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    Neuronal autophagy and mitophagy in Parkinson's disease. Molecular aspects of medicine Autophagy is the process by which cells can selectively or non-selectively remove damaged proteins and organelles. As the cell's main means of sequestering damaged mitochondria for removal, mitophagy is central to cellular function and survival. Research on autophagy and mitochondrial quality control has increased exponentially in relation to the pathogenesis of numerous disease conditions, from cancer and immune diseases to chronic neurodegenerative diseases like Parkinson's disease (PD). Understanding how components of the autophagic/mitophagic machinery are affected during disease, as well as the contextual relationship of autophagy with determining neuronal health and function, is essential to the goal of designing therapies for human disease. In this review, we will summarize key signaling molecules that consign damaged mitochondria for autophagic degradation, describe the relationship of genes linked to PD to autophagy/mitophagy dysfunction, and discuss additional roles of both mitochondrial and cytosolic pools of PTEN-induced kinase 1 (PINK1) in mitochondrial homeostasis, dendritic morphogenesis and inflammation. 10.1016/j.mam.2021.100972
    Recent Evidence in Epigenomics and Proteomics Biomarkers for Early and Minimally Invasive Diagnosis of Alzheimer's and Parkinson's Diseases. Mayo Sonia,Benito-León Julián,Peña-Bautista Carmen,Baquero Miguel,Cháfer-Pericás Consuelo Current neuropharmacology BACKGROUND:Alzheimer's (AD) and Parkinson's diseases (PD) show deposits of improperly folded modified proteins. Protein expression mechanisms are involved since the early stages. Several studies evaluated epigenomics and proteomics profiles in these patients, with promising results. In general, they focused on early, specific, and minimally invasive biomarkers for the diagnosis and prognosis of AD and PD. OBJECTIVES:This review aimed at summarizing results to find the most reliable evidence in the field. RESULTS:Among epigenomics studies, there is a focus on microRNAs (miRNAs) as candidate diagnostic biomarkers for AD or PD from blood samples like miR-342-3p, miR-107, miR-106a-5p, miR-106b- 5p, miR-195, and miR-19b. In addition, DNA methylation has been tested in a few works, obtaining significant differences in some genes (NCAPH2/LMF2 COASY, SPINT1, BDNFTREM1, TREM2, NPAS2, PDE4D), which could be useful for evaluating the disease progression as well as potential risk factors. Regarding proteomics, most of the studies were untargeted and used plasma or serum samples. In general, they highlighted the importance of coagulation, inflammation pathways, and oxidative stress. Among targeted studies, some proteins (phosphorylated tau, C reactive protein (CRP), interleukins, necrosis factors, transferrin, glial fibrillary acidic protein (GFAP), and neurofilaments) showed different plasma levels in AD and PD patients in comparison with healthy participants. Finally, a few studies have identified specific-AD and PD epigenetic and proteomic biomarkers (ApoE and oxidized DJ-1) in comparison with other similar pathologies. CONCLUSION:In general, there is a common lack of clinical validation of these potential biomarkers because of which its use in clinical practice is still limited. 10.2174/1570159X19666201223154009
    Identification of blood-based biomarkers for diagnosis and prognosis of Parkinson's disease: A systematic review of proteomics studies. Chelliah Shalini Sundramurthi,Bhuvanendran Saatheeyavaane,Magalingam Kasthuri Bai,Kamarudin Muhamad Noor Alfarizal,Radhakrishnan Ammu Kutty Ageing research reviews Parkinson's Disease (PD), a neurodegenerative disorder, is characterised by the loss of motor function and dopamine neurons. Therapeutic avenues remain a challenge due to lack of accuracy in early diagnosis, monitoring of disease progression and limited therapeutic options. Proteomic platforms have been utilised to discover biomarkers for numerous diseases, a tool that may benefit the diagnosis and monitoring of disease progression in PD patients. Therefore, this systematic review focuses on analysing blood-based candidate biomarkers (CB) identified via proteomics platforms for PD. This study systematically reviewed articles across six databases (EMBASE, Cochrane, Ovid Medline, Scopus, Science Direct and PubMed) published between 2010 and 2020. Of the 504 articles identified, 12 controlled-PD studies were selected for further analysis. A total of 115 candidate biomarkers (CB) were identified across selected 12-controlled studies, of which 23 CB were found to be replicable in more than two cohorts. Using the PANTHER Go-Slim classification system and STRING network, the gene function and protein interactions between biomarkers were analysed. Our analysis highlights Apolipoprotein A-I (ApoA-I), which is essential in lipid metabolism, oxidative stress, and neuroprotection demonstrates high replicability across five cohorts with consistent downregulation across four cohorts. Since ApoA-I was highly replicable across blood fractions, proteomic platforms and continents, its relationship with cholesterol, statin and oxidative stress as PD biomarker, its role in the pathogenesis of PD is discussed in this paper. The present study identified ApoA-I as a potential biomarker via proteomics analysis of PD for the early diagnosis and prediction of disease progression. 10.1016/j.arr.2021.101514
    Multimodal retinal imaging to detect and understand Alzheimer's and Parkinson's disease. Moons Lieve,De Groef Lies Current opinion in neurobiology Retinal neurodegeneration and visual dysfunctions have been reported in a majority of Alzheimer's and Parkinson's patients, and, in light of the quest for novel biomarkers for these neurodegenerative proteinopathies, the retina has been receiving increasing attention as an organ for diagnosing, monitoring, and understanding disease. Thinning of retinal layers, abnormalities in vasculature, and protein deposition can be imaged at unprecedented resolution, which offers a unique systems biology view on the cellular and molecular changes underlying these pathologies. It makes the retina not only a promising target for biomarker development, but it also suggests that novel fundamental insights into the pathophysiology of Alzheimer's and Parkinson's disease can be obtained by studying the retina-brain axis. 10.1016/j.conb.2021.07.007
    Glycemic Control, Diabetic Complications, and Risk of Dementia in Patients With Diabetes: Results From a Large U.K. Cohort Study. Zheng Bang,Su Bowen,Price Geraint,Tzoulaki Ioanna,Ahmadi-Abhari Sara,Middleton Lefkos Diabetes care OBJECTIVE:Type 2 diabetes is an established risk factor for dementia. However, the roles of glycemic control and diabetic complications in the development of dementia have been less well substantiated. This large-scale cohort study aims to examine associations of longitudinal HbA levels and diabetic complications with the risk of dementia incidence among patients with type 2 diabetes. RESEARCH DESIGN AND METHODS:Data of eligible patients with diabetes, aged ≥50 years in the U.K. Clinical Practice Research Datalink from 1987 to 2018, were analyzed. Time-varying Cox regressions were used to estimate adjusted hazard ratios (HRs) and 95% CIs for dementia risk. RESULTS:Among 457,902 patients with diabetes, 28,627 (6.3%) incident dementia cases were observed during a median of 6 years' follow-up. Patients with recorded hypoglycemic events or microvascular complications were at higher risk of dementia incidence compared with those without such complications (HR 1.30 [95% CI 1.22-1.39] and 1.10 [1.06-1.14], respectively). The HbA level, modeled as a time-varying exposure, was associated with increased dementia risk (HR 1.08 [95% CI 1.07-1.09] per 1% HbA increment) among 372,287 patients with diabetes with postdiagnosis HbA records. Similarly, a higher coefficient of variation of HbA during the initial 3 years of follow-up was associated with higher subsequent dementia risk (HR 1.03 [95% CI 1.01-1.04] per 1-SD increment). CONCLUSIONS:Higher or unstable HbA levels and the presence of diabetic complications in patients with type 2 diabetes are associated with increased dementia risk. Effective management of glycemia might have a significant role in maintaining cognitive health among older adults with diabetes. 10.2337/dc20-2850
    The Nrf2-NLRP3-caspase-1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease. Zhang Chenyu,Zhao Miao,Wang Bingwei,Su Zhijie,Guo Bingbing,Qin Lihua,Zhang Weiguang,Zheng Ruimao Redox biology Parkinson's disease (PD) is a chronic neurodegenerative disorder that is characterized by motor symptoms as a result of a loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), accompanied by chronic neuroinflammation, oxidative stress, formation of α-synuclein aggregates. Celastrol, a potent anti-inflammatory and anti-oxidative pentacyclic triterpene, has emerged as a neuroprotective agent. However, the mechanisms by which celastrol is neuroprotective in PD remain elusive. Here we show that celastrol protects against dopamine neuron loss, mitigates neuroinflammation, and relieves motor deficits in MPTP-induced PD mouse model and AAV-mediated human α-synuclein overexpression PD model. Whole-genome deep sequencing analysis revealed that Nrf2, NLRP3 and caspase-1 in SNc may be associated with the neuroprotective actions of celastrol in PD. By using multiple genetically modified mice (Nrf2-KO, NLRP3-KO and Caspase-1-KO), we identified that celastrol inhibits NLRP3 inflammasome activation, relieves motor deficits and nigrostriatal dopaminergic degeneration through Nrf2-NLRP3-caspase-1 pathway. Taken together, these findings suggest that Nrf2-NLRP3-caspase-1 axis may serve as a key target of celastrol in PD treatment, and highlight the favorable properties of celastrol for neuroprotection, making celastrol as a promising disease-modifying agent for PD. 10.1016/j.redox.2021.102134
    Association of Cerebrospinal Fluid Neurofilament Light Protein Levels With Cognition in Patients With Dementia, Motor Neuron Disease, and Movement Disorders. Olsson Bob,Portelius Erik,Cullen Nicholas C,Sandelius Åsa,Zetterberg Henrik,Andreasson Ulf,Höglund Kina,Irwin David J,Grossman Murray,Weintraub Daniel,Chen-Plotkin Alice,Wolk David,McCluskey Leo,Elman Lauren,Shaw Leslie M,Toledo Jon B,McBride Jennifer,Hernandez-Con Pilar,Lee Virginia M-Y,Trojanowski John Q,Blennow Kaj JAMA neurology Importance:Neuronal and axonal destruction are hallmarks of neurodegenerative diseases, but it is difficult to estimate the extent and progress of the damage in the disease process. Objective:To investigate cerebrospinal fluid (CSF) levels of neurofilament light (NFL) protein, a marker of neuroaxonal degeneration, in control participants and patients with dementia, motor neuron disease, and parkinsonian disorders (determined by clinical criteria and autopsy), and determine its association with longitudinal cognitive decline. Design, Setting, and Participants:In this case-control study, we investigated NFL levels in CSF obtained from controls and patients with several neurodegenerative diseases. Collection of samples occurred between 1996 and 2014, patients were followed up longitudinally for cognitive testing, and a portion were autopsied in a single center (University of Pennsylvania). Data were analyzed throughout 2016. Exposures:Concentrations of NFL in CSF. Main Outcomes and Measures:Levels of CSF NFL and correlations with cognition scores. Results:A total of 913 participants (mean [SD] age, 68.7 [10.0] years; 456 [49.9%] women) were included: 75 control participants plus 114 patients with mild cognitive impairment (MCI), 397 with Alzheimer disease, 96 with frontotemporal dementia, 68 with amyotrophic lateral sclerosis, 41 with Parkinson disease (PD), 19 with PD with MCI, 29 with PD dementia, 33 with dementia with Lewy bodies, 21 with corticobasal syndrome, and 20 with progressive supranuclear palsy. Cognitive testing follow-up occurred for 1 to 18 years (mean [SD], 0.98 [2.25] years); autopsy-verified diagnoses were available for 120 of 845 participants with diseases (14.2%). There was a stepwise increase in CSF NFL levels between control participants (median [range] score, 536 [398-777] pg/mL), participants with MCI (831 [526-1075] pg/mL), and those with Alzheimer disease (951 [758-1261] pg/mL), indicating that NFL levels increase with increasing cognitive impairment. Levels of NFL correlated inversely with baseline Mini-Mental State Examination scores (ρ, -0.19; P < .001) in the full cohort (n = 822) and annual score decline in the full cohort (ρ, 0.36, P < .001), participants with AD (ρ, 0.25; P < .001), and participants with FTD (ρ, 0.46; P = .003). Concentrations of NFL were highest in participants with amyotrophic lateral sclerosis (median [range], 4185 [2207-7453] pg/mL) and frontotemporal dementia (2094 [230-7744] pg/mL). In individuals with parkinsonian disorders, NFL concentrations were highest in those with progressive supranuclear palsy (median [range], 1578 [1287-3104] pg/mL) and corticobasal degeneration (1281 [828-2713] pg/mL). The NFL concentrations in CSF correlated with TDP-43 load in 13 of 17 brain regions in the full cohort. Adding NFL to β-amyloid 42, total tau, and phosphorylated tau increased accuracy of discrimination of diseases. Conclusions and Relevance:Levels of CSF NFL are associated with cognitive impairments in patients with Alzheimer disease and frontotemporal dementia. In other neurodegenerative disorders, NFL levels appear to reflect the intensity of the neurodegenerative processes. 10.1001/jamaneurol.2018.3746
    Serum immune markers and disease progression in an incident Parkinson's disease cohort (ICICLE-PD). Williams-Gray Caroline H,Wijeyekoon Ruwani,Yarnall Alison J,Lawson Rachael A,Breen David P,Evans Jonathan R,Cummins Gemma A,Duncan Gordon W,Khoo Tien K,Burn David J,Barker Roger A, Movement disorders : official journal of the Movement Disorder Society BACKGROUND:The immune system is a promising therapeutic target for disease modification in Parkinson's disease (PD), but appropriate immune-related biomarkers must be identified to allow patient stratification for trials and tracking of therapeutic effects. The objective of this study was to investigate whether immune markers in peripheral blood are candidate prognostic biomarkers through determining their relationship with disease progression in PD. METHODS:Serum samples were collected in incident PD cases and age-matched controls. Subjects were clinically evaluated at baseline and 18 and 36 months. Ten cytokines and C-reactive protein were measured, with data reduction using principal-component analysis, and relationships between component scores and motor (MDS Unified Parkinson's Disease Rating Scale - part 3) and cognitive (Mini Mental State Examination [MMSE]) measures of disease severity/progression were investigated. RESULTS:TNF-α, IL1-β, IL-2, and IL-10 were higher in PD (n = 230) than in controls (n = 93), P ≤ 0.001). Principal-component analysis of log-transformed data resulted in a 3-component solution explaining 51% of the variance. Higher "proinflammatory" and lower "anti-inflammatory" component scores were associated with more rapid motor progression over 36 months (P < 0.05), and higher "proinflammatory" component scores were associated with lower MMSE at all times (P < 0.05). Multiple linear regression analysis with adjustment for covariates confirmed "anti-inflammatory" component score was the strongest predictor of slower motor progression (β = -0.22, P = 0.002), whereas proinflammatory cytokines were associated with lower baseline MMSE (β = -0.175, P = 0.007). CONCLUSIONS:Serum immune marker profile is predictive of disease progression in PD and hence a potential prognostic biomarker. However, interventional trials are needed to clarify whether peripheral immune changes causally contribute to the progression of PD. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. 10.1002/mds.26563
