Journal of Parkinson's Disease - Volume 12, issue 8

Authors: Bloem, Bastiaan R. | Kalia, Lorraine V.

Article Type: Editorial

DOI: 10.3233/JPD-229010

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2283-2286, 2022

Authors: McFarthing, Kevin

Article Type: Article Commentary

DOI: 10.3233/JPD-229007

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2287-2288, 2022

Authors: Richard, Edo | Bloem, Bastiaan R.

Article Type: Editorial

Keywords: Parkinson’s disease, alpha-synuclein, cinpanemab, prasinezumab

DOI: 10.3233/JPD-225032

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2289-2291, 2022

Authors: Brundin, Patrik | Svoboda, Hanno | Bonni, Azad | Pagano, Gennaro

Article Type: Article Commentary

DOI: 10.3233/JPD-229008

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2293-2296, 2022

Authors: Schootemeijer, Sabine | Darweesh, Sirwan K.L. | de Vries, Nienke M.

Article Type: Research Article

Abstract:  Converging lines of evidence suggest that aerobic exercise impacts Parkinson’s disease (PD) motor symptoms and might slow it’s progression. We provide an overview of the ongoing randomized clinical trials (RCTs) on aerobic exercise in PD. We found six RCTs with sample sizes between 28 and 370 and a follow-up between 8 weeks and 18 months. PD motor symptoms is mostly used as primary outcome while various secondary outcomes are reported. We need more trials that use both clinical endpoints and markers of neuroplasticity, and provide insight into the optimal exercise mode, duration and intensity.

DOI: 10.3233/JPD-229006

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2297-2306, 2022

Authors: Björklund, Anders | Nilsson, Fredrik | Mattsson, Bengt | Hoban, Deirdre B. | Parmar, Malin

Article Type: Review Article

Abstract: Injections of pre-formed α-synuclein fibrils (PFFs) or overexpression of α-synuclein using AAV vectors are commonly used as models of Parkinson-like synucleinopathy in rats and mice. In the modified method reviewed here, the “SynFib ” model, the PFFs and the AAV vector are administered together unilaterally into the substantia nigra. This approach combines the key features of these two models, i.e., the generation of toxic α-synuclein aggregates and Lewy body-like inclusions, in combination with the increased vulnerability caused by increased cellular levels of α-synuclein. The combined AAV/PFF delivery offers several advantages over the standard PFF model due to the enhanced and …accelerated α-synuclein pathology and microglial response induced by the PFF seeds in the presence of an elevated α-synuclein level. Injection of the AAV/PFF mixture into the substantia nigra makes it possible to target a larger proportion of the nigral dopamine neurons and obtain a level of dopamine cell loss (>60%) needed to induce significant impairments in drug-induced and spontaneous motor tests. The SynFib model shares attractive features of the standard 6-OHDA lesion model: a single unilateral stereotaxic intervention; pathology and cell loss developing over a short time span; and the possibility to monitor the degenerative changes using tests of motor behavior. Show more

Keywords: adeno-associated virus, disease modeling, inflammation, motor behavior, mouse, Parkinson’s disease, pre-formed fibrils, rat

DOI: 10.3233/JPD-223452

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2307-2320, 2022

Authors: Coleman, Colin | Martin, Ian

Article Type: Review Article

Abstract: Aging is the greatest risk factor for Parkinson’s disease (PD), suggesting that mechanisms driving the aging process promote PD neurodegeneration. Several lines of evidence support a role for aging in PD. First, hallmarks of brain aging such as mitochondrial dysfunction and oxidative stress, loss of protein homeostasis, and neuroinflammation are centrally implicated in PD development. Second, mutations that cause monogenic PD are present from conception, yet typically only cause disease following a period of aging. Third, lifespan-extending genetic, dietary, or pharmacological interventions frequently attenuate PD-related neurodegeneration. These observations support a central role for aging in disease development and suggest that …new discoveries in the biology of aging could be leveraged to elucidate novel mechanisms of PD pathophysiology. A recent rapid growth in our understanding of conserved molecular pathways that govern model organism lifespan and healthspan has highlighted a key role for metabolism and nutrient sensing pathways. Uncovering how metabolic pathways involving NAD+ consumption, insulin, and mTOR signaling link to the development of PD is underway and implicates metabolism in disease etiology. Here, we assess areas of convergence between nervous system aging and PD, evaluate the link between metabolism, aging, and PD and address the potential of metabolic interventions to slow or halt the onset of PD-related neurodegeneration drawing on evidence from cellular and animal models. Show more

Keywords: Aging, Parkinson’s disease, metabolism, mitochondria

DOI: 10.3233/JPD-223363

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2321-2338, 2022

Authors: Chan, Dennis G. | Ventura, Katelyn | Villeneuve, Ally | Du Bois, Paul | Holahan, Matthew R.

