scholarly journals APOE and MAPT Are Associated With Dementia in Neuropathologically Confirmed Parkinson's Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Jon-Anders Tunold ◽  
Hanneke Geut ◽  
J. M. Annemieke Rozemuller ◽  
Sandra Pilar Henriksen ◽  
Mathias Toft ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Decline ◽  
Proportional Hazards ◽  
Age At Onset ◽  
Cox Proportional Hazards ◽  
Postmortem Brain ◽  
Tissue Samples ◽  
Postmortem Brain Tissue ◽  
Ε4 Allele

Introduction: Cognitive decline and dementia are common and debilitating non-motor phenotypic features of Parkinson's disease with a variable severity and time of onset. Common genetic variation of the Apolipoprotein E (APOE) and micro-tubule associated protein tau (MAPT) loci have been linked to cognitive decline and dementia in Parkinson's disease, although studies have yielded mixed results. To further elucidate the influence of APOE and MAPT variability on dementia in Parkinson's disease, we genotyped postmortem brain tissue samples of clinically and pathologically well-characterized Parkinson's donors and performed a survival analysis of time to dementia.Methods: We included a total of 152 neuropathologically confirmed Parkinson's disease donors with or without clinical dementia during life. We genotyped known risk variants tagging the APOE ε4 allele and MAPT H1/H2 inversion haplotype. Cox proportional hazards regression analyses adjusted for age at onset, sex and genetic principal components were performed to assess the association between the genetic variants and time from motor onset to onset of dementia.Results: We found that both the APOE ε4 allele (HR 1.82, 95 % CI 1.16–2.83, p = 0.009) and MAPT H1-haplotype (HR 1.71, 95 % CI 1.06–2.78, p = 0.03) were associated with earlier development of dementia in patients with Parkinson's disease.Conclusion: Our results provide further support for the importance of APOE ε4 and MAPT H1-haplotype in the etiology of Parkinson's disease dementia, with potential future relevance for risk stratification and patient selection for clinical trials of therapies targeting cognitive decline in Parkinson's disease.

scholarly journals Single-Cell RNA Sequencing in Parkinson’s Disease

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 368
Author(s):  
Shi-Xun Ma ◽  
Su Bin Lim
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Single Cell ◽  
Rna Sequencing ◽  
Rna Degradation ◽  
Postmortem Brain ◽  
Cell Type ◽  
New Findings ◽  
Postmortem Brain Tissue ◽  
Technical Challenges

Single-cell and single-nucleus RNA sequencing (sc/snRNA-seq) technologies have enhanced the understanding of the molecular pathogenesis of neurodegenerative disorders, including Parkinson’s disease (PD). Nonetheless, their application in PD has been limited due mainly to the technical challenges resulting from the scarcity of postmortem brain tissue and low quality associated with RNA degradation. Despite such challenges, recent advances in animals and human in vitro models that recapitulate features of PD along with sequencing assays have fueled studies aiming to obtain an unbiased and global view of cellular composition and phenotype of PD at the single-cell resolution. Here, we reviewed recent sc/snRNA-seq efforts that have successfully characterized diverse cell-type populations and identified cell type-specific disease associations in PD. We also examined how these studies have employed computational and analytical tools to analyze and interpret the rich information derived from sc/snRNA-seq. Finally, we highlighted important limitations and emerging technologies for addressing key technical challenges currently limiting the integration of new findings into clinical practice.

scholarly journals CXCL12 is involved in α-synuclein-triggered neuroinflammation of Parkinson’s disease

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Yuanyuan Li ◽  
Mengyue Niu ◽  
Aonan Zhao ◽  
Wenyan Kang ◽  
Zhichun Chen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cxcr4 Expression ◽  
Postmortem Brain ◽  
Primary Microglia ◽  
Postmortem Brain Tissue ◽  
Culture Models ◽  
Novel Target ◽  
The Relationship ◽  
Cell Culture Models

