Journal of Parkinson's Disease - Volume 9, issue 1

Authors: Grover, Timothy | Georgiev, Dejan | Kalliola, Rania | Mahlknecht, Philipp | Zacharia, André | Candelario, Joseph | Hyam, Jonathan | Zrinzo, Ludvic | Hariz, Marwan | Foltynie, Thomas | Limousin, Patricia | Jahanshahi, Marjan | Tripoliti, Elina

Article Type: Research Article

Abstract: Background: Subthalamic deep brain stimulation (STN-DBS) is an established treatment for late stage Parkinson’s disease (PD). Speech intelligibility (SI) and verbal fluency (VF) have been shown to deteriorate following chronic STN-DBS. It has been suggested that speech might respond favourably to low frequency stimulation (LFS). Objective: We examined how SI, perceptual speech characteristics, phonemic and semantic VF and processes underlying it (clustering and switching) respond to LFS of 60 and 80 Hz in comparison to high frequency stimulation (HFS) (110, 130 and 200 Hz). Methods: In this double-blind study, 15 STN-DBS PD patients (mean age 65, SD  = 5.8, …14 right handed, three females), were assessed at five stimulation frequencies: 60 Hz, 80 Hz, 110 Hz, 130 Hz and 200 Hz. In addition to the clinical neurological assessment of speech, VF and SI were assessed. Results: SI and in particular articulation, respiration, phonation and prosody improved with LFS (all p  < 0.05). Phonemic VF switching improved with LFS (p  = 0.005) but this did not translate to an improved phonemic VF score. A trend for improved semantic VF was found. A negative correlation was found between perceptual characteristics of speech and duration of chronic stimulation (all p  < 0.05). Conclusions: These findings highlight the need for meticulous programming of frequency to maximise SI in chronic STN-DBS. The findings further implicate stimulation frequency in changes to specific processes underlying VF, namely phonemic switching and demonstrate the potential to address such deficits through advanced adjustment of stimulation parameters. Show more

Keywords: Subthalamic nucleus, deep brain stimulation, Parkinson’s disease, speech intelligibility, verbal fluency, frequency

DOI: 10.3233/JPD-181368

Citation: Journal of Parkinson's Disease, vol. 9, no. 1, pp. 141-151, 2019

Authors: Ondo, William | Coss, Pablo | Christie, Melissa | Pascual, Belen

Article Type: Research Article

Abstract: Background: A new extended release levodopa capsule (C/L ERC), Rytary® , has demonstrated improved “on” time in fluctuating Parkinson’s disease patients, compared to optimally dosed immediate release levodopa. The milligram dosing, however, differs markedly and no empiric ratio or formula for dose conversion currently exists. Objective: To determine the most effective conversion strategy from C/L to C/L ERC. Methods: We reviewed fluctuating PD patients with problematic “off” time who were converted to C/L ERC using a semi-structured dose titration schedule, and collected data regarding basic efficacy, tolerability, and dosing, in order to determine an empirically based …dose conversion formula. We collected demographics, PD historic data, and other medication use. Results: Eighty fluctuating PD patients were given C/L ERC samples, 68 took at least one dose [46 male (67.6%), age 66.6±10.3 y], and 62 had adequate data for dose convergence calculations. At a mean follow-up of 119±101 days, [Range: 24–355 days], 43/68 (63.3%) remained on C/L ERC. CGI-I of “much improved” or “very much improved” was reported by 27/62 (43.5%) and dyskinesia scores from the Movement Disorder Society Unified Parkinson’s Disease Rating Scale item 4.1, (0–4 range)) tended to improve from 0.9±1.1 to 0.5±0.6, P  = 0.08. The mean individual daily ratio was 2.0±0.6 : 1, [range 1.0–3.5]. A lower number of baseline daily L-dopa doses predicted a higher conversion ratio, but pre-conversion dyskinesia did not. Conclusions: This retrospective study found that C/L ERC was generally well tolerated and preferred by many patients. The mean total daily conversion ratio is 2 : 1. Show more

