Altered Cortical Cholinergic Network in Parkinson's Disease at Different Stage: A Resting-State fMRI Study.

The cholinergic system is critical in Parkinson's disease (PD) pathology, which accounts for various clinical symptoms in PD patients. The substantia innominata (SI) provides the main source of cortical cholinergic innervation. Previous studies revealed cholinergic-related dysfunction in PD pathology at early stage. Since PD is a progressive disorder, alterations of cholinergic system function along with the PD progression have yet to be elucidated. Seventy-nine PD patients, including thirty-five early-stage PD patients (PD-E) and forty-four middle-to-late stage PD patients (PD-M), and sixty-four healthy controls (HC) underwent brain magnetic resonance imaging and clinical assessments. We employed seed-based resting-state functional connectivity analysis to explore the cholinergic-related functional alterations. Correlation analysis was used to investigate the relationship between altered functional connectivity and the severity of motor symptoms in PD patients. Results showed that both PD-E and PD-M groups exhibited decreased functional connectivity between left SI and left frontal inferior opercularis areas and increased functional connectivity between left SI and left cingulum middle area as well as right primary motor and sensory areas when comparing with HC. At advanced stages of PD, functional connectivity in the right primary motor and sensory areas was further increased. These altered functional connectivity were also significantly correlated with the Unified Parkinson's Disease Rating Scale motor scores. In conclusion, this study illustrated that altered cholinergic function plays an important role in the motor disruptions in PD patients both in early stage as well as during the progression of the disease.

Fixel-based analysis reveals fiber-specific alterations during the progression of Parkinson's disease.

Disruption of brain circuits is one of the core mechanisms of Parkinson's disease (PD). Understanding structural connection alterations in PD is important for effective treatment. However, due to methodological limitations, most studies were unable to account for confounding factors such as crossing fibers and were unable to identify damages to specific fiber tracts. In the present study, we aimed to demonstrate tract-specific white matter structural changes in PD patients and their relationship with clinical symptoms. Ninety-eight PD patients, divided into early (ES) and middle stage (MS) groups, and 76 healthy controls (HCs) underwent brain magnetic resonance imaging scans and clinical assessments. Fixel-based analysis was used to investigate fiber tract alterations in PD patients. Compared to HCs, the PD patients showed decreased fiber density (FD) in the corpus callosum (CC), increased FD in the cortical spinal tract (CST), and increased fiber-bundle cross-section (FC, log-transformed: log-FC) in the superior cerebellar peduncle (SCP). Analysis of variance (ANOVA) revealed significant differences in FD in the CST and log-FC in the SCP among the three groups. Post-hoc analysis revealed that the mean FD values of the CST were higher in ES and MS patient groups compared to HCs, and the mean log-FC values of the SCP were higher in ES and MS patient groups compared to HCs. Additionally, the FD values of the CC in PD patients were negatively correlated with the Unified Parkinson's Disease Rating Scale part-III (UPDRS-III) scores (r = -0.257, p = 0.032), Hamilton Depression Rating Scale 17 Items (HAMD-17) scores (r = -0.230, p = 0.033), and Hamilton Anxiety Scale (HAMA) scores (r = -0.248, p = 0.032). Moreover, log-FC values of the SCP (r = 0.274, p = 0.028) and FD values of the CST (r = 0.384, p < 0.001) were positively correlated with the UPDRS-III scores. We concluded that PD patients had both decreased and increased white matter integrity within specific fiber bundles. Additionally, these white matter alterations were different across disease stages, suggesting the occurrence of complex pathological and compensatory changes during the development of PD.

Brain structural correlates of depressive symptoms in Parkinson's disease patients at different disease stage.

Parkinson's disease (PD) pathology may damage emotion circuit and cause depression. We investigated whether the neural basis of depressive symptoms varies at different PD stages. Seventy-six healthy controls (HC) and 98 PD patients (divided into early and middle stage groups) underwent brain magnetic resonance imaging (MRI) and general neuropsychological tests. Voxel-based morphometry and tract-based analysis were used to study the association between brain structural alterations and the Hamilton Depression Scale 17 Item (HAMD-17) scores in different groups. Comparing with HC group, PD patients showed widespread brain alterations in both gray and white matter. The HAMD-17 scores were positively correlated with GM volume in the right pre-central gyrus of early PD patients. In the middle stage group, HAMD-17 scores were positively correlated with GM volume in midbrain and right superior temporal gyrus, and negatively associated with GM volume in left anterior cingulate and superior frontal gyrus. In white matter analysis, The HAMD-17 scores were positively correlated with fractional anisotropy value of the bilateral inferior fronto-occipital fasciculus in the early stage group, but not the middle stage group. We concluded that the neural basis of depressive symptoms might be distinct in different stages of PD, implying the need for differential treatments.