Article Type: Review Article

Abstract: The contribution of the microbiota to induce gastrointestinal inflammation is hypothesized to be a key component of alpha-synuclein (aSyn) aggregation within the gastrointestinal (GI) tract in the pathological progression of Parkinson’s disease (PD). The function of the GI tract is governed by a system of neurons that form part of the enteric nervous system (ENS). The ENS hosts  100–500 million nerve cells within two thin layers lining the GI tract. The gut-brain axis (GBA) is the major communication pathway between the ENS and the central nervous system. It has become increasingly clear that the microbiota in the gut are key …regulators of GBA function and help to maintain homeostasis in the immune and endocrine systems. The GBA may act as a possible etiological launching pad for the pathogenesis of age-related neurodegenerative diseases, such as PD, because of an imbalance in the gut microbiota. PD is a multi-faceted illness with multiple biological, immunological, and environmental factors contributing to its pathological progression. Interestingly, individuals with PD have an altered gut microbiota compared to healthy individuals. However, there is a lack of literature describing the relationship between microbiota composition in the gut and symptom progression in PD patients. This review article examines how the pathology and symptomology of PD may originate from dysregulated signaling in the ENS. We then discuss by targeting the imbalance within the gut microbiota such as prebiotics and probiotics, some of the prodromal symptoms might be alleviated, possibly curtailing the pathological spread of aSyn and ensuing debilitating motor symptoms. Show more

Keywords: Microbiome, Parkinson’s disease, alpha-synuclein, prodromal symptoms, probiotics, prebiotics, fecal microbiota transplantation, gastrointestinal tract

DOI: 10.3233/JPD-223461

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2339-2352, 2022

Authors: Kolicheski, Ana | Turcano, Pierpaolo | Tamvaka, Nicole | McLean, Pamela J. | Springer, Wolfdieter | Savica, Rodolfo | Ross, Owen A.

Article Type: Review Article

Abstract: Parkinson’s disease (PD) by its common understanding is a late-onset sporadic movement disorder. However, there is a need to recognize not only the fact that PD pathogenesis expands beyond (or perhaps to) the brain but also that many early-onset patients develop motor signs before the age of 50 years. Indeed, studies have shown that it is likely the protein aggregation observed in the brains of patients with PD precedes the motor symptoms by perhaps a decade. Studies on early-onset forms of PD have shown it to be a heterogeneous disease with multiple genetic and environmental factors determining risk of different …forms of disease. Genetic and neuropathological evidence suggests that there are α-synuclein centric forms (e.g., SNCA genomic triplication), and forms that are driven by a breakdown in mitochondrial function and specifically in the process of mitophagy and clearance of damaged mitochondria (e.g., PARKIN and PINK1 recessive loss-of-function mutations). Aligning genetic forms with recognized environmental influences will help better define patients, aid prognosis, and hopefully lead to more accurately targeted clinical trial design. Work is now needed to understand the cross-talk between these two pathomechanisms and determine a sense of independence, it is noted that autopsies studies for both have shown the presence or absence of α-synuclein aggregation. The integration of genetic and environmental data is critical to understand the etiology of early-onset forms of PD and determine how the different pathomechanisms crosstalk. Show more

Keywords: Parkinson’s disease, early-onset Parkinson’s disease, genetics, environment, risk factors

DOI: 10.3233/JPD-223380

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2353-2367, 2022

Authors: Mitchell, Eleanor | Chohan, Harneek | Bestwick, Jonathan P. | Noyce, Alastair J.

Article Type: Systematic Review

Abstract: Background: A substantial body of research has examined the relationship between alcohol consumption and risk of Parkinson’s disease (PD). Objective: To provide an updated systematic review and meta-analysis of observational studies examining the relationship between alcohol consumption and risk of PD. Methods: Eligible studies comparing PD risk in ever vs. never alcohol drinkers were sourced from six databases. Outcomes were pooled using standard meta-analysis techniques. Separate female and male estimates were generated from studies reporting sex-specific data. Additionally, cohort studies stratifying participants by quantity of alcohol intake were integrated in a dose-response analysis. Results: …52 studies were included, totaling 63,707 PD patients and 9,817,924 controls. Our meta-analysis supported a statistically significant overrepresentation of never drinkers among PD subjects; odds ratio (OR) for ever drinking alcohol 0.84 (95% confidence interval (CI) 0.76 – 0.92). A subgroup analysis revealed similar effect estimates in females and males. A further synthesis of seven cohort studies suggested a negative, dose-dependent association between alcohol and risk of PD. Conclusion: In the absence of a known neuroprotective pathway, there may be reason to doubt a true biological effect. The role of survivor bias, selection and recall bias, misclassification, and residual confounding requires consideration. Alternatively, observations might be attributable to reverse causation if those predestined for PD alter their alcohol habits during the preclinical phase. Major limitations of our study include high between-study heterogeneity (I2  = 93.2%) and lack of adjustment for key confounders, namely smoking status. Show more

Keywords: Parkinson’s disease, alcohols, ethanol, alcohol drinking, alcoholic beverages, systematic review, meta-analysis

DOI: 10.3233/JPD-223522

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2369-2381, 2022

Authors: Cui, Yusha | Cao, Shuangshuang | Li, Fangfei | Feng, Tao

Article Type: Research Article

Abstract: Background: Cognitive impairment is a clinical feature of multiple system atrophy (MSA). However, the prevalence and factors influencing the prevalence of cognitive impairment and dementia in MSA patients remain unclear. Objective: We aim to provide an estimate of the prevalence of cognitive impairment and dementia in patients with MSA and to evaluate the possible effect of demographic, clinical and methodological factors on the prevalence. Methods: We systematically searched the PubMed, Embase, and Web of science databases to identify studies that report the prevalence of cognitive impairment or dementia in MSA published up to February 2022. We …computed the estimates of the pooled prevalence using random-effects models. Heterogeneity was investigated by subgroup analyses and meta-regression. Differences between MSA patients with and without cognitive impairment in demographic and clinical features were explored. Results: A total of 23 studies comprising 2064 MSA patients were included in meta-analysis. The pooled prevalence of cognitive impairment in MSA patients was 37% (95% CI: 29% –45%), the prevalence of dementia was 11% (95% CI: 7% –15%). The subgroup analyses showed the prevalence of dementia in pathologically-confirmed MSA was 7% (95% CI: 0% –12%), in clinically diagnosed MSA was 14% (95% CI: 10% –18%). Cognitive impairment in MSA patients was associated with older age, lower education, longer disease duration and more severe motor symptoms. Conclusion: Cognitive impairment is a common non-motor symptom in MSA. Dementia can develop in a few patients with MSA as well, but usually in the late stage. Show more

