Management of intervenable factors to reduce vascular complications in patients with internal carotid artery occlusion treated by non-emergency endovascular treatment.

Objective: This study aims to identify risk factors for vascular complications during non-emergency endovascular treatment in patients with internal carotid artery occlusion (ICAO) and to propose potential interventions. Method: A retrospective analysis of 92 patients with ICAO who received non-emergency endovascular treatment in our center from 1 January 2018 to 31 June 2023, was conducted. The correlation between intraoperative vascular complications and potential risk factors was studied, and interaction analysis was performed. Results: Our findings revealed that the use of non-neurology guide wires to open vessels (adjusted OR: 4.1, 95%CI: 1.3-12.8; p = 0.014) and glycosylated hemoglobin (HbA1c) ≥ 6.5 mmol/L (adjusted OR: 3.2, 95%CI: 1.2-8.9; p = 0.023) was significantly associated with vascular complications in non-emergency endovascular treatment of ICAO patients. The restricted cubic spline (RCS) showed that the higher the HbA1c level, the higher the risk of vascular complications. Conclusion: The use of non-neurology guide wires for vessel opening during non-emergency endovascular treatment in patients with ICAO increases the risk of vascular complications. Preoperative assessment and management of HbA1c levels can reduce the incidence of intraoperative vascular complications.

The association of CSF biomarkers and cognitive decline with choroid plexus volume in early Parkinson's disease.

OBJECTIVE: This study aims to determine the link between choroid plexus (CP) volume and cognitive decline in patients with early-stage Parkinson's disease (PD) and to test whether pathological proteins in the cerebrospinal fluid (CSF) are involved in the modulation of any detrimental effects from CP volume. METHODS: Data on 95 early-stage PD patients with 5 years of follow-up were collected from the Parkinson's Progression Marker Initiative cohort. The patients were separated into three groups based on tertiles of baseline CP volume. We then used a linear mixed model for longitudinal analysis and conducted path analysis to investigate mediating effects. RESULTS: At baseline, the patients in both the upper and middle tertile group were older and had lower concentrations of CSF Aß1-42 than those in the lowest tertile group. Longitudinal analysis showed that the upper tertile group suffered from a more rapid cognitive decline in the Symbol Digit Modalities test, Hopkins Verbal Learning Test (HVLT)-retention, and HVLT delayed recalled score. Furthermore, path analysis showed that the pathological effects of CP volume on the 5-year decline in memory might be partly mediated by the CSF Aß1-42/αsyn ratio. CONCLUSION: CP enlargement could be an independent risk factor for decreased cognition in patients with early-stage PD, and this risk may be mediated by CSF pathological proteins.

Myo1d promotes alpha-synuclein transfer from brain microvascular endothelial cells to pericytes through tunneling nanotubes.

α-Synuclein preformed fibrils (α-syn PFF) in the blood can cross the blood-brain barrier and invade the central nervous system. Our previous study proved that α-syn PFF can be taken up by brain microvascular endothelial cells (BMVECs). Here, we found that α-syn PFF spread from BMVECs to pericytes with the highest transmission efficiency. We observed abundant tunneling nanotubes (TNTs) connecting BMVECs and pericytes, and α-syn PFF transmitted through these TNTs. Furthermore, α-syn PFF accumulation in BMVECs did not promote TNT formation, but activated the molecular motor Myo1d. Inhibition of Myo1d prevented α-syn PFF transfer from BMVECs to pericytes and decreased the colocalization of Myo1d and F-actin in BMVECs. In summary, we are the first to demonstrate that α-syn PFF spread from BMVECs to pericytes through a mechanism involving TNTs and myosin. Targeting Myo1d may be a promising approach to prevent α-syn spreading from the blood to the brain.

Motor progression phenotypes in early-stage Parkinson's Disease: A clinical prediction model and the role of glymphatic system imaging biomarkers.

