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Parkinsonism & Related Disorders Aug 2023Neuropsychiatric symptoms (NPS) in Lewy body dementias (LBD) occur frequently and early in disease progression. Such symptoms are associated with worse quality of life,...
INTRODUCTION
Neuropsychiatric symptoms (NPS) in Lewy body dementias (LBD) occur frequently and early in disease progression. Such symptoms are associated with worse quality of life, caregiver burden and functional limitations. Limited evidence exists, however, outlining the longitudinal relationship between NPS and cognitive decline in prodromal LBD.
METHODS
123 participants were derived from three cohort studies. Patients with mild cognitive impairment (MCI) relating to probable dementia with Lewy bodies (MCI-LB, n = 67) and Parkinson's disease (PD-MCI, n = 56) completed comprehensive cognitive and neuropsychiatric assessment and were followed up longitudinally. Linear regression and mixed effects models assessed the relationship between baseline NPS and cognition at baseline and over time.
RESULTS
In MCI-LB, overall NPS burden was associated with declines over time in executive function (p = 0.026) and processing speed (p = 0.028) and baseline aberrant motor behaviour was associated with declines in attention (p < 0.025). Anxiety was significantly associated with poorer visuospatial functioning (p = 0.016) at baseline and poorer attention both at baseline (p = 0.017) and across time points (p = 0.024). In PD-MCI, psychosis was associated with poorer executive functioning at baseline (p = 0.008) and across time points (p = 0.002) but had no association with changes longitudinally.
CONCLUSIONS
Core neuropsychiatric components of LBD are not strongly associated with cognition in prodromal disease. This may suggest that neuropathological mechanisms underlying NPS may not be the same as those underlying cognitive impairment. Non-core NPS, however, may be more directly associated with cognitive change. Future studies utilising neuroimaging techniques are needed to explore the neuropathological basis of NPS in prodromal LBD.
Topics: Humans; Lewy Body Disease; Alzheimer Disease; Longitudinal Studies; Quality of Life; Cognitive Dysfunction; Prodromal Symptoms
PubMed: 37441886
DOI: 10.1016/j.parkreldis.2023.105762 -
Expert Review of Molecular Diagnostics 2023Primary mitochondrial diseases (PMDs) comprise a large and heterogeneous group of genetic diseases that result from pathogenic variants in either nuclear DNA (nDNA) or... (Review)
Review
INTRODUCTION
Primary mitochondrial diseases (PMDs) comprise a large and heterogeneous group of genetic diseases that result from pathogenic variants in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Widespread adoption of next-generation sequencing (NGS) has improved the efficiency and accuracy of mtDNA diagnoses; however, several challenges remain.
AREAS COVERED
In this review, we briefly summarize the current state of the art in molecular diagnostics for mtDNA and consider the implications of improved whole genome sequencing (WGS), bioinformatic techniques, and the adoption of long-read sequencing, for PMD diagnostics.
EXPERT OPINION
We anticipate that the application of PCR-free WGS from blood DNA will increase in diagnostic laboratories, while for adults with myopathic presentations, WGS from muscle DNA may become more widespread. Improved bioinformatic strategies will enhance WGS data interrogation, with more accurate delineation of mtDNA and NUMTs (nuclear mitochondrial DNA segments) in WGS data, superior coverage uniformity, indirect measurement of mtDNA copy number, and more accurate interpretation of heteroplasmic large-scale rearrangements (LSRs). Separately, the adoption of diagnostic long-read sequencing could offer greater resolution of complex LSRs and the opportunity to phase heteroplasmic variants.
