study examined the differences in presentation of dysphagia between PD and CVA. Dysphagia presentation, swallow safety, and laryngeal kinematics were compared between two clinical cohorts. What factors best predicted airway invasion in each group were explored. Methods: 110 …swallow studies of individuals with PD and CVA who were referred for swallowing evaluation were obtained. Each video was analyzed for quantitative dysphagia presentation using the Videofluoroscopic Dysphagia Scale (VDS), swallow safety using the Penetration-Aspiration scale, and kinematic timings of the laryngeal vestibule (time-to-laryngeal vestibule closure [LVC] and closure duration [LVCd]). Results: Frequencies of penetration or aspiration were similar between groups. The PD group displayed significantly greater pharyngeal stage swallow impairment than CVA, with more frequent reduced laryngeal elevation and increased vallecular residue. The CVA group displayed significantly greater oral stage impairment, with prolonged oral transit times. Time-to-LVC was significantly prolonged and was the strongest predictor of airway invasion in the PD group, but not for CVA. Conclusion: Similar airway invasion rates for PD and CVA indicate the importance of screening for dysphagia in PD. Laryngeal kinematics as significant contributors to airway invasion in PD but not for CVA highlight the need for further research into these mechanisms and for targeted treatment approaches to dysphagia. Show more

Keywords: Dysphagia, Parkinson’s disease, stroke, swallowing disorders

DOI: 10.3233/JPD-223272

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2147-2159, 2022