BACKGROUND: Substantial heterogeneity of motor symptoms in Parkinson's disease (PD) poses a challenge to disease prediction. OBJECTIVES: The aim of this study was to construct a nomogram model that can distinguish different longitudinal trajectories of motor symptom changes in early-stage PD patients. METHODS: Data on 90 patients with 5-years of follow-up were collected from the Parkinson's Progression Marker Initiative (PPMI) cohort. We used a latent class mixed modeling (LCMM) to identify distinct progression patterns of motor symptoms, and backward stepwise logistic regression with baseline information was conducted to identify the potential predictors for motor trajectory and to develop a nomogram. The performance of the nomogram model was then evaluated using the optimism-corrected C-index for internal validation, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve for discrimination, the calibration curve for predictive accuracy, and decision curve analysis (DCA) for its clinical value. RESULTS: We identified two trajectories for motor progression patterns. The first, Class 1 (Motor deteriorated group), was characterized by sustained, continuously worsening motor symptoms, and the second, Class 2 (Motor stable group), had stable motor symptoms throughout the follow-up period. The best combination of 7 baseline variables was identified and assembled into the nomogram: Scopa-AUT [odds ratio (OR), 1.11; p = 0.091], Letter number sequencing (LNS) (OR, 0.76; p = 0.068), the asymmetry index of putamen (OR, 0.95; p = 0.034), mean caudate uptake (OR, 0.14; p = 0.086), CSF pTau/α-synuclein (OR, 0.00; p = 0.011), CSF tTau/Aß (OR, 25434806; p = 0.025), and the index for diffusion tensor image analysis along the perivascular space (ALPS-index) (OR, 0.02; p = 0.030). The nomogram achieved good discrimination, with an original AUC of 0.901 (95% CI, 0.813-0.989), and the bias-corrected concordance index (C-index) with 1,000 bootstraps was 0.834. The calibration curve and DCA also suggested both the high accuracy and clinical usefulness of the nomogram, respectively. CONCLUSIONS: This study proposes an effective nomogram to predict different motor progression patterns in early-stage PD. Furthermore, the imaging biomarker indicating glymphatic function could be an independent predictive factor for PD motor progression.

Cerebral Microvascular Injury Induced by Lag3-Dependent α-Synuclein Fibril Endocytosis Exacerbates Cognitive Impairment in a Mouse Model of α-Synucleinopathies.

The pathological accumulation of α-synuclein (α-Syn) and the transmission of misfolded α-Syn underlie α-synucleinopathies. Increased plasma α-Syn levels are associated with cognitive impairment in Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies, but it is still unknown whether the cognitive deficits in α-synucleinopathies have a common vascular pathological origin. Here, it is reported that combined injection of α-Syn preformed fibrils (PFFs) in the unilateral substantia nigra pars compacta, hippocampus, and cerebral cortex results in impaired spatial learning and memory abilities at 6 months post-injection and that this cognitive decline is related to cerebral microvascular injury. Moreover, insoluble α-Syn inclusions are found to form in primary mouse brain microvascular endothelial cells (BMVECs) through lymphocyte-activation gene 3 (Lag3)-dependent α-Syn PFFs endocytosis, causing poly(ADP-ribose)-driven cell death and reducing the expression of tight junction proteins in BMVECs. Knockout of Lag3 in vitro prevents α-Syn PFFs from entering BMVECs, thereby reducing the abovementioned response induced by α-Syn PFFs. Deletion of endothelial cell-specific Lag3 in vivo reverses the negative effects of α-Syn PFFs on cerebral microvessels and cognitive function. In short, this study reveals the effectiveness of targeting Lag3 to block the spread of α-Syn fibrils to endothelial cells in order to improve cognition.

The Association of the Glymphatic Function with Parkinson's Disease Symptoms: Neuroimaging Evidence from Longitudinal and Cross-Sectional Studies.

OBJECTIVE: Emerging pathological evidence suggests that there is an association between glymphatic dysfunction and the progression of Parkinson's disease (PD). However, the clinical evidence of this association remains lacking. METHODS: In this study, the index for diffusion tensor image analysis along the perivascular space (ALPS index) was calculated to evaluate glymphatic function. RESULTS: Overall, 289 patients with PD were enrolled in the cross-sectional study. The ALPS index was found to be negatively correlated with age, disease severity, and dyskinesia. In the longitudinal study, the information on a total of 95 PD patients with 5-year follow-up examinations was collected from the Parkinson's Progression Marker Initiative, 33 of which were classified into the low ALPS index group, and all others were classified into the mid-high ALPS index group based on the first tertile of the baseline ALPS index. The results of longitudinal regression indicated that there was a significant main group effect on autonomic dysfunction, as well as on activities of daily living. In addition, the low ALPS index group had faster deterioration in MDS-UPDRS part III and part II, Symbol Digit Modalities Test and Hopkins Verbal Learning Test. Path analysis showed that ALPS index acted as a significant mediator between tTau/ Aß1-42 and cognitive change in the Symbol Digit Modalities Test score at year 4 and year 5. INTERPRETATION: The ALPS index, an neuroimaging marker of glymphatic function, is correlated with PD disease severity, motor symptoms, and autonomic function, and is predictive of faster deterioration in motor symptoms and cognitive function. Additionally, glymphatic function may mediate the pathological role of toxic protein in cognitive decline. ANN NEUROL 2023;94:672-683.

