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BMC Neurology Jun 2024Parkinson's disease (PD) is a neurodegenerative disease for which no disease-modifying therapies exist. Preclinical and clinical evidence suggest that repeated exposure... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Parkinson's disease (PD) is a neurodegenerative disease for which no disease-modifying therapies exist. Preclinical and clinical evidence suggest that repeated exposure to intermittent hypoxia might have short- and long-term benefits in PD. In a previous exploratory phase I trial, we demonstrated that in-clinic intermittent hypoxia exposure is safe and feasible with short-term symptomatic effects on PD symptoms. The current study aims to explore the safety, tolerability, feasibility, and net symptomatic effects of a four-week intermittent hypoxia protocol, administered at home, in individuals with PD.
METHODS/DESIGN
This is a two-armed double-blinded randomized controlled trial involving 40 individuals with mild to moderate PD. Participants will receive 45 min of normobaric intermittent hypoxia (fraction of inspired oxygen 0.16 for 5 min interspersed with 5 min normoxia), 3 times a week for 4 weeks. Co-primary endpoints include nature and total number of adverse events, and a feasibility-tolerability questionnaire. Secondary endpoints include Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II and III scores, gait tests and biomarkers indicative of hypoxic dose and neuroprotective pathway induction.
DISCUSSION
This trial builds on the previous phase I trial and aims to investigate the safety, tolerability, feasibility, and net symptomatic effects of intermittent hypoxia in individuals with PD. Additionally, the study aims to explore induction of relevant neuroprotective pathways as measured in plasma. The results of this trial could provide further insight into the potential of hypoxia-based therapy as a novel treatment approach for PD.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT05948761 (registered June 20th, 2023).
Topics: Humans; Parkinson Disease; Hypoxia; Double-Blind Method; Male; Middle Aged; Female; Aged; Adult
PubMed: 38909201
DOI: 10.1186/s12883-024-03702-3 -
Sleep Medicine Jun 2024Parkinson's disease (PD) is a progressive neurodegenerative disorder, involving motor and non-motor symptoms (NMS). Sleep disturbances (SD) are the second most common... (Review)
Review
Parkinson's disease (PD) is a progressive neurodegenerative disorder, involving motor and non-motor symptoms (NMS). Sleep disturbances (SD) are the second most common NMS in PD and include rapid eye movement (REM) sleep behavior disorder (RBD), excessive daytime sleepiness and insomnia. Freezing of gait (FOG) is a gait impairment frequently reported in people with PD greatly hampering functional independence and quality of life. Presence of FOG has been associated with increased frequency and severity of NMS, including SD. Thus, the aim of this study was to systematically review the literature comparing the number of people with FOG in PD with (PD + SD) and without SD (PD-SD). By systematically searching PubMed and Web of Science databases to identify original peer-reviewed articles, 8 studies including 5251 people with PD (2025 PD + SD and 3226 PD-SD) met eligibility criteria and were included in the review. In 6 studies (4 studies investigating RBD, 2 studies investigating overall sleep quality), the group of PD + SD had higher prevalence of FOG compared with PD-SD. Although a limited number of studies, our findings suggest that PD + SD present more frequently FOG than PD-SD. More studies are required to investigate the possible mechanism underlying this association between FOG and sleep.
PubMed: 38908269
DOI: 10.1016/j.sleep.2024.06.001 -
EBioMedicine Jun 2024Research in healthy young adults shows that characteristic patterns of brain activity define individual "brain-fingerprints" that are unique to each person. However,...
BACKGROUND
Research in healthy young adults shows that characteristic patterns of brain activity define individual "brain-fingerprints" that are unique to each person. However, variability in these brain-fingerprints increases in individuals with neurological conditions, challenging the clinical relevance and potential impact of the approach. Our study shows that brain-fingerprints derived from neurophysiological brain activity are associated with pathophysiological and clinical traits of individual patients with Parkinson's disease (PD).
METHODS
We created brain-fingerprints from task-free brain activity recorded through magnetoencephalography in 79 PD patients and compared them with those from two independent samples of age-matched healthy controls (N = 424 total). We decomposed brain activity into arrhythmic and rhythmic components, defining distinct brain-fingerprints for each type from recording durations of up to 4 min and as short as 30 s.
