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.

The Efficacy and Safety of Pharmacological Treatments for Restless Legs Syndrome: Systemic Review and Network Meta-Analysis.

Although various drugs are currently used for restless legs syndrome (RLS) in clinic, selecting appropriate drugs for patients is difficult. This network meta-analysis (NMA) aimed to compare the efficacy and safety of different drugs. After literature searching and screening, 46 trials, including 10,674 participants are included in this NMA. The pooled results showed that, compared with placebo, only levodopa is inefficient to relieve symptoms of RLS. Cabergoline decreases IRLS scores to the greatest extent among all drugs (MD -11.98, 95% CI -16.19 to -7.78). Additionally, pramipexole is superior to ropinirole in alleviating symptoms of RLS (MD -2.52, 95% CI -4.69 to -0.35). Moreover, iron supplement alleviates RLS symptoms significantly compared with placebo in patient with iron deficiency (MD -5.15, 95% CI -8.99 to -1.31), but not for RLS patients with normal serum ferritin level (MD -2.22, 95% CI -6.99 to 2.56). For primary RLS, these drugs are also effective, while there is insufficient data to analyze drug efficacy in secondary RLS. We analyzed risk of common adverse effects of drugs including nausea, somnolence, fatigue, headache and nasopharyngitis. Alpha-2-delta ligands and DAs are favorable choices for both primary and secondary RLS because of their significant efficacy and good tolerability. Iron supplement can significantly alleviate symptoms of RLS patients with iron deficiency than placebo. We recommend gabapentin, gabapentin enacarbil, and pregabalin for clinicians for first consideration mainly because that they rarely cause augmentation. Oxycodone-naloxone could be considered in patients with severe or very severe RLS who failed in treatment with above drugs.

Glucose transporter 3 in neuronal glucose metabolism: Health and diseases.

Neurons obtain glucose from extracellular environment for energy production mainly depending on glucose transporter 3 (GLUT3). GLUT3 uptakes glucose with high affinity and great transport capacity, and is important for neuronal energy metabolism. This review summarized the role of neuronal GLUT3 in brain metabolism, function and development under both physiological conditions and in diseases, aiming to provide insights into neuronal glucose metabolism and its effect on brain. GLUT3 stabilizes neuronal glucose uptake and utilization, influences brain development and function, and ameliorates aging-related manifestations. Neuronal GLUT3 is regulated by synaptic activity, hormones, nutrition, insulin and insulin-like growth factor 1 in physiological conditions, and is also upregulated by hypoxia-ischemia. GLUT3-related neuronal glucose and energy metabolism is possibly involved in the pathogenesis, pathophysiological mechanism, progression or prognosis of brain diseases, including Alzheimer's disease, Huntington's disease, attention-deficit/hyperactivity disorder and epilepsy. GLUT3 may be a promising therapeutic target of these diseases. This review also briefly discussed the role of other glucose transporters in neuronal glucose metabolism, which work together with GLUT3 to sustain and stabilize glucose and energy supply for neurons. Deficiency in these glucose transporters may also participate in brain diseases, especially GLUT1 and GLUT4.

Levodopa responsiveness in Parkinson's disease patients and white matter alterations in diffusion tensor imaging: a cross-sectional tract-based spatial statistics study.

This study aimed to investigate the relationship between levodopa responsiveness and white matter alterations in Parkinson's disease patients using diffusion tensor imaging (DTI). Twenty-six recruited Parkinson's disease patients were evaluated using the Mini-Mental State Examination, Hoehn and Yahr scale (H&Y) and Unified Parkinson's Disease Rating Scale (UPDRS). Each patient underwent a DTI scan and an acute levodopa challenge test. The improvement rate of UPDRS-III was calculated, Parkinson's disease patients were grouped into a responsive group (improvement rate ≥30%) and a nonresponsive group (improvement rate <30%). The differences in fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity between the two groups were measured using tract-based spatial statistics. There was no difference in demographic features or baseline evaluations between groups. The UPDRS-III score after the challenge was higher in the nonresponsive group than that in the responsive group. Compared to the responsive group, patients in the nonresponsive group exhibited decreased fractional anisotropy in the corpus callosum; cingulum; left corona radiata; left internal capsule; left middle frontal gyrus; left superior longitudinal fasciculus and right somatosensory cortex. Mean diffusivity and radial diffusivity were increased in wide-ranging areas in the nonresponsive group. No difference was observed in axial diffusivity. White matter alterations in the abovementioned areas may affect the function of the dopaminergic network and thus may be associated with the levodopa response in Parkinson's disease patients. Further studies are needed to analyze the specific mechanism and pathological changes underlying these effects.

Plasma C-Reactive Protein Level and Outcome of Acute Ischemic Stroke Patients Treated by Intravenous Thrombolysis: A Systematic Review and Meta-Analysis.

