Journal of Parkinson's Disease - Volume 11, issue 3

Authors: Thaler, Avner | Omer, Nurit | Giladi, Nir | Gurevich, Tanya | Bar-Shira, Anat | Gana-Weisz, Mali | Goldstein, Orly | Kestenbaum, Meir | Shirvan, Julia C. | Cedarbaum, Jesse M. | Orr-Urtreger, Avi | Regev, Keren | Shenhar-Tsarfaty, Shani | Mirelman, Anat

Article Type: Research Article

Abstract: Background: Inflammation is an integral part of neurodegeneration including in Parkinson’s disease (PD). Ashkenazi Jews have high rates of genetic PD with divergent phenotypes among GBA -PD and LRRK2 -PD. The role of inflammation in the prodromal phase of PD and the association with disease phenotype has yet to be elucidated. Objective: To assess central and peripheral cytokines among PD patients with mutations in the LRRK2 and GBA genes and among non-manifesting carriers (NMC) of these mutations in order to determine the role of inflammation in genetic PD. Methods: The following cytokines were assessed …from peripheral blood and cerebrospinal fluid (CSF): TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10 and INF- γ . A comprehensive intake including general medical conditions, use of anti-inflammatory treatments, motor and cognitive assessments and additional laboratory measures were recorded, enabling the construction of the MDS probable prodromal score. Results: Data from 362 participants was collected: 31 idiopathic PD (iPD), 30 LRRK 2-PD, 77 GBA -PD, 3 homozygote GBA -PD, 3 GBA -LRRK2 -PD, 67 LRRK2 -NMC, 105 GBA -NMC, 14 LRRK2 -GBA -NMC, and 32 healthy controls. No between-group differences in peripheral or CSF cytokines were detected. No correlation between disease characteristics or risk for prodromal PD could be associated with any inflammatory measure. Conclusion: In this study, we could not detect any evidence on dysregulated immune response among GBA and LRRK2 PD patients and non-manifesting mutation carriers. Show more

Keywords: Parkinson’s disease, LRRK2, GBA, inflammation

DOI: 10.3233/JPD-212624

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1285-1296, 2021

Authors: Lawson, Rachael A. | Williams-Gray, Caroline H. | Camacho, Marta | Duncan, Gordon W. | Khoo, Tien K. | Breen, David P. | Barker, Roger A. | Rochester, Lynn | Burn, David J. | Yarnall, Alison J. | on behalf of the ICICLE-PD study group

Article Type: Research Article

Abstract: Background: Cognitive impairment is common in Parkinson’s disease (PD), with 80% cumulatively developing dementia (PDD). Objective: We sought to identify tests that are sensitive to change over time above normal ageing so as to refine the neuropsychological tests predictive of PDD. Methods: Participants with newly diagnosed PD (n  = 211) and age-matched controls (n  = 99) completed a range of clinical and neuropsychological tests as part of the ICICLE-PD study at 18-month intervals over 72 months. Impairments on tests were determined using control means (<1-2SD) and median scores. Mild cognitive impairment (PD-MCI) was classified using 1-2SD below normative …values. Linear mixed effects modelling assessed cognitive decline, while Cox regression identified baseline predictors of PDD. Results: At 72 months, 46 (cumulative probability 33.9%) participants had developed PDD; these participants declined at a faster rate in tests of global cognition, verbal fluency, memory and attention (p  < 0.05) compared to those who remained dementia-free. Impaired baseline global cognition, visual memory and attention using median cut-offs were the best predictors of early PDD (area under the curve [AUC] = 0.88, p  < 0.001) compared to control-generated cut-offs (AUC = 0.76–0.84, p  < 0.001) and PD-MCI (AUC = 0.64–0.81, p  < 0.001). Impaired global cognition and semantic fluency were the most useful brief tests employable in a clinical setting (AUC = 0.79, p  < 0.001). Conclusion: Verbal fluency, attention and memory were sensitive to change in early PDD and may be suitable tests to measure therapeutic response in future interventions. Impaired global cognition, attention and visual memory were the most accurate predictors for developing a PDD. Future studies could consider adopting these tests for patient clinical trial stratification. Show more

