Study on related risk factors of pain in de novo Parkinson's disease patients

Patients with autonomic neuropathy associated with Parkinson's disease often show reverse dipping pattern/nocturnal hypertension at 24-h ambulatory blood pressure (BP) monitoring (24-h ABPM) and diurnal orthostatic hypotension. The aim of the study was to evaluate cardiac alterations in Parkinson's disease patients with reverse dipping, in comparison with non-reverse dippers Parkinson's disease and essential hypertensive patients. A total of 26 consecutive Parkinson's disease patients with reverse dipping at 24-h ABPM and no previous history of hypertension were compared with 26 non-reverse Parkinson's disease patients matched for age, sex and 24-h mean BP, and 26 essential hypertensive patients matched for nighttime mean BP. None of the Parkinson's disease patients suffered from cardiovascular diseases or were treated with antihypertensive or antihypotensive drugs. Reverse dipping was defined by a systolic day-night BP difference less than 0% at 24-h ABPM. Left ventricular (LV) hypertrophy was defined by a LV mass index at least 115 g/m in men and at least 95 g/m in women. LV mass, indexed for BSA, was significantly higher in reverse dipping than non-reverse Parkinson's disease patients (respectively 90.2 ± 25.3 vs. 77.4 ± 13.3 g/m, P = 0.04), and was similar to essential hypertensive patients (91.6 ± 24.8, P = 0.92). LV hypertrophy was detected in five reverse dipping Parkinson's disease patients and four hypertensive patients, but was not present in non-reverse Parkinson's disease patients (P = 0.046). Nocturnal BP values, nocturnal BP load, weighted BP variability and age were found to correlate with the increased LV mass index. Reverse dipping and nocturnal hypertension are related to higher LV mass and increased prevalence of LV hypertrophy in Parkinson's disease patients.

Excessive daytime sleepiness is common in Parkinson's disease and has been associated with Parkinson's disease-related dementia. Narcoleptic features have been observed in Parkinson's disease patients with excessive daytime sleepiness and hypocretin cell loss has been found in the hypothalamus of Parkinson's disease patients, in association with advanced disease. However, studies on cerebrospinal fluid levels of hypocretin-1 (orexin A) in Parkinson's disease have been inconclusive. Reports of sleep studies in Parkinson's disease patients with and without excessive daytime sleepiness have also been disparate, pointing towards a variety of causes underlying excessive daytime sleepiness. In this study, we aimed to measure cerebrospinal fluid hypocretin-1 levels in Parkinson's disease patients with and without dementia and to study their relationship to dementia and clinical excessive daytime sleepiness, as well as to describe potentially related sleep architecture changes. Twenty-one Parkinson's disease patients without dementia and 20 Parkinson's disease patients with dementia, along with 22 control subjects without sleep complaints, were included. Both Epworth sleepiness scale, obtained with the help of the caregivers, and mini-mental state examination were recorded. Lumbar cerebrospinal fluid hypocretin-1 levels were measured in all individuals using a radio-immunoassay technique. Additionally, eight Parkinson's disease patients without dementia and seven Parkinson's disease patients with dementia underwent video-polysomnogram and multiple sleep latencies test. Epworth sleepiness scale scores were higher in Parkinson's disease patients without dementia and Parkinson's disease patients with dementia than controls (P < 0.01) and scores >10 were more frequent in Parkinson's disease patients with dementia than in Parkinson's disease patients without dementia (P = 0.04). Cerebrospinal fluid hypocretin-1 levels were similar among groups (controls = 321.15 +/- 47.15 pg/ml; without dementia = 300.99 +/- 58.68 pg/ml; with dementia = 309.94 +/- 65.95 pg/ml; P = 0.67), and unrelated to either epworth sleepiness scale or mini-mental state examination. Dominant occipital frequency awake was slower in Parkinson's disease patients with dementia than Parkinson's disease patients without dementia (P = 0.05). Presence of slow dominant occipital frequency and/or loss of normal non-rapid eye movement sleep architecture was more frequent among Parkinson's disease patients with dementia (P = 0.029). Thus, excessive daytime sleepiness is more frequent in Parkinson's disease patients with dementia than Parkinson's disease patients without dementia, but lumbar cerebrospinal fluid hypocretin-1 levels are normal and unrelated to severity of sleepiness or the cognitive status. Lumbar cerebrospinal fluid does not accurately reflect the hypocretin cell loss known to occur in the hypothalamus of advanced Parkinson's disease. Alternatively, mechanisms other than hypocretin cells dysfunction may be responsible for excessive daytime sleepiness and the sleep architecture alterations seen in these patients.

