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Scientific Reports Jun 2024Oropharyngeal dysphagia, or difficulty initiating swallowing, is a frequent problem in people with Parkinson's disease (PD) and can lead to aspiration pneumonia. The...
Oropharyngeal dysphagia, or difficulty initiating swallowing, is a frequent problem in people with Parkinson's disease (PD) and can lead to aspiration pneumonia. The efficacy of pharmacological options is limited. Postural strategies, such as a chin-down manoeuvre when drinking, have had some degree of success but may be difficult for people who have other limitations such as dementia or neck rigidity, to reproduce consistently. Using a user-centred design approach and a multidisciplinary team, we developed and tested an anti-choking mug for people with PD that helps angle the head in the optimum position for drinking. The design reflected anthropometric and ergonomic aspects of user needs with features including regulation of water flow rate and sip volume, an inner slope, a thickened handle and a wide base, which promoted a chin-down posture when used. Prototype testing using digital technology to compare neck flexion angles (the primary outcome), plus clinical outcomes assessed using standard tools (Swallowing Clinical Assessment Score in Parkinson's Disease (SCAS-PD) and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts II and III), found significant improvements in a range of parameters related to efficient swallowing and safe drinking when using the anti-choking mug versus a sham mug.
Topics: Parkinson Disease; Humans; Male; Female; Deglutition Disorders; Aged; User-Centered Design; Deglutition; Middle Aged; Airway Obstruction; Posture
PubMed: 38898235
DOI: 10.1038/s41598-024-65071-8 -
Nature Communications Jun 2024Pyroglutamylated RF-amide peptide (QRFP) is a peptide hormone with a C-terminal RF-amide motif. QRFP selectively activates a class A G-protein-coupled receptor (GPCR)...
Pyroglutamylated RF-amide peptide (QRFP) is a peptide hormone with a C-terminal RF-amide motif. QRFP selectively activates a class A G-protein-coupled receptor (GPCR) GPR103 to exert various physiological functions such as energy metabolism and appetite regulation. Here, we report the cryo-electron microscopy structure of the QRFP26-GPR103-G complex at 3.19 Å resolution. QRFP26 adopts an extended structure bearing no secondary structure, with its N-terminal and C-terminal sides recognized by extracellular and transmembrane domains of GPR103 respectively. This movement, reminiscent of class B1 GPCRs except for orientation and structure of the ligand, is critical for the high-affinity binding and receptor specificity of QRFP26. Mutagenesis experiments validate the functional importance of the binding mode of QRFP26 by GPR103. Structural comparisons with closely related receptors, including RY-amide peptide-recognizing GPCRs, revealed conserved and diversified peptide recognition mechanisms, providing profound insights into the biological significance of RF-amide peptides. Collectively, this study not only advances our understanding of GPCR-ligand interactions, but also paves the way for the development of novel therapeutics targeting metabolic and appetite disorders and emergency medical care.
Topics: Receptors, G-Protein-Coupled; Humans; Cryoelectron Microscopy; HEK293 Cells; Protein Binding; Ligands; Intercellular Signaling Peptides and Proteins
PubMed: 38897996
DOI: 10.1038/s41467-024-49030-5 -
International Journal of Oral Science Jun 2024Oral submucous fibrosis (OSF) is a chronic and inflammatory mucosal disease caused by betel quid chewing, which belongs to oral potentially malignant disorders. Abnormal...
Oral submucous fibrosis (OSF) is a chronic and inflammatory mucosal disease caused by betel quid chewing, which belongs to oral potentially malignant disorders. Abnormal fibroblast differentiation leading to disordered collagen metabolism is the core process underlying OSF development. The epithelium, which is the first line of defense against the external environment, can convert external signals into pathological signals and participate in the remodeling of the fibrotic microenvironment. However, the specific mechanisms by which the epithelium drives fibroblast differentiation remain unclear. In this study, we found that Arecoline-exposed epithelium communicated with the fibrotic microenvironment by secreting exosomes. MiR-17-5p was encapsulated in epithelial cell-derived exosomes and absorbed by fibroblasts, where it promoted cell secretion, contraction, migration and fibrogenic marker (α-SMA and collagen type I) expression. The underlying molecular mechanism involved miR-17-5p targeting Smad7 and suppressing the degradation of TGF-β receptor 1 (TGFBR1) through the E3 ubiquitination ligase WWP1, thus facilitating downstream TGF-β pathway signaling. Treatment of fibroblasts with an inhibitor of miR-17-5p reversed the contraction and migration phenotypes induced by epithelial-derived exosomes. Exosomal miR-17-5p was confirmed to function as a key regulator of the phenotypic transformation of fibroblasts. In conclusion, we demonstrated that Arecoline triggers aberrant epithelium-fibroblast crosstalk and identified that epithelial cell-derived miR-17-5p mediates fibroblast differentiation through the classical TGF-β fibrotic pathway, which provided a new perspective and strategy for the diagnosis and treatment of OSF.
