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BioRxiv : the Preprint Server For... Jun 2024Decreased excitability of pyramidal tract neurons in layer 5B (PT5B) of primary motor cortex (M1) has recently been shown in a dopamine-depleted mouse model of...
Decreased cellular excitability of pyramidal tract neurons in primary motor cortex leads to paradoxically increased network activity in simulated parkinsonian motor cortex.
Decreased excitability of pyramidal tract neurons in layer 5B (PT5B) of primary motor cortex (M1) has recently been shown in a dopamine-depleted mouse model of parkinsonism. We hypothesized that decreased PT5B neuron excitability would substantially disrupt oscillatory and non-oscillatory firing patterns of neurons in layer 5 (L5) of primary motor cortex (M1). To test this hypothesis, we performed computer simulations using a previously validated computer model of mouse M1. Inclusion of the experimentally identified parkinsonism-associated decrease of PT5B excitability into our computational model produced a paradoxical increase in rest-state PT5B firing rate, as well as an increase in beta-band oscillatory power in local field potential (LFP). In the movement-state, PT5B population firing and LFP showed reduced beta and increased high-beta, low-gamma activity of 20-35 Hz in the parkinsonian, but not in control condition. The appearance of beta-band oscillations in parkinsonism would be expected to disrupt normal M1 motor output and contribute to motor activity deficits seen in patients with Parkinson's disease (PD).
PubMed: 38948850
DOI: 10.1101/2024.05.23.595566 -
BioRxiv : the Preprint Server For... Jun 2024Parkinson's Disease (PD) is the second most common neurodegenerative disorder. Mutations in leucine-rich repeat kinase 2 (LRRK2), a multi-domain protein containing both...
Parkinson's Disease (PD) is the second most common neurodegenerative disorder. Mutations in leucine-rich repeat kinase 2 (LRRK2), a multi-domain protein containing both a kinase and a GTPase, are a leading cause of the familial form of PD. Pathogenic LRRK2 mutations increase LRRK2 kinase activity. While the bulk of LRRK2 is found in the cytosol, the protein associates with membranes where its Rab GTPase substrates are found, and under certain conditions, with microtubules. Integrative structural studies using single-particle cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) have revealed the architecture of microtubule-associated LRRK2 filaments, and that formation of these filaments requires LRRK2's kinase to be in the active-like conformation. However, whether LRRK2 can interact with and form filaments on microtubules in its autoinhibited state, where the kinase domain is in the inactive conformation and the N-terminal LRR domain covers the kinase active site, was not known. Using cryo-ET, we show that full-length LRRK2 can oligomerize on microtubules in its autoinhibited state. Both WT-LRRK2 and PD-linked LRRK2 mutants formed filaments on microtubules. While these filaments are stabilized by the same interfaces seen in the active-LRRK2 filaments, we observed a new interface involving the N-terminal repeats that were disordered in the active-LRRK2 filaments. The helical parameters of the autoinhibited-LRRK2 filaments are different from those reported for the active-LRRK2 filaments. Finally, the autoinhibited-LRRK2 filaments are shorter and less regular, suggesting they are less stable.
PubMed: 38948781
DOI: 10.1101/2024.06.18.599606 -
BioRxiv : the Preprint Server For... Jun 2024The protein alpha-synuclein (αSyn) plays a critical role in the pathogenesis of synucleinopathy, which includes Parkinson's disease and multiple system atrophy, and...
UNLABELLED
The protein alpha-synuclein (αSyn) plays a critical role in the pathogenesis of synucleinopathy, which includes Parkinson's disease and multiple system atrophy, and mounting evidence suggests that lipid dyshomeostasis is a critical phenotype in these neurodegenerative conditions. Previously, we identified that αSyn localizes to mitochondria-associated endoplasmic reticulum membranes (MAMs), temporary functional domains containing proteins that regulate lipid metabolism, including the de novo synthesis of phosphatidylserine. In the present study, we have analyzed the lipid composition of postmortem human samples, focusing on the substantia nigra pars compacta of Parkinson's disease and controls, as well as three less affected brain regions of Parkinson's donors. To further assess synucleinopathy-related lipidome alterations, similar analyses were performed on the striatum of multiple system atrophy cases. Our data show region-and disease-specific changes in the levels of lipid species. Specifically, our data revealed alterations in the levels of specific phosphatidylserine species in brain areas most affected in Parkinson's disease. Some of these alterations, albeit to a lesser degree, are also observed multiples system atrophy. Using induced pluripotent stem cell-derived neurons, we show that αSyn contributes to regulating phosphatidylserine metabolism at MAM domains, and that αSyn dosage parallels the perturbation in phosphatidylserine levels. Our results support the notion that αSyn pathophysiology is linked to the dysregulation of lipid homeostasis, which may contribute to the vulnerability of specific brain regions in synucleinopathy. These findings have significant therapeutic implications.