Keywords: Parkinson’s disease, levodopa, rytary

DOI: 10.3233/JPD-181427

Citation: Journal of Parkinson's Disease, vol. 9, no. 1, pp. 153-156, 2019

Authors: Zhang, Liping | Zhang, LingYu | Li, Lin | Hölscher, Christian

Article Type: Research Article

Abstract: Parkinson’s disease (PD) is a progressive neurological motor control disorder. A key feature is the loss of midbrain dopaminergic neurons and the accumulation of aggregated alpha-synuclein (α -syn). No current treatment is on the market that slows or halts disease progression. Previous studies have shown that glucagon-like peptide-1 (GLP-1) receptor agonists have neuroprotective effects in animal models of PD. In addition, in a phase II clinical trial, the GLP-1 receptor agonist exendin-4 has shown good protective effects in PD patients. In the present study, we have investigated the neuroprotective effects of the GLP-1 analogues semaglutide (25 nmol/kg ip. once every two …days for 30 days) and liraglutide (25 nmol/kg ip. once daily for 30 days) in the chronic MPTP mouse model of PD. Both drugs are currently on the market as a treatment for Type II diabetes. Our results show that both semaglutide and liraglutide improved MPTP-induced motor impairments. In addition, both drugs rescued the decrease of tyrosine hydroxylase (TH) levels, reduced the accumulation of α -syn, alleviated the chronic inflammation response in the brain, reduced lipid peroxidation, and inhibited the mitochondrial mitophagy signaling pathway, and furthermore increased expression of the key growth factor GDNF that protects dopaminergic neurons in the substantia nigra (SN) and striatum. Moreover, the long- acting GLP-1 analogue semaglutide was more potent compared with once daily liraglutide in most parameters measured in this study. Our results demonstrate that semaglutide may be a promising treatment for PD. A clinical trial testing semaglutide in PD patients will start shortly. Show more

Keywords: GLP-1, growth factors, incretin, inflammation, insulin, oxidative stress

DOI: 10.3233/JPD-181503

Citation: Journal of Parkinson's Disease, vol. 9, no. 1, pp. 157-171, 2019

Authors: Regidor, Ignacio | Santos-García, Diego | Catalán, Mar;ıa José | Puente, Vıctor | Valldeoriola, Francesc | Grandas, Francisco | Mir, Pablo | Parra, Juan Carlos | Arbelo, José Matías

Article Type: Research Article

Abstract: Background: Levodopa-carbidopa intestinal gel (LCIG) is effective in the treatment of advanced Parkinson’s disease (PD). However, the patients’ profile that might benefit from treatment with LCIG has not been characterized. Objective: This retrospective study explored the influence of disease duration (DD) on the effectiveness of LCIG and identified factors associated with treatment discontinuation in a cohort of advanced PD patients. Methods: Patients initiating LCIG therapy between Jan-2006 and Dec-2011 in 18 Spanish centers were included. Effectiveness in treating motor symptoms (MSs), non-motor symptoms (NMSs), and adverse events (AEs) occurrence was compared in DD≥10 or <10 years and …LCIG continuation/discontinuation groups. Factors associated with LCIG discontinuation were evaluated using univariate and multivariate analyses. Results: Overall, 177 PD patients were included (52.5% male; mean age 70.6±8.4 years; mean LCIG duration 35.6±18.6 months). Patients with DD≥10 years (n  = 125) experienced less reduction in “off” time (–29%) than those with DD <10 years (–38%; n  = 51; p  = 0.021), and reported more severe AEs (32.8% vs. 17.6%; p  = 0.043). DD did not significantly influence changes in NMSs or discontinuation rates. Fifty-four patients discontinued LCIG therapy, factors associated with discontinuation were higher percentages of waking day in the “off” state (OR, 1.028; 95% CI, 1.002–1.055; p  = 0.0360) and in the “on” state with troublesome dyskinesia (OR, 1.032; 95% CI, 1.002–1.064; p  = 0.0376) at baseline. Conclusions: Advanced PD patients with DD <10 years might benefit more from treatment with LCIG than patients with a longer DD. Although MSs severity at baseline was statistically associated with LCIG discontinuation, the probability was very low with little clinical significance. Show more

Keywords: Parkinson’s disease, levodopa-carbidopa intestinal gel, non-motor symptoms, global clinical impression

