Prevalent Parkinson's Disease Research Articles

Istradefylline/L‐DOPA Parkinson's disease therapy and energy coupling

AbstractBackgroundBoth dopamine and adenosine are physiologically involved in cellular energy metabolism.AimNovel approaches targeting delaying progression strategies for Parkinson's disease (PD) examined the effects of long‐term use of A2AR antagonist/istradefylline (IST) adjunct to L‐DOPA (LD), nutshell IST‐LD, with an expected energy coupling (EC) to attenuate neuronal excitotoxicity.MethodsA single‐center prospective open cohort study was conducted at the Department of Neurology, Okinawa Islands, Japan. The cohort included incident and prevalent PD cases that were non‐randomly assigned to the IST‐LD (n = 90) and LD (n = 157) groups, followed by an open‐label treatment in clinical practice from October 2013 to September 2020. Patients were evaluated using physician‐rated MDS‐UPDRS I/III, and patient‐rated MDS‐NMS using the total score, body weight, and blood biomarkers of EC.ResultsAs the primary clinical outcome, MDS‐UPDRS part III scores showed less worsening in the IST‐LD than in the LD group (1.29 ± 6.0 vs. 5.0 ± 6.5, p < 0.01) and off‐time Hoehn and Yahr stage (0.05 ± 0.49 vs. 0.26 ± 0.54, p < 0.01). As the secondary clinical outcome, the detected mean body weight losses were similar between the two groups; however, the evident linkage of the daily dose of LD and variations in the blood markers of IGF‐I and HKII, which were inferred as LD‐mediated energy demand effects, were partially attenuated by IST.ConclusionIST‐LD plays an essential role in behavioral outputs for patients with PD and might contribute to the interplay of energy‐consuming demands of LD with the attenuation of weight loss and emerging type 2 diabetes mellitus.

Blood-based biological ageing and red cell distribution width are associated with prevalent Parkinson's disease: findings from a large Italian population cohort.

Aging clocks tag the actual underlying age of an organism and its discrepancy with chronological age and have been reported to predict incident disease risk in the general population. However, the relationship with neurodegenerative risk and in particular with Parkinson's Disease (PD) remains unclear, with few discordant findings reporting associations with both incident and prevalent PD risk. To clarify this relationship, we computed a common aging clock based on blood markers and tested the resulting discrepancy with chronological age (ΔPhenoAge) for association with both incident and prevalent PD risk. In a large Italian population cohort - the Moli-sani study (N=23,437; age ≥ 35 years; 52% women) - we carried out both Cox Proportional Hazards regressions modelling ΔPhenoAge as exposure and incident PD as outcome, and linear models testing prevalent PD as exposure and ΔPhenoAge as outcome. All models were incrementally adjusted for age, sex, education level completed and other risk/protective factors previously associated with PD risk in the same cohort (prevalent dysthyroidism, hypertension, diabetes, use of oral contraceptives, exposure to paints, daily coffee intake and cigarette smoking). No significant association between incident PD risk (209 cases, median (IQR) follow-up time 11.19 (2.03) years) and PhenoAging was observed (Hazard Ratio [95% Confidence Interval] = 0.98 [0.71; 1.37]). However, a small but significant increase of ΔPhenoAge was observed in prevalent PD cases vs healthy subjects (β (Standard Error) = 1.39 (0.70)). An analysis of each component biomarker of PhenoAge revealed a significant positive association of prevalent PD status with red cell distribution width (RDW; β (SE) = 0.46 (0.18)). All the remaining markers did not show any significant evidence of association. The reported evidence highlights systemic effects of prevalent PD status on biological aging and red cell distribution width. Further cohort and functional studies may help shedding a light on the related pathways altered at the organism level in prevalent PD, like red cells variability, inflammatory and oxidative stress mechanisms.

Retinal Optical Coherence Tomography Features Associated With Incident and Prevalent Parkinson Disease.

