Targeting gut-brain axis through scalp-abdominal electroacupuncture in Parkinson's disease.

BACKGROUND: Evidence suggests that the pathogenesis of Parkinson's disease (PD) is initiated in the gut rather than in the brain. Thus, targeting the gut in early stages may have the potential to halt disease progression and alleviate symptoms. Various acupuncture techniques have been used to treat patients with PD and have shown promising results. However, previous acupuncture techniques focused on the brain and motor symptoms. We aimed to determine if targeting PD patients' gut-brain axis through electroacupuncture could be an effective, safe, and low-cost therapeutic option for management of non-motor and motor symptoms. METHODS: Thirty patients with mild to moderate PD were randomised into an intervention (n = 15) and a control group (n = 15). The intervention group received electroacupuncture twice a week for 30 min based on conventional drug treatment for 8 weeks. Conventional drug treatment was continued in the control group. The primary outcomes were changes in the score of clinical scales including the Non-motor Symptom Rating Scale (NMSS), PD Sleep Scale (PDSS), Bristol Stool Function Scale (BSFS), and Patient Associated Constipation and Quality of Life Scale (PAC-QOL). The secondary outcomes were the Unified PD Rating Scale (UPDRS) and Modified Hoehn-Yahr Staging Scale scores. Stool samples from the intervention group were collected before and after the procedure and were sent for gene sequencing. Adverse effects and personal impressions of the patients were noted during the course of the trial. RESULT: An 8-week course of scalp-abdominal electroacupuncture treatment was effective in improving the NMSS, PDSS, and UPDRS scores in patients with PD. Further, there was statistical significance in the two subdomains of NMSS, namely sleep/fatigue and miscellaneous, further implying the efficacy of acupuncture on sleep disturbance. However, although the current acupuncture treatment was gut targeted, it had no effect on BSFS or PAC-QOL. Apart from improved UPDRS motor scores and activities of daily living scores, acupuncture had no significant impact on scores of mentation, behaviour, mood, and therapy complications. Acupuncture did not alter the Hoehn and Yahr stage. Significant alterations in gut bacterial composition were detected in nine taxa at the genus level. The relative abundances of the genera Bacteroides and Parasutterella were significantly increased after the intervention, whereas the abundances of the genera Dialister, Hungatella, Barnesiella, Megasphaera, Allisonella, Intestinimon, and Moryella were significantly lower. CONCLUSION: An 8-week scalp-abdominal electroacupuncture treatment may be a complementary and alternative vehicle for PD patients. We detected nine taxa at the genus level which were significantly altered after treatment, emphasising the role of the gut-brain axis in the process.

Diffusion Tensor Imaging Reveals Deep Brain Structure Changes in Early Parkinson's Disease Patients with Various Sleep Disorders.