Keywords: Parkinson’s disease, neurocognitive disorders, cognitive dysfunction, neuropsychological tests

DOI: 10.3233/JPD-212581

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1297-1308, 2021

Authors: Tolosa, Eduardo | Ebersbach, Georg | Ferreira, Joaquim J. | Rascol, Olivier | Antonini, Angelo | Foltynie, Thomas | Gibson, Rachel | Magalhaes, Diogo | Rocha, J. Francisco | Lees, Andrew

Article Type: Research Article

Abstract: Background: A greater understanding of the everyday experiences of people with Parkinson’s disease (PD) and their carers may help improve clinical practice. Objective: The Parkinson’s Real-world Impact assesSMent (PRISM) study evaluated medication use, health-related quality of life (HRQoL) and the use of healthcare resources by people with PD and their carers. Methods: PRISM is an observational cross-sectional study, in which people with PD and their carers completed an online survey using structured questionnaires, including the Parkinson’s Disease Quality of Life Questionnaire (PDQ-39), Non-Motor Symptoms Questionnaire (NMSQuest) and Zarit Burden Interview (ZBI). Results: Data were …collected from 861 people with PD (mean age, 65.0 years; mean disease duration, 7.7 years) and 256 carers from six European countries. People with PD reported a large number of different co-morbidities, non-motor symptoms (mean NMSQuest score, 12.8), and impaired HRQoL (median PDQ-39 summary score, 29.1). Forty-five percent of people with PD reported at least one impulse control behaviour. Treatment patterns varied considerably between different European countries. Levodopa was taken in the last 12 months by 85.9% of participants, and as monotherapy by 21.8%. Carers, who were mostly female (64.8%) and the partner/spouse of the person with PD (82.1%), reported mild to moderate burden (mean ZBI total score, 26.6). Conclusions: The PRISM study sheds light on the lives of people with PD and those who care for them, re-emphasising the many challenges they face in everyday life. The study also provides insights into the current treatment of PD in Europe. Show more

Keywords: Caregivers, catechol o-methyltransferase inhibitors, comorbidity, dopamine agonists, Europe, levodopa, observational study, Parkinson’s disease, quality of life, surveys and questionnaires

DOI: 10.3233/JPD-212611

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1309-1323, 2021

Authors: Sieurin, Johanna | Zhan, Yiqiang | Pedersen, Nancy L. | Wirdefeldt, Karin

Article Type: Research Article

Abstract: Background: The relationship among neuroticism, smoking, and Parkinson’s disease (PD) is less examined. Objective: To examine the causal associations between neuroticism, smoking initiation, and the risk of PD. Methods: We performed a two-sample Mendelian randomization (MR) design in a network framework. Summary statistics from meta-analyses of genome-wide association studies (GWAS) were based on large cohorts of European ancestry. Study participants were from various cohort studies for neuroticism and smoking initiation, and case-control studies or cohort studies of PD from previously published GWAS meta-analyses. Patients with PD were ascertained from either clinical visit or self-reported. …Results: The two-sample MR analysis showed no evidence for a causal association between neuroticism and PD risk (odds ratio [OR] 0.86, 95%confidence intervals [CIs] 0.67 to 1.12). While we did not find a significant association between neuroticism and PD, one SNP, rs58879558 (located in MAPT region), was associated with both neuroticism and PD. We found a significant association of neuroticism on smoking initiation (OR: 1.10, 95%CI: 1.05 to 1.14). Further, our results provided evidence for a protective effect of smoking initiation on the risk of PD (OR: 0.75, 95%CI: 0.62 to 0.91). Conclusion: These findings do not support a causal association of neuroticism on PD risk. However, they provide evidence for a causal relationship between neuroticism and smoking initiation and a strong causal effect of smoking initiation on a reduced risk of PD. Show more

Keywords: Neuroticism, smoking, Parkinson’s disease, mendelian randomization.

