Journal of Parkinson's Disease - Volume 11, issue 2

Authors: Kim, Ryul | Park, Sangmin | Yoo, Dallah | Ju Suh, Young | Jun, Jin-Sun | Jeon, Beomseok

Article Type: Research Article

Abstract: Background/Objective: To compare the longitudinal trajectories of cognition according to the presence of the apolipoprotein E (APOE ) ɛ 4 allele in male and female Parkinson’s disease (PD) patients. Methods: This study included a total of 361 patients with recently diagnosed de novo PD (mean age [standard deviation], 61.4 [9.8 ] years). The patients were classified into the following groups: APOE ɛ 4 + /M (n  = 65), APOE ɛ 4-/M (n  = 173), APOE ɛ 4 + /F (n  = 25), and APOE ɛ 4-/F (n  = 98). Cognitive decline was assessed annually over 5 years of follow-up using the …Montreal Cognitive Assessment (MoCA). To assess the sex-specific impacts of the APOE ɛ 4 status on cognitive decline, we used generalized linear mixed effects (GLME) models separately for men, women, and the two sexes combined. Results: In the sex-stratified GLME models adjusted for covariates, the interaction results showed that the males with APOE ɛ 4 had a steeper rate of cognitive decline than those without APOE ɛ 4. In contrast, there was no significant interaction between APOE ɛ 4 and time on longitudinal MoCA performance in the females. The main effect of APOE ɛ 4 on the change in the MoCA score was not significant for either men or women. When the data from both men and women were used, the APOE ɛ 4 + /M group exhibited a steeper rate of cognitive decline than did the APOE ɛ 4 + /F and APOE ɛ 4-/F groups. These results were consistent with those of sensitivity analyses. Conclusion: Sex may be considered when APOE ɛ 4-related vulnerability to early cognitive decline is evaluated in PD patients. Show more

Keywords: APOE , apolipoprotein, cognition, Parkinson’s disease, sex

DOI: 10.3233/JPD-202288

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 497-505, 2021

Authors: Contaldi, Elena | Magistrelli, Luca | Milner, Anna Vera | Cosentino, Marco | Marino, Franca | Comi, Cristoforo

Article Type: Research Article

Abstract: Background: Management of motor complications (MC) represents a major challenge in the long-term treatment of Parkinson’s disease (PD) patients. In this context, the role of peripheral adaptive immunity may provide new insights, since neuroinflammatory mechanisms have been proved crucial in the disease. Objective: The aim of this study was to analyze the transcription factors genes involved in CD4 + T cells development to uncover specific molecular signatures in patients with (PMC) and without (WMC) motor complications. Methods: mRNA levels of CD4 + T lymphocytes transcription factor genes TBX21 , STAT1 , STAT3 , STAT4 , STAT6 , RORC , GATA3 …, FOXP3 , and NR4A2 were measured from 40 PD patients, divided into two groups according to motor complications. Also, 40 age- and sex-matched healthy controls were enrolled. Results: WMC patients had higher levels of STAT1 and NR4A2 (p  = 0.004; p  = 0.003), whereas in PMC we found higher levels of STAT6 (p  = 0.04). Also, a ROC curve analysis confirmed STAT1 and NR4A2 as feasible biomarkers to discriminate WMC (AUC = 0.76, 95%CI 0.59–0.92, p  = 0.005; AUC = 0.75, 95%CI 0.58–0.90, p  = 0.007). Similarly, STAT6 detected PMC patients (AUC = 0.69, 95%CI 0.52–0.86, p  = 0.037). Conclusion: These results provide evidence of different molecular signatures in CD 4 + T cells of PD patients with and without MC, thus suggesting their potential as biomarkers of MC development. Show more

Keywords: Parkinson’s disease, motor complications, CD4 + T lymphocytes transcription factors, peripheral immune system

DOI: 10.3233/JPD-202417

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 507-514, 2021

Authors: Shrigley, Shelby | Nilsson, Fredrik | Mattsson, Bengt | Fiorenzano, Alessandro | Mudannayake, Janitha | Bruzelius, Andreas | Ottosson, Daniella Rylander | Björklund, Anders | Hoban, Deirdre B. | Parmar, Malin

