Proportion Of Parkinson's Disease Patients Research Articles

The Endotoxin Hypothesis of Parkinson's Disease.

The endotoxin hypothesis of Parkinson's disease (PD) is the idea that lipopolysaccharide (LPS) endotoxins contribute to the pathogenesis of this disorder. LPS endotoxins are found in, and released from, the outer membrane of Gram-negative bacteria, for example in the gut. It is proposed that gut dysfunction in early PD leads to elevated LPS levels in the gut wall and blood, which promotes both α-synuclein aggregation in the enteric neurons and a peripheral inflammatory response. Communication to the brain via circulating LPS and cytokines in the blood and/or the gut-brain axis leads to neuroinflammation and spreading of α-synuclein pathology, exacerbating neurodegeneration in brainstem nuclei and loss of dopaminergic neurons in the substantia nigra, and manifesting in the clinical symptoms of PD. The evidence supporting this hypothesis includes: (1) gut dysfunction, permeability, and bacterial changes occur early in PD, (2) serum levels of LPS are increased in a proportion of PD patients, (3) LPS induces α-synuclein expression, aggregation, and neurotoxicity, (4) LPS causes activation of peripheral monocytes leading to inflammatory cytokine production, and (5) blood LPS causes brain inflammation and specific loss of midbrain dopaminergic neurons, mediated by microglia. If the hypothesis is correct, then treatment options might include: (1) changing the gut microbiome, (2) reducing gut permeability, (3) reducing circulating LPS levels, or (4) blocking the response of immune cells and microglia to LPS. However, the hypothesis has a number of limitations and requires further testing, in particular whether reducing LPS levels can reduce PD incidence, progression, or severity. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Work Loss and Direct and Indirect Costs Associated with Parkinson's Disease.

To examine work loss and indirect costs during the three-year periods prior to and following initial diagnosis of Parkinson's disease (PD) in patients and in spouses of PD patients, as well as direct costs of healthcare. This is a retrospective, observational cohort study using the MarketScan Commercial and Health and Productivity Management databases. A total of 286 employed PD patients and 153 employed spouses met all diagnostic and enrollment criteria for short-term disability (STD) analysis (PD Patient cohort and Caregiving Spouse cohort). The proportion of PD patients having a STD claim increased from roughly 5% and plateaued at around 12-14% starting in the year prior to first diagnosis of PD. The mean number of days lost from work due to STD per year increased from 1.4 days in the 3rd year prior to diagnosis to 8.6 days in the 3rd year after diagnosis (corresponding to an increase in indirect costs from $174 to $1104). STD use for spouses of patients with PD was lowest in the year after their spouses were diagnosed and then rose dramatically in the 2nd and 3rd years after the spouse's diagnosis. Total all-cause direct health-care costs increased during the years leading up to PD diagnosis and were highest in the years following diagnosis, with PD-related costs contributing ~20-30% of the total. PD has both a significant direct and indirect financial burden on patients and their spouses when analyzed for 3 years before and after diagnosis.

Progression of fatigue in Parkinson's disease - a 9-year follow-up.

Although highly disabling, the pathogenesis and evolution of fatigue in Parkinson's disease (PD) is largely unknown, and no sufficiently documented treatment currently exists. The aim of the present study was to investigate the evolution of fatigue during the first 9years after diagnosis. This study is part of the Norwegian ParkWest collaboration, a prospective population-based longitudinal cohort study. The present study comprised 191 newly diagnosed patients and 170 control participants. Fatigue was assessed by the Fatigue Severity Scale, with examinations at baseline and then every other year up to 9years of follow-up. Linear mixed models were applied to investigate possible variables associated with fatigue. It was found that there was a statistically significant increase in the proportion of PD patients with fatigue during the first 9years after diagnosis. A large proportion of patients had a significant increase or decrease in fatigue score between consecutive visits. In addition, the relative risk of persistent fatigue and ever having fatigue was higher than for controls. There were statistically significant longitudinal associations between higher levels of fatigue and female gender, comorbidity at baseline, depressive symptoms, dependency in activities of daily living and better cognitive functioning. Lower levels of fatigue were associated with the use of dopamine agonists. Fatigue is a common, severely limiting symptom in PD. This study demonstrates associations with other factors that could yield a better understanding of the symptom and thus possible treatment strategies, although further investigations are necessary to establish causal relationships.

Glucocerebrosidase and parkinsonism: lessons to learn.

