Brain functional network abnormalities in parkinson's disease with mild cognitive impairment.

Mild cognitive impairment in Parkinson's disease (PD-M) is related to a high risk of dementia. This study explored the whole-brain functional networks in early-stage PD-M. Forty-one patients with PD classified as cognitively normal (PD-N, n = 17) and PD-M (n = 24) and 24 demographically matched healthy controls (HC) underwent clinical and neuropsychological evaluations and resting-state functional magnetic resonance imaging. The global, regional, and modular topological characteristics were assessed in the brain functional networks, and their relationships to cognitive scores were tested. At the global level, PD-M and PD-N exhibited higher characteristic path length and lower clustering coefficient, local and global efficiency relative to HC. At the regional level, PD-M and PD-N showed lower nodal centrality in sensorimotor regions relative to HC. At the modular level, PD-M showed lower intramodular connectivity in default mode and cerebellum modules, and lower intermodular connectivity between default mode and frontoparietal modules than PD-N, correlated with Montreal Cognitive Assessment scores. Early-stage PD patients showed weaker small-worldization of brain networks. Modular connectivity alterations were mainly observed in patients with PD-M. These findings highlight the shared and distinct brain functional network dysfunctions in PD-M and PD-N, and yield insight into the neurobiology of cognitive decline in PD.

Impacts of Halogen Substitutions on Bisphenol A Compounds Interaction with Human Serum Albumin: Exploring from Spectroscopic Techniques and Computer Simulations.

Bisphenol A (BPA) is an endocrine-disrupting compound, and the binding mechanism of BPA with carrier proteins has drawn widespread attention. Halogen substitutions can significantly impact the properties of BPA, resulting in various effects for human health. Here, we selected tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA) to investigate the interaction between different halogen-substituted BPAs and human serum albumin (HSA). TBBPA/TCBPA spontaneously occupied site I and formed stable binary complexes with HSA. Compared to TCBPA, TBBPA has higher binding affinity to HSA. The effect of different halogen substituents on the negatively charged surface area of BPA was an important reason for the higher binding affinity of TBBPA to HSA compared to TCBPA. Hydrogen bonds and van der Waals forces were crucial in the TCBPA-HSA complex, while the main driving factor for the formation of the TBBPA-HSA complex was hydrophobic interactions. Moreover, the presence of TBBPA/TCBPA changed the secondary structure of HSA. Amino acid residues such as Lys199, Lys195, Phe211, Arg218, His242, Leu481, and Trp214 were found to play crucial roles in the binding process between BPA compounds and HSA. Furthermore, the presence of halogen substituents facilitated the binding of BPA compounds with HSA.

An insight into the interaction between Indisulam and human serum albumin: Spectroscopic method, computer simulation and in vitro cytotoxicity assay.

Indisulam (IDM) is a sulfanilamide anticancer agent and has been identified as a molecular glue recently. It shows potential for novel therapies development and brings more hope for curing human diseases. The affinity between molecular glues and plasma protein makes it significant to understand the characteristics of such substances. Therefore, the interaction between IDM and human serum albumin (HSA) was explored through solvent experiments, computer simulation experiments, enzyme kinetics experiments, and cell viability assay. The results revealed that IDM and HSA spontaneously formed stable binary complex with the binding constant of the order 105 M-1. IDM inserted in the site I of HSA, resulting the change in HSA secondary structure. And π electrons in IDM's benzene rings, as well as van der Waals forces and the H-bond, all helped to stabilize the HSA-IDM complex. The results of molecular dynamic simulation (MD) corresponded with the results from solvent experiment well. For instance, there were approximately 1-5 H-bonds between IDM and HSA. Lys199 and Arg218 were crucial energy contributors in the binding process. The esterase-like activity experiment confirmed that IDM inhibited the catalytic activity of HSA. In addition, cell experiment revealed that serum albumin can significantly reduce the cytotoxicity of IDM towards human embryonic kidney 293T (HEK293T) cells.

The potential impact of 6PPD and its oxidation product 6PPD-quinone on human health: A case study on their interaction with human serum albumin.

6PPD and its oxidation product, 6PPD-quinone have garnered widespread attention due to their adverse effects on aquatic ecosystems and human health, and are recognized as emerging pollutants. In this study, we investigated the interaction mechanism between 6PPD/6PPD-quinone and human serum albumin (HSA) through various experiments. Experimental findings reveal that the IC50 values of 6PPD-quinone and 6PPD against HEK293T cells were 11.78 and 40.04 µM, respectively. Additionally, the cytotoxicity of these compounds was regulated by HSA, displaying an inverse correlation with their binding affinity to HSA. Furthermore, 6PPD/6PPD-quinone can spontaneously insert into site I on HSA, forming a binary complex that induces changes in the secondary structure of HSA. However, their effects on the esterase-like activity of HSA exhibit a dichotomy. While 6PPD activates the esterase-like activity of HSA, 6PPD-quinone inhibits it. Molecular docking analyses reveal that both 6PPD and 6PPD-quinone interact with many amino acid residues on HSA, including TRP214, ARG222, ARG218, ALA291, PHE211. The π electrons on the benzene rings of 6PPD/6PPD-quinone play pivotal roles in maintaining the stability of complexes. Moreover, the stronger binding affinity observed between 6PPD and HSA compared to 6PPD-quinone, may be attributed to the larger negative surface potential of 6PPD.