DOI: 10.3233/JPD-181324

Citation: Journal of Parkinson's Disease, vol. 9, no. 1, pp. 173-182, 2019

Authors: Petersson, Per | Halje, Pär | Cenci, M. Angela

Article Type: Review Article

Abstract: The mechanisms and significance of basal ganglia oscillations is a fundamental research question engaging both clinical and basic investigators. In Parkinson’s disease (PD), neural activity in basal ganglia nuclei is characterized by oscillatory patterns that are believed to disrupt the dynamic processing of movement-related information and thus generate motor symptoms. Beta-band oscillations associated with hypokinetic states have been reviewed in several excellent previous articles. Here we focus on faster oscillatory phenomena that have been reported in association with a diverse range of motor states. We review the occurrence of different types of fast oscillations and the evidence supporting their pathophysiological …role. We also provide a general discussion on the definition, possible mechanisms, and translational value of synchronized oscillations of different frequencies in cortico-basal ganglia structures. Revealing how oscillatory phenomena are caused and spread in cortico-basal ganglia-thalamocortical networks will offer a key to unlock the neural codes of both motor and non-motor symptoms in PD. In preclinical therapeutic research, recording of oscillatory neural activities holds the promise to unravel mechanisms of action of current and future treatments. Show more

Keywords: Pathophysiology, movement disorders, bradykinesia, dyskinesia, animal models, cortex, thalamus

DOI: 10.3233/JPD-181480

Citation: Journal of Parkinson's Disease, vol. 9, no. 1, pp. 183-196, 2019

Authors: Vlaanderen, Floris P. | Rompen, Lonneke | Munneke, Marten | Stoffer, Marije | Bloem, Bastiaan R. | Faber, Marjan J.

Article Type: Research Article

Abstract: Background and Objectives: To improve the care for patients with chronic neurological conditions like Parkinson’s disease, identifying the core needs of patients is crucial. In this article, we present the Voice of the Customer approach (originally developed in the field of industry to probe the clients’ needs), a novel methodology to identify these needs. Methods: A group of 12 discussants carried out in depth interviews to patients (n  = 20), relatives (n  = 12) and healthcare professionals (n  = 11). The interviewers combined the most informative quotations into a comprehensive video, which was used as feedback to the interviewees. The interviewees …then identified the most important needs in a consensus meeting. Results and Conclusions: The approach revealed that patients were more concerned about the impact of Parkinson’s disease on their daily lives than about the bio-medical aspects of the disease. Their top unmet needs were: (1) more self management; (2) better interdisciplinary collaboration between different healthcare professionals; (3) more time to discuss the future and possible scenarios; and (4) a healthcare professional acting as a single point of access, acting as personal case manager, either to solve problems directly or to direct patients to the professional best equipped to address the problem at hand. These results can now be used to further optimize the care for patients with Parkinson’s disease. Show more

Keywords: Patient satisfaction, qualitative research, quality of health care, Parkinson’s disease

DOI: 10.3233/JPD-181431

Citation: Journal of Parkinson's Disease, vol. 9, no. 1, pp. 197-201, 2019

Authors: Cali, Francesco | Cantone, Mariagiovanna | Cosentino, Filomena Irene Ilaria | Lanza, Giuseppe | Ruggeri, Giuseppa | Chiavetta, Valeria | Salluzzo, Roberto | Ragalmuto, Alda | Vinci, Mirella | Ferri, Raffaele

Article Type: Research Article

Abstract: Technological innovation related to the advent and development of the Next-Generation Sequencing (NGS) has provided significant advances in the diagnosis of disorders with genetic and phenotypic variability, such as neurodegenerative diseases. However, the interpretation of NGS data often remains challenging, although advanced prediction tools have contributed to primarily assess the impact of some missense variants. Here, we report a patient with Parkinson’s disease (PD) and a family history of disease, in which a panel of 29 disease-causing or risk genes for PD were analyzed. We identified a new missense variant in the SNCA gene. Although this variant might be associated …with PD in this family, it has been currently classified as a “Variant of Unknown Significance” because of the lack of segregation with disease. Indeed, we subsequently found the same mutation in an unaffected sister. Nevertheless, this finding may help clinicians and researchers in questioning the causative role of genetic variants within the daily clinical and diagnostic settings. Show more

Keywords: Parkinsonism, parkinson’s disease, in silico mutation analyses, next generation sequencing