Topics: MicroRNAs; Oral Submucous Fibrosis; Humans; Fibroblasts; Arecoline; Epithelial Cells; Exosomes; Receptor, Transforming Growth Factor-beta Type I; Smad7 Protein; Cell Differentiation; Signal Transduction; Cell Movement; Ubiquitin-Protein Ligases; Areca
PubMed: 38897993
DOI: 10.1038/s41368-024-00302-2 -
Nature Communications Jun 2024Disrupted glucose metabolism and protein misfolding are key characteristics of age-related neurodegenerative disorders including Parkinson's disease, however their...
Disrupted glucose metabolism and protein misfolding are key characteristics of age-related neurodegenerative disorders including Parkinson's disease, however their mechanistic linkage is largely unexplored. The hexosamine biosynthetic pathway utilizes glucose and uridine-5'-triphosphate to generate N-linked glycans required for protein folding in the endoplasmic reticulum. Here we find that Parkinson's patient midbrain cultures accumulate glucose and uridine-5'-triphosphate, while N-glycan synthesis rates are reduced. Impaired glucose flux occurred by selective reduction of the rate-limiting enzyme, GFPT2, through disrupted signaling between the unfolded protein response and the hexosamine pathway. Failure of the unfolded protein response and reduced N-glycosylation caused immature lysosomal hydrolases to misfold and accumulate, while accelerating glucose flux through the hexosamine pathway rescued hydrolase function and reduced pathological α-synuclein. Our data indicate that the hexosamine pathway integrates glucose metabolism with lysosomal activity, and its failure in Parkinson's disease occurs by uncoupling of the unfolded protein response-hexosamine pathway axis. These findings offer new methods to restore proteostasis by hexosamine pathway enhancement.
Topics: Humans; Hexosamines; Lysosomes; Parkinson Disease; Unfolded Protein Response; Neurons; Induced Pluripotent Stem Cells; Mesencephalon; Glucose; Biosynthetic Pathways; Glycosylation; alpha-Synuclein; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)
PubMed: 38897986
DOI: 10.1038/s41467-024-49256-3 -
Gait & Posture Jun 2024Gait impairment is an early marker of Parkinson's disease (PD) and is frequently monitored to evaluate disease progression. Wearable sensors are increasingly being used...
BACKGROUND
Gait impairment is an early marker of Parkinson's disease (PD) and is frequently monitored to evaluate disease progression. Wearable sensors are increasingly being used to quantify gait in the real-world setting among people with PD (pwPD). Particularly, embedding wearables on devices or clothing that are worn daily may represent a useful strategy to improve compliance and regular monitoring of gait.
RESEARCH QUESTION
The current investigation examined the validity of innovative smart glasses to measure gait among pwPD.
METHODS
Participants wore the smart glasses and 6 APDM gait sensors simultaneously, while performing two walking tasks: the 3-meters Timed Up and Go test (TUG) and the 7-meters Stand and Walk (SAW) test. The following spatiotemporal gait parameters were calculated from the data collected using the two different devices: step time, step length, swing percentage, TUG duration, turn duration, and turn velocity.
RESULTS
A total of 31 pwPD (mean age=68.6±8.5 years; 35.48 % female(N=11), mean Unified Parkinson's Disease Rating Scale (UPDRS) total score=32.1±14.7) participated in the study. Smart glasses achieved high validity in measuring step time (ICC=0.92, p=0.01) and TUG duration (ICC=0.96, p=0.03) compared to APDM sensors. On the other hand, the smart glasses did not achieve adequate validity when measuring step length, swing percentage, turn duration or turn velocity.
SIGNIFICANCE
The current study suggests that smart glasses has the potential to measure TUG and step time in individuals living with PD. However, further research is needed to improve algorithms for sensors worn on the head.
