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Biomolecules Jun 2024One of the biggest problems in the treatment of idiopathic Parkinson's disease is the lack of new drugs that slow its progression. L-Dopa remains the star drug in the... (Review)
Review
One of the biggest problems in the treatment of idiopathic Parkinson's disease is the lack of new drugs that slow its progression. L-Dopa remains the star drug in the treatment of this disease, although it induces severe side effects. The failure of clinical studies with new drugs depends on the use of preclinical models based on neurotoxins that do not represent what happens in the disease since they induce rapid and expansive neurodegeneration. We have recently proposed a single-neuron degeneration model for idiopathic Parkinson's disease that requires years to accumulate enough lost neurons for the onset of motor symptoms. This single-neuron degeneration model is based on the excessive formation of aminochrome during neuromelanin synthesis that surpass the neuroprotective action of the enzymes DT-diaphorase and glutathione transferase M2-2, which prevent the neurotoxic effects of aminochrome. Although the neurotoxic effects of aminochrome do not have an expansive effect, a stereotaxic injection of this endogenous neurotoxin cannot be used to generate a preclinical model in an animal. Therefore, the aim of this review is to evaluate the strategies for pharmacologically increasing the expression of DT diaphorase and GSTM2-2 and molecules that induce the expression of vesicular monoamine transporter 2, such as pramipexole.
Topics: Humans; Parkinson Disease; Animals; Neurons; Nerve Degeneration; Glutathione Transferase; Neuroprotective Agents; Disease Models, Animal; Antiparkinson Agents
PubMed: 38927076
DOI: 10.3390/biom14060673 -
Biomolecules May 2024The primary nucleation process of α-synuclein (AS) that forms toxic oligomeric species is the early stage of the pathological cause of Parkinson's disease. It is...
The primary nucleation process of α-synuclein (AS) that forms toxic oligomeric species is the early stage of the pathological cause of Parkinson's disease. It is well-known that copper influences this primary nucleation process. While significant efforts have been made to solve the structures of polymorphic AS fibrils, the structures of AS oligomers and the copper-bound AS oligomers at the molecular level and the effect of copper concentrations on the primary nucleation are elusive. Here, we propose and demonstrate new molecular mechanism pathways of primary nucleation of AS that are tuned by distinct copper concentrations and by a specific copper-binding site. We present the polymorphic AS dimers bound to different copper-binding sites at the atomic resolution in high- and low-copper concentrations, using extensive molecular dynamics simulations. Our results show the complexity of the primary nucleation pathways that rely on the copper concentrations and the copper binding site. From a broader perspective, our study proposes a new strategy to control the primary nucleation of other toxic amyloid oligomers in other neurodegenerative diseases.
Topics: alpha-Synuclein; Copper; Binding Sites; Molecular Dynamics Simulation; Humans; Protein Multimerization; Protein Binding; Parkinson Disease
PubMed: 38927031
DOI: 10.3390/biom14060627 -
Journal of Neuroengineering and... Jun 2024People with Parkinson's Disease (PD) show abnormal gait patterns compromising their independence and quality of life. Among all gait alterations due to PD, reduced step...
INTRODUCTION
People with Parkinson's Disease (PD) show abnormal gait patterns compromising their independence and quality of life. Among all gait alterations due to PD, reduced step length, increased cadence, and decreased ground-reaction force during the loading response and push-off phases are the most common. Wearable biofeedback technologies offer the possibility to provide correlated single or multi-modal stimuli associated with specific gait events or gait performance, hence promoting subjects' awareness of their gait disturbances. Moreover, the portability and applicability in clinical and home settings for gait rehabilitation increase the efficiency in the management of PD. The Wearable Vibrotactile Bidirectional Interface (BI) is a biofeedback device designed to extract gait features in real-time and deliver a customized vibrotactile stimulus at the waist of PD subjects synchronously with specific gait phases. The aims of this study were to measure the effect of the BI on gait parameters usually compromised by the typical bradykinetic gait and to assess its usability and safety in clinical practice.