Cadaveric studies have shown disease-related neurodegeneration and other morphological abnormalities in the retina of individuals with Parkinson disease (PD); however, it remains unclear whether this can be reliably detected with in vivo imaging. We investigated inner retinal anatomy, measured using optical coherence tomography (OCT), in prevalent PD and subsequently assessed the association of these markers with the development of PD using a prospective research cohort. This cross-sectional analysis used data from 2 studies. For the detection of retinal markers in prevalent PD, we used data from AlzEye, a retrospective cohort of 154,830 patients aged 40 years and older attending secondary care ophthalmic hospitals in London, United Kingdom, between 2008 and 2018. For the evaluation of retinal markers in incident PD, we used data from UK Biobank, a prospective population-based cohort where 67,311 volunteers aged 40-69 years were recruited between 2006 and 2010 and underwent retinal imaging. Macular retinal nerve fiber layer (mRNFL), ganglion cell-inner plexiform layer (GCIPL), and inner nuclear layer (INL) thicknesses were extracted from fovea-centered OCT. Linear mixed-effects models were fitted to examine the association between prevalent PD and retinal thicknesses. Hazard ratios for the association between time to PD diagnosis and retinal thicknesses were estimated using frailty models. Within the AlzEye cohort, there were 700 individuals with prevalent PD and 105,770 controls (mean age 65.5 ± 13.5 years, 51.7% female). Individuals with prevalent PD had thinner GCIPL (-2.12 μm, 95% CI -3.17 to -1.07, p = 8.2 × 10-5) and INL (-0.99 μm, 95% CI -1.52 to -0.47, p = 2.1 × 10-4). The UK Biobank included 50,405 participants (mean age 56.1 ± 8.2 years, 54.7% female), of whom 53 developed PD at a mean of 2,653 ± 851 days. Thinner GCIPL (hazard ratio [HR] 0.62 per SD increase, 95% CI 0.46-0.84, p = 0.002) and thinner INL (HR 0.70, 95% CI 0.51-0.96, p = 0.026) were also associated with incident PD. Individuals with PD have reduced thickness of the INL and GCIPL of the retina. Involvement of these layers several years before clinical presentation highlight a potential role for retinal imaging for at-risk stratification of PD.

Trends in health service use among persons with Parkinson's disease by rurality: A population-based repeated cross-sectional study.

The global burden of Parkinson's disease (PD) has more than doubled over the past three decades, and this trend is expected to continue. Despite generally poorer access to health care services in rural areas, little previous work has examined health system use in persons with PD by rurality. We examined trends in the prevalence of PD and health service use among persons with PD by rurality in Ontario, Canada. We conducted a repeated, cross-sectional analysis of persons with prevalent PD aged 40+ years on April 1st of each year from 2000 to 2018 using health administrative databases and calculated the age-sex standardized prevalence of PD. Prevalence of PD was also stratified by rurality and sex. Negative binomial models were used to calculate rate ratios with 95% confidence intervals comparing rates of health service use in rural compared to urban residents in 2018. The age-sex standardized prevalence of PD in Ontario increased by 0.34% per year (p<0.0001) and was 459 per 100,000 in 2018 (n = 33,479), with a lower prevalence in rural compared to urban residents (401 vs. 467 per 100,000). Rates of hospitalizations and family physician visits declined over time in both men and women with PD in rural and urban areas, while rates of emergency department, neurologist, and other specialist visits increased. Adjusted rates of hospitalizations were similar between rural and urban residents (RR = 1.04, 95% CI [0.96, 1.12]), while rates of emergency department visits were higher among rural residents (RR = 1.35, 95% CI [1.27, 1.42]). Rural residents had lower rates of family physician (adjusted RR = 0.82, (95% CI [0.79, 0.84]) and neurologist visits (RR = 0.74, 95% CI [0.72, 0.77]). Lower rates of outpatient health service use among persons residing in rural regions, contrasting with higher rates of emergency department visits suggest inequities in access. Efforts to improve access to primary and specialist care for persons with PD in rural regions are needed.

Cognitive and Functional Trajectories in Older Adults With Prediagnostic Parkinson Disease.

