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

Authors: Heijmans, Margot | Wolters, Amée F. | Temel, Yasin | Kuijf, Mark L. | Michielse, Stijn

Article Type: Research Article

Abstract: Background: MRI is a valuable method to assist in the diagnostic work-up of Parkinson’s disease (PD). The olfactory tract (OT) has been proposed as a potential MRI biomarker for distinguishing PD patients from healthy controls. Objective: This study aims to further investigate whether diffusion measures of the OT differ between early stage PD patients and healthy controls. Methods: Twenty hyposmic/anosmic PD patients, 65 normosmic PD patients, and 36 normosmic healthy controls were evaluated and a 7T diffusion weighted image scan was acquired. Manual seed regions of interest were drawn in the OT region. Tractography of the …OT was performed using a deterministic streamlines algorithm. Diffusion measures (fractional anisotropy and mean- radial- and axial diffusivity) of the generated streamlines were compared between groups. Results: Diffusion measures did not differ between PD patients compared to healthy controls and between hyposmic/anosmic PD patients, normosmic PD patients, and normosmic healthy controls. A positive correlation was found between age and mean- and axial diffusivity within the hyposmic/anosmic PD subgroup, but not in the normosmic groups. A positive correlation was found between MDS-UPDRSIII scores and fractional anisotropy. Conclusion: This study showed that fiber tracking of the OT was feasible in both early stage PD and healthy controls using 7T diffusion weighted imaging data. However, 7T MRI diffusion measures of the OT are not useful as an early clinical biomarker for PD. Future work is needed to clarify the role of other OT measurements as a biomarker for PD and its different subgroups. Show more

Keywords: Parkinson’s disease, olfactory tract, diffusion weighted imaging, tractography, biomarker, ultra-high field imaging

DOI: 10.3233/JPD-223349

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2161-2170, 2022

Authors: Verschuur, Constant V.M. | Suwijn, Sven R. | de Haan, Rob J. | Boel, Judith A. | Post, Bart | Bloem, Bas R. | van Hilten, Johannes J. | van Laar, Teus | Tissingh, Gerrit | Munts, Alexander | Dijkgraaf, Marcel G.W. | de Bie, Rob M.A.

Article Type: Research Article

Abstract: Background: In the Levodopa in EArly Parkinson’s disease (LEAP) study, 445 patients were randomized to levodopa/carbidopa 100/25 mg three times per day for 80 weeks (early-start) or placebo for 40 weeks followed by levodopa/carbidopa 100/25 mg three times per day for 40 weeks (delayed-start). Objective: This paper reports the results of the economic evaluation performed alongside the LEAP-study. Methods: Early-start treatment was evaluated versus delayed-start treatment, in which the cost-effectiveness analysis (CEA) and the cost-utility analysis (CUA) were performed from the societal perspective, including health care costs among providers, non-reimbursable out-of-pocket expenses of patients, employer costs of sick …leave, and lowered productivity while at work. The outcome measure for the CEA was the extra cost per unit decrease on the Unified Parkinson’s Disease Rating Scale 80 weeks after baseline. The outcome measure for the CUA was the extra costs per additional quality adjusted life year (QALY) during follow-up. Results: 212 patients in the early-start and 219 patients in the delayed-start group reported use of health care resources. With savings of € 59 per patient (BCa 95% CI: –829, 788) in the early-start compared to the delayed-start group, societal costs were balanced. The early-start group showed a mean of 1.30 QALYs (BCa 95% CI: 1.26, 1.33) versus 1.30 QALYs (BCa 95% CI: 1.27, 1.33) for the delayed-start group. Because of this negligible difference, incremental cost-effectiveness and cost-utility ratios were not calculated. Conclusion: From an economic point of view, this study suggests that early treatment with levodopa is not more expensive than delayed treatment with levodopa. Show more

Keywords: Parkinson’s disease, levodopa, cost analysis

DOI: 10.3233/JPD-223247

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2171-2178, 2022

Authors: Betrouni, Nacim | Moreau, Caroline | Rolland, Anne-Sophie | Carrière, Nicolas | Viard, Romain | Lopes, Renaud | Kuchcinski, Gregory | Eusebio, Alexandre | Thobois, Stephane | Hainque, Elodie | Hubsch, Cecile | Rascol, Olivier | Brefel, Christine | Drapier, Sophie | Giordana, Caroline | Durif, Franck | Maltête, David | Guehl, Dominique | Hopes, Lucie | Rouaud, Tiphaine | Jarraya, Bechir | Benatru, Isabelle | Tranchant, Christine | Tir, Melissa | Chupin, Marie | Bardinet, Eric | Defebvre, Luc | Corvol, Jean-Christophe | Devos, David

