Journal of Parkinson's Disease - Volume 12, issue 4

Authors: Bloem, Bastiaan R. | Kordower, Jeffrey H.

Article Type: Editorial

Keywords: Parkinson’s disease, Linked Clinical Trials, neurodegeneration

DOI: 10.3233/JPD-229003

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1069-1072, 2022

Authors: McFarthing, Kevin | Rafaloff, Gary | Baptista, Marco | Mursaleen, Leah | Fuest, Rosie | Wyse, Richard K. | Stott, Simon R.W.

Article Type: Review Article

Abstract: Background: As the international community dealt with the ongoing COVID-19 pandemic, important progress continued to be made in the development of new drug-based therapies for the neurodegenerative condition of Parkinson’s disease (PD) in 2021. This progress included both “symptomatic treatments” (ST – improves/reduces symptoms of the condition) and “disease modifying treatments” (DMT - attempts to delay/slow progression by addressing the underlying biology of PD), which can be categorised further based on their mechanisms of action and class of drug. Objective: This report continues previous efforts to provide an overview of the pharmacological therapies - both ST and DMT …- in clinical trials for PD during 2021– 2022, with the aim of creating greater awareness and involvement in the clinical trial process. We also hope to stimulate collaboration amongst all stakeholders, including industry, academia, advocacy organizations, and most importantly patient community. Methods: We conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov and World Health Organisation (WHO) registries, and performed a breakdown analysis of studies that were active as of January 31st 2022. We also assessed active drug development projects that had completed one clinical phase but were yet to start the next. Results: There was a total of 147 clinical trials registered on the ClinicalTrials.gov website as active during the period of analysis. Of these trials, 91 (62%)were investigating STs, while 56 (38%)focused on DMTs. Approximately 1/3 of the studies (34.7%; 51 trials) were in Phase 1, while over half of the trials were in Phase 2 (50.3%; 74 trials). Only 15% (22 trials) of the studies were in Phase 3, of which only 3 trials were evaluating DMTs. Novel therapeutics (42%)were the most common type of agents being tested across all phases of testing, followed by repurposed agents (34%)and reformulations (20%). Conclusion: Despite significant global health constraints, the development of new drug-based therapies for PD continued in 2021. Hopefully with a shift towards a post-pandemic world in which COVID-19 is better managed, we will see an increase in the number of clinical trials focused on drug development for PD. The need for more Phase 3 studies for DMTs remains acute. Show more

Keywords: Clinical trials, studies, Parkinson’s, disease modification, neuroprotection, immunotherapy, inflammation, gene therapy

DOI: 10.3233/JPD-229002

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1073-1082, 2022

Authors: Fasano, Alessio | Mazzoni, Alberto | Falotico, Egidio

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is known to affect the brain motor circuits involving the basal ganglia (BG) and to induce, among other signs, general slowness and paucity of movements. In upper limb movements, PD patients show a systematic prolongation of movement duration while maintaining a sufficient level of endpoint accuracy. PD appears to cause impairments not only in movement execution, but also in movement initiation and planning, as revealed by abnormal preparatory activity of motor-related brain areas. Grasping movement is affected as well, particularly in the coordination of the hand aperture with the transport phase. In the last fifty years, numerous …behavioral studies attempted to clarify the mechanisms underlying these anomalies, speculating on the plausible role that the BG-thalamo-cortical circuitry may play in normal and pathological motor control. Still, many questions remain open, especially concerning the management of the speed-accuracy tradeoff and the online feedback control. In this review, we summarize the literature results on reaching and grasping in parkinsonian patients. We analyze the relevant hypotheses on the origins of dysfunction, by focusing on the motor control aspects involved in the different movement phases and the corresponding role played by the BG. We conclude with an insight into the innovative stimulation techniques and computational models recently proposed, which might be helpful in further clarifying the mechanisms through which PD affects reaching and grasping movements. Show more

Keywords: Reach and grasp, Parkinson’s disease, motor control, upper limb aiming movements, bradykinesia, hypokinesia, akinesia, basal ganglia, computational modelling, brain stimulation

DOI: 10.3233/JPD-213082

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1083-1113, 2022

Authors: Heim, Beatrice | Peball, Marina | Hammermeister, Johannes | Djamshidian, Atbin | Krismer, Florian | Seppi, Klaus

Article Type: Systematic Review

Abstract: Background: Essential tremor (ET) and the tremor of Parkinson’s disease (PD) are the most common tremors encountered in clinical practice. Especially in early disease stages, discrimination between the tremors of ET and PD can be challenging. Objective: The aim of this study was to evaluate the diagnostic accuracy of transcranial sonography (TCS) of the substantia nigra echogenicity for differential diagnosis of PD versus ET. Methods: A systematic PubMed search identified 512 studies. Sensitivity and specificity of substantia nigra hyperechogenicity was estimated. Data synthesis was carried applying a random effects bivariate binomial model. To assess study quality …and risk of bias, the QUADAS-2 tool was used. Results: Eighteen studies were suitable for analysis including 1,264 PD and 824 ET patients. The meta analysis showed a pooled sensitivity and specificity for TCS in the differential diagnosis of PD versus ET of 84.6% (95% CI, 79.4–88.6%) and 83.9% (95% CI, 78.4–88.2%), respectively. Furthermore, we found nearly similar results in sensitivity and specificity comparing TCS and DaTSCAN in a subgroup-analysis of three studies using both diagnostic tools including 107 patients with PD and 62 patients with ET. The QUADAS-2 toolbox revealed a high risk of bias regarding the methodological quality of patient selection. Conclusion: Substantia nigra hyperechogenicity yield high diagnostic accuracy for the discrimination of PD from ET. TCS is a low cost, widely available, non-invasive marker without radiation Therefore, a diagnostic algorithm based on presence or absence of substantia nigra hyperechogenicity is highly warranted. Show more

