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STAR Protocols Jun 2024Here we present an open-source behavioral platform and software solution for studying fine motor skills in mice performing reach-to-grasp task. We describe steps for...
Here we present an open-source behavioral platform and software solution for studying fine motor skills in mice performing reach-to-grasp task. We describe steps for assembling the box, training mice to perform the task, and processing the video with the custom software pipeline to analyze forepaw kinematics. The behavioral platform uses readily available and 3D-printed components and was designed to be affordable and universally reproducible. We provide the schematics, 3D models, code, and assembly instructions in the open GitHub repository.
PubMed: 38905103
DOI: 10.1016/j.xpro.2024.103140 -
Frontiers in Aging Neuroscience 2024To identify cortical and subcortical volume, thickness and cortical area features and the networks they constituted related to anxiety in Parkinson's disease (PD) using...
OBJECTIVE
To identify cortical and subcortical volume, thickness and cortical area features and the networks they constituted related to anxiety in Parkinson's disease (PD) using structural magnetic resonance imaging (sMRI), and to integrate multimodal features based on machine learning to identify PD-related anxiety.
METHODS
A total of 219 patients with PD were retrospectively enrolled in the study. 291 sMRI features including cortical volume, subcortical volume, cortical thickness, and cortical area, as well as 17 clinical features, were extracted. Graph theory analysis was used to explore structural networks. A support vector machine (SVM) combination model, which used both sMRI and clinical features to identify participants with PD-related anxiety, was developed and evaluated. The performance of SVM models were evaluated. The mean impact value (MIV) of the feature importance evaluation algorithm was used to rank the relative importance of sMRI features and clinical features within the model.
RESULTS
17 significant sMRI variables associated with PD-related anxiety was used to build a brain structural network. And seven sMRI and 5 clinical features with statistically significant differences were incorporated into the SVM model. The comprehensive model achieved higher performance than clinical features or sMRI features did alone, with an accuracy of 0.88, a precision of 0.86, a sensitivity of 0.81, an F1-Score of 0.83, a macro-average of 0.85, a weighted-average of 0.92, an AUC of 0.88, and a result of 10-fold cross-validation of 0.91 in test set. The sMRI feature right medialorbitofrontal thickness had the highest impact on the prediction model.
CONCLUSION
We identified the brain structural features and networks related to anxiety in PD, and developed and internally validated a comprehensive model with multimodal features in identifying.
PubMed: 38903898
DOI: 10.3389/fnagi.2024.1414855 -
Frontiers in Aging Neuroscience 2024Parkinson's disease (PD), the second most prevalent neurodegenerative condition, has a multifaceted etiology. Cathepsin-cysteine proteases situated within lysosomes...
BACKGROUND
Parkinson's disease (PD), the second most prevalent neurodegenerative condition, has a multifaceted etiology. Cathepsin-cysteine proteases situated within lysosomes participate in a range of physiological and pathological processes, including the degradation of harmful proteins. Prior research has pointed towards a potential link between cathepsins and PD; however, the precise causal relationship between the cathepsin family and PD remains unclear.
METHODS
This study employed univariate and multivariate Mendelian randomization (MR) analyses to explore the causal relationship between the nine cathepsins and Parkinson's disease (PD) risk. For the primary analysis, genome-wide association study (GWAS) summary statistics for the plasma levels of the nine cathepsins and PD was obtained from the INTERVAL study and the International Parkinson's Disease Genomics Consortium. GWAS for PD replication analysis were obtained from the FinnGen consortium, and a meta-analysis was performed for the primary and replication analyses to evaluate the association between genetically predicted cathepsin plasma levels and PD risk. After identifying significant MR estimates, genetic co-localization analyses were conducted to determine whether shared or distinct causal variants influenced both cathepsins and PD.
RESULTS
Elevated cathepsin B levels were associated with a decreased risk of PD in univariate MR analysis (odds ratio [OR] = 0.890, 95% confidence interval [CI]: 0.831-0.954, pFDR = 0.009). However, there was no indication that PD affected cathepsin B levels (OR = 0.965, 95% CI: 0.858-1.087, = 0.852). In addition, after adjusting for the remaining cathepsins, cathepsin B levels independently and significantly contributed to the reduced risk of PD in multivariate MR analysis (OR = 0.887, 95% CI: 0.823-0.957, = 0.002). The results of the replication MR analysis with the FinnGen GWAS for PD (OR = 0.921, 95% CI: 0.860-0.987, = 0.020) and meta-analysis (OR = 0.905, 95% CI: 0.862-0.951, < 0.001) were consistent with those of the primary analysis. Colocalization analysis did not provide any evidence of a shared causal variant between cathepsins and PD (PP.H4.abf = 0.005).