Keywords: Cognitive dysfunction, dementia, multiple system atrophy, prevalence

DOI: 10.3233/JPD-223444

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2383-2395, 2022

Authors: Brás, Inês C. | Khani, Mohammad H. | Vasili, Eftychia | Möbius, Wiebke | Riedel, Dietmar | Parfentev, Iwan | Gerhardt, Ellen | Fahlbusch, Christiane | Urlaub, Henning | Zweckstetter, Markus | Gollisch, Tim | Outeiro, Tiago F.

Article Type: Research Article

Abstract: Background: Various cellular pathways have been implicated in the transfer of disease-related proteins between cells, contributing to disease progression and neurodegeneration. However, the overall effects of protein transfer are still unclear. Objective: Here, we performed a systematic comparison of basic molecular mechanisms involved in the release of alpha-synuclein, Tau, and huntingtin, and evaluated functional effects upon internalization by receiving cells. Methods: Evaluation of protein release to the extracellular space in a free form and in extracellular vesicles using an optimized ultracentrifugation protocol. The extracellular effects of the proteins and extracellular vesicles in primary neuronal cultures were …assessed using multi-channel electrophysiological recordings combined with a customized spike sorting framework. Results: We demonstrate cells differentially release free-forms of each protein to the extracellular space. Importantly, neuronal activity is distinctly modulated upon protein internalization in primary cortical cultures. In addition, these disease-related proteins also occur in extracellular vesicles, and are enriched in ectosomes. Internalization of ectosomes and exosomes by primary microglial or astrocytic cells elicits the production of pro-inflammatory cytokines, and modifies spontaneous electrical activity in neurons. Objective: Overall, our study demonstrates that released proteins can have detrimental effects for surrounding cells, and suggests protein release pathways may be exploited as therapeutic targets in different neurodegenerative diseases. Show more

Keywords: Alpha-synuclein, extracellular vesicles, huntingtin, neuronal function, Tau

DOI: 10.3233/JPD-223516

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2397-2422, 2022

Authors: Liang, Feng | Chen, Cheng-Yu | Li, Yun-Pu | Ke, Yi-Ci | Ho, En-Pong | Jeng, Chih-Fan | Lin, Chin-Hsien | Chen, Shih-Kuo

Article Type: Research Article

Abstract: Background: Studies have shown different gut microbiomes in patients with Parkinson’s disease (PD) compared to unaffected controls. However, when the gut microbiota shift toward dysbiosis in the PD process remains unclear. Objective: We aim to investigate the changes in gut microbiota, locomotor function, and neuropathology longitudinally in PD rodent models. Methods: Fecal microbiota were longitudinally assessed by sequencing the V4–V5 region of the 16S ribosomal RNA gene in a human mutant α-synuclein over-expressing mouse model of PD, SNCA p.A53T mice, and the non-transgenic littermate controls. The locomotor function, neuronal integrity, and α-synuclein expression in the …different brain regions were compared between groups. Human fecal microbiota communities from 58 patients with PD and 46 unaffected controls were also analyzed using metagenomic sequencing for comparison. Results: Compared to non-transgenic littermate controls, the altered gut microbiota of the SNCA p.A53T mice can be detected as early as 2 months old, and the diurnal oscillation of the gut microbiome was dampened throughout PD progression starting from 4 months old. However, neuropathology changes and motor deficits were observed starting at 6 months old. Similar changes in altered gut microbiota were also observed in another PD genetic mouse model carrying the LRRK2 p.G2019S mutation at 2 months old. Among the commonly enriched gut microbiota in both PD genetic mouse models, the abundance of Parabateroides Merdae and Ruminococcus torques were also increased in human PD patients compared to controls. Conclusion: These findings revealed the altered gut microbiota communities and oscillations preceding the occurrence of neuropathy and motor dysfunction in the PD process. Show more

Keywords: Parkinson’s disease, gut microbiota, dysbiosis, circadian, daily oscillation, SNCA

DOI: 10.3233/JPD-223431

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2423-2440, 2022

Authors: Zhang, Keren | Paul, Kimberly C. | Jacobs, Jonathan P. | Chou, Hsiang-Chin (Lori) | Duarte Folle, Aline | Del Rosario, Irish | Yu, Yu | Bronstein, Jeff M. | Keener, Adrienne M. | Ritz, Beate