Article Type: Research Article

Abstract: Background: Human induced pluripotent stem cells (hiPSCs) have been proposed as an alternative source for cell replacement therapy for Parkinson’s disease (PD) and they provide the option of using the patient’s own cells. A few studies have investigated transplantation of patient-derived dopaminergic (DA) neurons in preclinical models; however, little is known about the long-term integrity and function of grafts derived from patients with PD. Objective: To assess the viability and function of DA neuron grafts derived from a patient hiPSC line with an α -synuclein gene triplication (AST18), using a clinical grade human embryonic stem cell (hESC) line …(RC17) as a reference control. Methods: Cells were differentiated into ventral mesencephalic (VM)-patterned DA progenitors using an established GMP protocol. The progenitors were then either terminally differentiated to mature DA neurons in vitro or transplanted into 6-hydroxydopamine (6-OHDA) lesioned rats and their survival, maturation, function, and propensity to develop α -synuclein related pathology, were assessed in vivo . Results: Both cell lines generated functional neurons with DA properties in vitro . AST18-derived VM progenitor cells survived transplantation and matured into neuron-rich grafts similar to the RC17 cells. After 24 weeks, both cell lines produced DA-rich grafts that mediated full functional recovery; however, pathological changes were only observed in grafts derived from the α -synuclein triplication patient line. Conclusion: This data shows proof-of-principle for survival and functional recovery with familial PD patient-derived cells in the 6-OHDA model of PD. However, signs of slowly developing pathology warrants further investigation before use of autologous grafts in patients. Show more

Keywords: Parkinson’s disease, alpha-synuclein, cell transplantation, dopaminergic neurons

DOI: 10.3233/JPD-202366

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 515-528, 2021

Authors: Zhang, Zijuan | Hao, Li | Shi, Ming | Yu, Ziyang | Shao, Simai | Yuan, Ye | Zhang, Zhenqiang | Hölscher, Christian

Article Type: Research Article

Abstract: Background: Glucagon-like peptide 2 (GLP-2) is a peptide hormone derived from the proglucagon gene expressed in the intestines, pancreas and brain. Some previous studies showed that GLP-2 improved aging and Alzheimer’s disease related memory impairments. Parkinson’s disease (PD) is a progressive neurodegenerative disorder, and to date, there is no particular medicine reversed PD symptoms effectively. Objective: The aim of this study was to evaluate neuroprotective effects of a GLP-2 analogue in the 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) PD mouse model. Methods: In the present study, the protease resistant Gly(2)-GLP-2 (50 nmol/kg ip.) analogue has been tested for …14 days by behavioral assessment, transmission electron microscope, immunofluorescence histochemistry, enzyme-linked immunosorbent assay and western blot in an acute PD mouse model induced by MPTP. For comparison, the incretin receptor dual agonist DA5-CH was tested in a separate group. Results: The GLP-2 analogue treatment improved the locomotor and exploratory activity of mice, and improved bradykinesia and movement imbalance of mice. Gly(2)-GLP-2 treatment also protected dopaminergic neurons and restored tyrosine hydroxylase expression levels in the substantia nigra. Gly(2)-GLP-2 furthermore reduced the inflammation response as seen in lower microglia activation, and decreased NLRP3 and interleukin-1β pro-inflammatory cytokine expression levels. In addition, the GLP-2 analogue improved MPTP-induced mitochondrial dysfunction in the substantia nigra. The protective effects were comparable to those of the dual agonist DA5-CH. Conclusion: The present results demonstrate that Gly(2)-GLP-2 can attenuate NLRP3 inflammasome-mediated inflammation and mitochondrial damage in the substantia nigra induced by MPTP, and Gly(2)-GLP-2 shows neuroprotective effects in this PD animal model. Show more

Keywords: GLP-1, growth factor, inflammation, insulin, mitochondria, Parkinson’s disease

DOI: 10.3233/JPD-202318

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 529-543, 2021

Authors: Siebner, Thomas Hartwig | Fugl Madelung, Christopher | Bendtsen, Flemming | Løkkegaard, Annemette | Hove, Jens Dahlgaard | Siebner, Hartwig Roman

Article Type: Research Article

Abstract: Background: Gastrointestinal dysfunction and related clinical symptoms are common in Parkinson’s disease (PD), but the underlying mechanisms are still poorly understood. Objective: In this study, we investigated how PD affects the postprandial vascular response in the splanchnic circulation. Methods: 23 patients with PD in the “ON-medication” state and 23 age- and sex-matched healthy control participants underwent serial phase-contrast magnetic resonance imaging (PC-MRI) to measure the postprandial blood flow response in the superior mesenteric artery (SMA). Participants ingested a standardized liquid test meal (∼400 kcal) and underwent four PC-MRI runs within the following hour. Each PC-MRI run …consisted of six consecutive measurements of SMA blood flow. Results: In both groups, standardized food intake triggered an increase of blood flow in the SMA, but absolute and relative increases in blood flow were attenuated in patients compared to the control group (p  < 0.001). While baseline blood flow in the SMA was comparable in both groups, the postprandial maximum blood flow was attenuated in patients (p  = 0.03). The temporal dynamics of the postprandial blood flow did not differ between groups. Postprandial SMA blood flow increase in patients correlated neither with subjective reports of non-motor symptoms or upper gastrointestinal complaints, nor with levodopa equivalent daily dose or disease duration. Blood glucose measurements in between the PC-MRI runs showed a smaller postprandial increase in blood glucose in the patient group (p  = 0.006). Conclusion: This study provides first-time evidence that patients with PD have an attenuated postprandial blood flow response in the SMA, indicating an impaired functional regulation of gastrointestinal perfusion in response to food intake in PD. Show more