    Plasma IL-6 and IL-17A Correlate with Severity of Motor and Non-Motor Symptoms in Parkinson's Disease. Green Holly F,Khosousi Shervin,Svenningsson Per Journal of Parkinson's disease The nature of the inflammatory response in Parkinson's disease (PD) remains to be better understood. Here, we used highly sensitive Single Molecule Array (SIMOA) technology to measure the levels of the inflammatory mediators Interleukin 6 (IL-6), Interleukin 17A (IL-17A), Tumour Necrosis Factor α (TNFα) and Transforming Growth Factor β (TGFβ) in plasma from PD patients and age- and gender-matched healthy controls. We report that IL-17A correlates with non-motor symptoms (NMS) scores, while IL-6 positively correlates with motor scores. We found no correlations between cytokines and disease duration suggesting that IL-6 and IL-17A are associated with disease severity rather than disease duration in this cohort, furthermore IL-17A may be involved in the underlying pathophysiology of NMS in PD. 10.3233/JPD-191699
    Peripheral blood inflammatory markers in early Parkinson's disease. Kim Ryul,Kim Han-Joon,Kim Aryun,Jang Mihee,Kim Ahro,Kim Yoon,Yoo Dallah,Im Jin Hee,Choi Ji-Hyun,Jeon Beomseok Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia The aim of this study was to characterize peripheral inflammatory markers in patients with early Parkinson's disease (PD) and to explore whether these markers contribute to motor and non-motor symptoms. We collected serum from patients with early PD (n = 58) and from healthy control subjects (n = 20). The following inflammatory markers were measured: interleukin (IL)-1β, IL-2, IL-6, IL-10, tumor necrosis factor-α, and high-sensitivity C-reactive protein. The Movement Disorders Society Unified Parkinson's Disease Rating Scale part 3 and Hoehn and Yahr stage were used to assess motor symptoms, and the Non-motor Symptoms Scale, the Cross-Cultural Smell Identification Test, the Montreal Cognitive Assessment, and the Composite Autonomic Symptom Score 31 (COMPASS-31) were used to assess non-motor symptoms. The levels of IL-1β, IL-2, and IL-6 were higher in the PD group than in the control group. However, only IL-1β among those markers remained significant after Bonferroni correction (P = 0.024). In the PD group, the anti-inflammatory cytokine IL-10 levels correlated positively with the COMPASS-31 score (r = 0.277, P = 0.035), whereas no correlation was found between the other inflammatory marker levels and motor or non-motor symptoms. Among the domains of the COMPASS-31, the IL-10 levels correlated only with the gastrointestinal domain (r = 0.358, P = 0.006). Our results suggest increased peripheral inflammation in the early stage of PD, but the role of inflammation in motor and non-motor symptoms is unclear. Although we found a correlation between IL-10 levels and gastrointestinal symptoms, this finding may simply reflect a protective response against inflammatory processes associated with the disease. 10.1016/j.jocn.2018.10.079
    CSF Cytokines in Aging, Multiple Sclerosis, and Dementia. Hu William T,Howell Jennifer Christina,Ozturk Tugba,Gangishetti Umesh,Kollhoff Alexander L,Hatcher-Martin Jaime M,Anderson Albert M,Tyor William R Frontiers in immunology Inflammation is a common process involved in aging, multiple sclerosis (MS), and age-related neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), but there is limited evidence for the effects of aging on inflammation in the central nervous system. We collected cerebrospinal fluid (CSF) from 105 healthy control subjects representing a wide age range (23-86), and analyzed levels of cytokines associated innate immunity (TNF-α) and different T-helper subtypes: interferon-gamma induced protein 10 (IP-10) for Th1, interleukin-10 (IL-10) for Th2, and interleukin 8 (IL-8/CXCL8) for Th17. We show that CSF levels of TNF-α, IP-10, and IL-8 all increased linearly with age, but levels of IL-10 demonstrated a U-shaped relationship with age. We further found greater age-related increases in TNF-α, IL-10, and IL-8 relative to increases in IP-10 levels, consistent with a shift from Th1 to other inflammatory phenotypes. Finally, when we analyzed the same four cytokines in people with neurological disorders, we found that MS and AD, but not PD or dementia with Lewy bodies, further accentuated the age-related shift from Th1- to non-Th1-related cytokines. We propose that CSF cytokine levels represent powerful surrogates of brain inflammation and aging, and some, but not all, neurological disorders accelerate the shift away from Th1 phenotypes. 10.3389/fimmu.2019.00480
    Diabetes mellitus and Parkinson's disease: dangerous liaisons between insulin and dopamine. De Iuliis Angela,Montinaro Ennio,Fatati Giuseppe,Plebani Mario,Colosimo Carlo Neural regeneration research The relationship between diabetes mellitus and Parkinson's disease has been described in several epidemiological studies over the 1960s to date. Molecular studies have shown the possible functional link between insulin and dopamine, as there is strong evidence demonstrating the action of dopamine in pancreatic islets, as well as the insulin effects on feeding and cognition through central nervous system mechanism, largely independent of glucose utilization. Therapies used for the treatment of type 2 diabetes mellitus appear to be promising candidates for symptomatic and/or disease-modifying action in neurodegenerative diseases including Parkinson's disease, while an old dopamine agonist, bromocriptine, has been repositioned for the type 2 diabetes mellitus treatment. This review will aim at reappraising the different studies that have highlighted the dangerous liaisons between diabetes mellitus and Parkinson's disease. 10.4103/1673-5374.320965
    Plasma cytokine profile in synucleinophaties with dementia. Usenko T S,Nikolaev M A,Miliukhina I V,Bezrukova A I,Senkevich K A,Gomzyakova N A,Beltceva Y A,Zalutskaya N M,Gracheva E V,Timofeeva A A,Petrova O A,Semenov A V,Lubimova N E,Totolyan A A,Pchelina S N Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia Immune response may play a pivotal role in the pathogenesis of the common synucleinopathy as Parkinson's disease (PD) and could be mediated with the accumulation of neurotoxic alpha-synuclein. There is limited evidence for immune response in another synucleinopathy as dementia with Lewy bodies (DLB). Recent data suggest that immune response may contribute to cognitive impairment. We aimed to estimate plasma cytokine profile in patients with synucleinopathies with dementia (PD dementia (PDD), DLB). Plasma cytokine levels (interferon-gamma (IFN-gamma), interleukin (IL)-4 (IL-4), IL-6, IL-10, tumor necrosis factor alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1)). were estimated in 16 patients with DLB, 19 patients with PDD, 28 patients with PD without dementia (PD) and 19 individuals without neurological disorders (controls) using Luminex array system. Cognitive status was assessed with the Mini-Mental State Examination (MMSE). TNF-alpha and IL-6 plasma levels were elevated in patients with synucleinopathies with dementia (DLB, PDD) compared to controls and IL-10 plasma level was increased in PDD compared to controls (p < 0.05). IFN-gamma levels were decreased in PD and PDD patients compared to controls (p < 0.001, p = 0.026, respectively) and in PD patients than in DLB patients (p = 0.032). Patients with PD, PDD, and DLB were characterized by increased plasma levels of MCP-1 compared to controls (p < 0.001). At the same time, no differences in TNF-alpha, IL-10, IL-6 plasma levels in PD patients compared to controls were found. Our study demonstrated more pronounced immune response in synucleinopathies associated with dementia compared to PD without demetia. 10.1016/j.jocn.2020.04.058
    The role of gut dysbiosis in Parkinson's disease: mechanistic insights and therapeutic options. Wang Qing,Luo Yuqi,Ray Chaudhuri K,Reynolds Richard,Tan Eng-King,Pettersson Sven Brain : a journal of neurology Parkinson's disease is a common neurodegenerative disorder in which gastrointestinal symptoms may appear prior to motor symptoms. The gut microbiota of patients with Parkinson's disease shows unique changes, which may be used as early biomarkers of disease. Alterations in the gut microbiota composition may be related to the cause or effect of motor or non-motor symptoms, but the specific pathogenic mechanisms are unclear. The gut microbiota and its metabolites have been suggested to be involved in the pathogenesis of Parkinson's disease by regulating neuroinflammation, barrier function and neurotransmitter activity. There is bidirectional communication between the enteric nervous system and the CNS, and the microbiota-gut-brain axis may provide a pathway for the transmission of α-synuclein. We highlight recent discoveries about alterations to the gut microbiota in Parkinson's disease and focus on current mechanistic insights into the microbiota-gut-brain axis in disease pathophysiology. Moreover, we discuss the interactions between the production and transmission of α-synuclein and gut inflammation and neuroinflammation. In addition, we draw attention to diet modification, the use of probiotics and prebiotics and faecal microbiota transplantation as potential therapeutic approaches that may lead to a new treatment paradigm for Parkinson's disease. 10.1093/brain/awab156
    Small fiber neuropathy in Parkinson's disease: A clinical, pathological and corneal confocal microscopy study. Kass-Iliyya Lewis,Javed Saad,Gosal David,Kobylecki Christopher,Marshall Andrew,Petropoulos Ioannis N,Ponirakis Georgios,Tavakoli Mitra,Ferdousi Maryam,Chaudhuri Kallol Ray,Jeziorska Maria,Malik Rayaz A,Silverdale Monty A Parkinsonism & related disorders UNLABELLED:Autonomic and somatic denervation is well established in Parkinson's disease (PD). OBJECTIVES:(1) To determine whether corneal confocal microscopy (CCM) can non-invasively demonstrate small nerve fiber damage in PD. (2) To identify relationships between corneal nerve parameters, intraepidermal nerve fiber density (IENFD) and clinical features of PD. METHODS:Twenty-six PD patients and 26 controls underwent CCM of both eyes. 24/26 PD patients and 10/26 controls underwent skin biopsies from the dorsa of both feet. PD patients underwent assessment of parasympathetic function [deep breathing heart rate variability (DB-HRV)], autonomic symptoms [scale for outcomes in Parkinson's disease - autonomic symptoms (SCOPA-AUT)], motor symptoms [UPDRS-III "ON"] and cumulative Levodopa dose. RESULTS:PD patients had significantly reduced corneal nerve fiber density (CNFD) with increased corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL) compared to controls. CNBD and CNFL but not CNFD correlated inversely with UPDRS-III and SCOPA-AUT. All CCM parameters correlated strongly with DB-HRV. There was no correlation between CCM parameters and disease duration, cumulative Levodopa dose or pain. IENFD was significantly reduced in PD compared to controls and correlated with CNFD and UPDRS-III. However, unlike CCM measures, IENFD correlated with disease duration and cumulative Levodopa dose but not with autonomic dysfunction. CONCLUSION:CCM identifies corneal nerve fiber pathology, which correlates with autonomic symptoms, parasympathetic deficits and motor scores in patients with PD. IENFD is also reduced and correlates with CNFD and motor symptoms but not parasympathetic deficits, indicating it detects different aspects of peripheral nerve pathology in PD. 10.1016/j.parkreldis.2015.10.019
    Potential use of corneal confocal microscopy in the diagnosis of Parkinson's disease associated neuropathy. Che Ning-Ning,Yang Hong-Qi Translational neurodegeneration Parkinson's disease (PD) is a chronic, progressive neurodegenerative disease affecting about 2-3% of population above the age of 65. In recent years, Parkinson's research has mainly focused on motor and non-motor symptoms while there are limited studies on neurodegeneration which is associated with balance problems and increased incidence of falls. Corneal confocal microscopy (CCM) is a real-time, non-invasive, in vivo ophthalmic imaging technique for quantifying nerve damage in peripheral neuropathies and central neurodegenerative disorders. CCM has shown significantly lower corneal nerve fiber density (CNFD) in patients with PD compared to healthy controls. Reduced CNFD is associated with decreased intraepidermal nerve fiber density in PD. This review provides an overview of the ability of CCM to detect nerve damage associated with PD. 10.1186/s40035-020-00204-3
    [Changes in corneal nerves fibers in the early stages of Parkinson's disease according to in vivo confocal microscopy (preliminary report)]. Avetisov S E,Karabanov A V,Surnina Z V,Gamidov A A Vestnik oftalmologii One of the research directions of the so-called non-motor manifestations of Parkinson's disease (PD) is associated with the assessment of structural and functional changes in the organ of vision. An assessment of the state of thin non-myelinated corneal nerve fibers (CNF) in Parkinson's disease seems to be promising considering the neurodegenerative nature of the disease, as well as the possibility of objective intravital assessment of both functional and structural changes in CNF. PURPOSE:To analyze the changes in the course and structure of corneal nerve fibers in the early stages of Parkinson's disease based on an objective algorithm of corneal confocal microscopy (CCM). MATERIAL AND METHODS:The study was conducted on a group of 16 patients aged 39 to 66 years with verified diagnosis of PD. In addition to standard neurological and ophthalmological examinations, all patients underwent IVCCM on a Heidelberg Retinal Tomograph device with special Rostock Cornea Module (HRT3 RCM), followed by processing of the obtained images using a uniquely designed analysis algorithm. RESULTS:A significant decrease in the directional anisotropy coefficient and an increase in the directional symmetry coefficient of the nerve fibers of the cornea were established (average values 3.15±1.08 and 0.92±0.04, respectively); in healthy individuals of the identical age range these indicators are 3.5±0.85 and 0.86±0.11, respectively. In addition, qualitative structural changes were noted, which consisted of an increase in the number of branches from the main nerve trunks, an increase in the tortuosity of CNF, multidirectionality, and "beaded" shape. In 9 cases, the presence of macrophages was revealed - dendritic Langerhans cells, which is an indirect sign of the inflammatory process. CONCLUSION:The preliminary nature of the results obtained in this study and the need for further research in this area are related, on the one hand, to a small sample of observations and, on the other hand, to the criterion used to assess the status of CNF based on a comparative analysis with conditionally normal indicators. In the future, in order to solve the problem of the uniqueness of changes in CNF and the possibility of using these changes as a marker for PD progression, longitudinal studies are required to reveal the presence or absence of a correlation between the stage of the disease, the results of known monitoring methods (e.g. electromyography) and quantitative indicators of the status of CNF. 10.17116/oftalma2020136052191
    Corneal confocal microscopy detects small fibre neurodegeneration in Parkinson's disease using automated analysis. Lim Sze Hway,Ferdousi Maryam,Kalteniece Alise,Kass-Iliyya Lewis,Petropoulos Ioannis N,Malik Rayaz A,Kobylecki Christopher,Silverdale Monty Scientific reports We studied the utility of corneal confocal microscopy (CCM) in detecting a reduction in corneal nerve parameters in a large cohort of patients with Parkinson's disease (PD) compared to controls using a fully automated potentially scalable method of analysis. We also assessed if CCM parameters are related to the severity and sub-type of PD. 98 participants with PD and 26 healthy controls underwent CCM with automated corneal nerve quantification, MDS-UPDRS III, Hoehn and Yahr scale, Montreal Cognitive Assessment, Parkinson's Disease Questionnaire-39 and PD subtype assessment. Corneal nerve fibre density (mean difference: - 5.00 no/mm, 95% confidence interval (CI) [- 7.89, - 2.12], p = 0.001), corneal nerve branch density (mean difference: - 10.71 no/mm, 95% CI [- 16.93, - 4.48], p = 0.003), corneal total branch density (mean difference: - 14.75 no/mm, 95% CI [- 23.58, - 5.92], p = 0.002), and corneal nerve fibre length (mean difference: - 2.57 mm/mm, 95% CI [- 4.02, - 1.12], p = 0.001) were significantly lower in PD participants compared to controls. There was no correlation between corneal nerve parameters and duration, severity or subtype of PD, cognitive function or quality of life. CCM with automated corneal nerve analysis identifies nerve fibre damage and may act as a biomarker for neurodegeneration in PD. 10.1038/s41598-020-76768-x