Abstract Background The mechanisms underlying the pathogenesis and progression of Parkinson’s disease (PD) remain elusive, but recent opinions and perspectives have focused on whether the inflammation process induced by microglia contributes to α-synuclein-mediated toxicity. Migration of microglia to the substantia nigra (SN) could precede neurodegeneration in A53T mice. We hypothesized that CXCL12 could be a mediator in the α-synuclein-induced migration of microglia. Methods After establishing appropriate animal and cell culture models, we explored the relationship between α-synuclein and CXCL12 in A53T mice, primary microglia, and BV-2 cell lines. We also explored the mechanisms of these interactions and the signaling processes involved in neuroinflammation. Results We confirmed the positive correlation between α-synuclein and CXCL12 in the postmortem brain tissue of PD patients and the upregulated CXCR4 expression in SN microglia of A53T mice. In addition, as expected, α-synuclein increased the production of CXCL12 in microglia via TLR4/IκB-α/NF-κB signaling. Importantly, CXCL12/CXCR4/FAK/Src/Rac1 signaling was shown to be involved in α-synuclein-induced microglial accumulation. Conclusions Our study suggests that CXCL12 could be a novel target for the prevention of α-synuclein-triggered ongoing microglial responses. Blocking CXCL12/CXCR4 may be a potential therapeutic approach for PD progression.

scholarly journals Associations between concussion and risk of diagnosis of psychological and neurological disorders: a retrospective population-based cohort study

2020 ◽  
Vol 8 (3) ◽  
pp. e000390
Author(s):  
Marc P Morissette ◽  
Heather J Prior ◽  
Robert B Tate ◽  
John Wade ◽  
Jeff R S Leiter
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cohort Study ◽  
Proportional Hazards ◽  
Geographical Location ◽  
International Classification Of Diseases ◽  
Population Based ◽  
Cox Proportional Hazards ◽  
Control Group ◽  
Increased Risk

ObjectiveTo investigate associations between concussion and the risk of follow-up diagnoses of attention-deficit hyperactivity disorder (ADHD), mood and anxiety disorders (MADs), dementia and Parkinson’s disease.DesignA retrospective population-based cohort study.SettingAdministrative health data for the Province of Manitoba between 1990–1991 and 2014–2015.ParticipantsA total of 47 483 individuals were diagnosed with a concussion using International Classification of Diseases (ICD) codes (ICD-9-CM: 850; ICD-10-CA: S06.0). All concussed subjects were matched with healthy controls at a 3:1 ratio based on age, sex and geographical location. Associations between concussion and conditions of interest diagnosed later in life were assessed using a stratified Cox proportional hazards regression model, with adjustments for socioeconomic status and pre-existing medical conditions.Results28 021 men (mean age ±SD, 25±18 years) and 19 462 women (30±21 years) were included in the concussion group, while 81 871 men (25±18 years) and 57 159 women (30±21 years) were included in the matched control group. Concussion was associated with adjusted hazard ratios of 1.39 (95% CI 1.32 to 1.46, p<0.001) for ADHD, 1.72 (95% CI 1.69 to 1.76; p<0.001) for MADs, 1.72 (95% CI 1.61 to 1.84; p<0.001) for dementia and 1.57 (95% CI 1.41 to 1.75; p<0.001) for Parkinson’s disease.ConclusionConcussion was associated with an increased risk of diagnosis for all four conditions of interest later in life.

scholarly journals An increased rate of longitudinal cognitive decline is observed in Parkinson's disease patients with low CSF Aß42 and an APOE ε4 allele

2019 ◽  
Vol 127 ◽  
pp. 278-286 ◽  
Author(s):  
Marian Shahid ◽  
Jeehyun Kim ◽  
Katherine Leaver ◽  
Taylor Hendershott ◽  
Delphine Zhu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Decline ◽  
Apoe Ε4 ◽  
Ε4 Allele

scholarly journals Milk and Fermented Milk Intake and Parkinson’s Disease: Cohort Study

Nutrients ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2763
Author(s):  
Erika Olsson ◽  
Liisa Byberg ◽  
Jonas Höijer ◽  
Lena Kilander ◽  
Susanna C. Larsson
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cohort Study ◽  
Proportional Hazards ◽  
Fermented Milk ◽  
Cox Proportional Hazards ◽  
Milk Intake ◽  
Milk Consumption ◽  
Hazard Ratios ◽  
Increased Risk