CONCLUSION
This genetic investigation supports the hypothesis that cathepsin B exerts a protective effect against PD. The quantification of cathepsin B levels could potentially serve as a predictive biomarker for susceptibility to PD, providing new insights into the pathomechanisms of the disease and possible interventions.
PubMed: 38903897
DOI: 10.3389/fnagi.2024.1380483 -
Frontiers in Computational Neuroscience 2024Under normal conditions the principal cells of the striatum, medium spiny neurons (MSNs), show structured cell assembly activity patterns which alternate sequentially...
Under normal conditions the principal cells of the striatum, medium spiny neurons (MSNs), show structured cell assembly activity patterns which alternate sequentially over exceedingly long timescales of many minutes. It is important to understand this activity since it is characteristically disrupted in multiple pathologies, such as Parkinson's disease and dyskinesia, and thought to be caused by alterations in the MSN to MSN lateral inhibitory connections and in the strength and distribution of cortical excitation to MSNs. To understand how these long timescales arise we extended a previous network model of MSN cells to include synapses with short-term plasticity, with parameters taken from a recent detailed striatal connectome study. We first confirmed the presence of sequentially switching cell clusters using the non-linear dimensionality reduction technique, Uniform Manifold Approximation and Projection (UMAP). We found that the network could generate non-stationary activity patterns varying extremely slowly on the order of minutes under biologically realistic conditions. Next we used Simulation Based Inference (SBI) to train a deep net to map features of the MSN network generated cell assembly activity to MSN network parameters. We used the trained SBI model to estimate MSN network parameters from brain slice calcium imaging data. We found that best fit network parameters were very close to their physiologically observed values. On the other hand network parameters estimated from Parkinsonian, decorticated and dyskinetic slice preparations were different. Our work may provide a pipeline for diagnosis of basal ganglia pathology from spiking data as well as for the design pharmacological treatments.
PubMed: 38903730
DOI: 10.3389/fncom.2024.1410335 -
Frontiers in Neuroscience 2024Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons characterized by muscle weakness, muscle twitching, and muscle wasting.... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons characterized by muscle weakness, muscle twitching, and muscle wasting. ALS is regarded as the third-most frequent neurodegenerative disease, subsequent to Alzheimer's disease (AD) and Parkinson's disease (PD). The World Health Organization (WHO) in 2007 declared that prolonged use of statins may induce development of ALS-like syndrome and may increase ALS risk. Subsequently, different studies have implicated statins in the pathogenesis of ALS. In contrast, results from preclinical and clinical studies highlighted the protective role of statins against ALS neuropathology. Recently, meta-analyses and systematic reviews illustrated no association between long-term use of statins and ALS risk. These findings highlighted controversial points regarding the effects of statins on ALS pathogenesis and risk. The neuroprotective effects of statins against the development and progression of ALS may be mediated by regulating dyslipidemia and inflammatory changes. However, the mechanism for induction of ALS neuropathology by statins may be related to the dysregulation of liver X receptor signaling (LXR) signaling in the motor neurons and reduction of cholesterol, which has a neuroprotective effect against ALS neuropathology. Nevertheless, the exact role of statins on the pathogenesis of ALS was not fully elucidated. Therefore, this narrative review aims to discuss the role of statins in ALS neuropathology.
PubMed: 38903602
DOI: 10.3389/fnins.2024.1422912 -
Journal of Advanced Pharmaceutical... 2024In this study, we delved into the hippocampal region to understand the effects of adipose stem cells (ADSCs) and rosemary extract (RE). Our main objective was to explore...