Keywords: Transcranial sonography, essential tremor, substantia nigra, hyperechogenicity, Parkinson’s disease

DOI: 10.3233/JPD-213012

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1115-1123, 2022

Authors: Javanshiri, Keivan | Drakenberg, Tove | Haglund, Mattias | Englund, Elisabet

Article Type: Research Article

Abstract: Background: Alpha-synucleinopathies (AS) are characterized by pathologic aggregations of alpha-synuclein (α -syn) in the central nervous system, and comprise dementia with Lewy bodies, Parkinson’s disease, and multiple system atrophy. Previous studies on AS have reported findings of α -syn pathology in the peripheral nervous system of multiple organs, including the heart. Objective: The aim of this study was to further investigate and confirm the presence of cardiac α -syn in AS compared to other major neurocognitive disorders in a neuropathologically confirmed cohort. Methods: All deceased patients with performed autopsy and with neuropathologically confirmed AS at the …Clinical Department of Pathology in Lund 2010–May 2021 were evaluated for inclusion. Cases with insufficiently sampled cardiac tissue or only limited neuropathological investigation were excluded. An age-matched group of individuals with other neurodegenerative diseases, having no α -syn in the CNS, served as controls. In total, 68 AS and 32 control cases were included in the study. Immunohistochemistry for detection of cardiac α -syn aggregates was performed. Results: The AS group had a significantly higher prevalence of cardiac α -syn pathology (p ≤0.001) than the control group, 82% and 0%, respectively. Conclusion: This study confirms the association between AS and the presence of cardiac α -syn in a neuropathologically confirmed cohort. This motivates further research on potential pathophysiological effects on cardiac function in AS patients. Show more

Keywords: Alpha-synuclein, cardiac nerve fibers, Lewy body disease, multiple system atrophy, Parkinson’s disease, synucleinopathies

DOI: 10.3233/JPD-223161

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1125-1131, 2022

Authors: Negrini, Matilde | Tomasello, Giuseppe | Davidsson, Marcus | Fenyi, Alexis | Adant, Cécile | Hauser, Swantje | Espa, Elena | Gubinelli, Francesco | Manfredsson, Fredric P. | Melki, Ronald | Heuer, Andreas

Article Type: Research Article

Abstract: Background: Preclinical rodent models for Parkinson’s disease (PD) based on viral human alpha-synuclein (h-αSyn) overexpression recapitulate some of the pathological hallmarks as it presents in humans, such as progressive cell loss and additional synucleinopathy in cortical and subcortical structures. Recent studies have combined viral vector-based overexpression of human wild-type αSyn with the sequential or simultaneous inoculation of preformed fibrils (PFFs) derived from human αSyn. Objective: The goal of the study was to investigate whether sequential or combined delivery of the AAV vector and the PFFs are equipotent in inducing stable neurodegeneration and behavioral deficits. Methods: Here …we compare between four experimental paradigms (PFFs only, AAV-h-αSyn only, AAV-h-αSyn with simultaneous PFFs, and AAV-h-αSyn with sequential PFFs) and their respective GFP control groups. Results: We observed reduction of TH expression and loss of neurons in the midbrain in all AAV (h-αSyn or GFP) injected groups, with or without additional PFFs inoculation. The overexpression of either h-αSyn or GFP alone induced motor deficits and dysfunctional dopamine release/reuptake in electrochemical recordings in the ipsilateral striatum. However, we observed a substantial formation of insoluble h-αSyn aggregates and inflammatory response only when h-αSyn and PFFs were combined. Moreover, the presence of h-αSyn induced higher axonal pathology compared to control groups. Conclusion: Simultaneous AAV and PFFs injections are equipotent in the presented experimental setup in inducing histopathological and behavioral changes. This model provides new and interesting possibilities for characterizing PD pathology in preclinical models and means to assess future therapeutic interventions. Show more

Keywords: AAV, alpha synuclein, behavioral deficits, dopamine, inflammation, motor deficits, Parkinson’s disease, phosphorylated synuclein, preclinical rodent model, preformed fibrils

DOI: 10.3233/JPD-212555

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1133-1153, 2022

Authors: Weinshel, Sarah | Irwin, David J. | Zhang, Panpan | Weintraub, Daniel | Shaw, Leslie M. | Siderowf, Andrew | Xie, Sharon X.

Article Type: Research Article

Abstract: Background: While cutoffs for abnormal levels of the cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ142 ), total tau (t-tau), phosphorylated tau (p-tau), and the ratios of t-tau/Aβ142 and p-tau/Aβ142 , have been established in Alzheimer’s disease (AD), biologically relevant cutoffs have not been studied extensively in Parkinson’s disease (PD). Objective: Assess the suitability and diagnostic accuracy of established AD-derived CSF biomarker cutoffs in the PD population. Methods: Baseline and longitudinal data on CSF biomarkers, cognitive diagnoses, and PET amyloid imaging in 423 newly diagnosed patients with PD from the Parkinson’s Progression Markers Initiative (PPMI) cohort …were used to evaluate established AD biomarker cutoffs compared with optimal cutoffs derived from the PPMI cohort. Results: Using PET amyloid imaging as the gold standard for AD pathology, the optimal cutoff of Aβ142 was higher than the AD cutoff, the optimal cutoffs of t-tau/Aβ142 and p-tau/Aβ142 were lower than the AD cutoffs, and their confidence intervals (CIs) did not overlap with the AD cutoffs. Optimal cutoffs for t-tau and p-tau to predict cognitive impairment were significantly lower than the AD cutoffs, and their CIs did not overlap with the AD cutoffs. Conclusion: Optimal cutoffs for the PPMI cohort for Aβ142 , t-tau/Aβ142 , and p-tau/Aβ142 to predict amyloid-PET positivity and for t-tau and p-tau to predict cognitive impairment differ significantly from cutoffs derived from AD populations. The presence of additional pathologies such as alpha-synuclein in PD may lead to disease-specific CSF biomarker characteristics. Show more