Prediction of hematoma expansion in spontaneous intracerebral hemorrhage using support vector machine.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is a devastating disease with high mortality rate. This study aimed to predict hematoma expansion in spontaneous ICH from routinely available variables by using support vector machine (SVM) method. METHODS: We retrospectively reviewed 1157 patients with spontaneous ICH who underwent initial computed tomography (CT) scan within 6 h and follow-up CT scan within 72 h from symptom onset in our hospital between September 2013 and August 2018. Hematoma region was manually segmented at each slice to guarantee the measurement accuracy of hematoma volume. Hematoma expansion was defined as a proportional increase of hematoma volume > 33% or an absolute growth of hematoma volume > 6 mL from initial CT scan to follow-up CT scan. Univariate and multivariate analyses were performed to assess the association between clinical variables and hematoma expansion. SVM machine learning model was developed to predict hematoma expansion. FINDINGS: 246 of 1157 (21.3%) patients experienced hematoma expansion. Multivariate analyses revealed the following 6 independent factors associated with hematoma expansion: male patient (odds ratio [OR] = 1.82), time to initial CT scan (OR = 0.73), Glasgow Coma Scale (OR = 0.86), fibrinogen level (OR = 0.72), black hole sign (OR = 2.52), and blend sign (OR = 4.03). The SVM model achieved a mean sensitivity of 81.3%, specificity of 84.8%, overall accuracy of 83.3%, and area under receiver operating characteristic curve (AUC) of 0.89 in prediction of hematoma expansion. INTERPRETATION: The designed SVM model presented good performance in predicting hematoma expansion from routinely available variables. FUND: This work was supported by Health Foundation for Creative Talents in Zhejiang Province, China, Natural Science Foundation of Zhejiang Province, China (LQ15H180002), the Science and Technology Planning Projects of Wenzhou, China (Y20180112), Scientific Research Staring Foundation for the Returned Overseas Chinese Scholars of Ministry of Education of China, and Project Foundation for the College Young and Middle-aged Academic Leader of Zhejiang Province, China. The funders had no role in study design, data collection, data analysis, interpretation, writing of the report.

Intrarenal delivery of bFGF-loaded liposome under guiding of ultrasound-targeted microbubble destruction prevent diabetic nephropathy through inhibition of inflammation.

Basic fibroblast growth factor (bFGF) has shown great therapeutic effects for diabetic nephropathy (DN). However, its clinical applications are limited due to its short half-life, low stability and poor penetration. Herein, a bFGF-loaded liposome (bFGF-lip) was constructed and combined with ultrasound-targeted microbubble destruction (UTMD) to overcome these drawbacks. bFGF-lip exhibited spherical morphology with a diameter of 171.1 ± 14.2 nm and a negative zeta potential of -5.15 ± 2.08 mV, exhibiting a sustained-release profile of bFGF. DN rat models were successfully induced by streptozotocin. After treatment with bFGF-lip + UTMD, the concentration of bFGF in kidney of DN rats was significantly enhanced in comparison with free bFGF treatment. Additionally, the morphology and the function of the kidneys were obviously recovered after bFGF-lip + UTMD treatment as shown by ultrasonography and histological analyse. The molecular mechanism was associated with the inhibition of renal inflammation. After treatment with bFGF-lip + UTMD, the activation of NF-κB was obviously reduced in the renal tissues, and downstream inflammatory mediators including TGF-ß1, MCP-1, IL-6 and IL-1ß were also down regulated. In addition, inflammation-induced cellular apoptosis of renal tubular cells was also significantly inhibited by detecting Bax, caspase-3 and Bcl-2. Therefore, bFGF-lip in combination with UTMD might be a potential strategy to reverse the progression of early DN.

Combination of coenzyme Q10-loaded liposomes with ultrasound targeted microbubbles destruction (UTMD) for early theranostics of diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most common and lethal microvascular complications of diabetes. This study aimed to explore whether coenzymeQ10 (CoQ10) as an antioxidant combined with ultrasound-targeted microbubble destruction (UTMD) could reverse the progress of early diabetic nephropathy (DN). CoQ10 has great potential to treat early DN. However, the clinical application of CoQ10 has been limited because of its low aqueous solubility and non-specific distribution. Therefore, CoQ10-loaded liposomes (CoQ10-lip) were prepared and combined with ultrasound microbubbles for the early theranostics of DN. CoQ10-lip exhibited a good round morphology with a diameter of 183±1.7nm and a negative zeta potential of -25.3mV, which was capable of prolonging the release of the encapsulated CoQ10. The early DN rat models were induced by streptozotocin (STZ) and confirmed by contrast-enhanced ultrasound (CEUS) and 24-h urinary albumin. After the administration of CoQ10-lip combined with the UTMD technique to rats with early DN, the morphology and function of the kidney were evaluated by ultrasonography, histological and molecular analyses. The renal hemodynamics were significantly improved, moreover, 24-h urinary protein, and oxidative stress indexes were modulated after treatment with CoQ10-lip+UTMD indicating recovery of renal function. An elevated level of Nphs2 protein and reduced caspase 3 level indicated the preservation of podocytes and inhibition of cell apoptosis after CoQ10-lip+UTMD treatment. The molecular mechanism was associated with the upregulation of Bcl-2 and the downregulation of Bax. Moreover, the combination of CoQ10-lip and ultrasound microbubbles demonstrated a better protective effect on the damaged kidney than the other groups (free CoQ10 or CoQ10-lip+/- UTMD). Conclusively, CoQ10-lip in combination with ultrasound microbubbles might be a potential strategy to reverse the progress of early DN.