Resting-state fMRI in Parkinson's disease patients with cognitive impairment: A meta-analysis

Adapting to post-COVID19 research in Parkinson's disease: Lessons from a multinational experience

Objective To investigate the apathy and neuropsychological characteristics of newly diagnosed Parkinson's disease (PD) patients. Methods Eighty-two newly diagnosed PD patients and 30 matched healthy controls by age, sex and education level were recruited in the present study.Apathy was assessed using Apathy Evaluation Scale (AES) and related factors, including age, sex, education level and disease duration were simultaneously evaluated.Unified Parkinson's Disease Rating Scale (UPDRS), Hamilton Depression Rating Scale (HAMD), as well as Montreal Cognitive Assessment (MoCA) were employed in order to respectively evaluate the motor function, depression and cognition. Results The AES scores in the PD patients were significantly higher when compared to the healthy controls. The prevalence of apathy and depression in the PD patients was 51.2%(42/82) and 19.5%(16/82), respectively. There were no statistically significant differences in age, sex, education level, UPDRS-Ⅱ/Ⅲ scores and MoCA scores between apathy (n=42) and no-apathy (n=40) PD patients (P>0.05), while the statistically significant difference in HAMD scores between apathy (n=42) and no-apathy (n=40)PD patients was shown (the HAMD scores of apathy PD patients were 10.61±3.30, the HAMD scores of no-apathy PD patients were 5.96±1.90, t=7.87, P<0.05). The correlation analysis indicated that there were no correlations between AES scores and the related factors, including age, education level, disease duration and UPDRS-Ⅱ/Ⅲ scores, but AES scores were positively correlated with HAMD scores. Conclusion In newly diagnosed PD patients, the apathy is independent of depression, motor dysfunction, as well as cognitive impairment, which may be an early signal for PD. Key words: Parkinson disease; Apathy; Neuropsychological test; Newly diagnosed

The association of Parkinson's disease and cancer had recently attracted renewed interest, and results are coming from well-designed epidemiologic studies (mainly cohort studies). In particular, the findings from Danish Parkinson's disease patients (1, 2) showed that the association between Parkinson's disease and melanoma was present both before and after the diagnosis of Parkinson's disease and was not explained by levodopa treatment. The suspicion that levodopa could increase the risk of melanoma was suggested in several clinical reports, the first of which appeared soon after the drug was introduced as a new therapy for Parkinson's disease in the early 1970s. The hypothesis seemed biologically plausible, but the evidence did not support a causal relationship (3-6). On the contrary, the increased risk of melanoma in Parkinson's disease patients is now well established, although a clear biological explanation is still lacking. For other cancers, the cohort study of the Danish Parkinson's disease patients confirmed an inverse association with smoking-related cancers (standardized incidence ratio: 0.38 for lung cancer and 0.47 for larynx cancer). This inverse association was first seen in 1966 by Hammond (7) and in 1976 by Doll and Peto (8).The study of Driver et al. (9) published in this issue of Cancer Epidemiology Biomarkers &amp; Prevention has the merit of reinforcing the evidence of an association between Parkinson's disease and melanoma in a prospective study with good control of confounding (and modifying) factors. A possible confounder of the association between melanoma and Parkinson's disease is social class, as melanoma and Parkinson's disease seem to be more frequent in higher socioeconomic status individuals with more opportunities for recreational (and thus intermittent) sun exposure. In contrast, this study clearly showed that socioeconomic factors could not be indicted as responsible for the association. Indeed, the “matching” for social class was elegantly done, recruiting both Parkinson's disease cases and controls from the Physician's Health Study cohort; the excess risk for melanoma remained.Nonetheless, the findings of this study raise a even more intriguing question. First, this study confirmed the decreased risk of cancers other than melanoma and, in particular, of smoking-related cancers, previously observed not only in Parkinson's disease patients (1, 2, 10) but also in those with other neurological diseases (11). Future studies should concentrate on an appropriately powered search for possible genetic factors that predispose to Parkinson's disease, but decrease cancer risk, perhaps via an increased tendency to apoptosis. This approach will be facilitated by the nature of Parkinson's disease, a disease with good survival, high incidence in western countries, and frequently affecting patients of upper socioeconomic status with a good compliance to follow-up, thus allowing cohort and nested case-control designs to provide sufficient power. However, second and more surprisingly, this study also showed that smokers among Parkinson's disease patients had fewer tobacco-related cancers than smokers in the reference group.Thus, there is an intriguing picture of fewer smokers among Parkinson's disease patients and even fewer tobacco-related cancers among Parkinson's disease patients who smoked. Although the first inverse association was already known, this second finding is completely new and suggests a gene-environment interaction. The authors hypothesized a role for CYP2D6 with a less efficient polymorphism among the Parkinson's disease patients, leading to poor toxin metabolism and to a decreased activation of pro-carcinogens present in tobacco smoke. Other factors could be involved, including other P450 enzymes or genes involved in the DNA excision-repair pathway. Certainly, further studies will help us to understand the biologic mechanisms.It is, therefore, time for a gene-environment study of melanoma and other cancers, measuring candidate genes (or a genome-wide scan) in the setting of a study with validated histories of sun exposure and tobacco smoking. Meanwhile, the study by Driver et al. itself, as further person-years accumulate, should be able to better estimate the risk of each type of cancer among Parkinson's disease patients.