Parkinson's disease (PD) is a progressive age-related movement disorder caused by dopaminergic neuron loss in the substantia nigra. Diffusion-based magnetic resonance imaging (MRI) studies­namely, diffusion tensor imaging (DTI)­have been performed in the context of PD, either with or without the involvement of sleep disorders (SDs), to deepen our understanding of cerebral microstructural alterations. Analyzing the clinical characteristics and neuroimaging features of SDs in early PD patients is beneficial for early diagnosis and timely invention. In our present study, we enrolled 36 early PD patients (31 patients with SDs and 5 patients without) and 22 healthy controls. Different types of SDs were assessed using the Rapid Eye Movement Sleep Behavior Disorder Questionnaire­Hong Kong, Epworth Sleepiness Scale, International Restless Legs Scale and PD Sleep Scale-2. Brain MRI examinations were carried out in all the participants, and a region-of-interest (ROI) analysis was used to determine the DTI-based fractional anisotropy (FA) values in the substantia nigra (SN), thalamus (Thal) and hypothalamus (HT). The results illustrate that SDs showed a higher prevalence in the early PD patients than in the healthy controls (86.11% vs. 27.27%). Early PD patients with nighttime problems (NPs) had longer courses of PD than those without (5.097 ± 2.925 vs. 2.200 ± 1.095; p < 0.05), and these patients with excessive daytime sleepiness (EDS) or restless legs syndrome (RLS) had more advanced Hoehn and Yahr stages (HY stage) than those without (1.522 ± 0.511 and 1.526 ± 0.513, respectively; both p < 0.05). Compared with the early PD patients without probable rapid eye movement sleep behavior disorder (pRBD), those with pRBD had longer courses, more advanced HY stages and worse motor and non-motor symptoms of PD (course(years), 3.385 ± 1.895 vs. 5.435 ± 3.160; HY stages, 1.462 ± 0.477 vs. 1.848 ± 0.553; UPDRS, 13.538 ± 7.333 vs. 21.783 ± 10.766; UPDRS, 6.538 ± 1.898 vs. 7.957 ± 2.345; all p < 0.05). In addition, the different number of SD types in early PD patients was significantly inversely associated with the severity of damage in the SN and HT. All of the early PD patients with various SDs had injuries in the SN, in whom the damage was more pronounced in patients with NP than those without. Moreover, early PD patients with NP, RLS or pRBD had worse degrees of HT damage than those without. The current study demonstrated the pathophysiological features and neuroimaging changes in early PD patients with various types of sleep disorders, which will help in early diagnosis and therapy.

The neuroprotective effects of paeoniflorin against MPP+-induced damage to dopaminergic neurons via the Akt/Nrf2/GPX4 pathway.

Paeoniflorin (PF), a water-soluble monoterpene glycoside extracted from the root of Paeonia lactiflora Pall, has been shown to exert neuroprotective effects against neurodegenerative diseases such as Parkinson's disease (PD). However, its underlying mechanisms remain unknown. Our results showed that at certain concentrations, PF alleviated 1-methyl-4-phenylpyridinium (MPP+)-induced morphological damage and inhibited neuronal ferroptosis. Moreover, our research indicated that the neuroprotective effect of PF could be partially blocked by ML385 (a nuclear factor erythroid-2-related factor 2 (Nrf2) inhibitor) and LY29400 (an Akt inhibitor). These findings suggest that PF protects against MPP+-induced neurotoxicity by preventing ferroptosis via activation of the Akt/Nrf2/Gpx4 pathway in vitro.

Benefits of Iron Chelators in the Treatment of Parkinson's Disease.

As a novel discovered regulated cell death pattern, ferroptosis has been associated with the development of Parkinson's disease (PD) and has attracted widespread attention. Nevertheless, the relationship between ferroptosis and PD pathogenesis is still unclear. This study aims to investigate the effect of iron overload on dopaminergic (DA) neurons and its correlation with ferroptosis. Here we use nerve growth factor (NGF) induced PC12 cells which are derived from pheochromocytoma of the rat adrenal to establish a classical PD in vitro model. We found significantly decreased cell viability in NGF-PC12 cell under ammonium ferric citrate (FAC) administration. Moreover, excessive intracellular iron ions induced the increase of (reactive oxygen species) ROS release as well as the decrease of mitochondrial membrane potential in PC12-NGF cells. In addition, we also found that overloaded iron can activate cell apoptosis and ferroptosis pathways, which led to cell death. Furthermore, MPP-induced PD cells were characterized by mitochondrial shrinkage, decreased expression of glutathione peroxidase 4 (Gpx4) and ferritin heavy chain (FTH1), and increased divalent metal transporter (DMT1) and transferrin receptor 1 (TfR1) expression level. In contrast, Lip-1 and DFO increased the expression level of GPX4 and FTH1 compared to MPP-induced PD cell. In conclusion, we indicated that overloaded intracellular iron contributes to neurons death via apoptosis and ferroptosis pathways, while DFO, an iron chelator, can inhibit ferroptosis in order to protect the neurons in vitro.

3D texture analyses within the substantia nigra of Parkinson's disease patients on quantitative susceptibility maps and R2∗ maps.