There is increasing interest in characterizing the earliest phases of Parkinson disease (PD). However, few studies have investigated prediagnostic trajectories of cognition and function. Our objective was to describe prediagnostic cognitive and functional trajectories in PD in older women and men. We studied 9,595 women and 5,795 men from 2 prospective cohort studies of community-dwelling elders followed up to 20 years. In individuals without prevalent PD, we estimated the associations of incident PD diagnosis with rates of change in cognition and function before and after diagnosis compared with healthy older adults using multivariate mixed-effects models. Over follow-up, 297 individuals developed incident PD. Interactions between the terms in our model and sex were statistically significant for the 3 outcomes (p < 0.001 for all), so we stratified results by sex. Compared with older men without PD, men who developed PD exhibited faster decline in global cognition (0.04 SD more annual change, p < 0.001), executive function (0.05 SD more annual change, p < 0.001), and functional status (0.06 SD more annual change, p < 0.001) in the prediagnostic period. Women who developed PD compared with women without PD displayed faster decline in executive function (0.02 SD more annual change, p = 0.006) and functional status in the prediagnostic period (0.07 SD more annual change, p < 0.001). Individuals with incident PD exhibit cognitive and functional decline during the prediagnostic phase that exceeds rates associated with normal aging. Better understanding heterogeneity in prodromal PD is essential to enable earlier diagnosis and identify impactful nonmotor symptoms in all subgroups.

Fracture risk in Parkinson's disease according to its severity and duration.

Parkinson's disease (PD) is reported to be associated with a high risk of fractures. Several studies found an association between severity and duration of PD and falls or bone mineral density, but those factors have not been considered in most previous research. The aim of this study was to determine the fracture risk in PD patients according to their disease severity and duration. This population-based, retrospective cohort study used data from the Korean National Health Insurance Service database. The study population included 10,333 patients with prevalent PD and 6,501,464 comparison cohort. Fracture risks according to the prevalence, severity, and duration of PD were evaluated using Cox proportional hazard methods. Fracture risk was elevated in PD patients at all sites compared with controls (adjusted hazard ratio [aHR] 1.49, 95% confidence interval [CI] 1.44-1.56 for any fracture). When comparing fracture sites, hip fractures showed the largest risk increase in PD patients (aHR 2.16, 95% CI 1.95-2.38). Among PD patients, the risk of any fracture increased linearly with PD severity and was highest in patients with severe disease (aHR 1.65, 95% CI 1.53-1.79 compared with controls). Meanwhile, no significant association was observed between PD duration and fracture risk. The prevalence of PD was related to an increased risk of fractures in this nationwide study, and PD severity was linearly associated with fracture risk. PD prevalence and severity should be considered when evaluating the risk factors of fracture in clinical practice.

Orthostatic Hypotension: A Prodromal Marker of Parkinson's Disease?

BackgroundOrthostatic hypotension is common in patients with Parkinson's disease (PD). However, it remains unknown whether orthostatic hypotension is a marker of prodromal PD or more advanced disease. The objectives of this study were to assess whether orthostatic hypotension is a prodromal marker of PD in the general population.MethodsThis study was embedded in the Rotterdam Study, a large prospective population‐based cohort in the Netherlands. We measured orthostatic hypotension in 6910 participants. First, we determined the relation between prevalent PD and orthostatic hypotension using logistic regression. Second, we followed PD‐free participants for the occurrence of PD until 2016 and studied the association between orthostatic hypotension and the risk of PD using Cox proportional hazards models. All models were adjusted for age and sex.ResultsAt baseline, the mean age ± standard deviation of the study population was 69.0 ± 8.8 years, and 59.1% were women. Orthostatic hypotension was present in 1245 participants (19.8%), and 62 participants (1.0%) had PD at the time of orthostatic hypotension measurement. Participants with PD were significantly more likely to have orthostatic hypotension (odds ratio, 1.88; 95% confidence interval, 1.09–3.24). During a median (interquartile range) follow‐up of 16.1 years (8.5–22.7 years), 122 participants were diagnosed with incident PD. Orthostatic hypotension at baseline was not associated with an increased risk of PD (hazard ratio, 0.97; 95% confidence interval, 0.59–1.58).ConclusionsOur study suggests that orthostatic hypotension is common in patients with PD, but that orthostatic hypotension is not associated with an increased risk of PD and thus is not a prodromal marker of PD in the general population. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Association of Circadian Abnormalities in Older Adults With an Increased Risk of Developing Parkinson Disease