METHODS
In this case series, seven subjects (age: 70.4 ± 8.1 years; H&Y: 2.7 ± 0.3) used the BI and performed a test on a 10-meter walkway (10mWT) and a two-minute walk test (2MWT) as pre-training (Pre-trn) and post-training (Post-trn) assessments. Gait tests were executed in random order with (Bf) and without (No-Bf) the activation of the biofeedback stimulus. All subjects performed three training sessions of 40 min to familiarize themselves with the BI during walking activities. A descriptive analysis of gait parameters (i.e., gait speed, step length, cadence, walking distance, double-support phase) was carried out. The 2-sided Wilcoxon sign-test was used to assess differences between Bf and No-Bf assessments (p < 0.05).
RESULTS
After training subjects improved gait speed (Pre-trn_No-Bf: 0.72(0.59,0.72) m/sec; Post-trn_Bf: 0.95(0.69,0.98) m/sec; p = 0.043) and step length (Pre-trn_No-Bf: 0.87(0.81,0.96) meters; Post-trn_Bf: 1.05(0.96,1.14) meters; p = 0.023) using the biofeedback during the 10mWT. Similarly, subjects' walking distance improved (Pre-trn_No-Bf: 97.5 (80.3,110.8) meters; Post-trn_Bf: 118.5(99.3,129.3) meters; p = 0.028) and the duration of the double-support phase decreased (Pre-trn_No-Bf: 29.7(26.8,31.7) %; Post-trn_Bf: 27.2(24.6,28.7) %; p = 0.018) during the 2MWT. An immediate effect of the BI was detected in cadence (Pre-trn_No-Bf: 108(103.8,116.7) step/min; Pre-trn_Bf: 101.4(96.3,111.4) step/min; p = 0.028) at Pre-trn, and in walking distance at Post-trn (Post-trn_No-Bf: 112.5(97.5,124.5) meters; Post-trn_Bf: 118.5(99.3,129.3) meters; p = 0.043). SUS scores were 77.5 in five subjects and 80.3 in two subjects. In terms of safety, all subjects completed the protocol without any adverse events.
CONCLUSION
The BI seems to be usable and safe for PD users. Temporal gait parameters have been measured during clinical walking tests providing detailed outcomes. A short period of training with the BI suggests improvements in the gait patterns of people with PD. This research serves as preliminary support for future integration of the BI as an instrument for clinical assessment and rehabilitation in people with PD, both in hospital and remote environments.
TRIAL REGISTRATION
The study protocol was registered (DGDMF.VI/P/I.5.i.m.2/2019/1297) and approved by the General Directorate of Medical Devices and Pharmaceutical Service of the Italian Ministry of Health and by the ethics committee of the Lombardy region (Milan, Italy).
Topics: Humans; Parkinson Disease; Aged; Male; Wearable Electronic Devices; Biofeedback, Psychology; Female; Gait Disorders, Neurologic; Middle Aged; Gait
PubMed: 38926876
DOI: 10.1186/s12984-024-01403-z -
BMC Surgery Jun 2024Lumbar degenerative conditions are a major cause of back pain and disability in individuals aged 45 and above. Gait analysis utilizes sensor technology to collect...
BACKGROUND
Lumbar degenerative conditions are a major cause of back pain and disability in individuals aged 45 and above. Gait analysis utilizes sensor technology to collect movement data, aiding in the evaluation of various gait aspects like spatiotemporal parameters, joint angles, neuromuscular activity, and joint forces. It is widely used in conditions such as cerebral palsy and knee osteoarthritis. This research aims to assess the effectiveness of 3D gait analysis in evaluating surgical outcomes and postoperative rehabilitation for lumbar degenerative disorders.
METHODS
A prospective self-controlled before-after study (n = 85) carried out at our Hospital (Sep 2018 - Dec 2021) utilized a 3D motion analysis system to analyze gait in patients with lumbar degenerative diseases. The study focused on the multifidus muscle, a crucial spinal muscle, during a minimally invasive lumbar interbody fusion surgery conducted by Shandong Weigao Pharmaceutical Co., Ltd. Pre- and postoperative assessments included time-distance parameters (gait speed, stride frequency, stride length, stance phase), hip flexion angle, and stride angle. Changes in 3D gait parameters post-surgery and during rehabilitation were examined. Pearson correlation coefficient was employed to assess relationships with the visual analog pain scale (VAS), Oswestry Disability Index (ODI), and Japanese Orthopedic Association (JOA) scores. Patient sagittal alignment was evaluated using "Surgimap" software from two types of lateral radiographs to obtain parameters like pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), lumbar lordosis (LL), intervertebral space height (DH), posterior height of the intervertebral space (PDH) at the operative segment, and anterior height of the intervertebral space (ADH).
