Interplay between the glymphatic system and neurotoxic proteins in Parkinson's disease and related disorders: current knowledge and future directions.

Parkinson's disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins, including α-synuclein, amyloid-ß, and tau, in addition to the impaired elimination of these neurotoxic protein. Atypical parkinsonism, which has the same clinical presentation and neuropathology as Parkinson's disease, expands the disease landscape within the continuum of Parkinson's disease and related disorders. The glymphatic system is a waste clearance system in the brain, which is responsible for eliminating the neurotoxic proteins from the interstitial fluid. Impairment of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease, as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal damage. Therefore, impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration. Previous evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson's disease and related disorders; however, many unanswered questions remain. This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson's disease and related disorders. The focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins, including loss of polarization of aquaporin-4 in astrocytic endfeet, sleep and circadian rhythms, neuroinflammation, astrogliosis, and gliosis. This review further delves into the underlying pathophysiology of the glymphatic system in Parkinson's disease and related disorders, and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.

Impact of cognition-related single nucleotide polymorphisms on brain imaging phenotype in Parkinson's disease.

Multiple single nucleotide polymorphisms may contribute to cognitive decline in Parkinson's disease. However, the mechanism by which these single nucleotide polymorphisms modify brain imaging phenotype remains unclear. The aim of this study was to investigate the potential effects of multiple single nucleotide polymorphisms on brain imaging phenotype in Parkinson's disease. Forty-eight Parkinson's disease patients and 39 matched healthy controls underwent genotyping and 7T magnetic resonance imaging. A cognitive-weighted polygenic risk score model was designed, in which the effect sizes were determined individually for 36 single nucleotide polymorphisms. The correlations between polygenic risk score, neuroimaging features, and clinical data were analyzed. Furthermore, individual single nucleotide polymorphism analysis was performed to explore the main effects of genotypes and their interactive effects with Parkinson's disease diagnosis. We found that, in Parkinson's disease, the polygenic risk score was correlated with the neural activity of the hippocampus, parahippocampus, and fusiform gyrus, and with hippocampal-prefrontal and fusiform-temporal connectivity, as well as with gray matter alterations in the orbitofrontal cortex. In addition, we found that single nucleotide polymorphisms in α-synuclein (SNCA) were associated with white matter microstructural changes in the superior corona radiata, corpus callosum, and external capsule. A single nucleotide polymorphism in catechol-O-methyltransferase was associated with the neural activities of the lingual, fusiform, and occipital gyri, which are involved in visual cognitive dysfunction. Furthermore, DRD3 was associated with frontal and temporal lobe function and structure. In conclusion, imaging genetics is useful for providing a better understanding of the genetic pathways involved in the pathophysiologic processes underlying Parkinson's disease. This study provides evidence of an association between genetic factors, cognitive functions, and multi-modality neuroimaging biomarkers in Parkinson's disease.

Diffusion along perivascular spaces as marker for impairment of glymphatic system in Parkinson's disease.

The brain glymphatic system is involved in the clearance of misfolding α-synuclein, the impaired glymphatic system may contribute to the progression of Parkinson's disease (PD). We aimed to analyze the diffusion tensor image along the perivascular space (DTI-ALPS) and perivascular space (PVS) burden to reveal the relationship between the glymphatic system and PD. A cross-sectional study using a 7 T MRI of 76 PD patients and 48 controls was performed to evaluate the brain's glymphatic system. The DTI-ALPS and PVS burden in basal ganglia were calculated. Correlation analyses were conducted between DTI-ALPS, PVS burden and clinical features. We detected lower DTI-ALPS in the PD subgroup relative to controls, and the differences were more pronounced in patients with Hoehn & Yahr stage greater than two. The decreased DTI-ALPS was only evident in the left hemisphere in patients in the early stage but involved both hemispheres in more advanced PD patients. Decreased DTI-ALPS were also correlated with longer disease duration, higher Unified Parkinson's Disease Rating Scale motor score (UPDRS III) and UPDRS total scores, as well as higher levodopa equivalent daily dose. Moreover, the decreased DTI-ALPS correlated with increased PVS burden, and both indexes correlated with PD disease severity. This study demonstrated decreased DTI-ALPS in PD, which might initiate from the left hemisphere and progressively involve right hemisphere with the disease progression. Decreased DTI-ALPS index correlated with increased PVS burden, indicating that both metrics could provide supporting evidence of an impaired glymphatic system. MRI evaluation of the PVS burden and diffusion along PVS are potential imaging biomarkers for PD for disease progression.