Endothelial LRP1-ICD Accelerates Cognition-Associated Alpha-Synuclein Pathology and Neurodegeneration through PARP1 Activation in a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons and accumulation of misfolded alpha-synuclein (αSyn) into Lewy bodies. In addition to motor impairment, PD commonly presents with cognitive impairment, a non-motor symptom with poor outcome. Cortical αSyn pathology correlates closely with vascular risk factors and vascular degeneration in cognitive impairment. However, how the brain microvasculature regulates αSyn pathology and neurodegeneration remains unclear. Here, we constructed a rapidly progressive PD model by injecting alpha-synuclein preformed fibrils (αSyn PFFs) into the cerebral cortex and striatum. Brain capillaries in mice with cognitive impairment showed a reduction in diameter and length after 6 months, along with string vessel formation. The intracellular domain of low-density lipoprotein receptor-related protein-1 (LRP1-ICD) was upregulated in brain microvascular endothelium. LRP1-ICD promoted αSyn PFF uptake and exacerbated endothelial damage and neuronal apoptosis. Then, we overexpressed LRP1-ICD in brain capillaries using an adeno-associated virus carrying an endothelial-specific promoter. Endothelial LRP1-ICD worsened αSyn PFF-induced vascular damage, αSyn pathology, or neuron death in the cortex and hippocampus, resulting in severe motor and cognitive impairment. LRP1-ICD increased the synthesis of poly(adenosine 5'-diphosphate-ribose) (PAR) in the presence of αSyn PFFs. Inhibition of PAR polymerase 1 (PARP1) prevented vascular-derived injury, as did loss of PARP1 in the endothelium, which was further implicated in endothelial cell proliferation and inflammation. Together, we demonstrate a novel vascular mechanism of cognitive impairment in PD. These findings support a role for endothelial LRP1-ICD/PARP1 in αSyn pathology and neurodegeneration, and provide evidence for vascular protection strategies in PD therapy.

Renin-angiotensin system blockers affect cognitive decline in Parkinson's disease: The PPMI dataset.

OBJECTIVE: To explore the potential clinical effects of renin-angiotensin system blocker (RASB, angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs)) in patients from the Parkinson's Progress Marker Initiative (PPMI) study database. METHODS: One hundred and seven untreated, newly diagnosed PD patients with hypertension, from the PPMI were included. We measured cognitive performance, biomarkers in CSF, and magnetic resonance imaging (MRI) during the five follow-up years for patients exposed or not to renal-angiotensin system blockers. Sixteen PD patients with hypertension underwent [18F]florbetaben positron emission tomography (PET) scanning. SUVRs of region of interest (ROI) were calculated and compared within different groups. RESULT: Treatment with ARBs but not ACEIs improved global cognitive function evaluated by MoCA score in PD patients with hypertension compared to other hypertensive medicines up to 5 years follow up. Specifically, ARBs improved visuospatial, memory, executive abilities, processing speed attention test scores in PD. There was no significant impact of ARBs on α-syn, tau, Aß in CSF. RASBs reduced [18F] florbetaben uptake in cortex and subcortex nuclei in the brain. CONCLUSIONS: These results show potential protective effect with ARBs in cognitive impairment of parkinson's disease with hypertension.

TGR5 Agonist INT-777 Alleviates Inflammatory Neurodegeneration in Parkinson's Disease Mouse Model by Modulating Mitochondrial Dynamics in Microglia.