Keywords: Parkinson’s disease, non-motor symptoms, postprandial blood flow, magnetic resonance imaging, gastrointestinal dysfunction

DOI: 10.3233/JPD-202341

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 545-557, 2021

Authors: Sezgin, Mine | Kicik, Ani | Bilgic, Basar | Kurt, Elif | Bayram, Ali | Hanagası, Hasmet | Tepgec, Fatih | Toksoy, Guven | Gurvit, Hakan | Uyguner, Oya | Gokcay, Gulden | Demiralp, Tamer | Emre, Murat

Article Type: Research Article

Abstract: Background: There is evidence that alterations in functional connectivity (FC) of the striatocortical circuits may appear before the onset of clinical symptoms of Parkinson’s disease (PD). Objective: The aim of this study was to investigate FC of the striatocortical circuitry in asymptomatic carriers of heterozygous glucocerebrosidase (GBA ) mutations, which pose a significant risk for developing PD. Methods: Twenty-one parents of confirmed Gaucher disease patients who were carrying heterozygous GBA mutations and 18 healthy individuals matched for age and gender were included. GBA mutation analysis was performed in all participants. Clinical evaluation included neurological …examination, Mini Mental State Examination, and UPDRS Part III. Structural and functional MRI data of 18 asymptomatic GBA mutation carriers (asGBA mc) and 17 healthy controls (HC) were available. FC was analyzed with seed-based approach. Results: Eleven asymptomatic mutation carriers had heterozygous p.L483P mutation, 6 subjects heterozygous p.N409S mutation and 1 subject heterozygous p.R392G mutation in GBA gene. Mini-Mental State Examination mean score was 28.77 (±1.16) and 29.64 (±0.70) in asGBA mc and HC groups, respectively (p  = 0.012). Significant increased connectivity Conclusion: Our results suggest that alterations in striatocortical FC can be detected in asymptomatic heterozygous GBA mutation carriers who are at risk of developing PD. These findings may provide insight into network changes during the asymptomatic phase of PD. Show more

Keywords: Parkinson’s disease, glucoserobrosidase, GBA, functional connectivity, resting state fMRI

DOI: 10.3233/JPD-202295

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 559-568, 2021

Authors: Mazza, Melissa Conti | Nguyen, Victoria | Beilina, Alexandra | Karakoleva, Ema | Coyle, Michael | Ding, Jinhui | Bishop, Christopher | Cookson, Mark R.

Article Type: Research Article

Abstract: Background: Coding mutations in the LRRK2 gene, encoding for a large protein kinase, have been shown to cause familial Parkinson’s disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, suggesting that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci around LRRK2 and one of its proposed substrates, RAB29, as contributors towards the lifetime risk of sporadic PD. Objective: Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, we set out to determine whether there are …any consequences on brain function with aging after deletion of both genes. Methods: We generated a double knockout mouse model and performed a battery of motor and non-motor behavioral tests. We then investigated postmortem assays to determine the presence of PD-like pathology, including nigral dopamine cell count, astrogliosis, microgliosis, and striatal monoamine content. Results: Behaviorally, we noted only that 18–24-month Rab29-/- and double (Lrrk2-/- /Rab29-/- ) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in the outcomes that represented PD-like pathology. Conclusion: These results suggest that depletion of both LRRK2 and RAB29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans. Show more

Keywords: LRRK2, RAB29, dopamine, Parkinson’s disease, behavior

DOI: 10.3233/JPD-202172

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 569-584, 2021

Authors: George, Sonia | Tyson, Trevor | Rey, Nolwen L. | Sheridan, Rachael | Peelaerts, Wouter | Becker, Katelyn | Schulz, Emily | Meyerdirk, Lindsay | Burmeister, Amanda R. | von Linstow, Christian U. | Steiner, Jennifer A. | Galvis, Martha L. Escobar | Ma, Jiyan | Pospisilik, J. Andrew | Labrie, Viviane | Brundin, Lena | Brundin, Patrik