Article Type: Research Article

Abstract: Background: Dopamine responsiveness (dopa-sensitivity) is an important parameter in the management of patients with Parkinson’s disease (PD). For quantification of this parameter, patients undergo a challenge test with acute Levodopa administration after drug withdrawal, which may lead to patient discomfort and use of significant resources. Objective: Our objective was to develop a predictive model combining clinical scores and imaging. Methods: 350 patients, recruited by 13 specialist French centers and considered for deep brain stimulation, underwent an acute L-dopa challenge (dopa-sensitivity > 30%), full assessment, and MRI investigations, including T1w and R2* images. Data were randomly divided into a …learning base from 10 centers and data from the remaining centers for testing. A machine selection approach was applied to choose the optimal variables and these were then used in regression modeling. Complexity of the modelling was incremental, while the first model considered only clinical variables, the subsequent included imaging features. The performances were evaluated by comparing the estimated values and actual values Results: Whatever the model, the variables age, sex, disease duration, and motor scores were selected as contributors. The first model used them and the coefficients of determination (R2 ) was 0.60 for the testing set and 0.69 in the learning set (p  < 0.001). The models that added imaging features enhanced the performances: with T1w (R2  = 0.65 and 0.76, p  < 0.001) and with R2* (R2  = 0.60 and 0.72, p  < 0.001). Conclusion: These results suggest that modeling is potentially a simple way to estimate dopa-sensitivity, but requires confirmation in a larger population, including patients with dopa-sensitivity < 30% Show more

Keywords: Dopamine, dopa-sensitivity, prediction modelling, MRI

DOI: 10.3233/JPD-223334

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2179-2190, 2022

Authors: Jahanshahi, Marjan | Leimbach, Friederike | Rawji, Vishal

Article Type: Research Article

Abstract: Background: Subthalamic nucleus deep brain stimulation (STN-DBS) successfully controls the motor symptoms of Parkinson’s disease (PD) but has associated cognitive side-effects. Objective: Establish the short- and long-term cognitive effects of STN-DBS in PD. Methods: Both the short-term and long-term effects of STN-DBS on cognition were examined through evaluation of the controlled studies that compared patients with STN-DBS to unoperated PD patients, thus controlling for illness progression. We also reviewed the literature to identify the factors that influence cognitive outcome of STN-DBS in PD. Results: The meta-analysis of the short-term cognitive effects of STN-DBS …revealed moderate effect sizes for semantic and phonemic verbal fluency and small effect sizes for psychomotor speed and language, indicating greater decline in the STN-DBS operated than the unoperated patients in these cognitive domains. The longer-term STN-DBS results from controlled studies indicated rates of cognitive decline/dementia up to 32%; which are no different from the rates from the natural progression of PD. Greater executive dysfunction and poorer memory pre-operatively, older age, higher pre-operative doses of levodopa, and greater axial involvement are some of the factors associated with worse cognition after STN-DBS in PD. Conclusion: This evidence can be used to inform patients and their families about the short-term and long-term risks of cognitive decline following STN-DBS surgery and aid the team in selection of suitable candidates for surgery. Show more

Keywords: Parkinson’s disease, deep brain stimulation, subthalamic nucleus, cognition, short-term, long-term, meta-analysis

DOI: 10.3233/JPD-223446

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2191-2209, 2022

Authors: Vignoud, Gaëtan | Desjardins, Clément | Salardaine, Quentin | Mongin, Marie | Garcin, Béatrice | Venance, Laurent | Degos, Bertrand

Article Type: Research Article

Abstract: Background: Among motor symptoms of Parkinson’s disease (PD), including rigidity and resting tremor, bradykinesia is a mandatory feature to define the parkinsonian syndrome. MDS-UPDRS III is the worldwide reference scale to evaluate the parkinsonian motor impairment, especially bradykinesia. However, MDS-UPDRS III is an agent-based score making reproducible measurements and follow-up challenging. Objective: Using a deep learning approach, we developed a tool to compute an objective score of bradykinesia based on the guidelines of the gold-standard MDS-UPDRS III. Methods: We adapted and applied two deep learning algorithms to detect a two-dimensional (2D) skeleton of the hand composed …of 21 predefined points, and transposed it into a three-dimensional (3D) skeleton for a large database of videos of parkinsonian patients performing MDS-UPDRS III protocols acquired in the Movement Disorder unit of Avicenne University Hospital. Results: We developed a 2D and 3D automated analysis tool to study the evolution of several key parameters during the protocol repetitions of the MDS-UPDRS III. Scores from 2D automated analysis showed a significant correlation with gold-standard ratings of MDS-UPDRS III, measured with coefficients of determination for the tapping (0.609) and hand movements (0.701) protocols using decision tree algorithms. The individual correlations of the different parameters measured with MDS-UPDRS III scores carry meaningful information and are consistent with MDS-UPDRS III guidelines. Conclusion: We developed a deep learning-based tool to precisely analyze movement parameters allowing to reliably score bradykinesia for parkinsonian patients in a MDS-UPDRS manner. Show more