Disruption in circadian activity rhythms is very common in older adults, particularly among those with neurodegenerative diseases, including Parkinson disease (PD). However, whether circadian disruption could be a prodrome for PD is unclear. To determine the association between rest-activity rhythm (RAR) and risk of incident PD and to explore whether this association is independent of nighttime sleep disturbances. The ancillary sleep study of the longitudinal cohort Osteoporotic Fractures in Men Study (MrOS) was conducted from December 1, 2003, to March 31, 2005. Of the 3135 community-dwelling men enrolled in the MrOS sleep study, 3049 had technically adequate RAR data; of these, 119 were excluded for having prevalent PD or missing incident data, leaving 2930 men without PD at baseline. Data were analyzed from February 1 through August 31, 2019. Twenty four-hour RAR parameters (amplitude, mesor, robustness, and acrophase) generated by wrist actigraphy-extended cosinor analysis. Incident PD based on physician diagnosis. Multivariable logistic regression was used to determine the association between quartiles of RAR parameters and risk of incident PD. Among the 2930 men included in the analysis (mean [SD] age, 76.3 [5.5] years), 78 (2.7%) developed PD during 11 years of follow-up. After accounting for all covariates, the risk of PD increased with decreasing circadian amplitude (strength of the rhythm) (odds ratio [OR] per 1-SD decrease, 1.77; 95% CI, 1.30-2.41), mesor (mean level of activity) (OR per 1-SD decrease, 1.64; 95% CI, 1.22-2.21), or robustness (how closely activity follows a cosine 24-hour pattern) (OR per 1-SD decrease, 1.54; 95% CI, 1.14-2.07) (P < .005 for trend). Those in the lowest quartile of amplitude, mesor, or robustness had approximately 3 times the risk of developing PD compared with those in the highest quartile of amplitude (OR, 3.11; 95% CI, 1.54-6.29), mesor (OR, 3.04; 95% CI, 1.54-6.01), and robustness (OR, 2.65; 95% CI, 1.24-5.66). The association remained after further adjustment for nighttime sleep disturbances and duration in the lowest compared with the highest quartile (OR for amplitude, 3.56 [95% CI, 1.68-7.56]; OR for mesor, 3.24 [95% CI, 1.52-6.92]; and OR for robustness, 3.34 [95% CI, 1.45-7.67]). These associations were somewhat attenuated, but the pattern remained similar after excluding PD cases developed within 2 years after baseline in the lowest compared with the highest quartile (OR for amplitude, 2.40 [95% CI, 1.15-5.00]; OR for mesor, 2.76 [95% CI, 1.35-5.67]; and OR for robustness, 2.33 [95% CI, 1.07-5.07]). Acrophase was not significantly associated with risk of PD. In this cohort study, reduced circadian rhythmicity was associated with an increased risk of incident PD, suggesting it may represent an important prodromal feature for PD. Future studies are needed to determine whether circadian disruption could also be a risk factor for PD and whether strategies to improve circadian function affect the risk of PD.

Cannabidiol increases the nociceptive threshold in a preclinical model of Parkinson's disease

Medications that improve pain threshold can be useful in the pharmacotherapy of Parkinson's disease (PD). Pain is a prevalent PD's non-motor symptom with a higher prevalence of analgesic drugs prescription for patients. However, specific therapy for PD-related pain are not available. Since the endocannabinoid system is expressed extensively in different levels of pain pathway, drugs designed to target this system have promising therapeutic potential in the modulation of pain. Thus, we examined the effects of the 6-hydroxydopamine- induced PD on nociceptive responses of mice and the influence of cannabidiol (CBD) on 6-hydroxydopamine-induced nociception. Further, we investigated the pathway involved in the analgesic effect of the CBD through the co-administration with a fatty acid amide hydrolase (FAAH) inhibitor, increasing the endogenous anandamide levels, and possible targets from anandamide, i.e., the cannabinoid receptors subtype 1 and 2 (CB1 and CB2) and the transient receptor potential vanilloid type 1 (TRPV1). We report that 6-hydroxydopamine- induced parkinsonism decreases the thermal and mechanical nociceptive threshold, whereas CBD (acute and chronic treatment) reduces this hyperalgesia and allodynia evoked by 6-hydroxydopamine. Moreover, ineffective doses of either FAAH inhibitor or TRPV1 receptor antagonist potentialized the CBD-evoked antinociception while an inverse agonist of the CB1 and CB2 receptor prevented the antinociceptive effect of the CBD. Altogether, these results indicate that CBD can be a useful drug to prevent the parkinsonism-induced nociceptive threshold reduction. They also suggest that CB1 and TRPV1 receptors are important for CBD-induced analgesia and that CBD could produce these analgesic effects increasing endogenous anandamide levels.

