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Microglia activation is observed in various neurodegenerative diseases. Recent advances in single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified microglia in specific states correlate with pathological hallmarks and are associated with specific functions. Microglia both exert protective function by phagocytosing and clearing pathological protein aggregates and play detrimental roles due to excessive uptake of protein aggregates, which would lead to microglial phagocytic ability impairment, neuroinflammation, and eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes microglia into a pro-inflammatory phenotype and accelerates disease progression. Microglia also act as a mobile vehicle to propagate protein aggregates. Extracellular vesicles released from microglia and autophagy impairment in microglia all contribute to pathological progression and neurodegeneration. Thus, enhancing microglial phagocytosis, reducing microglial-mediated neuroinflammation, inhibiting microglial exosome synthesis and secretion, and promoting microglial conversion into a protective phenotype are considered to be promising strategies for the therapy of neurodegenerative diseases. Here we comprehensively review the biology of microglia and the roles of microglia in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies and Huntington’s disease. We also summarize the possible microglia-targeted interventions and treatments against neurodegenerative diseases with preclinical and clinical evidence in cell experiments, animal studies, and clinical trials.

Background Freezing of gait (FOG) is a common, disabling symptom of Parkinson’s disease (PD), but the mechanisms and treatments of FOG remain great challenges for clinicians and researchers. The main focus of this review is to summarize the possible mechanisms underlying FOG, the risk factors for screening and predicting the onset of FOG, and the clinical trials involving various therapeutic strategies. In addition, the limitations and recommendations for future research design are also discussed. Main body In the mechanism section, we briefly introduced the physiological process of gait control and hypotheses about the mechanism of FOG. In the risk factor section, gait disorders, PIGD phenotype, lower striatal DAT uptake were found to be independent risk factors of FOG with consistent evidence. In the treatment section, we summarized the clinical trials of pharmacological and non-pharmacological treatments. Despite the limited effectiveness of current medications for FOG, especially levodopa resistant FOG, there were some drugs that showed promise such as istradefylline and rasagiline. Non-pharmacological treatments encompass invasive brain and spinal cord stimulation, noninvasive repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) and vagus nerve stimulation (VNS), and physiotherapeutic approaches including cues and other training strategies. Several novel therapeutic strategies seem to be effective, such as rTMS over supplementary motor area (SMA), dual-site DBS, spinal cord stimulation (SCS) and VNS. Of physiotherapy, wearable cueing devices seem to be generally effective and promising. Conclusion FOG model hypotheses are helpful for better understanding and characterizing FOG and they provide clues for further research exploration. Several risk factors of FOG have been identified, but need combinatorial optimization for predicting FOG more precisely. Although firm conclusions cannot be drawn on therapeutic efficacy, the literature suggested that some therapeutic strategies showed promise.

Alzheimer’s disease (AD) is the most common neurodegenerative disease and the most common cause of dementia. Among various pathophysiological aspects, microglia are considered to play important roles in the pathogenesis of AD. Genome wide association studies (GWAS) showed that the majority of AD risk genes are highly or exclusively expressed in microglia, underscoring the critical roles of microglia in AD pathogenesis. Recently, omics technologies have greatly advanced our knowledge of microglia biology in AD. Omics approaches, including genomics, epigenomics, transcriptomics, proteomics, and metabolomics/lipidomics, present remarkable opportunities to delineate the underlying mechanisms, discover novel diagnostic biomarkers, monitor disease progression, and shape therapeutic strategies for diseases. In this review, we summarized research based on microglial “omics” analysis in AD, especially the recent research advances in the identification of AD-associated microglial subsets. This review reinforces the important role of microglia in AD and advances our understanding of the mechanism of microglia in AD pathogenesis. Moreover, we proposed the value of microglia-based omics in the development of therapeutic strategies and biomarkers for AD.