Article Type: Research Article

Abstract: Background: Increasing evidence connects the gut microbiome to Parkinson’s disease (PD) etiology, but little is known about microbial contributions to PD progression and its clinical features. Objective: We aim to explore the association between the gut microbiome with PD, and the microbial association with PD-specific clinical features. Methods: In a community-based case-control study of 96 PD patients and 74 controls, microbiome data were obtained from 16S rRNA gene sequencing of fecal samples, and analyzed for microbial diversity, taxa abundance, and predicted functional pathways that differed in PD patients and controls, and their association …with PD-specific features (disease duration, motor subtypes, L-DOPA daily dose, and motor function). Results: PD patients’ gut microbiome showed lower species diversity (p  = 0.04) and were compositionally different (p  = 0.002) compared to controls but had a higher abundance of three phyla (Proteobacteria, Verrucomicrobiota, Actinobacteria) and five genera (Akkermansia, Enterococcus, Hungatella, and two Ruminococcaceae) controlling for sex, race, age, and sequencing platform. Also, 35 Metacyc pathways were predicted to be differentially expressed in PD patients including biosynthesis, compound degradation/utilization/assimilation, generation of metabolites and energy, and glycan pathways. Additionally, the postural instability gait dysfunction subtype was associated with three phyla and the NAD biosynthesis pathway. PD duration was associated with the Synergistota phylum, six genera, and the aromatic compound degradation pathways. Two genera were associated with motor function. Conclusion: PD patients differed from controls in gut microbiome composition and its predicted metagenome. Clinical features were also associated with bacterial taxa and altered metabolic pathways of interest for PD progression. Show more

Keywords: Parkinson’s disease, gut microbiome, brain-gut axis, Unified Parkinson’s Disease Rating Scale

DOI: 10.3233/JPD-223500

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2441-2452, 2022

Authors: Nolano, Maria | Caporaso, Giuseppe | Manganelli, Fiore | Stancanelli, Annamaria | Borreca, Ilaria | Mozzillo, Stefania | Tozza, Stefano | Dubbioso, Raffaele | Iodice, Rosa | Vitale, Floriana | Koay, Shiwen | Vichayanrat, Ekawat | da Silva, Fernanda Valerio | Santoro, Lucio | Iodice, Valeria | Provitera, Vincenzo

Article Type: Research Article

Abstract: Background: The role of peripheral phosphorylated-α-Synuclein (p-α-syn) deposition on nerve degeneration in synucleinopathies is still unknown. Objective: To assess the cutaneous neural distribution of p-α-Syn deposits and its correlation with clinical data and with morphology and function of cutaneous sensory and autonomic nerves in early Parkinson’s disease (PD) and multiple system atrophy-parkinson type (MSA-p). Methods: We recruited 57 PD (F/M = 21/36; age 63.5±9.4 years) and 43 MSA-p (F/M = 16/27; age 62.3±9.0 years) patients within 2 years from motor symptoms. We applied questionnaires and clinical scales, sensory thresholds, and sudomotor testing to assess severity of motor and non-motor involvement …and sensory and autonomic dysfunction. We quantified, in skin biopsy from thigh, leg, and fingertip, epidermal, pilomotor, and sudomotor nerve fibers, Meissner corpuscles and intrapapillary myelinated endings and the neural distribution of p-α-syn deposits. Results: Compared to controls, we found a cutaneous denervation paralleling functional and clinical impairment. Sensory and autonomic denervation was more severe in MSA-p than in PD. Deposits of p-α-syn were found in the majority of patients, with no significant differences among sites in both groups. Higher occurrence of p-α-syn deposits in autonomic nerves differentiated (p  < 0.01) PD from MSA-p. p-α-syn deposits correlated positively with sudomotor function, epidermal, pilomotor and sudomotor nerve densities, and inversely with non-motor symptoms and disease progression. Conclusion: Our work demonstrated an early peripheral sensory and autonomic involvement in synucleinopathies, more severe in MSA-p than in PD. Higher p-α-syn deposits in autonomic nerves differentiated PD from MSA-p. p-α-syn deposits were associated with preserved innervation and slower disease progression. Show more

Keywords: Autonomic and somatic cutaneous nerves, phosphorylated α-synuclein, skin biopsy, sudomotor function

DOI: 10.3233/JPD-223421

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2453-2468, 2022

Authors: Zhang, Dongling | Yao, Junye | Sun, Junyan | Tong, Qiqi | Zhu, Silei | Wang, Junling | Chen, Lili | Ma, Jinghong | He, Hongjian | Wu, Tao

Article Type: Research Article

Abstract: Background: The utility of imaging methods to detect iron content in the substantia nigra pars compacta (SNc) and free water imaging in the posterior substantia nigra (pSN) has the potential to be imaging markers for the detection of Parkinson’s disease (PD). Objective: This study aimed to compare the discriminative power of above methods, and whether the combination can improve the diagnostic potential of PD. Methods: Quantitative susceptibility mapping (QSM) and diffusion-weighted data were obtained from 41 healthy controls (HC), 37 patients with idiopathic REM sleep behavior disorder (RBD), and 65 patients with PD. Mean QSM values …of bilateral SNc and mean isotropic volume fraction (Viso ) values of bilateral pSN (mean QSM|Viso values of bilateral SNc|pSN) were separately calculated and compared among the groups. Results: Mean QSM|Viso values of bilateral SNc|pSN were significantly higher for RBD and PD patients compared to HC and were significantly higher in PD patients than in RBD patients. The power of the mean QSM|Viso values of bilateral SNc|pSN and combined mean QSM and Viso values was 0.873, 0.870, and 0.961 in discriminating PD and HC, 0.779, 0.719, and 0.864 in discriminating RBD from HC, 0.634, 0.636, and 0.689 in discriminating PD and RBD patients. Conclusion: QSM and free water imaging have similar discriminative power in the detection of prodromal and clinical PD, while combination of these two methods increases discriminative power. Our findings suggest that the combination of QSM and free water imaging has the potential to become an imaging marker for the diagnosis of PD. Show more

Keywords: Iron accumulation, free water, quantitative susceptibility mapping, isotropic volume fraction, Parkinson’s disease