Keywords: Parkinson’s disease, Alzheimer’s disease, cerebrospinal fluid, cutoff, PET

DOI: 10.3233/JPD-212989

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1155-1167, 2022

Authors: Zhu, Shaochun | Bäckström, David | Forsgren, Lars | Trupp, Miles

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA) present with similar movement disorder symptoms but distinct protein aggregates upon pathological examination. Objective: Discovery and validation of candidate biomarkers in parkinsonian disorders for differential diagnosis of subgroup molecular etiologies. Methods: Untargeted liquid chromatography (LC)-mass spectrometry (MS) proteomics was used for discovery profiling in cerebral spinal fluid (CSF) followed by LC-MS/MS based multiple reaction monitoring for validation of candidates. We compared clinical variation within the parkinsonian cohort including PD subgroups exhibiting tremor dominance (TD) or postural instability gait disturbance and those with detectable …leukocytes in CSF. Results: We have identified candidate peptide biomarkers and validated related proteins with targeted quantitative multiplexed assays. Dopamine-drug naïve patients at first diagnosis exhibit reduced levels of signaling neuropeptides, chaperones, and processing proteases for packaging of self-aggregating peptides into dense core vesicles. Distinct patterns of biomarkers were detected in the parkinsonian disorders but were not robust enough to offer a differential diagnosis. Different biomarker changes were detected in male and female patients with PD. Subgroup specific candidate biomarkers were identified for TD PD and PD patients with leukocytes detected in CSF. Conclusion: PD, MSA, and PSP exhibit overlapping as well as distinct protein biomarkers that suggest specific molecular etiologies. This indicates common sensitivity of certain populations of selectively vulnerable neurons in the brain, and distinct therapeutic targets for PD subgroups. Our report validates a decrease in CSF levels of self-aggregating neuropeptides in parkinsonian disorders and supports the role of native amyloidogenic proteins in etiologies of neurodegenerative diseases. Show more

Keywords: Neurodegeneration, parkinsonism, proteomics, mass-spectrometry, cerebrospinal fluid, biomarkers

DOI: 10.3233/JPD-213031

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1169-1189, 2022

Authors: Prasuhn, Jannik | Strautz, Robert | Lemmer, Felicitas | Dreischmeier, Shalida | Kasten, Meike | Hanssen, Henrike | Heldmann, Marcus | Brüggemann, Norbert

Article Type: Research Article

Abstract: Background: Degeneration of dopaminergic neurons within the brainstem substantia nigra (SN) is both a pathological hallmark of Parkinson’s disease (PD) and a major contributor to symptom expression. Therefore, non-invasive evaluation of the SN is critical for diagnosis and evaluation of disease progression. Hyperechogenicity (HE+) on midbrain transcranial sonography (TCS) supports the clinically established diagnosis of PD. Further, postmortem studies suggest involvement of neuromelanin (NM) loss and iron deposition in nigral neurodegeneration and HE+ emergence. However, the associations between HE+ and signs of nigral NM loss and iron deposition revealed by magnetic resonance imaging (MRI) have not been examined. …Objective: To elucidate the magnetic resonance- (MR-) morphological representation of the HE+ by NM-weighted (NMI) and susceptibility-weighted MRI (SWI). Methods: Thirty-four PD patients and 29 healthy controls (HCs) received TCS followed by NMI and SWI. From MR images, two independent raters manually identified the SN, placed seeds in non-SN midbrain areas, and performed semi-automated SN segmentation with different thresholds based on seed mean values and standard deviations. Masks of the SN were then used to extract mean area, mean signal intensity, maximal signal area, maximum signal (for NMI), and minimum signal (for SWI). Results: There were no significant differences in NMI- and SWI-based parameters between patients and HCs, and no significant associations between HE+ extent and NMI- or SWI-based parameters. Conclusion: HE+ on TCS appears unrelated to PD pathology revealed by NMI and SWI. Thus, TCS and MRI parameters should be considered complementary, and the pathophysiological correlates of the HE+ require further study. Show more

Keywords: Disease progression, dopaminergic neurons, hyperechogenicity, magnetic resonance imaging, melanins, neuromelanin, neuromelanin-weighted imaging, Parkinson’s disease, substantia nigra, susceptibility-weighted imaging, transcranial sonography, ultrasonography

DOI: 10.3233/JPD-213000

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1191-1200, 2022

Authors: Nguyen, Tinh Thi | Kim, Yun Joong | Lai, Thuy Thi | Nguyen, Phuong Thi | Koh, Young Ho | Nguyen, Linh Thi Nhat | Ma, Hyeo-il | Kim, Young Eun