Topics: Humans; Genome, Mitochondrial; DNA, Mitochondrial; Mitochondrial Diseases; Sequence Analysis, DNA; Computational Biology; High-Throughput Nucleotide Sequencing
PubMed: 37642407
DOI: 10.1080/14737159.2023.2241365 -
European Journal of Pharmacology Jul 2024Parkinson's Disease (PD) is a progressive neurodegenerative disorder expected to increase by over 50% by 2030 due to increasing life expectancy. The disease's hallmarks... (Review)
Review
Parkinson's Disease (PD) is a progressive neurodegenerative disorder expected to increase by over 50% by 2030 due to increasing life expectancy. The disease's hallmarks include slow movement, tremors, and postural instability. Impaired protein processing is a major factor in the pathophysiology of PD, leading to the buildup of aberrant protein aggregates, particularly misfolded α-synuclein, also known as Lewy bodies. These Lewy bodies lead to inflammation and further death of dopaminergic neurons, leading to imbalances in excitatory and inhibitory neurotransmitters, causing excessive uncontrollable movements called dyskinesias. It was previously suggested that a complex interplay involving hereditary and environmental variables causes the specific death of neurons in PD; however, the exact mechanism of the association involving the two primary modifiers is yet unknown. An increasing amount of research points to the involvement of epigenetics in the onset and course of several neurological conditions, such as PD. DNA methylation, post-modifications of histones, and non-coding RNAs are the primary examples of epigenetic alterations, that is defined as alterations to the expression of genes and functioning without modifications in DNA sequence. Epigenetic modifications play a significant role in the development of PD, with genes such as Parkin, PTEN-induced kinase 1 (PINK1), DJ1, Leucine-Rich Repeat Kinase 2 (LRRK2), and alpha-synuclein associated with the disease. The aberrant epigenetic changes implicated in the pathophysiology of PD and their impact on the design of novel therapeutic approaches are the primary focus of this review.
Topics: Humans; Parkinson Disease; Epigenesis, Genetic; Animals; DNA Methylation; alpha-Synuclein
PubMed: 38754537
DOI: 10.1016/j.ejphar.2024.176641 -
BMJ (Clinical Research Ed.) Apr 2024The TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) statement was published in 2015 to provide the minimum...
The TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) statement was published in 2015 to provide the minimum reporting recommendations for studies developing or evaluating the performance of a prediction model. Methodological advances in the field of prediction have since included the widespread use of artificial intelligence (AI) powered by machine learning methods to develop prediction models. An update to the TRIPOD statement is thus needed. TRIPOD+AI provides harmonised guidance for reporting prediction model studies, irrespective of whether regression modelling or machine learning methods have been used. The new checklist supersedes the TRIPOD 2015 checklist, which should no longer be used. This article describes the development of TRIPOD+AI and presents the expanded 27 item checklist with more detailed explanation of each reporting recommendation, and the TRIPOD+AI for Abstracts checklist. TRIPOD+AI aims to promote the complete, accurate, and transparent reporting of studies that develop a prediction model or evaluate its performance. Complete reporting will facilitate study appraisal, model evaluation, and model implementation.
Topics: Humans; Prognosis; Models, Statistical; Decision Support Techniques; Checklist
PubMed: 38626948
DOI: 10.1136/bmj-2023-078378 -
Neuroscience and Biobehavioral Reviews Mar 2024When listening to music, we naturally move our bodies rhythmically to the beat, which can be pleasurable and difficult to resist. This pleasurable sensation of wanting... (Review)
Review
When listening to music, we naturally move our bodies rhythmically to the beat, which can be pleasurable and difficult to resist. This pleasurable sensation of wanting to move the body to music has been called "groove." Following pioneering humanities research, psychological and neuroscientific studies have provided insights on associated musical features, behavioral responses, phenomenological aspects, and brain structural and functional correlates of the groove experience. Groove research has advanced the field of music science and more generally informed our understanding of bidirectional links between perception and action, and the role of the motor system in prediction. Activity in motor and reward-related brain networks during music listening is associated with the groove experience, and this neural activity is linked to temporal prediction and learning. This article reviews research on groove as a psychological phenomenon with neurophysiological correlates that link musical rhythm perception, sensorimotor prediction, and reward processing. Promising future research directions range from elucidating specific neural mechanisms to exploring clinical applications and socio-cultural implications of groove.
Topics: Humans; Music; Brain; Sensation; Auditory Perception
PubMed: 38141692
DOI: 10.1016/j.neubiorev.2023.105522 -
The Journal of Cell Biology Jun 2024Stress granules and P-bodies are ribonucleoprotein (RNP) granules that accumulate during the stress response due to the condensation of untranslating mRNPs. Stress...