Blood biomarkers associated with cognitive decline in early stage and drug-naive Parkinson's disease patients

Parkinson's disease (PD) patients have higher mortality than individuals without PD. However, most of the previous studies were based on prevalent cases and few examined the potential effects of duration and smoking on the survival of PD patients. We compared the survival experience of 288 men with incident PD diagnosed between 1986 and 2000 with that of 51,012 men free of PD in the Health Professionals Follow-up Study. As of January 2002, 92 deaths occurred among PD cases and 8,485 among men without PD. After controlling for age, men with PD had 60% higher mortality than those without PD (95% CI: 1.3-2.0). PD mortality was strongly related to disease duration: compared with men without PD, the age-adjusted relative risk for PD patients was 1.1 during the first 5 years from diagnosis, 2.3 from 5 to 10 years, and 3.5 after 10 years (P < 0.0001 for trend). As expected, cigarette smoking was strongly and positively associated with total mortality among men free of PD (comparing >30 pack-years vs. never smokers, relative risk, 2.0; P < 0.0001 for trend), but this association was not observed among PD patients (RR: 1.0; P = 0.95 for trend). This study confirms that PD patients have a higher mortality than individuals without PD and that the excess mortality increases with disease duration. However, smoking seems to impose little additional risk among PD patients in this large cohort of health professionals.

Parkinson's disease (PD) is a neurodegenerative pathology characterized by the degeneration of midbrain dopamine neurons, whose development and maintenance in brain is related to the transcription factor NR4A2 (also called Nurr1). Notably, NR4A2 is a neuroprotective agent with anti-inflammatory role in microglia and astrocytes. Furthermore, mutations in NR4A2 gene are associated to the familial form of PD, and its gene expression level is down-regulated in blood obtained from PD patients. NR4A2 belongs to the NR4A subfamily consisting of three members: NR4A1, NR4A2, and NR4A3. The NR4A subfamily shares high degree of homology in their molecular structure and cooperates in a spectrum of functions ranging from central nervous system to immune control during physiological and pathological conditions. Considering the close functional link between the member of NR4A subfamily, we performed a gene expression analysis of NR4A1, NR4A2, and NR4A3 in peripheral blood obtained from PD patients and healthy controls (HC). Then, in order to evaluate possible involvement of the NR4A subfamily in other neurodegenerative processes, we carried out the same analysis on blood obtained from Alzheimer's disease (AD) patients. A correlation between clinical features and gene expression was also evaluated. We found a marked down-regulated gene expression of the NR4A subfamily obtained from PD patients, but only a NR4A1 decrease in AD patients compared to HC. This study reports that the entire NR4A subfamily and not only NR4A2 could be systemically involved in PD suggesting that the study of these factors could be a promising approach to develop PD therapy.