Background Acute lithium toxicity can cause cerebellar impairment, but long-term follow-up data are limited. We describe a case of acute lithium intoxication followed by progressive cerebellar atrophy and permanent cerebellar dysfunction. Case presentation Five years ago, a previously healthy 38-year-old man developed a clinical syndrome consistent with neuroleptic malignant syndrome (NMS)-like syndrome in the setting of acute lithium and quetiapine toxicity. On admission, the serum lithium concentration was 4.07 mmol/L and the cerebrospinal fluid lithium concentration was 2.45 mmol/L. Continuous renal replacement therapy (CRRT) was initiated, and cerebrospinal fluid lavage was also performed as documented in the outside hospital records. Serum lithium levels subsequently decreased to below 0.2 mmol/L. After treatment, consciousness improved. However, he developed a persistent cerebellar syndrome, characterized by ataxia, gait instability, and dysarthria. Brain magnetic resonance imaging one year later revealed cerebellar atrophy. Over five years of follow-up, severe ataxia persisted, and serial MRI showed progressive isolated cerebellar atrophy without supratentorial structural abnormalities. Conclusions This case suggests that severe acute lithium toxicity may be associated with progressive cerebellar degeneration, even after normalization of serum lithium levels. Clinicians should consider long-term follow-up for neurological sequelae in individuals suffering from acute lithium intoxication.

Ulcerative colitis (UC) is a chronic, recurrent inflammatory bowel disease. UC confronts with severe challenges including the unclear pathogenesis and lack of specific diagnostic markers, demanding for identifying predictive biomarkers for UC diagnosis and treatment. We perform immune infiltration and weighted gene co-expression network analysis on gene expression profiles of active UC, inactive UC, and normal controls to identify UC related immune cell and hub genes. Neutrophils, M1 macrophages, activated dendritic cells, and activated mast cells are significantly enriched in active UC. MMP-9, CHI3L1, CXCL9, CXCL10, CXCR2 and S100A9 are identified as hub genes in active UC. Specifically, S100A9 is significantly overexpressed in mice with colitis. The receiver operating characteristic curve demonstrates the excellent performance of S100A9 expression in diagnosing active UC. Inhibition of S100A9 expression reduces DSS-induced colonic inflammation. These identified biomarkers associated with activity in UC patients enlighten the new insights of UC diagnosis and treatment.

Gait impairments are among the most common and disabling symptoms of Parkinson’s disease and worsen as the disease progresses. Early detection and diagnosis of subtype-specific gait deficits, as well as progression monitoring, can help to implement effective and preventive personalized treatment for PD patients. Yet, the gait features have not been fully studied in PD and its motor subtypes. To characterize comprehensive and objective gait alterations and to identify the potential gait biomarkers for early diagnosis, subtype differentiation, and disease severity monitoring. We analyzed gait parameters related to upper/lower limbs, trunk and lumbar, and postural transitions from 24 tremor-dominant (TD) and 20 postural instability gait difficulty (PIGD) dominant PD patients who were in early stage and 39 matched healthy controls (HC) during the Timed Up and Go test using wearable sensors. Results show: (1) Both TD and PIGD groups showed restricted backswing range in bilateral lower extremities and more affected side (MAS) arm, reduced trunk and lumbar rotation range in the coronal plane, and low turning efficiency. The receiver operating characteristic (ROC) analysis revealed these objective gait features had high discriminative value in distinguishing both PD subtypes from the HC with the area under the curve (AUC) values of 0.7~0.9 ( p  < 0.01). (2) Subtle but measurable gait differences existed between TD and PIGD patients before the onset of clinically apparent gait impairment. (3) Specific gait parameters were significantly associated with disease severity in TD and PIGD subtypes. Objective gait biomarkers based on wearable sensors may facilitate timely and personalized gait treatments in PD subtypes through early diagnosis, subtype differentiation, and disease severity monitoring.