    Deep Brain Stimulation for Freezing of Gait in Parkinson's Disease With Early Motor Complications. Barbe Michael T,Tonder Lisa,Krack Paul,Debû Bettina,Schüpbach Michael,Paschen Steffen,Dembek Till A,Kühn Andrea A,Fraix Valerie,Brefel-Courbon Christine,Wojtecki Lars,Maltête David,Damier Phillippe,Sixel-Döring Friederike,Weiss Daniel,Pinsker Marcus,Witjas Tatiana,Thobois Stephane,Schade-Brittinger Carmen,Rau Jörn,Houeto Jean-Luc,Hartmann Andreas,Timmermann Lars,Schnitzler Alfons,Stoker Valerie,Vidailhet Marie,Deuschl Günther, Movement disorders : official journal of the Movement Disorder Society BACKGROUND:Effects of DBS on freezing of gait and other axial signs in PD patients are unclear. OBJECTIVE:Secondary analysis to assess whether DBS affects these symptoms within a large randomized controlled trial comparing DBS of the STN combined with best medical treatment and best medical treatment alone in patients with early motor complications (EARLYSTIM-trial). METHODS:One hundred twenty-four patients were randomized in the stimulation group and 127 patients in the best medical treatment group. Presence of freezing of gait was assessed in the worst condition based on item-14 of the UPDRS-II at baseline and follow-up. The posture, instability, and gait-difficulty subscore of the UPDRS-III, and a gait test including quantification of freezing of gait and number of steps, were performed in both medication-off and medication-on conditions. RESULTS:Fifty-two percent in both groups had freezing of gait at baseline based on UPDRS-II. This proportion decreased in the stimulation group to 34%, but did not change in the best medical treatment group at 24 months (P = 0.018). The steps needed to complete the gait test decreased in the stimulation group and was superior to the best medical treatment group (P = 0.016). The axial signs improved in the stimulation group compared to the best medical treatment group (P < 0.01) in both medication-off and medication-on conditions. CONCLUSIONS:Within the first 2 years of DBS, freezing of gait and other axial signs improved in the medication-off condition compared to best medical treatment in these patients. © 2019 International Parkinson and Movement Disorder Society. 10.1002/mds.27892
    Associations Between Tau, β-Amyloid, and Cognition in Parkinson Disease. Winer Joseph R,Maass Anne,Pressman Peter,Stiver Jordan,Schonhaut Daniel R,Baker Suzanne L,Kramer Joel,Rabinovici Gil D,Jagust William J JAMA neurology Importance:Multiple disease processes are associated with cognitive impairment in Parkinson disease (PD), including Lewy bodies, cerebrovascular disease, and Alzheimer disease. It remains unknown whether tau pathology relates to cognition in patients with PD without dementia. Objective:To compare tau aggregation in patients with PD who are cognitively normal (PD-CN), patients with PD with mild cognitive impairment (PD-MCI), and healthy control participants, and evaluate the relationships between β-amyloid (Aβ), tau, and cognition in patients with PD who did not have dementia. Design, Setting, and Participants:This cross-sectional study recruited 30 patients with Parkinson disease (15 with PD-CN and 15 with PD-MCI) from a tertiary care medical center and research institutions from July 2015 through October 2016. One patient with PD-MCI did not receive a magnetic resonance imaging scan and thus was excluded from all analyses; 29 patients with PD were included in the present study. Participants underwent tau positron emission tomographic (PET) scanning with fluorine 18-labeled AV-1451, Aβ PET scanning with carbon 11-labeled Pittsburgh compound B, magnetic resonance imaging, cognitive testing, and neurologic evaluation. Imaging measures were compared with 49 healthy control participants. Main Outcomes and Measures:Outcomes were tau PET measurements of groups of patients with PD-CN and PD-MCI. We hypothesized that tau aggregation across groups would be related to age and Aβ status. Results:Of the 78 participants, 47 (60%) were female, and the mean (SD) age was 71.1 (6.6) years. Six patients with PD (21%) were Aβ-positive, of whom 1 was mildly cognitively impaired; 23 were Aβ-negative (79%). (Of the 49 healthy controls, 25 were Aβ-negative and 24 Aβ-positive.) Voxelwise contrasts of whole-brain tau PET uptake between patients with PD-CN and patients with PD-MCI, and additionally between all patients with PD and Aβ-negative controls, did not reveal significant differences. Tau PET binding did not differ between patients with PD-MCI and PD-CN in brain regions reflecting Alzheimer disease Braak stages 1/2, 3/4, or 5/6, and did not differ from Aβ-negative healthy older adults. Mean (SD) tau PET binding was significantly elevated in Aβ-positive patients with PD relative to Aβ-negative patients with PD within brain regions reflecting Alzheimer disease Braak stage 3/4 (1.22 [0.07] vs 1.14 [0.07]; P = .03) and Braak stage 5/6 (1.20 [0.07] vs 1.11 [0.08]; P = .02). Conclusions and Relevance:These findings suggest that patterns of cortical Aβ and tau do not differ in people with PD-CN, people with PD-MCI, and healthy older adults. Age, Aβ, and tau do not differentiate patients with PD-CN and PD-MCI. Tau deposition is related to Aβ status and age in both people with PD and healthy older adults. Cognitive deficits in people with PD without dementia do not appear to reflect measureable Alzheimer disease. 10.1001/jamaneurol.2017.3713
    Can neuroimaging predict dementia in Parkinson's disease? Lanskey Juliette H,McColgan Peter,Schrag Anette E,Acosta-Cabronero Julio,Rees Geraint,Morris Huw R,Weil Rimona S Brain : a journal of neurology Dementia in Parkinson's disease affects 50% of patients within 10 years of diagnosis but there is wide variation in severity and timing. Thus, robust neuroimaging prediction of cognitive involvement in Parkinson's disease is important: (i) to identify at-risk individuals for clinical trials of potential new treatments; (ii) to provide reliable prognostic information for individuals and populations; and (iii) to shed light on the pathophysiological processes underpinning Parkinson's disease dementia. To date, neuroimaging has not made major contributions to predicting cognitive involvement in Parkinson's disease. This is perhaps unsurprising considering conventional methods rely on macroscopic measures of topographically distributed neurodegeneration, a relatively late event in Parkinson's dementia. However, new technologies are now emerging that could provide important insights through detection of other potentially relevant processes. For example, novel MRI approaches can quantify magnetic susceptibility as a surrogate for tissue iron content, and increasingly powerful mathematical approaches can characterize the topology of brain networks at the systems level. Here, we present an up-to-date overview of the growing role of neuroimaging in predicting dementia in Parkinson's disease. We discuss the most relevant findings to date, and consider the potential of emerging technologies to detect the earliest signs of cognitive involvement in Parkinson's disease. 10.1093/brain/awy211
    Integrated Plasma and Neuroimaging Biomarkers Associated with Motor and Cognition Severity in Parkinson's Disease. Chen Chih-Hao,Lee Bo-Ching,Lin Chin-Hsien Journal of Parkinson's disease BACKGROUND/OBJECTIVE:Easily accessible biomarkers are crucial for disease-modifying clinical trials in patients with Parkinson's disease (PD). We investigated integrated plasma and neuroimaging biomarkers correlating with motor and cognitive severity in PD patients. METHODS:This cross-sectional study enrolled 170 participants (12 controls and 158 PD patients). Plasma α-synuclein and neurofilament light chain (NfL) level, and global and regional cortical thickness (CTh) on brain MRI were analyzed to predict advanced motor stage (Hoehn & Yahr stage ≥3), and PD dementia (PDD, MMSE score <26). RESULTS:Plasma α-synuclein and NfL levels were higher in PD patients than controls (both P < 0.0001 for α-synuclein and NfL). Plasma NfL levels were significantly elevated in patients with advanced motor stage (P = 0.008) or PDD; α-synuclein was elevated in the advanced motor stage group. Global CTh was thinner in patients with PDD than controls (2.33±0.19 mm vs 2.43±0.14 mm, P = 0.06). Among PD patients, higher α-synuclein was associated with thinner limbic CTh, whereas higher NfL was associated with thinner temporal CTh and insular CTh. The accuracy of predicting advanced motor stage using age and sex alone (area under the curve [AUC] 0.63) was significantly improved by the addition of plasma α-synuclein and NfL, and temporal and insula CTh (full model, AUC 0.77, P = 0.004). The accuracy of predicting PDD using age and sex alone (AUC 0.82) increased by incorporating plasma α-synuclein and NfL, and temporal and insula CTh as full model (AUC 0.87, P = 0.047). CONCLUSIONS:Integrated plasma and neuroimaging biomarkers reflect both motor and cognitive aspects of PD severity. 10.3233/JPD-191766
    TMEM106B Effect on cognition in Parkinson disease and frontotemporal dementia. Tropea Thomas F,Mak Jordan,Guo Michael H,Xie Sharon X,Suh Eunran,Rick Jacqueline,Siderowf Andrew,Weintraub Daniel,Grossman Murray,Irwin David,Wolk David A,Trojanowski John Q,Van Deerlin Vivianna,Chen-Plotkin Alice S Annals of neurology OBJECTIVE:Common variants near TMEM106B associate with risk of developing frontotemporal dementia (FTD). Emerging evidence suggests a role for TMEM106B in neurodegenerative processes beyond FTD. We evaluate the effect of TMEM106B genotype on cognitive decline across multiple neurogenerative diseases. METHODS:We longitudinally followed 870 subjects with diagnoses of Parkinson disease (PD; n = 179), FTD (n = 179), Alzheimer disease (AD; n = 300), memory-predominant mild cognitive impairment (MCI; n = 75), or neurologically normal control subjects (NC; n = 137) at the University of Pennsylvania (UPenn). All participants had annual Mini-Mental State Examination (MMSE; median follow-up duration = 3.0 years) and were genotyped at TMEM106B index single nucleotide polymorphism rs1990622. Genotype effects on cognition were confirmed by extending analyses to additional cognitive instruments (Mattis Dementia Rating Scale-2 [DRS-2] and Montreal Cognitive Assessment [MoCA]) and to an international validation cohort (Parkinson's Progression Markers Initiative [PPMI], N = 371). RESULTS:The TMEM106B rs1990622 allele, linked to increased risk of FTD, associated with greater MMSE decline over time in PD subjects but not in AD or MCI subjects. For FTD subjects, rs1990622 associated with more rapid decrease in MMSE only under the minor-allele, rs1990622 , dominant model. Among PD patients, rs1990622 carriers from the UPenn cohort demonstrated more rapid longitudinal decline in DRS-2 scores. Finally, in the PPMI cohort, TMEM106B risk allele carriers demonstrated more rapid longitudinal decline in MoCA scores. INTERPRETATION:Irrespective of cognitive instrument or cohort assessed, TMEM106B acts as a genetic modifier for cognitive trajectory in PD. Our results implicate lysosomal dysfunction in the pathogenesis of cognitive decline in 2 different proteinopathies. ANN NEUROL 2019;85:801-811. 10.1002/ana.25486
    Sequence of clinical and neurodegeneration events in Parkinson's disease progression. Brain : a journal of neurology Dementia is one of the most debilitating aspects of Parkinson's disease. There are no validated biomarkers that can track Parkinson's disease progression, nor accurately identify patients who will develop dementia and when. Understanding the sequence of observable changes in Parkinson's disease in people at elevated risk for developing dementia could provide an integrated biomarker for identifying and managing individuals who will develop Parkinson's dementia. We aimed to estimate the sequence of clinical and neurodegeneration events, and variability in this sequence, using data-driven statistical modelling in two separate Parkinson's cohorts, focusing on patients at elevated risk for dementia due to their age at symptom onset. We updated a novel version of an event-based model that has only recently been extended to cope naturally with clinical data, enabling its application in Parkinson's disease for the first time. The observational cohorts included healthy control subjects and patients with Parkinson's disease, of whom those diagnosed at age 65 or older were classified as having high risk of dementia. The model estimates that Parkinson's progression in patients at elevated risk for dementia starts with classic prodromal features of Parkinson's disease (olfaction, sleep), followed by early deficits in visual cognition and increased brain iron content, followed later by a less certain ordering of neurodegeneration in the substantia nigra and cortex, neuropsychological cognitive deficits, retinal thinning in dopamine layers, and further deficits in visual cognition. Importantly, we also characterize variation in the sequence. We found consistent, cross-validated results within cohorts, and agreement between cohorts on the subset of features available in both cohorts. Our sequencing results add powerful support to the increasing body of evidence suggesting that visual processing specifically is affected early in patients with Parkinson's disease at elevated risk of dementia. This opens a route to earlier and more precise detection, as well as a more detailed understanding of the pathological mechanisms underpinning Parkinson's dementia. 10.1093/brain/awaa461
    Plasma Metabolomic Markers of Insulin Resistance and Diabetes and Rate of Incident Parkinson's Disease. Molsberry Samantha,Bjornevik Kjetil,Hughes Katherine C,Zhang Zhongli Joel,Jeanfavre Sarah,Clish Clary,Healy Brian,Schwarzschild Michael,Ascherio Alberto Journal of Parkinson's disease BACKGROUND:Although there is evidence of shared dysregulated pathways between diabetes and Parkinson's disease, epidemiologic research on an association between the two diseases has produced inconsistent results. OBJECTIVE:We aimed to assess whether known metabolomic markers of insulin resistance and diabetes are also associated with Parkinson's disease development. METHODS:We conducted a nested case-control study among Nurses' Health Study and Health Professionals Follow-up Study participants who had provided blood samples up to twenty years prior to Parkinson's diagnosis. Cases were matched to risk-set sampled controls by age, sex, fasting status, and time of blood collection. Participants provided covariate information via regularly collected cohort questionnaires. We used conditional logistic regression models to assess whether plasma levels of branched chain amino acids, acylcarnitines, glutamate, or glutamine were associated with incident development of Parkinson's disease. RESULTS:A total of 349 case-control pairs were included in this analysis. In the primary analyses, none of the metabolites of interest were associated with Parkinson's disease development. In investigations of the association between each metabolite and Parkinson's disease at different time intervals prior to diagnosis, some metabolites showed marginally significant association but, after correction for multiple testing, only C18 : 2 acylcarnitine was significantly associated with Parkinson's disease among subjects for whom blood was collected less than 60 months prior to case diagnosis. CONCLUSIONS:Plasma levels of diabetes-related metabolites did not contribute to predict risk of Parkinson's disease. Further investigation of the relationship between pre-diagnostic levels of diabetes-related metabolites and Parkinson's disease in other populations is needed to confirm these findings. 10.3233/JPD-191896