Stress granules and P-bodies are ribonucleoprotein (RNP) granules that accumulate during the stress response due to the condensation of untranslating mRNPs. Stress granules form in part by intermolecular RNA-RNA interactions and can be limited by components of the RNA chaperone network, which inhibits RNA-driven aggregation. Herein, we demonstrate that the DEAD-box helicase DDX6, a P-body component, can also limit the formation of stress granules, independent of the formation of P-bodies. In an ATPase, RNA-binding dependent manner, DDX6 limits the partitioning of itself and other RNPs into stress granules. When P-bodies are limited, proteins that normally partition between stress granules and P-bodies show increased accumulation within stress granules. Moreover, we show that loss of DDX6, 4E-T, and DCP1A increases P-body docking with stress granules, which depends on CNOT1 and PAT1B. Taken together, these observations identify a new role for DDX6 in limiting stress granules and demonstrate that P-body components can influence stress granule composition and docking with P-bodies.
Topics: Adenosine Triphosphatases; Processing Bodies; RNA; Stress Granules; Humans; Cell Line, Tumor; DEAD-box RNA Helicases
PubMed: 38536035
DOI: 10.1083/jcb.202306022 -
Neuron Jul 2023Cortical responses to visual stimuli are believed to rely on the geniculo-striate pathway. However, recent work has challenged this notion by showing that responses in...
Cortical responses to visual stimuli are believed to rely on the geniculo-striate pathway. However, recent work has challenged this notion by showing that responses in the postrhinal cortex (POR), a visual cortical area, instead depend on the tecto-thalamic pathway, which conveys visual information to the cortex via the superior colliculus (SC). Does POR's SC-dependence point to a wider system of tecto-thalamic cortical visual areas? What information might this system extract from the visual world? We discovered multiple mouse cortical areas whose visual responses rely on SC, with the most lateral showing the strongest SC-dependence. This system is driven by a genetically defined cell type that connects the SC to the pulvinar thalamic nucleus. Finally, we show that SC-dependent cortices distinguish self-generated from externally generated visual motion. Hence, lateral visual areas comprise a system that relies on the tecto-thalamic pathway and contributes to processing visual motion as animals move through the environment.
Topics: Mice; Animals; Superior Colliculi; Visual Pathways; Thalamus; Thalamic Nuclei; Pulvinar; Geniculate Bodies
PubMed: 37172584
DOI: 10.1016/j.neuron.2023.04.022 -
Frontiers in Immunology 2023Pulmonary surfactant (PS), a complex mixture of lipids and proteins, is essential for maintaining proper lung function. It reduces surface tension in the alveoli,... (Review)
Review
Pulmonary surfactant (PS), a complex mixture of lipids and proteins, is essential for maintaining proper lung function. It reduces surface tension in the alveoli, preventing collapse during expiration and facilitating re-expansion during inspiration. Additionally, PS has crucial roles in the respiratory system's innate defense and immune regulation. Dysfunction of PS contributes to various respiratory diseases, including neonatal respiratory distress syndrome (NRDS), adult respiratory distress syndrome (ARDS), COVID-19-associated ARDS, and ventilator-induced lung injury (VILI), among others. Furthermore, PS alterations play a significant role in chronic lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). The intracellular stage involves storing and releasing a specialized subcellular organelle known as lamellar bodies (LB). The maturation of these organelles requires coordinated signaling to organize their intracellular organization in time and space. LB's intracellular maturation involves the lipid composition and critical processing of surfactant proteins to achieve proper functionality. Over a decade ago, the supramolecular organization of lamellar bodies was studied using electron microscopy. In recent years, novel bioimaging tools combining spectroscopy and microscopy have been utilized to investigate the intracellular organization of lamellar bodies temporally and spatially. This short review provides an up-to-date understanding of intracellular LBs. Hyperspectral imaging and phasor analysis have allowed identifying specific transitions in LB's hydration, providing insights into their membrane dynamics and structure. A discussion and overview of the latest approaches that have contributed to a new comprehension of the trafficking and structure of lamellar bodies is presented.