RESULTS
By the 6th week post-operation, significant improvements were observed in the VAS score, JOA score, and ODI score of the patients compared to preoperative values (P < 0.05), along with notable enhancements in 3D gait quantification parameters (P < 0.05). Pearson correlation analysis revealed a significant positive correlation between improvements in 3D gait quantification parameters and VAS score, JOA score, and ODI value (all P < 0.001).
CONCLUSION
3D gait analysis is a valuable tool for evaluating the efficacy of surgery and rehabilitation training in patients.
Topics: Humans; Male; Gait Analysis; Female; Middle Aged; Prospective Studies; Lumbar Vertebrae; Spinal Fusion; Aged; Treatment Outcome; Imaging, Three-Dimensional; Intervertebral Disc Degeneration; Pain Measurement; Disability Evaluation
PubMed: 38926745
DOI: 10.1186/s12893-024-02486-0 -
Scientific Reports Jun 2024Visual hallucinations in Lewy body disease (LBD) can be differentiated based on phenomenology into minor phenomena (MVH) and complex hallucinations (CVH). MVH include a...
Visual hallucinations in Lewy body disease (LBD) can be differentiated based on phenomenology into minor phenomena (MVH) and complex hallucinations (CVH). MVH include a variety of phenomena, such as illusions, presence and passage hallucinations occurring at early stages of LBD. The neural mechanisms of visual hallucinations are largely unknown. The hodotopic model posits that the hallucination state is due to abnormal activity in specialized visual areas, that occurs in the context of wider network connectivity alterations and that phenomenology of VH, including content and temporal characteristics, may help identify brain regions underpinning these phenomena. Here we investigated both the topological and hodological neural basis of visual hallucinations integrating grey and white matter imaging analyses. We studied LBD patients with VH and age matched healthy controls (HC). VH were assessed using a North-East-Visual-Hallucinations-Interview that captures phenomenological detail. Then we applied voxel-based morphometry and tract based spatial statistics approaches to identify grey and white matter changes. First, we compared LBD patients and HC. We found a reduced grey matter volume and a widespread damage of white tracts in LBD compared to HC. Then we tested the association between CVH and MVH and grey and white matter indices. We found that CVH duration was associated with decreased grey matter volume in the fusiform gyrus suggesting that LBD neurodegeneration-related abnormal activity in this area is responsible for CVH. An unexpected finding was that MVH severity was associated with a greater integrity of white matter tracts, specifically those connecting dorsal, ventral attention networks and visual areas. Our results suggest that networks underlying MVH need to be partly intact and functional for MVH experiences to occur, while CVH occur when cortical areas are damaged. The findings support the hodotopic view and the hypothesis that MVH and CVH relate to different neural mechanisms, with wider implications for the treatment of these symptoms in a clinical context.
Topics: Humans; Hallucinations; Lewy Body Disease; Gray Matter; Female; White Matter; Male; Aged; Magnetic Resonance Imaging; Aged, 80 and over; Case-Control Studies; Middle Aged
PubMed: 38926597
DOI: 10.1038/s41598-024-65536-w -
Health Expectations : An International... Jun 2024Nonmotor symptoms (NMSs) are frequently experienced by people with Parkinson's disease (PD) and are often perceived as their most bothersome symptoms. However, these...
BACKGROUND
Nonmotor symptoms (NMSs) are frequently experienced by people with Parkinson's disease (PD) and are often perceived as their most bothersome symptoms. However, these remain poorly understood with suboptimal clinical management. These unmet needs are an important determinant of health-related quality of life (QoL) in PD.
OBJECTIVE
The aim of this study was to gain insights into the experience of living with the NMS of PD in real-time using participatory action methodology.
METHOD
Using the photovoice method, 14 people with PD took photographs to document their experiences of living with the NMS of PD. They composed corresponding written narratives to capture the impact of NMS on their daily activities and QoL. In total, 152 photographs and corresponding narratives were analysed using thematic analysis with an inductive approach.
RESULTS
Four interrelated themes were identified. Emotional well-being and sense of self encompassed a process of adjustment to living with PD. Engaging in valued activities, adopting a positive mindset and utilising coping strategies were thought to enhance confidence and self-esteem. Social support and societal awareness highlighted the importance of supportive relationships and socialising to aid participation and avoid isolation. Barriers to social engagement included the unpredictability of NMS and nonvisible NMS being neglected or misunderstood.