Article Type: Research Article

Abstract: Background: α -Synuclein (α -syn) is the predominant protein in Lewy-body inclusions, which are pathological hallmarks of α -synucleinopathies, such as Parkinson’s disease (PD) and multiple system atrophy (MSA). Other hallmarks include activation of microglia, elevation of pro-inflammatory cytokines, as well as the activation of T and B cells. These immune changes point towards a dysregulation of both the innate and the adaptive immune system. T cells have been shown to recognize epitopes derived from α -syn and altered populations of T cells have been found in PD and MSA patients, providing evidence that these cells can be key to …the pathogenesis of the disease. Objective To study the role of the adaptive immune system with respect to α -syn pathology. Methods: We injected human α -syn preformed fibrils (PFFs) into the striatum of immunocompromised mice (NSG) and assessed accumulation of phosphorylated α -syn pathology, proteinase K-resistant α -syn pathology and microgliosis in the striatum, substantia nigra and frontal cortex. We also assessed the impact of adoptive transfer of naïve T and B cells into PFF-injected immunocompromised mice. Results: Compared to wildtype mice, NSG mice had an 8-fold increase in phosphorylated α -syn pathology in the substantia nigra. Reconstituting the T cell population decreased the accumulation of phosphorylated α -syn pathology and resulted in persistent microgliosis in the striatum when compared to non-transplanted mice. Conclusion: Our work provides evidence that T cells play a role in the pathogenesis of experimental α -synucleinopathy. Show more

Keywords: Parkinson’s disease, multiple system atrophy, alpha-synuclein, phosphorylated alpha-synuclein, T lymphocytes, microglia

DOI: 10.3233/JPD-202351

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 585-603, 2021

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

Article Type: Research Article

Abstract: Background: Co-occurrence of β-amyloid (Aβ) pathology has been reported in Parkinson’s disease (PD), and Aβ deposition in the brain may contribute to cognitive decline in patients with PD. Whether striatal dopamine uptake and cognitive status differ with amyloid deposition has been reported in only a few studies. Objective: The purpose of this study was to investigate the association among striatal dopaminergic availability, Aβ-positivity, and motor and cognitive status in early and non-demented PD. Methods: A total of 98 newly-diagnosed, non-medicated, and non-demented patients with PD were included in this study. Cognitive status was assessed using neuropsychological …testing. Patients with mild cognitive impairment (MCI) were stratified into two groups: amnestic MCI (aMCI) and non-amnestic MCI (naMCI). Patient motor status was examined using the Unified Parkinson’s Disease Rating Scale (UPDRS) and positron emission tomography (PET) with 18 F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane (18 F-FP-CIT). All patients also underwent 18 F-florbetaben (18 F-FBB) PET and were divided based on the results into Aβ-positive and Aβ-negative groups. Results: Eighteen patients had Aβ-positivity in 18 F-FBB PET and 67 had MCI. Sixteen of 18 with Aβ-positive patients had MCI. The Aβ-positive group had higher frequency of MCI, especially amnestic-type, and lower dopaminergic activities in the left ventral striatum, but not with UPDRS motor score. Conclusion: Amyloid pathology was associated with MCI, especially amnestic-subtype, in early and non-demented PD patients and with low dopaminergic activities in the left ventral striatum. This finding suggests that PD patients with Aβ-positivity have AD-related cognitive pathophysiology in PD and associated impaired dopaminergic availability in the ventral striatum can affect the pathophysiology in various ways. Show more

Keywords: Parkinson’s disease, mild cognitive impairment, dopamine transporter, amyloid, motor, positron emission tomography

DOI: 10.3233/JPD-202496

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 605-613, 2021

Authors: Dinur, Tama | Becker-Cohen, Michal | Revel-Vilk, Shoshana | Zimran, Ari | Arkadir, David

Article Type: Short Communication

Abstract: Low penetrance of Parkinson’s disease (PD) associated with GBA pathogenic variants indicates the presence of modifiers genes. Clusters of PD cases in certain families with GBA variants would serve as a strong evidence for the clinical relevance of such modifiers. We studied eight family trees of non-Parkinsonian, GBA -N370S homozygote, Gaucher probands, with multiple cases of PD. Differences in PD risk associated with different GBA variants were balanced by variant homozygosity. In these families, all PD cases stemmed from only one of the proband’s parents. This observation provides a direct epidemiological evidence for genetic modifiers determining PD …risk in GBA variant carriers. Show more

Keywords: Parkinson’s disease, Gaucher disease, allele penetrance, pedigrees

DOI: 10.3233/JPD-202422

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 615-618, 2021