Topics: Adult; Infant, Newborn; Humans; Pulmonary Surfactants; COVID-19; Pulmonary Disease, Chronic Obstructive; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn
PubMed: 37638003
DOI: 10.3389/fimmu.2023.1250350 -
Blood Pressure Dec 2024Cuffless blood pressure measurement technologies have attracted significant attention for their potential to transform cardiovascular monitoring. This updated narrative... (Review)
Review
Cuffless blood pressure measurement technologies have attracted significant attention for their potential to transform cardiovascular monitoring. This updated narrative review thoroughly examines the challenges, opportunities, and limitations associated with the implementation of cuffless blood pressure monitoring systems. Diverse technologies, including photoplethysmography, tonometry, and ECG analysis, enable cuffless blood pressure measurement and are integrated into devices like smartphones and smartwatches. Signal processing emerges as a critical aspect, dictating the accuracy and reliability of readings. Despite its potential, the integration of cuffless technologies into clinical practice faces obstacles, including the need to address concerns related to accuracy, calibration, and standardization across diverse devices and patient populations. The development of robust algorithms to mitigate artifacts and environmental disturbances is essential for extracting clear physiological signals. Based on extensive research, this review emphasizes the necessity for standardized protocols, validation studies, and regulatory frameworks to ensure the reliability and safety of cuffless blood pressure monitoring devices and their implementation in mainstream medical practice. Interdisciplinary collaborations between engineers, clinicians, and regulatory bodies are crucial to address technical, clinical, and regulatory complexities during implementation. In conclusion, while cuffless blood pressure monitoring holds immense potential to transform cardiovascular care. The resolution of existing challenges and the establishment of rigorous standards are imperative for its seamless incorporation into routine clinical practice. The emergence of these new technologies shifts the paradigm of cardiovascular health management, presenting a new possibility for non-invasive continuous and dynamic monitoring. The concept of cuffless blood pressure measurement is viable and more finely tuned devices are expected to enter the market, which could redefine our understanding of blood pressure and hypertension.
Topics: Humans; Blood Pressure; Reproducibility of Results; Blood Pressure Determination; Hypertension; Photoplethysmography
PubMed: 38245864
DOI: 10.1080/08037051.2024.2304190 -
Journal of the American Society of... Jul 2023Endocytosis, recycling, and degradation of proteins are essential functions of mammalian cells, especially for terminally differentiated cells with limited regeneration...
SIGNIFICANCE STATEMENT
Endocytosis, recycling, and degradation of proteins are essential functions of mammalian cells, especially for terminally differentiated cells with limited regeneration rates and complex morphology, such as podocytes. To improve our understanding on how disturbances of these trafficking pathways are linked to podocyte depletion and slit diaphragm (SD) injury, the authors explored the role of the small GTPase Rab7, which is linked to endosomal, lysosomal, and autophagic pathways, using as model systems mice and Drosophila with podocyte-specific or nephrocyte-specific loss of Rab7, and a human podocyte cell line depleted for Rab7. Their findings point to maturation and fusion events during endolysosomal and autophagic maturation as key processes for podocyte homeostasis and function and identify altered lysosomal pH values as a putative novel mechanism for podocytopathies.
BACKGROUND
Endocytosis, recycling, and degradation of proteins are essential functions of mammalian cells, especially for terminally differentiated cells with limited regeneration rates, such as podocytes. How disturbances within these trafficking pathways may act as factors in proteinuric glomerular diseases is poorly understood.
METHODS
To explore how disturbances in trafficking pathways may act as factors in proteinuric glomerular diseases, we focused on Rab7, a highly conserved GTPase that controls the homeostasis of late endolysosomal and autophagic processes. We generated mouse and Drosophila in vivo models lacking Rab7 exclusively in podocytes or nephrocytes, and performed histologic and ultrastructural analyses. To further investigate Rab7 function on lysosomal and autophagic structures, we used immortalized human cell lines depleted for Rab7.
RESULTS
Depletion of Rab7 in mice, Drosophila , and immortalized human cell lines resulted in an accumulation of diverse vesicular structures resembling multivesicular bodies, autophagosomes, and autoendolysosomes. Mice lacking Rab7 developed a severe and lethal renal phenotype with early-onset proteinuria and global or focal segmental glomerulosclerosis, accompanied by an altered distribution of slit diaphragm proteins. Remarkably, structures resembling multivesicular bodies began forming within 2 weeks after birth, prior to the glomerular injuries. In Drosophila nephrocytes, Rab7 knockdown resulted in the accumulation of vesicles and reduced slit diaphragms. In vitro , Rab7 knockout led to similar enlarged vesicles and altered lysosomal pH values, accompanied by an accumulation of lysosomal marker proteins.
CONCLUSIONS
Disruption within the final common pathway of endocytic and autophagic processes may be a novel and insufficiently understood mechanism regulating podocyte health and disease.
Topics: Animals; Mice; Humans; Kidney Glomerulus; Podocytes; Endosomes; Drosophila; Kidney; Mammals
PubMed: 37022133
DOI: 10.1681/ASN.0000000000000126