Both homo- (causing autosomal-recessive Gaucher's disease; GD) and heterozygous mutations in the glucocerebrosidase gene (GBA) are associated with Parkinson's disease (PD), and represent the most robust known genetic susceptibility factors identified in PD. Since the accumulation of α-synuclein has been considered critical to the pathogenesis of PD among several possible pathways through which glucocerebrosidase (GCase) deficiency may promote the pathogenesis of PD, particular attention was given to the reciprocity with α-synuclein levels, lysosomal dysfunction, endoplasmatic reticulum-Golgi trafficking of GCase, dysregulation of calcium homeostasis and mitochondrial abnormalities. The proportion of PD patients that carry GBA mutations is estimated to be approximately between 5 and 10%. Individual PD patients with or without GBA mutations cannot be discriminated on clinical or pathological grounds. However, GBA mutation carriers may have slightly earlier age at PD onset, more likely have a positive family history for PD, and more prevalent non-motor symptoms when compared to those patients who are not carriers. Establishing the concept of GBA-related PD promoted a search for the pathogenic mechanisms through which GCase deficiency may influence pathogenesis of PD, suggesting that targeting the GCase-lysosomal pathway might be a rational approach for the development of neuroprotective drugs in PD.

Olfactory function combined with morphology distinguishes Parkinson's disease.

This study aimed to examine whether the volume of the olfactory bulbs and tracts (OB & T) on magnetic resonance imaging (MRI) is useful for differentiating Parkinson's disease (PD) from PD-related disorders. The study group comprised 13 patients with PD, 11 with multiple system atrophy (MSA), five with progressive supranuclear palsy, and five with corticobasal degeneration (PSP/CBD). All patients were evaluated using the odor stick identification test for Japanese (OSIT-J), (123)I-meta-iodobenzylguanidine (MIBG) scintigraphy, and brain MRI. OB & T areas on 1-mm-thick coronal images were measured and summed for volumes. We examined relationships between olfactory function and volume, and cardiovascular dysautonomia. We defined the cut-off values for OSIT-J score or MIBG uptake and OB & T volume to discriminate PD from PD-related disorders and calculated the proportional rate of PD in four categorized groups. OB & T volume was smaller in PD than in MSA or PSP/CBD (p < 0.05 each). The cut-off for detecting PD patients was OSIT-J score <8, heart/mediastinum ratio <1.6, and OB & T volume <270 mm(3). In the group with OSIT-J score <8 and OB & T volume <270 mm(3), the proportion of PD patients among all patients with PD-related disorders was 91%. The rate of probable PD gradually increased as OSIT-J score and OB & T volume decreased (p < 0.001). Although preliminary, these data obtained from a combined morphological and functional evaluation of OB or cardiovascular dysautonomia could be useful for further differential of PD and other PD-related disorders.

Lack of exacerbation of neurodegeneration in a double transgenic mouse model of mutant LRRK2 and tau.

LRRK2 (leucine-rich repeat kinase) mutations constitute the most common cause of familial Parkinson's disease (PD). Microtubule-associated protein tau mutations cause a group of neurodegenerative diseases termed tauopathies. Genome-wide association studies show that, after α-synuclein, polymorphisms in the tau gene have the second strongest genetic association with PD. In a proportion of PD patients with LRRK2 mutations, and in several transgenic animal models of LRRK2, tau hyperphosphorylation and aggregation, rather than α-synuclein aggregation, are the most prominent neuropathologic findings. To further examine the relationship between LRRK2 and tau, we crossed LRRK2 R1441G BAC transgenic mice (Mus musculus) with tau P301S mutant transgenic mice and characterized their behavioral, neuropathological and biochemical phenotypes. We found that the combination of the two mutations does not increase tau hyperphosphorylation or aggregation nor does it exacerbate the behavioral and pathological deficits previously described in the tau P301S mice. The double-mutant mice had no shortening of lifespan and no worsening of motor or memory deficits. There was no increase in the aggregation of tau or α-synuclein. Dopaminergic neuron cell counts and striatal levels of dopamine and its metabolites were unaltered. There was no exacerbation of cell loss, microgliosis or astrogliosis in multiple brain regions. These results suggest that LRRK2 and tau do not interact to exacerbate behavioral, biochemical or pathological abnormalities in neurodegeneration and that LRRK2 and tau exert their pathogenic effects through independent mechanisms.

The associations between fatigue, apathy, and depression in Parkinson's disease.

