Journal of Parkinson's disease最新文献

Background: Mutations in GBA1, which encodes the lysosome enzyme β-glucocerebrosidase (also referred to as acid β-glucosidase or GCase), are the most common genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Evidence also suggests that loss of GCase activity is implicated in PD without GBA1 mutations. Consequently, therapies targeting GCase are actively being pursued as potential strategies to modify the progression of PD and related synucleinopathies. Despite this significant interest in GCase as a therapeutic target, the lack of well-characterized GCase antibodies continues to impede progress in the development of GCase-targeted therapies.

Objective: This study aims to independently evaluate human GCase (hGCase) antibodies to provide recommendations for western blot, immunofluorescence, immunoprecipitation, and AlphaLISA (Amplified Luminescent Proximity Homogeneous Assay) assays.

Methods: Two mouse monoclonal antibodies, hGCase-1/17 and hGCase-1/23, were raised against hGCase using imiglucerase, the recombinant enzyme developed to treat patients, as the antigen. These novel antibodies, alongside commonly used antibodies in the field, underwent evaluation in a variety of assays.

Results: The characterization of hGCase-1/17 and hGCase-1/23 using genetic models including GBA1 loss-of-function human neuroglioma H4 line and neurons differentiated from human embryonic stem cells revealed their remarkable specificity and potency in immunofluorescence and immunoprecipitation assays. Furthermore, a hGCase AlphaLISA assay with excellent sensitivity, a broad dynamic range, and suitability for high throughput applications was developed using hGCase-1/17 and hGCase-1/23, which enabled a sandwich assay configuration.

Conclusions: The hGCase immunofluorescence, immunoprecipitation, and AlphaLISA assays utilizing hGCase-1/17 and hGCase-1/23 will not only facilitate improved investigations of hGCase biology, but can also serve as tools to assess the distribution and effectiveness of GCase-targeted therapies for PD and related synucleinopathies.

Psychological stress, a state of mental strain caused by mentally or physically threatening situations, plays a significant role in Parkinson's disease (PD). Motor symptoms worsen during acute stress and common non-motor symptoms in PD, such as anxiety and depression, are linked to chronic stress. Although evidence in humans is lacking, animal models of PD suggest that chronic stress can accelerate dopaminergic cell death. This suggests that stress-reducing interventions have not only symptomatic, but perhaps also disease-modifying effects. Our objective was to identify the most promising strategies for stress-reduction in PD and to analyze their potential value for disease-modification. An unstructured literature search was performed, primarily focusing on papers published between 2020-2023. Several large clinical trials have tested the efficacy of aerobic exercise and mindfulness-based interventions on PD symptoms. The evidence is promising, but not definitive yet: some exercise trials found a reduction in stress-related symptoms, whereas others did not or did not report it. In the majority of trials, biological measures of stress and of disease progression are missing. Furthermore, follow-up periods were generally too short to measure disease-modifying effects. Hence, mechanisms underlying the intervention effects remain largely unclear. These effects may consist of attenuating progressive neurodegeneration (measured with MRI-markers of substantia nigra integrity or cortical thickness), or a strengthening of compensatory cerebral mechanisms (measured with functional neuroimaging), or both. Lifestyle interventions are effective for alleviating stress-related symptoms in PD. They hold potential for exerting disease-modifying effects, but new evidence in humans is necessary to fulfill that promise.

Background: Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) has emerged as a potent treatment for alleviating motor symptoms in Parkinson's disease (PD). Despite its effectiveness, the impact of high frequency STN-DBS on cerebellar oscillations remains unclear, posing an intriguing challenge for neural modulation. Given the direct and indirect connections between the STN and cerebellum, we investigated whether STN-DBS affects cerebellar oscillations.

Objective: To observe the effects of STN-DBS on cerebellar oscillations in patients with PD.

Methods: We recruited 15 PD patients receiving STN-DBS. Electroencephalographic (EEG) signals were recorded from cerebellar regions during resting-state conditions in both the OFF-DBS and STN-DBS conditions. Our analyses centered on spectral features, particularly theta and beta oscillations, guided by prior research and correlation tests to investigate the relationship between oscillatory changes and motor symptom severity.