Investigation on the interaction of aromatic organophosphate flame retardants with human serum albumin via computer simulations, multispectroscopic techniques and cytotoxicity assay.

Organophosphate flame retardants (OPFRs) are newly emerging estrogenic environmental pollutants, which attracted widespread public interest owing to their potential threats to human. Here, the interaction between two typical aromatic OPFRs, TPHP/EHDPP and HSA was researched by different experiments. Experimental results indicated that TPHP/EHDPP can insert the site I of HSA and be encircled by several amino acid residues, Asp451, Glu292, Lys195, Trp214 and Arg218 played vital roles in this binding process. At 298 K, the Ka value of TPHP-HSA complex was 5.098 × 104 M-1, and the Ka value of EHDPP-HSA was 1.912 × 104 M-1. Except H-bonds and van der Waals forces, the π-electrons on the phenyl ring of aromatic-based OPFRs played a pivotal role in maintaining the stability of the complexes. The content alterations of HSA were observed in the present of TPHP/EHDPP. The IC50 values of TPHP and EHDPP were 157.9 µM and 31.14 µM to GC-2spd cells, respectively. And the existence of HSA has a regulatory effect on the reproductive toxicity of TPHP/EHDPP. In addition, the results of present work implied Ka values of OPFRs and HSA are possible to be a useful parameter for evaluating their relative toxicity.

Alterations in the conformation and function of human serum albumin induced by the binding of methyl hydrogen phthalate.

Phthalate esters (PAEs) are widely used as plasticizer components in production. Methyl hydrogen phthalate (MHP) is a metabolite of dimethyl phthalate (DMP, a kind of PAEs), and its toxic residues accumulate in the nature and can enter the human body. Here, the interaction between MHP and human serum albumin (HSA) was probed by using multi-spectral, computer simulations, and biochemical techniques. The results showed that MHP was spontaneously embedded in site I of HSA to form a complex by H-bonds and van der Waals forces (ΔH < 0, ΔS < 0). The binding constant (Ka) of the HSA-MHP system was 1.136 ± 0.026 × 104 M-1 (298 K). The combination of MHP produced conformational variations of HSA, as shown by the 3D fluorescence spectrum, CD spectra, and molecular dynamics simulation. Additionally, molecular docking indicated that MHP was surrounded by multiple residues, such as Lys199, Leu203, Phe206, and Trp214. Specifically, Lys199 and Trp214 exerted a crucial effect on the interaction of HSA and MHP. The residues with important energy contribution were mostly located in site I. The ASA values of the aromatic amino acids of HSA changed after combining with MHP. The Rg and SASA values of HSA increased after adding MHP, suggesting that the structure of HSA was less compact. Moreover, the esterase-like activity of HSA increased after adding MHP to HSA, indicating that MHP may disturb the normal physiological activities in the human body. This study was helpful to understand the biological function of MHP and provided some insights for its side effect in the human body.

Brain network topology and future development of freezing of gait in Parkinson's disease: a longitudinal study.

BACKGROUND: Freezing of gait (FOG) is a common disabling gait disturbance in Parkinson's disease (PD). The objectives of this study were to explore alterations in the topological organization of whole-brain functional networks in patients with PD who will develop FOG. METHODS: We recruited 20 patients with PD who developed FOG (PD-FOGt) during a 5-year follow-up period, 20 patients with PD who did not developed FOG (PD-FOGn) within the follow-up period, and 20 healthy control subjects. Using graph theory approaches, we performed a comparative analysis of the topological organization of whole-brain functional networks among the groups, and further explored their potential relationships with latency to develop FOG. RESULTS: At baseline, the global topological properties of functional brain networks in PD-FOGt and PD-FOGn showed no abnormalities. Additionally, regarding regional topological properties, compared with PD-FOGn patients, PD-FOGt patients exhibited decreased nodal centrality in the left middle frontal gyrus (MFG). Although there were no significant differences compared with PD-FOGn patients, the PD-FOGt group exhibited the lowest nodal centrality values in the frontal cortex (left gyrus rectus), and visual cortex (bilateral inferior occipital gyrus and left fusiform gyrus), and the highest nodal centrality values in the cerebellum (vermis_6) among the three groups. However, no relationship was found between the nodal centrality in above brain regions and latency to develop FOG. CONCLUSION: This study demonstrates the disrupted regional topological organization might contribute to the future development of FOG in PD patients, especially associated with damage to the left MFG.