In this study, we delved into the hippocampal region to understand the effects of adipose stem cells (ADSCs) and rosemary extract (RE). Our main objective was to explore how these substances influence spatial memory, neurotrophins, and changes in antioxidant enzymes. Moreover, we meticulously investigated the impact of dopamine deficiency, a notable characteristic linked with Parkinson's disease (PD), on memory impairment. This study comprised five groups of Wistar rats - all male, all selected randomly. We labeled two of these gatherings "lesion" (L) and "sham" (SH). Each got injections in the bilateral form with 6 μg - one group getting saline, while another got 6-OHDA. From couple weeks before the neurotoxin injection to 8 weeks later on, our lesion cohort was treated with rosemary at a dosage rate of 50 mg/kg body weight - let's call it RE for simplicity sake. Moreover, there is also this other lot, designated as cell-transplanted lesion group or catchy exercise (CE) as we prefer to interpret them; they had cell transplants conducted exactly 7 days after receiving their respective injections. Bringing up the rear, we got a group treated with both cell transplant and rosemary (CE+R). We performed spatial memory tests at 4 weeks, then again at 8. At the end of eighth week, the brains were extracted for q-PCR, enzymatic and immunohistochemical studies. Turning our gaze toward a comparison between the CE+R and CE groups versus the L group, we spot an intriguing drop in escape latency time. There is also more time spent in quadrants. Digging deeper into this matter, the CE+R bunch unveiled a clear surge when it comes to the expression of four genes, namely NGF, BDNF, NT3, and NT4! This was notable especially while comparing with both R and even other fellows from its very own broader group - CE. In a bit complex bit related to enzyme activity now, there is some good news as well for those in favor of potent antioxidants such as GPx or SOD. CE + R group, showed a significant increase of GPX and SOD enzymes, compared to the SH and L groups, and a significant decrease of MDA activity as compared to other treated groups. A significant decrease of escape latency and increase of time in quadrant were observed in the CE+R and CE groups compared to L group. What's more, the levels of MDA in the CE+R group plummeted significantly when set up against the SH group. Wrapping things up, a definite downscale was observed in the density of GFAP-positive cells throughout different regions located within the hippocampus; this decline presented itself not solely in treatment groups but gripped onto those falling under SH as well, especially when compared to its comrade - the L group. Using ADSCs and taking RE orally have shown promising results in improving memory issues linked with PD.
PubMed: 38903548
DOI: 10.4103/JAPTR.JAPTR_319_23 -
Frontiers in Human Neuroscience 2024A neurogenic dysphagia is dysphagia caused by problems with the central and peripheral nervous systems, is particularly prevalent in conditions such as Parkinson's... (Review)
Review
A neurogenic dysphagia is dysphagia caused by problems with the central and peripheral nervous systems, is particularly prevalent in conditions such as Parkinson's disease and stroke. It significantly impacts the quality of life for affected individuals and causes additional burdens, such as malnutrition, aspiration pneumonia, asphyxia, or even death from choking due to improper eating. Physical therapy offers a non-invasive treatment with high efficacy and low cost. Evidence supporting the use of physical therapy in dysphagia treatment is increasing, including techniques such as neuromuscular electrical stimulation, sensory stimulation, transcranial direct current stimulation, and repetitive transcranial magnetic stimulation. While initial studies have shown promising results, the effectiveness of specific treatment regimens still requires further validation. At present, there is a lack of scientific evidence to guide patient selection, develop appropriate treatment regimens, and accurately evaluate treatment outcomes. Therefore, the primary objectives of this review are to review the results of existing research, summarize the application of physical therapy in dysphagia management, we also discussed the mechanisms and treatments of physical therapy for neurogenic dysphagia.
PubMed: 38903410
DOI: 10.3389/fnhum.2024.1404398 -
Frontiers in Neurology 2024This study aimed to identify possible prognostic factors determining early tremor relapse after Magnetic Resonance guided Focused Ultrasound Surgery (MRgFUS) thalamotomy...
PURPOSE
This study aimed to identify possible prognostic factors determining early tremor relapse after Magnetic Resonance guided Focused Ultrasound Surgery (MRgFUS) thalamotomy in patients with essential tremor (ET) and Parkinson's disease (PD).
METHODS
Nine patients (six ET and three PD) who underwent Vim MRgFUS thalamotomy in a single institution and developed early re-emergent tremor were analyzed. A control group of patients matched pairwise for sex, pathology, age, disease duration, and skull density ratio (SDR) was selected to compare the technical-procedural data and MR imaging evidence. MR imaging findings compared between groups included lesion shape and volume in multiparametric sequences, as well as Fractiona Anisotropy (FA) and Apparent Diffusion Coefficient (ADC) values derived from Diffusion Tensor Imaging Diffusion Weighted Imaging (DTI) and Diffusion Weighted Imaging (DWI) sequences.
