Corpus callosum and cerebellum participate in semantic dysfunction of Parkinson's disease: a diffusion tensor imaging-based cross-sectional study.

Language dysfunction is common in Parkinson's disease (PD) patients, among which, the decline of semantic fluency is usually observed. This study aims to explore the relationship between white matter (WM) alterations and semantic fluency changes in PD patients. 127 PD patients from the Parkinson's Progression Markers Initiative cohort who received diffusion tensor imaging scanning, clinical assessment and semantic fluency test (SFT) were included. Tract-based special statistics, automated fiber quantification, graph-theoretical and network-based analyses were performed to analyze the correlation between WM structural changes, brain network features and semantic fluency in PD patients. Fractional anisotropy of corpus callosum, anterior thalamic radiation, inferior front-occipital fasciculus, and uncinate fasciculus, were positively correlated with SFT scores, while a negative correlation was identified between radial diffusion of the corpus callosum, inferior longitudinal fasciculus, and SFT scores. Automatic fiber quantification identified similar alterations with more details in these WM tracts. Brain network analysis positively correlated SFT scores with nodal efficiency of cerebellar lobule VIII, and nodal local efficiency of cerebellar lobule X. WM integrity and myelin integrity in the corpus callosum and several other language-related WM tracts may influence the semantic function in PD patients. Damage to the cerebellum lobule VIII and lobule X may also be involved in semantic dysfunction in PD patients.

Cerebellar and cerebral white matter changes in Parkinson's disease with resting tremor.

PURPOSE: Cerebellum modulates the amplitude of resting tremor in Parkinson's disease (PD) via cerebello-thalamo-cortical (CTC) circuit. Tremor-related white matter alterations have been identified in PD patients by pathological studies, but in vivo evidence is limited; the influence of such cerebellar white matter alterations on tremor-related brain network, including CTC circuit, is also unclear. In this study, we investigated the cerebral and cerebellar white matter alterations in PD patients with resting tremor using diffusion tensor imaging (DTI). METHODS: In this study, 30 PD patients with resting tremor (PDWR), 26 PD patients without resting tremor (PDNR), and 30 healthy controls (HCs) from the Parkinson's Progression Markers Initiative (PPMI) cohort were included. Tract-based spatial statistics (TBSS) and region of interest-based analyses were conducted to determine white matter difference. Correlation analysis between DTI measures and clinical characteristics was also performed. RESULTS: In the whole brain, TBSS and region of interest-based analyses identified higher fractional anisotropy (FA) value, lower mean diffusivity (MD) value, and lower radial diffusivity (RD) in multiple fibers. In the cerebellum, TBSS analysis revealed significantly higher FA value, decreased RD value as well as MD value in multiple cerebellar tracts including the inferior cerebellar peduncle (ICP) and middle cerebellar peduncle (MCP) when comparing the PDWR with HC, and higher FA value in the MCP when compared with PDNR. CONCLUSION: We identified better white matter integrity in the cerebrum and cerebellum in PDWR indicating a potential association between the cerebral and cerebellar white matter and resting tremor in PD.

Epileptiform Discharges Reduce Neuronal ATP Production by Inhibiting F0F1-ATP Synthase Activity via A Zinc-α2-Glycoprotein-Dependent Mechanism.

Neuronal energy metabolism dysfunction, especially adenosine triphosphate (ATP) supply decrease, is observed in epilepsy and associated with epileptogenesis and prognosis. Zinc-α2-glycoprotein (ZAG) is known as an important modulator of energy metabolism and involved in neuronal glucose metabolism, fatty acid metabolism, and ketogenesis impairment in seizures, but its effect on neuronal ATP synthesis in seizures and the specific mechanism are unclear. In this study, we verified the localization of ZAG in primary cultured neuronal mitochondria by using double-labeling immunofluorescence, immune electron microscopy, and western blot. ZAG level in neuronal mitochondria was modulated by lentiviruses and detected by western blot. The F0F1-ATP synthase activity, ATP level, and acetyl-CoA level were measured. The binding between ZAG and F0F1-ATP synthase was determined by coimmunoprecipitation. We found that both ZAG and F0F1-ATP synthase existed in neuronal mitochondria, and there was mutual binding between them. Epileptiform discharge-induced decrease of mitochondrial ZAG level was reversed by ZAG overexpression. Epileptiform discharge or ZAG knockdown decreased F0F1-ATP synthase activity and ATP level in neurons, which were reversed by ZAG overexpression, while overexpression of ZAG along only increased F0F1-ATP synthase activity but not increased ATP level. Meanwhile, neither epileptiform discharges nor changes of ZAG level can alter the acetyl-CoA level. Moreover, epileptiform discharge did not alter F0F1-ATP synthase level. In conclusion, epileptiform discharge-induced ZAG decrease in neuronal mitochondria is correlated to F0F1-ATP synthase activity inhibition, which may possibly lead to ATP supply impairments. ZAG may be a potential therapeutic target for treating neuronal energy metabolism dysfunction in seizures with further researches.