Background and Aim: Parkinson’s disease's common symptoms are anxiety and depression and play a determinant role in the quality of a patient’s life. Numerous studies identified several risk factors but very few investigated the specific risk factors associated with Parkinson's disease (PD). The objective of the present study was to assess the depression and anxiety among Parkinson’s disease patients, prevalence, risk factors, and impact on life’s quality. Methodology: This cross-sectional study was conducted on 78 Parkinson’s disease patients at the department of Psychiatry &amp; Behavioral Sciences LGH Lahore, Pakistan and Div HQ hospital, Mirpur AJK in collaboration with Neurology department for the duration from 15 May 2021 to 15 November 2021. All the patients were assessed for anxiety and depression. Unified Parkinson’s Disease Rating Scale (UPDRS) and Holmes and Rahe scale were used for the evaluation of staging and severity among Parkinson’s disease patients. Clinically diagnosed Parkinson’s disease patients aged between 25 and 85 years and stages 1 to 4 on the H-Y scale were enrolled. Patients with movement disorders other than PD, atypical Parkinson's, deep brain stimulation (DBS), visual loss, and secondary Parkinsonism were excluded. Ethical approval was taken from the institutional ethical committee. Depression and anxiety impact on life quality were assessed using World Health Organization Quality of Life (WHOQOL)-BREF. Results: Of the total 78 Parkinson’s disease patients, the prevalence of depression and anxiety was 26 (33.3%) and 32 (41.03%) respectively. About 40 were male and 38 were female patients. The overall mean age was 67±5.9 years. The young population was more susceptible to anxiety and depression was significantly higher in females. The depression and anxiety overlap were in 19 (24.4%) patients. The UPDRS and H-Y scale variance accounted for depression 34.5% and anxiety 38.9%. The severity and advanced disease stage were depression independent predictors whereas younger age and severity were anxiety main predictors. Overall, anxiety and depression had adverse impacts on life quality of Parkinson’s disease patients. Conclusion: Depression and anxiety were found in 33.3% and 41.03% of current Parkinson's disease patients, respectively. Depression and anxiety are relatively common in Parkinson's disease. The main risk factors for developing depression were female gender, low socioeconomic status, and a history of depression. Anxiety was associated with a young age and a history of anxiety. Both had a negative effect on one's quality of life. Keywords: Depression, Anxiety, Risk factors, Prevalence

MicroRNAs are reportedly involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease and multiple system atrophy. We previously identified 7 differentially expressed microRNAs in Parkinson's disease patients and control sera (miR-30c, miR-31, miR-141, miR-146b-5p, miR-181c, miR-214, and miR-193a-3p). To investigate the expression levels of the 7 serum microRNAs in Parkinson's disease and multiple system atrophy, 23 early Parkinson's disease patients (who did not take any anti- Parkinson's disease drugs), 23 multiple system atrophy patients, and 24 normal controls were recruited at outpatient visits in this study. The expression levels of the 7 microRNAs in serum were detected using quantitative real-time polymerase chain reaction. A receiver operating characteristic curve was used to evaluate whether microRNAs can differentially diagnose Parkinson's disease and multiple system atrophy. Clinical scales were used to analyze the correlations between serum microRNAs and clinical features. The results indicated that miR-214 could distinguish Parkinson's disease from the controls, and another 3 microRNAs could differentiate multiple system atrophy from the controls (miR-141, miR-193a-3p, and miR-30c). The expression of miR-31, miR-141, miR-181c, miR-193a-3p, and miR-214 were lower in multiple system atrophy than in Parkinson's disease (all P < 0.05). Combinations of microRNAs accurately discriminated Parkinson's disease from multiple system atrophy (area under the receiver operating characteristic curve = 0.951). For the correlation analysis, negative correlations were discovered between the expression of miR-214 and the Hamilton Anxiety Scale and Parkinson's Disease Non-Motor Symptom scores (all P < 0.05). Our results demonstrate that the distinctive characteristics of microRNAs differentiate Parkinson's disease and multiple system atrophy patients from healthy controls and may be used for the early diagnosis of Parkinson's disease and multiple system atrophy.

Parkinson's Disease and development of levodopa induced motor complications: Influence of baseline features and first medical approach