    Immune profiling of plasma-derived extracellular vesicles identifies Parkinson disease. Vacchi Elena,Burrello Jacopo,Di Silvestre Dario,Burrello Alessio,Bolis Sara,Mauri Pierluigi,Vassalli Giuseppe,Cereda Carlo W,Farina Cinthia,Barile Lucio,Kaelin-Lang Alain,Melli Giorgia Neurology(R) neuroimmunology & neuroinflammation OBJECTIVE:To develop a diagnostic model based on plasma-derived extracellular vesicle (EV) subpopulations in Parkinson disease (PD) and atypical parkinsonism (AP), we applied an innovative flow cytometric multiplex bead-based platform. METHODS:Plasma-derived EVs were isolated from PD, matched healthy controls, multiple system atrophy (MSA), and AP with tauopathies (AP-Tau). The expression levels of 37 EV surface markers were measured by flow cytometry and correlated with clinical scales. A diagnostic model based on EV surface markers expression was built via supervised machine learning algorithms and validated in an external cohort. RESULTS:Distinctive pools of EV surface markers related to inflammatory and immune cells stratified patients according to the clinical diagnosis. PD and MSA displayed a greater pool of overexpressed immune markers, suggesting a different immune dysregulation in PD and MSA vs AP-Tau. The receiver operating characteristic curve analysis of a compound EV marker showed optimal diagnostic performance for PD (area under the curve [AUC] 0.908; sensitivity 96.3%, specificity 78.9%) and MSA (AUC 0.974; sensitivity 100%, specificity 94.7%) and good accuracy for AP-Tau (AUC 0.718; sensitivity 77.8%, specificity 89.5%). A diagnostic model based on EV marker expression correctly classified 88.9% of patients with reliable diagnostic performance after internal and external validations. CONCLUSIONS:Immune profiling of plasmatic EVs represents a crucial step toward the identification of biomarkers of disease for PD and AP. 10.1212/NXI.0000000000000866
    Diabetes mellitus and Parkinson disease. Pagano Gennaro,Polychronis Sotirios,Wilson Heather,Giordano Beniamino,Ferrara Nicola,Niccolini Flavia,Politis Marios Neurology OBJECTIVE:To investigate whether diabetes mellitus is associated with Parkinson-like pathology in people without Parkinson disease and to evaluate the effect of diabetes mellitus on markers of Parkinson pathology and clinical progression in drug-naive patients with early-stage Parkinson disease. METHODS:We compared 25 patients with Parkinson disease and diabetes mellitus to 25 without diabetes mellitus, and 14 patients with diabetes mellitus and no Parkinson disease to 14 healthy controls (people with no diabetes mellitus or Parkinson disease). The clinical diagnosis of diabetes mellitus was confirmed by 2 consecutive fasting measurements of serum glucose levels >126 mL/dL. Over a 36-month follow-up period, we then investigated in the population with Parkinson disease whether the presence of diabetes mellitus was associated with faster motor progression or cognitive decline. RESULTS:The presence of diabetes mellitus was associated with higher motor scores ( < 0.01), lower striatal dopamine transporter binding ( < 0.05), and higher tau CSF levels ( < 0.05) in patients with Parkinson disease. In patients with diabetes but without Parkinson disease, the presence of diabetes mellitus was associated with lower striatal dopamine transporter binding ( < 0.05) and higher tau ( < 0.05) and α-synuclein ( < 0.05) CSF levels compared to healthy controls. At the Cox survival analysis in the population of patients with Parkinson disease, the presence of diabetes mellitus was associated with faster motor progression (hazard ratio = 4.521, 95% confidence interval = 1.468-13.926; < 0.01) and cognitive decline (hazard ratio = 9.314, 95% confidence interval = 1.164-74.519; < 0.05). CONCLUSIONS:Diabetes mellitus may predispose toward a Parkinson-like pathology, and when present in patients with Parkinson disease, can induce a more aggressive phenotype. 10.1212/WNL.0000000000005475
    Dopamine-responsive and dopamine-resistant resting tremor in Parkinson disease. Zach Heidemarie,Dirkx Michiel F,Roth Dominik,Pasman Jaco W,Bloem Bastiaan R,Helmich Rick C Neurology OBJECTIVE:We tested the hypothesis that there are 2 distinct phenotypes of Parkinson tremor, based on interindividual differences in the response of resting tremor to dopaminergic medication. We also investigated whether this pattern is specific to tremor by comparing interindividual differences in the dopamine response of tremor to that of bradykinesia. METHODS:In this exploratory study, we performed a levodopa challenge in 76 tremulous patients with Parkinson tremor. Clinical scores (Movement Disorders Society-sponsored version of the Unified Parkinson's Disease Rating Scale part III) were collected "off" and "on" a standardized dopaminergic challenge (200/50 mg dispersible levodopa-benserazide). In both sessions, resting tremor intensity was quantified using accelerometry, both during rest and during cognitive coactivation. Bradykinesia was quantified using a speeded keyboard test. We calculated the distribution of dopamine-responsiveness for resting tremor and bradykinesia. In 41 patients, a double-blinded, placebo-controlled dopaminergic challenge was repeated after approximately 6 months. RESULTS:The dopamine response of resting tremor, but not bradykinesia, significantly departed from a normal distribution. A cluster analysis on 3 clinical and electrophysiologic markers of tremor dopamine-responsiveness revealed 3 clusters: dopamine-responsive, intermediate, and dopamine-resistant tremor. A repeated levodopa challenge after 6 months confirmed this classification. Patients with dopamine-responsive tremor had greater disease severity and tended to have a higher prevalence of dyskinesia. CONCLUSION:Parkinson resting tremor can be divided into 3 partially overlapping phenotypes, based on the dopamine response. These tremor phenotypes may be associated with different underlying pathophysiologic mechanisms, requiring a different therapeutic approach. 10.1212/WNL.0000000000010316
    Advances in markers of prodromal Parkinson disease. Postuma Ronald B,Berg Daniela Nature reviews. Neurology Efforts to develop neuroprotective therapy for Parkinson disease (PD) are focusing on the early stages of disease, which offer the best opportunity to intervene. Early PD can be divided into preclinical, prodromal and clinical stages; in this Review, we focus on the prodromal stage and markers that can be used to identify prodromal PD. We consider the necessary properties of a marker, before providing an overview of the proven and potential markers of prodromal PD, including clinical nonmotor markers, clinical motor markers, neuroimaging markers and tissue biomarkers. Markers for which the ability to predict conversion to PD is supported by the strongest evidence include olfactory loss, REM sleep behaviour disorder and constipation. Markers with the highest diagnostic strength include REM sleep behaviour disorder, dopaminergic imaging and subtle motor parkinsonism. The lead time - the period between the appearance of a marker and conversion to PD - is highly variable between markers, ranging from 5 years for impaired motor performance to >20 years for autonomic symptoms. The cost of screening for these markers also varies dramatically: some require just questionnaires, whereas others require sophisticated scanning techniques. Finally, we summarize how prodromal and risk markers can be combined to estimate the probability that an individual has prodromal PD, with a focus on the International Parkinson Disease and Movement Disorders Society (MDS) Prodromal Parkinson Criteria. 10.1038/nrneurol.2016.152
    Gut Microbiome Signatures of Risk and Prodromal Markers of Parkinson Disease. Heinzel Sebastian,Aho Velma T E,Suenkel Ulrike,von Thaler Anna-Katharina,Schulte Claudia,Deuschle Christian,Paulin Lars,Hantunen Sari,Brockmann Kathrin,Eschweiler Gerhard W,Maetzler Walter,Berg Daniela,Auvinen Petri,Scheperjans Filip Annals of neurology OBJECTIVE:Alterations of the gut microbiome in Parkinson disease (PD) have been repeatedly demonstrated. However, little is known about whether such alterations precede disease onset and how they relate to risk and prodromal markers of PD. We investigated associations of these features with gut microbiome composition. METHODS:Established risk and prodromal markers of PD as well as factors related to diet/lifestyle, bowel function, and medication were studied in relation to bacterial α-/β-diversity, enterotypes, and differential abundance in stool samples of 666 elderly TREND (Tübingen Evaluation of Risk Factors for Early Detection of Neurodegeneration) study participants. RESULTS:Among risk and prodromal markers, physical activity, occupational solvent exposure, and constipation showed associations with α-diversity. Physical activity, sex, constipation, possible rapid eye movement sleep behavior disorder (RBD), and smoking were associated with β-diversity. Subthreshold parkinsonism and physical activity showed an interaction effect. Among other factors, age and urate-lowering medication were associated with α- and β-diversity. Physical inactivity and constipation were highest in individuals with the Firmicutes-enriched enterotype. Constipation was lowest and subthreshold parkinsonism least frequent in individuals with the Prevotella-enriched enterotype. Differentially abundant taxa were linked to constipation, physical activity, possible RBD, smoking, and subthreshold parkinsonism. Substantia nigra hyperechogenicity, olfactory loss, depression, orthostatic hypotension, urinary/erectile dysfunction, PD family history, and the prodromal PD probability showed no significant microbiome associations. INTERPRETATION:Several risk and prodromal markers of PD are associated with gut microbiome composition. However, the impact of the gut microbiome on PD risk and potential microbiome-dependent subtypes in the prodrome of PD need further investigation based on prospective clinical and (multi)omics data in incident PD cases. ANN NEUROL 2020;88:320-331. 10.1002/ana.25788
    Corneal Confocal Microscopy Identifies Parkinson's Disease with More Rapid Motor Progression. Lim Sze Hway,Ferdousi Maryam,Kalteniece Alise,Mahfoud Ziyad R,Petropoulos Ioannis N,Malik Rayaz A,Kobylecki Christopher,Silverdale Monty Movement disorders : official journal of the Movement Disorder Society BACKGROUND:Corneal confocal microscopy (CCM) is a noninvasive, reproducible ophthalmic technique to quantify corneal small nerve fiber degeneration. CCM demonstrates small nerve fiber damage in Parkinson's disease (PD), but its role as a longitudinal biomarker of PD progression has not been explored. OBJECTIVE:The aim of this study was to assess corneal nerve morphology using CCM in relation to disease progression in PD. METHODS:Sixty-four participants with PD were assessed at baseline and at 12-month follow-up. Participants underwent CCM with automated corneal nerve quantification and assessment of Movement Disorder Society Unified Parkinson's Disease Rating Scale, Hoehn and Yahr stage, and Montreal Cognitive Assessment. RESULTS:Corneal nerve fiber density (CNFD), corneal nerve branch density, corneal nerve fiber length, corneal total branch density, and corneal nerve fiber area were significantly lower in participants with PD compared with healthy control subjects. Worsening of Movement Disorder Society Unified Parkinson's Disease Rating Scale part III score over 12 months was significantly greater in participants with a CNFD in the lowest compared with the highest quartile at baseline (mean difference: 6.0; 95% CI: 1.0-10.9; P = 0.019). There were no significant changes in CNFD, corneal nerve branch density, corneal nerve fiber length, corneal total branch density, corneal nerve fiber area, or corneal nerve fiber width between baseline and 12-month follow-up. CONCLUSIONS:CCM identifies neurodegeneration in patients with PD, especially those who show the greatest progression in neurological disability. CCM may be a useful tool to help enrich clinical trials with those likely to exhibit more rapid progression and reduce required sample size and cost of studies. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. 10.1002/mds.28602
    Cognitive decline in Parkinson disease. Aarsland Dag,Creese Byron,Politis Marios,Chaudhuri K Ray,Ffytche Dominic H,Weintraub Daniel,Ballard Clive Nature reviews. Neurology Dementia is a frequent problem encountered in advanced stages of Parkinson disease (PD). In recent years, research has focused on the pre-dementia stages of cognitive impairment in PD, including mild cognitive impairment (MCI). Several longitudinal studies have shown that MCI is a harbinger of dementia in PD, although the course is variable, and stabilization of cognition - or even reversal to normal cognition - is not uncommon. In addition to limbic and cortical spread of Lewy pathology, several other mechanisms are likely to contribute to cognitive decline in PD, and a variety of biomarker studies, some using novel structural and functional imaging techniques, have documented in vivo brain changes associated with cognitive impairment. The evidence consistently suggests that low cerebrospinal fluid levels of amyloid-β, a marker of comorbid Alzheimer disease (AD), predict future cognitive decline and dementia in PD. Emerging genetic evidence indicates that in addition to the APOE*ε4 allele (an established risk factor for AD), GBA mutations and SCNA mutations and triplications are associated with cognitive decline in PD, whereas the findings are mixed for MAPT polymorphisms. Cognitive enhancing medications have some effect in PD dementia, but no convincing evidence that progression from MCI to dementia can be delayed or prevented is available, although cognitive training has shown promising results. 10.1038/nrneurol.2017.27
    Parkinson disease. Poewe Werner,Seppi Klaus,Tanner Caroline M,Halliday Glenda M,Brundin Patrik,Volkmann Jens,Schrag Anette-Eleonore,Lang Anthony E Nature reviews. Disease primers Parkinson disease is the second-most common neurodegenerative disorder that affects 2-3% of the population ≥65 years of age. Neuronal loss in the substantia nigra, which causes striatal dopamine deficiency, and intracellular inclusions containing aggregates of α-synuclein are the neuropathological hallmarks of Parkinson disease. Multiple other cell types throughout the central and peripheral autonomic nervous system are also involved, probably from early disease onwards. Although clinical diagnosis relies on the presence of bradykinesia and other cardinal motor features, Parkinson disease is associated with many non-motor symptoms that add to overall disability. The underlying molecular pathogenesis involves multiple pathways and mechanisms: α-synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport and neuroinflammation. Recent research into diagnostic biomarkers has taken advantage of neuroimaging in which several modalities, including PET, single-photon emission CT (SPECT) and novel MRI techniques, have been shown to aid early and differential diagnosis. Treatment of Parkinson disease is anchored on pharmacological substitution of striatal dopamine, in addition to non-dopaminergic approaches to address both motor and non-motor symptoms and deep brain stimulation for those developing intractable L-DOPA-related motor complications. Experimental therapies have tried to restore striatal dopamine by gene-based and cell-based approaches, and most recently, aggregation and cellular transport of α-synuclein have become therapeutic targets. One of the greatest current challenges is to identify markers for prodromal disease stages, which would allow novel disease-modifying therapies to be started earlier. 10.1038/nrdp.2017.13