Iron accumulation in the substantia nigra (SN) is spatially heterogeneous, yet no study has quantitatively evaluated how the texture of quantitative susceptibility maps (QSM) and R2∗ might evolve with Parkinson's disease (PD) and healthy controls (HC). The aim of this study was to discriminate between patients with PD and HC using texture analysis in the SN from QSM and R2∗ maps. QSM and R2∗ maps were obtained from 28 PD patients and 28 HC on a clinical 3T MR imaging scanner using 3D multi-echo gradient-echo sequence. The first- and second- order texture features of the QSM and R2∗ images were obtained to evaluate group differences using two-tailed t-test. After correction for multiple comparisons, for the first-order analysis, the susceptibility of SN from patients with PD was significantly greater (p = 0.017) compared with the SN from HC. For the second-order texture analysis, angular second moment, entropy, and sum of entropy showed significant differences in QSM (p < 0.001) and R2∗ maps (p < 0.01). In addition, correlation, contrast, sum of variance and difference of variance, significantly separated the subject groups in QSM maps (p < 0.05) but not in R2∗ images. Receiver operating characteristic analysis showed that entropy and sum of entropy of the QSM maps in the SN yielded the highest performance for differentiating PD patients from HC (area under the curve = 0.89). In conclusion, most first- and second- order QSM texture features successfully distinguished PD patients from HC and significantly outperformed R2∗ texture analysis. The second-order texture features were more accurate and sensitive than first-order texture features for classifying PD patients.

Multiple Kernel Learning Based Classification of Parkinson's Disease With Multi-Modal Transcranial Sonography.

Parkinson's Disease (PD) is the most common motor neurodegenerative disease in elderly population. Transcranial sonography (TCS) has become a popular imaging tool for diagnosis of PD in clinical practice. Moreover, several pioneering work have developed the computer-aided diagnosis (CAD) for PD with the transcranial B-mode sonography (TBS). It is worth noting that TCS not only has the TBS modality, but also can image the blood flow of major cerebral arteries, which is named transcranial Doppler sonography (TDS). TDS also has been applied to evaluate PD patients with orthostatic hypotension. However, the TDS-based CAD for PD has not been investigated. Since TBS and TDS provide the complementary structural and functional information about brain, it is feasible to develop a multi-modal TCS-based CAD for PD by combining both TBS and TDS. Therefore, in this work, we propose a multiple kernel learning (MKL) based CAD for PD with multi-modal TCS imaging. Particularly, the statistical and texture features are extracted from the midbrain region from TBS images, and the features about blood flow are calculated from the spectrum curves in TDS. The multi-modal features are then fed to a MKL classifier for classification of PD. The experimental results show that the multi-modal TCS-based method outperforms both the single-modal TBS- and TDS-based algorithm, which suggests the feasibility and effectiveness of combining TBS and TDS for diagnosis of PD.

Multiple Empirical Kernel Mapping Based Broad Learning System for Classification of Parkinson's Disease With Transcranial Sonography.

Transcranial sonography (TCS) has become more popular for diagnosis of Parkinson's disease (PD), and the TCS-based computer-aided diagnosis (CAD) for PD also attracts considerable attention, in which classifier is a critical component. Broad learning system (BLS) is a newly proposed single layer feedforward neural network for classification. In BLS, the original input features are mapped to several new feature representations to form the feature nodes, and then these mapped features are expanded to enhancement nodes by random mapping in a wide sense. However, random mapping performed for enhancement nodes is too simple and the generated features lack interpretability together with relative low representation. In this work, we propose a multiple empirical kernel mapping (MEKM) based BLS (MEKM-BLS) algorithm, which adopts MEKM to map the data of feature nodes to enhancement nodes. MEKM-BLS then has more meaningful enhancement layer in feedforward neural network. Moreover, the experiment for PD diagnosis with TCS shows that MEKM-BLS achieves superior performance to the original BLS algorithm.