Milk and fermented milk consumption has been linked to health and mortality but the association with Parkinson’s disease (PD) is uncertain. We conducted a study to investigate whether milk and fermented milk intakes are associated with incident PD. This cohort study included 81,915 Swedish adults (with a mean age of 62 years) who completed a questionnaire, including questions about milk and fermented milk (soured milk and yogurt) intake, in 1997. PD cases were identified through linkage with the Swedish National Patient and Cause of Death Registers. Multivariable-adjusted hazard ratios were obtained from Cox proportional hazards regression models. During a mean follow-up of 14.9 years, 1251 PD cases were identified in the cohort. Compared with no or low milk consumption (<40 mL/day), the hazard ratios of PD across quintiles of milk intake were 1.29 (95% CI 1.07, 1.56) for 40–159 mL/day, 1.19 (95% CI 0.99, 1.42) for 160–200 mL/day, 1.29 (95% CI 1.08, 1.53) for 201–400 mL/day, and 1.14 (95% CI 0.93, 1.40) for >400 mL/day. Fermented milk intake was not associated with PD. We found a weak association between milk intake and increased risk of PD but no dose–response relationship. Fermented milk intake was not associated with increased risk of PD.

Cognitive Change in Newly-Diagnosed Patients with Parkinson's Disease: A 5-Year Follow-up Study

2013 ◽  
Vol 19 (6) ◽  
pp. 695-708 ◽  
Author(s):  
Mark Broeders ◽  
Daan C. Velseboer ◽  
Rob de Bie ◽  
Johannes D. Speelman ◽  
Dino Muslimovic ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Decline ◽  
Age At Onset ◽  
Cognitive Change ◽  
Healthy Controls ◽  
Newly Diagnosed ◽  
Cognitive Changes ◽  
Cognitive Domains ◽  
Healthy Elderly

AbstractCognitive change is frequently observed in patients with Parkinson's disease (PD). However, the exact profile and extent of cognitive impairments remain unclear due to the clinical heterogeneity of PD and methodological issues in many previous studies. In this study, we aimed to examine the severity, frequency, and profile of cognitive changes in newly diagnosed PD patients over 5 years. At baseline and after 3 and 5 years, a hospital-based sample of PD patients (n = 59) and healthy controls (n = 40) were given neuropsychological tests covering six cognitive domains. Patients showed greater decline over time than healthy controls on all cognitive domains, except for attention. The profile of decline showed that psychomotor speed and memory were most affected. At the individual level 53% of the patients showed more cognitive decline than controls. Age at onset and memory impairment at baseline predicted cognitive decline. Cognitive functions in PD patients show greater decline in most domains than in healthy elderly over the course of 5 years. Due to selection bias as a result of attrition, the actual degree of decline may be greater than reported here. (JINS, 2013, 19, 1–14)

Stochastic Epigenetic Mutations Influence Parkinson’s Disease Risk, Progression, and Mortality

2021 ◽  
pp. 1-12
Author(s):  
Gary K. Chen ◽  
Qi Yan ◽  
Kimberly C. Paul ◽  
Cynthia D.J. Kusters ◽  
Aline Duarte Folle ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Proportional Hazards ◽  
Disease Risk ◽  
Cox Proportional Hazards ◽  
Motor Symptom ◽  
Time To Death ◽  
Normal Site ◽  
Minimum Score ◽  
Symptom Progression

Background: Stochastic epigenetic mutations (SEM) reflect a deviation from normal site-specific methylation patterns. Epigenetic mutation load (EML) captures the accumulation of SEMs across an individual’s genome and may reflect dysfunction of the epigenetic maintenance system in response to epigenetic challenges. Objective: We investigate whether EML is associated with PD risk and time to events (i.e., death and motor symptom decline). Methods: We employed logistic regression and Cox proportional hazards regression to assess the association between EML and several outcomes. Our analyses are based on 568 PD patients and 238 controls from the Parkinson’s disease, Environment and Genes (PEG) study, for whom blood-based methylation data was available. Results: We found an association for PD onset and EML in all genes (OR = 1.90; 95%CI 1.52-2.37) and PD-related genes (OR = 1.87; 95%CI 1.50-2.32). EML was also associated with time to a minimum score of 35 points on the motor UPDRS exam (OR = 1.28; 95%CI 1.06-1.56) and time to death (OR = 1.29, 95%CI 1.11-1.49). An analysis of PD related genes only revealed five intragenic hotspots of high SEM density associated with PD risk. Conclusion: Our findings suggest an enrichment of methylation dysregulation in PD patients in general and specifically in five PD related genes. EML may also be associated with time to death and motor symptom progression in PD patients.