Normal-sized basal ganglia perivascular space related to motor phenotype in Parkinson freezers.

Changes in basal ganglia (BG) perivascular spaces (PVSs) are related to motor and cognitive behaviors in Parkinson's disease (PD). However, the correlation between the initial motor phenotype and PVSs distribution/burden in PD freezing of gait (FOG) remains unclear. In addition, the normal-sized PVSs (nPVSs) have not been well-studied. With high-resolution 7T-MRI, we studied nPVSs burden in BG, thalamus, midbrain and centrum semiovale. The numbers and volume of nPVSs were assessed in 10 healthy controls, 10 PD patients without FOG, 20 with FOG [10 tremor dominant (TD), 10 non-TD subtype]. Correlation analyses were further performed in relation to clinical parameters. In this proof of concept study, we found that the nPVS burden of bilateral and right BG were significantly higher in freezers. A negative correlation existed between the tremor score and BG-nPVSs count. A positive correlation existed between the levodopa equivalent daily dose and BG-nPVSs count. The nPVS burden correlated with the progression to FOG in PD, but the distribution and burden of nPVS differ in TD vs. non-TD subtypes. High resolution 7T-MRI is a sensitive and reliable tool to evaluate BG-nPVS, and may be a useful imaging marker for predicting gait impairment that may evolve into FOG in PD.

The Association Between the Gut Microbiota and Parkinson's Disease, a Meta-Analysis.

Patients with Parkinson's disease (PD) were often observed with gastrointestinal symptoms, which preceded the onset of motor symptoms. Neuropathology of PD has also been found in the enteric nervous system (ENS). Many studies have reported significant PD-related alterations of gut microbiota. This meta-analysis was performed to evaluate the differences of gut microbiota between patients with PD and healthy controls (HCs) across different geographical regions. We conducted a systematic online search for case-control studies detecting gut microbiota in patients with PD and HCs. Mean difference (MD) and 95% confidence interval (CI) were calculated to access alterations in the abundance of certain microbiota families in PD. Fifteen case-control studies were included in this meta-analysis study. Our results showed significant lower abundance levels of Prevotellaceae (MD = -0.37, 95% CI = -0.62 to -0.11), Faecalibacterium (MD = -0.41, 95% CI: -0.57 to -0.24), and Lachnospiraceae (MD = -0.34, 95% CI = -0.59 to -0.09) in patients with PD compared to HCs. Significant higher abundance level of Bifidobacteriaceae (MD = 0.38, 95%; CI = 0.12 to 0.63), Ruminococcaceae (MD = 0.58, 95% CI = 0.07 to 1.10), Verrucomicrobiaceae (MD = 0.45, 95% CI = 0.21 to 0.69), and Christensenellaceae (MD = 0.20, 95% CI = 0.07 to 0.34) was also found in patients with PD. Thus, shared alterations of certain gut microbiota were detected in patients with PD across different geographical regions. These PD-related gut microbiota dysbiosis might lead to the impairment of short-chain fatty acids (SCFAs) producing process, lipid metabolism, immunoregulatory function, and intestinal permeability, which contribute to the pathogenesis of PD.

The role of brain perivascular space burden in early-stage Parkinson's disease.

