MicroRNA-218-5p-Ddx41 axis restrains microglia-mediated neuroinflammation through downregulating type I interferon response in a mouse model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Microglia-mediated neuroinflammation has been largely considered one of main factors to the PD pathology. MicroRNA-218-5p (miR-218-5p) is a microRNA that plays a role in neurodevelopment and function, while its potential function in PD and neuroinflammation remains unclear. METHODS: We explore the involvement of miR-218-5p in the PD in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model. The miR-218-5p agomir used for overexpression was delivered into the substantia nigra (SN) by bilateral stereotaxic infusions. The loss of dopaminergic (DA) neurons and microglial inflammation in the SN was determined using Western blotting and immunofluorescence. Motor function was assessed using the rotarod test. RNA sequencing (RNA-seq) was performed to explore the pathways regulated by miR-218-5p. The target genes of miR-218-5p were predicted using TargetScan and confirmed using dual luciferase reporter assays. The effects of miR-218-5p on microglial inflammation and related pathways were verified in murine microglia-like BV2 cells. To stimulate BV2 cells, SH-SY5Y cells were treated with 1-methyl-4-phenylpyridinium (MPP+) and the conditioned media (CM) were collected. RESULTS: MiR-218-5p expression was reduced in both the SN of MPTP-induced mice and MPP+-treated BV2 cells. MiR-218-5p overexpression significantly alleviated MPTP-induced microglial inflammation, loss of DA neurons, and motor dysfunction. RNA sequence and gene set enrichment analysis showed that type I interferon (IFN-I) pathways were upregulated in MPTP-induced mice, while this upregulation was reversed by miR-218-5p overexpression. A luciferase reporter assay verified that Ddx41 was a target gene of miR-218-5p. In vitro, miR-218-5p overexpression or Ddx41 knockdown inhibited the IFN-I response and expression of inflammatory cytokines in BV2 cells stimulated with MPP+-CM. CONCLUSIONS: MiR-218-5p suppresses microglia-mediated neuroinflammation and preserves DA neurons via Ddx41/IFN-I. Hence, miR-218-5p-Ddx41 is a promising therapeutic target for PD.

Multi-organ involvement caused by Scedosporium apiospermum infection after near drowning: a case report and literature review.

BACKGROUND: Scedosporium apiospermum (S. apiospermum) is a rare fungal pathogen that causes disseminated infections. It rarely affects immunocompetent individuals and has a poor prognosis. CASE PRESENTATION: A 37-year-old woman presented with multiple lesions in the lungs, brain, and eyes, shortly after near drowning in a car accident. The primary symptoms were chest tightness, limb weakness, headache, and poor vision in the left eye. S. apiospermum infection was confirmed by metagenomic next-generation sequencing (mNGS) of intracranial abscess drainage fluid, although intracranial metastases were initially considered. After systemic treatment with voriconazole, her symptoms improved significantly; however, she lost vision in her left eye due to delayed diagnosis. CONCLUSION: While S. apiospermum infection is rare, it should be considered even in immunocompetent patients. Prompt diagnosis and treatment are essential. Voriconazole may be an effective treatment option.

The bacterial pathogen Pseudomonas plecoglossicida, its epidemiology, virulence factors, vaccine development, and host-pathogen interactions.

OBJECTIVE: Pseudomoans plecoglossicida has been identified as a fish pathogen since 2000 and has caused serious infections in cultured Large Yellow Croakers Larimiththys crocea in coastal eastern China during recent years. METHODS: Published literatures of this pathogen have been reviewed. RESULT: Several strains with high genomic similarity have been isolated and identified; the bacteria induce natural infection at lower water temperatures (12.0-25.5°C) and induce numerous granulomas and nodules in the visceral organs of croakers. Researchers have investigated the epidemiology of P. plecoglossicida infection, identified major virulence factors, searched for pathogenic genes, analyzed host-pathogen interactions, and endeavored to develop efficient vaccines. CONCLUSION: This paper provides an overview of these research advances to elucidate the virulence mechanisms of the pathogen and to promote vaccine development against infection.