Quantifying iron deposition within the substantia nigra of Parkinson's disease by quantitative susceptibility mapping.

BACKGROUND: Iron deposition within the substantia nigra (SN) has been postulated to play a vital role in Parkinson's disease (PD). The aim of this study was to explore the inherent link of PD patients between their substantia nigra iron accumulation and clinical status using quantitative susceptibility mapping (QSM) which is now considered to be the only quantitative imaging technique of brain iron deposition. METHODS: 44 PD patients and 31 age- and gender-matched healthy controls underwent quantitative susceptibility mapping (QSM) were recruited in this study. We firstly divided the patients into mild symptom severity (MSP) and advanced symptom severity (ASP) groups concerning their disease stage, aiming to illuminate the relationship between iron deposition in SN of PD and disease progression. Then, we classified the patients with Parkinson's disease into three subgroups: tremor-dominant PD (TD), akinetic/rigidity-dominant PD (AR), mixed-PD (M) according to their dominant motor symptoms in order to investigate whether there are any effects of SN iron accumulation to different subtypes of PD patients. RESULTS: Compared to healthy controls, patients with PD have increased QSM magnetic values in the substantia nigra (138.039±37.320 vs 179.553±65.715; P=0.001). More prominent statistically significance of the difference of SN iron deposition between healthy controls (HC) and advanced symptom severity (ASP) subgroup was displayed (138.039±37.320 vs 232.827±92.040; P<0.001). Besides, among the three clinical phenotypes both TD and AR subgroup showed significant difference compared with healthy controls concerning the QSM values (138.039±37.320 vs 185.864±99.851; P=0.013; 188.148±52.958 vs 138.039±37.320; P=0.001). Furthermore, the iron content in the SN of PD patients was significantly correlated with the Hoehn-Yahr stage, the Unified Parkinson's Disease Rating Scale (UPDRS), Montgomery Asberg Depression Rating Scale (MADRS) and Hamilton Anxiety Scale (HAMA) scores (r=0.417, P=0.005; r=0.300, P=0.048; r=0.540, P<0.001; r=0.553, P<0.001). In MSP the significantly correlation was displayed only in MADRS, HAMA scores (r=0.429, P=0.013; r=0.492, P=0.004), when disease progressed into advanced severity stage all these clinical measures (Hoehn-Yahr stage, UPDRS-3, UPDRS, HAMA, and MADRS scores) we had recruited into this study shown prominent correlation to SN iron content (r=0.650, P=0.030; r=0.709, P=0.015; r=0.708, P=0.015; r=0.758, P=0.007; r=0.683, P=0.020). In the three phenotypes the correlation between iron content and MADRS, HAMA scores (r=0.686, P=0.002; r=0.633, P=0.006) was found in AR subgroups exclusively. CONCLUSIONS: Patients with PD exhibited significantly higher magnetic susceptibility values, especially in those who are in advanced disease severity stage, which confirmed that iron accumulation in the SN is in line with Parkinson's disease progression. Furthermore, we testified that there are actually some inherent effects of substantia nigra iron deposition to the clinical symptoms of Parkinson's disease. Moreover, it seems that akinetic/rigidity-dominant PD subgroup was affected most by SN iron accumulation.

Proteomic analysis and comparison of intra­ and extracranial cerebral atherosclerosis responses to hyperlipidemia in rabbits.