Perivascular space (PVS) is associated with neurodegenerative diseases, while its effect on Parkinson's disease (PD) remains unclear. We aimed to investigate the clinical and neuroimaging significance of PVS in basal ganglia (BG) and midbrain in early-stage PD. We recruited 40 early-stage PD patients and 41 healthy controls (HCs). Both PVS number and volume were calculated to evaluate PVS burden on 7 T magnetic resonance imaging images. We compared PVS burden between PD and HC, and conducted partial correlation analysis between PVS burden and clinical and imaging features. PD patients had a significantly more serious PVS burden in BG and midbrain, and the PVS number in BG was significantly correlated to the PD disease severity and L-dopa equivalent dosage. The fractional anisotropy and mean diffusivity values of certain subcortical nuclei and white matter fibers within or nearby the BG and midbrain were significantly correlated with the ipsilateral PVS burden indexes. Regarding to the midbrain, the difference between bilateral PVS burden was, respectively, correlated to the difference between fiber counts of white fiber tract passing through bilateral substantia nigra in PD. Our study suggests that PVS burden indexes in BG are candidate biomarkers to evaluate PD motor symptom severity and aid in predicting medication dosage. And our findings also highlight the potential correlations between PVS burden and both grey and white matter microstructures.

Differential Expression of microRNA Profiles and Wnt Signals in Stem Cell-Derived Exosomes During Dopaminergic Neuron Differentiation.

The role of secreted exosomes during dopaminergic (DA) neuron differentiation is still unknown. To investigate the roles of exosomes in DA neuron fate specification, we profiled exosomal microRNAs (miRNAs) during DA neuron differentiation of epiblast-derived stem cells (EpiSCs). There were 26 miRNAs differentially expressed (relative fold >2, p < 0.05) in EpiSC-derived exosomes at 0, 2, 4, 6, 8, 10, 12, and 14 days of DA epiblast differentiation. Among them, 23 exosomic miRNAs were significantly increased, including miR-124, miR-132, miR-133b, miR-218, miR-9, miR-34b, miR-34c, and miR-135a2, while three exosomic miRNAs (miR-214, miR-7a, and miR-302b) were decreased, when compared with control samples. Bioinformatics analysis by DIANA-mirPath demonstrated that extracellular matrix-receptor interaction, signaling pathways regulating pluripotency of stem cells, FoxO signaling pathway, DA synapse, Wnt signaling pathway, GABAergic synapse, and neurotrophin signaling pathway were significantly enriched in DA differentiation-related miRNA signature (all p-values <0.012). Furthermore, messenger RNAs for nine DA neuronal markers tyrosine hydroxylase (TH), Nr4a2, Pitx3, Drd1a, Lmx1a, Lmx1b, Foxa1, Dmrt5, and Slc18a2 were significantly increased expressed over time in exosomes derived from differentiated EpiSCs. Interestingly, adding with exosomes derived from EpiSC induction experiment resulted in a twofold increase of TH-positive neurons production (35% vs. 17%, p < 0.01) during DA neuronal differentiation from mouse embryonic stem cells (ESCs). In summary, our results suggested exosomal miRNAs are potential regulators of DA neuron differentiation. More importantly, EpiSC-derived exosomes could promote the generation of DA neuron differentiation from ESCs.

ALFF and ReHo Mapping Reveals Different Functional Patterns in Early- and Late-Onset Parkinson's Disease.

Heterogeneity between late-onset Parkinson's disease (LOPD) and early-onset Parkinson's disease (EOPD) is mainly reflected in the following aspects including genetics, disease progression, drug response, clinical manifestation, and neuropathological change. Although many studies have investigated these differences in relation to clinical significance, the functional processing circuits and underlying neural mechanisms have not been entirely understood. In this study, regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) maps were used to explore different spontaneous brain activity patterns in EOPD and LOPD patients. Abnormal synchronizations were found in the motor and emotional circuits of the EOPD group, as well as in the motor, emotional, and visual circuits of the LOPD group. EOPD patients showed functional activity change in the visual, emotional and motor circuits, and LOPD patients only showed increased functional activity in the emotional circuits. In summary, the desynchronization process in the LOPD group was relatively strengthened, and the brain areas with changed functional activity in the EOPD group were relatively widespread. The results might point out different impairments in the synchronization and functional activity for EOPD and LOPD patients.

