Confinement Effects on Reorientation Dynamics of Water Confined within Graphite Nanoslits.

Molecular dynamics simulations were used to investigate the reorientation dynamics of water confined within graphite nanoslits of size less than 2 nm, where molecules formed inner and interfacial layers parallel to the confining walls. Significantly related to molecular reorientations, the hydrogen-bond (HB) network of nanoconfined water therein was scrutinized by HB configuration fractions compared to those of bulk water and the influences on interfacial-molecule orientations relative to a nearby C atom plate. The second-rank orientation time correlation functions (OTCFs) of nanoconfined water were calculated and found to follow stretched-exponential, power-law, and power-law decays in a time series. To understand this naïve behavior of reorientation relaxation, the approach of statistical mechanics was adopted in our studies. In terms of the orientation Van Hove function (OVHF), an alternative meaning was given to the second-rank OTCF, which is a measure of the deviation of the OVHF between a molecular system and free molecules in random orientations. Indicated by the OVHFs at related time scales, the stretched-exponential decay of the second-rank OTCF resulted from molecules evacuating out of HB cages formed by their neighbors. After the evacuations, the inner molecules relaxed at relatively fast rates toward random orientations, but the interfacial molecules reoriented at slow rates due to restrictions by hydrophobic interactions with graphite walls. The first power-law decay of the second-rank OTCF was attributed to the distinct relaxation rates of inner and interfacial molecules within a graphite nanoslit. When the inner molecules were completely random in orientation, the second-rank OTCFs changed to another power law decay with a power smaller than the first one.

Effect of acute levodopa challenge test on cerebral blood flow in Parkinson's disease with the supine-to-standing transcranial Doppler test.

BACKGROUND: Levodopa, a common drug that improves symptoms of Parkinson's disease (PD), can induce a reduction in blood pressure (BP); however, the effect of levodopa on cerebral blood flow (CBF) remains unclear. OBJECTIVES: To observe the changes in BP and CBF during active standing before and after the acute levodopa challenge test (ALCT) and analyse the influencing factors of CBF in patients with PD. METHODS: BP and CBF velocity were simultaneously recorded by continuous beat-to-beat non-invasive BP monitoring and transcranial Doppler at supine and orthostatic positions twice, before and after ALCT. The patients were divided into two groups according to those with increased and decreased CBF at baseline after ALCT to analyse the influencing factors. RESULTS: We examined 64 patients with PD (59.2 ± 11.6 years, 33 males). BP decreased at all timepoints after ALCT, while there was no significant change in the magnitude of the drop in BP induced by standing. CBF was reduced after ALCT, especially within 15 s to 1 min of standing (15 s: 48.95 ± 13.50 vs. 44.93 ± 13.26, p < 0.001; 30 s: 52.46 ± 12.06 vs. 50.11 ± 12.56, p = 0.033; 1 min: 52.19 ± 11.83 vs. 50.17 ± 13.21, p = 0.044). Lower body mass index (ß = -0.280, p = 0.027) was an independent factor associated with CBF reduction after ALCT. CONCLUSIONS: Additional attention should be paid to changes in CBF and BP within 1 min after standing in patients with PD taking levodopa, especially in those with low bodyweight.

Alzheimer's Disease Related Biomarkers Were Associated with Amnestic Cognitive Impairment in Parkinson's Disease: A Cross-Sectional Cohort Study.

BACKGROUND: Cognitive impairment is common in patients with Parkinson's disease (PD) and occurs through multiple mechanisms, including Alzheimer's disease (AD) pathology and the involvement of α-synucleinopathies. We aimed to investigate the pathological biomarkers of both PD and AD in plasma and neuronal extracellular vesicles (EVs) and their association with different types of cognitive impairment in PD patients. METHODS: A total of 122 patients with PD and 30 healthy controls were included in this cross-sectional cohort study between March 2021 and July 2023. Non-dementia PD patients were divided into amnestic and non-amnestic groups according to the memory domain of a neuropsychological assessment. Plasma and neuronal EV biomarkers, including α-synuclein (α-syn), beta-amyloid (Aß), total tau (T-tau), phosphorylated tau181 (p-tau181), and glial fibrillary acidic protein (GFAP), were measured using a single-molecule array and a chemiluminescence immunoassay, respectively. RESULTS: Neuronal EV but not plasma α-syn levels, were significantly increased in PD as compared to healthy controls, and they were positively associated with UPDRS part III scores and the severity of cognitive impairment. A lower plasma Aß42 level and higher neuronal EV T-tau level were found in the amnestic PD group compared to the non-amnestic PD group. CONCLUSIONS: The results of the current study demonstrate that neuronal EV α-syn levels can be a sensitive biomarker for assisting in the diagnosis and disease severity prediction of PD. Both AD and PD pathologies are important factors in cognitive impairment associated with PD, and AD pathologies are more involved in amnestic memory deficit in PD.

The differences of orthostatic hypotension in patients with Parkinson's disease and multiple system atrophy.