The present study aimed to investigate protein expression levels of intra­ and extracranial atherosclerosis in rabbits following administration of a high­fat diet. Rabbits were randomly divided into control (group A; n=9) and high­fat diet (group B; n=9) groups. At week 12, tissues were sectioned from the common carotid artery (CCA) and middle cerebral artery (MCA). Pathological analysis was performed. Differential protein expression levels were examined by 2­D gel electrophoresis (2­DE) and mass spectrometry (MS) analysis and validated by western blotting. Serum lipid levels, the intima­media thickness (IMT) and degree of atherosclerosis of the CCA and MCA were increased at week 12 in the high­fat diet group compared with rabbits that received a normal diet. 2­DE and MS analysis of the protein extracted from CCA and MCA detected >439 different proteins; the expression of 25 proteins was altered, and 8 proteins [albumin A chain, tropomyosin α­1 chain (TPM1), heat shock protein 70 (HSP70), α­smooth muscle actin, ß­galactose binding agglutinin, TPM4 isoform 2, cell keratin 9, single octylic acid glyceride ß­2) demonstrated significant alterations in expression levels. Due to limited antibody sources, only three differentially expressed proteins (TPM1, HSP70 and α­smooth muscle actin) were examined by western blotting. The results of our previous study demonstrated that hyperlipidemia affected the IMT of intracranial and extracranial cerebral arteries. In the present study, protein expression levels of TPM1 and α­smooth muscle actin from extracranial cerebral arteries were significantly increased compared with intracranial cerebral arteries; however, protein expression levels of HSP70 from intracranial cerebral arteries was increased compared with extracranial cerebral arteries. The differences may be closely associated with cell proliferation and metastasis, and oxidoreduction, in intra­ and extracranial cerebral atherosclerosis. HSP70 may have protective properties against atherosclerosis via underlying anti­inflammatory mechanisms, furthermore, differential protein expression levels (TPM1, HSP70 and α­smooth muscle actin) between intra­ and extracranial cerebral arteries may facilitate the identification of novel biological markers for the diagnosis and treatment of cerebral arteriosclerosis.

A Retrospective Study of thrombolysis with 0.6 mg/kg Recombinant Tissue Plasminogen Activator (rt-PA) in Mild Stroke.

We sought to assess the safety, effectiveness and cost of 0.6 mg/kg rt-PA treatment for patients with acute mild stroke and to compare that with 0.9 mg/kg. We retrospectively analyzed consecutive acute ischemic stroke patients who had a NIHSS score ≤5 at admission and who were treated with rt-PA within 4.5 hours of symptom onset. The demographic data, clinical outcomes and hospitalization cost were analyzed. A total of 108 patients were included. Forty six patients (42.6%) received a 0.6 mg/kg dosage of rt-PA. The baseline characteristics of the two groups were well matched (p > 0.05). Regarding the safety and effectiveness, the 0.6 mg/kg dosage group had a comparable proportion of symptomatic intracranial hemorrhage (sICH) (0.6 mg/kg, 4.3% vs 0.9 mg/kg, 4.8%; p > 0.05), early neurological deterioration (END) (19.6% vs 17.7%; p > 0.05), in-hospital mortality (4.3% vs 1.6%; p > 0.05), and a similar rate of favorable functional outcome (mRS score 0-1) at 3 months (73.9% vs 71.0%; p > 0.05) to those who received the standard dosage. However, the hospital cost was markedly lower in the 0.6 mg/kg group (0.6 mg/kg, 3,401.7 USD vs 0.9 mg/kg, 4,157.4 USD; p < 0.01). Our study suggest that 0.6 mg/kg rt-PA shared similar effectiveness and safety profile compared with that of 0.9 mg/kg in treating mild stroke, but cost less.

Distribution of ischemic infarction and stenosis of intra- and extracranial arteries in young Chinese patients with ischemic stroke.