PubMed: 38897002
DOI: 10.1016/j.gaitpost.2024.06.001 -
Health Expectations : An International... Jun 2024Women and those with younger onset Parkinson's Disease (YOPD) are typically diagnosed later and face unique situations and challenges. This essay aims to raise awareness...
INTRODUCTION
Women and those with younger onset Parkinson's Disease (YOPD) are typically diagnosed later and face unique situations and challenges. This essay aims to raise awareness of the difficulties in diagnosing YOPD and the need for a personalised approach to care for women with YOPD.
METHODS
Two professional women with YOPD (academic physiotherapist and practicing dentist) and a female neurologist (clinician academic) came together to write a narrative essay on their personal experience and perspectives in relation to women and YOPD.
RESULTS
The essay outlines how the experience of diagnosis is likened to a complex puzzle box with many interlocking components that are hidden and difficult to solve. The concerns of the women about their identity, work, family and the future, with most supports targeting those that are older and retired are outlined.
CONCLUSION
It is concluded that YOPD is a complex puzzle to solve, but can be done by understanding all the intricate interlocking components of the puzzle and combined with greater awareness could lead to earlier diagnosis and the delivery of successful person-centred care.
PATIENT OR PUBLIC CONTRIBUTION
People with lived experience were involved in the essay conception and writing.
Topics: Humans; Parkinson Disease; Female; Middle Aged; Age of Onset
PubMed: 38896007
DOI: 10.1111/hex.14116 -
Frontiers in Digital Health 2024To introduce MexOMICS, a Mexican Consortium focused on establishing electronic databases to collect, cross-reference, and share health-related and omics data on the...
OBJECTIVE
To introduce MexOMICS, a Mexican Consortium focused on establishing electronic databases to collect, cross-reference, and share health-related and omics data on the Mexican population.
METHODS
Since 2019, the MexOMICS Consortium has established three electronic-based registries: the Mexican Twin Registry (TwinsMX), Mexican Lupus Registry (LupusRGMX), and the Mexican Parkinson's Research Network (MEX-PD), designed and implemented using the Research Electronic Data Capture web-based application. Participants were enrolled through voluntary participation and on-site engagement with medical specialists. We also acquired DNA samples and Magnetic Resonance Imaging scans in subsets of participants.
RESULTS
The registries have successfully enrolled a large number of participants from a variety of regions within Mexico: TwinsMX ( = 2,915), LupusRGMX ( = 1,761) and MEX-PD ( = 750). In addition to sociodemographic, psychosocial, and clinical data, MexOMICS has collected DNA samples to study the genetic biomarkers across the three registries. Cognitive function has been assessed with the Montreal Cognitive Assessment in a subset of 376 MEX-PD participants. Furthermore, a subset of 267 twins have participated in cognitive evaluations with the Creyos platform and in MRI sessions acquiring structural, functional, and spectroscopy brain imaging; comparable evaluations are planned for LupusRGMX and MEX-PD.
CONCLUSIONS
The MexOMICS registries offer a valuable repository of information concerning the potential interplay of genetic and environmental factors in health conditions among the Mexican population.
PubMed: 38895515
DOI: 10.3389/fdgth.2024.1344103 -
BioRxiv : the Preprint Server For... Jun 2024Amyloid plaque deposition is recognized as the primary pathological hallmark of Alzheimer's disease(AD) that precedes other pathological events and cognitive symptoms....
Amyloid plaque deposition is recognized as the primary pathological hallmark of Alzheimer's disease(AD) that precedes other pathological events and cognitive symptoms. Plaque pathology represents itself with an immense polymorphic variety comprising plaques with different stages of amyloid fibrillization ranging from diffuse to fibrillar, mature plaques. The association of polymorphic Aβ plaque pathology with AD pathogenesis, clinical symptoms and disease progression remains unclear. Advanced chemical imaging tools, such as functional amyloid microscopy combined with MALDI mass spectrometry imaging (MSI), are now enhanced by deep learning algorithms. This integration allows for precise delineation of polymorphic plaque structures and detailed identification of their associated Aβ compositions. We here set out to make use of these tools to interrogate heterogenic plaque types and their associated biochemical architecture. Our findings reveal distinct Aβ signatures that differentiate diffuse plaques from fibrilized ones, with the latter showing substantially higher levels of Aβx-40. Notably, within the fibrilized category, we identified a distinct subtype known as coarse-grain plaques. Both in sAD and fAD brain tissue, coarse grain plaques contained more Aβx-40 and less Aβx-42 compared with cored plaques. The coarse grain plaques in both sAD and fAD also showed higher levels of neuritic content including paired helical filaments (PHF-1)/phosphorylated phospho Tau-immunopositive neurites. Finally, the Aβ peptide content in coarse grain plaques resembled that of vascular Aβ deposits (CAA) though with relatively higher levels of Aβ1-42 and pyroglutamated Aβx-40 and Aβx-42 species in coarse grain plaques. This is the first of its kind study on spatial biochemical characterization of different plaque morphotypes demonstrating the potential of the correlative imaging techniques used that further increase the understanding of heterogeneous AD pathology. Linking the biochemical characteristics of amyloid plaque polymorphisms with various AD etiologies and toxicity mechanisms is crucial. Understanding the connection between plaque structure and disease pathogenesis can enhance our insights. This knowledge is particularly valuable for developing and advancing novel, amyloid-targeting therapeutics.
