Higher Risk Of Parkinson's Disease Research Articles

Social isolation and the risk of Parkinson disease in the UK biobank study

Parkinson disease (PD) has become one of the most rapidly growing causes of disability among the older population and social isolation is a major concern in the PD community. However, the relationship between social isolation and future risk of PD remains unclear. This study included 192,340 participants aged 60 or older who were free of dementia and PD at baseline from the UK Biobank study. Social isolation was measured using a composite score derived from three questions on number in household, frequency of friend/family visits, and leisure/social activities. Incident PD cases were identified through electronic health records. Multivariable-adjusted Cox regression models were used to compute the hazard ratio (HR) and 95% confidence interval (CI). Among the 192,340 participants (mean [standard deviation] age, 64.2 [2.9] years; 103,253 [53.7%] women), 89,075 (46.3%) participants were in the least isolated group and 26,161 (13.6%) were in the most isolated group. Over a median follow-up of 12.5 years, 2048 incident PD cases were documented. Compared to the least isolated group, the multivariable-adjusted HRs (95% CIs) for PD were 1.00 (0.91−1.10) for the moderately isolated group and 1.19 (1.05−1.36) for the most isolated group (P-trend = 0.04). The observed association was independent of the genetic susceptibility to PD and consistent in subgroup analyses. Social isolation was associated with a higher risk of PD regardless of genetic risk. Our findings highlighted the importance of developing screening and intervention strategies for social isolation among older adults to reduce the risk of PD.

Contribution of Nutritional, Lifestyle, and Metabolic Risk Factors to Parkinson's Disease.

Modifiable risk factors for Parkinson's disease (PD) are poorly known. The aim is to evaluate independent associations of different nutritional components, physical activity, and sedentary behavior and metabolic factors with the risk of PD. In this population-based prospective cohort study using the data of the United Kingdom Biobank (from 2006-2010), 502,017 men and women who were free from PD (International Classification of Diseases 10th edition; "G20") at baseline were included. We implemented a Cox proportion hazard's model to evaluate the associations of different levels of physical activity, sitting time, sleep habits, diet quality, alcohol and coffee consumption, smoking, and body mass index with PD risk, adjusting for several confounding variables. During a median follow-up of 12.8 years, lifestyle factors including vigorous physical activity (hazard ration [HR] = 0.84; 95% confidence interval [CI], 0.75-0.94), low-to-moderate sitting time (HR = 0.89; 95% CI, 0.81-0.97), and high sleep quality (HR = 0.89; 95% CI, 0.80-0.99) were associated with a reduced risk of PD. Small amounts of coffee (HR = 0.88; 95% CI, 0.82-0.95), red meat (HR = 0.86; 95% CI, 0.76-0.97), and current smoking (HR = 0.65; 95% CI, 0.56-0.75) were also associated with a lower risk of PD, whereas alcohol intake (HR = 1.29; 95% CI, 1.06-1.56) with higher PD risk. Secondary analysis, including metabolic risk factors, confirmed these findings and highlighted the potential protective effect of plasma vitamin D and uric acid, but of low-density lipoprotein-cholesterol, triglycerides, and C-reactive protein as well. Vigorous physical activity, reduced sitting time, good sleep quality together with small coffee intake and vitamin D supplementation are potentially neuroprotective lifestyle interventions for the prevention of PD. © 2024 International Parkinson and Movement Disorder Society.

The role of peripheral inflammation-related biomarkers in distinguishing Parkinson's disease