Article Type: Research Article

Abstract: Background: Mutations in PTEN-induced putative kinase 1 (PINK1 ) cause autosomal recessive Parkinson’s disease (PD) and contribute to the risk of sporadic PD. However, the relationship between PD-related PINK1 mutations and alpha-synuclein (α-syn) aggregation—a main pathological component of PD—remains unexplored. Objective: To investigate whether α-syn pathology is exacerbated in the absence of PINK1 after α-syn preformed fibril (PFF) injection in a PD mouse model and its effects on neurodegeneration. Methods: In this study, 10-week-old Pink1 knockout (KO) and wildtype (WT) mice received stereotaxic unilateral striatal injection of recombinant mouse α-syn PFF. Then, α-syn pathology …progression, inflammatory responses, and neurodegeneration were analyzed via immunohistochemistry, western blot analysis, and behavioral testing. Results: After PFF injection, the total α-syn levels significantly increased, and pathological α-syn was markedly aggregated in Pink1 KO mice compared with Pink1 WT mice. Then, earlier and more severe neuronal loss and motor deficits occurred. Moreover, compared with WT mice, Pink1 KO mice had evident microglial/astrocytic immunoreactivity and prolonged astrocytic activation, and a higher rate of protein phosphatase 2A phosphorylation, which might explain the greater α-syn aggravation and neuronal death. Conclusion: The loss of Pink1 function accelerated α-syn aggregation, accumulation and glial activation, thereby leading to early and significant neurodegeneration and behavioral impairment in the PD mouse model. Therefore, our findings support the notion that PINK1 dysfunction increases the risk of synucleinopathy. Show more

Keywords: Alpha-synuclein, PTEN-induced putative kinase 1, Protein phosphatase 2A, Inflammation, Parkinson’s disease

DOI: 10.3233/JPD-213065

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1201-1217, 2022

Authors: Chen, Szu-Ju | Chen, Chieh-Chang | Liao, Hsin-Yu | Wu, Yu-Wei | Liou, Jyh-Ming | Wu, Ming-Shiang | Kuo, Ching-Hua | Lin, Chin-Hsien

Article Type: Research Article

Abstract: Background: Emerging evidence suggests that gut dysbiosis contributes to Parkinson’s disease (PD) by signaling through microbial metabolites. Hippuric acid (HA), indole derivatives, and secondary bile acids are among the most common gut metabolites. Objective: To examine the relationship of systemic concentrations of these microbial metabolites associated with changes of gut microbiota, PD status, and severity of PD. Methods: We enrolled 56 patients with PD and 43 age- and sex-matched healthy participants. Motor and cognitive severity were assessed with Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III motor score and the Mini-Mental State Examination (MMSE), …respectively. Plasma concentrations of targeted gut metabolites were measured with liquid chromatography-tandem mass spectrometry. Gut microbiota was analyzed with shotgun metagenomic sequencing. Results: Compared with controls, PD patients had significantly higher plasma levels of HA, indole-3-propionic acid (IPA), deoxycholic acid (DCA), and glycodeoxycholic acid (GDCA). After adjustment for age and sex in a multivariate logistic regression analysis, plasma levels of HA (odds ratio [OR] 3.21, p  < 0.001), IPA (OR 2.59, p  = 0.031), and GDCA (OR 2.82, p  = 0.036) were associated with positive PD status. Concentrations of these gut metabolites did not correlate with MDS-UPDRS part III score or MMSE after adjustment for confounders. Microbial metabolite levels were associated with the relative abundance of pro-inflammatory gut bacteria. Conclusion: Aberrant gut microbial metabolites of HA, indole derivatives and secondary bile acids associated with specific gut microbiota changes were observed in patients with PD. Show more

Keywords: Parkinson’s disease, microbial metabolite, gut microbiota, gut–brain axis, bile acid, hippuric acid, indole derivative

DOI: 10.3233/JPD-223179

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1219-1230, 2022

Authors: Brezovar, Simon | Pažek, Lucija | Kavčič, Martin | Georgiev, Dejan | Trošt, Maja | Flisar, Dušan

Article Type: Research Article

Abstract: Background: While deep brain stimulation of the subthalamic nucleus (STN-DBS) significantly improves motor deficits in patients with Parkinson’s disease (PD), it is still unclear whether it affects personality functioning. Objective: The objective of the present study was to examine personality changes in patients with PD after STN-DBS from the perspectives of both the patients and caregivers. Moreover, by assessing the premorbid personalities of the patients, we tried to determine individual vulnerability to STN-DBS-induced personality changes. Methods: In total, 27 patients and their caregivers participated in our retrospective observational study. They were asked to assess the patients’ …personality changes with the Iowa Scale of Personality Changes (ISPC) and the patients’ premorbid personalities with the Big Five Inventory (BFI). Results: Caregivers reported significant personality changes in the ISPC domains of Executive Disturbance (p  = 0.01) and Disturbed Social Behavior (p  = 0.02). Most of the ISPC domains were positively correlated with Conscientiousness, while Executive Disturbance was negatively correlated with Neuroticism of the BFI scale. Conclusion: Our results show that executive and social functioning are the two most vulnerable domains in patients with PD after STN-DBS, especially in those patients who score higher for neuroticism and lower for conscientiousness on the BFI scale. The results of our study may provide movement disorder specialists with better counseling options and better selection of DBS candidates. Caregivers’ perspective might contribute significantly in understanding postoperative personality changes. Show more

Keywords: Parkinson’s disease, deep brain stimulation, personality changes

DOI: 10.3233/JPD-212879

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1231-1240, 2022

Authors: Lench, Daniel H. | Keith, Kathryn | Wilson, Sandra | Padgett, Lucas | Benitez, Andreana | Ramakrishnan, Viswanathan | Jensen, Jens H. | Bonilha, Leonardo | Revuelta, Gonzalo J.