    The role of brain vasculature in neurodegenerative disorders. Sweeney Melanie D,Kisler Kassandra,Montagne Axel,Toga Arthur W,Zlokovic Berislav V Nature neuroscience Adequate supply of blood and structural and functional integrity of blood vessels are key to normal brain functioning. On the other hand, cerebral blood flow shortfalls and blood-brain barrier dysfunction are early findings in neurodegenerative disorders in humans and animal models. Here we first examine molecular definition of cerebral blood vessels, as well as pathways regulating cerebral blood flow and blood-brain barrier integrity. Then we examine the role of cerebral blood flow and blood-brain barrier in the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis. We focus on Alzheimer's disease as a platform of our analysis because more is known about neurovascular dysfunction in this disease than in other neurodegenerative disorders. Finally, we propose a hypothetical model of Alzheimer's disease biomarkers to include brain vasculature as a factor contributing to the disease onset and progression, and we suggest a common pathway linking brain vascular contributions to neurodegeneration in multiple neurodegenerative disorders. 10.1038/s41593-018-0234-x
    Vascular parkinsonism--characteristics, pathogenesis and treatment. Korczyn Amos D Nature reviews. Neurology Parkinson disease is a primary degenerative disease of the brain, but parkinsonism can also result from a variety of vascular disorders. Vascular parkinsonism (VP) most frequently presents as lower body parkinsonism, a condition that is accompanied by the development of white matter lesions (WMLs) and lacunes in the brain. Patients with lower body parkinsonism exhibit gait impairment and go on to develop urinary incontinence, abnormal pyramidal responses and cognitive decline. However, WMLs and lacunes are also common observations among elderly individuals who do not have parkinsonism, which causes difficulty in determining the pathogenetic mechanisms that lead to VP. In addition, imaging studies suggest that many pathological and clinical features are common to VP and Binswanger disease, a type of small vessel vascular dementia. This Review summarizes current understanding of the clinical characteristics of VP, as well as knowledge gained from neuroimaging and nuclear imaging of the pathological features of VP. The lack of current treatment options, and the emergence of new therapies such as cerebrospinal fluid drainage, are also discussed. Finally, consideration is given to whether the overlap between VP and Binswanger disease means that these two disorders should be considered as part of the same disease entity. 10.1038/nrneurol.2015.61
    A clinically useful MRI marker of PD? Fyfe Ian Nature reviews. Neurology 10.1038/s41582-018-0109-5
    White Matter Hyperintensities, Dopamine Loss, and Motor Deficits in De Novo Parkinson's Disease. Jeong Seong Ho,Lee Hye Sun,Jung Jin Ho,Baik Kyoungwon,Lee Yang Hyun,Yoo Han Soo,Sohn Young H,Chung Seok Jong,Lee Phil Hyu Movement disorders : official journal of the Movement Disorder Society BACKGROUND:White matter hyperintensities, prevalent in patients with Parkinson's disease (PD), significantly affect parkinsonian motor symptoms. The objective of this study was to investigate the relationship between white matter hyperintensities and nigrostriatal dopamine depletion and their interaction or mediating effects on motor symptoms in patients with drug-naive early-stage PD. METHODS:This cross-sectional study enrolled 501 patients with de novo PD who initially underwent [ F] N-(3-fluoropropyl)-2β-carbonethoxy-3β-(4-iodophenyl) nortropane positron emission tomography and brain magnetic resonance imaging scans between April 2009 and September 2015 in a tertiary-care university hospital. We quantified dopamine transporter availability in each striatal subregion and assessed the severity of periventricular and lobar white matter hyperintensities using the Scheltens scale. The relationship between white matter hyperintensities, dopamine transporter availability in the posterior putamen, and Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was assessed using multivariate linear regression and mediation analyses. RESULTS:Periventricular and frontal white matter hyperintensities were generally associated with dopamine transporter availability in striatal subregions after adjusting for age at symptom onset, sex, disease duration, and vascular risk factors. There was an interaction effect between periventricular white matter hyperintensities and dopamine transporter availability in the posterior putamen for the axial motor score. The effect of white matter hyperintensities on UPDRS total score and bradykinesia subscore was indirectly mediated by dopamine transporter availability in the posterior putamen, whereas the axial sub-score was directly affected by white matter hyperintensities. CONCLUSIONS:This study suggests that the detrimental effect of white matter hyperintensities on parkinsonian motor symptoms is more relevant and independent for axial motor impairments in the status of mildly decreased striatal dopamine transporter availability. © 2021 International Parkinson and Movement Disorder Society. 10.1002/mds.28510
    Clinicoradiological comparison between vascular parkinsonism and Parkinson's disease. Vale Thiago Cardoso,Caramelli Paulo,Cardoso Francisco Journal of neurology, neurosurgery, and psychiatry OBJECTIVE:To compare the clinical and radiological features of vascular parkinsonism (VP) and Parkinson's disease (PD). METHODS:Cross-sectional study where 15 patients with VP (8 (53.3%) men; aged 75.7 ± 10.4 years) and 30 patients with PD (17 (56.7%) men; aged 67.3 ± 7.5 years) underwent motor and cognitive evaluation and brain MRI. RESULTS:Patients with VP were, on average, 8.4 years older (p = 0.004); all had arterial hypertension. They presented with a sudden onset of parkinsonism (80%) and a rapidly progressive clinical course (53.3%). Predominant lower body parkinsonism (p<0.001), postural instability (p=0.003) with freezing of gait (p<0.001) and falls (p<0.001), urinary incontinence (p < 0.001) and pyramidal signs (p<0.001) were more common in patients with VP. Movement Disorders Society's Unified PD Rating Scale (MDS-UPDRS) scores were higher in patients with VP (p=0.005 in 'OFF' state and p<0.001 in 'ON' state). They had greater cognitive impairment and 12 (80%) fulfilled diagnostic criteria for probable vascular dementia. Most patients with VP had brain MRI changes: multiple lacunar infarcts (66.7%) or extensive white matter disease (26.7%). CONCLUSIONS:VP can be clinically distinguished from PD based on sudden onset of parkinsonism at an older age, characterised by lower body predominance, urinary incontinence, pyramidal signs, postural instability with freezing of gait and falls, and dementia. 10.1136/jnnp-2014-307867
    Vascular, inflammatory and metabolic risk factors in relation to dementia in Parkinson's disease patients with type 2 diabetes mellitus. Wang Ting,Yuan Feilan,Chen Zhenze,Zhu Shuzhen,Chang Zihan,Yang Wanlin,Deng Bin,Que Rongfang,Cao Peihua,Chao Yinxia,Chan Lingling,Pan Ying,Wang Yanping,Xu Linting,Lyu Qiurong,Chan Piu,Yenari Midori A,Tan Eng-King,Wang Qing Aging There are limited data on vascular, inflammatory, metabolic risk factors of dementia in Parkinson's disease (PD) with type 2 diabetes mellitus (DM) (PD-DM). In a study of 928 subjects comprising of 215 PD with DM (including 31 PD-DM with dementia, PD-DMD), 341 PD without DM (including 31 PD with dementia, PDD) and 372 DM without PD (including 35 DM with dementia, DMD) patients, we investigated if vascular, inflammatory, metabolic, and magnetic resonance imaging (MRI) markers were associated with dementia in PD-DM. Lower fasting blood glucose (FBG<5mmol/L, OR=4.380; 95%CI: 1.748-10.975; p=0.002), higher homocysteine (HCY>15mol/L, OR=3.131; 95%CI: 1.243-7.888; p=0.015) and hyperlipidemia (OR=3.075; 95%CI: 1.142-8.277; p=0.026), increased age (OR=1.043; 95%CI: 1.003-1.084; p=0.034) were the most significant risk factors in PDD patients. Lower low-density lipoprotein cholesterol (LDL-C<2mmol/L, OR=4.499; 95%CI: 1.568-12.909; p=0.005) and higher fibrinogen (>4g/L, OR=4.066; 95%CI: 1.467-11.274; p=0.007) were the most significant risk factors in PD-DMD patients. The area under the curve (AUC) for fibrinogen and LDL-C was 0.717 (P=0.001), with a sensitivity of 80.0% for the prediction of PD-DMD.In summary, we identified several factors including LDL-C and fibrinogen as significant risk factors for PD-DMD and these may have prognostic and treatment implications. 10.18632/aging.103776
    Parkinson's Disease and the Gut: Symptoms, Nutrition, and Microbiota. Yemula Nehal,Dietrich Celina,Dostal Vaclav,Hornberger Michael Journal of Parkinson's disease Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, characterized by symptoms of bradykinesia, rigidity, postural instability, and tremor. Recently, there has been a growing focus on the relationship between the gut and the development of PD. Emerging to the forefront, an interesting concept has developed suggesting that the initial pathophysiological changes occur in the gastrointestinal tract before changes are seen within the brain. This review is aimed at highlighting the relationship between PD and the gastrointestinal tract, along with the supporting evidence for this. Firstly, we will focus on the gastrointestinal conditions and symptoms which commonly affects patients, including both upper and lower gastrointestinal issues. Secondly, the impact of nutrition and diet on neurological health and PD physiology, with particular emphasis on commonly consumed items including macronutrients and micronutrients. Finally, variability of the gut microbiome will also be discussed and its link with both the symptoms and signs of PD. The evidence presented in this review highly suggests that the initial pathogenesis in the gut may proceed the development of prodromal PD subtypes, and therefore building on this further could be imperative and lead to earlier diagnosis with new and improved therapeutics. 10.3233/JPD-212707
    DNA methylation changes associated with Parkinson's disease progression: outcomes from the first longitudinal genome-wide methylation analysis in blood. Henderson-Smith Adrienne,Fisch Kathleen M,Hua Jianping,Liu Ganqiang,Ricciardelli Eugenia,Jepsen Kristen,Huentelman Mathew,Stalberg Gabriel,Edland Steven D,Scherzer Clemens R,Dunckley Travis,Desplats Paula Epigenetics Parkinson's Disease (PD) is a common neurodegenerative disorder currently diagnosed based on the presentation of characteristic movement symptoms. Unfortunately, patients exhibiting these symptoms have already undergone significant dopaminergic neuronal loss. Earlier diagnosis, aided by molecular biomarkers specific to PD, would improve overall patient care. Epigenetic mechanisms, which are modified by both environment and disease pathophysiology, are emerging as important components of neurodegeneration. Alterations to the PD methylome have been reported in epigenome-wide association studies. However, the extent to which methylation changes correlate with disease progression has not yet been reported; nor the degree to which methylation is affected by PD medication. We performed a longitudinal genome-wide methylation study surveying ~850,000 CpG sites in whole blood from 189 well-characterized PD patients and 191 control individuals obtained at baseline and at a follow-up visit ~2 y later. We identified distinct patterns of methylation in PD cases versus controls. Importantly, we identified genomic sites where methylation changes longitudinally as the disease progresses. Moreover, we identified methylation changes associated with PD pathology through the analysis of PD cases that were not exposed to anti-parkinsonian therapy. In addition, we identified methylation sites modulated by exposure to dopamine replacement drugs. These results indicate that DNA methylation is dynamic in PD and changes over time during disease progression. To the best of our knowledge, this is the first longitudinal epigenome-wide methylation analysis for Parkinson's disease and reveals changes associated with disease progression and in response to dopaminergic medications in the blood methylome. 10.1080/15592294.2019.1588682
    Metabolomics profiling reveals altered lipid metabolism and identifies a panel of lipid metabolites as biomarkers for Parkinson's disease related anxiety disorder. Dong Mei-Xue,Hu Ling,Wei You-Dong,Chen Guang-Hui Neuroscience letters OBJECTIVES:Anxiety disorder is a common non-motor symptom in patient with Parkinson's disease (PD). We aimed to explore its pathogenesis and identify plasma biomarkers using untargeted metabolomics analysis. METHODS:Consecutive PD patients and healthy controls were recruited. Clinical data were assessed and patients with Parkinson's disease related anxiety disorder (PDA) were recognized. Fast plasma samples were obtained and untargeted liquid chromatography-mass spectrometry-based metabolomics analysis was performed. Based on the differentially expressed metabolites from the above metabolomics analysis, correlation analyses and receiver operating characteristic curves (ROC) were further employed. RESULTS:According to the clinical data, PDA patients had lower plasma levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, and apolipoprotein B. There were thirty-nine differentially expressed metabolites in PDA patients when compared with the other two groups from the metabolomics analysis, respectively. Fourteen lipid metabolites were simultaneously altered between these two groups, and all of them were significantly decreased. They can be further subcategorized into fatty acyls, glycerolipids, sterol lipids, sphingolipids, and prenol lipids. The plasma levels of thirteen metabolites were negatively correlated with HAMA scores except 10-oxo-nonadecanoic acid. Based on the ROC curves, the fourteen lipid metabolites can be diagnostic biomarkers for PDA patients separately and the areas under the curve of the fourteen lipid metabolites ranged from 0.681 to 0.798. CONCLUSIONS:Significantly lower plasma lipoproteins can be found in PDA patients. A panel of fourteen lipid metabolites were also significantly decreased and can be clinical biomarkers for the diagnosis of PDA patients. 10.1016/j.neulet.2021.135626
    Lipid Metabolism is the common pathologic mechanism between Type 2 Diabetes Mellitus and Parkinson's disease. Zhang Xi,Fan Yu,Luo Yuping,Jin Lingjing,Li Siguang International journal of medical sciences Although increasing evidence has suggested crosstalk between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM), the common mechanisms between the two diseases remain unclear. The aim of our study was to characterize the interconnection between T2DM and PD by exploring their shared biological pathways and convergent molecules. The intersections among the differentially expressed genes (DEGs) in the T2DM dataset GSE95849 and PD dataset GSE6613 from the Gene Expression Omnibus (GEO) database were identified as the communal DEGs between the two diseases. Then, an enrichment analysis, protein-protein interaction (PPI) network analysis, correlation analysis, and transcription factor-target regulatory network analysis were performed for the communal DEGs. As a result, 113 communal DEGs were found between PD and T2DM. They were enriched in lipid metabolism, including protein modifications that regulate metabolism, lipid synthesis and decomposition, and the biological effects of lipid products. All these pathways and their biological processes play important roles in both diseases. Fifteen hub genes identified from the PPI network could be core molecules. Their function annotations also focused on lipid metabolism. According to the correlation analysis and the regulatory network analysis based on the 15 hub genes, Sp1 transcription factor (SP1) could be a key molecule since it affected other hub genes that participate in the common mechanisms between PD and T2DM. In conclusion, our analyses reveal that changes in lipid metabolism could be a key intersection between PD and T2DM, and that SP1 could be a key molecule regulating these processes. Our findings provide novel points for the association between PD and T2DM. 10.7150/ijms.46456