Impaired serine metabolism complements LRRK2-G2019S pathogenicity in PD patients

Parkinson's disease (PD) is a multifactorial disorder with complex etiology. The most prevalent PD associated mutation, LRRK2-G2019S is linked to familial and sporadic cases. Based on the multitude of genetic predispositions in PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patients' genetic background act as susceptibility factors for developing PD. To assess LRRK2-G2019S modifiers, we used human induced pluripotent stem cell-derived neuroepithelial stem cells (NESCs). Isogenic controls distinguish between LRRK2-G2019S dependent and independent cellular phenotypes. LRRK2-G2019S patient and healthy mutagenized lines showed altered NESC self-renewal and viability, as well as impaired serine metabolism. In patient cells, phenotypes were only partly LRRK2-G2019S dependent, suggesting a significant contribution of the genetic background. In this context we identified the gene serine racemase (SRR) as a novel patient-specific, developmental, genetic modifier contributing to the aberrant phenotypes. Its enzymatic product, d-serine, rescued altered cellular phenotypes. Susceptibility factors in the genetic background, such as SRR, could be new targets for early PD diagnosis and treatment.

Professional occupation and the risk of Parkinson's disease

Background and purposeCreativity in Parkinson's disease (PD) is strongly related to dopaminergic activity and medication. We hypothesized that patients with PD, including those who are in the pre‐diagnostic phase of PD, are prone to choose highly structured ‘conventional’ professional occupations and avoid highly creative ‘artistic’ occupations.MethodsAt baseline of the population‐based Rotterdam Study, we asked 12 147 individuals aged ≥45 years about their latest occupation and categorized occupations according to the RIASEC model. Participants underwent baseline and follow‐up (median 11 years) examinations for PD. We determined associations of artistic (versus any other occupation) and conventional (versus any other occupation) occupations with PD. Additionally, we pooled our results with a recently published case–control study (Radboud Study).ResultsAt baseline, conventional occupations were common [n = 4356 (36%)], whereas artistic occupations were rare [n = 137 (1%)]. There were 217 patients with PD, including 91 with prevalent PD and 126 with incident PD. The risk of PD varied substantially across occupational categories (chi‐square, 14.61; P = 0.01). The penalized odds ratio (OR) of artistic occupations for PD was 0.19 [95% confidence interval (CI), 0.00–1.31; P = 0.11], whereas the OR of conventional occupations for PD was 1.23 (95% CI, 0.95–1.66; P = 0.10). The direction and magnitude of ORs were similar in cross‐sectional and longitudinal subsamples. Pooled ORs across the Rotterdam and Radboud Studies were 0.20 (95% CI, 0.08–0.52; P < 0.001) for artistic and 1.23 (95% CI, 0.92–1.67; P = 0.08) for conventional occupations.ConclusionsThe risk of PD varies substantially by choice of professional occupation. Our findings suggest that dopaminergic degeneration affects choice of occupation, which may start in the pre‐diagnostic phase of PD.

Do We Need to Rethink the Epidemiology and Healthcare Utilization of Parkinson's Disease in Germany?