SIGNIFICANCE STATEMENT
Synucleinopathy is a complex group of neurodegenerative disorders whose causes and underlying mechanisms remain unknown. In this work, we examined synucleinopathy postmortem brain samples and patient-derived neuron models and identified the functional impairment of the mitochondrial-associated endoplasmic reticulum membrane (MAM) domain, which facilitates lipid regulation. The protein alpha-synuclein is associated with synucleinopathy and increasing levels result in the mislocalization of this protein and the disruption of MAM domains, which, in turn, results in lipid and membrane composition alterations. Specifically, we report that increased alpha-synuclein expression impairs the regulation of phosphatidylserine synthase 2 and the levels of phosphatidylserine in cellular membranes from affected cells. Our study offers mechanistic insight tying alpha-synuclein pathology and lipid dysregulation as seminal factors in synucleinopathy, which may have pathogenic and therapeutic implications.
PubMed: 38948777
DOI: 10.1101/2024.06.17.599406 -
BioRxiv : the Preprint Server For... Jun 2024Early diagnosis and biomarker discovery to bolster the therapeutic pipeline for Parkinson's disease (PD) are urgently needed. In this study, we leverage the large-scale...
UNLABELLED
Early diagnosis and biomarker discovery to bolster the therapeutic pipeline for Parkinson's disease (PD) are urgently needed. In this study, we leverage the large-scale whole-blood total RNA-seq dataset from the Accelerating Medicine Partnership in Parkinson's Disease (AMP PD) program to identify PD-associated RNAs, including both known genes and novel circular RNAs (circRNA) and enhancer RNAs (eRNAs). There were 1,111 significant marker RNAs, including 491 genes, 599 eRNAs, and 21 circRNAs, that were first discovered in the PPMI cohort (FDR < 0.05) and confirmed in the PDBP/BioFIND cohorts (nominal < 0.05). Functional enrichment analysis showed that the PD-associated genes are involved in neutrophil activation and degranulation, as well as the TNF-alpha signaling pathway. We further compare the PD-associated genes in blood with those in post-mortem brain dopamine neurons in our BRAINcode cohort. 44 genes show significant changes with the same direction in both PD brain neurons and PD blood, including neuroinflammation-associated genes , , and . Finally, we built a novel multi-omics machine learning model to predict PD diagnosis with high performance (AUC = 0.89), which was superior to previous studies and might aid the decision-making for PD diagnosis in clinical practice. In summary, this study delineates a wide spectrum of the known and novel RNAs linked to PD and are detectable in circulating blood cells in a harmonized, large-scale dataset. It provides a generally useful computational framework for further biomarker development and early disease prediction.
SIGNIFICANCE STATEMENT
Early and accurate diagnosis of Parkinson's disease (PD) is urgently needed. However, biomarkers for early detection of PD are still lacking. Also, the limit of sample size remains one of the main pitfalls of current PD biomarker studies. We employed an analysis of large-scale whole-blood RNA-seq data. By identifying 1,111 significant marker RNAs, we establish a robust foundation for early PD detection, which implicated in neutrophil activation, degranulation, and TNF-alpha signaling, offer unprecedented insights into PD pathogenesis. Our multi-omics machine learning model, boasting an AUC of 0.89, outperforms previous studies, promising a transformative tool for precise PD diagnosis in clinical settings. This study marks a pivotal step toward enhanced biomarker development and early disease prediction.
PubMed: 38948706
DOI: 10.1101/2024.06.18.599639 -
Turkish Journal of Physical Medicine... Jun 2024The study aimed to evaluate the effects of aerobic exercise applied with bodyweight-supported treadmill (BWSTT) or cycle ergometer (CE) in Parkinson's patients.
OBJECTIVES
The study aimed to evaluate the effects of aerobic exercise applied with bodyweight-supported treadmill (BWSTT) or cycle ergometer (CE) in Parkinson's patients.
PATIENTS AND METHODS
In the prospective single-blind study, 38 Parkinson's patients with Hoehn-Yahr Stage 1-3 were randomized into the CE and BWSTT groups between May 2019 and March 2020. Evaluations before and after six weeks of treatment included a six-min walking test with a software device as the primary outcome and functional balance tests (Tinetti balance and gait test, one-leg stance balance test) as secondary outcomes. Both groups received 40 min of aerobic exercise three days per week with conventional rehabilitation and various methods. CE and BWSTT groups were created. The aerobic exercise program was designed based on treatment recommendations for Parkinson's patients of the American College of Sports Medicine (CE test, with the Karvonen formula, 40-60% reserve). Posttreatment and pretreatment evaluations were compared within and between groups.