Background: Multiple system atrophy (MSA) and Parkinson's disease (PD) have similar clinical presentations in their early stages. Orthostatic hypotension (OH) is a common autonomic dysfunction associated with MSA and PD. Heart rate (HR) and systolic blood pressure (SBP) changes are measured in response to the active standing test, which is widely used to screen for cardiovascular autonomic function. Objectives and methods: Overall, 255 patients (67 MSA, 188 PD) underwent continuous beat-to-beat non-invasive BP monitoring and active standing test. The total standing time was 10 min, and the BP differences between both groups were compared to determine whether the ΔHR/ΔSBP can differentiate both conditions. Results: Classical orthostatic hypotension (COH) (52%) and initial OH (19%) were most common in MSA and PD, respectively. MSA had a higher HR (75.0 ± 9.7 vs. 71.0 ± 10.7, P = 0.008) than PD in the supine position. SBP (135.70 ± 15.68 mmHg vs. 127.31 ± 15.14 mmHg, P = 0.106), diastolic BP (78.45 ± 12.36 mmHg vs. 67.15 ± 13.39 mmHg, P = 0.009) and HR (73.94 ± 8.39 bpm vs. 71.08 ± 13.52 bpm, P = 0.389) at baseline were higher in MSA-COH than in PD-COH. After adjusting for age and disease duration, the ΔHR/ΔSBP-10 min significantly discriminated MSA-COH from PD-COH (P = 0.031). An ΔHR/ΔSBP-10 min of 0.517 showed a sensitivity of 67% and specificity of 84% (AUC = 0.77, 95% CI: 0.63-0.91). Conclusion: The SBP, diastolic BP, and HR were higher in the supine position; however, ΔHR and ΔSBP were lower after standing in MSA patients than in PD patients. The ΔHR/ΔSBP-10 min discriminated between MSA-COH and PD-COH with quiet acceptable accuracy.

The mechanism of impaired delayed recall verbal memory function in Parkinson's disease with orthostatic hypotension: a multiple imaging study.

Introduction: Orthostatic hypotension (OH) frequently accompanies autonomic dysfunction and is an important risk factor for cognitive impairment in Parkinson's disease (PD). However, the association between different cognitive functions and OH in PD patients is not yet fully understood. Methods: This study aimed to evaluate the scores of different cognitive domains and multiple parameters using different imaging techniques on PD patients with or without OH. A total number of 31 PD patients with OH (n = 20) and without OH (n = 11) were recruited from the Department of Neurology, Beijing Xuanwu Hospital for this study. All patients underwent beat-to-beat non-invasive blood pressure recordings and an active standing test to evaluate neurogenic OH and a global neuropsychological test to assess cognitive function. All patients underwent dynamic cerebral autoregulation (dCA) measurement, brain magnetic resonance imaging (MRI), and brain 18fluorine-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). Results: The results showed that OH patients had poor delayed recall verbal memory when compared with the PD patients without OH (1.75 ± 1.59 vs. 3.10 ± 1.73, p = 0.042). The dCA test indicated a significant difference in the right very low-frequency (VLF) gain between two groups (1.27 ± 0.17 vs. 1.10 ± 0.26, p = 0.045) and the brain 18F-FDG PET/CT indicated a significant difference in the SUV (right medial temporal lobe) to SUV (occipital lobe) ratio (0.60 ± 0.08 vs. 0.67 ± 0.11, p = 0.049). Meanwhile, these two imaging parameters were negatively correlated (p < 0.001). Furthermore, the score of a delayed recall verbal memory in the OH group was positively correlated with the right medial temporal lobe to occipital lobe ratio (p < 0.001) and was negatively correlated with the right VLF gain (p = 0.023). Discussion: PD with OH patients had poor delayed recall memory, which might have been caused by the decreased metabolic dysfunction of specific medial temporal lobe due to the impaired dCA ability.

Impaired Cerebral Autoregulation in Parkinson's Disease: An Orthostatic Hypotension Analysis.

Orthostatic hypotension (OH) is an early non-motor manifestation of Parkinson's disease (PD). However, the underlying mechanism of hemodynamic changes in patients with PD and OH remains unclear. This study aimed to investigate the dynamic cerebral autoregulation changes in patients with PD with OH. Ninety patients with PD and 20 age- and sex-matched healthy controls (HCs) were recruited. The patients' non-invasive blood pressure (BP) and cerebral blood flow velocity were simultaneously recorded at supine and orthostatic positions during the active standing test (AST). Transfer function analysis was used to determine autoregulatory parameters including gain [i.e., damping effect of dynamic cerebral autoregulation (dCA) on the magnitude of BP oscillation] and phase difference (i.e., the time delay of the cerebral blood flow response to BP). Sixteen patients (17.8%) in the PD population were diagnosed with OH (PD-OH). The AST results were normal for 74 patients (82.2%) (PD-NOR). In the supine position, the PD-OH group had a lower phase degree than the PD-NOR group (50.3 ± 23.4 vs. 72.6 ± 32.2 vs. 68.9 ± 12.1, p = 0.020); however, no significant difference was found upon comparing with the HC group. In the orthostatic position, the normalized gain was significantly higher for the symptomatic OH group than for the asymptomatic OH group and HC group (1.50 ± 0.58 vs. 0.97 ± 0.29 vs. 1.10 ± 0.31, p = 0.019). A symptomatic OH in the PD population indicates an impaired cerebral autoregulation ability in the orthostatic position. Cerebral autoregulation tends to be impaired in the supine position in the OH population.