α-Synuclein induces Th17 differentiation and impairs the function and stability of Tregs by promoting RORC transcription in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons (DA) and the accumulation of Lewy body deposits composed of alpha-Synuclein (α-Syn), which act as antigenic epitopes to drive cytotoxic T-cell responses in PD. Increased T helper 17 (Th17) cells and dysfunctional regulatory T cells (Tregs) have been reported to be associated with the loss of DA in PD. However, the mechanism underlying the Th17/Treg imbalance remains unknown. METHODS: Here, we examined the percentage of Th17 cells, the percentage of Tregs and the α-Syn level and analysed their correlations in the peripheral blood of PD patients and in the substantia nigra pars compacta (SNpc) and spleen of MPTP-treated mice and A53 transgenic mice. We assessed the effect of α-Syn on the stability and function of Tregs and the differentiation of Th17 cells and evaluated the role of retinoid-related orphan nuclear receptor (RORγt) upregulation in α-Syn stimulation in vivo and in vitro. RESULTS: We found that the α-Syn level and severity of motor symptoms were positively correlated with the increase in Th17 cells and decrease in Tregs in PD patients. Moreover, α-Syn stimulation led to the loss of Forkhead box protein P3 (FOXP3) expression in Tregs, accompanied by the acquisition of IL-17A expression. Increased Th17 differentiation was detected upon α-Syn stimulation when naïve CD4+ T cells were cultured under Th17-polarizing conditions. Mechanistically, α-Syn promotes the transcription of RORC, encoding RORγt, in Tregs and Th17 cells, leading to increased Th17 differentiation and loss of Treg function. Intriguingly, the increase in Th17 cells, decrease in Tregs and apoptosis of DA were suppressed by a RORγt inhibitor (GSK805) in MPTP-treated mice. CONCLUSION: Together, our data suggest that α-Syn promotes the transcription of RORC in circulating CD4+ T cells, including Tregs and Th17 cells, to impair the stability of Tregs and promote the differentiation of Th17 cells in PD. Inhibition of RORγt attenuated the apoptosis of DA and alleviated the increase in Th17 cells and decrease in Tregs in PD.

Upregulated hexokinase 2 expression induces the apoptosis of dopaminergic neurons by promoting lactate production in Parkinson's disease.

Parkinson's disease (PD) is characterized by impaired mitochondrial function and decreased ATP levels. Aerobic glycolysis and lactate production have been shown to be upregulated in dopaminergic neurons to sustain ATP levels, but the effect of upregulated glycolysis on dopaminergic neurons remains unknown. Since lactate promotes apoptosis and α-synuclein accumulation in neurons, we hypothesized that the lactate produced upon upregulated glycolysis is involved in the apoptosis of dopaminergic neurons in PD. In this study, we examined the expression of hexokinase 2 (HK2) and lactate dehydrogenase (LDH), the key enzymes in glycolysis, and lactate levels in the substantia nigra pars compacta (SNpc) of a MPTP-induced mouse model of PD and in MPP+-treated SH-SY5Y cells. We found that the expression of HK2 and LDHA and the lactate levels were markedly increased in the SNpc of MPTP-treated mice and in MPP+-treated SH-SY5Y cells. Exogenous lactate treatment led to the apoptosis of SH-SY5Y cells. Intriguingly, lactate production and the apoptosis of dopaminergic neurons were suppressed by the application of 3-bromopyruvic acid (3-Brpa), a HK2 inhibitor, or siRNA both in vivo and in vitro. 3-Brpa treatment markedly improved the motor behaviour of MPTP-treated mice in pole test and rotarod test. Mechanistically, lactate increases the activity of adenosine monophosphate-activated protein kinase (AMPK) and suppresses the phosphorylation of serine/threonine kinase 1 (Akt) and mammalian target of rapamycin (mTOR). Together, our data suggest that upregulated HK2 and LDHA and increased lactate levels prompt the apoptosis of dopaminergic neurons in PD. Inhibition of HK2 expression attenuated the apoptosis of dopaminergic neurons by downregulating lactate production and AMPK/Akt/mTOR pathway in PD.

Characterization of 4 deletion mutants of Pseudomonas plecoglossicida and their potential for live attenuated vaccines in large yellow croaker (Larimichthys crocea).

