Journal of Parkinson's Disease - Volume 12, issue 5

Authors: Devignes, Quentin | Daoudi, Sami | Viard, Romain | Lopes, Renaud | Betrouni, Nacim | Kuchcinski, Gregory | Rolland, Anne-Sophie | Moreau, Caroline | Defebvre, Luc | Bardinet, Eric | Bonnet, Marie | Brefel-Courbon, Christine | Delmaire, Christine | El Mountassir, Fouzia | Fluchère, Frédérique | Fradet, Anne | Giordana, Caroline | Hainque, Elodie | Houvenaghel, Jean-François | Jarraya, Béchir | Klinger, Hélène | Maltête, David | Marques, Ana | Meyer, Mylène | Rascol, Olivier | Rouaud, Tiphaine | Tir, Melissa | Wirth, Thomas | Corvol, Jean-Christophe | Devos, David | Dujardin, Kathy | for the PREDISTIM working group

Article Type: Research Article

Abstract: Background: Parkinson’s disease mild cognitive impairment (PD-MCI) is frequent and heterogenous. There is no consensus about its influence on subthalamic deep brain stimulation (STN-DBS) outcomes. Objective: To determine the prevalence of PD-MCI and its subtypes in candidates to STN-DBS. Secondarily, we sought to identify MRI structural markers associated with cognitive impairment in these subgroups. Methods: Baseline data from the French multicentric PREDISTIM cohort were used. Candidates to STN-DBS were classified according to their cognitive performance in normal cognition (PD-NC) or PD-MCI. The latter included frontostriatal (PD-FS) and posterior cortical (PD-PC) subtypes. Between-group comparisons were performed on …demographical and clinical variables as well as on T1-weighted MRI sequences at the cortical and subcortical levels. Results: 320 patients were included: 167 (52%) PD-NC and 153 (48%) PD-MCI patients. The latter group included 123 (80%) PD-FS and 30 (20%) PD-PC patients. There was no between-group difference regarding demographic and clinical variables. PD-PC patients had significantly lower global efficiency than PD-FS patients and significantly worse performance on visuospatial functions, episodic memory, and language. Compared to PD-NC, PD-MCI patients had cortical thinning and radiomic-based changes in the left caudate nucleus and hippocampus. There were no significant differences between the PD-MCI subtypes. Conclusion: Among the candidates to STN-DBS, a significant proportion has PD-MCI which is associated with cortical and subcortical alterations. Some PD-MCI patients have posterior cortical deficits, a subtype known to be at higher risk of dementia. Show more

Keywords: Cortical thickness, dual syndrome hypothesis, radiomics, shape analysis, voxel-based morphometry

DOI: 10.3233/JPD-223232

Citation: Journal of Parkinson's Disease, vol. 12, no. 5, pp. 1507-1526, 2022

Authors: Gibson, Lucy L. | Pollak, Thomas A. | Heslegrave, Amanda | Hye, Abdul | Batzu, Lucia | Rota, Silvia | Trivedi, Dhaval | Nicholson, Timothy R. | ffytche, Dominic | Zetterberg, Henrik | Chaudhuri, K. Ray | Aarsland, Dag

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms are common and important to people with Parkinson’s disease (PD), but their etiology is poorly understood. Plasma neurofilament light (NfL) and p-tau181 are biomarkers of neuro-axonal degeneration and tau pathology respectively, which have yet to be explored in association with the affective and psychotic symptoms in PD. Objective: To investigate the relationship between plasma NfL and p-tau181 with the affective and psychotic symptoms in PD. Methods: We assessed the baseline concentration of plasma NfL and p-tau181 in a cohort of 108 patients with PD and 38 healthy controls. A subgroup of patients (n … = 63) were assessed annually with clinical measures for up to 7 years. Psychotic symptoms were assessed using the Non-Motor Symptom Scale and affective symptoms were measured in the Hospital Anxiety and Depression Scale. Results: Baseline plasma NfL was a significant predictor of psychotic symptoms longitudinally across the study adjusted for age, Hoehn and Yahr stage, duration of follow up, duration of disease, baseline levodopa and dopamine agonist medication, and baseline cognition: (OR 8.15 [95% CI 1.40–47.4], p  = 0.020). There was no association between NfL concentration and the cumulative prevalence of affective symptoms. Plasma p-tau181 concentration was not associated with psychotic or affective symptoms. Conclusion: These findings suggest psychotic symptoms are associated with greater neurodegeneration in PD. Further studies are needed to explore NfL as a potential biomarker for psychosis in PD. Show more