Impaired dynamic cerebral autoregulation: A potential mechanism of orthostatic hypotension and dementia in Parkinson's disease.

Background: Orthostatic hypotension (OH) and cognitive impairment are common non-motor symptoms of Parkinson's disease (PD). This study aimed to investigate whether impaired dynamic cerebral autoregulation (dCA) is associated with OH and Parkinson's disease dementia (PDD), and analyze the related risk factors in patients with PDD. Materials and methods: We enrolled 89 patients with PD and 20 age- and sex-matched healthy controls (HCs). Cognition and different cognitive domains were assessed by the Montreal Cognitive Assessment scale. Non-invasive continuous beat-to-beat blood pressure and cerebral blood flow velocity were assessed using a servo-controlled finger plethysmograph and transcranial Doppler, respectively. dCA was examined using supine and orthostatic changes with transfer function analysis to derive the autoregulatory parameters of phase, gain, and coherence. Logistic regression analysis was performed to determine the risk factors for PDD. Results: We found that 21 (23.6%) patients with PD had OH. These patients showed worse cognitive performance in specific cognitive tasks, such as language and orientation. The patients with OH also had poorer dCA; the very low frequency (VLF) phase in two different postures was lower than that in patients without OH as well as HCs (both P < 0.05). And the normalized gain in the VLF and low frequency (LF) in standing position was higher in PD patients with and without OH than in HCs. PDD patients also had significantly higher LF normalized gain when standing than patients without dementia (P = 0.015), indicating impaired dCA. LF normalized gain in standing (odds ratio: 3.756, 95% confidence interval: 1.241-11.367) and education were significantly associated with PDD. Conclusion: Diminished dCA may represent a potential mechanism for OH and cognitive impairment and low educational level might be a significant factor contributing to the increased risk of PDD.

Amniotic Membrane Enhances the Characteristics and Function of Stem Cell-Derived Retinal Pigment Epithelium Sheets by Inhibiting the Epithelial-Mesenchymal Transition.

Human pluripotent stem cell-derived retinal pigment epithelium (iRPE) is an attractive cell source for disease modeling and cell replacement therapy of retinal disorders with RPE defects. However, there are still challenges to develop appropriate culture conditions close to in vivo microenvironment to generate iRPE sheets, which mimic more faithfully the characteristics and functions of the human RPE cells. Here, we developed a simple, novel platform to construct authentic iRPE sheets using human amniotic membrane (hAM) as a natural scaffold. The decellularized hAM (dAM) provided a Bruch's membrane (BM)-like bioscaffold, supported the iRPE growth and enhanced the epithelial features, polarity distribution and functional features of iRPE cells. Importantly, RNA-seq analysis was performed to compare the transcriptomes of iRPE cells cultured on different substrates, which revealed the potential mechanism that dAM supported and promoted iRPE growth was the inhibition of epithelial-mesenchymal transition (EMT). The tissue-engineered iRPE sheets survived and kept monolayer when transplanted into the subretinal space of rabbits. All together, our results indicate that the dAM imitating the natural BM allows for engineering authentic human RPE sheets, which will provide valuable biomaterials for disease modeling, drug screening and cell replacement therapy of retinal degenerative diseases. STATEMENT OF SIGNIFICANCE: Engineered RPE sheets have a great advantage over RPE cell suspension for transplantation as they support RPE growth in an intact monolayer which RPE functions are dependent on. The substrates for RPE culture play a critical role to maintain the physiological functions of the RPE in stem cell therapies for patients with retinal degeneration. In this study, we constructed engineered iRPE sheets on the decellularized human amniotic membrane scaffolds, which contributed to enhancing epithelial features, polarity distribution and functional features of iRPE. dAM exhibited the ability of anti-epithelial mesenchymal transition to support iRPE growth. Furthermore, the results of transplantation in vivo demonstrated the feasibility of iRPE sheets in retina regenerative therapy. Engineering RPE sheets on dAM is a promising strategy to facilitate the development of iRPE replacement therapy and retinal disease modeling.

Case Report: Progressive Asymmetric Parkinsonism Secondary to CADASIL Without Dementia.

Parkinsonism is a rare phenotype of cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL), all of which involve cognitive decline. Normal cognition has not been reported in previous disease studies. Here we report the case of a 60-year-old female patient with a 2-year history of progressive asymmetric parkinsonism. On examination, she showed severe parkinsonism featuring bradykinesia and axial and limb rigidity with preserved cognition. Magnetic resonance imaging (MRI) revealed white matter hyperintensity in the external capsule and periventricular region. Dopaminergic response was limited. A missense mutation c.1630C>T (p.R544C) on the NOTCH3 gene was identified on whole-exome sequencing, which confirmed the diagnosis of vascular parkinsonism secondary to CADASIL. A diagnosis of CADASIL should be considered in asymmetric parkinsonism without dementia. Characteristic MRI findings support the diagnosis.