BackgroundPeripheral inflammation plays a significant role in Parkinson's disease (PD). Conflicting studies on whether inflammatory indicators in blood could serve as biomarkers to distinguish PD. ObjectiveInclude a wider range of biomarkers and control confounding factors to comprehensively evaluate the value of peripheral inflammation-related indicators. MethodsA total of 80 PD patients were recruited and 80 one-to-one matched healthy controls (HCs). The levels of B-cell, T-cell, and natural killer (NK)-cell in blood were measured using flow cytometry. The levels of neurodegeneration-related proteins in serum were detected and clinical blood test results were collected. Multivariable logistic regression analysis was conducted to explore the role of significant variables in PD. Receiver operating characteristic curve analysis was performed to assess the potential value of these variables. ResultsCompared to HCs, PD patients showed lower levels of lymphocyte, B-cell, T-cell, high-density lipoprotein cholesterol (HDL-C) and lymphocyte-to-monocyte ratio, while the levels of neutrophil, NK-cell, β-amyloid40, neurofilament light chain, neutrophil-to-lymphocyte ratio, and neutrophil-to-HDL-C ratio (NHR) were increased. A higher B-cell count was associated with a lower risk of PD, while higher levels of NK-cell and NHR were associated with a higher risk of PD. B-cell, NK-cell and NHR have potential value in distinguishing PD from non-PD. B-cell and NHR levels were significantly correlated with PD dyskinesia scores. ConclusionsB-cell, NK-cell, and NHR may potentially contribute to distinguishing PD patients from HCs. There could be a correlation between the number of B-cell, the level of NHR, and the severity of PD dyskinesia.

Statin use and the risk of Parkinson's disease in persons with diabetes: A nested case-control study.

Persons with diabetes may have an elevated risk of Parkinson's disease (PD). Statin use could also modify the progression of PD. The aim was to study whether there is an association between statin exposure and risk of PD in persons with diabetes. A nationwide, nested case-control study restricted to people with diabetes was performed as part of nationwide register-based Finnish study on PD (FINPARK). Study included 2017 PD cases and their 7934 matched controls without PD. Persons with PD were diagnosed between 1999 and 2015, and statin use (1995-2015) was determined from Prescription Register. In the main analysis, exposure at least 3 years before outcome was considered. Cumulative exposure was categorized into tertiles, and associations were analysed with conditional logistic regression (adjusted with comorbidities and number of antidiabetic drugs). Prevalence of statin use was similar in PD cases and controls, with 54.2% of cases and 54.4% controls exposed before the lag time (adjusted odds ratio [aOR] =1.03; 95% confidence interval [CI]: 0.92-1.15). Those in the highest cumulative statin exposure tertile had higher risk of PD than statin nonusers (aOR =1.22; 95% CI: 1.04-1.43), or those in the lowest cumulative statin exposure tertile (aOR =1.29; 95% CI: 1.07-1.57). Our nationwide study that controlled for diabetes duration and used 3-year lag between exposure and outcome to account for reverse causality does not provide support for the hypothesis that statin use decreases the risk of PD.

Prediabetes and the incidence of Parkinson's disease: A meta-analysis.

Diabetes has been associated with an elevated risk of Parkinson's disease (PD), yet the relationship between prediabetes (PreD) and the incidence of PD in the adult population remains unclear. Therefore, a systematic review and meta-analysis was conducted to evaluate if PreD is also associated with a higher risk of PD. We conducted comprehensive searches of the PubMed, Embase, and Web of Science databases to identify relevant observational studies with longitudinal follow-up. The random-effects model was employed to synthesize the data, mitigating the potential impact of study heterogeneity on the outcomes. Our analysis incorporated seven datasets from five cohort studies, encompassing 18,170,592 adult participants without a PD diagnosis at baseline. Among them, 2,432,148 (13.3%) had PreD. During the follow-up, a total of 46,682 patients were diagnosed with PD. The pooled results indicated that PreD was associated with an increased incidence of PD (risk ratio [RR] 1.09, 95% confidence interval [CI] 1.02 - 1.16; P = 0.02; I2 = 52%), after adjusting for potential confounding factors such as age, sex, body mass index (BMI), and smoking. Subsequent pilot subgroup analyses suggested that the association between PreD and PD might not be significantly influenced by the country of the study, its design, age or sex of the participants, definition of PreD, or the quality scores of the study (P for subgroup difference all > 0.05). In conclusion, adult population with PreD may have a mildly increased risk of developing PD compared to those with normoglycemia.

Genetic landscape of Parkinson's disease and related diseases in Luxembourg.