Epidemiological aspects of Parkinson's disease (PD), co-occurring diseases and medical healthcare utilization of PD patients are still largely elusive. Based on claims data of 3.7 million statutory insurance members in Germany in 2015 the prevalence and incidence of PD was determined. PD cases had at least one main hospital discharge diagnosis of PD, or one physician diagnosis confirmed by a subsequent or independent diagnosis or by PD medication in 2015. Prevalence of (co-)occurring diseases, mortality, and healthcare measures in PD cases and matched controls were compared. In 2015, 21,714 prevalent PD cases (standardized prevalence: 511.4/100,000 persons) and 3,541 incident PD cases (standardized incidence: 84.1/100,000 persons) were identified. Prevalence of several (co-)occurring diseases/complications, e.g., dementia (PD/controls: 39/13%), depression (45/22%), bladder dysfunction (46/22%), and diabetes (35/31%), as well as mortality (10.7/5.8%) differed between PD cases and controls. The annual healthcare utilization was increased in PD cases compared to controls, e.g., regarding mean ± SD physician contacts (15.2 ± 7.6/12.2 ± 7.3), hospitalizations (1.3 ± 1.8/0.7 ± 1.4), drug prescriptions (overall: 37.7 ± 24.2/21.7 ± 19.6; anti-PD medication: 7.4 ± 7.4/0.1 ± 0.7), assistive/therapeutic devices (47/30%), and therapeutic remedies (57/16%). The standardized prevalence and incidence of PD in Germany as well as mortality in PD may be substantially higher than reported previously. While frequently diagnosed with co-occurring diseases/complications, such as dementia, depression, bladder dysfunction and diabetes, the degree of healthcare utilization shows large variability between PD patients. These findings encourage a rethinking of the epidemiology and healthcare utilization in PD, at least in Germany. Longitudinal studies of insurance claims data should further investigate the individual and epidemiological progression and healthcare demands in PD.

Inflammatory Bowel Disease and Parkinson's Disease: A Nationwide Swedish Cohort Study.

Few studies have examined the association between inflammatory bowel disease (IBD) and Parkinson's disease (PD). To estimate the incidence and relative risk of PD development in a cohort of adult IBD, we included all incident IBD patients (n = 39,652) in the Swedish National Patient Register (NPR) between 2002 and 2014 (ulcerative colitis [UC]: n = 24,422; Crohn's disease [CD]: n = 11,418; IBD-unclassified [IBD-U]: n = 3812). Each IBD patient was matched for sex, age, year, and place of residence with up to 10 reference individuals (n = 396,520). In a cohort design, all incident PD occurring after the index date was included from the NPR. In a case-control design, all incident PD occurring before the index date was included. The association between IBD and PD and vice versa was investigated by multivariable Cox and logistic regression. In IBD, there were 103 cases of incident PD, resulting in hazard ratios (HRs) for PD of 1.3 (95% confidence interval [CI], 1.0-1.7; P = 0.04) in UC, 1.1 (95% CI, 0.7-1.7) in CD, and 1.7 (95% CI, 0.8-3.0) in IBD-U. However, these effects disappeared when adjusting for number of medical visits during follow-up to minimize potential surveillance bias. In a case-control analysis, IBD patients were more likely to have prevalent PD at the time of IBD diagnosis than matched controls, with odds ratios of 1.4 (95% CI, 1.2-1.8) in all IBD patients, 1.4 (95% CI, 1.1-1.9) for UC, and 1.6 (95% CI, 1.1-2.3) for CD patients alone. IBD is associated with an increased risk of PD, but some of this association might be explained by surveillance bias. 10.1093/ibd/izy190_video1izy190.video15785623138001.

Association of Restless Legs Syndrome With Incident Parkinson's Disease.

The association between restless legs syndrome (RLS) and Parkinson's disease (PD) has been extensively studied with inconclusive results; therefore, we prospectively examined the associations of the presence of RLS with development of incident PD. From a nationally representative prospective cohort of almost 3.5 million US veterans (age: 60 ± 14 years, 93% male, median follow-up time of 7.8 years [interquartile range: 6.4-8.4 years]), we created a propensity-matched cohort of 100882 PD-free patients and examined the association between prevalent RLS and incident PD. This association was also assessed in the entire cohort. Associations were examined using Cox models. There were 68 incident PD events (0.13%, incidence rate 1.87 [1.48-2.37]/10000 patient-years) in the RLS-negative group, and 185 incident PD events (0.37%, incidence rate 4.72 [4.09-5.45]/10000 patient-years) in the RLS-positive group in the propensity-matched cohort. Prevalent RLS was associated with more than twofold higher risk of incident PD (hazard ratio [HR]: 2.57, 95% confidence interval [CI]: 1.95-3.39) compared to RLS-negative patients. Qualitatively similar results were found when we examined the entire 3.5 million cohort: Prevalent RLS was associated with more than twofold higher risk of incident PD (multivariable adjusted HR: 2.81, 95%CI: 2.41-3.27). RLS and PD share common risk factors. In this large cohort of US veterans, we found that prevalent RLS is associated with higher risk of incident PD during 8 years of follow-up, suggesting that RLS could be an early clinical feature of incident PD.