To search for live attenuated vaccines (LAV) candidates against Pseudomonas plecoglossicida, the causative agent of the visceral granulomas disease in farmed large yellow croaker (Larimichthys crocea), two type Ⅵ secretion systems (T6SS) and a predicted α/ß fold family hydrolase encoding gene, ORF4885 were targeted to construct deletion mutants. The biological profiles of 4 mutants were characterized; LD50 to the croakers detected, in vivo survival post-infection investigated， relative percent of survival (RPS) of the croakers 28d post-vaccination determined, and transcription of five immunity-related genes of the treated fish was quantified. On comparison to the WT, the mutants revealed similar growth curves in 11h; swarming motility of Δ4885 declined significantly at 72h post-incubation (P < 0.05); ΔS1Δ4885 showed significantly poor biofilm formation and weak resistance to fish serum bactericidal activity (P < 0.05). LD50 of the mutants were much higher than the WT, indication of strong virulence attenuation; in vivo survival test showed the mutant ΔS1Δ4885 and ΔS1ΔS3 were eliminated by the host 10d post-infection, demonstration of the safety and potentiality to be LAV candidates. Immunization with the mutant ΔS1Δ4885 provided higher RPS than ΔS1ΔS3. Transcription of IgT was significant in all immunized groups while IgM increased only in intraperitoneally injected groups. This study successfully searched a quite safe and strong immunogenic LAV candidate to defeat P. plecoglossicida infection.

Preliminary studies on the different roles of T6SSs in pathogenicity of Pseudomonas plecoglossicida NB2011.

Pseudomonas plecoglossicida, the causative agent of visceral granulomas in the large yellow croaker (Larimichthys crocea) in China, encodes three sets of type Ⅵ secretion systems (T6SS1-3). The purpose of this study was to characterize the different roles of T6SSs involved in infection. In-frame deletion of T6SSs was constructed, which resulted in 8 mutants. Competition against E. coli DH5α, virulence against the croaker and in vivo survival ability of the mutants were tested. The expression and secretion of Hcp by P. plecoglossicida NB2011 were investigated. The results showed T6SS2 mutant failed to inhibit the growth of E. coli, which is an indication of T6SS2 acting against environmental bacteria. The LD50 value of T6SS1 mutant strongly increased; T6SS2 and T6SS3 mutants were similar to that of the wild type; and the virulence of double deletion or triple deletion mutant was drastically alleviated, indicating that T6SS1 being one of the major virulence factors, and T6SS2 and T6SS3 directly or indirectly being involved in the pathogenicity. T6SS1 mutant disappeared in the fish spleen in 3 days, while other strains kept increasing, indicating the T6SS1 stimulation bacteria replication in vivo. Hcp1 secreted at 12-28°C and Hcp2 secreted at 12-35°C, while Hcp3 secretion not detected in vitro. This study has thrown some insights on the understanding of pathogenicity mechanisms of this pathogen.

The NLRP3 Inflammasome is Involved in the Pathogenesis of Parkinson's Disease in Rats.

The etiology and pathogenesis of Parkinson's disease (PD) are complicated and have not been fully elucidated, but an important association has been identified between inflammation and PD. In this study, we investigated the role of the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing (NLRP) 3 inflammasome, consisting of NLRP3, caspase-1 and cytokines of the IL-1 family, in lipopolysaccharide (LPS)-induced and 6-hydroxydopamine (6-OHDA)-induced PD rats. Microinjection of different doses of caspase-1 inhibitor (Ac-YVAD-CMK, 300 or 1200 ng/rat) was performed for seven consecutive days. Then, rotational behavior, the number of dopamine (DA) neurons in the substantia nigra pars compacta (SNc), and the mRNA and protein expression levels of NLRP3 inflammasome components were measured 14 days after the microinjection setup was established. Results showed that high mRNA and protein expression levels of NLRP3 inflammasome components were observed in the injected side of the LPS- and 6-OHDA-induced PD rats; Ac-YVAD-CMK inhibited the mRNA and protein expression of NLRP3 inflammasome components in both LPS- and 6-OHDA-induced PD rats. Moreover, the number of rotations was significantly decreased, and the number of DA neurons in the SNc improved. Our data indicate that the NLRP3 inflammasome participates in the pathogenesis of PD and that inhibiting the downstream pathway of the NLRP3/caspase-1/IL-1ß axis can alleviate the occurrence of PD symptoms, providing a new basis for the prevention and treatment of PD.

Quantitative assessment of iron deposition in Parkinson's disease using enhanced T2 star-weighted angiography.