Keywords: Bradykinesia, deep learning, Parkinson’s disease, MDS-UPDRS III

DOI: 10.3233/JPD-223445

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2211-2222, 2022

Authors: Sibley, Krista | Girges, Christine | Candelario, Joseph | Milabo, Catherine | Salazar, Maricel | Esperida, John Onil | Dushin, Yuriy | Limousin, Patricia | Foltynie, Thomas

Article Type: Research Article

Abstract: Background: Parkinson’s disease severity is typically measured using the Movement Disorder Society Unified Parkinson’s disease rating scale (MDS-UPDRS). While training for this scale exists, users may vary in how they score a patient with the consequence of intra-rater and inter-rater variability. Objective: In this study we explored the consistency of an artificial intelligence platform compared with traditional clinical scoring in the assessment of motor severity in PD. Methods: Twenty-two PD patients underwent simultaneous MDS-UPDRS scoring by two experienced MDS-UPDRS raters and the two sets of accompanying video footage were also scored by an artificial intelligence video …analysis platform known as KELVIN. Results: KELVIN was able to produce a summary score for 7 MDS-UPDRS part 3 items with good inter-rater reliability (Intraclass Correlation Coefficient (ICC) 0.80 in the OFF-medication state, ICC 0.73 in the ON-medication state). Clinician scores had exceptionally high levels of inter-rater reliability in both the OFF (0.99) and ON (0.94) medication conditions (possibly reflecting the highly experienced team). There was an ICC of 0.84 in the OFF-medication state and 0.31 in the ON-medication state between the mean Clinician and mean Kelvin scores for the equivalent 7 motor items, possibly due to dyskinesia impacting on the KELVIN scores. Conclusion: We conclude that KELVIN may prove useful in the capture and scoring of multiple items of MDS-UPDRS part 3 with levels of consistency not far short of that achieved by experienced MDS-UPDRS clinical raters, and is worthy of further investigation. Show more

Keywords: Artificial intelligence, clinical trials, digital measures, Parkinson’s disease, remote monitoring

DOI: 10.3233/JPD-223493

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2223-2233, 2022

Authors: Ophey, Anja | Wenzel, Julian | Paul, Riya | Giehl, Kathrin | Rehberg, Sarah | Eggers, Carsten | Reker, Paul | van Eimeren, Thilo | Kalbe, Elke | Kambeitz-Ilankovic, Lana

Article Type: Research Article

Abstract: Background: Working memory (WM) training (WMT) is a popular intervention approach against cognitive decline in patients with Parkinson’s disease (PD). However, heterogeneity in WM responsiveness suggests that WMT may not be equally efficient for all patients. Objective: The present study aims to evaluate a multivariate model to predict post-intervention verbal WM in patients with PD using a supervised machine learning approach. We test the predictive potential of novel learning parameters derived from the WMT and compare their predictiveness to other more commonly used domains including demographic, clinical, and cognitive data. Methods: 37 patients with PD (age: …64.09±8.56, 48.6% female, 94.7% Hoehn & Yahr stage 2) participated in a 5-week WMT. Four random forest regression models including 1) cognitive variables only, 2) learning parameters only, 3) both cognitive and learning variables, and 4) the entire set of variables (with additional demographic and clinical data, ‘all’ model), were built to predict immediate and 3-month-follow-up WM. Result: The ‘all’ model predicted verbal WM with the lowest root mean square error (RMSE) compared to the other models, at both immediate (RMSE = 0.184; 95% -CI=[0.184;0.185]) and 3-month follow-up (RMSE = 0.216; 95% -CI=[0.215;0.217]). Cognitive baseline parameters were among the most important predictors in the ‘all’ model. The model combining cognitive and learning parameters significantly outperformed the model solely based on cognitive variables. Conclusion: Commonly assessed demographic, clinical, and cognitive variables provide robust prediction of response to WMT. Nonetheless, inclusion of training-inherent learning parameters further boosts precision of prediction models which in turn may augment training benefits following cognitive interventions in patients with PD. Show more

Keywords: Parkinson’s disease, precision medicine, supervised machine learning, cognition, cognitive aging, working memory, internet-based intervention, clinical trial