DOI: 10.3233/JPD-171292

Citation: Journal of Parkinson's Disease, vol. 9, no. 1, pp. 203-206, 2019

Authors: Santiago, Anthony | Langston, James W. | Gandhy, Rita | Dhall, Rohit | Brillman, Salima | Rees, Linda | Barlow, Carrolee

Article Type: Research Article

Abstract: Background: Wearable sensors provide accurate, continuous objective measurements, quantifying the variable motor states of patients with Parkinson’s disease (PD) in real time. Objectives: To evaluate the impact of using continuous objective measurement using the Personal KinetiGraph™ (PKG® ) Movement Recording System in the routine clinical care of patients with PD (PwP). Methods: Physicians employed the use of the PKG in patients for whom they were seeking objective measurement. Patients wore a PKG data logger for ≥6 days during routine daily living activities. During the survey period of December 2015 through July 2016, physician surveys were completed …by four Movement Disorder Specialists for whom measurements from the PKG were available during a subsequent routine clinic visit. Results: Of 112 completed physician surveys, 46 (41%) indicated the PKG provided relevant additional information sufficient to consider adjusting their therapeutic management plan; 66 (59%) indicated the PKG provided no further information to support a therapeutic decision differing from that made during a routine clinical evaluation. Upon further review of these 46 surveys, 36 surveys (78%) revealed the information provided by the PKG ultimately resulted in adjusting the patient’s medical management. Conclusions: The PKG provided novel additional information beyond that captured during a routine clinic visit sufficient to change the medical management of PwP. Physicians adjusted treatment nearly a third of the time based on data provided by real-time, remote monitoring outside the clinic setting. The use of the PKG may provide for better informed therapeutic decisions, improving the quality of life for PwP. Show more

Keywords: Parkinson’s disease, remote monitoring, wearable sensors, objective assessment, continuous measurement, capacitive sensor

DOI: 10.3233/JPD-181373

Citation: Journal of Parkinson's Disease, vol. 9, no. 1, pp. 207-219, 2019

Authors: Sturm, Deborah | Folkerts, Ann-Kristin | Kalbe, Elke

Article Type: Research Article

Abstract: Background: Despite a growing research literature on caregiver burden in progressive diseases (e.g., dementia), the experiences and needs of family members of patients with Parkinson′ s disease (PD), especially of those who are not caring primarily, are underinvestigated. Furthermore, there is only limited evidence for interventions for PD relatives. Objective: The aim of this cross-sectional study was to assess the intervention needs of PD family members. Methods: 133 relatives of PD patients were asked about the essential topics and the appropriate format of a psychoeducational group intervention by means of a standardized questionnaire. …Results: The sample consisted of 67 caregivers (CG) and 66 non-caregivers (nCG). CGs and nCGs were mainly female (75% vs. 64%) and patients’ spouses (97% vs. 59%). CGs were about 15 years older than nCGs. Both groups were considerably burdened by patients’ disease, and 84% of the CGs and 90% of the nCGs were convinced about the subjective benefit of a group intervention. The majority of the CGs rated stress management, coping with emotional distress, receiving social support, and different information modules as essential topics. In comparison, more than half of the nCGs voted for sharing experiences with other relatives, as well as for different information modules. Most individuals preferred two-hour sessions in the late afternoon (once or twice a week) with a maximum of ten participants. Conclusions: This study contributes to an increased understanding of PD families’ needs and might inform future studies concerning the development of needs-based and low-threshold support programs. Show more

Keywords: Parkinson’s disease, caregivers, family, psychological stress, health services, social support, surveys and questionnaires

DOI: 10.3233/JPD-181456

Citation: Journal of Parkinson's Disease, vol. 9, no. 1, pp. 221-227, 2019

Authors: Arnaldi, Dario | Meles, Sanne K. | Giuliani, Alessandro | Morbelli, Silvia | Renken, Remco J. | Janzen, Annette | The REMPET Study Group | Mayer, Geert | Jonsson, Cathrine | Oertel, Wolfgang H. | Nobili, Flavio | Leenders, Klaus L. | Pagani, Marco

Collaborators: Sittig-Wiegand, Elisabeth | Depboylu, Candan | Reetz, Kathrin | Overeem, Sebastiaan | Pijpers, Angelique | Reesink, Fransje E. | van Laar, Teus | Teune, Laura K. | Höffken, Helmut | Luster, Marcus | Timmermann, Lars | Kesper, Karl | Adriaanse, Sofie M. | Booij, Jan | Sambuceti, Gianmario | Girtler, Nicola