To explore the genetic architecture of PD in the Luxembourg Parkinson's Study including cohorts of healthy people and patients with Parkinson's disease (PD) and atypical parkinsonism (AP). 809 healthy controls, 680 PD and 103 AP were genotyped using the Neurochip array. We screened and validated rare single nucleotide variants (SNVs) and copy number variants (CNVs) within seven PD-causing genes (LRRK2, SNCA, VPS35, PRKN, PARK7, PINK1 and ATP13A2). Polygenic risk scores (PRSs) were generated using the latest genome-wide association study for PD. We then estimated the role of common variants in PD risk by applying gene-set-specific PRSs. We identified 60 rare SNVs in seven PD-causing genes, nine of which were pathogenic in LRRK2, PINK1 and PRKN. Eleven rare CNVs were detected in PRKN including seven duplications and four deletions. The majority of PRKN SNVs and CNVs carriers were heterozygous and not differentially distributed between cases and controls. The PRSs were significantly associated with PD and identified specific molecular pathways related to protein metabolism and signal transduction as drivers of PD risk. We performed a comprehensive genetic characterization of the deep-phenotyped individuals of the Luxembourgish Parkinson's Study. Heterozygous SNVs and CNVs in PRKN were not associated with higher PD risk. In particular, we reported novel digenic variants in PD related genes and rare LRRK2 SNVs in AP patients. Our findings will help future studies to unravel the genetic complexity of PD.

The association between migraine and Parkinson's disease: a nationwide cohort study.

Clinical studies have suggested an association between migraine and the occurrence of Parkinson's disease (PD). However, it is unknown whether migraine affects PD risk. We aimed to investigate the incidence of PD in patients with migraine and to determine the risk factors affecting the association between migraine and PD incidence. Using the Korean National Health Insurance System database (2002-2019), we enrolled all Koreans aged ≥40 years who participated in the national health screening program in 2009. International Classification of Diseases (10th revision) diagnostic codes and Rare Incurable Diseases System diagnostic codes were used to define patients with migraine (within 12 months of enrollment) and newly diagnosed PD. We included 214,193 patients with migraine and 5,879,711 individuals without migraine. During 9.1 years of follow-up (55,435,626 person-years), 1,973 (0.92%) and 30,664 (0.52%) individuals with and without migraine, respectively, were newly diagnosed with PD. Following covariate adjustment, patients with migraine showed a 1.35-fold higher PD risk than individuals without migraine. The incidence of PD was not significantly different between patients with migraine with aura and those without aura. In males with migraine, underlying dyslipidemia increased the risk of PD (p=0.012). In contrast, among females with migraine, younger age (<65 years) increased the risk of PD (p=0.038). Patients with migraine were more likely to develop PD than individuals without migraine. Preventive management of underlying comorbidities and chronic migraine may affect the incidence of PD in these patients. Future prospective randomized clinical trials are warranted to clarify this association.

Loneliness and Risk of Parkinson Disease

Loneliness is associated with morbidity and mortality, including higher risk of neurodegenerative diseases. To our knowledge, no study has examined whether the association between loneliness and detrimental outcomes extends to Parkinson disease (PD). To assess whether loneliness is associated with risk of incident PD and whether the association is independent of other risk factors or modified by age, sex, and genetic vulnerability. This prospective cohort study included a population-based sample of UK Biobank participants aged 38 to 73 years with loneliness data and without a diagnosis of PD at baseline who were first assessed from March 13, 2006, to October 1, 2010, and followed up to October 9, 2021. Feeling lonely and covariates that are known risk factors for or prodromal features of PD. Incident PD was ascertained through UK National Health Service health records. Of 491 603 participants (mean [SD] age, 56.54 [8.09] years; 54.4% female), 2822 developed PD during the 15-year follow-up. Individuals who reported being lonely had a higher risk of PD (hazard ratio [HR], 1.37; 95% CI, 1.25-1.51), an association that remained after accounting for demographic factors, socioeconomic status, social isolation, PD polygenetic risk score, smoking, physical activity, body mass index, diabetes, hypertension, stroke, myocardial infarction, depression, and ever seeing a psychiatrist (fully adjusted model: HR 1.25; 95% CI, 1.12-1.39). The association between loneliness and incident PD was not moderated by sex (HR for interaction, 0.98; 95% CI, 95% CI, 0.81-1.18), age (HR for interaction, 0.99; 95% CI, 0.98-1.01), or polygenic risk score (HR for interaction, 0.93; 95% CI, 0.85-1.02). Contrary to expectations for a prodromal syndrome, when stratified by time, loneliness was not associated with risk for incident PD during the first 5 years (HR, 1.15; 95% CI, 0.91-1.45) but was associated with PD risk during the subsequent 10 years (HR, 1.32; 95% CI, 1.19-1.46). This large cohort study found that loneliness was associated with risk of incident PD across demographic groups and independent of depression and other prominent risk factors and genetic risk. The findings add to the evidence that loneliness is a substantial psychosocial determinant of health.