Keywords: Neurofilament light, p-tau, psychosis, neuropsychiatric symptoms, biomarker, Parkinson’s disease

DOI: 10.3233/JPD-223182

Citation: Journal of Parkinson's Disease, vol. 12, no. 5, pp. 1527-1538, 2022

Authors: Usnich, Tatiana | Hanssen, Henrike | Lohmann, Katja | Lohse, Christina | Klein, Christine | Kasten, Meike | Brüggemann, Norbert | on behalf of the EPIPARK Study Group

Article Type: Short Communication

Abstract: Patients with Parkinson’s disease (PD) carrying variants in the Glucocerebrosidase (GBA) gene (GBA -PD) suffer from orthostatic symptoms more frequently than idiopathic PD patients (IPD). Systematic measurements of the blood pressure have not yet been performed. In the present study, a prospective analysis of 33 GBA -PD and 313 IPD patients was carried out. Systolic blood pressure upon changing from the supine to the upright position dropped more strongly in GBA -PD compared to IPD patients. Diastolic blood pressure and heart rate did not differ between groups. This study provides further evidence for a pronounced involvement of the autonomic …nervous system in GBA -PD. Show more

Keywords: Autonomic symptoms, GBA, orthostatic hypotension, Parkinson’s disease

DOI: 10.3233/JPD-223197

Citation: Journal of Parkinson's Disease, vol. 12, no. 5, pp. 1539-1544, 2022

Authors: Tseng, Kuan-Yin | Kuo, Tung-Tai | Wang, Vicki | Huang, Eagle Yi-Kung | Ma, Kuo-Hsing | Olson, Lars | Hoffer, Barry J. | Chen, Yuan-Hao

Article Type: Research Article

Abstract: Background: L-DOPA-induced dyskinesia (LID), occurring with aberrant processing of exogenous L-DOPA in the dopamine-denervated striatum, is a main complication of levodopa treatment in Parkinson’s disease. Objective: To characterize the effects of the vesicular antagonist tetrabenazine (TBZ) on L-DOPA-induced behavior, neurochemical signals, and underlying protein expressions in an animal model of Parkinson’s disease. Methods: 20-week-old MitoPark mice were co-treated or separately administered TBZ and L-DOPA for 14 days. Abnormal involuntary movements (AIMs) and locomotor activity were analyzed. To explore dopamine (DA) transmission, fast scan cyclic voltammetry was used to assess presynaptic DA dynamics in striatal slices following …treatments. PET imaging with 4-[18F]-PE2I, ADAM and immunoblotting assays were used to detect receptor protein changes in the DA-denervated striatum. Finally, nigrostriatal tissues were collected for HPLC measures of DA, serotonin and their metabolites. Results: A single injection of TBZ given in the interval between the two L-DOPA/Carbidopa treatments significantly attenuated L-DOPA-induced AIMs expression and locomotor hyperactivity. TBZ was shown to reduce tonic and phasic release of DA following L-DOPA treatment in DA-denervated striatal tissue. In the DA-depleted striatum, TBZ decreased the expression of L-DOPA-enhanced D1 receptors and the serotonin reuptake transporter. Neurochemical analysis indicated that TBZ attenuated L-DOPA-induced surges of DA levels by promoting DA turnover in the nigrostriatal system. Conclusions: Our findings demonstrate that TBZ diminishes abnormal striatal DA transmission, which involves the ability of TBZ to modulate the presymptomatic dynamics of DA, and then mitigate aberrant release of exogenous L-DOPA from nerve terminals. The results support the potential of repositioning TBZ to counteract LID development. Show more

Keywords: Parkinson’s disease, dopamine, L-DOPA-induced dyskinesia, tetrabenazine, serotonin transporter

DOI: 10.3233/JPD-223195

Citation: Journal of Parkinson's Disease, vol. 12, no. 5, pp. 1545-1565, 2022

Authors: Sampedro, Frederic | Martínez-Horta, Saul | Marín-Lahoz, Juan | Pagonabarraga, Javier | Kulisevsky, Jaime

