Journal of Parkinson's Disease - Volume 11, issue 4

Authors: Park, Sang Hyun | Nam, Ga Eun | Han, Kyungdo | Huh, Youn | Kim, Wonsock | Lee, Min-Kyung | Koh, Eun-Sil | Kim, Eun Sook | Kim, Mee Kyung | Kwon, Hyuk-Sang | Kim, Seon Mee | Cho, Kyung Hwan | Park, Yong Gyu

Article Type: Research Article

Abstract: Background: The longitudinal association between dynamic changes in the metabolic syndrome (MS) status and Parkinson’s disease (PD) has been poorly studied. Objective: We examined whether dynamic changes in MS status are associated with altered risk for PD. Methods: This study was a nationwide retrospective cohort study. We enrolled 5,522,813 individuals aged≥40 years who had undergone health examinations under the National Health Insurance Service between 2009 and 2010 (two health examinations with a 2-year interval). Participants were followed up until the end of 2017. The participants were categorized into four groups according to MS status changes over …2 years: non-MS, improved MS, incident MS, and persistent MS groups. Multivariable Cox hazard regression was performed. Results: During the 7-year median follow-up, there were 20,524 cases of newly developed PD. Compared with non-MS group, improved, incident, and persistent MS groups for 2 years were significantly associated with higher risks of PD (model 3; hazard ratio: 1.12, 95%confidence interval: 1.06–1.19 [improved MS]; 1.15, 1.09–1.22 [incident MS]; and 1.25, 1.20–1.30 [persistent MS]). Individuals with incident and persistent abdominal obesity, low levels of high-density lipoprotein cholesterol, hypertriglyceridemia, and hyperglycemia had a significantly increased risks of PD compared with those without either condition over 2 years. Conclusion: Persistent and incident MS and its components may be risk factors for incident PD. Ever exposure to MS may also be associated with PD risk. Appropriate intervention for preventing and improving MS may be crucial in decreasing the PD incidence. Show more

Keywords: Metabolic syndrome, Parkinson’s disease, metabolic change, cohort

DOI: 10.3233/JPD-212589

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1751-1759, 2021

Authors: Youssef, Priscilla | Kim, Woojin S. | Halliday, Glenda M. | Lewis, Simon J.G. | Dzamko, Nicolas

Article Type: Research Article

Abstract: Background: The identification of reliable biomarkers in Parkinson’s disease (PD) would provide much needed diagnostic accuracy, a means of monitoring progression, objectively measuring treatment response, and potentially allowing patient stratification within clinical trials. Whilst the assessment of total alpha-synuclein in biofluids has been identified as a promising biomarker, conflicting trends in these levels across patient plasma samples relative to controls has limited its use. Different commercially available assay platforms that have been used to measure alpha-synuclein may contribute to different study outcomes. Objective: To compare different platform immunoassays for the measurement of total alpha-synuclein using the same plasma …samples from 49 PD patients and 47 controls. Methods: Total plasma alpha-synuclein concentrations were assessed using the BioLegend, MesoScale Discovery, and Quanterix platform in plasma samples from PD patients and matched controls. Results: A significant increase in total plasma alpha-synuclein was observed in PD patients using the Biolegend (10%), Mesoscale Discovery (13%) and Quanterix (39%) assays. The Mesoscale Discovery and Quanterix assays showed the strongest correlations (r  = 0.78, p  < 0.0001) with each other, whilst the Quanterix platform demonstrated the lowest variation and highest effect size. Inclusion of age, sex and hemoglobin levels as covariates in the analysis of total alpha-synuclein improved the ability of all three immunoassays to detect a significant difference between patients and controls. Conclusion: All three immunoassays were sensitive enough to detect group level differences between PD patients and controls, with the largest effect size observed with the Quanterix assay. These results may help inform assay choices in ongoing clinical trials. Show more