FINDINGS
The arrhythmic spectral components of cortical activity in patients with Parkinson's disease are more variable over short periods, challenging the definition of a reliable brain-fingerprint. However, by isolating the rhythmic components of cortical activity, we derived brain-fingerprints that distinguished between patients and healthy controls with about 90% accuracy. The most prominent cortical features of the resulting Parkinson's brain-fingerprint are mapped to polyrhythmic activity in unimodal sensorimotor regions. Leveraging these features, we also demonstrate that Parkinson's symptom laterality can be decoded directly from cortical neurophysiological activity. Furthermore, our study reveals that the cortical topography of the Parkinson's brain-fingerprint aligns with that of neurotransmitter systems affected by the disease's pathophysiology.
INTERPRETATION
The increased moment-to-moment variability of arrhythmic brain-fingerprints challenges patient differentiation and explains previously published results. We outline patient-specific rhythmic brain signaling features that provide insights into both the neurophysiological signature and symptom laterality of Parkinson's disease. Thus, the proposed definition of a rhythmic brain-fingerprint of Parkinson's disease may contribute to novel, refined approaches to patient stratification. Symmetrically, we discuss how rhythmic brain-fingerprints may contribute to the improved identification and testing of therapeutic neurostimulation targets.
FUNDING
Data collection and sharing for this project was provided by the Quebec Parkinson Network (QPN), the Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer's Disease (PREVENT-AD; release 6.0) program, the Cambridge Centre for Aging Neuroscience (Cam-CAN), and the Open MEG Archives (OMEGA). The QPN is funded by a grant from Fonds de Recherche du Québec - Santé (FRQS). PREVENT-AD was launched in 2011 as a $13.5 million, 7-year public-private partnership using funds provided by McGill University, the FRQS, an unrestricted research grant from Pfizer Canada, the Levesque Foundation, the Douglas Hospital Research Centre and Foundation, the Government of Canada, and the Canada Fund for Innovation. The Brainstorm project is supported by funding to SB from the NIH (R01-EB026299-05). Further funding to SB for this study included a Discovery grant from the Natural Sciences and Engineering Research Council of Canada of Canada (436355-13), and the CIHR Canada research Chair in Neural Dynamics of Brain Systems (CRC-2017-00311).
PubMed: 38908100
DOI: 10.1016/j.ebiom.2024.105201 -
Current Opinion in Cell Biology Jun 2024Dysfunction in mitochondrial maintenance and trafficking is commonly correlated with the development of neurodegenerative disorders such as Parkinson's disease and... (Review)
Review
Dysfunction in mitochondrial maintenance and trafficking is commonly correlated with the development of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. Thus, biomedical research has been dedicated to understanding how architecturally complex neurons maintain and transport their mitochondria. However, the systems that coordinate mitochondrial QC (quality control) dynamics and trafficking in response to neuronal activity and stress are less understood. Additionally, the degree of integration between the processes of mitochondrial trafficking and QC is unclear. Recent work indicates that mitochondrial motility modulators (i.e., anchors and tethers) help coordinate mitochondrial health by mediating distinct, stress-level-appropriate QC pathways following mitochondrial damage. This review summarizes current evidence supporting the role of two mitochondrial motility modulators, Syntaphilin and Mitofusin 2, in coordinating mitochondrial QC to promote neuronal health. Exploring motility modulators' intricate regulatory molecular landscape may reveal new therapeutic targets for delaying disease progression and enhancing neuronal survival post-insult.
PubMed: 38908094
DOI: 10.1016/j.ceb.2024.102383 -
Ecotoxicology and Environmental Safety Jun 2024Exposure to carbon disulfide (CS) is a recognized risk factor in the pathogenesis of Parkinson's disease, yet the underlying mechanisms of deleterious effects on...