Glucose metabolism impairment in Parkinson's disease.

Impairments in systematic and regional glucose metabolism exist in patients with Parkinson's disease (PD) at every stage of the disease course, and such impairments are associated with the incidence, progression, and special phenotypes of PD, which affect each physiological process of glucose metabolism including glucose uptake, glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, and pentose phosphate shunt pathway. These impairments may be attributed to various mechanisms, such as insulin resistance, oxidative stress, abnormal glycated modification, blood-brain-barrier dysfunction, and hyperglycemia-induced damages. These mechanisms could subsequently cause excessive methylglyoxal and reactive oxygen species production, neuroinflammation, abnormal aggregation of protein, mitochondrial dysfunction, and decreased dopamine, and finally result in energy supply insufficiency, neurotransmitter dysregulation, aggregation and phosphorylation of α-synuclein, and dopaminergic neuron loss. This review discusses the glucose metabolism impairment in PD and its pathophysiological mechanisms, and briefly summarized the currently-available therapies targeting glucose metabolism impairment in PD, including glucagon-likepeptide-1 (GLP-1) receptor agonists and dual GLP-1/gastric inhibitory peptide receptor agonists, metformin, and thiazoledinediones.

The nano-windmill exerts superior anti-inflammatory effects via reducing choline uptake to inhibit macrophage activation.

Macrophages' activation plays a central role during the development and progression of inflammation, while the regulation of metabolic reprogramming of macrophages has been recently identified as a novel strategy for anti-inflammatory therapies. Our previous studies have found that tetrahedral framework nucleic acid (tFNA) plays a mild anti-inflammatory effect by inhibiting macrophage activation, but the specific mechanism remains unclear. Here, by metabolomics and RNA sequencing, choline uptake is identified to be significantly repressed by decreased slc44a1 expression in tFNA-treated activated macrophages. Inspired by this result, combined with the excellent delivery capacities of tFNA, siR-slc44a1 is loaded into the tFNA to develop a new tFNA-based small interfering RNA (siRNA) delivery system named 'nano-windmill,' which exhibits a synergetic role by targeting slc44a1, finally blowing up the anti-inflammatory effects of tFNA to inhibit macrophages activation via reducing choline uptake. By confirming its anti-inflammatory effects in chronic (periodontitis) and acute (sepsis) inflammatory disease, the tFNA-based nanomedicine developed for inflammatory diseases may provide broad prospects for tFNA upgrading and various biological applications such as anti-inflammatory.

Risk factors related to early neurological deterioration in lacunar stroke and its influence on functional outcome.