DOI: 10.3233/JPD-223499

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2469-2478, 2022

Authors: Wen, Jiaqi | Guo, Tao | Wu, Jingjing | Bai, Xueqin | Zhou, Cheng | Wu, Haoting | Liu, Xiaocao | Chen, Jingwen | Cao, Zhengye | Gu, Luyan | Pu, Jiali | Zhang, Baorong | Zhang, Minming | Guan, Xiaojun | Xu, Xiaojun

Article Type: Research Article

Abstract: Background: In Parkinson’s disease (PD), excessive iron deposition in the substantia nigra may exacerbate α-synuclein aggregation, facilitating the degeneration of dopaminergic neurons and their neural projection. Objective: To investigate the interaction effect between nigral iron deposition and PD status on brain networks. Methods: Eighty-five PD patients and 140 normal controls (NC) were included. Network function and nigral iron were measured using multi-modality magnetic resonance imaging. According to the median of nigral magnetic susceptibility of NC (0.095 ppm), PD and NC were respectively divided into high and low nigral iron group. The main and interaction effects were investigated …by mixed effect analysis. Results: The main effect of disease was observed in basal ganglia network (BGN) and visual network (VN). The interaction effect between nigral iron and PD status was observed in left inferior frontal gyrus and left insular lobe in BGN, as well as right middle occipital gyrus, right superior temporal gyrus, and bilateral cuneus in VN. Furthermore, multiple mediation analysis revealed that the functional connectivity of interaction effect clusters in BGN and medial VN partially mediated the relationship between nigral iron and Unified Parkinson’s Disease Rating Scale II score. Conclusion: Our study demonstrates an interaction of nigral iron deposition and PD status on brain networks, that is, nigral iron deposition is associated with the change of brain network configuration exclusively when in PD. We identified a potential causal mediation pathway for iron to affect disease severity that was mediated by both BGN dysfunction and VN hyperfunction in PD. Show more

Keywords: Parkinson’s disease, nigral iron, brain networks, quantitative susceptibility mapping, functional magnetic resonance imaging, interaction

DOI: 10.3233/JPD-223372

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2479-2492, 2022

Authors: Horsager, Jacob | Okkels, Niels | Hansen, Allan K. | Damholdt, Malene F. | Andersen, Katrine H. | Fedorova, Tatyana D. | Munk, Ole Lajord | Danielsen, Erik H. | Pavese, Nicola | Brooks, David J. | Borghammer, Per

Article Type: Research Article

Abstract: Background: Cholinergic degeneration is strongly associated with cognitive decline in patients with Parkinson’s disease (PD) but may also cause motor symptoms and olfactory dysfunction. Regional differences are striking and may reflect different PD related symptoms and disease progression patterns. Objective: To map and quantify the regional cerebral cholinergic alterations in non-demented PD patients. Methods: We included 15 non-demented PD patients in early-moderate disease stage and 15 age- and sex-matched healthy controls for [18 F]FEOBV positron emission tomography imaging. We quantitated regional variations using VOI-based analyses which were supported by a vertex-wise cluster analysis. Correlations between imaging …data and clinical and neuropsychological data were explored. Results: We found significantly decreased [18 F]FEOBV uptake in global neocortex (38%, p  = 0.0002). The most severe reductions were seen in occipital and posterior temporo-parietal regions (p  < 0.0001). The vertex-wise cluster analysis corroborated these findings. All subcortical structures showed modest non-significant reductions. Motor symptoms (postural instability and gait difficulty) and cognition (executive function and composite z-score) correlated with regional [18 F]FEOBV uptake (thalamus and cingulate cortex/insula/hippocampus, respectively), but the correlations were not statistically significant after multiple comparison correction. A strong correlation was found between interhemispheric [18 F]FEOBV asymmetry, and motor symptom asymmetry of the extremities (r  = 0.84, p  = 0.0001). Conclusion: Cortical cholinergic degeneration is prominent in non-demented PD patients, but more subtle in subcortical structures. Regional differences suggest uneven involvement of cholinergic nuclei in the brain and may represent a window to follow disease progression. The correlation between asymmetric motor symptoms and neocortical [18 F]FEOBV asymmetry indicates that unilateral cholinergic degeneration parallels ipsilateral dopaminergic degeneration. Show more

Keywords: Cholinergic, [18F]FEOBV, Parkinson’s disease, positron emission tomography, vesicular acetylcholine transporter

DOI: 10.3233/JPD-223489

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2493-2506, 2022

Authors: Wang, Lina | Ji, Min | Sun, Huimin | Gan, Caiting | Zhang, Heng | Cao, Xingyue | Yuan, Yongsheng | Zhang, Kezhong