    Effects of metformin exposure on neurodegenerative diseases in elderly patients with type 2 diabetes mellitus. Kuan Yi-Chun,Huang Kuang-Wei,Lin Cheng-Li,Hu Chaur-Jong,Kao Chia-Hung Progress in neuro-psychopharmacology & biological psychiatry Epidemiological evidence reveals that patients with type 2 diabetes mellitus (T2DM) have an increased risk of neurodegenerative diseases (NDs), including dementia and Parkinson's disease (PD). The effects of metformin exposure on dementia and PD risk in patients with T2DM are unknown. We evaluated the effects of metformin exposure on the risk of dementia and PD in patients with T2DM. We performed a cohort study by using Taiwan's National Health Insurance Research Database. We recruited 4651 patients in the metformin cohort and a comparable number of nonmetformin controls by using propensity score matching. Multivariate Cox proportional hazards regression was used to estimate the effects of metformin on the risk of dementia and PD after adjustment for several confounding factors. During the 12-year follow-up, the metformin cohort exhibited a higher risk of PD than the nonmetformin cohort (hazard ratio [HR]: 2.27, 95% confidence interval [CI]=1.68-3.07). The metformin cohort had an increased risk of all-cause dementia (HR: 1.66, 95% CI=1.35-2.04). Moreover, metformin exposure increased the risk of Alzheimer's disease (HR: 2.13, 95% CI=1.20-3.79) and vascular dementia (HR: 2.30, 95% CI=1.25-4.22). The effects of exposure duration and dosage on dementia and PD occurrence were also observed. Long-term metformin exposure in patients with T2DM may lead to the development of NDs, including dementia and PD. Additional large-scale, prospective controlled trials are required to confirm the observed association in patients with T2DM. 10.1016/j.pnpbp.2017.06.002
    microRNA Profiles in Parkinson's Disease Prefrontal Cortex. Hoss Andrew G,Labadorf Adam,Beach Thomas G,Latourelle Jeanne C,Myers Richard H Frontiers in aging neuroscience OBJECTIVE:The goal of this study was to compare the microRNA (miRNA) profile of Parkinson's disease (PD) frontal cortex with normal control brain, allowing for the identification of PD specific signatures as well as study the disease-related phenotypes of onset age and dementia. METHODS:Small RNA sequence analysis was performed from prefrontal cortex for 29 PD samples and 33 control samples. After sample QC, normalization and batch correction, linear regression was employed to identify miRNAs altered in PD, and a PD classifier was developed using weighted voting class prediction. The relationship of miRNA levels to onset age and PD with dementia (PDD) was also characterized in case-only analyses. RESULTS:One twenty five miRNAs were differentially expressed in PD at a genome-wide level of significance (FDR q < 0.05). A set of 29 miRNAs classified PD from non-diseased brain (93.9% specificity, 96.6% sensitivity). The majority of differentially expressed miRNAs (105/125) showed an ordinal relationship from control, to PD without dementia (PDN), to PDD. Among PD brains, 36 miRNAs classified PDD from PDN (sensitivity = 81.2%, specificity = 88.9%). Among differentially expressed miRNAs, miR-10b-5p had a positive association with onset age (q = 4.7e-2). CONCLUSIONS:Based on cortical miRNA levels, PD brains were accurately classified from non-diseased brains. Additionally, the PDD miRNA profile exhibited a more severe pattern of alteration among those differentially expressed in PD. To evaluate the clinical utility of miRNAs as potential clinical biomarkers, further characterization and testing of brain-related miRNA alterations in peripheral biofluids is warranted. 10.3389/fnagi.2016.00036
    Serum Uric Acid and the Risk of Dementia: A Systematic Review and Meta-Analysis. Zhou Zhike,Zhong Shanshan,Liang Yifan,Zhang Xiaoqian,Zhang Rongwei,Kang Kexin,Qu Huiling,Xu Ying,Zhao Chuansheng,Zhao Mei Frontiers in aging neuroscience This meta-analysis aimed to evaluate the relationship between serum uric acid (UA) and the risk of dementia and its subtypes. Embase, PubMed, and Web of Science were searched from inception to July 2020. Random-effect models were employed to analyze the standard mean difference (SMD) with the corresponding 95% confidence intervals (CI). Twenty-three eligible studies involving 5,575 participants were identified. The overall results showed lower levels of UA in dementia relative to non-dementia controls [SMD = -0.32 (-0.64; -0.01) = 0.04]. The subgroup analysis of the type of dementia demonstrated a significant association of UA with Alzheimer's disease (AD) [SMD = -0.58 (-1.02; -0.15) = 0.009] and Parkinson's disease with dementia (PDD) [SMD = -0.33 (-0.52; -0.14) = 0.001] but not with vascular dementia (VaD). The stratification analysis of the concentrations of UA revealed that the UA quartile 1-2 was negatively correlated with dementia and neurodegenerative subtypes ( < 0.05), whereas a positive correlation of UA quartile 4 with dementia was noted ( = 0.028). Additionally, the meta-regression analysis on confounders showed that not age, body mass index, diabetes mellitus, hypertension, or smoking but education ( = 0.003) exerted an influence of the UA in the risk estimate of dementia. Low concentrations of UA (< 292 μmol/L or 4.91 mg/dL) is a potential risk factor for AD and PDD but not for VaD. The mechanism of different concentrations of the UA in dementia needs to be confirmed through further investigation. 10.3389/fnagi.2021.625690
    Blood RNA biomarkers in prodromal PARK4 and rapid eye movement sleep behavior disorder show role of complexin 1 loss for risk of Parkinson's disease. Lahut Suna,Gispert Suzana,Ömür Özgür,Depboylu Candan,Seidel Kay,Domínguez-Bautista Jorge Antolio,Brehm Nadine,Tireli Hülya,Hackmann Karl,Pirkevi Caroline,Leube Barbara,Ries Vincent,Reim Kerstin,Brose Nils,den Dunnen Wilfred F,Johnson Madrid,Wolf Zsuzsanna,Schindewolf Marc,Schrempf Wiebke,Reetz Kathrin,Young Peter,Vadasz David,Frangakis Achilleas S,Schröck Evelin,Steinmetz Helmuth,Jendrach Marina,Rüb Udo,Başak Ayşe Nazlı,Oertel Wolfgang,Auburger Georg Disease models & mechanisms Parkinson's disease (PD) is a frequent neurodegenerative process in old age. Accumulation and aggregation of the lipid-binding SNARE complex component α-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity have been intensely investigated. In view of the physiological roles of SNCA in blood to modulate vesicle release, we studied blood samples from a new large pedigree with gene duplication (PARK4 mutation) to identify effects of SNCA gain of function as potential disease biomarkers. Downregulation of complexin 1 () mRNA was correlated with genotype, but the expression of other Parkinson's disease genes was not. In global RNA-seq profiling of blood from presymptomatic PARK4 indviduals, bioinformatics detected significant upregulations for platelet activation, hemostasis, lipoproteins, endocytosis, lysosome, cytokine, Toll-like receptor signaling and extracellular pathways. In PARK4 platelets, stimulus-triggered degranulation was impaired. Strong , and mRNA upregulations were validated in PARK4. When analysing individuals with rapid eye movement sleep behavior disorder, the most specific known prodromal stage of general PD, only blood levels were altered. Validation experiments confirmed an inverse mutual regulation of and mRNA levels. In the 3'-UTR of the gene we identified a single nucleotide polymorphism that is significantly associated with PD risk. In summary, our data define as a PD risk factor and provide functional insights into the role and regulation of blood SNCA levels. The new blood biomarkers of PARK4 in this Turkish family might become useful for PD prediction. 10.1242/dmm.028035
    Integrative network analysis unveils convergent molecular pathways in Parkinson's disease and diabetes. Santiago Jose A,Potashkin Judith A PloS one BACKGROUND:Shared dysregulated pathways may contribute to Parkinson's disease and type 2 diabetes, chronic diseases that afflict millions of people worldwide. Despite the evidence provided by epidemiological and gene profiling studies, the molecular and functional networks implicated in both diseases, have not been fully explored. In this study, we used an integrated network approach to investigate the extent to which Parkinson's disease and type 2 diabetes are linked at the molecular level. METHODS AND FINDINGS:Using a random walk algorithm within the human functional linkage network we identified a molecular cluster of 478 neighboring genes closely associated with confirmed Parkinson's disease and type 2 diabetes genes. Biological and functional analysis identified the protein serine-threonine kinase activity, MAPK cascade, activation of the immune response, and insulin receptor and lipid signaling as convergent pathways. Integration of results from microarrays studies identified a blood signature comprising seven genes whose expression is dysregulated in Parkinson's disease and type 2 diabetes. Among this group of genes, is the amyloid precursor protein (APP), previously associated with neurodegeneration and insulin regulation. Quantification of RNA from whole blood of 192 samples from two independent clinical trials, the Harvard Biomarker Study (HBS) and the Prognostic Biomarker Study (PROBE), revealed that expression of APP is significantly upregulated in Parkinson's disease patients compared to healthy controls. Assessment of biomarker performance revealed that expression of APP could distinguish Parkinson's disease from healthy individuals with a diagnostic accuracy of 80% in both cohorts of patients. CONCLUSIONS:These results provide the first evidence that Parkinson's disease and diabetes are strongly linked at the molecular level and that shared molecular networks provide an additional source for identifying highly sensitive biomarkers. Further, these results suggest for the first time that increased expression of APP in blood may modulate the neurodegenerative phenotype in type 2 diabetes patients. 10.1371/journal.pone.0083940
    Mild cognitive impairment as a risk factor for Parkinson's disease dementia. Hoogland Jeroen,Boel Judith A,de Bie Rob M A,Geskus Ronald B,Schmand Ben A,Dalrymple-Alford John C,Marras Connie,Adler Charles H,Goldman Jennifer G,Tröster Alexander I,Burn David J,Litvan Irene,Geurtsen Gert J, Movement disorders : official journal of the Movement Disorder Society BACKGROUND:The International Parkinson and Movement Disorder Society criteria for mild cognitive impairment in PD were recently formulated. OBJECTIVES:The aim of this international study was to evaluate the predictive validity of the comprehensive (level II) version of these criteria by assessment of their contribution to the hazard of PD dementia. METHODS:Individual patient data were selected from four separate studies on cognition in PD that provided information on demographics, motor examination, depression, neuropsychological examination suitable for application of level II criteria, and longitudinal follow-up for conversion to dementia. Survival analysis evaluated the predictive value of level II criteria for cognitive decline toward dementia as expressed by the relative hazard of dementia. RESULTS:A total of 467 patients were included. The analyses showed a clear contribution of impairment according to level II mild cognitive impairment criteria, age, and severity of PD motor symptoms to the hazard of dementia. There was a trend of increasing hazard of dementia with declining neuropsychological performance. CONCLUSIONS:This is the first large international study evaluating the predictive validity of level II mild cognitive impairment criteria for PD. The results showed a clear and unique contribution of classification according to level II criteria to the hazard of PD dementia. This finding supports their predictive validity and shows that they contribute important new information on the hazard of dementia, beyond known demographic and PD-specific factors of influence. © 2017 International Parkinson and Movement Disorder Society. 10.1002/mds.27002
    Proteomics and bioinformatics approaches for the identification of plasma biomarkers to detect Parkinson's disease. Dong Wenwen,Qiu Chang,Gong Dawei,Jiang Xu,Liu Wan,Liu Weiguo,Zhang Li,Zhang Wenbin Experimental and therapeutic medicine The aim of the present study was to screen for biomarkers of Parkinson's disease (PD) using proteomics and bioinformatics approaches. PD patients were divided into three groups: Those without surgery (PD1 group); those who had undergone deep brain stimulation (DBS) surgery without electrode stimulation (PD2 group); and those who had undergone DBS surgery with 1 month of electrode stimulation (PD3 group). The non-Parkinson control group (CK group) was also involved. Quantitative proteomic analysis of human sera was performed through the use of tandem mass tag markers and liquid chromatography-mass spectrometry (LC-MS)-based techniques. For the proteins with quantitative information, a systematic bioinformatics analysis was then performed, including protein annotation, functional classification, functional enrichment and cluster analysis based on functional enrichment. Of the 739 proteins identified, quantitative information was available for 644. With regard to differential expression, 18 upregulated and 21 downregulated proteins were screened in the PD1/CK comparison group; 12 upregulated and 12 downregulated proteins in the PD2/PD1 comparison group; and 16 upregulated and 19 downregulated proteins in the PD3/PD2 comparison group. Coiled-coil domain-containing protein 154 (CCDC154) and tripartite motif-containing protein 3 (TRIM3) were key proteins involved in the molecular mechanisms of PD, participating in intracellular vesicle, ubiquitin protein ligase and transition metal ion-binding activities. After DBS surgery, desert hedgehog protein (DHH) was downregulated, whereas neuropilin-2 (NRP2) was upregulated; these participated in the ensheathment of neurons and the semaphorin receptor complex, respectively. The expression level of chloride intracellular channel protein 1 (CLIC1) was increased after 1 month of electrode stimulation following DBS. By combining proteomic approaches and LC-MS methods, significant proteins including CCDC154, TRIM3, DHH, NRP2 and CLIC1 were detected with high specificity and sensitivity. These may be used as novel biomarkers for early diagnosis of PD and the future development of treatments. 10.3892/etm.2019.7888
    Altered gut microbiota and inflammatory cytokine responses in patients with Parkinson's disease. Lin Chin-Hsien,Chen Chieh-Chang,Chiang Han-Lin,Liou Jyh-Ming,Chang Chih-Min,Lu Tzu-Pin,Chuang Eric Y,Tai Yi-Cheng,Cheng Chieh,Lin Han-Yi,Wu Ming-Shiang Journal of neuroinflammation OBJECTIVE:Emerging evidence suggests that gut microbiome composition alterations affect neurodegeneration through neuroinflammation in the pathogenesis of Parkinson's disease (PD). Here, we evaluate gut microbiota alterations and host cytokine responses in a population of Taiwanese patients with PD. METHODS:Fecal microbiota communities from 80 patients with PD and 77 age and gender-matched controls were assessed by sequencing the V3-V4 region of the 16S ribosomal RNA gene. Diet and comorbidities were controlled in the analyses. Plasma concentrations of IL-1β, IL-2, IL-4, IL-6, IL-13, IL-18, GM-CSF, IFNγ, and TNFα were measured by a multiplex immunoassay and relationships between microbiota, clinical characteristics, and cytokine levels were analyzed in the PD group. We further examined the cytokine changes associated with the altered gut microbiota seen in patients with PD in another independent cohort of 120 PD patients and 120 controls. RESULTS:Microbiota from patients with PD was altered relative to controls and dominated by Verrucomicrobia, Mucispirillum, Porphyromonas, Lactobacillus, and Parabacteroides. In contrast, Prevotella was more abundant in controls. The abundances of Bacteroides were more increased in patients with non-tremor PD subtype than patients with tremor subtype. Bacteroides abundance was correlated with motor symptom severity defined by UPDRS part III motor scores (rho = 0.637 [95% confidence interval 0.474 to 0.758], P < 0.01). Altered microbiota was correlated with plasma concentrations of IFNγ and TNFα. There was a correlation between Bacteroides and plasma level of TNFα (rho = 0.638 [95% CI: 0.102-0.887], P = 0.02); and a correlation between Verrucomicrobia abundance and plasma concentrations of IFNγ (rho = 0.545 [95% CI - 0.043-0.852], P = 0.05). The elevated plasma cytokine responses were confirmed in an additional independent 120 patients with PD and 120 controls (TNFα: PD vs. control 8.51 ± 4.63 pg/ml vs. 4.82 ± 2.23 pg/ml, P < 0.01; and IFNγ: PD vs. control: 38.45 ± 7.12 pg/ml vs. 32.79 ± 8.03 pg/ml, P = 0.03). CONCLUSIONS:This study reveals altered gut microbiota in PD and its correlation with clinical phenotypes and severity in our population. The altered plasma cytokine profiles associated with gut microbiome composition alterations suggest aberrant immune responses may contribute to inflammatory processes in PD. 10.1186/s12974-019-1528-y