Article Type: Research Article

Abstract: Background: Background: Parkinson’s disease (PD) patients who develop freezing of gait (FOG) have reduced mobility and independence. While some patients experience improvement in their FOG symptoms with dopaminergic therapies, a subset of patients have little to no response. To date, it is unknown what changes in brain structure underlie dopa-response and whether this can be measured using neuroimaging approaches. Objective: We tested the hypothesis that structural integrity of brain regions (subthalamic nucleus and globus pallidus internus, GPi) which link basal ganglia to the mesencephalic locomotor region (MLR), a region involved in automatic gait, would be associated with …FOG response to dopaminergic therapy. Methods: In this observational study, thirty-six participants with PD and definite FOG were recruited to undergo diffusion kurtosis imaging (DKI) and multiple assessments of dopa responsiveness (UPDRS scores, gait times ON versus OFF medication). Results: The right GPi in participants with dopa-unresponsive FOG showed reduced fractional anisotropy, mean kurtosis (MK), and increased radial diffusivity relative to those with dopa-responsive FOG. Furthermore, using probabilistic tractography, we observed reduced MK and increased mean diffusivity along the right GPi-MLR tract in dopa-unresponsive FOG. MK in the right GPi was associated with a subjective dopa-response for FOG (r  = –0.360, df = 30, p  = 0.043) but not overall motor dopa-response. Conclusion: These results support structural integrity of the GPi as a correlate to dopa-response in FOG. Additionally, this study suggests DKI metrics may be a sensitive biomarker for clinical studies targeting dopaminergic circuitry and improvements in FOG behavior. Show more

Keywords: Freezing, Parkinson’s disease, connectivity, neuroimaging, gait, dopamine, tractography, L-DOPA

DOI: 10.3233/JPD-213062

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1241-1250, 2022

Authors: Strelow, Joshua N. | Baldermann, Juan C. | Dembek, Till A. | Jergas, Hannah | Petry-Schmelzer, Jan N. | Schott, Frederik | Dafsari, Haidar S. | Moll, Christian K.E. | Hamel, Wolfgang | Gulberti, Alessandro | Visser-Vandewalle, Veerle | Fink, Gereon R. | Pötter-Nerger, Monika | Barbe, Michael T.

Article Type: Research Article

Abstract: Background: Freezing of gait (FOG) is among the most common and disabling symptoms of Parkinson’s disease (PD). Studies show that deep brain stimulation (DBS) of the subthalamic nucleus (STN) can reduce FOG severity. However, there is uncertainty about pathways that need to be modulated to improve FOG. Objective: To investigate whether STN-DBS effectively reduces FOG postoperatively and whether structural connectivity of the stimulated tissue explains variance of outcomes. Methods: We investigated 47 patients with PD and preoperative FOG. Freezing prevalence and severity was primarily assessed using the Freezing of Gait Questionnaire (FOG-Q). In a subset of …18 patients, provoked FOG during a standardized walking course was assessed. Using a publicly available model of basal-ganglia pathways we determined stimulation-dependent connectivity associated with postoperative changes in FOG. A region-of-interest analysis to a priori defined mesencephalic regions was performed using a disease-specific normative connectome. Results: Freezing of gait significantly improved six months postoperatively, marked by reduced frequency and duration of freezing episodes. Optimal stimulation volumes for improving FOG structurally connected to motor areas, the prefrontal cortex and to the globus pallidus. Stimulation of the lenticular fasciculus was associated with worsening of FOG. This connectivity profile was robust in a leave-one-out cross-validation. Subcortically, stimulation of fibers crossing the pedunculopontine nucleus and the substantia nigra correlated with postoperative improvement. Conclusion: STN-DBS can alleviate FOG severity by modulating specific pathways structurally connected to prefrontal and motor cortices. More differentiated FOG assessments may allow to differentiate pathways for specific FOG subtypes in the future. Show more

Keywords: Basal-ganglia pathways, deep brain stimulation, dorsolateral prefrontal cortex, freezing of gait, Freezing of Gait Questionnaire, globus pallidus, lenticular fasciculus, nucleus subthalamicus, supplementary motor area, Unified Parkinson’s Disease Rating Scale

DOI: 10.3233/JPD-212997

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1251-1267, 2022

Authors: Vinke, R. Saman | Selvaraj, Ashok K. | Geerlings, Martin | Georgiev, Dejan | Sadikov, Aleksander | Kubben, Pieter L. | Doorduin, Jonne | Praamstra, Peter | Bloem, Bastiaan R. | Bartels, Ronald H.M.A. | Esselink, Rianne A.J.

Article Type: Research Article

Abstract: Background: Bilateral deep brain stimulation of the subthalamic nucleus (STN-DBS) has become a cornerstone in the advanced treatment of Parkinson’s disease (PD). Despite its well-established clinical benefit, there is a significant variation in the way surgery is performed. Most centers operate with the patient awake to allow for microelectrode recording (MER) and intraoperative clinical testing. However, technical advances in MR imaging and MRI-guided surgery raise the question whether MER and intraoperative clinical testing still have added value in DBS-surgery. Objective: To evaluate the added value of MER and intraoperative clinical testing to determine final lead position in awake …MRI-guided and stereotactic CT-verified STN-DBS surgery for PD. Methods: 29 consecutive patients were analyzed retrospectively. Patients underwent awake bilateral STN-DBS with MER and intraoperative clinical testing. The role of MER and clinical testing in determining final lead position was evaluated. Furthermore, interobserver variability in determining the MRI-defined STN along the planned trajectory was investigated. Clinical improvement was evaluated at 12 months follow-up and adverse events were recorded. Results: 98% of final leads were placed in the central MER-track with an accuracy of 0.88±0.45 mm. Interobserver variability of the MRI-defined STN was 0.84±0.09. Compared to baseline, mean improvement in MDS-UPDRS-III, PDQ-39 and LEDD were 26.7±16.0 points (54%) (p  < 0.001), 9.0±20.0 points (19%) (p  = 0.025), and 794±434 mg/day (59%) (p  < 0.001) respectively. There were 19 adverse events in 11 patients, one of which (lead malposition requiring immediate postoperative revision) was a serious adverse event. Conclusion: MER and intraoperative clinical testing had no additional value in determining final lead position. These results changed our daily clinical practice to an asleep MRI-guided and stereotactic CT-verified approach. Show more