Article Type: Research Article

Abstract: Background: Freezing of gait (FOG) in Parkinson’s disease (PD), especially the “L-dopa-unresponsive” subtype, is associated with the dysfunction of non-dopaminergic circuits. Objective: We sought to determine whether cortical sensorimotor inhibition evaluated by short-latency afferent inhibition (SAI) related to cholinergic and gamma-aminobutyric acid (GABA)-ergic activities is impaired in PD patients with L-dopa-unresponsive FOG (ONOFF-FOG). Methods: SAI protocol was performed in 28 PD patients with ONOFF-FOG, 15 PD patients with “off” FOG (OFF-FOG), and 25 PD patients without FOG during medication “on” state. Additionally, 10 ONOFF-FOG patients underwent SAI testing during both “off” and “on” states. Twenty healthy …controls participated in this study. Gait was measured objectively using a portable Inertial Measurement Unit system, and participants performed 5-meter Timed Up and Go single- and dual-task conditions. Spatiotemporal gait characteristics and their variability were determined. FOG manifestations and cognition were assessed with clinical scales. Results: Compared to controls, PD patients without FOG and with OFF-FOG, ONOFF-FOG PD patients showed significantly reduced SAI. Further, dopaminergic therapy had no remarkable effect on this SAI alterations in ONOFF-FOG. Meanwhile, OFF-FOG patients presented decreased SAI only relative to controls. PD patients with ONOFF-FOG exhibited decreased gait speed, stride length, and increased gait variability relative to PD patients without FOG and controls under both walking conditions. For ONOFF-FOG patients, significant associations were found between SAI and FOG severity, gait characteristics and variability. Conclusion: Reduced SAI was associated with severe FOG manifestations, impaired gait characteristics and variability in PD patients with ONOFF-FOG, suggesting the impaired thalamocortical cholinergic-GABAergic SAI pathways underlying ONOFF-FOG. Show more

Keywords: Freezing of gait, cholinergic activity, pedunculopontine nucleus, short-latency afferent inhibition, transcranial magnetic stimulation, Parkinson’s disease

DOI: 10.3233/JPD-223498

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2507-2518, 2022

Authors: Contin, Manuela | Lopane, Giovanna | Belotti, Laura M.B. | Galletti, Margherita | Cortelli, Pietro | Calandra-Buonaura, Giovanna

Article Type: Research Article

Abstract: Background: Different studies, mostly with limited cohorts, have suggested the effects of patients’ characteristics on levodopa (LD) pharmacokinetics. Objective: We primarily aimed at investigating in a large population the relationship between patients’ features and LD kinetic variables, to assess the main demographic and clinical predictors of LD clinical pharmacokinetics. Methods: The study was retrospective, based on data collected from subjects with parkinsonism on chronic LD undergoing LD therapeutic monitoring (TM). LD TM includes serial quantitative motor tests and blood samples to measure plasma drug concentrations after each subject’s chronically taken first-morning LD dose intake. …Results: Five hundred patients, 308 males (61.6%), mean (SD) age of 65 (10.1) years were included. Parkinsonian symptoms and LD therapy lasted 5.5 (4.5) and 3.4 (3.9) years, respectively. MDS-UPDRS part III “off” score was 28.8 (15.2). LD dose was 348.2 (187.1) mg/day. From multiple linear regression analysis, test dose, sex, type of LD decarboxylase inhibitor, weight and MDS-UPDRS part III score were linear predictors of both LD peak plasma concentration (Cmax ) (R2  = 0.52) and area under the 3-h plasma concentration-time curve (AUC) (R2  = 0.71), while age was a further predictor only for AUC. Besides test dose, sex was the strongest independent contributing variable to LD AUC, which resulted 27% higher in females compared to males. Conclusion: This is the largest collection of data on the relationship between demographic and clinical-therapeutic variables and LD kinetics in patients with parkinsonian symptoms. As a main clinically practical finding, women might require a 25% reduced weight-normalized LD dose compared with men to achieve the same LD bioavailability. Show more

Keywords: Levodopa, pharmacokinetics, sex, dopa decarboxylase inhibitors, levodopa therapeutic monitoring, levodopa-induced dyskinesias, pharmacodynamics

DOI: 10.3233/JPD-223374

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2519-2530, 2022

Authors: Paschen, Steffen | Hansen, Clint | Welzel, Julius | Albrecht, Judith | Atrsaei, Arash | Aminian, Kamiar | Zeuner, Kirsten E. | Romijnders, Robbin | Warmerdam, Elke | Urban, Paul Peter | Berg, Daniela | Maetzler, Walter

Article Type: Research Article

Abstract: Background: Orthostatic hypotension (OH) in Parkinson’s disease (PD) is frequent and associated with impairments in quality of life and reduced activities of daily living. Abdominal binders (AB) and compression stockings (CS) have been shown to be effective non-pharmacological treatment options. Objective: Here, we investigate the effect of AB versus CS on physical activity using a digital mobility outcome (sit to stand [STS] frequency) collected in the usual environment as a primary endpoint. Methods: We enrolled 16 PD patients with at least moderate symptomatic OH. In a randomized, single-blinded, controlled, crossover design, participants were assessed without OH …treatment over 1 week (baseline), then were given AB or CS for 1 week and subsequently switched to the other treatment arm. The primary outcome was the number of real-life STS movements per hour as assessed with a lower back sensor. Secondary outcomes included real-life STS duration, mean/systolic/diastolic blood pressure drop (BPD), orthostatic hypotension questionnaire (OHQ), PD quality of life (PDQ-39), autonomic symptoms (SCOPA-AUT), non-motor symptoms (NMSS), MDS-UPDRS, and activities of daily living (ADL/iADL). Results: Real-life STS frequency on CS was 4.4±4.1 per hour compared with 3.6±2.2 on AB and 3.6±1.8 without treatment (p  = 1.0). Concerning the secondary outcomes, NMSS showed significant improvement with CS and AB. OHQ and SCOPA-AUT improved significantly with AB but not CS, and mean BPD drop worsened with CS but not AB. Mean STS duration, PDQ-39, MDS-UPDRS, ADL, and iADL did not significantly change. Conclusion: Both AB and CS therapies do not lead to a significant change of physical activity in PD patients with at least moderate symptomatic OH. Secondary results speak for an effect of both therapies concerning non-motor symptoms, with superiority of AB therapy over CS therapy. Show more