Article Type: Research Article

Abstract: Background/Objective: Idiopathic REM sleep behavior disorder (iRBD) often precedes Parkinson’s disease (PD) and other alpha-synucleinopathies. The aim of the study is to investigate brain glucose metabolism of patients with RBD and PD by means of a multidimensional scaling approach, using18 F-FDG-PET as a biomarker of synaptic function. Methods: Thirty-six iRBD patients (64.1±6.5 y, 32 M), 72 PD patients, and 79 controls (65.6±9.4 y, 53 M) underwent brain 18 F-FDG-PET. PD patients were divided according to the absence (PD, 32 subjects; 68.4±8.5 y, 15 M) or presence (PDRBD, 40 subjects; 71.8±6.6 y, 29 M) of RBD. 18 F-FDG-PET scans were used to independently discriminate subjects belonging to …four categories: controls (RBD no, PD no), iRBD (RBD yes, PD no), PD (RBD no, PD yes) and PDRBD (RBD yes, PD yes). Results: The discriminant analysis was moderately accurate in identifying the correct category. This is because the model mostly confounds iRBD and PD, thus the intermediate classes. Indeed, iRBD, PD and PDRBD were progressively located at increasing distance from controls and are ordered along a single dimension (principal coordinate analysis) indicating the presence of a single flux of variation encompassing both RBD and PD conditions. Conclusion: Data-driven approach to brain 18 F-FDG-PET showed only moderate discrimination between iRBD and PD patients, highlighting brain glucose metabolism heterogeneity among such patients. iRBD should be considered as a marker of an ongoing condition that may be picked-up in different stages across patients and thus express different brain imaging features and likely different clinical trajectories. Show more

Keywords: REM sleep behavior disorder, Parkinson’s disease, 18F-FDG-PET, synucleinopathy

DOI: 10.3233/JPD-181468

Citation: Journal of Parkinson's Disease, vol. 9, no. 1, pp. 229-239, 2019

Authors: Chung, Seok Jong | Yoo, Han Soo | Lee, Hye Sun | Lee, Phil Hyu | Sohn, Young H.

Article Type: Research Article

Abstract: Background: Aberrant plasticity is closely linked to the development of levodopa-induced dyskinesia (LID) in Parkinson’s disease (PD). Objective: This study investigated whether dominant-side patients with PD exhibit a shorter time to LID development, based on the hypothesis that the dominant hemisphere may have greater plasticity than non-dominant-side patients. Methods: We analyzed data from 387 right-handed patients with PD who exhibited asymmetric motor deficits and received PD medications for ≥2 years (191 dominant-side and 196 non-dominant-side patients). The influence of side onset on time for LID development was assessed by Kaplan-Meier estimates and time-dependent Cox regression models …based on the 5-year time point, after adjusting for age at PD onset, dopamine transporter activity in the posterior putamen, and daily levodopa dose. Results: LID developed in 46 (23.4%) patients with non-dominant-side PD and in 35 (18.1%) patients with dominant-side PD. The Kaplan-Meier analyses revealed that non-dominant-side patients developed LID earlier than dominant-side patients (p  = 0.027). The time-dependent Cox regression models showed that the risk of LID within 5 years of treatment was significantly higher in non-dominant-side than in dominant-side patients (hazard ratio 1.954; p  = 0.034), whereas the risk after 5 years was similar between groups (p  = 0.528). Conclusions: The present study demonstrated that LID developed earlier in non-dominant-side than in dominant-side patients with PD. These results suggested a greater potential of synaptic plasticity in the dominant hemisphere that may exert a protective role for the development of LID compared to the non-dominant hemisphere. Show more

Keywords: Dyskinesia, laterality of motor control, neural plasticity, Parkinson’s disease, risk factors

DOI: 10.3233/JPD-181512

Citation: Journal of Parkinson's Disease, vol. 9, no. 1, pp. 241-247, 2019

Authors: Bloem, Bastiaan R. | Helmich, Rick C. | Tilanus, Tiane | van de Warrenburg, Bart P.

Article Type: Short Communication

DOI: 10.3233/JPD-181541

Citation: Journal of Parkinson's Disease, vol. 9, no. 1, pp. 249-250, 2019