BACKGROUND: It has been reported that R2* is a sensitive marker for iron deposition. The aim of this study was to quantitatively assess iron deposition in Parkinson's disease (PD) using changes of R2* in enhanced T2 star-weighted angiography (ESWAN) and to discuss the value of ESWAN for PD. METHODS: Fifty-four primary PD patients and twenty-eight healthy individuals were examined by ESWAN in the 3·0 T magnetic resonance imaging system. The R2* values were measured from the deep gray nuclei (including the substantia nigra [SN], red nuclei, globus pallidus, putamina, caudate nuclei, and thalami). The unified PD rating scale (UPDRS) III assessment, the nonmotor symptoms scale (NMSS), and the mini mental state examination (MMSE) were used to rate all the patients. RESULTS: The comparison of the R* values between the deep gray nuclei on the same side of the PD patients and the control group revealed significant differences in the SN and red nuclei (P < 0.05). There was a significant difference between Hoehn and Yahr (HY) 1 and HY2-4 patients in terms of the values of the SN. There was a slight correlation between the R* values of the SN of the PD patients (HY >1) and the UPDRS III ratings. No correlation between the R* signal values in the PD patients and the NMSS and MMSE scales was found. CONCLUSION: Iron concentrations in the regions of interest may represent the severity of the PD motor symptoms, and whether they are related to the nonmotor symptoms remains a question for further investigation. ESWAN offers special advantages in determining iron depositions in the brain and in enabling a sensitive diagnosis of PD, although further study is necessary.

Scylla serrata reovirus p35 protein expressed in Escherichia coli cells alters membrane permeability.

To promote viral entry, replication, release, and spread to neighboring cells, many cytolytic animal viruses encode proteins responsible for modification of host cell membrane permeability and for formation of ion channels in host cell membranes. Scylla serrata reovirus (SsRV) is a major pathogen that can severely damage mud crab (S. serrata) aquaculture. Protein p35, which is encoded by segment 10 of SsRV, contains two transmembrane domains. In this study, we found that SsRV p35 can induce membrane permeability changes when expressed in Escherichia coli. SsRV p35 expressed in bacterial cells existed as monomers under reducing conditions but formed homodimers and homotrimers under non-reducing conditions. These findings demonstrate that p35 may act as a viroporin; further studies are needed to elucidate the detailed structure-function relationships of this protein.

Coexistence of Parkinson's disease and myasthenia gravis: A case report and literature review.

The coexistence of Parkinson's disease (PD) and myasthenia gravis (MG) is rare. When similar symptoms of both diseases overlap, it is challenging to make a concomitant diagnosis of PD and MG. The present study describes the case of a patient with concomitant PD and MG. In addition, a systematic literature review was conducted by searching PubMed and Embase for reports on all patients with concomitant PD and MG, which were then grouped and compared according to different preexisting diseases. Finally, a total of 47 cases of concomitant PD and MG (35 men; 12 women), including the present case, were analyzed. The median age of the patients at first diagnosis was 66.59±9.91 years. The interval between the two diseases varied from 2 months to 22 years. Based on the sequential occurrence of these two diseases, the patients were categorized into three groups: The prePD-MG (30 cases), preMG-PD (12 cases), and coPD-MG (5 cases) groups. In the prePD-MG group, the onset age of MG was older and head drop was more common. In the preMG-PD group, the patients were more likely to have comorbid immune diseases.

Third ventricular width by transcranial sonography is associated with cognitive impairment in Parkinson's disease.

BACKGROUND: One-fourth of Parkinson's disease (PD) patients suffer from cognitive impairment. However, few neuroimaging markers have been identified regarding cognitive impairment in PD. OBJECTIVE: This study aimed to explore the association between third ventricular width by transcranial sonography (TCS) and cognitive decline in PD. METHOD: Participants with PD were recruited from one medical center in China. Third ventricular width was assessed by TCS, and cognitive function was analyzed by the Mini-Mental State Examination (MMSE). Receiver operating characteristic (ROC) analysis and Cox model analysis were utilized to determine the diagnostic and predictive accuracy of third ventricular width by TCS for cognitive decline in PD patients. RESULT: A total of 174 PD patients were recruited. Third ventricular width was negatively correlated with MMSE scores. ROC analysis suggested that the optimal cutoff point for third ventricular width in screening for cognitive impairment in PD was 4.75 mm (sensitivity 62.7%; specificity 75.6%). After 21.5 (18.0, 26.0) months of follow-up in PD patients without cognitive impairment, it was found that those with a third ventricular width greater than 4.75 mm exhibited a 7.975 times higher risk of developing cognitive impairment [hazard ratio = 7.975, 95% CI 1.609, 39.532, p = 0.011] compared with patients with a third ventricular width less than 4.75 mm. CONCLUSION: Third ventricular width based on TCS emerged as an independent predictor of developing cognitive impairment in PD patients.