    Bioinformatic analysis of microRNA expression in Parkinson's disease. Hao Bin,Chen Xin,Dai Dongwei,Zou Chao,Wu Xi,Chen Jianchun Molecular medicine reports Parkinson's disease (PD) is a type of movement disorder caused by loss of dopamine‑producing neurons in the midbrain. In order to identify the synergistic microRNA (miRNA) pattern in PD, miRNA and mRNA double expression profiles of PD were downloaded. Differentially expressed miRNA and mRNA were identified [P<0.01, following false discovery rate (FDR) correction]. A cumulative hypergeometric distribution test was then performed to identify synergistic miRNAs (P<0.01, following FDR correction). Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotations were performed to analyze the miRNA regulatory target genes. Subsequently, a synergistic miRNA network was constructed and miRNAs exhibiting a high degree were identified. In total, 200 differentially expressed miRNA and 2,966 differentially expressed mRNA were identified. In addition, 1,502 synergistic miRNA interactions were identified, and miRNAs regulated 304 target genes in total. The GO and KEGG analysis demonstrated that these target genes were enriched in biosynthetic and cellular biosynthetic processes, the assembly of cellular components in morphogenesis, mitogen‑activated protein kinase signaling, myometrial relaxation and contraction pathways as well as calcium regulation. The miRNA network demonstrated that miR‑627, miR‑634, miR‑514, miR‑563 and miR‑613 had a high degree. miRNA with a high degree may be associated with the pathogenesis of PD and, therefore, may assist in the diagnosis and therapy of PD. 10.3892/mmr.2014.2837
    Profiling novel metabolic biomarkers for Parkinson's disease using in-depth metabolomic analysis. Han Wei,Sapkota Shraddha,Camicioli Richard,Dixon Roger A,Li Liang Movement disorders : official journal of the Movement Disorder Society OBJECTIVE:To profile the amine/phenol submetabolome to determine potential metabolite biomarkers associated with Parkinson's disease (PD) and PD with incipient dementia. METHODS:At baseline of a 3-wave (18-month intervals) longitudinal study, serum samples were collected from 42 healthy controls and 43 PD patients. By wave 3 (year 3), 16 PD patients were diagnosed with dementia and were classified as PD with incipient dementia at baseline. Metabolomic profiling using dansylation isotope labeling liquid chromatography mass spectrometry was conducted to compare controls with the full PD, PD with no dementia, and PD with incipient dementia groups. RESULTS:Metabolomic analyses detected 719 common metabolites in 80% of the samples. Some were significantly altered in pairwise comparison of different groups (fold change of >1.2 or <0.83 with q < 0.05). We discriminated PD and controls by using a 5-metabolite panel, vanillic acid, 3-hydroxykynurenine, isoleucyl-alanine, 5-acetylamino-6-amino-3-methyluracil, and theophylline. The receiver operating characteristic curve produced an area-under-the-curve value of 0.955 with 87.5% sensitivity and 93.0% specificity. In comparing PD with no dementia with PD with incipient dementia, we used an 8-metabolite panel, His-Asn-Asp-Ser, 3,4-dihydroxyphenylacetone, desaminotyrosine, hydroxy-isoleucine, alanyl-alanine, putrescine [-2H], purine [+O] and its riboside. This produced an area-under-the-curve value of 0.862 with 80.0% sensitivity and 77.0% specificity. CONCLUSIONS:The significantly altered metabolites can be used to differentiate (1) PD patients from healthy controls with high accuracy and (2) the stable PD with no dementia group from those with incipient dementia. Following further validation in larger cohorts, these metabolites could be used for both discrimination and establishing prognosis in PD. © 2017 International Parkinson and Movement Disorder Society. 10.1002/mds.27173
    Potential Therapeutic Drugs for Parkinson's Disease Based on Data Mining and Bioinformatics Analysis. Xu Chuan,Chen Jiajun,Xu Xia,Zhang Yingyu,Li Jia Parkinson's disease The objective is to search potential therapeutic drugs for Parkinson's disease based on data mining and bioinformatics analysis and providing new ideas for research studies on "new application of conventional drugs." Method differential gene candidates were obtained based on data mining of genes of PD brain tissue, original gene data analysis, differential gene crossover, pathway enrichment analysis, and protein interaction, and potential therapeutic drugs for Parkinson's disease were obtained through drug-gene relationship. . 250 common differential genes were obtained from 3 research studies, and 31 differential gene candidates were obtained through gene enrichment analysis and protein interaction. 10 drugs such as metformin hydrochloride were directly or indirectly correlated to differential gene candidates. . Potential therapeutic drugs that may be used for prevention and treatment of Parkinson's disease were discovered through data mining and bioinformatics analysis, which provided new ideas for research and development of drugs. Results showed that metformin hydrochloride and other drugs had certain therapeutical effect on Parkinson's disease, and melbine (DMBG) can be used for treatment of Parkinson's disease and type 2 diabetes patients. 10.1155/2018/3464578
    An Integrated Network Analysis of mRNA and Gene Expression Profiles in Parkinson's Disease. Wang Yaping,Wang Zhiyun Medical science monitor : international medical journal of experimental and clinical research BACKGROUND Parkinson's disease (PD) is a degenerative neurologic disease. This study aimed to undertake bioinformatics analysis using the publicly available Gene Expression Omnibus (GEO) database to integrate mRNA expression data from patients with PD and to compare differentially expressed genes (DEGs) in tissue from the substantia nigra and whole blood from patients with PD and normal controls. MATERIAL AND METHODS Integrated network analysis included GEO datasets to identify DEGs in the substantia nigra and whole blood of patients with PD. Bioinformatics analysis was used to identify the roles of the DEGs and included the development of protein-protein interaction (PPI) networks and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Expression levels of DEGs were validated using GSE100054. RESULTS In patients with PD, there were 1,076 upregulated DEGs and 1,075 down-regulated DEGs in the substantia nigra tissue, and 699 upregulated and 930 down-regulated DEGs in whole blood samples. The apoptotic process, the mitogen-activated protein kinase (MAPK) signaling pathway, the Wnt signaling pathway, and the Notch signaling pathway were significantly enriched in DEGs in the substantia nigra in PD. In both the substantia nigra and whole blood, the most common DEGs were significantly enriched in lysosomes, PD, Alzheimer's disease, Huntington's disease. SORT1 and CRYAB were the hub proteins in the network of the substantia nigra; PSMA1 and SDHA were the hub proteins in the network of whole blood in PD. CONCLUSIONS DEGs, including SORT1, CRYAB, PSMA1, and SDHA may have roles in the pathogenesis of PD through the MAPK, Wnt, and Notch signaling pathways. 10.12659/MSM.920846
    Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease. Ibanez Laura,Bahena Jorge A,Yang Chengran,Dube Umber,Farias Fabiana H G,Budde John P,Bergmann Kristy,Brenner-Webster Carol,Morris John C,Perrin Richard J,Cairns Nigel J,O'Donnell John,Álvarez Ignacio,Diez-Fairen Monica,Aguilar Miquel,Miller Rebecca,Davis Albert A,Pastor Pau,Kotzbauer Paul,Campbell Meghan C,Perlmutter Joel S,Rhinn Herve,Harari Oscar,Cruchaga Carlos,Benitez Bruno A Acta neuropathologica communications Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson's disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta, total tau, and phosphorylated tau as quantitative traits in genetic studies have provided novel insights into Alzheimer's disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson's disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson's disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta levels (effect = - 0.5, p = 9.2 × 10). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson's disease risk meta-analysis were associated with Parkinson's disease status (p = 0.035) and the genomic architecture of CSF amyloid beta (R = 2.29%; p = 2.5 × 10). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta levels (p = 7.3 × 10). Two-sample Mendelian Randomization revealed that CSF amyloid beta plays a role in Parkinson's disease (p = 1.4 × 10) and age at onset (p = 7.6 × 10), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ε4 allele was associated with significantly lower levels of CSF amyloid beta (p = 3.8 × 10), higher mean cortical binding potentials (p = 5.8 × 10), and higher Braak amyloid beta score (p = 4.4 × 10). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson's disease, CSF amyloid beta, and APOE. 10.1186/s40478-020-01072-8
    Longitudinal Change of DAT SPECT in Parkinson's Disease and Multiple System Atrophy. Sakakibara Satoko,Hashimoto Rina,Katayama Taiji,Kenjyo Masakuni,Yokokawa Yuki,Saito Yufuko,Hirakawa Akihiro,Ito Mizuki,Nakamura Tomohiko,Hara Kazuhiro,Hashizume Atsushi,Aiba Ikuko,Inukai Akira,Katsuno Masahisa Journal of Parkinson's disease BACKGROUND:Both Parkinson's disease (PD) and multiple system atrophy (MSA) are neurodegenerative disorder affecting striatonigral system. Although various lines of evidence demonstrate that dopaminergic neuron degeneration emerges before the onset of motor symptoms in PD, preclinical/prodromal progression of neurodegeneration is far less understood in MSA. OBJECTIVE:The aim of this study was to clarify the difference in the progression of dopaminergic degeneration in MSA and PD using dopamine transporter single-photon emission computed tomography (DAT SPECT). METHODS:We analyzed longitudinal data of the specific binding ratio (SBR), a measure of striatal radiotracer uptake, in DAT SPECT from 7 patients with MSA-C, 5 patients with MSA-P, and 18 patients with PD. We performed 2.7±0.7 scans with an interval of 9.85±6.00 months for MSA and 2 scans with an interval of 2.16±0.16 years for PD. RESULTS:The rate of SBR decline was faster in both subtypes of MSA compared with PD, but the value was similar between MSA-P and MSA-C. The estimated SBR at the onset of initial motor symptoms was lower in PD and MSA-P than in MSA-C, especially in the predominantly affected side. SBR of the predominantly affected side starts to decrease before the onset of motor symptoms in PD and MSA-P, whereas the initiation of SBR decline is around the onset in MSA-C individuals. The decline of SBR in the less affected side was not clearly shown before the onset in MSA-P or MSA-C. CONCLUSIONS:Our results suggest that the SBR in DAT SPECT analysis is an important pathophysiological marker reflecting the disease- and subtype-specific progression of dopaminergic degeneration in MSA and PD. 10.3233/JPD-191710
    Bioinformatics analysis raises candidate genes in blood for early screening of Parkinson's disease. Zhang Yi,Yao Li,Liu Wei,Li Wei,Tian Chan,Wang Zhao Yang,Liu Di Biomedical and environmental sciences : BES Parkinson's disease (PD) is a typical degenerative disease, which is characterized by the most obvious symptoms of movement dysfunction, including shaking, rigidity, slowness of movement and difficulty in walking and gait. This disease can not be clearly identified through laboratory tests at present, thus application of high-throughput technique in studying the expression profiles of PD helps to find the genetic markers for its early diagnosis. Studies on expression profiles of neurodegenerative diseases have revealed the novel genes and pathways involved in the progress of illness. In this study, the expression profiles of PD in blood were compared, showing that 181 differentially expressed genes (DEG) exhibit a similar expression trend both in patients and in normal controls. These genes are enriched significantly in some biological processes, including development, response to drugs, and DNA-dependent regulation of transcription, etc, highlighting that the genetic markers can be used in early diagnosis of PD. 10.3967/bes2014.074
    Integrated transcriptome expression profiling reveals a novel lncRNA associated with L-DOPA-induced dyskinesia in a rat model of Parkinson's disease. Han Chun-Lei,Liu Yun-Peng,Sui Yun-Peng,Chen Ning,Du Ting-Ting,Jiang Ying,Guo Chen-Jia,Wang Kai-Liang,Wang Qiao,Fan Shi-Ying,Shimabukuro Michitomo,Meng Fan-Gang,Yuan Fang,Zhang Jian-Guo Aging Levodopa-induced dyskinesia (LID) is a common complication of chronic dopamine replacement therapy in the treatment of Parkinson's disease (PD). Long noncoding RNAs regulate gene expression and participate in many biological processes. However, the role of long noncoding RNAs in LID is not well understood. In the present study, we examined the lncRNA transcriptome profile of a rat model of PD and LID by RNA sequence and got a subset of lncRNAs, which were gradually decreased during the development of PD and LID. We further identified a previously uncharacterized long noncoding RNA, NONRATT023402.2, and its target genes glutathione S-transferase omega 2 and prostaglandin E receptor ()3. All of them were decreased in the PD and LID rats as shown by quantitative real-time PCR, fluorescence hybridization and western blotting. Pearson's correlation analysis showed that their expression was positively correlated with the dyskinesia score of LID rats. experiments by small interfering RNA confirmed that slicing NONRATT023402 inhibited and and promoted the inflammatory response. These results demonstrate that NONRATT023402.2 may have inhibitive effects on the development of PD and LID. 10.18632/aging.102652
    miRNAs and target genes in the blood as biomarkers for the early diagnosis of Parkinson's disease. Liu Xiaoting,Chen Jinhu,Guan Tianyuan,Yao Hui,Zhang Wenpei,Guan Zhenlong,Wang Yanqin BMC systems biology BACKGROUND:Parkinson's disease (PD) is the second most common neurodegenerative disease, and it is a multifactorial disease with no definite diagnostic index. The aim of this study is to construct a molecular network to find molecules that play important roles in the progression of PD with the goal of using them diagnostically and for early intervention. RESULTS:We downloaded two gene expression profiles (GSE54536 and GSE100054) from the Expression Omnibus (GEO) database to analyze possible markers. The Genes were analyzed with GEO2R. There were 1790 and 967 differentially expressed genes (DEGs) in GSE54536 and GSE100054 respectively. A total of 125 genes co-exist in the DEGs of the two data sets. KEGG pathway analysis showed that 125 DEGs were enriched in Aldosterone synthesis and secretion, Gap junctions, Platelet activation, Rap1 signaling pathway, and Estrogen signaling pathway. There were 20 hub genes among 125 DEGs analyzed by PPI that involved in Platelet activation, Inflammatory response, Innate immune response, B cell receptor signaling, Stimulatory C-type lectin receptor signaling, Lipopolysaccharide response, Leukocyte migration, and Regulation of cell proliferation. Additionally, 42 differences in miRNAs were found in GSE100054. We constructed a miRNA-mRNA regulatory network depicting interactions between the predicted genes and the 125 DEGs. 34 miRNA-mRNA pairs were obtained. We found GNAQ and TMTC2 were the most important mRNAs in the network analyzed by Cytoscape APP centiscape, and their degrees in centiscape2.2 were all 10. has-miR-142 was the most important miRNA (the highest degree is 4 in centiscape2.2), which forms miRNA-mRNA pairs with GNAQ, TMTC2, BEND2, and KYNU. CONCLUSIONS:This study provides data of potential biomarkers and therapeutic targets for PD diagnosis and treatment. Among them, hsa-miR-142 is a critical miRNA in the PD network, and may be involved in PD progression by regulating GNAQ, TMTC2, BEND2, and KYNU. 10.1186/s12918-019-0680-4