Results: In the mid-cerebellar (Cbz) region, we observed a significant increase in the relative power in all frequency bands, including theta and beta oscillations during STN-DBS, showing the global effect of DBS. Importantly, the correlation results indicated significant associations between mid-cerebellar (Cbz) beta power during the OFF condition and motor severity, which were not evident during STN-DBS. Interestingly, correlations between beta power and motor severity were not observed at the mid-occipital (Oz) and mid-frontal (Cz) regions. Notably, signal similarity analyses demonstrated no evidence of volume conduction effects between the mid-cerebellar (Cbz) and nearby mid-occipital (Oz) regions.

Conclusions: While these findings provide valuable insights into the complex interplay between STN-DBS and neural oscillations, further research is essential to decipher their precise functional significance and clinical implications. Understanding these intricacies may contribute to the optimization of DBS therapies for PD.

Background: Pain fluctuations are a characteristic phenomenon in advanced Parkinson's disease (PD), but their temporal association with motor and non-motor symptom (NMS) fluctuations remains largely enigmatic. Moreover, data on their importance for disease severity perception and health-related quality-of-life (hr-QoL) is limited.

Objective: To dissect pain fluctuations with respect to pain type and frequency patterns, and their association with motor and non-motor fluctuations.

Methods: Prospective observational cohort study in advanced PD assessing symptom fluctuations by simultaneous hourly ratings using the PD Home diary (Off, On, Dyskinetic state), a pain diary (assessing 9 pain types) and a non-motor diary (10 key NMS) based on validated instruments.

Results: Forty-seven out of 55 eligible participants with fluctuating PD (51% men, median age 65, median disease duration 10 years) had sufficient datasets (>95% of hours) from 2 consecutive days. Pain was reported in 35% of waking hours with clear circadian rhythm peaking in early morning Off periods and clustering during motor Off state (49% of Off state hours with pain). Main NMS co-fluctuating with pain were "Fatigue" and "Inner Restlessness". Simultaneous assessment of global disease severity by participants revealed that pain was associated with worse disease severity only in motor On and Dyskinetic state but not in Off state, which translated into significant correlations of daily pain times with hr-QoL only during motor On and Dyskinetic state.

Conclusions: Aside from treating motor Off periods, specific recognition of pain particularly during motor On and Dyskinetic state comprises an important aspect for disease management in advanced PD.

Background: Given the growing evidence for an environmental contribution to the etiology of Parkinson's disease (PD), searching for local and regional differences in PD prevalence in multiple areas across the world may further clarify the role of environmental toxins.

Objective: To provide local and regional prevalence estimates of PD in Poland.

Methods: We analyzed the prevalence of PD and its trend over the last decade (2010 to 2019) based on data from the National Health Fund in Poland. We specifically examined sex differences in PD prevalence, as well as differences across Polish regions.

Results: During the above period, the prevalence of PD in Poland increased from 226 per 100,000 to 269 per 100,000 inhabitants. Unexpectedly, we found that PD was 1.2-times more common in women than men. The increase in prevalence over the past decade was different between both sexes: an increase from 250 to 283 per 100,000 for women (13.3% increase), and from 200 to 254 per 100,000 for men (27.1% increase). In addition, we observed differences in prevalence across different Polish regions, with some regions having up to 51% lower prevalence rates than others.

Conclusions: The prevalence of PD in Poland is in line with previously reported prevalence rates across Europe. However, unlike the situation in most of the world, PD was more prevalent in women than men. We discuss several possible explanations as well as potential measures that might help to reduce the growth of PD.

Background: Autonomic dysfunction precedes endothelial dysfunction in Parkinson's disease (PD) and causes blood pressure and circulation abnormalities that are highly disruptive to one's quality of life. While exercise interventions have proven helpful for motor symptoms of PD, improving associated non-motor symptoms is limited. Low-intensity resistance training with blood flow restriction (LIRT-BFR) improves autonomic dysfunction in non-PD patients and high-intensity resistance training (HIRT) is recommended for motor symptom improvements for people with PD (PwPD).

Objective: To determine the effects of LIRT-BFR and HIRT on homocysteine and autonomic and endothelial function in PwPD and to determine the hemodynamic loads during LIRT-BFR and HIRT in PwPD using a novel exercise protocol.

Methods: Thirty-eight PwPD were assigned LIRT-BFR, HIRT or to a control (CNTRL) group. The LIRT-BFR and HIRT groups exercised three days per week for four weeks. The LIRT-BFR protocol used 60% limb occlusion pressure (LOP) and performed three sets of 20 repetitions at 20% of the one-repetition maximum (1RM). The HIRT group performed three sets of eight repetitions at 80% 1RM. The CNTRL group was asked to continue their normal daily routines.