Parkinson's disease (PD) is one of the most common chronic progressive neurodegenerative diseases that affects both motor and non-motor functions. Bile acids modulate the immune system by targeting brain receptors. INT-777, a 6α-ethyl-23(S)-methyl derivative of cholic acid (S-EMCA), acts as an agonist for Takeda G protein-coupled receptor-5 (TGR5) and has neuroprotective properties. However, the effects of INT-777 on PD have not yet been investigated. In a subchronic PD model, mice treated with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) developed motor deficits and cognitive impairment that were ameliorated after intranasal administration of INT-777. INT-777 prevented MPTP-induced neurodegeneration and microglia activation in the substantia nigra pars compacta, hippocampus, and cortical layer V. Based on bioinformatics and wet lab data, INT-777 inhibited microglia activation by suppressing the release of tumor necrosis factor alpha (TNF-α) in the hippocampus, along with secondary chemokines (C-C motif ligand 3 (CCL3) and CCL6) in these three brain regions. INT-777 inhibited TNF-α production by repairing mitochondrial damage, which was associated with nuclear factor-erythroid 2-related factor-2 (NRF2) activation and p62/LC3B-mediated autophagy. INT-777 reversed the downregulation of heme oxygenase-1 (HO1), NAD(P)H quinone oxidoreductase-1 (NQO1) and accumulation of p62 in microglia treated with 1-methyl-4-phenylpyridinium (MPP+). However, TGR5 knockdown in microglia abolished INT-777's inhibition of TNF-α release, resulting in neuronal death. Therefore, PD cognitive impairment is associated with hippocampal TNF-α elevation as a result of mitochondrial damage in microglia. Our data reveal the potential role of TGR5 in modulating inflammation-mediated neurodegeneration in PD, and provides new insights for bile acid metabolites as promising disease-modifying drugs for PD.

Reduced Retinal Microvascular Perfusion in Patients With Stroke Detected by Optical Coherence Tomography Angiography.

Currently there is a shortage of biomarkers for stroke, one of the leading causes of death and disability in aging populations. Retinal vessels offer a unique and accessible "window" to study the microvasculature in vivo. However, the relationship between the retinal microvasculature and stroke is not entirely clear. To investigate the retinal microvascular characteristics in stroke, we recruited patients with stroke and age-matched control subjects from a tertiary hospital in China. The macular vessel density (VD) in the superficial capillary plexus (SCP) and deep capillary plexus (DCP), foveal avascular zone (FAZ) metrics, and optical coherence tomography angiography (OCTA) measured optic disc VD were recorded for analysis. A total of 189 patients with stroke and 195 control subjects were included. After adjusting for sex, visual acuity, systolic and diastolic blood pressure, a history of smoking, levels of hemoglobulin (HbA1c), cholesterol, and high-density lipoprotein (HDL), the macular VD of SCP and DCP in all sectors was decreased in patients with stroke. In the stroke group, the VD around the FAZ and the VD of the optic disk were lower. Logistic regression found the parafovea-superior-hemi VD of DCP > 54.53% [odds ratio (OR): 0.169] as a protective factor of stroke. Using the integration of all OCTA parameters and traditional risk factors, the area under the receiver operating characteristic (AUC) curve of distinguishing patients with stroke was 0.962, with a sensitivity of 0.944 and a specificity of 0.871. Our study demonstrates that the retinal VD is decreased in patients with stroke independently of the traditional risk factors of stroke, which may shed light on the monitoring of stroke using the retinal microvascular parameters.

Identifying Parkinson's disease with mild cognitive impairment by using combined MR imaging and electroencephalogram.

OBJECTIVES: To analyse the changes of quantitative electroencephalogram (qEEG) and cortex structural magnetic resonance (MR) imaging in Parkinson's disease with mild cognitive impairment (PD-MCI) and to explore the "composite marker"-based machine learning model in identifying PD-MCI. METHODS: Retrospective analysis of patients with PD identified 36 PD-MCI and 35 PD with normal cognition (PD-NC). QEEG features of power spectrum and structural MR features of cortex based on surface-based morphometry (SBM) were extracted. Support vector machine (SVM) was established using combined features of structural MR and qEEG to identify PD-MCI. Feature importance evaluation algorithm of mean impact value (MIV) was established to sort the vital characteristics of qEEG and structural MR. RESULTS: Compared with PD-NC, PD-MCI showed a statistically significant difference in 5 leads and waves of qEEG and 7 cortical region features of structural MR. The SVM model based on these qEEG and structural MR features yielded an accuracy of 0.80 in the training set and had a high prediction accuracy of 0.80 in the test set (sensitivity was 0.78, specificity was 0.83, area under the receiver operating characteristic curve was 0.77), which was higher than the model built by the feature separately. QEEG features of theta wave in C3 had a marked impact on the model for classification according to the MIV algorithm. CONCLUSIONS: PD-MCI is characterized by widespread structural and EEG abnormality. "Composite markers" could be valuable for the individualized diagnosis of PD-MCI by machine learning. KEY POINTS: • Explore the brain abnormalities in Parkinson's disease with mild cognitive impairment by using the quantitative electroencephalogram and cortex structural MR simultaneously. • Multimodal features based support vector machine for identifying Parkinson's disease with mild cognitive impairment has an acceptable performance. • Theta wave in C3 is the most influential feature of qEEG and cortex structure MR imaging in identifying Parkinson's disease with mild cognitive impairment using support vector machine.