Exposure to carbon disulfide (CS) is a recognized risk factor in the pathogenesis of Parkinson's disease, yet the underlying mechanisms of deleterious effects on mitochondrial integrity have remained elusive. Here, through establishing CS exposure models in rat and SH-SY5Y cells, we demonstrated that highly expressed α-synuclein (α-Syn) is transferred to mitochondria via membrane proteins such as Tom20 and leads to mitochondrial dysfunction and mitochondrial oxidative stress, which ultimately causes neuronal injury. We first found significant mitochondrial damage and oxidative stress in CS-exposed rat midbrain and SH-SY5Y cells and showed that mitochondrial oxidative stress was the main factor of mitochondrial damage by Mitoquinone intervention. Further experiments revealed that CS exposure led to the accumulation of α-Syn in mitochondria and that α-Syn co-immunoprecipitated with mitochondrial membrane proteins. Finally, the use of an α-Syn inhibitor (ELN484228) and small interfering RNA (siRNA) effectively mitigated the accumulation of α-Syn in neurons, as well as the inhibition of mitochondrial membrane potential, caused by CS exposure. In conclusion, our study identifies the translocation of α-Syn to mitochondria and the impairment of mitochondrial function, which has important implications for the broader understanding and treatment of neurodegenerative diseases associated with environmental toxins.
PubMed: 38908057
DOI: 10.1016/j.ecoenv.2024.116613 -
Microbiome Jun 2024
PubMed: 38907261
DOI: 10.1186/s40168-024-01846-5 -
BMC Medical Informatics and Decision... Jun 2024Patient-reported outcome (PRO) is a distinct and indispensable dimension of clinical characteristics and recent advances have made remote PRO measurement possible. Sex...
BACKGROUND
Patient-reported outcome (PRO) is a distinct and indispensable dimension of clinical characteristics and recent advances have made remote PRO measurement possible. Sex difference in PRO of Parkinson's disease (PD) is hardly extensively researched.
METHODS
A smartphone-based self-management platform, offering remote PRO measurement for PD patients, has been developed. A total of 1828 PD patients, including 1001 male patients and 827 female patients, were enrolled and completed their PRO submission through this platform.
RESULTS
Sex differences in PROs have been identified. The female group had a significantly lower height, weight, and body mass index (BMI) than the male group (P < 0.001). For motor symptoms, a higher proportion of patients reporting dyskinesia was observed in the female group. For non-motor symptoms, there is a higher percentage (P < 0.001) as well as severity (P = 0.016) of depression in the female group. More male patients reported hyposmia, lisp, drooling, dysuria, frequent urination, hypersexuality, impotence, daytime sleepiness, and apathy than females (P < 0.05). In contrast, more female patients reported headache, palpation, body pain, anorexia, nausea, urinal incontinence, anxiety, insomnia (P < 0.05) than males.
CONCLUSIONS
We provide evidence for sex differences in PD through the data collected from our platform. These results highlighted the importance of gender in clinical decision-making, and also support the feasibility of remote PRO measurement through a smartphone-based self-management platform in patients with PD.
Topics: Humans; Parkinson Disease; Male; Female; Smartphone; Pilot Projects; Self-Management; Cross-Sectional Studies; Middle Aged; Aged; Patient Reported Outcome Measures; Sex Factors; Mobile Applications
PubMed: 38907208
DOI: 10.1186/s12911-024-02569-1 -
NPJ Parkinson's Disease Jun 2024Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by mitochondrial dysfunction and accumulation of alpha-synuclein (α-Syn)-containing...
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by mitochondrial dysfunction and accumulation of alpha-synuclein (α-Syn)-containing protein aggregates known as Lewy bodies (LB). Here, we investigated the entry of α-Syn into mitochondria to cause mitochondrial dysfunction and loss of cellular fitness in vivo. We show that α-Syn expressed in yeast and human cells is constitutively imported into mitochondria. In a transgenic mouse model, the level of endogenous α-Syn accumulation in mitochondria of dopaminergic neurons and microglia increases with age. The imported α-Syn is degraded by conserved mitochondrial proteases, most notably NLN and PITRM1 (Prd1 and Cym1 in yeast, respectively). α-Syn in the mitochondrial matrix that is not degraded interacts with respiratory chain complexes, leading to loss of mitochondrial DNA (mtDNA), mitochondrial membrane potential and cellular fitness decline. Importantly, enhancing mitochondrial proteolysis by increasing levels of specific proteases alleviated these defects in yeast, human cells, and a PD model of mouse primary neurons. Together, our results provide a direct link between α-synuclein-mediated cellular toxicity and its import into mitochondria and reveal potential therapeutic targets for the treatment of α-synucleinopathies.