Vaccination efficiency of surface antigens and killed whole cell of Pseudomonas putida in large yellow croaker (Pseudosciaena crocea).

Large yellow croaker (Pseudosciaena crocea), a major marine fish aquacultured in the southeastern coastal region of China, has become endangered by the pathogen Pseudomonas putida in recent years. P. putida infections occur in low water temperatures when fish reduce food intake, thus oral antibiotic administration is not practical. Therefore, vaccination may be the only method to prevent the infection. In the present study, main surface antigens of P. putida, including lipopolysaccharide (LPS), outer membrane proteins (OMP), extracellular biofilm polysaccharide (EPS), and formalin-killed cell (FKC) bacterin, were prepared and the fish vaccinated. On post-immunization day 28, serum antibody titers, phagocytic responses of leukocytes, and lysozyme activities of the fish were evaluated. The efficiency of vaccination was tested by artificial challenge via intraperitoneal injection of live bacteria on post-immunization day 28 and 35, respectively. The results showed that although significant humoral and innate immune responses were elicited in all vaccination groups, the challenge produced similar poor protection in both tests, with a relative percent survival (RPS) of 0-40%. Although the EPS group showed a complete lack of protection, LPS reached the highest RPS value (40%), suggesting that LPS may be involved in protection immunity against the pathogen. Further analysis of the ultra-structures of tissues from infected fish via TEM revealed macrophage survival and intracellular replication ability of the pathogen. New strategies for development might put more emphasis on efficient clearance of intracellular bacteria. The present study is the first to report vaccination against the fish pathogen P. putida and the first investigation of intracellular survival of this pathogen in host macrophages.

Diagnostic Performance of Putaminal Hypointensity on Susceptibility MRI in Distinguishing Parkinson Disease from Progressive Supranuclear Palsy: A Meta-Analysis.

Background: Idiopathic Parkinson's disease (IPD) and progressive supranuclear palsy (PSP) have similar clinical signs and symptoms, making accurate clinical diagnosis difficult. T2* gradient echo (T2* GRE), susceptibility-weighted imaging (SWI), and quantitative susceptibility mapping (QSM) are susceptibility MR imaging sequences that provide more information about brain iron levels than other conventional MR imaging. Objective: This study aimed to evaluate the diagnostic power of putaminal hypointensity on T2* GRE, SWI, and QSM in distinguishing PSP from IPD. Methods: Eligible studies were identified via systematic searches of PubMed and Clarivate Analytics® Web of Science® Core Collection. Studies that satisfied the inclusion and exclusion criteria were reviewed. A meta-analysis was conducted using the hierarchical summary receiver operating characteristic curve approach. Results: Our literature search of the two databases yielded 562 primary articles, 10 of which were deemed relevant and only six were eligible for further analyses. We performed a meta-analysis of putaminal hypointensity measurements: 438 patients with IPD and 109 patients with PSP were enrolled in the quantitative synthesis. The meta-analysis of six studies with 547 patients revealed a sensitivity of 69% (95% confidence interval (CI): 33%-90%) and specificity of 91% (95% CI: 80%-96%) for putaminal hypointensity on T2* GRE, SWI, or QSM distinguishing PSP from IPD. Conclusions: Putaminal hypointensity on T2* GRE, SWI, or QSM is able to distinguish patients with PSP from those with IPD with high specificity. Further multicenter prospective studies on patients are needed to verify our results.

CCL5 promotes LFA-1 expression in Th17 cells and induces LCK and ZAP70 activation in a mouse model of Parkinson's disease.