L-Asparaginase Exerts Neuroprotective Effects in an SH-SY5Y-A53T Model of Parkinson's Disease by Regulating Glutamine Metabolism.

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and involves deficiencies in alpha-synuclein (α-Syn) degradation. Effective therapeutic strategies for PD are urgently needed. L-asparaginase (L-ASNase) has been developed for therapeutic applications in many fields because it catalyzes the hydrolysis of asparagine and glutamine in cancer cells, which may also activate autophagy and induce the degradation of accumulated α-Syn. However, the efficacy and related mechanism of L-ASNase in PD remain poorly understood. Methods: We determined the correlation between L-ASNase and autophagic degradation of α-Syn in a cell model of PD. Mitochondrial function and apoptosis were examined in the presence or absence of L-ASNase. Then, we applied GC-MS/MS targeted amino acid metabolomics analysis to validate the amino acid regulation induced by L-ASNase treatment. Glutamine was added to verify whether the neuroprotective effect was induced by deprivation of glutamine. α-Syn-related autophagy and mitochondrial fusion/fission dynamics were detected to explore the mechanism of L-ASNase-based therapy in PD. Results: L-ASNase activated the autophagic degradation of α-Syn in a cell model of PD without cytotoxicity at specific concentrations/times. Under these conditions, L-ASNase showed substantial neuroprotective effects, including improvements in mitochondrial function and decreased apoptosis. Through GC-MS/MS targeted analysis, glutamine metabolism was identified as the target of L-ASNase in PD treatment, and the neuroprotective effect of L-ASNase was reduced after glutamine supplementation. Conclusions: Our study demonstrated for the first time that L-ASNase had a neuroprotective effect on a cell model of PD through a moderate deprivation of glutamine, which induced autophagic activation and mitochondrial fusion. Therefore, we demonstrated that L-ASNase could be a promising and effective drug for PD treatment.

Endovascular recanalization for symptomatic subacute and chronically occluded internal carotid artery: feasibility, safety, a modified radiographic classification system, and clinical outcomes.

PURPOSE: To evaluate the feasibility and safety of endovascular recanalization for symptomatic subacute and chronic internal carotid artery occlusion (ICAO); to propose a newly modified radiographic classification of ICAO that can rigorously identify suitable candidates for endovascular ICAO treatment. METHODS: We included 42 consecutive patients who had ICAO with ischaemic symptoms refractory to medical therapy. We examined the symptomatology, complications, follow-up results and radiographic images of ICAO receiving attempted endovascular treatment. We attempted to stratify all radiographic images into categories based on morphological occlusion patterns, occlusion segments and distal ICA reconstitution on digital subtraction angiography (DSA). RESULTS: Four types (A-D) of radiographic ICAO were identified. We redefined type B as having a tapered stump but no distal lumen. The rate of successful recanalization was 83.33% (35/42 ICAOs; type A, 18/20; type B, 7/10; type C, 10/11; type D, 0/1). The perioperative complication rate was 11.90% (5/42), including 3 asymptomatic distal embolisms, 1 symptomatic cerebral infarction and 1 asymptomatic carotid artery dissection. None of these technique-related complications led to severe neurological damage or death. Modified Rankin Scale (mRS) scores after 1-20 months of follow-up were significantly decreased in successfully revascularized patients (P < 0.001). There was no significant change in mRS scores in the 7 patients in whom recanalization failed (P > 0.05). CONCLUSIONS: Endovascular recanalization seems to achieve technical success and clinical improvement for symptomatic subacute and chronic ICAO. Additionally, our newly modified radiographic classification of ICAO may be valuable in assessing the technical feasibility and safety of procedures in symptomatic ICAO patients.