Results: LIRT-BFR significantly improved orthostatic hypotension (p = 0.026), homocysteine levels (p < 0.001), peripheral circulation (p = 0.003), supine blood pressure (p = 0.028) and heart rate variability (p = 0.041); LIRT-BFR improved homocysteine levels (p < 0.018), peripheral circulation (p = 0.005), supine blood pressure (p = 0.007) and heart rate variability (p = 0.047) more than HIRT; and hemodynamic loads for LIRT-BFR and HIRT were similar.

Conclusions: LIRT-BFR may be more effective than HIRT for autonomic and endothelial function improvements in PwPD and hemodynamic loads may be lessened in LIRT-BFR protocols using single-joint exercises with intermittent blood flow restriction. Further research is needed to determine if non-motor symptoms improve over time and if results are sustainable.

Deep brain stimulation (DBS) is an advanced treatment in Parkinson's disease. We describe a 71-year-old patient in whom the DBS got infected with Mycobacterium bovis shortly after intravesical BCG instillations as an adjuvant treatment of bladder cancer. The DBS internal pulse generator and extension wires had to be replaced, and the patient was treated successfully with rifampicin, isoniazid, and ethambutol during three months. This case suggests that physicians need to be aware of the risk of this kind of infection and add a specific Mycobacterial test to the regular cultures.

Background: Parkinson's disease (PD) is characterized by striatal dopamine deficiency. Since dopamine cannot cross the digestive and blood-brain barriers, its precursor, levodopa (L-DOPA), remains the mainstay of treatment. However, the significant pharmacokinetic (Pk) and pharmacodynamic (Pd) limitations of L-DOPA, combined with the severity of PD, may trigger motor and non-motor complications, for which continuous dopaminergic delivery therapies have been developed.

Objective: The aim of this study was to review the literature on the Pk/Pd limitations of L-DOPA and how current treatments of continuous dopaminergic administration ameliorate these problems, in order to identify the need for new therapeutic avenues.

Methods: A comprehensive literature search was carried out using PubMed and 75 articles were initially extracted. Following independent screening by two reviewers and consideration of eligibility, 10 articles were chosen for further analysis. Information concerning the Pk/Pd of L-DOPA was classified for each article.

Results: Pk/Pd problems notably include: (i) restricted digestive and cerebral absorption; (ii) unnecessary peripheral distribution; (iii) short half-life; (iv) age- and PD-induced decline of central aromatic L-amino acid decarboxylase; (v) misdistribution in many cells; and (vii) pulsatile stimulation of dopaminergic receptors. Current treatments only slightly ameliorate some of these problems.

Conclusions: Many Pk/Pd constraints are not resolved by existing continuous dopaminergic delivery therapies. This highlights the significant gap between these treatments and the ideal of continuous dopaminergic stimulation.

Background: People with Parkinson's disease (PwPD) exhibit various sexual difficulties (SDs) that may be due to motor and/or nonmotor symptoms or the use of antiparkinsonian medication. SDs are often underreported by PwPD and underexplored by physicians.

Objective: This study aimed to explore the SDs experienced by PwPD and create a scale for assessing them.

Methods: A corpus of items was generated from semistructured interviews to represent the experience of PwPD as closely as possible. The number of items was reduced according to the psychometric properties, and the scale's structure was subsequently examined. The final phase consisted of measuring the scale's validity and reliability.

Results: After assessment of the original corpus of 59 items by PwPD and clinicians, a 25-item version was obtained. The analysis of item properties led to the removal of fifteen items. An exploratory factor analysis of the first 10-item version with a first PwPD sample identified four components of the SDs among PwPD: "low sexual esteem," "sexual displeasure," "impact on sexual position" and "hypersexuality." With a second PwPD sample, a confirmatory factor analysis demonstrated a satisfactory fit between the model with four components and the data. The 10-item scale had good internal consistency and good temporal reliability.

Conclusions: The Parkinson's Disease Sexual Difficulties Scale (PD-SDS) is a valid screening tool that facilitates the investigation of and communication about PD-related SDs. It is intended to improve the identification of vulnerable PwPD and to target the domain of sexual experience impacted by PD to better support PwPD.