Background: Parkinson's disease (PD), which is associated to autoimmune disorders, is characterized by the pathological deposition of alpha-synuclein (α-Syn) and loss of dopaminergic (DA) neurons. Th17 cells are thought to be responsible for the direct loss of DA neurons. C-C chemokine ligand 5 (CCL5) specifically induces Th17 cell infiltration into the SN. However, the specific effect of CCL5 on Th17 cells in PD and the relationship between CCL5 and lymphocyte function-associated antigen-1 (LFA-1) expression in Th17 cells are unknown. Methods: We evaluated the effects of CCL5 on LFA-1 expression in Th17 cells in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and examined Th17 cell differentiation upon CCL5 stimulation in vitro. Furthermore, we assessed the effects of CCL5 on tyrosine kinase zeta-chain-associated protein kinase 70 (ZAP70) and lymphocyte-specific protein tyrosine kinase (LCK) activity in CCL5-stimulated Th17 cells in vivo and in vitro. Results: CCL5 increased the proportion of peripheral Th17 cells in MPTP-treated mice, LFA-1 expression on Th17 cells, and Th17 cell levels in the SN of MPTP-treated mice. CCL5 promoted Th17 cell differentiation and LFA-1 expression in naive T cells in vitro. Moreover, CCL5 increased Th17 cell differentiation and LFA-1 expression by stimulating LCK and ZAP70 activation in naive CD4+ T cells. Inhibiting LCK and ZAP70 activation reduced the proportion of peripheral Th17 cells and LFA-1 surface expression in MPTP-treated mice, and Th17 cell levels in the SN also significantly decreased. Conclusion: CCL5, which increased Th17 cell differentiation and LFA-1 protein expression by activating LCK and ZAP70, could increase the Th17 cell number in the SN, induce DA neuron death and aggravate PD.

A systematic review and meta-analysis of inflammatory biomarkers in Parkinson's disease.

Neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD), but controversies persist. Studies reporting concentrations of blood or cerebrospinal fluid (CSF) markers for patients with PD and controls were included and extracted. Pooled Hedges'g was adopted to illustrate comparisons, and covariates were used to explore sources of heterogeneity. Finally, 152 studies were included. Increased IL-6, TNF-α, IL-1ß, STNFR1, CRP, CCL2, CX3CL1, and CXCL12 levels and decreased INF-γ and IL-4 levels were noted in the PD group. In addition, increased CSF levels of IL-6, TNF-α, IL-1ß, CRP and CCL2 were revealed in patients with PD compared to controls. Consequently, significantly altered levels of inflammatory markers were verified between PD group and control, suggesting that PD is accompanied by inflammatory responses in both the peripheral blood and CSF. This study was registered with PROSPERO, CRD42022349182.

Freezing of gait is a risk factor for cognitive decline in Parkinson's disease.

BACKGROUNDS: Freezing of gait (FOG) and cognitive impairment are serious symptoms of Parkinson's disease (PD). Understanding the association between FOG and cognition may help formulate specific interventions for PD individuals. OBJECTIVES: We aimed to investigate the associations of cognitive impairment in different domains with FOG status using multiple neuropsychological tests. METHODS: Two cohorts including 691 and 104 participants were recruited from Parkinson's progression markers initiative (PPMI) and central China, respectively. All participants underwent FOG assessment and neuropsychological tests, and 595 individuals from PPMI and 51 from central China were enrolled for longitudinal observation. Cross-sectional and longitudinal associations between cognition and FOG status were evaluated using multivariable-adjusted models. RESULTS: Worse cognitive performances were observed in patients with FOG compared to those without FOG in both cohorts (ß = - 0.020, p < 0.001) using multivariate-adjusted models. Moreover, patients with progressive FOG during follow-up manifested more serious cognitive declines (HR = 1.40, 95% CI = 1.07-1.80). The FOG was mainly associated with the decline of executive, attention, and orientation. Furthermore, FOG was associated with higher levels of cognition-related biomarkers including T-tau, P-tau, and NfL in cerebrospinal fluid (p < 0.050). CONCLUSIONS: FOG is a risk factor for cognitive decline in PD, which emphasizes the need for early detection and monitoring of cognitive changes and interventions on cognitive impairments in PD patients with FOG.

Estimated glomerular filtration rate is a biomarker of cognitive impairment in Parkinson's disease.