CONCLUSION
Findings demonstrated the far-reaching impact of nonmotor aspects of PD on emotional, occupational and social dimensions. These needs could be addressed through person-centred and comprehensive approaches to care.
PATIENT OR PUBLIC CONTRIBUTION
This study utilised a participatory research approach allowing participants to choose the subjects that mattered to them and how to present their results. Additionally, a group workshop was held with people with PD, their family members and healthcare professionals to guide theme development.
Topics: Humans; Parkinson Disease; Female; Male; Quality of Life; Aged; Middle Aged; Photography; Adaptation, Psychological; Social Support; Activities of Daily Living; Self Concept; Aged, 80 and over; Qualitative Research
PubMed: 38924637
DOI: 10.1111/hex.14124 -
Science Advances Jun 2024Mutations in cause Gaucher disease and are the most important genetic risk factor for Parkinson's disease. However, analysis of transcription at this locus is...
Mutations in cause Gaucher disease and are the most important genetic risk factor for Parkinson's disease. However, analysis of transcription at this locus is complicated by its highly homologous pseudogene, . We show that >50% of short RNA-sequencing reads mapping to also map to . Thus, we used long-read RNA sequencing in the human brain, which allowed us to accurately quantify expression from both and . We discovered significant differences in expression compared to short-read data and identify currently unannotated transcripts of both and . These included protein-coding transcripts from both genes that were translated in human brain, but without the known lysosomal function-yet accounting for almost a third of transcription. Analyzing brain-specific cell types using long-read and single-nucleus RNA sequencing revealed region-specific variations in transcript expression. Overall, these findings suggest nonlysosomal roles for and with implications for our understanding of the role of in health and disease.
Topics: Humans; Glucosylceramidase; Pseudogenes; Brain; Molecular Sequence Annotation; Parkinson Disease; Gaucher Disease; Sequence Analysis, RNA
PubMed: 38924406
DOI: 10.1126/sciadv.adk1296 -
Annals of Clinical and Translational... Jun 2024Transcranial sonography (TCS) is a noninvasive neuroimaging technique, visualizing deep brain structures and the ventricular system. Although widely employed in...
OBJECTIVE
Transcranial sonography (TCS) is a noninvasive neuroimaging technique, visualizing deep brain structures and the ventricular system. Although widely employed in diagnosing various movement disorders, such as Parkinson's disease and dystonia, by detecting disease-specific abnormalities, the specific characteristics of the TCS in cerebellar ataxia remain inconclusive. We aimed to assess the potential value of TCS in patients with cerebellar ataxias for disease diagnosis and severity assessment.
METHODS
TCS on patients with genetic and acquired cerebellar ataxia, including 94 with spinocerebellar ataxias (SCAs) containing 10 asymptomatic carriers, 95 with cerebellar subtype of multiple system atrophy (MSA-C), and 100 healthy controls (HC), was conducted. Assessments included third ventricle width, substantia nigra (SN) and lentiform nucleus (LN) echogenicity, along with comprehensive clinical evaluations and genetic testing.
RESULTS
The study revealed significant TCS abnormalities in patients with cerebellar ataxia, such as enlarged third ventricle widths and elevated rates of hyperechogenic SN and LN. TCS showed high accuracy in distinguishing patients with SCA or MSA-C from HC, with an AUC of 0.870 and 0.931, respectively. TCS abnormalities aided in identifying asymptomatic SCA carriers, effectively differentiating them from HC, with an AUC of 0.725. Furthermore, third ventricle width was significantly correlated with SARA and ICARS scores in patients with SCA3 and SCOPA-AUT scores in patients with MSA-C. The SN area and SARA or ICARS scores in patients with SCA3 were also positively correlated.
INTERPRETATION
Our findings illustrate remarkable TCS abnormalities in patients with cerebellar ataxia, serving as potential biomarkers for clinical diagnosis and progression assessment.
PubMed: 38924300
DOI: 10.1002/acn3.52131 -
Annals of Clinical and Translational... Jun 2024Informative biomarkers are an urgent need in the management of amyotrophic lateral sclerosis. Serum cardiac troponin T is elevated in the majority of amyotrophic lateral...