Objective: Parkinson's disease (PD) patients are known to suffer from pain, anxiety, and depression, but the exact degree of association between the two is unknown. As many PD patients also suffer from physical impairments, this cross-sectional case-control study sets out to compare and determine the case-ness of pain, anxiety and depression in PD patients that suffer with or without symptomatic osteoarthritis (OA). The goal of this study, therefore, was to observe if additional pain associated with comorbid OA in PD patients is correlated with greater depression and anxiety rates. The importance of understanding the burden of pain and increased depression severity of PD and OA patients is so that they may be screened appropriately based on the symptoms, which may increase their overall quality of life.Methods:This cross-sectional case-control study included 3 groups of 34 patients and 78 healthy age and gender-matched control participants. PD patients with symptomatic OA (PD+OA), PD patients without symptomatic OA (PD), patients with symptomatic OA but no PD (OA), and healthy control participants (Control). A PD patient group with Restless Legs Syndrome (PD+RLS) of 27 patients was also included. All participants completed questionnaires to assess for pain, depression, and anxiety.Results:PD+OA and PD patients had worsened depression severity and were more likely to report anxiety and depression case-ness than OA patients. PD+OA patients were more likely to complain about paresthestic and akasthisic pain, but less likely to complain about aching pain compared to PD patients and OA patients. PD+OA patients were more likely to have greater pain severity, and were more likely to report radiating and sharp pain than PD+RLS patients. PD+OA patients were also more likely to report higher depression case-ness than PD+RLS patients.Conclusion:PD with OA seems to be linked with specific pain characteristics (akathisia and paraesthesia) as well as heightened overall pain severity and pain interference in comparison to OA alone, PD alone and PD with RLS. PD is also correlated with depression severity and anxiety case-ness in OA when compared to the OA alone, PD alone and PD with RLS.

Background: Palliative care in Parkinson's Disease (PD) patients considerably differs from palliative care in oncology patients. Integrated care models are a concept to support patients and improve management of PD symptoms. However, it is not known if the access to PD patients at the end of life can be achieved through integrated care models.Aim: To analyze an integrated model of care for PD patients with the aim to identify if this integrated model of care has access to PD patients at the end of life.Material and Methods: The Cologne Parkinson's network was designed as a randomized, controlled prospective clinical trial in order to increase quality of life of PD patients. This innovative model of care integrated a neurologist in private practice, a movement disorder specialist of the University Hospital and a PD nurse. Mortality rates of PD patients during the study period of 6 months were registered and compared with mortality rates of the general population of Germany according to the Federal Statistical Office of Germany. The retrospective post-hoc analysis was conducted after completion of the initial study at the University Hospital and neurologists' practices in the greater area of Cologne, Germany. Eligible patients had a diagnosis of idiopathic PD and were aged 25–85 years.Results: Parkinson's Disease patients in this trial had an even slightly lower mortality rate as the general population (1.66 v. 2.1%). These results are contradictory and speak for a substantial proportion of late-stage disease patients, who have not been adequately included in this study or have been better treated within this trial. The mean disease duration of patients in this study was around 6 years which resembles the lower range of the mean disease duration at death of PD patients in general.Conclusions: The results of our post-hoc analysis show, that accessing PD patients in the last phase of their disease is extremely difficult and nearly fails in spite of an integrated care approach. Reasons for poor access and loss of follow-up at the end of life have to be identified and care models for PD patients until the end of life should be developed urgently.

The mechanism underlying the motor fluctuations that develop after long-term L-dopa therapy is not fully known. It has been speculated that malabsorption of L-dopa from the small intestine occurs. It was reported that gastric retention in Parkinson's disease (PD) patients with motor fluctuations is increased as compared with that in PD without fluctuations. Because L-dopa therapy may worsen the symptoms of delayed gastric emptying (GE), it was not clear whether the delayed GE of PD patients with motor fluctuation was affected by L-dopa therapy. We assessed GE in PD patients with and without motor fluctuations. We investigated GE in 40 patients with PD under long-term L-dopa therapy, 20 fluctuators with "delayed-on" and "noon" phenomena, 20 nonfluctuators, and 20 healthy volunteers. GE was examined by the 13C-acetate breath test ((13)CABT) [the half emptying time (HET), the peak time of the (13)C-%-dose-excess curve (T(max))], with expirations collected for 4 h after a test meal and analyzed for (13)CO(2) using an infrared (IR) spectrophotometer. The T(max) of GE as assessed using the (13)C-ABT was significantly delayed in all PD patients as compared with controls (P = 0.002). The HET was significantly delayed in all PD patients as compared with controls (P < 0.001). The T(max) and HET were not significantly delayed in PD patients with motor fluctuations as compared with PD patients without motor fluctuations. These results demonstrated that GE is commonly delayed in PD patients with long-term L-dopa therapy. Delayed GE does not differ between PD patients with and without motor fluctuations. This finding demonstrated that the motor fluctuation in PD may not be influenced by GE.