Keywords: Abdominal binder, compression stockings, orthostatic hypotension, Parkinson’s disease, sit-to-stand, blood pressure drop

DOI: 10.3233/JPD-223406

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2531-2541, 2022

Authors: Folkerts, Ann-Kristin | Haarmann, Lena | Nielsen, Jörn | Saliger, Jochen | Eschweiler, Mareike | Karbe, Hans | Allert, Niels | Vida, Viktoria | Trenkwalder, Claudia | Kruse, Annika | Oelsner, Henriette | Ebersbach, Georg | Kalbe, Elke

Article Type: Research Article

Abstract: Background: Fear of progression (FoP) is a reactive, conscious concern about chronic disease progression and its consequences which may limit quality of life substantially. Only one study has examined FoP in Parkinson’s disease (PD), showing the second highest FoP scores among chronic diseases. Objective: To examine FoP prevalence and to exploratorily analyze determinants of FoP in PD. Methods: Within a multicenter cross-sectional study, 120 PD inpatients (age: 64.45±9.20; 60.8% male; UPDRS-III: 28.86±16.12) were examined with the FoP questionnaire (FoP-Q; max. 20 points). Stepwise multiple linear regression analysis examined sociodemographic, clinical, and (neuro-) psychological determinants of FoP. …Results: With a mean FoP-Q score of 8.08±2.17, 63.0% of the patients were classified with moderate FoP and 17.6% with dysfunctional (i.e., severe) FoP. The highest scores were shown for the subscale ‘loss of autonomy’. Increased levels of anxiety, less self-efficacy, female gender, current employment, and lower health literacy were identified as significant determinants associated with FoP. Conclusion: With more than 80% of patients showing moderate to dysfunctional FoP, it must be regarded as a frequent symptom in PD, which needs to be further understood and addressed in clinical practice. Clinical parameters like PD duration and severity were no determinants for FoP, indicating that FoP awareness must be considered by professionals at all disease stages. Show more

Keywords: Parkinson’s disease, fear of progression, disease progression, anxiety, self-efficacy, health literacy, cross-sectional study

DOI: 10.3233/JPD-223314

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2543-2553, 2022

Authors: Doppler, Christopher E.J. | Smit, Julia | Hommelsen, Maximilian | Seger, Aline | Okkels, Niels | Horsager, Jacob | Kinnerup, Martin | Hansen, Allan K. | Fedorova, Tatyana D. | Knudsen, Karoline | Otto, Marit | Nahimi, Adjmal | Fink, Gereon R. | Borghammer, Per | Sommerauer, Michael

Article Type: Research Article

Abstract: Background: Although sleep disturbances are highly prevalent in patients with Parkinson’s disease, sleep macroarchitecture metrics show only minor changes. Objective: To assess alterations of the cyclic alternating pattern (CAP) as a critical feature of sleep microarchitecture in patients with prodromal, recent, and established Parkinson’s disease. Methods: We evaluated overnight polysomnography for classic sleep macroarchitecture and CAP metrics in 68 patients at various disease stages and compared results to 22 age- and sex-matched controls. Results: Already at the prodromal stage, patients showed a significantly reduced CAP rate as a central characteristic of sleep microarchitecture. Temporal …characteristics of CAP showed a gradual change over disease stages and correlated with motor performance. In contrast, the sleep macroarchitecture metrics did not differ between groups. Conclusion: Data suggest that alterations of sleep microarchitecture are an early and more sensitive characteristic of Parkinson’s disease than changes in sleep macroarchitecture. Show more

Keywords: REM sleep behavior disorder, Parkinson’s disease, cyclic alternating pattern, microsleep, polysomnography

DOI: 10.3233/JPD-223442

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2555-2560, 2022

Authors: Pavelka, Lukas | Rauschenberger, Armin | Landoulsi, Zied | Pachchek, Sinthuja | Marques, Taina | Gomes, Clarissa P.C. | Glaab, Enrico | May, Patrick | Krüger, Rejko

Article Type: Research Article

Abstract: Background: The hypothesis of body-first vs. brain-first subtype of PD has been proposed with REM-Sleep behavior disorder (RBD) defining the former. The body-first PD presumes an involvement of the brainstem in the pathogenic process with higher burden of autonomic dysfunction. Objective: To identify distinctive clinical subtypes of idiopathic Parkinson’s disease (iPD) in line with the formerly proposed concept of body-first vs. brain-first subtypes in PD, we analyzed the presence of probable RBD (pRBD), sex, and the APOE ɛ 4 carrier status as potential sub-group stratifiers. Methods: A total of 400 iPD …patients were included in the cross-sectional analysis from the baseline dataset with a completed RBD Screening Questionnaire (RBDSQ) for classifying as pRBD by using the cut-off RBDSQ≥6. Multiple regression models were applied to explore (i) the effect of pRBD on clinical outcomes adjusted for disease duration and age, (ii) the effect of sex on pRBD, and (iii) the association of APOE ɛ 4 and pRBD. Results: iPD-pRBD was significantly associated with autonomic dysfunction (SCOPA-AUT), level of depressive symptoms (BDI-I), MDS-UPDRS I, hallucinations, and constipation, whereas significantly negatively associated with quality of life (PDQ-39) and sleep (PDSS). No significant association between sex and pRBD or APOE ɛ4 and pRBD in iPD was found nor did we determine a significant effect of APOE ɛ4 on the PD phenotype. Conclusion: We identified an RBD-specific PD endophenotype, characterized by predominant autonomic dysfunction, hallucinations, and depression, corroborating the concept of a distinctive body-first subtype of PD. We did not observe a significant association between APOE ɛ4 and pRBD suggesting both factors having an independent effect on cognitive decline in iPD. Show more