DOI: 10.3233/JPD-223448

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2235-2247, 2022

Authors: Zwicker, Jocelyn | Qureshi, Danial | Talarico, Robert | Webber, Colleen | Watt, Christine | Kim, WooJin | Milani, Christina | Ramanathan, Usha | Mestre, Tiago | Tanuseputro, Peter

Article Type: Research Article

Abstract: Background: The end-of-life period is associated with disproportionately higher health care utilization and cost at the population level but there is little data in Parkinson’s disease (PD). Objective: The goals of this study were to 1) compare health care use and associated cost in the last year of life between decedents with and without PD, and 2) identify factors associated with palliative care consultation and death in hospital. Methods: Using linked administrative datasets held at ICES, we conducted a retrospective, population-based cohort study of all Ontario, Canada decedents from 2015 to 2017. We examined demographic data, …rate of utilization across healthcare sectors, and cost of health care services in the last year of life. Results: We identified 291,276 decedents of whom 12,440 (4.3%) had a diagnosis of PD. Compared to decedents without PD, decedents with PD were more likely to be admitted to long-term care (52% vs. 23%, p  < 0.001) and received more home care (69.0 vs. 41.8 days, p  < 0.001). Receipt of palliative homecare or physician palliative home consultation were associated with lower odds of dying in hospital (OR: 0.24, 95% CI: 0.19– 0.30, and OR: 0.38, 95% CI: 0.33– 0.43, respectively). Mean cost of care in the last year of life was greater for decedents with PD ($68,391 vs. $59,244, p  < 0.001). Conclusion: Compared to individuals without PD, individuals with PD have higher rates of long-term care, home care and higher health care costs in the last year of life. Palliative care is associated with a lower rate of hospital death. Show more

Keywords: Parkinson’s disease, end-of-life care, health service utilization, healthcare costs, administrative data, cohort studies

DOI: 10.3233/JPD-223429

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2249-2259, 2022

Authors: Fründt, Odette | Fadhel, Mazen | Heesen, Christoph | Seddiq Zai, Susan | Gerloff, Christian | Vettorazzi, Eik | Pöttgen, Jana | Buhmann, Carsten

Article Type: Research Article

Abstract: Background: Based on data regarding the prevalence of Parkinson’s disease (PD), the prevalence of impulsive control disorders (ICD) in PD, and the percentage of PD patients driving a car, it has to be assumed that at least 50,000 PD patients with ICD in Germany actively drive a car. However, these patients might be at risk for unsafe driving due to ICD-related dysfunctions such as failure to resist an impulse or temptation, to control an act or other altered neurobehavioral processes. Objective: This study determines the influence of ICD on driving ability in PD. Methods: We prospectively …compared driving simulator performance of 23 PD patients with and 23 matched patients without ICD. ICD had to be socially compensated and presence was defined clinically for primary and questionnaire-based (QUIP-RS) for post-hoc analyses. Furthermore, between-group comparisons of driving-relevant neuropsychological tests were executed. Results: Except from a lower blinking frequency when changing lanes, overall driving safety of patients with ICD did not differ significantly from those without—regardless of the clinical or QUIP-RS-based ICD definition. ICD severity did not correlate with driving performance, but the latter correlated significantly with mean reaction times and certain neuropsychiatric tests (MoCA, TMT-A, TAP-M “flexibility” and DBQ “error”). Conclusion: Clinically compensated ICD does not seem to impair driving safety in PD patients. Rather, cognitive and attentional deficits appear to be clinical markers for driving uncertainty. Show more

Keywords: Parkinson’s disease, impulse control disorders, car driving, driving safety

DOI: 10.3233/JPD-223420

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2261-2275, 2022

Authors: Campese, Nicole | Leys, Fabian | Wenning, Gregor K. | Fanciulli, Alessandra

Article Type: Research Article

Abstract: Multiple system atrophy (MSA) is a rare, rapidly progressive neurodegenerative disorder of the adulthood, characterized by autonomic failure, parkinsonian and cerebellar features in various combinations. Distinguishing MSA from common clinical look-alikes such as Parkinson's disease, other atypical parkinsonian disorders or alternative causes of sporadic adult-onset cerebellar ataxia may be difficult, especially at early disease stages. Nonetheless, some simple and cost-effective screening tools help detecting important red flags guiding towards a MSA diagnosis. Here we outline which clinical pearls and bedside tests may disclose autonomic dysfunction in multiple domains, enabling an early MSA diagnosis and, even more importantly, personalized treatment.

Keywords: Dysautonomia, multiple system atrophy, neurogenic bladder, orthostatic hypotension, parkinsonian disorders, vasomotor control

DOI: 10.3233/JPD-223357

Citation: Journal of Parkinson's Disease, vol. 12, no. 7, pp. 2277-2281, 2022