Association of allergic disease with Parkinson's disease: A nationally representative retrospective cohort study

BackgroundThe association of allergic diseases such as allergic rhinitis, asthma, and atopic dermatitis with Parkinson's disease (PD) risk is yet unclear. In the few preceding studies, a short follow-up duration was followed for a relatively small study population, and lifestyle behaviors were not adjusted for. Therefore, there is a need for large-scale observation studies on the association of allergic disease with PD risk after considering lifestyle behaviors. MethodsThe study population consisted of 398,936 participants aged 40 years or older who underwent health screening before 1 January 2005 from the Korean National Health Insurance Service database. Starting from 1 January 2005, all participants were followed up until the date of PD event, death, or 31 December 2019. The adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for the risk of PD were calculated using multivariable Cox proportional hazards regression. ResultsCompared to non-allergic disease participants, allergic disease patients had a higher risk for PD (aHR 1.18, 95% CI 1.07–1.30) and especially, allergic rhinitis patients had a higher risk for PD (aHR 1.14, 95% CI 1.00–1.29). Allergic disease was associated with a higher risk for PD (aHR 1.24, 95% CI 1.01–1.52) among participants who were never smokers, did not consume alcohol, and exercised regularly. ConclusionsAllergic rhinitis was associated with a higher risk for PD compared to participants without allergic rhinitis. This risk-increasing association of allergic rhinitis with PD was preserved even among people with healthy lifestyle behaviors.

Risk of Parkinson Disease Among Service Members at Marine Corps Base Camp Lejeune

An increased risk of Parkinson disease (PD) has been associated with exposure to the solvent trichloroethylene (TCE), but data are limited. Millions of people in the US and worldwide are exposed to TCE in air, food, and water. To test whether the risk of PD is higher in veterans who served at Marine Corps Base Camp Lejeune, whose water supply was contaminated with TCE and other volatile organic compounds (VOCs), compared with veterans who did not serve on that base. This population-based cohort study examined the risk for PD among all Marines and Navy personnel who resided at Camp Lejeune, North Carolina (contaminated water) (n = 172 128), or Camp Pendleton, California (uncontaminated water) (n = 168 361), for at least 3 months between 1975 and 1985, with follow-up from January 1, 1997, until February 17, 2021. Veterans Health Administration and Medicare databases were searched for International Classification of Diseases diagnostic codes for PD or other forms of parkinsonism and related medications and for diagnostic codes indicative of prodromal disease. Parkinson disease diagnoses were confirmed by medical record review. Water supplies at Camp Lejeune were contaminated with several VOCs. Levels were highest for TCE, with monthly median values greater than 70-fold the permissible amount. Risk of PD in former residents of Camp Lejeune relative to residents of Camp Pendleton. In those without PD or another form of parkinsonism, the risk of being diagnosed with features of prodromal PD were assessed individually and cumulatively using likelihood ratio tests. Health data were available for 158 122 veterans (46.4%). Demographic characteristics were similar between Camp Lejeune (5.3% women, 94.7% men; mean [SD] attained age of 59.64 [4.43] years; 29.7% Black, 6.0% Hispanic, 67.6% White; and 2.7% other race and ethnicity) and Camp Pendleton (3.8% women, 96.2% men; mean [SD] age, 59.80 [4.62] years; 23.4% Black, 9.4% Hispanic, 71.1% White, and 5.5% other race and ethnicity). A total of 430 veterans had PD, with 279 from Camp Lejeune (prevalence, 0.33%) and 151 from Camp Pendleton (prevalence, 0.21%). In multivariable models, Camp Lejeune veterans had a 70% higher risk of PD (odds ratio, 1.70; 95% CI, 1.39-2.07; P < .001). No excess risk was found for other forms of neurodegenerative parkinsonism. Camp Lejeune veterans also had a significantly increased risk of prodromal PD diagnoses, including tremor, anxiety, and erectile dysfunction, and higher cumulative prodromal risk scores. The study's findings suggest that the risk of PD is higher in persons exposed to TCE and other VOCs in water 4 decades ago. Millions worldwide have been and continue to be exposed to this ubiquitous environmental contaminant.