Gene-Environment Interaction in Parkinson's Disease: Coffee, ADORA2A, and CYP1A2

Background and Purpose: Drinking caffeinated coffee has been reported to provide protection against Parkinson's disease (PD). Caffeine is an adenosine A2A receptor (encoded by the gene ADORA2A) antagonist that increases dopaminergic neurotransmission and Cytochrome P450 1A2 (gene: CYP1A2) metabolizes caffeine; thus, gene polymorphisms in ADORA2A and CYP1A2 may influence the effect coffee consumption has on PD risk. Methods: In a population-based case-control study (PASIDA) in Denmark (1,556 PD patients and 1,606 birth year- and gender-matched controls), we assessed interactions between lifetime coffee consumption and 3 polymorphisms in ADORA2A and CYP1A2 for all subjects, and incident and prevalent PD cases separately using logistic regression models. We also conducted a meta-analysis combining our results with those from previous studies. Results: We estimated statistically significant interactions for ADORA2A rs5760423 and heavy vs. light coffee consumption in incident (OR interaction = 0.66 [95% CI 0.46-0.94], p = 0.02) but not prevalent PD. We did not observe interactions for CYP1A2 rs762551 and rs2472304 in incident or prevalent PD. In meta-analyses, PD associations with daily coffee consumption were strongest among carriers of variant alleles in both ADORA2A and CYP1A2. Conclusion: We corroborated results from a previous report that described interactions between ADORA2A and CYP1A2 polymorphisms and coffee consumption. Our results also suggest that survivor bias may affect results of studies that enroll prevalent PD cases.

LRRK2 BAC transgenic rats develop progressive, L-DOPA-responsive motor impairment, and deficits in dopamine circuit function.

Mutations in leucine-rich repeat kinase 2 (LRRK2) lead to late-onset, autosomal dominant Parkinson's disease, characterized by the degeneration of dopamine neurons of the substantia nigra pars compacta, a deficit in dopamine neurotransmission and the development of motor and non-motor symptoms. The most prevalent Parkinson's disease LRRK2 mutations are located in the kinase (G2019S) and GTPase (R1441C) encoding domains of LRRK2. To better understand the sequence of events that lead to progressive neurophysiological deficits in vulnerable neurons and circuits in Parkinson's disease, we have generated LRRK2 bacterial artificial chromosome transgenic rats expressing either G2019S or R1441C mutant, or wild-type LRRK2, from the complete human LRRK2 genomic locus, including endogenous promoter and regulatory regions. Aged (18–21 months) G2019S and R1441C mutant transgenic rats exhibit L-DOPA-responsive motor dysfunction, impaired striatal dopamine release as determined by fast-scan cyclic voltammetry, and cognitive deficits. In addition, in vivo recordings of identified substantia nigra pars compacta dopamine neurons in R1441C LRRK2 transgenic rats reveal an age-dependent reduction in burst firing, which likely results in further reductions to striatal dopamine release. These alterations to dopamine circuit function occur in the absence of neurodegeneration or abnormal protein accumulation within the substantia nigra pars compacta, suggesting that nigrostriatal dopamine dysfunction precedes detectable protein aggregation and cell death in the development of Parkinson's disease. In conclusion, our longitudinal deep-phenotyping provides novel insights into how the genetic burden arising from human mutant LRRK2 manifests as early pathophysiological changes to dopamine circuit function and highlights a potential model for testing Parkinson's therapeutics.

Groundwater pesticide levels and the association with Parkinson disease.

It is unclear whether exposure to environmentally relevant levels of pesticides in groundwater is associated with an increased risk of Parkinson disease (PD). The purpose of this study was to examine the relationship between PD and pesticide levels in groundwater. This cross-sectional study included 332 971 Medicare beneficiaries, including 4207 prevalent cases of PD from the 2007 Colorado Medicare Beneficiary Database. Residential pesticide levels were estimated from a spatial model based on 286 well water samples with atrazine, simazine, alachlor, and metolachlor measurements. A logistic regression model with known PD risk factors was used to assess the association between residential groundwater pesticide levels and prevalent PD. We found that for every 1.0 µg/L of pesticide in groundwater, the risk of PD increases by 3% (odds ratio = 1.03; 95% confidence interval: 1.02-1.04) while adjusting for age, race/ethnicity, and gender suggesting that higher age-standardized PD prevalence ratios are associated with increasing levels of pesticides in groundwater.