Memantine Mitigates Oligodendrocyte Damage after Repetitive Mild Traumatic Brain Injury.

Repetitive mild traumatic brain injury (rmTBI; e.g., sports concussions) is common and results in significant cognitive impairment, white matter injury and increased risk of neurodegeneration. Targeted therapies for rmTBI are lacking, though evidence from other injury models indicates that targeting N-methyl-d-aspartate (NMDA) receptor (NMDAR)-mediated glutamatergic toxicity might mitigate rmTBI-induced injury. We have previously shown that the NMDAR antagonist memantine lessens axonal injury and restores long term potentiation after rmTBI. Here, we evaluated whether the protective effects of memantine include oligodendrocyte specific mechanisms, as prior studies suggest that oligodendrocytes are particularly vulnerable to glutamatergic toxicity. Mice were subjected to rmTBI injury (5 injuries in 5 days) and randomized to treatment with memantine or with vehicle (n = 32/group). At the molecular level, oligodendrocyte counts and function (myelin basic protein, MBP) were assessed by immunohistochemistry and western blot at days 3, 7 and 28 days after the last injury. Axon integrity was assessed by neurofilament light chain (NF-l) expression and axonal ultrastructure was evaluated by electron microscopy. Compared to vehicle-treated mice, memantine-treated mice were protected against oligodendrocyte loss and decreased MBP expression at subacute time points after injury. Memantine treatment also protected against axon damage assessed by NF-l expression. These data suggest that the therapeutic effects of post-concussive NMDAR antagonism may in part work through oligodendrocyte specific mechanisms, which may have implications for long term neurodegenerative sequelae after multiple concussions.

A Follow-up Study of Cerebral Microbleeds in Patients Who Received Stents for Symptomatic Cerebral Artery Stenosis.

BACKGROUND: The aims of this study were to explore (i) the dynamic changes in cerebral microbleeds (CMBs) in patients with symptomatic cerebral artery stenosis who received endovascular stent-assisted angioplasty and (ii) the risk factors associated with the new incidence of CMBs as well as whether CMBs increased the risk of vascular events in these patients. METHODS: Clinical information and magnetic resonance images were collected on admission and 3 months after endovascular stent-assisted angioplasty. Based on susceptibility-weighted imaging, the patients were divided into groups with or without newly developed CMBs, and between-group differences in risk factors were compared. We also compared whether CMBs increased the risk of vascular events among those patients. RESULTS: Seventy-three patients completed the relevant follow-up examinations. After an average follow-up period of 109 days, 7 (9.6%) patients showed new CMBs. A univariate analysis showed that the number of lacunar infarcts and the increase in systolic blood pressure were higher in patients with new CMBs than in those without new CMBs, and these differences were significant (P = 0.034, P = 0.001). Increased systolic blood pressure was an independent risk factor for developing new CMBs (P = 0.017). CONCLUSIONS: CMBs may be a continuously progressing cerebral small-vessel disease. The newly developed CMBs in patients with intracranial and/or extracranial stents were associated with increased systolic blood pressure but not with the number of baseline CMBs.

Characteristics of gray matter morphological change in Parkinson's disease patients with semantic abstract reasoning deficits.

BACKGROUND: Semantic abstract reasoning(SAR) is an important executive domain that is involved in semantic information processing and enables one to make sense of the attributes of objects, facts and concepts in the world. We sought to investigate whether Parkinson's disease subjects(PDs) have difficulty in SAR and to examine the associated pattern of gray matter morphological changes. METHODS: Eighty-six PDs and 30 healthy controls were enrolled. PDs were grouped into PD subjects with Similarities preservation(PDSP, n = 62) and PD subjects with Similarities impairment(PDSI, n = 24)according to their performance on the Similarities subtest of the Wechsler Adult Intelligence Scale. Brain structural images were captured with a 3T MRI scanner. Surface-based investigation of cortical thickness and automated segmentation of deep gray matter were conducted using FreeSurfer software. RESULTS: PDs performed notably worse on the Similarities test than controls(F = 13.56, P < 0.001).In the PDSI group, cortical thinning associated with Similarities scores was found in the left superior frontal, left superior parietal and left rostral middle frontal regions. Notable atrophy of the bilateral hippocampi was observed, but only the right hippocampus volume was positively correlated with the Similarities scores of the PDSI group. DISCUSSION: PDs have difficulty in SAR, and this limitation may be associated with impaired conceptual abstraction and generalization along with semantic memory deficits. Cortical thinning in the left frontal and parietal regions and atrophy in the right hippocampus may explain these impairments among Chinese PDs.