Keywords: Parkinson’s disease, ELISA, SIMOA, alpha-synuclein, blood

DOI: 10.3233/JPD-212694

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1761-1772, 2021

Authors: Dos Santos, Altair B. | Skaanning, Line K. | Mikkelsen, Eyd | Romero-Leguizamón, Cesar R. | Kristensen, Morten P. | Klein, Anders B. | Thaneshwaran, Siganya | Langkilde, Annette E. | Kohlmeier, Kristi A.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a neurodegenerative disorder associated with insoluble pathological aggregates of the protein α -synuclein. While PD is diagnosed by motor symptoms putatively due to aggregated α -synuclein-mediated damage to substantia nigra (SN) neurons, up to a decade before motor symptom appearance, patients exhibit sleep disorders (SDs). Therefore, we hypothesized that α -synuclein, which can be present in monomeric, fibril, and other forms, has deleterious cellular actions on sleep-control nuclei. Objective: We investigated whether native monomer and fibril forms of α -synuclein have effects on neuronal function, calcium dynamics, and cell-death-induction in two sleep-controlling nuclei: …the laterodorsal tegmentum (LDT), and the pedunculopontine tegmentum (PPT), as well as the motor-controlling SN. Methods: Size exclusion chromatography, Thioflavin T fluorescence assays, and circular dichroism spectroscopy were used to isolate structurally defined forms of recombinant, human α -synuclein. Neuronal and viability effects of characterized monomeric and fibril forms of α -synuclein were determined on LDT, PPT, and SN neurons using electrophysiology, calcium imaging, and neurotoxicity assays. Results: In LDT and PPT neurons, both forms of α -synuclein induced excitation and increased calcium, and the monomeric form heightened putatively excitotoxic neuronal death, whereas, in the SN, we saw inhibition, decreased intracellular calcium, and monomeric α -synuclein was not associated with heightened cell death. Conclusion: Nucleus-specific differential effects suggest mechanistic underpinnings of SDs’ prodromal appearance in PD. While speculative, we hypothesize that the monomeric form of α -synuclein compromises functionality of sleep-control neurons, leading to the presence of SDs decades prior to motor dysfunction. Show more

Keywords: Biomarkers, excessive daytime sleepiness, mechanism of disease, neurodegenerative diseases, neuronal alterations, prodromal phase, REM sleep behavior disorder

DOI: 10.3233/JPD-212554

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1773-1790, 2021

Authors: Folke, Jonas | Arkan, Sertan | Martinsson, Isak | Aznar, Susana | Gouras, Gunnar | Brudek, Tomasz | Hansen, Christian

Article Type: Research Article

Abstract: Background: α-synuclein (α-syn) aggregation contributes to the progression of multiple neurodegenerative diseases. We recently found that the isoform b of the co-chaperone DNAJB6 is a strong suppressor of α-syn aggregation in vivo and in vitro . However, nothing is known about the role of the endogenous isoform b of DNAJB6 (DNAJB6b) in health and disease, due to lack of specific antibodies. Objective: Here we generated a novel anti-DNAJB6b antibody to analyze the localization and expression of this isoform in cells, in tissue and in clinical material. Methods: To address this we used immunocytochemistry, immunohistochemistry, as …well as a novel quantitative DNAJB6 specific ELISA method. Results: The endogenous protein is mainly expressed in the cytoplasm and in neurites in vitro , where it is found more in dendrites than in axons. We further verified in vivo that DNAJB6b is expressed in the dopaminergic neurons of the substantia nigra pars compacta (SNpc ), which is a neuronal subpopulation highly sensitive to α-syn aggregation, that degenerate to a large extend in patients with Parkinson’s disease (PD) and multiple system atrophy (MSA). When we analyzed the expression levels of DNAJB6b in brain material from PD and MSA patients, we found a downregulation of DNAJB6b by use of ELISA based quantification. Interestingly, this was also true when analyzing tissue from patients with progressive supranuclear palsy, a taupathic atypical parkinsonian disorder. However, the total level of DNAJB6 was upregulated in these three diseases, which may indicate an upregulation of the other major isoform of DNAJB6, DNAJB6a. Conclusion: This study shows that DNAJB6b is downregulated in several different neurodegenerative diseases, which makes it an interesting target to further investigate in relation to amyloid protein aggregation and disease progression. Show more

Keywords: Alpha-synuclein, clinical samples, DNAJB6, neurodegeneration, synucleinopathy

DOI: 10.3233/JPD-202512

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1791-1803, 2021

Authors: Fellgett, Alison | Middleton, C. Adam | Munns, Jack | Ugbode, Chris | Jaciuch, David | Wilson, Laurence G. | Chawla, Sangeeta | Elliott, Christopher J.H.