Rate of cognitive decline in premotor Parkinson's disease: A prospective study (NEDICES)

Previous research has documented cognitive impairment in the early stages of Parkinson's disease (PD). It is not known when this decline starts or if decline progresses at an accelerated rate during the premotor period of the disorder. In this population-based prospective study of older people (≥65 years) from the Neurological Disorders in Central Spain (NEDICES) cohort, we compared the rates of cognitive decline in 3 groups: (1) non-PD elderly controls; (2) prevalent PD patients (those diagnosed with the disease at baseline, 1994-95); and (3) premotor PD subjects (those diagnosed with the disease at follow up, 1997-98, but not at baseline). A 37-item version of the Mini-Mental State Examination (37-MMSE) was administered in the 2 visits of the study. From 2487 participants (age, 72.8 ± 6.0 years), including 2429 controls, we recruited 21 premotor PD cases, and 37 prevalent PD cases. At baseline, the mean 37-MMSE score was 28.5 ± 4.7 in prevalent cases, 28.1 ± 4.6 in premotor cases, and 29.9 ± 5.0 in controls (P = .046). During the 3-year follow-up period, there was a significant score decline of 2.4 ± 4.6 points in prevalent cases versus 0.2 ± 4.1 points in premotor cases and 0.3 ± 4.0 points in controls (Kruskal-Wallis test, P = .03). In the NEDICES cohort, cognitive test scores of prevalent PD cases declined at a rate above and beyond that observed in premotor PD cases and in controls. The rate of cognitive decline in premotor PD and controls was similar. Our data suggest that a decline in global cognitive function does not occur in premotor PD.

Self-Reported Dysphagia and Its Correlates Within a Prevalent Population of People with Parkinson’s Disease

Many people with Parkinson's disease (PD) experience dysphagia; however, the prevalence of dysphagia in people with PD is unknown. We studied a prevalent population of PD cases. All of those who consented to participate were assessed for anxiety, depression, cognitive function, and quality of life using standard rating scales. Anyone who answered "yes" to either one of the two questions: Do you have difficulty swallowing food/liquid or tablets? and Do you cough after eating/drinking? was considered to have dysphagia. Question 7 of the Unified Parkinson's Disease Rating Scale (UPDRS) was also used to identify dysphagia. Of 106 prevalent PD cases, 75 (38 males) patients consented to examination and assessment. The prevalence of dysphagia was 32.0% (n=24; 11 males). Using the response to UPDRS Question 7 as an indicator of the impact of swallowing problems on the patient, there were significant correlations with cognitive function, anxiety, depression, quality of life, and UPDRS-reported gait disturbance, postural instability and problems with falling. There was no correlation with disease duration, age, or gender. Almost one third of the participants reported dysphagia. There was a strong correlation between dysphagia and gross motor skills; patients reporting such problems should be screened for swallowing problems.

Care requirements of a prevalent population of people with idiopathic Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative condition in the UK. Care needs increase as the disease progresses, but there are very few published data in relation to this. the aim of this study was to elicit the care requirements for a prevalent PD population and compare these to a similarly aged background population. all people diagnosed with idiopathic PD from within a defined area of north-east England were asked to participate in this study. Those who agreed to participate were assessed using a number of standard rating scales including Hoehn and Yahr stage, Unified Parkinson's Disease Rating Scale (UPDRS), Hospital Anxiety and Depression Scale, Parkinson's Disease Questionaire-39 and Mini-Mental State Examination (MMSE). In addition, participants were asked whether they had experienced hallucinations. Social and demographic information (e.g. age, sex and place of abode) was also recorded. from all cases (n = 161), 135 people (83.8%) agreed to participate. Of these, 19 (14.1%) were living in residential or nursing homes, representing 1.6% of the total nursing/residential home residents in the study area. Participants had a mean age of 74.8 years and disease duration of 5.6 years. Those in care were significantly older and had significantly poorer Hoehn and Yahr, MMSE and UPDRS scores. PD patients in institutional care have poorer cognitive function, are older, have later stage disease and worse functional ability than those living at home.