Rheumatoid Arthritis and Risk of Parkinson Disease in Korea

Although it has been postulated that chronic inflammation caused by rheumatoid arthritis (RA) contributes to the development of Parkinson disease (PD), the association between these 2 conditions has yet to be determined. To evaluate the association between RA and subsequent PD risk. This retrospective cohort study used the Korean National Health Insurance Service database to collect population-based, nationally representative data on patients with RA enrolled from 2010 to 2017 and followed up until 2019 (median follow-up, 4.3 [IQR, 2.6-6.4] years after a 1-year lag). A total of 119 788 patients who were first diagnosed with RA (83 064 with seropositive RA [SPRA], 36 724 with seronegative RA [SNRA]) were identified during the study period and included those who underwent a national health checkup within 2 years before the RA diagnosis date (64 457 patients). After applying exclusion criteria (eg, age <40 years, other rheumatic diseases, previous PD), 54 680 patients (39 010 with SPRA, 15 670 with SNRA) were included. A 1:5 age- and sex-matched control group of patients without RA was also included for a total control population of 273 400. Rheumatoid arthritis as defined using International Classification of Diseases, Tenth Revision codes M05 for SPRA and M06 (except M06.1 and M06.4) for SNRA; prescription of any disease-modifying antirheumatic drug; and enrollment in the Korean Rare and Intractable Diseases program. The main outcome was newly diagnosed PD. Data were analyzed from May 10 through August 1, 2022, using Cox proportional hazards regression analyses. From the 328 080 individuals analyzed (mean [SD] age, 58.6 [10.1] years; 74.9% female and 25.1% male), 1093 developed PD (803 controls and 290 with RA). Participants with RA had a 1.74-fold higher risk of PD vs controls (95% CI, 1.52-1.99). An increased risk of PD was found in patients with SPRA (adjusted hazard ratio [aHR], 1.95; 95% CI, 1.68-2.26) but not in patients with SNRA (aHR, 1.20; 95% CI, 0.91-1.57). Compared with the SNRA group, those with SPRA had a higher risk of PD (aHR, 1.61; 95% CI, 1.20-2.16). There was no significant interaction between covariates on risk of PD. In this study, RA was associated with an increased risk of PD, and seropositivity of RA conferred an augmented risk of PD. The findings suggest that physicians should be aware of the elevated risk of PD in patients with RA and promptly refer patients to a neurologist at onset of early motor symptoms of PD without synovitis.

Cognitive impairment in REM-sleep behaviour disorder and individuals at risk of Parkinson's disease

BackgroundMild cognitive impairment (MCI) is commonly present at the time of Parkinson's Disease (PD) diagnosis, but its prevalence amongst individuals at increased risk of PD is unclear. MethodsCognition was assessed using the Montreal Cognitive Assessment (MoCA) in 208 participants in the PREDICT-PD study, and 25 participants with REM-sleep behaviour disorder (RBD). Prevalence of MCI level I was determined in all participants, and level II MCI in the RBD sub-group. ResultsTotal MoCA scores were worse in the higher risk than the lower risk group defined as those below the 15th percentile of risk (p = 0.009), and in the RBD group compared to all healthy participants (p < 0.001). The prevalence of MCI level I was 12.8% in the lower-risk, 21.9% in the higher-risk (within the highest 15th percentile) and 64% in RBD participants; 66% of RBD participants had MCI level II with multi-domain MCI, but particularly attention and memory deficits. ConclusionsCognitive impairment is increased in different groups at higher risk of PD, particularly in the subgroup formally diagnosed with RBD.