Background Parkinson’s disease (PD) is often clinically associated with posture instability and more easily falling. The Berg balance scale is a clinical indicator commonly used to subjectively evaluate a patient’s balance ability. Meanwhile, computerized force platforms have been used in research on postural control. The various parameters obtained from posturography are interpreted to assess balance ability. The present study aims to explore the correlations between posturographic variables and the BBS, and furthermore to efficiently evaluate postural instability and fall risk of early and moderate PD patients. Methods A total of 46 PD patients were involved in the experiment. Patients were asked to perform BBS tests and force platform tests under eye open (EO) and eye closed (EC) conditions. The recorded COP signal was analyzed with the time domain statistical method, the frequency domain method of Power Spectral Density (PSD), and structural methods of Stabilogram Diffusion Analysis (SDA), Sway Density Plot (SDP) to retrieve different posturographic variables. The correlation between posturographic variables under EO and EC conditions with BBS was compared statistically. The significantly correlated posturographic parameters were then applied to analyze posturographic differences between different groups: faller vs. non-faller (patients with/without a history of falls in the past 12 months). Results Among the different posturographic parameters, the prediction ellipse area, the slope of the regression line at a high-frequency band of PSD in the medial-lateral (ML) direction, the crossover point of the regression lines of SDA in the anterior-posterior (AP) direction, and the distance between successive peaks of SDP had significant correlations with BBS. These selected BBS-related parameters also showed significant differences between faller and non-faller. The selected posturographic parameters can be used as effective indicators to evaluate the balance ability of Parkinson’s disease patients.

BackgroundTransoral endoscopic thyroid surgery via the vestibular approach (TOETVA) has been gradually accepted worldwide due to its scar-free effect on the neck. Even central cervical lymphadenectomy has been performed in some cases of papillary thyroid carcinoma (PTC). However, there are few reports involving lateral neck dissection with TOETVA. In this study, we attempted to perform selective lateral neck dissection (SLND) for PTC via a transoral vestibular approach.MethodsThis prospective study was conducted from January 2016 to December 2018 in twenty PTC patients with unilateral T1 tumors without capsular invasion and patients with abnormal level III and IV lymph nodes who underwent SLND via a transoral vestibular approach.ResultsEndoscopic surgery was successfully accomplished in all 20 PTC patients. The mean age was 29.2 ± 5.5 (20–41) years. The mean operation time was 146.0 ± 18.7 (114–193) min. The average postoperative hospital stay was 6.8 ± 1.3 (5–10) days. The mean number of removed nodes was 7.4 ± 2.5 (4–12) in the central neck and 10.9 ± 2.8 (6–16) in the lateral neck, and the positive yield amounts were 2.0 ± 1.2 (0–4) and 2.7 ± 1.9 (0–6), respectively. No major complications occurred except for 1 case of transient unilateral recurrent laryngeal nerve palsy and two cases of effusion in the operative area. No evidence of persistent or recurrent disease was observed in these patients during a mean follow-up of 24.3 ± 9.1 (6–36) months. The cosmetic results and protection of personal privacy of this procedure were excellent.ConclusionEndoscopic SLND via the transoral vestibular approach is feasible, safe, and effective for selected PTCs. A multicenter large comparative study is necessary.

Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized with dopaminergic neuron (DaN) loss within the substantia nigra (SN). Despite bulk studies focusing on intracellular mechanisms of PD inside DaNs, few studies have explored the pathogeneses outside DaNs, or between DaNs and other cells. Here, we set out to probe the implication of intercellular communication involving DaNs in the pathogeneses of PD at a systemic level with bioinformatics methods. We harvested three online published single-cell/single-nucleus transcriptomic sequencing (sc/snRNA-seq) datasets of human SN (GSE126838, GSE140231 and GSE157783) from the Gene Expression Omnibus (GEO) database, and integrated them with one of the latest integration algorithms called Harmony. We then applied CellChat, the latest cell-cell communication analytic algorithm, to our integrated dataset. We first found that the overall communication quantity was decreased while the overall communication strength was enhanced in PD sample compared with control sample. We then focused on the intercellular communication where DaNs are involved, and found that the communications between DaNs and other cell types via certain signaling pathways were selectively altered in PD, including some growth factors, neurotrophic factors, chemokines, etc. pathways. Our bioinformatics analysis showed that the alteration in intercellular communications involving DaNs might be a previously underestimated aspect of PD pathogeneses with novel translational potential.

Railways around the world are experiencing growth in traffic flow, but the problem concerning how to optimize the utilization of capacity is still demands significant research. To accommodate the increasing traffic demand, the high-speed railway operator in China is interested in understanding the potential benefit of adopting reasonable headway to balance the safety and efficiency of train operations. In this study, a compress timetable scheduling model based on the UIC Code 406 method is presented to evaluate the line capacity. In this model, train headway is not pre-fixed as in the existing research, but considers the actual operating conditions and is calculated using actual running data. The results of the case study show that refined headway calculations generally have positive capacity effects.