Article Type: Research Article

Abstract: Background: Inherited mutations in the LRRK2 protein are common causes of Parkinson’s disease, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S . An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10. Objective: To determine if Rab10 is necessary for LRRK2-induced pathophysiological responses in the neurons that control movement, vision, circadian …activity, and memory. These four systems were chosen because they are modulated by dopaminergic neurons in both humans and flies. Methods: LRRK2 -G2019S was expressed in Drosophila dopaminergic neurons and the effects of Rab10 depletion on Proboscis Extension, retinal neurophysiology, circadian activity pattern (‘sleep’), and courtship memory determined in aged flies. Results: Rab10 loss-of-function rescued LRRK2 -G2019S induced bradykinesia and retinal signaling deficits. Rab10 knock-down, however, did not rescue the marked sleep phenotype which results from dopaminergic LRRK2 -G2019S . Courtship memory is not affected by LRRK2, but is markedly improved by Rab10 depletion. Anatomically, both LRRK2-G2019S and Rab10 are seen in the cytoplasm and at the synaptic endings of dopaminergic neurons. Conclusion: We conclude that, in Drosophila dopaminergic neurons, Rab10 is involved in some, but not all, LRRK2-induced behavioral deficits. Therefore, variations in Rab expression may contribute to susceptibility of different dopaminergic nuclei to neurodegeneration seen in people with Parkinson’s disease. Show more

Keywords: Bradykinesia, circadian rhythms, courtship memory, dopamine, Drosophila, Leucine-rich-repeat-kinase2, sleep, vision

DOI: 10.3233/JPD-202421

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1805-1820, 2021

Authors: Diwakarla, Shanti | McQuade, Rachel M. | Constable, Remy | Artaiz, Olivia | Lei, Enie | Barnham, Kevin J. | Adlard, Paul A. | Cherny, Robert A. | Di Natale, Madeleine R. | Wu, Hongyi | Chai, Xin-yi | Lawson, Victoria A. | Finkelstein, David I. | Furness, John B.

Article Type: Research Article

Abstract: Background: Gastrointestinal (GI) complications, that severely impact patient quality of life, are a common occurrence in patients with Parkinson’s disease (PD). Damage to enteric neurons and the accumulation of alpha-synuclein in the enteric nervous system (ENS) are thought to contribute to this phenotype. Copper or iron chelators, that bind excess or labile metal ions, can prevent aggregation of alpha-synuclein in the brain and alleviate motor-symptoms in preclinical models of PD. Objective: We investigated the effect of ATH434 (formally PBT434), a small molecule, orally bioavailable, moderate-affinity iron chelator, on colonic propulsion and whole gut transit in A53T alpha-synuclein transgenic …mice. Methods: Mice were fed ATH434 (30 mg/kg/day) for either 4 months (beginning at ∼15 months of age), after the onset of slowed propulsion (“treatment group”), or for 3 months (beginning at ∼12 months of age), prior to slowed propulsion (“prevention group”). Results: ATH434, given after dysfunction was established, resulted in a reversal of slowed colonic propulsion and gut transit deficits in A53T mice to WT levels. In addition, ATH434 administered from 12 months prevented the slowed bead expulsion at 15 months but did not alter deficits in gut transit time when compared to vehicle-treated A53T mice. The proportion of neurons with nuclear Hu+ translocation, an indicator of neuronal stress in the ENS, was significantly greater in A53T than WT mice, and was reduced in both groups when ATH434 was administered. Conclusion: ATH434 can reverse some of the GI deficits and enteric neuropathy that occur in a mouse model of PD, and thus may have potential clinical benefit in alleviating the GI dysfunctions associated with PD. Show more

Keywords: Parkinson’s disease, colonic propulsion, gut dysfunction, alpha-synuclein, ATH434, enteric neuropathy

DOI: 10.3233/JPD-212731

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1821-1832, 2021

Authors: Beach, Thomas G. | Adler, Charles H. | Sue, Lucia I. | Shill, Holly A. | Driver-Dunckley, Erika | Mehta, Shyamal H. | Intorcia, Anthony J. | Glass, Michael J. | Walker, Jessica E. | Arce, Richard | Nelson, Courtney M. | Serrano, Geidy E.