Backgrounds: The relationship between kidney function and cognitive impairment in Parkinson's disease (PD) is poorly understood and underexplored. This study aims to explore whether renal indices can serve as indicators to monitor the cognitive impairment of PD. Methods: A total of 508 PD patients and 168 healthy controls from the Parkinson's Progression Markers Initiative (PPMI) were recruited, and 486 (95.7%) PD patients underwent longitudinal measurements. The renal indicators including serum creatinine (Scr), uric acid (UA), and urea nitrogen, as well as UA/Scr ratio and estimated glomerular filtration rate (eGFR), were measured. Cross-sectional and longitudinal associations between kidney function and cognitive impairment were evaluated using multivariable-adjusted models. Results: eGFR was associated with lower levels of cerebrospinal fluid (CSF) Aß1-42 (p = 0.0156) and α-synuclein (p = 0.0151) and higher serum NfL (p = 0.0215) in PD patients at baseline. Longitudinal results showed that decreased eGFR predicted a higher risk of cognitive impairment (HR = 0.7382, 95% CI = 0.6329-0.8610). Additionally, eGFR decline was significantly associated with higher rates of increase in CSF T-tau (p = 0.0096), P-tau (p = 0.0250), and serum NfL (p = 0.0189), as well as global cognition and various cognitive domains (p < 0.0500). The reduced UA/Scr ratio was also linked to higher NfL levels (p = 0.0282) and greater accumulation of T-tau (p = 0.0282) and P-tau (p = 0.0317). However, no significant associations were found between other renal indices and cognition. Conclusion: eGFR is altered in PD subjects with cognitive impairment, and predict larger progression of cognitive decline. It may assist identifying patients with PD at risk of rapid cognitive decline and have the potential to monitoring responses to therapy in future clinical practice.

Molecular characterization of eight segments of Scylla serrata reovirus (SsRV) provides the complete genome sequence.

Scylla serrata reovirus (SsRV) is one of the most prevalent viral pathogens of mud crabs (S. serrata). Of the 12 double-stranded RNA (dsRNA) genomic segments (S1-S12), the three largest (S1-S3) and S7 were sequenced previously and were shown to have no or only low sequence homology to known members within the family Reoviridae. The sequences of the remaining segments, S4-S6 and S8-S12, are reported here. With the exception of S4, all have single open reading frames (ORFs) on their positive strands, and the terminal sequences 5'-AUAAA(U)/(C) (A)/(U)…G(A)/(G) (A)/(U) (A)/(C)AAC(G)/(U)AU-3' are conserved among currently and previously sequenced segments. S4 contains two out-of-phase ORFs on the positive strand, suggesting that this segment is bicistronic. The ORFs of segments S4-S6 and S8-S12 have low or no homology to other reovirus genes, with the exception that all of the SsRV segments have high sequence similarity to those of mud crab reovirus (MCRV) and share the same 5'- and 3'-terminal nucleotide sequences, suggesting that the two viruses belong to the same species in the family Reoviridae. Analysis of virion proteins revealed that SsRV contains at least eight structural proteins, with sizes ranging from 25 to 160 kDa.

A nomogram based on iron metabolism can help identify apathy in patients with Parkinson's disease.

Backgrounds: Apathy is common in Parkinson's disease (PD) but difficult to identify. Growing evidence suggests that abnormal iron metabolism is associated with apathy in PD. We aimed to investigate the clinical features and iron metabolism of apathetic patients with PD, and construct a nomogram for predicting apathy in PD. Methods: Data of 201 patients with PD were analyzed. Demographic data, Apathy Scale (AS) assessments, and serum iron metabolism parameters were obtained. Spearman correlations were used to assess relationships between AS scores and iron metabolism parameters, separately for male and female patients. Additionally, a nomograph for detecting apathetic patients with PD was built based on the results of logistic regression analysis. Results: The serum transferrin (TRF, p < 0.0024) concentration and total iron binding capacity (TIBC, p < 0.0024) were lower in the apathetic group after Bonferroni correction, and they were negatively associated with AS scores in male participants with PD (TRF, r = -0.27, p = 0.010; TIBC, r = -0.259, p = 0.014). The nomogram was developed by incorporating the following five parameters: age, sex, serum iron concentration, TIBC and Hamilton Depression Rating Scale (HAMD) scores, which showed good discrimination and calibration, with a consistency index of 0.799 (95% confidence interval = 0.732-0.865). Conclusion: Abnormal iron metabolism may contribute to apathy in PD, especially among men. TIBC levels in combination with HAMD scores can be effectively used for the prediction of apathetic patients with PD.