PubMed: 38906862
DOI: 10.1038/s41531-024-00733-y -
Brain Stimulation Jun 2024Enhancing slow waves, the electrophysiological (EEG) manifestation of non-rapid eye movement (NREM) sleep, could potentially benefit patients with Parkinson's disease...
BACKGROUND
Enhancing slow waves, the electrophysiological (EEG) manifestation of non-rapid eye movement (NREM) sleep, could potentially benefit patients with Parkinson's disease (PD) by improving sleep quality and slowing disease progression. Phase-targeted auditory stimulation (PTAS) is an approach to enhance slow waves, which are detected in real-time in the surface EEG signal.
OBJECTIVE
We aimed to test whether the local-field potential of the subthalamic nucleus (STN-LFP) can be used to detect frontal slow waves and assess the electrophysiological changes related to PTAS.
METHODS
We recruited patients diagnosed with PD and undergoing Percept™ PC neurostimulator (Medtronic) implantation for the deep brain stimulation of STN (STN-DBS) in a two-step surgery. Patients underwent three full-night recordings, including one between-surgeries recording and two during rehabilitation, one with DBS+ (on) and one with DBS- (off). Surface EEG and STN-LFP signals from Percept PC were recorded simultaneously, and PTAS was applied during sleep in all three recording sessions.
RESULTS
Our results show that during NREM sleep, slow waves of the cortex and STN are time-locked. PTAS application resulted in power and coherence changes, which can be detected in STN-LFP.
CONCLUSION
Our findings suggest the feasibility of implementing PTAS using solely STN-LFP signal for slow wave detection, thus without a need for an external EEG device alongside the implanted neurostimulator. Moreover, we propose options for more efficient STN-LFP signal preprocessing, including different referencing and filtering to enhance the reliability of cortical slow wave detection in STN-LFP recordings.
PubMed: 38906529
DOI: 10.1016/j.brs.2024.06.007 -
PloS One 2024In Ontario, despite the increasing prevalence of Parkinson's disease (PD), barriers to access-to-care for people with Parkinson's disease (PwP) and their caregivers are...
In Ontario, despite the increasing prevalence of Parkinson's disease (PD), barriers to access-to-care for people with Parkinson's disease (PwP) and their caregivers are not well understood. The objective of this study is to examine spatial patterns of health care utilization among PwP and identify factors associated with PD-related health care utilization of individuals in Ontario. We employed a retrospective, population-based study design involving administrative health data to identify PwP as of March 31, 2018 (N = 35,482) using a previously validated case definition. An enhanced 2-step floating catchment area method was used to measure spatial accessibility to PD care and a descriptive spatial analysis was conducted to describe health service utilization by geographic area and specialty type. Negative binomial regression models were then conducted to identify associated geographic, socioeconomic, comorbidity and demographic factors. There was marked spatial variability in PD-related service utilization, with neurology and all provider visits being significantly higher in urban areas (CMF>1.20; p<0.05) and family physician visits being significantly higher (CMF >1.20; p<0.05) in more rural areas and remote areas. More frequent visits to family physicians were associated with living in rural areas, while less frequent visitation was associated with living in areas of low spatial accessibility with high ethnic concentration. Visits to neurologists were positively associated with living in areas of high spatial accessibility and with high ethnic concentration. Visits to all providers were also positively associated with areas of high spatial accessibility. For all outcomes, less frequent visits were found in women, older people, and those living in more deprived areas as years living with PD increased. This study demonstrates the importance of geographic, socioeconomic and individual factors in determining PwP's likelihood of accessing care and type of care provided. Our results can be expected to inform the development of policies and patient care models aimed at improving accessibility among diverse populations of PwP.
Topics: Humans; Parkinson Disease; Ontario; Female; Male; Aged; Patient Acceptance of Health Care; Middle Aged; Retrospective Studies; Aged, 80 and over; Health Services Accessibility; Adult; Rural Population; Socioeconomic Factors
PubMed: 38905210
DOI: 10.1371/journal.pone.0305062