Hyperglycemic crisis and Parkinson disease: A retrospective cohort study based on nationwide data

IntroductionHyperglycemic crisis episode (HCE) suggests a poor control of diabetes, which may increase the risk of Parkinson disease (PD). This study aimed to clarify this issue since literature remains unclear.Material and methodsPatients with diabetes with and without HCE matched at a 1:1 ratio by age, sex, and index date between 2000 and 2002 from the Taiwan National Health Insurance Research Database were identified for analyses. Comparison of PD between patients with diabetes with and without HCE was performed by follow-up until 2012. Independent predictors for PD were also investigated among all patients.ResultsA total of 10,056 patients with diabetes with HCE and an identical number of patients with diabetes without HCE were included in the study. The mean age and male ratio were 62.0 years and 52.1%, respectively in both cohorts. Patients with HCE were found to have higher prevalence rates of hypertension, renal disease, hyperlipidemia, mental disorder, chronic obstructive pulmonary disease, liver disease, and head injury than those without HCE. Patients with HCE for ≥3 times had a higher risk for PD (adjusted hazard ratio [AHR]: 1.27; 95% confidence interval [CI]: 1.05-1.54) compared to those without HCE; however, patients with HCE for 1 or 2 times were not at high risk. Older age except ≥85 years, hypertension, hyperlipidemia, and mental disorder were also independent predictors for PD.ConclusionsHCE for ≥3 times is associated with PD. Close follow-up in older patients with HCE as well as control of hypertension, hyperlipidemia, and mental disorder are warranted.

Chapter 10 - Genetic mechanism vs genetic subtypes: The example of GBA

Genetic variants in GBA, encoding the lysosomal enzyme glucocerebrosidase (GCase), are common risk factors for Parkinson's disease (PD). Genotype-phenotype studies have demonstrated that different types of GBA variants have differential effects on the phenotype. Variants could be classified as mild or severe depending on the type of Gaucher disease they cause in the biallelic state. It was shown that severe GBA variants, as compared to mild variants, are associated with higher risk of PD, earlier age at onset, and faster progression of motor and nonmotor symptoms. The observed difference in phenotype might be caused by a diversity of cellular mechanisms related to the particular variants. The lysosomal function of GCase is thought to play a significant role in the development of GBA-associated PD, and other mechanisms such as endoplasmic reticulum retention, mitochondrial dysfunction, and neuroinflammation have also been suggested. Moreover, genetic modifiers such as LRRK2, TMEM175, SNCA, and CTSB can either affect GCase activity or modulate risk and age at onset of GBA-associated PD. To achieve ideal outcomes with precision medicine, therapies will have to be tailored to individuals with specific variants, potentially in combination with known modifiers.

Assessing the association between white matter lesions and Parkinson's disease.

The association between white matter (WM) lesions and Parkinson's disease (PD) was not fully established. We therefore applied Mendelian randomization (MR) analyses to identify the causal effect between white matter lesions and PD. We performed a bidirectional two-sample Mendelian randomization (MR) study to investigate the association between three WM phenotypes-white matter hyperintensities (WMH, N = 18,381), fractional anisotropy (FA, N = 17,673), and mean diffusivity (MD, N = 17,467)-with PD (N = 482,730) using summary statistics from genome-wide association studies (GWAS). The inverse variance weighted (IVW), weighted median, MR-Egger, and MR-PRESSO methods were used to evaluate the causal estimate. Significant evidence was suggested that higher MD was associated with a higher PD risk (OR = 1.049, 95% CI = 1.018-1.081, p = 0.022) when the outlier was removed using MR-PRESSO method. Moreover, genetically predicted PD was associated with a lower WMH load (IVW β =- 0.047, 95% CI =- 0.085 to - 0.009, p = 0.016) and a higher FA (β = 0.185, 95% CI = 0.021-0.349, p = 0.027). No evidence of pleiotropy was found using MR-Egger intercept. Our findings provided genetic support that white matter microstructural integrity lesions might increase the risk of PD. However, genetically predicted PD was potentially associated with a lower load of white matter lesions.