RESULTS
The six-week aerobic exercise program was completed by 16 participants (9 males, 7 females; mean age: 65.9±8.1; range, 47 to 78 years) in the CE group and 15 participants (9 males, 6 females; mean age: 62.5±7.5; range, 49 to 79 years) in the BWSTT group. The demographic characteristics of the patients were similar. Primary and secondary outcomes were significantly different after treatment than before treatment in both groups. There were no significant differences between the groups in outcomes.
CONCLUSION
The results showed that both methods are effective and not superior to each other. Aerobic exercise programs led by experienced clinicians can benefit patients.
PubMed: 38948648
DOI: 10.5606/tftrd.2024.11991 -
National Science Review Jun 2024
PubMed: 38948151
DOI: 10.1093/nsr/nwae187 -
Cureus May 2024Alzheimer's and Parkinson's diseases are among the most prevalent neurodegenerative conditions affecting aging populations globally, presenting significant challenges in... (Review)
Review
Alzheimer's and Parkinson's diseases are among the most prevalent neurodegenerative conditions affecting aging populations globally, presenting significant challenges in early diagnosis and management. This narrative review explores the pivotal role of advanced neuroimaging techniques in detecting and managing these diseases at early stages, potentially slowing their progression through timely interventions. Recent advancements in MRI, such as ultra-high-field systems and functional MRI, have enhanced the sensitivity for detecting subtle structural and functional changes. Additionally, the development of novel amyloid-beta tracers and other emerging modalities like optical imaging and transcranial ultrasonography have improved the diagnostic accuracy and capability of existing methods. This review highlights the clinical applications of these technologies in Alzheimer's and Parkinson's diseases, where they have shown improved diagnostic performance, enabling earlier intervention and better prognostic outcomes. Moreover, the integration of artificial intelligence (AI) and longitudinal research is emerging as a promising enhancement to refine early detection strategies further. However, this review also addresses the technical, ethical, and accessibility challenges in the field, advocating for the more extensive use of advanced imaging technologies to overcome these barriers. Finally, we emphasize the need for a holistic approach that incorporates both neurological and psychiatric perspectives, which is crucial for optimizing patient care and outcomes in the management of neurodegenerative diseases.
PubMed: 38947709
DOI: 10.7759/cureus.61335 -
Frontiers in Public Health 2024There is a paucity of studies that compare older adults' attitudes toward Euthanasia in two different terminal illnesses. Moreover, these studies did not relate to...
BACKGROUND
There is a paucity of studies that compare older adults' attitudes toward Euthanasia in two different terminal illnesses. Moreover, these studies did not relate to potentially influencing psycho-social factors. The current study aimed to examine the impact of a diverse range of variables on attitudes among older adults toward Euthanasia in two medical conditions: cancer and Parkinson's disease.
METHODS
A total of 501 individuals aged 75 and above participated in the study. Attitudes toward Euthanasia were measured using vignettes which described two conditions: an 80-year-old man with metastatic cancer and another man in an advanced stage of Parkinson's disease. The questionnaire included measures of relevant experience (with a close family member or a friend dying from a terminal illness), self-efficacy, will to live, satisfaction with life, will to prolong life, fear of death and dying, social support, and psycho-social characteristics. The data were analyzed using hierarchical linear regression models.
RESULTS
A more positive attitude toward Euthanasia was found in the case of cancer compared to Parkinson's disease. Being a woman, having more years of education, lower level of religiosity, greater fear of death and dying and higher self-efficacy contributes to more favorable attitudes toward Euthanasia in both end-of life conditions.
CONCLUSIONS
The finding that attitudes toward Euthanasia are statistically significantly more positive in the case of cancer compared to Parkinson's disease can be attributed to the greater prevalence of cancer in the population, and to the public's awareness of the suffering associated with each of these medical conditions. Beyond the important role of the socio-demographic characteristics of gender, education, and religiosity, it appears that fear of death and dying and self-efficacy are important psychological factors in explaining attitudes toward Euthanasia in both illnesses among older people. These findings shed light on older adults' attitudes toward Euthanasia in debilitating illnesses.