scholarly journals Evolution of Apathy in Early Parkinson's Disease: A 4-Years Prospective Cohort Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Ruwei Ou ◽  
Junyu Lin ◽  
Kuncheng Liu ◽  
Zheng Jiang ◽  
Qianqian Wei ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Proportional Hazards ◽  
Rating Scale ◽  
Early Stage ◽  
Cox Proportional Hazards ◽  
Lars Score ◽  
Disease Rating ◽  
Non Motor Symptoms

Objective: We investigated the prevalence, evolution, associated factors, and risk factors of apathy in a cohort of patients with early-stage Parkinson's disease (PD), who underwent a 4-years prospective follow-up.Methods: This study included 188 patients with PD (baseline disease duration &lt;3 years) who underwent an annual evaluation using the Lille Apathy Rating Scale (LARS). Based on the cut-off value of −21 observed on the LARS, patients were categorized as PD with and without apathy. The generalized estimating equations (GEE) model was utilized to determine the factors associated with apathy, and the Cox proportional-hazards regression model was used to determine the predictors of apathy.Results: Apathy increased from a baseline rate of 18.6–28.8% after 4 years; notably, this rate was not persistent across patients' visits. The LARS score was independently associated with the male sex (B 8.131, p = 0.009), low Frontal Assessment Battery (FAB) scores (B 0.567, p = 0.011), low attention scores on the Montreal Cognitive Assessment (MOCA) test (B 0.217, p = 0.026), high Hamilton Depression Rating Scale (HDRS) scores (B 1.362, p &lt; 0.001), high Unified Parkinson's Disease Rating Scale (UPDRS) part III scores (B 1.147, p &lt; 0.001), and prolonged follow-up time (B 1.785, p = 0.048). A high HDRS score was the only predictor of apathy in PD [hazard ratio (HR) 1.043, p = 0.026].Conclusions: The risk of apathy is higher in men with progressive PD accompanied by disease-specific motor and non-motor symptoms. Depression during early-stage PD is a primary risk factor for apathy in PD.

scholarly journals Differential Changes in Postsynaptic Density Proteins in Postmortem Huntington’s Disease and Parkinson’s Disease Human Brains

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
C. Fourie ◽  
E. Kim ◽  
H. Waldvogel ◽  
J. M. Wong ◽  
A. McGregor ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Immunohistochemical Analysis ◽  
Synaptic Proteins ◽  
Postmortem Brain ◽  
Postmortem Brain Tissue ◽  
Human Brains

NMDA and AMPA-type glutamate receptors and their bound membrane-associated guanylate kinases (MAGUKs) are critical for synapse development and plasticity. We hypothesised that these proteins may play a role in the changes in synapse function that occur in Huntington’s disease (HD) and Parkinson’s disease (PD). We performed immunohistochemical analysis of human postmortem brain tissue to examine changes in the expression of SAP97, PSD-95, GluA2 and GluN1 in human control, and HD- and PD-affected hippocampus and striatum. Significant increases in SAP97 and PSD-95 were observed in the HD and PD hippocampus, and PSD95 was downregulated in HD striatum. We observed a significant increase in GluN1 in the HD hippocampus and a decrease in GluA2 in HD and PD striatum. Parallel immunohistochemistry experiments in the YAC128 mouse model of HD showed no change in the expression levels of these synaptic proteins. Our human data show that major but different changes occur in glutamatergic proteins in HD versus PD human brains. Moreover, the changes in human HD brains differ from those occurring in the YAC128 HD mouse model, suggesting that unique changes occur at a subcellular level in the HD human hippocampus.

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