Risk of Neurodegenerative Diseases in Patients With Acromegaly: A Cohort Study.

A few recent studies have reported an association between insulin-like growth factor-1 (IGF-1) and neurodegenerative disease, but there was no report on any association between acromegaly and neurodegenerative disease. We investigated whether the risk of Alzheimer disease (AD), Parkinson disease, and other neurodegenerative diseases was increased among patients with acromegaly using nationwide data of Korea. We studied the association between acromegaly and Parkinson disease and dementia in 1,611 patients with acromegaly and controls (age-matched and sex-matched 8,055 participants with no diagnosis of acromegaly) from the National Health Insurance System database between 2006 and 2016 with a mean follow-up period of 7.34 years. Cox proportional hazards regression analysis was used to assess the risk of all outcomes in patients with acromegaly compared with controls with adjusting for age, sex, household income, place, type 2 diabetes, hypertension, and dyslipidemia. The average age of the patients with acromegaly and the controls was 54.16 years (40.4% men). The incidence rate of Parkinson disease in patients with acromegaly (1.54 per 1,000 person-years) was significantly higher than that in the control group (0.55 per 1,000 person-years) (log-rank test p = 0.001). Acromegaly was associated with a higher risk of Parkinson disease (hazard ratio [HR] = 2.609, 95% CI: 1.410-2.609) than the control. In addition, acromegaly was associated with a higher risk of all-cause dementia (HR = 2.299, 95% CI: 1.362-3.881), Alzheimer disease (HR = 2.228, 95% CI: 1.191-4.168), and non-AD dementia (HR = 6.553, 95% CI: 1.754-24.482) than the control during the first 3 years after diagnosis and treatment. In subgroup analysis, diabetes was associated with higher risk of all-cause dementia (P for interaction = 0.028) in patients with acromegaly compared with controls. Our study results suggest that acromegaly is associated with neurodegenerative disease. Further study is needed on the association between IGF-1/growth hormone level and neurodegenerative disease.

Copper induces microglia-mediated neuroinflammation through ROS/NF-κB pathway and mitophagy disorder.

The epidemiological correlation between copper exposure and higher risk of Parkinson disease (PD) has been recognized for a long time, and microglia-mediated neuroinflammation has reported to be an important component of the pathogenesis of PD. The present study aimed to investigate the role of microglial activation and neuroinflammation in copper neurotoxicity and the underlying mechanism of copper-induced activation of microglia. Based on the inflammatory changes in mouse brain tissues, the activation of microglia, the loss of dopaminergic neurons and the aggregation of α-syn were found in the substantia nigra. In this study we found that copper significantly caused inflammatory activation of BV2 cells. Importantly, copper increased the level of reactive oxygen species (ROS) in BV2 cells, and then activated the NF-κB pathway which acted as an early survival signal. Further study indicated that sustained copper accumulation in BV2 cells led to the decrease of mitochondrial membrane potential, reduction of Parkin and PINK1 expression, increase of P62 expression and LC3BⅡ/I ratio, as well as upregulation of NLRP3/caspase1/GSDMD axis proteins. In addition, the increased release of inflammatory factors was rescued by redox agent, NF-κB pathway inhibitor and mitophagy inducer. This work illustrated that copper exposure activates microglia to secrete inflammatory products, resulting in the pyroptosis of dopaminergic neurons, which was related to the early activation of ROS/NF-κB pathway and subsequent mitophagy disorder in BV2 cells.

Identification of ADP/ATP Translocase 1 as a Novel Glycoprotein and Its Association with Parkinson's Disease.