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

DOI: 10.3233/JPD-223149

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1269-1278, 2022

Authors: Dash, Deepa | Cote, Diane | Conway, Jennifer | Grimes, David | Mestre, Tiago A.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder with a myriad of motor and non-motor symptoms. Although deep brain stimulation (DBS) has a dramatic impact in the lives of people with PD, care delivery remains complex. There is a lack of evidence on the implementation and role of integrated care and self-management support in people with PD and chronic DBS. Objective: To evaluate care needs, implementation and impact of a pragmatic network for PD care, the Integrated Parkinson Care Network (IPCN) in people with PD and chronic DBS. Methods: This is a subgroup analyses of …a 6-month, pre–post design, single-centre, phase 2 study to assess a patient-centred care model based on integrated care, self-management support in PD (IPCN), focusing on those participants with chronic DBS. Results: We included 22 people with PD and chronic DBS (median time since DBS - 30 months). The mean age was 63.9 (7.6) years and mean disease duration was 15.2 (6.9) years. The top three care priorities were speech (54.5%), mobility (40.9%) and mood (31.8%). After the IPCN program, there was a positive change in the perception of support for chronic care (Patient Assessment of Chronic Illness Care +: –0.84; 95% CI: –1.2 to –0.5) and self-management (5As: –0.77; 95% CI: –1.1 to –0.4), along with quality of life (PDQ8 : 7.1, 95% CI:1.8 –12.4). Conclusion: The IPCN is a care delivery model that addresses specific care needs of people with PD and chronic DBS. The current study showed its feasibility and warrants further evaluation. Show more

Keywords: Parkinson’s disease, deep brain stimulation, care, quality of life

DOI: 10.3233/JPD-212911

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1279-1284, 2022

Authors: Van Hienen, Marle M. | Kuiper, Roy | Middelkoop, Huub A.M. | Van Hilten, Jacobus J. | Contarino, Maria Fiorella | Geraedts, Victor J.

Article Type: Research Article

Abstract: Background: Caregivers of Parkinson’s disease (PD) patients provide important support during the pre- and postoperative phase of deep brain stimulation (DBS). High levels of caregiver burden have been reported after DBS. However, a comparison between preoperative and postoperative burden and associated factors has been insufficiently studied. Objective: To investigate the influence of DBS on caregiver burden, and to identify the differential impact of patient-related factors on caregiver burden before and after DBS. Methods: Consecutive patients referred for DBS eligibility screening or during one-year follow-up assessments were included. Caregiver burden was measured with the short Zarit Burden …Interview (ZBI-12). Inverse Probability Weighting (IPW) was used to compare caregiver burden between preoperative and postoperative assessments. Results: We included 47 patients (24 screening, 23 follow-up) (median age 65 years, 29.4% female sex). DBS did not impact caregiver burden (screening: median ZBI-12 9.5 (IQR 3.25, 16.75); follow-up median ZBI-12 6 (IQR 4, 14); IPW-coefficient 0.57 (95% CI –2.75, 3.89)). Worse caregiver burden during DBS screening was associated with worse patient-related scores on depressive symptoms, anxiety, QoL, and impulsiveness. Worse scores on depressive symptoms, anxiety, apathy, postural-instability-gait-disorder, and QoL were associated with worse caregiver burden at one-year follow-up. Conclusion: DBS appears not associated with changes in caregiver burden. Various symptoms are valued differently between screening and follow-up assessments in terms of caregiver burden. Early recognition of caregivers “at risk” may improve guidance of patient-caregiver dyads throughout the DBS process. Show more

Keywords: Parkinson’s disease, caregiver burden, deep brain stimulation, quality of life, epidemiology

DOI: 10.3233/JPD-213093

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1285-1293, 2022

Authors: Oonk, Nicol G.M. | Movig, Kris L.L. | van der Palen, Job | Nibourg, Simone A.F. | Koehorst-ter Huurne, Kirsten | Nijmeijer, Henk-Willem | van Kesteren, Mirjam E. | Dorresteijn, Lucille D.A.

Article Type: Research Article

Abstract: Background: Drug therapy is important for controlling symptoms in Parkinson’s disease (PD). However, it often results in complex medication regimens and could easily lead to drug related problems (DRP), suboptimal adherence and reduced treatment efficacy. A structured medication review (SMR) could address these issues and optimize therapy, although little is known about clinical effects in PD patients. Objective: To analyze whether an SMR improves quality of life (QoL) in PD. Methods: In this multicenter randomized controlled trial, half of the 202 PD patients with polypharmacy received a community pharmacist-led SMR. The control group received usual care. …Assessments at baseline, and after three and six months comprised six validated questionnaires. Primary outcome was PD specific QoL [(PDQ-39; range 0 (best QoL) – 100 (worst QoL)]. Secondary outcomes were disability score, non-motor symptoms, general health status, and personal care giver’s QoL. Furthermore, DRPs, proposed interventions, and implemented modifications in medication schedules were analyzed. Results: No improvement in QoL was seen six months after an SMR, with a non-significant treatment effect difference of 2.09 (–0.63;4.80) in favor of the control group. No differences were found in secondary outcomes. In total, 260 potential DRPs were identified (2.6 (±1.8) per patient), of which 62% led to drug therapy optimization. Conclusion: In the current setting, a community pharmacist-led SMR did not improve QoL in PD patients, nor improved other pre-specified outcomes. Show more

Keywords: Parkinson’s disease, quality of life, drug therapy, medication adherence, drug administration schedule, clinical trials, pharmacists