Fatigue and apathy are two of the most common and most disabling non-motor symptoms of Parkinson's disease (PD). They have a high coincidence and can often be confused; moreover, their relationship is not fully understood. The aim of our study was to describe the coincidence of apathy with different fatigue domains in the presence/absence of depression and to separately describe the associations of different aspects of primary and secondary fatigue with apathy and other clinical and disease-related factors. A total of 151 non-demented patients with PD were examined using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Starkstein Apathy Scale, Multidimensional Fatigue Inventory (MFI), Beck Depression Inventory-II, and Epworth Sleepiness Scale. The prevalence and severity of fatigue and apathy were significantly higher in depressed PD patients. However, our results show that depression, fatigue, and apathy can be clearly distinguished in PD. Apathy was associated with the MFI's-reduced motivation domain in both depressed and non-depressed patients. However, apathy was associated with mental fatigue aspects only in non-depressed patients, and it was not related to the physical aspects of fatigue in any of the studied groups. Although the pathophysiology of fatigue and apathy in PD is clearly multifactorial, in a proportion of PD patients, these symptoms are associated with depression, dopaminergic depletion in the mesocorticolimbic structures, and disruption of the prefrontal cortex-basal ganglia axis. Therefore, in some PD patients, adequate management of depression and optimal dopaminergic medication may improve both fatigue and apathy.

The study of subjective and objective evaluation of sleep disturbances in Parkinson's disease

Background Sleep disorder is one of the most common non-motor symptoms in Parkinson's disease (PD) patients. At present, there are subjective and objective tools to evaluate sleep disorders. Nevertheless, previous studies commonly used single subjective questionnaires or objective examinations. Therefore, we used the combinations of subjective and objective tools to analyze clinical characteristics of sleep disturbances in PD and investigated differences and consistence between subjective and objective tools. Methods One hundred and sixteen PD patients were eligible to participate into this study. All participants were evaluated by Pittsburgh Sleep Quality Index (PSQI), Unified Parkinson's Disease Rating Scale (UPDRS) in on condition, Hoehn-Yahr (H-Y) stage, Hamilton Depression Rating Scale (HAMD 24 items), Montreal Cognitive Assessment (MoCA), Epworth Sleepiness Scale (ESS), and underwent a video-polysomnography (Video-PSG). Results According to PSQI score of 116 PD patients, the proportion of PD patients with sleep disturbances (PSQI ≥ 7) was 50% (N = 58). Compared to PD patients without sleep disturbances, PD patients with sleep disturbances had lower score of MoCA (23.34 ± 3.50 vs 24.89 ± 3.52; t = 2.377, P = 0.019), higher score of UPDRSⅠ[4.00 (2.00, 5.00) vs 3.00 (2.00, 5.00); U = - 2.306, P = 0.021], UPDRSⅡ[12.00 (9.00, 16.00) vs 10.00 (6.00, 13.00); U = - 1.995, P = 0.046], higher levodopa equivalent daily dose [LED, (508.14 ± 335.85) vs (394.06 ± 236.40) mg/d; t = - 2.115, P = 0.037]. Although PD patients with sleep disturbances had more score of UPDSR Ⅲ and higher H-Y stage, the differences were not significant (P > 0.05). On the other hand, decreased total sleep time (TST), reduced sleep efficiency (SE), increased sleep latency (SL), decreased non-rapid eye movement (NREM) sleep stage Ⅱ time were found for PD patients with sleep disturbances (P 0.05, for all). The score of PSQI was positively correlated with the score of ESS (r = 0.200, P = 0.032), HAMD (r = 0.202, P = 0.030), UPDRSⅠ (rs = 0.266, P = 0.004) and Ⅱ (rs = 0.254, P = 0.007), LED (r = 0.213, P = 0.022), SL (rs = 0.211, P = 0.023). Moreover, the score of PSQI was negatively correlated with TST (r = -0.231, P = 0.003), SE (r = -0.192, P = 0.039) and MoCA (r = -0.236, P = 0.011). Conclusion PD patients with sleep disturbances had worse cognition impairment, more mood disorders, decreased activity of daily life. Meanwhile, most of PSG parameters were altered in PD patients with sleep disturbances. Moreover, the severity of sleep disturbances in PD patients was correlated with these factors. Overall sleep quality of PD patients assessed with the objective tool could be predicted by the subjective scale. However, to evaluate sleep architecture and other sleep disorders for PD patients, the objective tools (such as Video-PSG monitoring) are necessary to be used.