Design of Friction Stir Welding Tool for Avoiding Root Flaws.

In order to improve material flow behavior during friction stir welding and avoid root flaws of weld, a tool with a half-screw pin and a tool with a tapered-flute pin are suggested. The effect of flute geometry in tool pins on material flow velocity is investigated by the software ANSYS FLUENT. Numerical simulation results show that high material flow velocity appears near the rotational tool and material flow velocity rapidly decreases with the increase of distance away from the axis of the tool. Maximum material flow velocity by the tool with the tapered-flute pin appears at the beginning position of flute and the velocity decreases with the increase of flow length in flute. From the view of increasing the flow velocity of material near the bottom of the workpiece or in the middle of workpiece, the tool with the half-screw pin and the tool with the tapered-flute pin are both better than the conventional tool.

Poly[[[µ(2)-1,1'-(butane-1,4-di-yl)bis-(1H-imidazole)-κN:N](µ(2)-2,6-di-methyl-pyridine-3,5-dicarboxyl-ato-κO:O)zinc] dihydrate].

In the title coordination polymer, {[Zn(C(9)H(7)NO(4))(C(10)H(14)N(4))]·2H(2)O}(n), the Zn(II) ion displays a distorted tetra-hedral geometry with two imidazole N atoms from two 1,1'-(butane-1,4-di-yl)bis-(imidazole) (bbi) ligands and two carboxyl-ate O atoms from two 2,6-dimethyl-pyridine-3,5-dicarboxyl-ate (dpdc) ligands. The bbi and dpdc ligands bridge the Zn(II) ions, forming layers parallel to (011). O-H⋯O and O-H⋯N hydrogen bonds and π-π inter-actions between the imidazole rings [centroid-centroid distance = 3.807 (5) Å] connect the layers. Two of the three uncoordinated water mol-ecules are disordered, each over two 0.25-occupancy positions.

[Uptake of radionuclides from soil to plant and the discovery of 226Ra, 232Th hyperaccumulator].

11 sorts of plant samples and corresponding soil samples were collected in Conghua and Taishan, Pearl River Delta. The specific activity of 238U, 226Ra, 232Th and 40K of samples were investigated by using HPGe-gamma-ray spectra analysis. The results showed that the average specific activity of 238U, 226Ra, 232Th and 40K in soil samples were 151.8, 146.3, 226.6, 665.5 Bq/kg, which were higher than the average values of China and the world. The concentration of 238U in all sort of plants are very low and most of them are lower than detection limit, while the values of 226Ra, 232Th and 40K were high. The contents of 226Ra and 232Th in Dicranopteris dichotoma were the highest, whose average specific activity is 285.9, 986.2 Bq/kg respectively. The average bioconcentration factors (BFs)of 26Ra, 232Th of Dicranopteris dichotoma were 2.20, 4.23, respectively, the other 10 sort of plants have BFs of 2266Ra, 232Th were in the range of 10(-1)-10(-2). The bioconcentration factors and the translocation factors of 226Ra, 232Th of Dicranopteris dichotoma. were all bigger than 1, so Dicranopteris dichotoma can be defined as hyperaccumulator of 226Ra and 232Th.

Spontaneous volume transition of polyampholyte nanocomposite hydrogels based on pure electrostatic interaction.

A circular system is employed in this paper to investigate the swelling behaviors of polyampholyte hydrogels; this circular system can effectively eliminate the disturbance of various factors and keep the surrounding environment constant. It is found that there exists a spontaneous volume transition to the collapsed state of polyampholyte hydrogels, which is attributed to the overshooting effect, and the transition can occur repeatedly under certain conditions. (13)C NMR is employed to investigate the swelling behavior of polyampholyte hydrogels. The swelling kinetics of polyampholyte hydrogels under various circular media and various circular runs are also investigated in this paper. All the results suggest that the spontaneous volume transition to the collapsed state of polyampholyte hydrogels is dominated by pure electrostatic interaction between different charges in polymer chains.