    Genomewide association study of Parkinson's disease clinical biomarkers in 12 longitudinal patients' cohorts. Movement disorders : official journal of the Movement Disorder Society BACKGROUND:Several reports have identified different patterns of Parkinson's disease progression in individuals carrying missense variants in GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinson's disease, however, has not been well studied. OBJECTIVES:To test the association between genetic variants and the clinical features of Parkinson's disease on a genomewide scale. METHODS:We accumulated individual data from 12 longitudinal cohorts in a total of 4093 patients with 22,307 observations for a median of 3.81 years. Genomewide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently identified disease-risk variants, were also investigated post hoc for candidate associations with these phenotypes. RESULTS:Two variants were genomewide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (hazard ratio 2.04 [1.58-2.62]; P value = 3.46E-8). Rs61863020(G>A), an intergenic variant and expression quantitative trait loci for α-2A adrenergic receptor, was associated with a lower prevalence of insomnia at baseline (odds ratio 0.63 [0.52-0.75]; P value = 4.74E-8). In the targeted analysis, we found 9 associations between known Parkinson's risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K; rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and an APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients. CONCLUSIONS:We identified novel genetic factors associated with heterogeneity of Parkinson's disease. The results can be used for validation or hypothesis tests regarding Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society. 10.1002/mds.27845
    Identification of therapeutic targets for Parkinson's disease via bioinformatics analysis. Dong Na,Zhang Xueqing,Liu Qingjun Molecular medicine reports The present study aimed to identify molecular targets that have important roles in the progression of Parkinson's disease. The gene expression profile dataset GSE7621 and the microRNA (miRNA) expression profile dataset GSE16658 were downloaded from the Gene Expression Omnibus database. R programing software was used to identify differentially expressed genes and miRNAs. Subsequently, enriched Gene Ontology terms of differentially expressed genes were obtained using the Database for Annotation, Visualization and Integrated Discovery. Target genes of differentially expressed miRNAs were identified using the starBase database and a miRNA‑gene regulatory network was constructed using Cytoscape software. A total of 391 differentially expressed genes and 88 differentially expressed miRNAs were identified. Gene Ontology terms that were associated with nervous system activity, including synapse and dopamine metabolic process, were shown to be enriched in the differentially expressed genes. A total of 620 target genes were identified from the differentially expressed miRNAs, and 10 overlaps were identified between these target genes and differentially expressed genes. Furthermore, 10 miRNA‑gene regulation pairs were obtained between the overlaps and differentially expressed miRNAs. In conclusion, the present study used bioinformatics analysis of gene and miRNA expression profile datasets, and identified potential therapeutic targets for Parkinson's disease. 10.3892/mmr.2016.6044
    Bioinformatic analysis for the identification of key candidate genes and pathways in the substantia nigra in Parkinson's disease. Liu Hongbin,Huang Yongjun,Li Jinyi Journal of integrative neuroscience Parkinson's disease is one of the most common diseases in the elderly population, and the substantia nigra is generally involved in the disease process; however, the signaling pathways and related genes underlying Parkinson's disease remain unclear. This study integrated three cohorts of profile datasets to elucidate the potential key candidate genes and pathways in Parkinson's disease. The expression profiles of GSE8397, GSE20186 and GSE49036 were included 55 available substantia nigra tissue samples from individuals diagnosed with Parkinson's disease and 33 substantia nigra tissue samples from healthy controls. These samples were integrated and thoroughly analyzed. Differentially expressed genes (DEGs) were sorted, and candidate genes and pathway enrichments were analyzed. A DEG-associated protein-protein interaction network analysis was performed. 27 shared downregulated DEGs were identified from the three GSE datasets. The DEGs were clustered based on function and signaling pathway with significant enrichment analysis. 52 edges were identified from the DEG protein-protein interaction network complex, which included dopamine metabolism, nerve conduction, reduced neuronal toxicity and proliferation pathways. Using integrated bioinformatic analysis, we identified candidate genes and pathways in Parkinson's disease that could improve our understanding of underlying molecular events, which could be potential therapeutic targets for Parkinson's disease. 10.3233/JIN-180091
    Alpha-Synuclein as a Biomarker for Parkinson's Disease. Atik Anzari,Stewart Tessandra,Zhang Jing Brain pathology (Zurich, Switzerland) Parkinson's disease (PD) is a common neurodegenerative disorder, characterized pathologically by the presence of α-synuclein (α-syn)-rich Lewy bodies. As clinical diagnosis of PD is challenging, misdiagnosis is common, highlighting the need for disease-specific and early stage biomarkers. Both early diagnosis of PD and adequate tracking of disease progression could significantly improve outcomes for patients, particularly in regard to existing and future disease modifying treatments. Given its critical roles in PD pathogenesis, α-syn may be useful as a biomarker of PD. The aim of this review is, therefore, to summarize the efficacy of tissue and body fluid α-syn measurements in the detection of PD as well as monitoring disease progression. In comparison to solid tissue specimens and biopsies, biofluid α-syn levels may be the most promising candidates in PD diagnosis and progression based on specificity, sensitivity and availability. Although α-syn has been tested most extensively in cerebrospinal fluid (CSF), the relatively invasive procedure for collecting CSF is not suitable in most clinical settings, leading to investigation of plasma, blood and saliva as alternatives. The exploration of combined biomarkers, along with α-syn, to improve diagnostic accuracy is also likely required. 10.1111/bpa.12370
    DJ-1 as a Biomarker of Parkinson's Disease. Saito Yoshiro Advances in experimental medicine and biology Parkinson's disease is a progressive, age-related, neurodegenerative disorder, and oxidative stress is an important mediator in its pathogenesis. DJ-1 has been identified as a causative gene of a familial form of Parkinson's disease, PARK7, and plays a significant role in antioxidative defense, protecting cells from oxidative stress. A cysteine residue of DJ-1 at position 106 (Cys-106) is preferentially oxidized under oxidative stress. This reactive Cys-106 plays a critical role in the biological function of DJ-1, which could act as a sensor of oxidative stress by regulating antioxidative defense depending on Cys-106 oxidation. Thus, the levels of Cys-106-oxidized DJ-1 (oxDJ-1) could be a possible biomarker of oxidative stress. This chapter focuses on the properties of DJ-1 and oxDJ-1 levels as a biomarker of Parkinson's disease. In particular, the usability of these biomarkers to prevent and treat this neurodegenerative disease is discussed. Further, this section deals with the importance of identifying a biomarker of early-phase Parkinson's disease. Finally, this chapter summarizes the features of oxDJ-1 levels in the brain and blood as a biomarker candidate for early-phase Parkinson's disease based on our results using oxDJ-1-specific antibodies. 10.1007/978-981-10-6583-5_10
    Validation of the MDS clinical diagnostic criteria for Parkinson's disease. Postuma Ronald B,Poewe Werner,Litvan Irene,Lewis Simon,Lang Anthony E,Halliday Glenda,Goetz Christopher G,Chan Piu,Slow Elizabeth,Seppi Klaus,Schaffer Eva,Rios-Romenets Silvia,Mi Taomian,Maetzler Corina,Li Yuan,Heim Beatrice,Bledsoe Ian O,Berg Daniela Movement disorders : official journal of the Movement Disorder Society BACKGROUND:In 2015, the International Parkinson and Movement Disorder Society published clinical diagnostic criteria for Parkinson's disease. These criteria aimed to codify/reproduce the expert clinical diagnostic process and to help standardize diagnosis in research and clinical settings. Their accuracy compared with expert clinical diagnosis has not been tested. The objectives of this study were to validate the International Parkinson and Movement Disorder Society diagnostic criteria against a gold standard of expert clinical diagnosis, and to compare concordance/accuracy of the International Parkinson and Movement Disorder Society criteria to 1988 United Kingdom Brain Bank criteria. METHODS:From 8 centers, we recruited 626 parkinsonism patients (434 PD, 192 non-PD). An expert neurologist diagnosed each patient as having PD or non-PD, regardless of International Parkinson and Movement Disorder Society criteria (gold standard, clinical diagnosis). Then a second neurologist evaluated the presence/absence of each individual item from the International Parkinson and Movement Disorder Society criteria. The overall accuracy/concordance rate, sensitivity, and specificity of the International Parkinson and Movement Disorder Society criteria compared with the expert gold standard were calculated. RESULTS:Of 434 patients diagnosed with PD, 94.5% met the International Parkinson and Movement Disorder Society criteria for probable PD (5.5% false-negative rate). Of 192 non-PD patients, 88.5% were identified as non-PD by the criteria (11.5% false-positive rate). The overall accuracy for probable PD was 92.6%. In addition, 59.3% of PD patients and only 1.6% of non-PD patients met the International Parkinson and Movement Disorder Society criteria for clinically established PD. In comparison, United Kingdom Brain Bank criteria had lower sensitivity (89.2%, P = 0.008), specificity (79.2%, P = 0.018), and overall accuracy (86.4%, P < 0.001). Diagnostic accuracy did not differ according to age or sex. Specificity improved as disease duration increased. CONCLUSIONS:The International Parkinson and Movement Disorder Society criteria demonstrated high sensitivity and specificity compared with the gold standard, expert diagnosis, with sensitivity and specificity both higher than United Kingdom Brain Bank criteria. © 2018 International Parkinson and Movement Disorder Society. 10.1002/mds.27362
    Movement disorder society criteria for clinically established early Parkinson's disease. Berg Daniela,Adler Charles H,Bloem Bastiaan R,Chan Piu,Gasser Thomas,Goetz Christopher G,Halliday Glenda,Lang Anthony E,Lewis Simon,Li Yuan,Liepelt-Scarfone Inga,Litvan Irene,Marek Kenneth,Maetzler Corina,Mi Taomian,Obeso José,Oertel Wolfgang,Olanow C Warren,Poewe Werner,Rios-Romenets Silvia,Schäffer Eva,Seppi Klaus,Heim Beatrice,Slow Elizabeth,Stern Matthew,Bledsoe Ian O,Deuschl Günther,Postuma Ronald B Movement disorders : official journal of the Movement Disorder Society BACKGROUND:In 2015, the International Parkinson and Movement Disorder Society published clinical diagnostic criteria for Parkinson's disease (PD). Although recent validation studies suggest high accuracy, one unmet need is for highly specific criteria for clinical trials in early/de novo PD. OBJECTIVES:The objective of this study was to generate and test a PD diagnostic criteria termed "clinically established early PD." METHODS:We modified the Movement Disorder Society criteria to increase specificity for early PD by removing all disease duration components and changing red flags to absolute exclusions. We then estimated the sensitivity/specificity of clinically established early PD criteria in patients with disease duration <5 years, selected from a 626-patient validation study. RESULTS:After documentation of parkinsonism, 18 individual exclusion criteria are assessed that preclude the diagnosis of "clinically established early PD." Among 212 PD and 152 non-PD patients, the estimated specificity was 95.4%, with 69.8% sensitivity. CONCLUSIONS:We describe high-specificity criteria for de novo PD, which are freely available for use in clinical trials. © 2018 International Parkinson and Movement Disorder Society. 10.1002/mds.27431
    MDS clinical diagnostic criteria for Parkinson's disease. Postuma Ronald B,Berg Daniela,Stern Matthew,Poewe Werner,Olanow C Warren,Oertel Wolfgang,Obeso José,Marek Kenneth,Litvan Irene,Lang Anthony E,Halliday Glenda,Goetz Christopher G,Gasser Thomas,Dubois Bruno,Chan Piu,Bloem Bastiaan R,Adler Charles H,Deuschl Günther Movement disorders : official journal of the Movement Disorder Society This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical diagnosis; the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations; these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity). The Movement Disorder Society criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, the Movement Disorder Society criteria will need continuous revision to accommodate these advances. 10.1002/mds.26424
    MDS clinical diagnostic criteria for Parkinson's disease in China. Li Jun,Jin Miao,Wang Li,Qin Bin,Wang Kang Journal of neurology The Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (MDS-PD Criteria) was introduced by the Movement Disorder Society in 2015 for research purposes. However, its use for clinical diagnosis of Parkinson disease still needs further revision. This study compares the UK-Criteria versus MDS-PD Criteria in the clinical diagnosis of Parkinson disease referred to the China-Japan Friendship Hospital of Beijing, China. To compare the MDS-PD Criteria with the UK-Criteria and discuss the feasibility of the clinical application of MDS-PD Criteria as a general guide to clinical diagnosis of PD in Chinese PD patients. 150 patients of neurology clinic of China-Japan Friendship Hospital of Beijing were recruited in our research. They were divided into three groups: UK-Criteria group, MDS-PD Criteria group and a combined group of UK and MDS-PD Criteria. Clinical history was collected while physical and auxiliary examinations were done by a trained neurologist according to the corresponding criteria. An interrater reliability analysis using the Kappa statistic claimed substantial agreement (κ = 0.626) between the MDS-PD Criteria and the UK-Criteria. The differences between the diagnostic results of these two criteria were statistically significant by paired Chi-square test (p = 0.000). It was found that levodopa-induced dyskinesia had a good positive predictive value, while early bulbar impairment and inspiratory dysfunction presented a negative predictive value. The MDS-PD Criteria emphasize the importance of non-motor symptoms, keeping the motor symptoms as the core for the clinical diagnosis of PD, and establish categories of diagnosis features and levels of certainty which are more complete and organized to be used and replicated by non specialized physicians to evaluated patients with Parkinsonism. The higher sensitivity of MDS-PD Criteria compared with UK-Criteria is worth being widely used in clinical work. 10.1007/s00415-016-8370-2