Poor self-awareness of levodopa-induced dyskinesias in Parkinson's disease: Clinical features and mechanisms

ObjectivesTo study the factors and possible mechanisms associated with decreased self-awareness of levodopa-induced dyskinesias (LIDs) in patients with Parkinson's disease (PD). MethodsWe enrolled 30 PD patients with LIDs. Patients were video-recorded in an “on” phase while experiencing LIDs. LIDs were objectively rated by means of the Unified Dyskinesias Rating Scale (UDyRS) by two movement disorders specialists while examining the patients. Patients were asked to rate the body site and the severity of their LIDs according to the 5-point UDyRS. Patients then rated their own LIDs while watching the video recording of themselves. Lastly, the patients rated the LIDs of other reference PD patients on a video recording. The same reference video recordings were shown to 15 healthy individuals matched for age, gender and education. ResultsSeven of the 30 PD patients investigated were subjectively unaware of the presence of their LIDs. The majority of patients, however, recognized their LIDs when watching video recording of themselves. Patients displayed a specific poor self-awareness of trunk LIDs, in both the subjective evaluation and in the video recording-based subjective evaluation. By contrast PD patients correctly recognized LIDs in video recordings of reference PD patients. Poor self-awareness correlated with predominance of motor symptoms on the left body side. ConclusionsPoor self-awareness of LIDs is present in a proportion of PD patients as a form of anosognosia. The poor self-awareness of LIDs in the trunk is likely to be due to a complex interplay involving both anosognosic mechanisms and deficits in proprioceptive axial kinesthesia.

Social and clinical determinants of quality of life in Parkinson’s disease in Austria: a cohort study

Parkinson's disease (PD) is associated with a reduction of health-related quality of life (HrQoL). Demographic and clinical determinants of HrQoL in PD have been previously investigated, but less is known about its social determinants. Data on HrQoL in Austrian patients with PD are not available. The objective of this cross-sectional survey was to evaluate HrQoL of Austrian patients with PD and to provide a comprehensive analysis of its social and clinical determinants. Outpatients (n = 100) with idiopathic PD were recruited in the Department of Neurology of the University Innsbruck. Clinical status was estimated using the Unified Parkison's Disease Rating Scale (UPDRS). HrQoL was evaluated using a generic instrument, the EuroQol (EQ5D and EQ-VAS). Independent determinants of HrQoL were assessed in multivariate regression analysis. The proportion of PD patients with moderate or severe problems in at least one dimension of the EQ5D was significantly higher than in the general population (90.1 vs. 35.1%, P < 0.001). The mean EQ-VAS score in PD was lower than in the general population (48.9 +/- 19.6 vs. 77.0 +/- 20.8, P < 0.001). Social support (number of household members) was identified as an independent social determinant of HrQoL. Demographic and clinical determinants were age, depression, UPDRS and motor fluctuations. The analysis of determinants of HrQoL showed that a greater attention should be paid to social support and home care. Our data on HrQoL in PD should be considered in the development of new health care programs.

Naturalistic evaluation of entacapone in patients with signs and symptoms of L-dopa wearing-off

ABSTRACTObjective: To evaluate the effectiveness of entacapone in the management of levodopa wearing-off in Parkinson's disease (PD) in a naturalistic, real-life setting.Research design and methods: This prospective, open-label, observational study included patients with idiopathic PD. Patients were eligible for inclusion if they had been taking 3–5 doses of levodopa per day for ≥2 months and had shown signs of levodopa wearing-off for ≥1 month. Subjects received entacapone (recommended dose: 1 × 200 mg tablet with each levodopa dose) for 28 days. Patients were asked to complete a wearing-off questionnaire and the eight-question Parkinson's Disease Questionnaire Quality of Life assessment (PDQ-8). Activities of daily living (both in the on and off states) were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) part II. Clinical Global Impression (CGI) of severity of PD-related symptoms was assessed using a modified CGI tool.Patient global assessment of severity of PD symptoms was also obtained.Results: A total of 341 patients were enrolled by 68 physicians across Canada. At Day 28, 56.9% of the subjects indicated improvement compared to baseline on the modified CGI of change (CGI-C); 21.4% reported no change. Improvements were also observed on the UPDRS II and the PDQ-8. Benefit from entacapone appeared to be relatively uniform across subgroups (e.g., number of daily levodopa doses, use of other anti-PD medications).Study limitations: The results of this study may be biased due to factors inherent in open-label, community-based trials (e.g., compliance). This is, however, reflective of everyday clinical practice.Conclusions: In this naturalistic, real-life study, the addition of entacapone to levodopa therapy provided benefits in quality of life and activities of daily living for a substantial proportion of PD patients experiencing wearing-off.