DOI: 10.3233/JPD-213021

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1295-1306, 2022

Authors: Kerkemeyer, Linda | Claus, Inga | Kutscher, Michelle | von Stülpnagel, Vanessa | zur Nieden, Pauline | PNM + steering committee | Huchtemann, Tessa | Warnecke, Tobias

Article Type: Research Article

Abstract: Background: To improve Parkinson’s disease (PD) care, interdisciplinary and patient-centered treatment is mandatory. A key problem in many healthcare systems is the limited and unspecific communication among different healthcare professionals. Optimal collaboration between various professionals involved is indispensable. Parkinson’s Network Münsterland + (PNM +) is an interdisciplinary network of medical and non-medical experts involved in the treatment of PD patients in Germany. Objective: The aim of this evaluation was to analyze the network structures of PNM+ as well as communication and collaboration between PNM + partners. Methods: A mixed methods approach was applied consisting of a social network analysis, a validated …questionnaire on team effectiveness and semi-structured interviews focusing on perceived barriers and supportive aspects of PNM + . Results: Quantitative and qualitative data suggested increased collaboration between professionals within PNM + . The reciprocity of connections was 0.522 in the network of professional contacts. Regular exchanges in terms of interdisciplinary panel meetings and working groups stimulated knowledge transfer, leading to greater specialization of general neurologists and therapists in PD. The progressive density of the network from 0.136 to 0.279 illustrates the growing cooperation of PNM + partners. Interviewed partners requested more patient-specific collaboration but expected this to happen as the network evolved. Overall, PNM + has already improved both diagnosis and therapy thanks to knowledge transfer. Structured treatment recommendations helped to improve communication between healthcare professionals. Conclusion: PNM+ stimulated exchange between different healthcare professionals involved in the treatment of PD patients. This overcomes specific barriers within Germany’s highly fragmented healthcare system, such as the lack of communication between these disciplines. Show more

Keywords: Parkinson’s disease, community care networks, interdisciplinary health team, interdisciplinary communication

DOI: 10.3233/JPD-213072

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1307-1317, 2022

Authors: Stang, Cole D. | Mullan, Aidan F. | Camerucci, Emanuele | Hajeb, Mania | Turcano, Pierpaolo | Martin, Peter | Mielke, Michelle M. | Josephs, Keith A. | Splett, Matthew | Abler, Victor | Boeve, Bradley F. | Bower, James H. | Savica, Rodolfo

Article Type: Research Article

Abstract: BACKGROUND: Parkinson’s disease (PD)-associated psychosis is a well-known non-motor complication, occurring years after diagnosis of PD. Incidence data vary across different studies highlighting a need for long-term observation and clinical definition. OBJECTIVE: To determine the incidence of psychosis in patients with PD and to investigate their survival in an incident cohort study from 1991–2010 in Olmsted County, MN. METHODS: We used the Rochester Epidemiology Project to define an incident-cohort study of parkinsonism (1991–2010) in Olmsted County, MN. A movement-disorder specialist reviewed the electronic medical records and applied diagnosis criteria to PD. Psychosis was diagnosed using of …NINDS/NIMH unified criteria. RESULTS: We identified 669 cases of parkinsonism; 297 patients were clinically diagnosed with PD. 114/297 (38.4%) patients had evidence of psychosis (60% male); the median onset age of psychosis was 79.4 years. The incidence of Parkinson’s disease psychosis (PDP) was 4.28/100 person-years. PDP patients had a 71% increased risk of death compared to PD patients. In PD patients without psychosis, men had 73.4% increased risk of death compared to women, whereas no significant sex difference was observed among PDP men vs. women. Of 114 patients diagnosed with psychosis, 59 were treated with antipsychotics. There was no significant difference in survival between treated and untreated patients. CONCLUSION: PDP increased the odds of death compared to PD patients. Men with PD without psychosis had greater odds of death compared to women; however, in PD with psychosis the odds of death were comparable among sexes. Lastly, treatment with anti-psychotics did not significantly affect survival. Show more

Keywords: Parkinsonism, psychosis, hallucinations, delirium, antipsychotics

DOI: 10.3233/JPD-213035

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1319-1327, 2022

Authors: Béreau, Matthieu | Castrioto, Anna | Lhommée, Eugénie | Maillet, Audrey | Gérazime, Aurélie | Bichon, Amélie | Pélissier, Pierre | Schmitt, Emmanuelle | Klinger, Hélène | Longato, Nadine | Fraix, Valérie | Benatru, Isabelle | Durif, Franck | Azulay, Jean-Philippe | Moro, Elena | Broussolle, Emmanuel | Tranchant, Christine | Anheim, Mathieu | Thobois, Stéphane | Krack, Paul

Article Type: Research Article

Abstract: Background: Fatigue is a frequent and troublesome symptom present from the early stages of Parkinson’s disease (PD). Objective: To examine the relationship between fatigue and the neuropsychiatric triad, which includes apathy, depression, and anxiety, in de novo PD. Methods: We performed a cross-sectional study including 197 patients with de novo PD and assessed fatigue using the Parkinson’s Disease Fatigue Scale (PDFS-16). We evaluated motor status using the Unified Parkinson’s Disease Rating Scale (UPDRS) part III score and evaluated neuropsychiatric status using the Ardouin Scale of Behavior in Parkinson’s Disease (ASBPD). We carried out univariate …and multivariate analyses to model association between motor signs, non-motor signs, and fatigue risk. Results: Frequency of fatigue (28.9%) was of the same order of magnitude as that of apathy. PD patients with fatigue reported a lower quality of life than patients without fatigue (p  < 0.0001). The ASBPD showed that patients with fatigue had higher scores for depressed mood (p  < 0.0001), anxiety (p  < 0.0001), and apathy (p  < 0.0001). In the univariate analysis, fatigue score was positively correlated with apathy, depression, anxiety, and the neuropsychiatric triad as a whole, and to a lesser extent with female sex, hyperemotivity, and the UPDRS part III score. In the multivariate analysis, after adjusting for sex and motor status, the fatigue score remained significantly correlated with apathy (OR = 11.17 [4.33–28.78], p  < 0.0001) and depression (OR = 4.28 [1.39–13.12], p  = 0.01), but not with anxiety (OR = 0.94 [0.34–2.58], p  = 0.9). Conclusion: We propose that the neuropsychiatric triad could be expanded to include fatigue. Show more