DOI: 10.3233/JPD-202522

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1325-1334, 2021

Authors: Yoo, Sang-Won | Ha, Seunggyun | Yoon, Hyukjin | Yoo, Ji-Yeon | Lee, Kwang-Soo | Kim, Joong-Seok

Article Type: Research Article

Abstract: Background: Orthostatic hypotension (OH) may antedate Parkinson’s disease (PD) or be found in early stages of the disease. OH may induce a PD brain to chronic hypotensive insults. 18 F-Florbetaben (18 F-FBB) tracer has a high first-pass influx rate and can be used with positron emission tomography (PET) as a surrogate marker for early- and late-phase evaluation of cerebral perfusion and cerebral amyloidosis, respectively. Objective: In this study, we evaluated whether 18 F-FBB uptake in the early- and late-phases of PD was related to OH. This study manipulated the imaging modality to illustrate the physiology of cerebral flow …with OH in PD (PD + OH). Methods: A group of 73 early-stage PD patients was evaluated with a head-up tilt-test and 18 F-FBB PET imaging. The cognitive status was assessed by a comprehensive battery of neuropsychological tests. PET images were normalized, and both early- and late-phase standardized uptake value ratios (SUVRs) of pre-specified regions were obtained. The associations between regional SUVRs and OH and cognitive status were analyzed. Results: Twenty (27.4%) participants had OH. Thirteen (17.8%) patients were interpreted as having amyloid pathology based on regional 18 F-FBB uptake. Early-phase SUVRs were higher in specific brain regions of PD + OH patients than those without OH. However, late-phase SUVRs did not differ between the groups. The early-phase SUVRs were not influenced by amyloid burden or by interaction between amyloid and orthostatic hypotension. Cognitive functions were not disparate when PD + OH patients were contrasted with non-OH patients in this study. Conclusion: Cerebral blood flow was elevated in patients with early PD + OH. This finding suggests augmented cerebral perfusion in PD + OH might be a compensatory regulation in response to chronic OH. Show more

Keywords: Parkinson’s disease, orthostatic hypotension, cerebral perfusion, cerebral autoregulation, 18F-Florbetaben (FBB), positron emission tomography

DOI: 10.3233/JPD-212596

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1335-1344, 2021

Authors: Villar-Conde, Sandra | Astillero-Lopez, Veronica | Gonzalez-Rodriguez, Melania | Villanueva-Anguita, Patricia | Saiz-Sanchez, Daniel | Martinez-Marcos, Alino | Flores-Cuadrado, Alicia | Ubeda-Bañon, Isabel

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a prevalent neurodegenerative disease that is pathologically described as a six-stage α-synucleinopathy. In stage 4, α-synuclein reaches the hippocampus, inducing cognitive deficits, from which it progresses to the isocortex, leading to dementia. Among hippocampal fields, cornu ammonis 2 is particularly affected by this α-synucleinopathy and critical for cognitive decline. Volumetric studies using magnetic resonance imaging have produced controversial results, with only some reporting volume loss, whereas stereological data obtained using nonspecific markers do not reveal volume changes, neural or glial loss. Proteomic analysis has not been carried out in the hippocampus of patients with …PD. Objective: This study aims to explain hippocampal changes in patients with PD at the cellular and proteomic levels. Methods: α-Synuclein inclusions, volume and neural (NeuN), microglial (Iba-1) and astroglial (GFAP) populations were stereologically analyzed. SWATH-MS quantitative proteomic analysis was also conducted. Results: Area fraction fractionator probe revealed a higher area fraction α-synucleinopathy in cornu ammonis 2 . No volume change, neurodegeneration, microgliosis or astrogliosis was detected. Proteomic analysis identified 1,634 proteins, of which 83 were particularly useful for defining differences among PD and non-PD groups. Among them, upregulated (PHYIP, CTND2, AHSA1 and SNTA1) and downregulated (TM163, REEP2 and CSKI1) proteins were related to synaptic structures in the diseased hippocampus. Conclusion: The distribution of α-synuclein in the hippocampus is not associated with volumetric, neural or glial changes. Proteomic analysis, however, reveals a series of changes in proteins associated with synaptic structures, suggesting that hippocampal changes occur at the synapse level during PD. Show more

Keywords: Parkinson disease, hippocampus, human, alpha synuclein, neurons, microglia, astrocytes