Article Type: Research Article

Abstract: Background: Apathy represents a core neuropsychiatric symptom in Parkinson’s disease (PD). As there is currently no established effective treatment for apathy in PD, further investigating the biological origin of this symptom is needed to design novel therapeutic strategies. Among the multiple neurotransmitter alterations that have been associated with apathy, the involvement of extra-striatal dopaminergic degeneration remains to be fully explored. Objective: To investigate whether apathy in PD reflects increased dopaminergic degeneration extending beyond striatal regions. Methods: In the de novo PD cohort of the Parkinson’s Progression Markers Initiative (PPMI), we performed whole-brain I123 -Ioflupane Single Photon …Emission Computed Tomography (DAT-SPECT) analyses to characterize cross-sectional and longitudinal differences in DAT uptake associated with the presence of apathy. We also assessed the relationship between apathy and cognition in this sample, as apathy has been suggested to herald cognitive decline. Results: Apathetic PD patients (N  = 70) had similar sociodemographic, clinical, and biomarker profiles compared to the non-apathetic group (N  = 333) at baseline. However, apathy was associated with an increased risk of developing cognitive impairment after a four-year follow-up period (p  = 0.006). Compared to non-apathetic patients, apathetic patients showed a widespread reduction of extra-striatal DAT uptake at baseline as well as an increased longitudinal loss of DAT uptake (corrected p  < 0.05). Conclusions: Isolated apathy in PD is associated with extra-striatal dopaminergic degeneration. As this abnormal dopamine depletion was in turn related to cognitive performance, this might explain, at least partially, the increased risk of apathetic PD patients to develop cognitive impairment or dementia. Show more

Keywords: Apathy, DAT, extra-striatal, Parkinson’s disease

DOI: 10.3233/JPD-223223

Citation: Journal of Parkinson's Disease, vol. 12, no. 5, pp. 1567-1574, 2022

Authors: Bange, Manuel | Gonzalez-Escamilla, Gabriel | Lang, Nadine Sandra Claudia | Ding, Hao | Radetz, Angela | Herz, Damian Marc | Schöllhorn, Wolfgang Immanuel | Muthuraman, Muthuraman | Groppa, Sergiu

Article Type: Research Article

Abstract: Background: Gait impairments are common in Parkinson’s disease (PD). The pathological mechanisms are complex and not thoroughly elucidated, thus quantitative and objective parameters that closely relate to gait characteristics are critically needed to improve the diagnostic assessments and monitor disease progression. The substantia nigra is a relay structure within basal ganglia brainstem loops that is centrally involved in gait modulation. Objective: We tested the hypothesis that quantitative gait biomechanics are related to the microstructural integrity of the substantia nigra and PD-relevant gait abnormalities are independent from bradykinesia-linked speed reductions. Methods: Thirty-eight PD patients and 33 age-matched …control participants walked on a treadmill at fixed speeds. Gait parameters were fed into a principal component analysis to delineate relevant features. We applied the neurite orientation dispersion and density imaging (NODDI) model on diffusion-weighted MR-images to calculate the free-water content as an advanced marker of microstructural integrity of the substantia nigra and tested its associations with gait parameters. Results: Patients showed increased duration of stance phase, load response, pre-swing, and double support time, as well as reduced duration of single support and swing time. Gait rhythmic alterations associated positively with the free-water content in the right substantia nigra in PD, indicating that patients with more severe neurodegeneration extend the duration of stance phase, load response, and pre-swing. Conclusion: The results provide evidence that gait alterations are not merely a byproduct of bradykinesia-related reduced walking speed. The data-supported association between free-water and the rhythmic component highlights the potential of substantia nigra microstructure imaging as a measure of gait-dysfunction and disease-progression. Show more

Keywords: Parkinson’s disease, gait, substantia nigra, free-water, diffusion-weighted imaging

DOI: 10.3233/JPD-223225

Citation: Journal of Parkinson's Disease, vol. 12, no. 5, pp. 1575-1590, 2022

Authors: Kehagia, Angie A. | North, Tracie K. | Grose, Jane | Jeffery, Alison N. | Cocking, Laura | Chapman, Rebecca | Carroll, Camille

Article Type: Research Article

Abstract: Background: Recruitment and retention of participants in clinical trials for Parkinson’s disease (PD) is challenging. A qualitative study embedded in the PD STAT multi-centre randomised controlled trial of simvastatin for neuroprotection in PD explored the motivators, barriers and challenges of participants, care partners and research staff. Objective: To outline a set of considerations informing a patient-centred approach to trial recruitment, retention, and delivery. Method: We performed semi-structured interviews and focus groups with a subset of trial participants and their care partners. Quantitative and qualitative data were obtained through surveys circulated among the 235 participants across 23 UK …sites at the beginning, middle and end of the 2-year trial. We also interviewed and surveyed research staff at trial closure. Results: Twenty-seven people with PD, 6 care partners and 9 researchers participated in interviews and focus groups. A total of 463 trial participant survey datasets were obtained across three timepoints, and 53 staff survey datasets at trial closure. Trial participants discussed the physical and psychological challenges they faced, especially in the context of OFF state assessments, relationships, and communication with research staff. Care partners shared their insights into OFF state challenges, and the value of being heard by research teams. Research staff echoed many concerns with suggestions on flexible, person-centred approaches to maximising convenience, comfort, and privacy. Conclusion: These considerations, in favour of person-centred research protocols informed by the variable needs of participants, care partners and staff, could be developed into a set of recommendations for future trials. Show more