Keywords: Idiopathic Parkinson’s disease, probable REM-Sleep behavior disorder, RBDSQ, non-motor symptoms, APOE, stratification

DOI: 10.3233/JPD-223511

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2561-2573, 2022

Authors: Lennaerts-Kats, Herma | Ebenau, Anne | Kanters, Silvia | Bloem, Bastiaan R. | Vissers, Kris C.P. | Dijkstra, Bauke W. | Meinders, Marjan J. | Groot, Marieke M.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is an increasingly prevalent and progressive degenerative disease. Palliative care for PD should be integrated into the routine care for people with PD. However, PD health care professionals typically lack knowledge of palliative care, highlighting the necessity of educational programs in this field. Objective: To determine the effectiveness of a multidisciplinary blended learning program for health care professionals specialized in PD in the Netherlands. Methods: We used a pre-posttest intervention design. The intervention consisted of an e-learning in combination with an online network meeting in which the participating health care professionals discussed …palliative care for PD with specialists from the field of palliative care. Outcome variables included self-rated level of knowledge (scale 1-10), familiarity with specialized palliative care services (5-point Likert scale) and the validated End-of-Life Professional Caregiver Survey (EPCS). Results: A total of 1029 participants from sixteen different disciplines, all active in the care for people with PD, with a mean age of 45 years and 13 years of working experience, followed the blended learning program. Self-rated level of knowledge improved from 4.75 to 5.72 (0.96; p  < 0.001; 95% CI change = [0.85 . . . 1.08]. Familiarity with palliative care services also increased by 1.06 (from 1.85 to 2.90; p =<0.001; 95% CI change = [1.00 . . . 1.12]). Conclusion: A blended learning program can improve self-rated knowledge about palliative care and its services. Such programs might be a first step towards optimal integration of palliative care expertise and services within PD-care. Show more

Keywords: Parkinson’s disease, palliative care, blended learning, e-learning, health care professionals, multidisciplinary, education

DOI: 10.3233/JPD-223539

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2575-2584, 2022

Authors: Domingos, Josefa | de Lima, Ana Ligia Silva | Steenbakkers-van der Pol, Tessa | Godinho, Catarina | Bloem, Bastiaan R. | de Vries, Nienke M.

Article Type: Research Article

Abstract: Background: People with Parkinson’s disease (PD) benefit from boxing exercise. Adding kicking variations to the boxing may provide additional benefit to improve balance. However, the benefits and adherence to such trainings is unknown. Objective: To explore the feasibility, safety, and benefits on balance of boxing training combined with kicking techniques in comparison to boxing without kicking in PD. Methods: Participants were randomized to group-based boxing training with kicking techniques (BK) or to group-based boxing alone training (BO). Both groups trained for one hour, once a week, for a period of 10 weeks. Participants were assessed at …baseline and ten weeks post-intervention for difference in balance, fear of falling, balance confidence, walking ability, and quality of life. Results: Twenty-nine people with PD (median age 64 years; median disease duration 5 years) participated. Both interventions were feasible and acceptable for all participants. No adverse events occurred. Most participants (BK 80%; BO 75%) were satisfied with the training. We found no significant between group difference on either the primary (Mini-BEST) or secondary outcomes. The within group comparison showed that balance improved in both groups after the intervention (BK 22.60 (2.7) to 25.33 (2.64) p  = 0.02; BO 23.09 (3.44) to 25.80 (2.39); p  = 0.01 on the Mini BEST test). Conclusion: Both types of boxing seem to be feasible and safe. Adding kicking techniques to boxing does not improve balance significantly more than boxing alone. Incorporation of kicking may be a valuable addition to the exercise therapy repertoire. Show more

Keywords: Parkinson’s disease, boxing, exercise, balance, kicking, physiotherapy

DOI: 10.3233/JPD-223447

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2585-2593, 2022

Authors: Badihian, Negin | Jackson, Lauren M. | Klassen, Bryan T. | Hassan, Anhar | Low, Phillip A. | Singer, Wolfgang | Coon, Elizabeth A.

Article Type: Short Communication

Abstract: The course of patients with multiple system atrophy (MSA) who undergo deep brain stimulation (DBS) is unclear. In a retrospective review of 1,496 patients with MSA evaluated at our institutions from 1998–2021, 12 patients underwent DBS; 9 had a diagnosis of Parkinson’s disease at the time of surgery. Nine patients reported initial improvement in at least one symptom and 7 experienced overall worsening following DBS. All patients had at least one red flag sign or symptom suggesting atypical parkinsonism prior to surgery. Considering overall poor outcomes of DBS in MSA, we recommend careful consideration of red flags in patient selection.

Keywords: Parkinson’s disease, multiple system atrophy, parkinsonism, ataxia, deep brain stimulation

DOI: 10.3233/JPD-223504

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2595-2600, 2022

Authors: Rocanières, Pierre | Lamure, Sylvain | Geny, Christian | Hillaire-Buys, Dominique | Faillie, Jean-Luc | Bres, Virginie

Article Type: Letter

DOI: 10.3233/JPD-223496

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2601-2603, 2022

Article Type: Other

DOI: 10.3233/JPD-229009

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2605-2607, 2022