OBJECTIVE: To identify risk factors for early neurological deterioration (END) in acute lacunar stroke patients and its influence on functional outcome. METHODS: Consecutive acute lacunar stroke patients defined by magnetic resonance imaging (MRI) between January 2018 and June 2020 were included in the study. END was defined as any persisting increase in National Institutes of Health Stroke Scale (NIHSS) score of ⩾ 2 points post admission, and favorable outcome was defined as a modified Rankin Scale (mRS) of 0-2 at discharge. Univariable and multivariable logistic regression were performed to identify risk factors related to END, as well as the influence of END on functional outcome. RESULTS: Among a total of 638 lacunar stroke patients (420 males (65.8%), median age 66 years (interquartile range (IQR): 56-74)), 108 (16.9%) developed END, and 94.4% (102/108) of the END occurred within 72 h post admission. Admission NIHSS score (adjusted odds ratio (aOR) 1.132, 95% confidence interval (CI) 1.046-1.225, p = 0.002), female (aOR 2.752, 95% CI 1.277-5.933, p = 0.010), admission systolic blood pressure (SBP) (160-179 mm Hg) (aOR 9.395, 95% CI 4.310-20.479, p < 0.001) and admission SBP (⩾180 mm Hg) (aOR 16.030, 95% CI 5.991-42.891, p < 0.001) were significantly associated with END. Delay time from onset to admission (aOR 0.995, 95% CI 0.990-1.000, p = 0.031), SBP dropping (⩾20 mm Hg) within 3 days or when END occurred (aOR 0.037, 95% CI 0.016-0.086, p < 0.001) and thalamic lacunar infarction (aOR 0.098, 95% CI 0.012-0.827, p = 0.033) were inversely associated with END. END (aOR 12.374, 95% CI 6.881-22.254, p < 0.001) and higher admission NIHSS score (aOR 1.488, 95% CI 1.359-1.629, p < 0.001) predicted unfavorable outcome at discharge. CONCLUSION: END in lacunar stroke patients is common and is associated with unfavorable outcome. Admission high SBP is a potentially modifiable risk factor for prevention of END, but this needs further investigation.

Levodopa responsiveness and white matter alterations in Parkinson's disease: A DTI-based study and brain network analysis: A cross-sectional study.

BACKGROUND: Patients with Parkinson's disease (PD) present various responsiveness to levodopa, but the cause of such differences in levodopa responsiveness is unclear. Previous studies related the damage of brain white matter (WM) to levodopa responsiveness in PD patients, but no study investigated the relationship between the structural brain network change in PD patients and their levodopa responsiveness. METHODS: PD patients were recruited and evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS). Each patient received a diffusion tensor imaging (DTI) scan and an acute levodopa challenge test. The improvement rate of UPDRS-III was calculated. PD patients were grouped into irresponsive group (improvement rate < 30%) and responsive group (improvement rate ≥ 30%). Tract-based spatial statistics (TBSS), deterministic tracing (DT), region of interest (ROI) analysis, and automatic fiber identification (AFQ) analyses were performed. The structural brain network was also constructed and the topological parameters were calculated. RESULTS: Fifty-four PD patients were included. TBSS identified significant differences in fractional anisotropy (FA) values in the corpus callosum and other regions of the brain. DT and ROI analysis of the corpus callosum found a significant difference in FA between the two groups. Graph theory analysis showed statistical differences in global efficiency, local efficiency, and characteristic path length. CONCLUSION: PD patients with poor responsiveness to levodopa had WM damage in multiple brain areas, especially the corpus callosum, which might cause disruption of information integration of the structural brain network.

A review on pathology, mechanism, and therapy for cerebellum and tremor in Parkinson's disease.

Tremor is one of the core symptoms of Parkinson's disease (PD), but its mechanism is poorly understood. The cerebellum is a growing focus in PD-related researches and is reported to play an important role in tremor in PD. The cerebellum may participate in the modulation of tremor amplitude via cerebello-thalamo-cortical circuits. The cerebellar excitatory projections to the ventral intermediate nucleus of the thalamus may be enhanced due to PD-related changes, including dopaminergic/non-dopaminergic system abnormality, white matter damage, and deep nuclei impairment, which may contribute to dysregulation and resistance to levodopa of tremor. This review summarized the pathological, structural, and functional changes of the cerebellum in PD and discussed the role of the cerebellum in PD-related tremor, aiming to provide an overview of the cerebellum-related mechanism of tremor in PD.

Electrochemical Behaviour and Chemical Species of Sm(II) in AlCl3 -NaCl with Different Lewis Acidity.