Reclassification of patients with tremor syndrome and comparisons of essential tremor and essential tremor-plus patients.

BACKGROUND: The new essential tremor (ET)-plus nomenclature was proposed by the 2018 Tremor Consensus Criteria. However, few studies have adopted this usage and the clinical differences between ET and ET-plus remains unclear. To address this issue, we reclassified and compared the characteristics of ET and ET-plus patients in a large Chinese tremor cohort. METHODS: In this cross-sectional observational study, 766 patients originally diagnosed with ET underwent neurological examination. Scale ratings were used to evaluate motor and non-motor symptoms, and quality of life (QoL). We then reclassified the ET cohort and compared demographic and clinical characteristics between ET and ET-plus patients. A logistic regression analysis was used to explore whether the presence of neurological soft signs in ET-plus was associated with tremor severity or QoL. RESULTS: Among 665 clinically confirmed ET syndrome patients, 274 were ET and 391 were ET-plus. The most prevalent neurological soft sign was resting tremor. ET-plus patients were older, had older age at onset and longer disease duration. ET-plus patients recorded higher scores in tremor severity evaluations and lower in cognitive evaluations, whereas a higher proportion of patients presented with depression or anxiety symptoms. Resting tremor and questionable cerebellar signs were associated with tremor severity. Cognitive impairment was associated with worse QoL. CONCLUSIONS: ET-plus patients were older, had longer disease durations, worse tremor manifestations, and more distinct non-motor symptoms. Certain additional soft signs of ET-plus were associated with tremor severity or worse QoL. ET-plus patients may include advanced ET patients with additional neurological soft signs presenting along with disease progression.

Topologically Disrupted Gray Matter Networks in Drug-Naïve Essential Tremor Patients With Poor Sleep Quality.

Background: Sleep disturbances are widespread among patients with essential tremor (ET) and may have adverse effects on patients' quality of life. However, the pathophysiology underlying poor quality of sleep (QoS) in patients with ET remains unclear. Our study aimed to identify gray matter (GM) network alterations in the topological properties of structural MRI related to QoS in patients with ET. Method: We enrolled 45 ET patients with poor QoS (SleET), 59 ET patients with normal QoS (NorET), and 66 healthy controls (HC), and they all underwent a three-dimensional T1-weighted MRI scan. We used a graph-theoretical approach to investigate the topological organization of GM morphological networks, and individual morphological brain networks were constructed according to the interregional similarity of GM volume distributions. Furthermore, we performed network-based statistics, and partial correlation analyses between topographic features and clinical characteristics were conducted. Results: Global network organization was disrupted in patients with ET. Compared with the NorET group, the SleET group exhibited disrupted topological GM network organization with a shift toward randomization. Moreover, they showed altered nodal centralities in mainly the frontal, temporal, parietal, and cerebellar lobes. Morphological connection alterations within the default mode network (DMN), salience, and basal ganglia networks were observed in the SleET group and were generally more extensive than those in the NorET and HC groups. Alterations within the cerebello-thalamo-(cortical) network were only detected in the SleET group. The nodal degree of the left thalamus was negatively correlated with the Fahn-Tolosa-Marin Tremor Rating Scale score (r = -0.354, p =0.027). Conclusion: Our findings suggest that potential complex interactions underlie tremor and sleep disruptions in patients with ET. Disruptions within the DMN and the cerebello-thalamo-(cortical) network may have a broader impact on sleep quality in patients with ET. Our results offer valuable insight into the neural mechanisms underlying poor QoS in patients with ET.

Disrupted Brain Functional Network Topology in Essential Tremor Patients With Poor Sleep Quality.

Sleep disturbances, especially poor quality of sleep (QoS), are common among essential tremor (ET) patients and may have adverse effects on their quality of life, but the etiology driving the poor QoS in these individuals remains inadequately understood. Few data are available on the neuroimaging alterations of ET with poor QoS. Thirty-eight ET patients with poor QoS (SleET), 48 ET patients with normal QoS (NorET), and 80 healthy controls (HCs) participated in this study. All subjects underwent a 3.0-T magnetic resonance imaging (MRI) scan for resting-state functional MRI data collection. Then, the whole-brain functional connectome was constructed by thresholding the partial correlation matrices of 116 brain regions. Graph theory and network-based statistical analyses were performed. We used a non-parametric permutation test for group comparisons of topological metrics. Partial correlation analyses between the topographical features and clinical characteristics were conducted. The SleET and NorET groups exhibited decreased clustering coefficients, global efficiency, and local efficiency and increased the characteristic path length. Both of these groups also showed reduced nodal degree and nodal efficiency in the left superior dorsolateral frontal gyrus, superior frontal medial gyrus (SFGmed), posterior cingulate gyrus (PCG), lingual gyrus, superior occipital gyrus, right middle occipital gyrus, and right fusiform gyrus. The SleET group additionally presented reduced nodal degrees and nodal efficiency in the right SFGmed relative to the NorET and HC groups, and nodal efficiency in the right SFGmed was negatively correlated with the Pittsburgh Sleep Quality Index score. The observed impaired topographical organizations of functional brain networks within the central executive network (CEN), default mode network (DMN), and visual network serve to further our knowledge of the complex interactions between tremor and sleep, adding to our understanding of the underlying neural mechanisms of ET with poor QoS.