Striatal silent lacunar infarction is associated with changes to the substantia nigra in patients with early-stage Parkinson's disease: A diffusion kurtosis imaging study.

A recent study has shown that striatal silent infarction may occur secondary to the degeneration of dopaminergic neurons in the substantia nigra (SN) of mice. However, it is uncertain whether this phenomenon occurs in patients with early-stage Parkinson's disease (PD) and can be detected by diffusion kurtosis imaging (DKI). A total of 72 untreated patients with early-stage PD underwent conventional MRI and DKI. Participants were divided into control and striatal silent lacunar infarction (SSLI) groups. The differences in mean kurtosis (MK) values of the SN, Hoehn-Yahr (H-Y) staging, and Unified Parkinson's Disease Rating Scale (UPDRS) III score between groups, were analyzed. Linear regression analysis was used to correlate age, SSLI count, silent lacunar infarction count in other brain areas and age-related white matter change score with MK values of the SN. Spearman correlation coefficient analysis was used to correlate MK values of the SN and SSLI count with H-Y staging and UPDRS III score. There was no significant difference in the severity of disease between two groups; however, MK values of the SN with SSLI present were significantly higher than in SN without SSLI. In addition, SSLI count had linear correlation with MK values of the SN, which had positive correlation with H-Y-staging and UPDRS III score. SSLI is associated with structural changes to the SN in patients with early-stage PD, detectable by DKI, and may aggravate their motor impairments.

The role of p38MAPK signal pathway in the neuroprotective mechanism of limb postconditioning against rat cerebral ischemia/reperfusion injury.

It has been reported that remote ischemic postconditioning was able to protect from a harmful ischemia occurring in brain. In the present study, we investigated the role of p38 MAPK signal pathway in the process of neuroprotection and anti-apoptosis following remote limb ischemic postconditioning on rat focal cerebral ischemia/reperfusion (I/R) model. Male Sprague-Dawley rats were divided randomly into four groups: the sham-operated group, I/R group, limb ischemic postconditioning (LPostC) group, and LPostC+SB203580 (p38 MAPK inhibitor) group. Focal ischemia was induced by transient middle cerebral artery occlusion. Limb ischemic postconditioning was implemented by brief cycles of femoral artery occlusion. At 24h after modeling, we analyzed the neurological deficit score, assessed the cerebral tissue morphology by H-E staining, and evaluated neuronal apoptosis by TUNEL staining. The protein expression levels of p-p38 or p-ATF2 (phospho-activating transcription factor 2) in the penumbra region were detected by western blotting or immunohistochemical staining. Our findings revealed that LPostC relieved cerebral ischemia/reperfusion injury by decreasing neurological score, improving neuronal morphological changes in the ischemic penumbra area, and reducing neuronal apoptosis. In addition, LPostC or LPostC+SB203580 attenuated the increase in p-p38 and p-ATF2 levels in ischemia/reperfusion brain tissue. These results indicate that the protective effects of LPostC against cerebral I/R injury may be related to the attenuation of neuronal apoptosis and the suppression of p38 MAPK-ATF2 pathway.

RIT2 polymorphism is associated with Parkinson's disease in a Han Chinese population.

Recently, a meta-analysis including 5 large genome-wide association studies has identified rs12456492 variant of RIT2 gene as a novel risk locus for Parkinson's disease (PD) in Caucasian populations. However, the association between RIT2 polymorphism and PD risk has not been positively replicated in Asian population yet. We detected the genotypes of rs12456492 in 524 PD patients and 521 control subjects from a Han Chinese population. The allele and genotype distribution of rs12456492 variant were significantly different between PD patients and controls (allele p = 0.001, genotype p = 0.002). Logistic regression analysis showed that the G-carrying genotype (AG + GG) individuals exhibited a nearly 1.4-fold increased risk for PD compared with the AA genotype carriers (OR = 1.390; 95% confidence interval = 1.079-1.791; p = 0.011). Our data support that the carriage of G allele of rs12456492 variant of RIT2 gene significantly increases the risk for PD in Han Chinese population, suggesting a potential role of RIT2 in the etiology of PD.