DOI: 10.3233/JPD-202465

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1345-1365, 2021

Authors: Dijkstra, Bauke W. | Gilat, Moran | Cofré Lizama, L. Eduardo | Mancini, Martina | Bergmans, Bruno | Verschueren, Sabine M.P. | Nieuwboer, Alice

Article Type: Research Article

Abstract: Background: People with Parkinson’s disease and freezing of gait (FOG; freezers) suffer from pronounced postural instability. However, the relationship between these phenomena remains unclear and has mostly been tested in paradigms requiring step generation. Objective: To determine if freezing-related dynamic balance deficits are present during a task without stepping and determine the influence of dopaminergic medication on dynamic balance control. Methods: Twenty-two freezers, 16 non-freezers, and 20 healthy age-matched controls performed mediolateral weight-shifts at increasing frequencies when following a visual target projected on a screen (MELBA task). The amplitude and phase shift differences between center of …mass and target motion were measured. Balance scores (Mini-BESTest), 360° turning speed and the freezing ratio were also measured. Subjects with Parkinson’s disease were tested ON and partial OFF (overnight withdrawal) dopaminergic medication. Results: Freezers had comparable turning speed and balance scores to non-freezers and took more levodopa. Freezers produced hypokinetic weight-shift amplitudes throughout the MELBA task compared to non-freezers (p  = 0.002), which were already present at task onset (p  < 0.001). Freezers also displayed an earlier weight-shift breakdown than controls when OFF-medication (p  = 0.008). Medication improved mediolateral weight-shifting in freezers and non-freezers. Freezers decreased their freezing ratio in response to medication. Conclusion: Hypokinetic weight-shifting proved a marked postural control deficit in freezers, while balance scores and turning speed were similar to non-freezers. Both weight-shift amplitudes and the freezing ratio were responsive to medication in freezers, suggesting axial motor vigor is levodopa-responsive. Future work needs to test whether weight-shifting and freezing severity can be further ameliorated through training. Show more

Keywords: Parkinson disease, freezing of gait, levodopa, postural balance

DOI: 10.3233/JPD-202370

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1367-1380, 2021

Authors: Chandler, Julie M. | Nair, Radhika | Biglan, Kevin | Ferries, Erin A. | Munsie, Leanne M. | Changamire, Tich | Patel, Nick

Article Type: Research Article

Abstract: Background: Characterizing patients with Parkinson’s disease (PD) and cognitive impairment is important toward understanding their natural history. Objective: Understand clinical, treatment, and cost characteristics of patients with PD pre- and post-cognitive impairment (memory loss/mild cognitive impairment/dementia or dementia treatment) recognition. Methods: 2,711 patients with PD newly diagnosed with cognitive impairment (index) were identified using administrative claims data. They were matched (1:1) on age and gender to patients with PD and no cognitive impairment (controls). These two cohorts were compared on patient characteristics, healthcare resource utilization, and total median costs for 3 years pre- and post-index using …Chi-square tests, t -tests, and Wilcoxon rank-sum tests. Logistic regression was used to identify factors predicting cognitive impairment. Results: Comorbidity indices for patients with cognitive impairment increased during the 6-year study period, especially after the index. Enrollment in Medicare Advantage Prescription Drug plans vs. commercial (OR = 1.60), dual Medicare/Medicaid eligibility (OR = 1.36), cerebrovascular disease (OR = 1.24), and PD medication use (OR = 1.46) were associated with a new cognitive impairment diagnosis (all p  < 0.05). A greater proportion of patients with cognitive impairment had hospitalizations and emergency department visits and higher median total healthcare costs than controls for each year pre- and post-index. Conclusion: In patients with PD newly diagnosed with cognitive impairment, comorbidity burden, hospitalizations, emergency department visits, and total costs peaked 1-year pre- and post-identification. These data coupled with recommendations for annual screening for cognitive impairment in PD support the early diagnosis and management of cognitive impairment in order to optimize care for patients and their caregivers. Show more