BACKGROUND: The distribution of cerebral ischemic infarction and stenosis in ischemic stroke may vary with age-group, race and gender. This study was conducted to understand the risk factors and characteristics of cerebral infarction and stenosis of vessels in young Chinese patients with ischemic stroke. METHODS: This was a retrospective study, from January 2007 to July 2012, of 123 patients ≤50 years diagnosed with acute ischemic stroke. Patient characteristics were compared according to sex (98 males and 25 females) and age group (51 patients were ≤45 years and 72 patients were 46-50 years). Characteristics of acute ischemic infarction were studied by diffusion weighted imaging. Stenosis of intra- and extracranial arteries was diagnosed by duplex sonography, head magnetic resonance angiography (MRA) or cervical MRA. RESULTS: Common risk factors were hypertension (72.4 %), dyslipidemia (55.3 %), smoking (54.4 %) and diabetes (33.3 %). Lacunar Infarction was most common in our patients (41.5 %). Partial anterior circulation infarction was predominant in females (52.0 vs 32.7 %; P = 0.073) and posterior circulation infarction in males (19.8 vs 4 %; P = 0.073). Multiple brain infarctions were found in 38 patients (30.9 %). Small artery atherosclerosis was found in 54 patients (43.9 %), with higher prevalence in patients of the 46-50 years age-group. Intracranial stenosis was more common than extracranial stenosis, and middle cerebral artery stenosis was most prevalent (27.3 %). Stenosis in the anterior circulation was more frequent than in the posterior circulation (P < 0.001). CONCLUSIONS: In these young patients, hypertension, smoking, dyslipidemia and diabetes were common risk factors. Intracranial stenosis was most common. The middle cerebral artery was highly vulnerable.

Effect of dyslipidemia on intima-media thickness of intra- and extracranial atherosclerosis by regulating the expression of hsp70 in rabbits.

The aim of this study was to explore the effect of dyslipidemia on intima-media thickness (IMT) of Intra- and extracranial atherosclerosis by regulating the expression of heat shock protein 70 (HSP70) in rabbits. Twenty-seven male white rabbits were randomly divided into normal control group A, high fat group B and high fat + endothelial injury operation group C (each group was 9), we measured lipids and obtained tissues from different cerebral arteries including Bilateral common carotid artery (CCA), Internal carotid artery (ICA), middle cerebral artery (MCA) and vertebral artery (VA). Pathological analysis were done, western blot analysis was used to detect the expression of HSP70 in CCA and MCA. The Serum lipid levels were overall significantly increased at 12(th) week in Group B and Group C compared to normal control (P < 0.05); at 12(th) week, the IMT of CCA and MCA in group B and C were showed significant increment compared with Group A; the correlation between HDL/CHOL/LDL and IMT of different cerebral arteries are as follows: MCA > ICA > CCA > VA; between TG and IMT of different cerebral arteries: VA > ICA > MCA > CCA; the expression of HSP70 from MCA were increased compared with CCA in group B and group C (P < 0.05). Significant positive correlations were observed between hyperlipidemia and different cerebral arteries. Hyperlipidemia has more impact on IMT of intracranial cerebral arteries. The expression of HSP70 from intracranial cerebral arteries is significantly increased. The mechanisms underlied was speculated that might be involved in inhibiting the inflammatory via HSP70.

Influence of internal carotid artery stenosis, blood pressure, glycated hemoglobin, and hemoglobin level on fMRI signals of stroke patients.

OBJECTIVES: To identify the effect of internal carotid artery (ICA) stenosis, blood pressure (BP), glycated hemoglobin (HbA1c), and hemoglobin level on blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signals in stroke patients. METHODS: A total of 18 stroke patients with acute cerebral infarction (13 males and 5 females) and 13 age-matched healthy controls (5 males and 8 females) were recruited. Among 18 stroke patients, 8 had significant ICA stenosis (> 50%) and 10 had nonsignificant ICA stenosis (< 50%). During handgrip task, stroke patients and normal controls were allowed to use their hands coincided with infarction and right hands, respectively. RESULTS: The mean BOLD signals in patients with significant ICA stenosis were significantly less than that in patients with nonsignificant ICA stenosis. Mean arterial pressure (MAP) was significantly correlated with activated voxels of Brodmann area 4 (P < 0.01) and total activated voxels (P  =  0.007), whereas hemoglobin and HbA1c showed no significant correlation with activated voxels of Brodmann area 4 or total activated voxels (P > 0.05). CONCLUSION: It is suggested that both ICA stenosis and arterial BP could influence BOLD signal, while HbA1c and hemoglobin level had no effect on BOLD signal.