Topics: Humans; Male; Female; Parkinson Disease; Aged, 80 and over; Aged; Attitude to Death; Neoplasms; Euthanasia; Surveys and Questionnaires; Self Efficacy; Terminal Care
PubMed: 38947343
DOI: 10.3389/fpubh.2024.1393535 -
World Journal of Orthopedics Jun 2024Dual mobility (DM) bearings have gained significant attention in the field of total hip arthroplasty (THA) as a valid treatment option in cases of revision for... (Review)
Review
Dual mobility (DM) bearings have gained significant attention in the field of total hip arthroplasty (THA) as a valid treatment option in cases of revision for instability after THA whereas its use in primary THA is still a matter of debate. This manuscript explores the pathology, incidence, diagnosis, treatment options, prognosis, ongoing studies in the literature, and future perspectives related to the use of DM bearings employed in primary THA. DM bearings are primarily designed to address one of the major concerns in THA: Instability of the prosthetic hip. Instability is both for the surgeon and the patient a devastating postoperative complication, leading to significant pain and subsequent apprehension by the patient and may require revision surgeries. The use of DM implants poses the worry of wear-related complications, such as accelerated polyethylene wear and osteolysis, which also pose challenges to long-term implant survival. This technique has seen a steady rise in recent years, with multiple studies reporting favorable outcomes. The incidence of their utilization varies among institutions and surgeons, reflecting differing preferences and patient populations. The diagnosis of instability and wear-related complications in THA often involves clinical assessment, imaging modalities such as X-rays, computed tomography scans, and sometimes advanced imaging techniques like magnetic resonance imaging. DM bearings can be considered as an option when patients present neurologic pathologies such as Parkinson's disease or recurrent dislocations after THA. DM bearings provide an additional articulation point within the implant, facilitating a greater range of motion and inherent stability. This design allows for reduced risk of dislocation and improved functional outcomes. Various implant manufacturers offer different designs and sizes of DM bearings to suit individual patient needs. Current literature suggests that the use of DM bearings in primary THA has demonstrated promising outcomes in terms of enhanced stability, reduced dislocation rates, and improved patient satisfaction. However, long-term studies with larger patient cohorts are necessary to establish the durability and longevity of these implants. Several ongoing studies are investigating the role of DM bearings in primary THA. These studies focus on evaluating long-term implant survivorship, assessing wear patterns, analyzing patient-reported outcomes, and comparing the effectiveness of DM bearings with traditional THA designs. The future of DM bearings in primary THA holds potential for further advancements. Research efforts are aimed at refining implant materials, optimizing designs, and studying the influence of surgical techniques on implant performance. Additionally, continued investigation into the long-term outcomes and cost-effectiveness of DM bearings will play a crucial role in shaping their future use. While further research is warranted, the current evidence supports their potential as a beneficial solution in improving surgical outcomes and patient satisfaction.
PubMed: 38947268
DOI: 10.5312/wjo.v15.i6.512 -
European Journal of Neurology Jul 2024Parkinson's disease (PD) is an age-related condition characterized by substantial phenotypic variability. Consequently, pathways and proteins involved in biological...
BACKGROUND AND PURPOSE
Parkinson's disease (PD) is an age-related condition characterized by substantial phenotypic variability. Consequently, pathways and proteins involved in biological aging, such as the central aging pathway comprising insulin-like growth factor 1-α-Klotho-sirtuin 1-forkhead box O3-peroxisome proliferator-activated receptor γ, may potentially influence disease progression.
METHODS
Cerebrospinal fluid (CSF) levels of α-Klotho in 471 PD patients were examined. Of the 471 patients, 96 carried a GBA1 variant (PD GBA1), whilst the 375 non-carriers were classified as PD wild-type (PD WT). Each patient was stratified into a CSF α-Klotho tertile group based on the individual level. Kaplan-Meier survival curves and Cox regression analysis stratified by tertile groups were conducted. These longitudinal data were available for 255 patients. Follow-up times reached from 8.4 to 12.4 years. The stratification into PD WT and PD GBA1 was undertaken to evaluate potential continuum patterns, particularly in relation to CSF levels.
RESULTS
Higher CSF levels of α-Klotho were associated with a significant later onset of cognitive impairment. Elevated levels of α-Klotho in CSF were linked to higher Montreal Cognitive Assessment scores in male PD patients with GBA1 mutations.
CONCLUSIONS
Our results indicate that higher CSF levels of α-Klotho are associated with a delayed cognitive decline in PD. Notably, this correlation is more prominently observed in PD patients with GBA1 mutations, potentially reflecting the accelerated biological aging profile characteristic of individuals harboring GBA1 variants.
PubMed: 38946703
DOI: 10.1111/ene.16388