RESULTS
We did not find statistically significant differences in gender and age between the two groups. Technical and procedural parameters were also similar in both treatment groups. In MRI analysis, we found lesions of similar size but with greater caudal extension in the control group with stable outcomes compared to patients with tremor relapse.
CONCLUSION
In our analysis of early recurrences after thalamotomy with focused ultrasound, there were neither technical and procedural differences nor prognostic factors related to lesion size or ablation temperatures. Greater caudal extension of the lesion in patients without recurrence might suggest the importance of spatial consolidation during treatment.
PubMed: 38903176
DOI: 10.3389/fneur.2024.1356613 -
Frontiers in Neurology 2024Conventional care in Parkinson's disease (PD) faces limitations due to the significant time and location commitments needed for regular assessments, lacking quantitative...
INTRODUCTION
Conventional care in Parkinson's disease (PD) faces limitations due to the significant time and location commitments needed for regular assessments, lacking quantitative measurements. Telemonitoring offers clinicians an opportunity to evaluate patient symptomatology throughout the day during activities of daily living.
METHODS
The progression of PD symptoms over a two-year period was investigated in patients undergoing traditional evaluation, supplemented by insights from ambulatory measurements. Physicians integrated a telemonitoring device, the PDMonitor, into daily practice, using it for informed medication adjustments.
RESULTS
Statistical analyses examining intra-subject changes for 17 subjects revealed a significant relative decrease of -43.9% in the device-reported percentage of time spent in "OFF" state (from 36.2 to 20.3%). Following the 24-month period, the majority of the subjects improved or exhibited stable symptom manifestation. In addition to positively impacting motor symptom control, telemonitoring was found to enhance patient satisfaction about their condition, medication effectiveness, and communication with physicians.
DISCUSSION
Considering that motor function is significantly worsened over time in patients with PD, these findings suggest a positive impact of objective telemonitoring on symptoms control. Patient satisfaction regarding disease management through telemonitoring can potentially improve adherence to treatment plans. In conclusion, remote continuous monitoring paves the way for a paradigm shift in PD, focusing on actively managing and potentially improve symptoms control.
PubMed: 38903169
DOI: 10.3389/fneur.2024.1415970 -
BioRxiv : the Preprint Server For... Apr 2024Lysosomes are dynamic cellular structures that adaptively remodel their membrane in response to stimuli, including membrane damage. We previously uncovered a process we...
Lysosomes are dynamic cellular structures that adaptively remodel their membrane in response to stimuli, including membrane damage. We previously uncovered a process we term LYTL (LYsosomal Tubulation/sorting driven by Leucine-Rich Repeat Kinase 2 [LRRK2]), wherein damaged lysosomes generate tubules sorted into mobile vesicles. LYTL is orchestrated by the Parkinson's disease-associated kinase LRRK2 that recruits the motor adaptor protein and RHD family member JIP4 to lysosomes via phosphorylated RAB proteins. To identify new players involved in LYTL, we performed unbiased proteomics on isolated lysosomes after LRRK2 kinase inhibition. Our results demonstrate that there is recruitment of RILPL1 to ruptured lysosomes via LRRK2 activity to promote phosphorylation of RAB proteins at the lysosomal surface. RILPL1, which is also a member of the RHD family, enhances the clustering of LRRK2-positive lysosomes in the perinuclear area and causes retraction of LYTL tubules, in contrast to JIP4 which promotes LYTL tubule extension. Mechanistically, RILPL1 binds to p150 , a dynactin subunit, facilitating the transport of lysosomes and tubules to the minus end of microtubules. Further characterization of the tubulation process revealed that LYTL tubules move along tyrosinated microtubules, with tubulin tyrosination proving essential for tubule elongation. In summary, our findings emphasize the dynamic regulation of LYTL tubules by two distinct RHD proteins and pRAB effectors, serving as opposing motor adaptor proteins: JIP4, promoting tubulation via kinesin, and RILPL1, facilitating tubule retraction through dynein/dynactin. We infer that the two opposing processes generate a metastable lysosomal membrane deformation that facilitates dynamic tubulation events.
PubMed: 38903076
DOI: 10.1101/2024.04.02.587808