Protein glycosylation plays a crucial role in central nervous system, and abnormal glycosylation has major implications for human diseases. This study aims to evaluate an etiological implication of the variation in glycosylation for Parkinson's disease (PD), a neurodegenerative disorder. Based on a PD mouse model constructed by the intraperitoneal injection with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, glycosylation variation was accessed using biotinylated lectin of dolichos biflorus agglutinin (DBA) specific for the exposed N-acetylgalactosamine linked to glycoprotein. Consequently, a glycoprotein with a significantly reduced N-acetylgalactosamination was identified as ADP/ATP translocase 1 (ANT1) by lectin affinity chromatography coupled with MALDI-TOF MS/MS (mass spectrometry), and confirmed by the analysis of dual co-immunofluorescence and Western blot. A tissue-specific distribution of de-N-acetylgalactosaminated ANT1 was found to be correlated with high risk of PD. At cellular level, an obvious co-aggregation between ANT1 and DBA was only found in the MPP+-induced PD-like cell model using dual co-immunofluorescence. Thus, we found that ANT1 was a potential glycoprotein with terminal N-acetylgalactosamine moiety, and the variation of glycosylation in ANT1 was associated with PD. This investigation provides an innovative insight in protein glycosylation with PD pathogenesis.

Psychotropic medication use and Parkinson's disease risk amongst older women.

ObjectiveTo examine associations of antidepressant, anxiolytic and hypnotic use amongst older women (≥65 years) with incident Parkinson's Disease (PD), using data from Women's Health Initiative linked to Medicare claims.MethodsPD was defined using self‐report, first diagnosis, medications and/or death certificates and psychotropic medications were ascertained at baseline and 3‐year follow‐up. Cox regression models were constructed to calculate adjusted hazard ratios (aHR) with 95% confidence intervals (CI), controlling for socio‐demographic, lifestyle and health characteristics, overall and amongst women diagnosed with depression, anxiety and/or sleep disorders (DASD).ResultsA total of 53,996 WHI participants (1,756 PD cases)—including 27,631 women diagnosed with DASD (1,137 PD cases)—were followed up for ~14 years. Use of hypnotics was not significantly associated with PD risk (aHR = 0.98, 95% CI: 0.82, 1.16), whereas PD risk was increased amongst users of antidepressants (aHR = 1.75, 95% CI: 1.56, 1.96) and anxiolytics (aHR = 1.48, 95% CI: 1.25, 1.73). Compared to non‐users of psychotropic medications, those who used 1 type had ~50% higher PD risk, whereas those who used ≥2 types had ~150% higher PD risk. Women who experienced transitions in psychotropic medication use (‘use to non‐use’ or ‘non‐use to use’) between baseline and 3‐year follow‐up had higher PD risk than those who did not. We obtained similar results with propensity scoring and amongst DASD‐diagnosed women.InterpretationThe use of antidepressants, anxiolytics or multiple psychotropic medication types and transitions in psychotropic medication use was associated with increased PD risk, whereas the use of hypnotics was not associated with PD risk amongst older women.

Genome Sequencing in the Parkinson Disease Clinic.

Background and ObjectivesGenetic variants affect both Parkinson disease (PD) risk and manifestations. Although genetic information is of potential interest to patients and clinicians, genetic testing is rarely performed during routine PD clinical care. The goal of this study was to examine interest in comprehensive genetic testing among patients with PD and document reactions to possible findings from genome sequencing in 2 academic movement disorder clinics.MethodsIn 203 subjects with PD (age = 63 years, 67% male), genome sequencing was performed and filtered using a custom panel, including 49 genes associated with PD, parkinsonism, or related disorders, as well as a 90-variant PD genetic risk score. Based on the results, 231 patients (age = 67 years, 63% male) were surveyed on interest in genetic testing and responses to vignettes covering (1) familial risk of PD (LRRK2); (2) risk of PD dementia (GBA); (3) PD genetic risk score; and (4) secondary, medically actionable variants (BRCA1).ResultsGenome sequencing revealed a LRRK2 variant in 3% and a GBA risk variant in 10% of our clinical sample. The genetic risk score was normally distributed, identifying 41 subjects with a high risk of PD. Medically actionable findings were discovered in 2 subjects (1%). In our survey, the majority (82%) responded that they would share a LRRK2 variant with relatives. Most registered unchanged or increased interest in testing when confronted with a potential risk for dementia or medically actionable findings, and most (75%) expressed interest in learning their PD genetic risk score.DiscussionOur results highlight broad interest in comprehensive genetic testing among patients with PD and may facilitate integration of genome sequencing in clinical practice.