A compound heterozygous PINK1-associated juvenile Parkinson's disease with pregnancy in Chinese.

BACKGROUND: PINK1 mutations are the second most common cause of recessive, early-onset Parkinson's disease (EOPD), of which 15% are cases of juvenile PD. PD is a progressive neurological disease that primarily affects middle-aged and older people. Thus PD patients experiencing pregnancy is uncommon, especially in patients with juvenile PD caused by PINK1 mutations. We are first to report a woman from a Chinese family diagnosed with sporadic juvenile PD and treated with levodopa/benserazide throughout pregnancy. METHODS: Whole exome sequencing was performed on this patient, and pedigree verification was performed on her parents. This patient received levodopa/benserazide treatment with regular outpatient follow-up exams. RESULTS: Whole exome sequencing and Sanger sequencing identified a heterozygous nonsense mutation (c.1474C > T, p.R492X) and a splicing mutation (c.1488 + 1G > A) that were in exon 7 of the PINK1 gene, co-segregating with the PD phenotype and exhibiting an autosomal recessive pattern. With regular outpatient follow-up exams, this patient delivered a healthy boy without complications. Her PD symptoms were stable with the levodopa/benserazide treatment throughout her pregnancy except in the postpartum period. CONCLUSION: Our findings further demonstrated the safety of levodopa with dopa-decarboxylase treatment in PINK1-associated juvenile PD during pregnancy.

Disrupted Brain Network Topology in Drug-naïve Essential Tremor Patients with and Without Depression : A Resting State Functional Magnetic Resonance Imaging Study.

PURPOSE: This study was carried out to investigate brain functional connectome and its potential relationships with the disease severity and emotion function in patients with essential tremor with and without depressive symptoms by using resting-state functional magnetic resonance imaging and graph theory approaches. METHODS: In this study 33 essential tremor patients with depression, 45 essential tremor patients without depression and 79 age and gender-matched healthy controls were recruited to undergo a 3.0­T imaging scan. The whole brain functional connectome was constructed by thresholding the partial correlation matrices of 116 brain regions, and the topologic properties were analyzed by using graph theory approaches and network-based statistic approaches. Nonparametric permutation test was also used for group comparisons of topological metrics. Correlation analyses between topographic features and the clinical characteristics were performed. RESULTS: The functional connectome in both essential tremor patients with and without depression showed abnormalities at the global level (decrease in clustering coefficient, global efficiency, and local efficiency but increase in characteristic path length) and at the nodal level (decrease nodal centralities in the cerebellum, motor cortex, prefrontal-limbic regions, default mode network) (p < 0.05, false discovery rate corrected). Moreover, essential tremor patients with depression showed higher node efficiency in superior frontal gyrus and posterior cingulate gyrus compared to essential tremor without depression. CONCLUSION: Our results may provide insights into the underlying pathophysiology of essential tremor patients with and without depression and aid the development of some potential biomarkers of the depressive symptoms in patients with essential tremor.

Whole-exome sequencing in early-onset Parkinson's disease among ethnic Chinese.

Although early-onset Parkinson's disease (EOPD) has a more penetrant genetic etiology, the genetic architecture of EOPD remains unclear. The objectives of this study were to assess the genetic and clinical features of EOPD among ethnic Chinese from mainland China. Using whole-exome sequencing, we performed genetic analyses of 240 participants including 193 with sporadic and 47 with familial EOPD (age of onset <50 years). In total, 18 patients (7.5%) harbored pathogenic or likely pathogenic variants in known PD genes. Among these variants, biallelic variants in Parkin and PINK1 were responsible for 4.2% of cases, and rare likely pathogenic variants in LRRK2 (1.7%) also appeared to be a relatively common cause of EOPD. Notably, 7.5% of patients carried risk variants in either LRRK2 or GBA, which should also be considered for EOPD. Nevertheless, 41 patients (17.1%) had rare variants of unknown significance. In conclusion, our findings provide a better understanding of the genetic architecture of PD among ethnic Chinese, and the pathogenicity of numerous rare variants should be further investigated.