OBJECTIVE
Informative biomarkers are an urgent need in the management of amyotrophic lateral sclerosis. Serum cardiac troponin T is elevated in the majority of amyotrophic lateral sclerosis patients and increases with disease progression. We sought to establish the informative value of cardiac troponin T with regard to respiratory function, a major prognostic factor in amyotrophic lateral sclerosis.
METHODS
In this retrospective observation, we analyzed two independent hospital-based cohorts (d = discovery cohort; v = validation cohort) regarding serum cardiac troponin T (n = 298; n = 49), serum neurofilament light chain (n = 117; n = 17), and respiratory tests (n = 93; n = 49).
RESULTS
Serum cardiac troponin T, in contrast to serum neurofilament levels, was associated with the respiratory domain of the revised amyotrophic lateral sclerosis functional rating scale and with pulmonary function parameters, namely forced vital capacity % (r = -0.45, p = 0.001) and slow vital capacity % (r = -0.50, p = 0.001). Serum cardiac troponin T reliably discriminated benchmarks of slow vital capacity <80% (AUC 0.73, 95% CI 0.62-0.84) and <50% (AUC 0.80, 95% CI 0.68-0.93), forced vital capacity <80% (AUC 0.72, 95% CI 0.61-0.83) and <50% (AUC 0.79, 95% CI 0.67-0.91).
INTERPRETATION
Our findings position cardiac Troponin T as a valuable serum biomarker in amyotrophic lateral sclerosis, complementing neurofilaments and expanding the understanding of underlying physiological mechanisms. In clinical practice, serum cardiac troponin T can flag benchmarks of compromised respiratory function.
PubMed: 38923228
DOI: 10.1002/acn3.52126 -
JAMA Network Open Jun 2024Poor sleep quality greatly impairs quality of life and accelerates deterioration in patients with Parkinson disease (PD), but current remedies remain limited.... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Poor sleep quality greatly impairs quality of life and accelerates deterioration in patients with Parkinson disease (PD), but current remedies remain limited. Acupuncture, used as an adjunctive therapy with anti-Parkinson medications, has shown positive effects in patients with PD. However, high-quality clinical evidence to support the effectiveness of acupuncture for patients with PD and poor sleep quality is lacking.
OBJECTIVE
To assess the safety and efficacy of real acupuncture (RA) vs sham acupuncture (SA) as an adjunctive therapy for patients with PD who have poor sleep quality.
DESIGN, SETTING, AND PARTICIPANTS
This single-center randomized clinical trial was performed at The First Affiliated Hospital of Guangzhou University of Chinese Medicine in China from February 18, 2022, to February 18, 2023. Patients with PD and sleep complaints were recruited and randomized (1:1) to receive RA or SA treatment for 4 weeks. Data analysis was performed from April 12 to August 17, 2023.
INTERVENTION
Treatment with RA or SA for 4 weeks.
MAIN OUTCOMES AND MEASURES
The main outcome was the change in Parkinson Disease Sleep Scale (PDSS) scores measured at baseline, after 4 weeks of treatment, and at 8 weeks of follow-up.
RESULTS
Of the 83 participants enrolled, 78 (94.0%) completed the intervention and were included in the analysis. Their mean (SD) age was 64.1 (7.9) years; 41 (52.6%) were men and 37 (47.4%) were women. A significant increase in PDSS scores from baseline was observed for both the RA group (29.65 [95% CI, 24.65-34.65]; P < .001) and the SA group (10.47 [95% CI, 5.35-15.60]; P < .001). Compared with the SA group, the RA group had a significant increase in PDSS scores after 4 weeks of treatment (19.75 [95% CI, 11.02-28.49]; P < .001) and at 8 weeks of follow-up (20.24 [95% CI, 11.51-28.98]; P < .001).
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, acupuncture proved beneficial in improving sleep quality and quality of life among patients with PD. These findings suggest that the therapeutic effects of acupuncture could continue for up to 4 weeks.
TRIAL REGISTRATION
Chinese Clinical Trial Registry Identifier: ChiCTR2200060655.
Topics: Humans; Parkinson Disease; Female; Male; Acupuncture Therapy; Middle Aged; Aged; Sleep Quality; Quality of Life; Treatment Outcome; Sleep Wake Disorders; China
PubMed: 38922617
DOI: 10.1001/jamanetworkopen.2024.17862