Keywords: Parkinson’s disease, fatigue, apathy, depression, motivation

DOI: 10.3233/JPD-213116

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1329-1337, 2022

Authors: Bliwise, Donald L. | Karroum, Elias G. | Greer, Sophia A. | Factor, Stewart A. | Trotti, Lynn Marie

Article Type: Research Article

Abstract: Background: The association between restless legs syndrome (RLS) and Parkinson’s disease (PD) remains controversial, with epidemiologic and descriptive evidence suggesting some potential overlap while mechanistic/genetic studies suggesting relative independence of the conditions. Objective: To examine a known, objectively measured endophenotype for RLS, periodic leg movements (PLMS) in sleep, in patients with PD and relate that objective finding to restless legs symptoms. Methods: We performed polysomnography for one (n  = 8) or two (n  = 67) consecutive nights in 75 PD patients and examined the association of PLMS with restless legs symptoms. Results: We found no association …between restless legs symptoms and PLMS in PD. Prevalence of both was similar to data reported previously in other PD samples. Conclusion: We interpret these results as suggesting that restless legs symptoms in PD patients may represent a different phenomenon and pathophysiology than RLS in the non-PD population. Show more

Keywords: Restless legs, periodic leg movements in sleep, Parkinson’s disease

DOI: 10.3233/JPD-213100

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1339-1344, 2022

Authors: Tosin, Michelle H.S. | Simuni, Tanya | Stebbins, Glenn T. | Cedarbaum, Jesse M.

Article Type: Research Article

Abstract: Background: Summary scores of current clinical rating scales do not appear sensitive enough to quantify changes in disease progression in early Parkinson’s disease (PD) clinical trials. An alternate approach might be to track the appearance of new or emergent symptoms (ES) over time as a measure of disease progression. Objective: Explore the potential utility of patient reported ES as an outcome measure during the early phase of PD. Methods: We analyzed data from the MDS-UPDRS Parts IB (non-motor) and II (motor) Experiences of Daily Living scales over two years in the STEADY-PD3 study. We assessed the …number of ES reported in each part of the scale in both participants who started symptomatic treatment and those who did not (STx-yes/no) in two periods: between 0 and 12-months (Year 1), and 13 and 24-months (Year 2). Results: Of 331 participants, 87% developed ES, and 55% started STx in Year 1. The median number of Part IB ES did not significantly differ between STx groups, but ES in Part II were significantly more frequent in the STx-yes group. Of 148 participants who remained STx-no into Year 2, 77% developed ES, and 42% started STx. Again, Part II, but not Part IB ES were more frequent the STx-yes group. Using these results, a sample size of ∼90 per group would be required to detect a 30% reduction in combined Part IB and II ES over 12 months. Conclusion: Assessing ES of patient-reported experiences of daily living may provide a useful marker for tracking PD progression. Show more

Keywords: Parkinson’s disease, clinimetrics, activities of daily living, patient outcome assessment, severity of illness index

DOI: 10.3233/JPD-223170

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1345-1351, 2022

Authors: Kal, Elmar C. | Ellmers, Toby J. | Fielding, Anna E. | Hardeman, Lotte | Coito, Juliana | Joyce, Lauren | Young, William R.

Article Type: Short Communication

Abstract: Freezing of gait (FOG) can severely compromise daily functioning in people with Parkinson’s disease. Inability to initiate a step from FOG is likely underpinned, at least in part, by a deficient preparatory weight-shift. Conscious attempts to weight-shift in preparation to step can improve success of initiating forward steps following FOG. However, FOG often occurs during turning, where weight-shifting is more complex and risk of falling is higher. We explored the effectiveness of a dance-based (‘cha-cha’) weight-shifting strategy to re-initiate stepping following FOG during turning. Results suggest that this simple movement strategy can enhance turning steps following FOG, without compromising safety.

Keywords: Parkinson’s disease, freezing of gait, cueing, step initiation, anticipatory postural adjustment, weight-shifting, festination

DOI: 10.3233/JPD-213125

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1353-1358, 2022

Authors: Meinders, Marjan J. | Donnelly, Anne C. | Sheehan, Margaret | Bloem, Bastiaan R.

Article Type: Short Communication

Abstract: The proactive inclusion of patients in the design and execution of clinical studies has been an emerging focus for decades. Such participatory research helps to design studies better, by addressing relevant research questions and defining outcomes that matter to patients. Yet, much remains to be learned about the best methods and exact impacts of patient engagement in research in general, and more specifically, about the specific challenges that come with Parkinson’s disease. Here we present the lived experiences of patient researchers living with Parkinson’s disease, as a motivation for the value of their perspectives in research and as a call …to action for empirical research on how to successfully include patient researchers. Show more

Keywords: Patient participation, patient advocacy, patient preference, Parkinson’s disease

DOI: 10.3233/JPD-223190

Citation: Journal of Parkinson's Disease, vol. 12, no. 4, pp. 1359-1363, 2022