Sleep disruption, daytime somnolence and ‘sleep attacks’ in Parkinson's disease: a clinical survey in PD patients and age‐matched healthy volunteers

Recent case reports of 'sleep attacks' (SA) in patients with Parkinson's disease (PD) generated concerns about drug-induced daytime somnolence in this population. However, there are nearly no comparative data on sleep and vigilance problems between PD patients and normal controls. We performed a cross-sectional survey in PD patients and age-matched controls using a structured questionnaire on PD history, treatments, co-morbidity, activities of daily living, habits, exercise, sleep pattern, driving, pre-existing nocturnal problems, daytime somnolence, episodes of SA and the circumstances in which such episodes occurred. Daytime somnolence was also measured with the Epworth Sleepiness Scale (ESS) and sleep quality with the Pittsburgh Sleep Quality Index (PSQI). 176 PD patients and 174 controls were included. The same proportion of PD patients (27%) and controls (32%) reported episodes of SA, but these were more frequent in PD patients and occurred more frequently during situations requiring attention (10.8% vs. 1.7%, p<10(-3)). More PD patients had abnormal daytime somnolence (ESS) and poor sleeping quality (PSQI). The most consistent factor associated with SA was the duration of levodopa therapy and the predictive value of an abnormal ESS score was rather poor (40.7%). Abnormal daytime somnolence and poor sleep quality at night are more frequent in PD patients than in normals. However, SA are reported in both groups, although less frequently in the normals during activities that requires attention.

Pattern of intrusions in verbal recall: Comparison of Alzheimer's disease, Parkinson's disease, and frontal lobe dementia

Although some researchers have suggested that intrusions in word list learning are more frequent in Alzheimer's disease, recent studies have shown that this might not be true. In fact, intrusions are common in many neurological degenerative diseases. The goal of the present study was to examine the types of intrusions made by three groups of patients, namely patients with Parkinson's disease (PD), Alzheimer's disease (AD), and dementia with prominent frontal lobe semiology (FD). Although PD patients learned more words (trials 1 to 5 on the RAVLT) than the two other groups, there was no significant difference in the total number of intrusions. However, significant differences between groups were observed for nonrelated intrusions, the proportion of PD patients (15.4%) being lower than the proportion of AD (45.5%) and FD (45.8%) patients with this type of intrusions. No other type of intrusions (same category, recurring, phonemic) significantly differentiated between the three groups. The proactive interference effect (PI), measured as the difference between first recall of list A and list B recall, was stronger in PD than in the two other groups, reflecting the strong positive correlation between total number of words recalled on the RAVLT and severity of the PI effect. Prior list intrusions (intrusions from list A while recalling list B items) were significantly more pronounced in FD than in the two other groups. Finally, free associations (series of intrusions related to one another but not to the target items) were observed almost exclusively in FD patients. These findings illustrate some qualitative differences between various neurological degenerative diseases. They also stress the marked similarities between AD and FD with regards to verbal learning.

Mitochondrial DNA transmission of the mitochondrial defect in Parkinson's disease.

Several groups have identified mitochondrial complex I deficiency in Parkinson's disease (PD) substantia nigra and in platelets. A search for any mitochondrial DNA (mtDNA) mutation underlying this defect has not yet produced any consistent result. We have made use of a mtDNA-less (p0) cell line to determine if the complex I deficiency follows the genomic transplantation of platelet mtDNA. From a preselected group of PD patients with low platelet complex I activity, 7 patients were used for detailed study. All 7 patients were used for mixed cybrid analysis and demonstrated a selective 25% deficiency of complex I activity. Individual clonal analysis of A549 p0/PD platelet fusion cybrids from 1 of the patients expressed combined complex I and IV deficiencies with 25% and 20% decreased activities in the PD clones, respectively. Histocytochemical, immunocytochemical, and cellular functional imaging studies of these clones showed the cells within the clones were heterogeneous with respect to cytochrome c oxidase (COX) function, COX I content, and mitochondrial respiratory chain activity. These results are in agreement with a previous study and support the proposition that an mtDNA abnormality may underlie the mitochondrial defect in at least a proportion of PD patients. This p0 technology may serve as a means to identify the subgroup of PD patients in whom an mtDNA defect may contribute to development of the disease.