Keywords: Parkinson’s disease, mild cognitive impairment, dementia, cost

DOI: 10.3233/JPD-202190

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1381-1392, 2021

Authors: Piscicelli, Céline | Castrioto, Anna | Jaeger, Marie | Fraix, Valerie | Chabardes, Stephan | Moro, Elena | Krack, Paul | Debû, Bettina | Pérennou, Dominic

Article Type: Research Article

Abstract: Background: Verticality perception is frequently altered in Parkinson’s disease (PD) with Pisa syndrome (PS). Is it the cause or the consequence of the PS? Objective: We tested the hypothesis that both scenarios coexist. Methods: We performed a double-blind within-person randomized trial (NCT02704910) in 18 individuals (median age 63.5 years) with PD evolving for a median of 17.5 years and PS for 2.5 years and treated with bilateral stimulation of the subthalamus nuclei (STN-DBS) for 6.5 years. We analyzed whether head and trunk orientations were congruent with the visual (VV) and postural (PV) vertical, and whether switching …on one or both sides of the STN-DBS could modulate trunk orientation via verticality representation. Results: The tilted verticality perception could explain the PS in 6/18 (33%) patients, overall in three right-handers (17%) who showed net and congruent leftward trunk and PV tilts. Two of the 18 (11%) had an outstanding clinical picture associating leftward: predominant parkinsonian symptoms, whole-body tilt (head –11°, trunk –8°) and transmodal tilt in verticality perception (PV –10°, VV –8.9°). Trunk orientation or VV were not modulated by STN-DBS, whereas PV tilts were attenuated by unilateral or bilateral stimulations if it was applied on the opposite STN. Conclusion: In most cases of PS, verticality perception is altered by the body deformity. In some cases, PS seems secondary to a biased internal model of verticality, and DBS on the side of the most denervated STN attenuated PV tilts with a quasi-immediate effect. This is an interesting track for further clinical studies. Show more

Keywords: Deep brain stimulation, neuromodulation, Parkinson’s disease, Pisa syndrome, spatial cognition, subthalamic nuclei, verticality perception

DOI: 10.3233/JPD-202388

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1393-1408, 2021

Authors: Honeycutt, Lucy | Gagnon, Jean-François | Pelletier, Amélie | Montplaisir, Jacques Y. | Gagnon, Geneviève | Postuma, Ronald B.

Article Type: Research Article

Abstract: Background: Depression and anxiety are common in synucleinopathies and often present during prodromal stages, including idiopathic/isolated REM sleep behavior disorder (iRBD). However, the specific profiles of depression/anxiety and their predictive values for phenoconversion remain unclear. Objective: To assess the predominant manifestations, predictive value, and changes over time in depressive and anxiety symptoms in iRBD. Methods: Patients with polysomnography-confirmed iRBD (n  = 114) and healthy controls (n  = 44) were recruited. The Beck Depression Inventory and Beck Anxiety Inventory were administered at baseline, which was repeated prospectively over follow-up. Factor solutions were generated to delineate symptom clusters within the …scales, and to help disentangle primary mood symptoms from other neurodegenerative confounds. Total scores, individual scale items, and factors were evaluated to 1) compare patients and controls, 2) assess progression of symptoms over time, and 3) assess predictive value for phenoconversion. Results: At baseline, iRBD patients had more severe depressive (9.0 = 6.7 vs 5.8 = 4.8) and anxiety (7.0 = 7.9 vs 4.5 = 6.0) symptoms than controls. Increased scores were seen in numerous individual scale items and most scales’ factors. For depressive symptoms, there was no progression of total scores or factors over time. However, anxiety scores worsened slightly over prospective follow-up (annual slope = 0.58 points, p  < 0.05). Over an average 2.4 = 3.1-year follow-up, 37 patients phenoconverted and 72 remained disease-free. Neither baseline depressive nor anxiety symptoms predicted phenoconversion to clinical neurodegenerative disease. Conclusions: Depressive and anxiety symptoms are common in iRBD. However, they do not predict phenoconversion and show only modest progression over time, solely for anxiety. Show more

Keywords: REM sleep behaviour disorder, depression, anxiety, progression, prodromal

DOI: 10.3233/JPD-212625

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1409-1416, 2021