PubMed: 38895368
DOI: 10.1101/2024.06.03.596890 -
Sensors (Basel, Switzerland) Jun 2024Postural instability is a common complication in advanced Parkinson's disease (PD) associated with recurrent falls and fall-related injuries. The test of retropulsion,...
Postural instability is a common complication in advanced Parkinson's disease (PD) associated with recurrent falls and fall-related injuries. The test of retropulsion, consisting of a rapid balance perturbation by a pull in the backward direction, is regarded as the gold standard for evaluating postural instability in PD and is a key component of the neurological examination and clinical rating in PD (e.g., MDS-UPDRS). However, significant variability in test execution and interpretation contributes to a low intra- and inter-rater test reliability. Here, we explore the potential for objective, vision-based assessment of the pull test (vPull) using 3D pose tracking applied to single-sensor RGB-Depth recordings of clinical assessments. The initial results in a cohort of healthy individuals ( = 15) demonstrate overall excellent agreement of vPull-derived metrics with the gold standard marker-based motion capture. Subsequently, in a cohort of PD patients and controls ( = 15 each), we assessed the inter-rater reliability of vPull and analyzed PD-related impairments in postural response (including pull-to-step latency, number of steps, retropulsion angle). These quantitative metrics effectively distinguish healthy performance from and within varying degrees of postural impairment in PD. vPull shows promise for straightforward clinical implementation with the potential to enhance the sensitivity and specificity of postural instability assessment and fall risk prediction in PD.
Topics: Humans; Parkinson Disease; Postural Balance; Male; Female; Middle Aged; Aged; Accidental Falls; Reproducibility of Results; Posture; Adult
PubMed: 38894463
DOI: 10.3390/s24113673 -
Sensors (Basel, Switzerland) May 2024Excessive stride variability is a characteristic feature of cerebellar ataxias, even in pre-ataxic or prodromal disease stages. This study explores the relation of...
Excessive stride variability is a characteristic feature of cerebellar ataxias, even in pre-ataxic or prodromal disease stages. This study explores the relation of variability of arm swing and trunk deflection in relationship to stride length and gait speed in previously described cohorts of cerebellar disease and healthy elderly: we examined 10 patients with spinocerebellar ataxia type 14 (SCA), 12 patients with essential tremor (ET), and 67 healthy elderly (HE). Using inertial sensors, recordings of gait performance were conducted at different subjective walking speeds to delineate gait parameters and respective coefficients of variability (CoV). Comparisons across cohorts and walking speed categories revealed slower stride velocities in SCA and ET patients compared to HE, which was paralleled by reduced arm swing range of motion (RoM), peak velocity, and increased CoV of stride length, while no group differences were found for trunk deflections and their variability. Larger arm swing RoM, peak velocity, and stride length were predicted by higher gait velocity in all cohorts. Lower gait velocity predicted higher CoV values of trunk sagittal and horizontal deflections, as well as arm swing and stride length in ET and SCA patients, but not in HE. These findings highlight the role of arm movements in ataxic gait and the impact of gait velocity on variability, which are essential for defining disease manifestation and disease-related changes in longitudinal observations.
Topics: Humans; Male; Gait; Female; Aged; Arm; Walking Speed; Middle Aged; Torso; Movement; Cerebellar Diseases; Walking; Biomechanical Phenomena; Range of Motion, Articular; Essential Tremor
PubMed: 38894268
DOI: 10.3390/s24113476