AlCl3 -NaCl was utilized as an electrolyte in this work due to its low melting point and Lewis acidity, in which samarium exists in two oxidation states, Sm(III) and Sm(II), resulting in unique electrochemical behaviours. Sm metal dissolves in AlCl3 -NaCl melt to form SmCl2 , which is verified by electrochemical and spectroscopic techniques. As the Lewis acidity of the melt increases, the diffusion coefficient of Sm(II) gradually increases, and the activation energy of diffusion decreases. Moreover, an additional co-reduction peak of Sm3+ and AlCl4 - is observed to be more positive than that of Al(0)/Al(III) in Lewis basic melt, which may be tightly correlated with the variation of Sm(II) coordination in AlCl3 -NaCl melt and ligand variation from Cl- to AlCl4 - and Al2 Cl7 - as the Lewis acidity of the AlCl3 -NaCl melt increases, according to the in situ electronic absorption spectra of Sm in this melt.

Chemical Species Transformation during the Dissolution Process of U3O8 and UO3 in the LiCl-KCl-AlCl3 Molten Salt.

In this work, we investigated the dissolution behavior of U3O8 and UO3 in the LiCl-KCl molten salt using 2.9 or 9.5 wt % AlCl3 as a chlorination agent under an argon atmosphere at 450 °C. Ultraviolet-visible/Ultraviolet-visible-near infrared absorption spectroscopy (UV-vis/UV-vis-NIR), fluorescence emission spectroscopy (FL), X-ray absorption fine structure (XAFS), and electrochemical techniques were used to systematically study the chemical species and the transformation of the dissolved products of U3O8 and UO3. It was found that with the aid of AlCl3, the initial products of U3O8 and UO3 dissolution were different. The initial products of U3O8 were UO2Cl42- and UCl62-, while the initial product of UO3 dissolution was UO2Cl42-. Interestingly, regardless of U3O8 or UO3, with the increase of AlCl3 content, the UO2Cl42- in their dissolved products showed a tendency to transform into UCl62-. In addition, UCl4 was produced by mixing 0.05 g of U3O8/UO3 powders with 10 times the amount of AlCl3 and heating them at 300 °C for 2 h. This work focuses on the pyrochemical reprocessing of spent oxide fuels, deepening the understanding of the dissolution of uranium oxides in higher oxidation states, and enriching the knowledge of uranium in the transformation of chemical species in molten salts.

In-situ anodic precipitation process for highly efficient separation of aluminum alloys.

Electrorefining process has been widely used to separate and purify metals, but it is limited by deposition potential of the metal itself. Here we report in-situ anodic precipitation (IAP), a modified electrorefining process, to purify aluminium from contaminants that are more reactive. During IAP, the target metals that are more cathodic than aluminium are oxidized at the anode and forced to precipitate out in a low oxidation state. This strategy is fundamentally based on different solubilities of target metal chlorides in the NaAlCl4 molten salt rather than deposition potential of metals. The results suggest that IAP is able to efficiently and simply separate components of aluminum alloys with fast kinetics and high recovery yields, and it is also a valuable synthetic approach for metal chlorides in low oxidation states.

Competitive Coordination of Chloride and Fluoride Anions Towards Trivalent Lanthanide Cations (La3+ and Nd3+ ) in Molten Salts.

Molten salt electrolysis is a vital technique to produce high-purity lanthanide metals and alloys. However, the coordination environments of lanthanides in molten salts, which heavily affect the related redox potential and electrochemical properties, have not been well elucidated. Here, the competitive coordination of chloride and fluoride anions towards lanthanide cations (La3+ and Nd3+ ) is explored in molten LiCl-KCl-LiF-LnCl3 salts using electrochemical, spectroscopic, and computational approaches. Electrochemical analyses show that significant negative shifts in the reduction potential of Ln3+ occur when F- concentration increases, indicating that the F- anions interact with Ln3+ via substituting the coordinated Cl- anions, and confirm [LnClx Fy ]3-x-y (ymax =3) complexes are prevailing in molten salts. Spectroscopic and computational results on solution structures further reveal the competition between Cl- and F- anions, which leads to the formation of four distinct Ln(III) species: [LnCl6 ]3- , [LnCl5 F]3- , [LnCl4 F2 ]3- and [LnCl4 F3 ]4- . Among them, the seven-coordinated [LnCl4 F3 ]4- complex possesses a low-symmetry structure evidenced by the pattern change of Raman spectra. After comparing the polarizing power (Z/r) among different metal cations, it was concluded that Ln-F interaction is weaker than that between transition metal and F- ions.