Keywords: Parkinson’s disease, clinical trial, participation, recruitment, retention, OFF assessment, consent, patient-centred, qualitative, PPI

DOI: 10.3233/JPD-212987

Citation: Journal of Parkinson's Disease, vol. 12, no. 5, pp. 1591-1604, 2022

Authors: Day, Jacob O. | Smith, Stephen | Noyce, Alastair J. | Alty, Jane | Jeffery, Alison | Chapman, Rebecca | Carroll, Camille

Article Type: Short Communication

Abstract: Digital health technologies (DHTs) have great potential for use as clinical trial outcomes; however, practical issues need to be addressed in order to maximise their benefit. We describe our experience of incorporating two DHTs as secondary/exploratory outcome measures in PD STAT, a randomised clinical trial of simvastatin in people with Parkinson’s disease. We found much higher rates of missing data in the DHTs than the traditional outcome measures, in particular due to technical and software difficulties. We discuss methods to address these obstacles in terms of protocol design, workforce training and data management.

Keywords: Parkinson’s disease, clinical trials, digital outcomes, sensors, data management

DOI: 10.3233/JPD-223162

Citation: Journal of Parkinson's Disease, vol. 12, no. 5, pp. 1605-1609, 2022

Authors: Wuehr, Max | Schmidmeier, Florian | Katzdobler, Sabrina | Fietzek, Urban M. | Levin, Johannes | Zwergal, Andreas

Article Type: Research Article

Abstract: Background: Postural instability is a major disabling factor in patients with advanced Parkinson’s disease (PD) and often resistant to treatment. Previous studies indicated that imbalance in PD may be reduced by low-intensity noisy galvanic vestibular stimulation (nGVS). Objective: To investigate the potential mode of action of this therapeutic effect. In particular, we examined whether nGVS-induced reductions of body sway in PD are compatible with stochastic resonance (SR), a mechanism by which weak sensory noise stimulation can paradoxically enhance sensory information transfer. Methods: Effects of nGVS of varying intensities (0–0.7 mA) on body sway were examined in 15 …patients with PD standing with eye closed on a posturographic force plate. We assumed a bell-shaped response curve with maximal reductions of sway at intermediate nGVS intensities to be indicative of SR. An established SR-curve model was fitted on individual patient outcomes and three experienced human raters had to judge whether responses to nGVS were consistent with the exhibition of SR. Results: nGVS-induced reductions of body sway compatible with SR were found in 10 patients (67%) with optimal improvements of 23±13%. In 7 patients (47%), nGVS-induced sway reductions exceeded the minimally important clinical difference (optimal improvement: 30±10%), indicative of strong SR. This beneficial effect was more likely in patients with advanced PD (R  = 0.45; p  = 0.045). Conclusions: At least half of the assessed patients showed robust improvements in postural balance compatible with SR when treated with low-intensity nGVS. In particular, patients with more advanced disease stages and imbalance may benefit from the non-invasive and well-tolerated treatment with nGVS. Show more

Keywords: Balance, body sway, galvanic vestibular stimulation, Parkinson’s disease, stochastic resonance

DOI: 10.3233/JPD-213127

Citation: Journal of Parkinson's Disease, vol. 12, no. 5, pp. 1611-1618, 2022

Authors: Kawada, Tomoyuki

Article Type: Letter

Abstract: I discussed the risk of phenoconversions from idiopathic/isolated REM sleep behavior disorder (iRBD). Comorbidity with iRBD, such as obstructive sleep apnea, may accerelate the risk of α-synuclein-related neurodegenerative diseases. Further studies are needed to specify the risk factors of phenoconversion from iRBD.

Keywords: α-synuclein-related neurodegenerative diseases, rapid eye movement sleep behavior disorder, risk factors

DOI: 10.3233/JPD-223306

Citation: Journal of Parkinson's Disease, vol. 12, no. 5, pp. 1619-1620, 2022