Article Type: Research Article

Abstract: Background: Braak and others have proposed that Lewy-type α-synucleinopathy in Parkinson’s disease (PD) may arise from an exogenous pathogen that passes across the gastric mucosa and then is retrogradely transported up the vagus nerve to the medulla. Objective: We tested this hypothesis by immunohistochemically staining, with a method specific for p-serine 129 α-synuclein (pSyn), stomach and vagus nerve tissue from an autopsy series of 111 normal elderly subjects, 33 with incidental Lewy body disease (ILBD) and 53 with PD. Methods: Vagus nerve samples were taken adjacent to the carotid artery in the neck. Stomach samples were …taken from the gastric body, midway along the greater curvature. Formalin-fixed paraffin-embedded sections were immunohistochemically stained for pSyn, shown to be highly specific and sensitive for α-synuclein pathology. Results: Median disease duration for the PD group was 13 years. In the vagus nerve none of the 111 normal subjects had pSyn in the vagus, while 12/26 ILBD (46%) and 32/36 PD (89%) subjects were pSyn-positive. In the stomach none of the 102 normal subjects had pSyn while 5/30 (17%) ILBD and 42/52 (81%) of PD subjects were pSyn-positive. Conclusion: As there was no pSyn in the vagus nerve or stomach of subjects without brain pSyn, these results support initiation of pSyn in the brain. The presence of pSyn in the vagus nerve and stomach of a subset of ILBD cases indicates that synucleinopathy within the peripheral nervous system may occur, within a subset of individuals, at preclinical stages of Lewy body disease. Show more

Keywords: Pathology, etiology, autopsy, gastrointestinal, peripheral nerve, pathogenesis

DOI: 10.3233/JPD-212733

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1833-1843, 2021

Authors: Chen, Yong-Ping | Gu, Xiao-Jing | Song, Wei | Hou, Yan-Bing | Ou, Ru-Wei | Zhang, Ling-Yu | Liu, Kun-Cheng | Su, Wei-Ming | Cao, Bei | Wei, Qian-Qian | Zhao, Bi | Wu, Ying | Shang, Hui-Fang

Article Type: Research Article

Abstract: Background: Genetic studies have indicated that variants in several lysosomal genes are risk factors for idiopathic Parkinson’s disease (PD). However, the role of lysosomal genes in PD in Asian populations is largely unknown. Objective: This study aimed to analyze rare variants in lysosomal related genes in Chinese population with early-onset and familial PD. Methods: In total, 1,136 participants, including 536 and 600 patients with sporadic early-onset PD (SEOPD) and familial PD, respectively, underwent whole-exome sequencing to assess the genetic etiology. Rare variants in PD were investigated in 67 candidate lysosomal related genes (LRGs), including 15 lysosomal …function-related genes and 52 lysosomal storage disorder genes. Results: Compared with the autosomal dominant PD (ADPD) or SEOPD cohorts, a much higher proportion of patients with multiple rare damaging variants of LRGs were found in the autosomal recessive PD (ARPD) cohort. At a gene level, rare damaging variants in GBA and MAN2B1 were enriched in PD, but in SCARB2 , MCOLN1 , LYST , VPS16 , and VPS13C were much less in patients. At an allele level, GBA p. Leu483Pro was found to increase the risk of PD. Genotype-phenotype correlation showed no significance in the clinical features among patients carrying a discrepant number of rare variants in LRGs. Conclusion: Our study suggests rare variants in LRGs might be more important in the pathogenicity of ARPD cases compared with ADPD or SEOPD. We further confirm rare variants in GBA are involve in PD pathogenecity and other genes associated with PD identified in this study should be supported with more evidence. Show more

Keywords: Parkinson’s disease, lysosomal genes, rare variants, burden analysis, genotype-phenotype correction

DOI: 10.3233/JPD-212658

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1845-1855, 2021

Authors: Brown, Gregory L. | Camacci, Mona L. | Kim, Sean D. | Grillo, Stephanie | Nguyen, James V. | Brown, Douglas A. | Ullah, Sarah P. | Lewis, Mechelle M. | Du, Guangwei | Kong, Lan | Sundstrom, Jeffrey M. | Huang, Xuemei | Bowie, Esther M.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is marked clinically by motor symptoms and pathologically by Lewy bodies and dopamine neuron loss in the substantia nigra pars compacta (SNc). Higher iron accumulation, assessed by susceptibility MRI, also is observed as PD progresses. Recently, evidence has suggested that PD affects the retina. Objective: To better understand retinal alterations in PD and their association to clinical and SNc iron-related imaging metrics. Methods: Ten PD and 12 control participants (2 eyes each) from an ongoing PD imaging biomarker study underwent enhanced depth imaging optical coherence tomography evaluation. Choroidal (vascular) thickness and nerve …layers were measured in 4 subregions [superior, temporal, inferior, and nasal] and at 3 foveal distances (1, 1.5, and 3 mm). These metrics were compared between PD and control groups. For significantly different metrics, their associations with clinical [levodopa equivalent daily dosage (LEDD), motor and visuospatial function] and SNc susceptibility MRI metrics [R2* and quantitative susceptibility mapping (QSM)] were explored. Results: Compared to control participants, PD participants had a thicker choroid (p  = 0.005), but no changes in nerve layers. Higher mean choroidal thickness was associated with lower LEDD (p  < 0.01) and better visuospatial function (p  < 0.05). Subregion analyses revealed higher choroidal thickness correlated with lower LEDD and better motor and visuospatial measures. Higher mean choroidal thickness also was associated with lower nigral iron MRI (p  < 0.05). Conclusion: A small cohort of PD research participants displayed higher choroidal thickness that was related to better clinical performance and less nigral pathology. These intriguing findings warrant further investigation. Show more

Keywords: Choroid, optical coherence tomography, Parkinson’s disease, retina, susceptibility MRI, visuospatial function

DOI: 10.3233/JPD-212676

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1857-1868, 2021

Authors: Ye, Zheng | Hanssen, Henrike | Steinhardt, Julia | Tronnier, Volker | Rasche, Dirk | Brüggemann, Norbert | Münte, Thomas F.

Article Type: Research Article

Abstract: Background: Maintaining and manipulating sequences online is essential for language and memory. In Parkinson’s disease (PD), poor performance in sequencing tasks has been associated with basal ganglia dysfunction, especially subthalamic hyperactivity. Objective: This study is aimed to investigate the impact of high-frequency subthalamic nucleus (STN) deep brain stimulation (DBS) on sequence processing in PD. Methods: Twenty-nine patients with PD (17 women) completed a ‘before/after’ sentence task and a digit ordering task with STN DBS ON and OFF. In the sentence task, patients read a sequence of events expressed in the actual order of occurrence (‘after’ sentences) …or reversed order (‘before’ sentences) for comprehension. In the digit task, patients recalled a sequence of ordered digits (ordered trials) or reordered and recalled random digits in ascending order (random trials). Volumes of tissue activated (VTAs) were estimated for the motor and associative STN. Results: Patients were slower with STN DBS ON versus OFF in both tasks, although their motor symptoms were significantly improved under DBS. In the sentence task, patients showed higher ordering-related reaction time costs (‘before’ > ‘after’) with DBS ON versus OFF. Moreover, patients with larger left associative VTAs, smaller total motor VTAs, and more daily exposure to dopaminergic drugs tended to show larger reaction time cost increases under DBS. In the digit ordering task, patients with too large or too small right associative VTAs tended to show larger reaction time cost increases under DBS. Conclusion: Stimulating the STN, especially its associative part, might impair sequence processing in language and memory. Show more

Keywords: Parkinson’s disease, subthalamic nucleus, deep brain stimulation, sentence comprehension, temporal connectives, sequential working memory

DOI: 10.3233/JPD-212778

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1869-1879, 2021