INTRODUCTION: The plasma C-reactive protein (CRP) level in predicting prognosis of acute ischemic stroke (AIS) patients receiving intravenous thrombolysis (IVT) is not yet established. This study is aiming to investigate the relationship between the plasma CRP level and outcome of AIS patients receiving IVT. METHODS: PubMed and EMBASE were searched for relevant studies that evaluated the relationship between the CRP level and outcome of AIS patients receiving IVT. STATA 12.0 was used to pool the data for meta-analysis. RESULTS: In total, 8 studies were included. Six studies reported a positive relationship between the high CRP level and unfavorable outcome at 3 months. Five studies associated the high plasma CRP level with high mortality at 3 months. And meta-analysis further confirmed that the high CRP level was related to unfavorable outcomes (odds ratio [OR] = 1.716, 95% CI: 1.170-2.517, p = 0.006) and mortality (OR = 2.751, 95% CI: 1.613-4.693, p < 0.001) at 3 months. However, an elevated CRP level was not found to increase the risk of symptomatic intracerebral hemorrhage. CONCLUSION: A high plasma CRP level was associated with a 3-month poor outcome of AIS patients treated with IVT. CRP may be used as a biomarker for the risk stratification of AIS patients as candidates receiving IVT or other alternative therapy such as mechanical thrombectomy.

Zinc-α2-glycoprotein relieved seizure-Induced neuronal glucose uptake impairment via insulin-like growth factor 1 receptor-regulated glucose transporter 3 expression.

Glucose hypometabolism is observed in epilepsy and promotes epileptogenesis. Glucose hypometabolism in epilepsy may be attributed to decreased neuronal glucose uptake, but its molecular mechanism remains unclear. Zinc-α2-glycoprotein (ZAG) is related to glucose metabolism and is reported to suppress seizures. The anti-epileptic effect of ZAG may be attributed to its regulation of neuronal glucose metabolism. This study explored the effect of ZAG on neuronal glucose uptake and its molecular mechanism via insulin-like growth factor 1 receptor (IGF1R)-regulated glucose transporter 3 (GLUT-3) expression. The ZAG level was modulated by lentivirus in primary culture neurons. Neuronal seizure models were induced by Mg2+ -free artificial cerebrospinal fluid. We assessed neuronal glucose uptake by the 2-NBDG method and Glucose Uptake Colorimetric Assay Kit. IGF1R was activated by IGF1 and blocked by AXL1717. The expression and distribution of IGF1R and GLUT-3, together with IGF1R phosphorylation, were measured by western blot. The binding between ZAG and IGF1R was determined by coimmunoprecipitation. Neuronal glucose uptake and GLUT-3 expression were significantly decreased by seizure or ZAG knockdown, whereas ZAG over-expression or IGF1 treatment reversed this decrease. The effect of ZAG on neuronal glucose uptake and GLUT-3 expression was blocked by AXL1717. ZAG increased IGF1R distribution and phosphorylation possibly by binding. Additionally, IGF1R increased GLUT-3 activity by increasing GLUT-3 expression. In epilepsy/seizure, neuronal glucose uptake suppression may be attributed to a decrease in ZAG, which suppresses neuronal GLUT-3 expression by regulating the activity of IGF1R. ZAG, IGF1R, and GLUT-3 may be novel potential therapeutic targets of glucose hypometabolism in epilepsy and seizures.

Parkinson's Disease-Related Risk of Suicide and Effect of Deep Brain Stimulation: Meta-Analysis.

BACKGROUND: Previous studies investigated the risk of suicide in patients with Parkinson's disease (PD) but reported discrepant results. Deep brain stimulation (DBS) is an effective therapy for PD, while its effect on suicide risk has seldom been researched. This meta-analysis aimed to estimate the risk of suicide and/or suicidal ideation in PD patients and in PD patients who underwent DBS. METHODS: Relevant articles published in the PubMed or EMBASE or CNKI database from 1990 to December 2019 were sourced, and the combined standardized mortality rate (SMR) or odds ratio (OR) was pooled. RESULT: A total of 1070 articles were found. After screening, 4 cross-sectional studies, 4 cohort studies, 2 randomized controlled trial studies, and 2 case-control studies were included in this meta-analysis. Pooled data indicated that PD patients may have increased risk of suicide (lnSMR, 0.459; 95% confidence interval (CI), 0.286 to 0.632; p < 0.001). No significant difference was found in the risk of suicide when comparing PD patients who underwent DBS with PD patients who received only drug therapy (OR = 2.844, 95%CI: 0.619 to 13.072, p=0.179). DBS may increase the risk of suicide and/or suicidal ideation in PD patients compared with general population (lnSMR = 3.383, 95%CI: 2.839 to 3.927, p < 0.001). CONCLUSION: PD patients have higher risk of suicide and/or suicidal ideation compared with controls, while PD patients who received DBS tend to have an increased risk of suicide or suicidal ideation. Psychological evaluation is needed in PD patients, and pre- and post-operation evaluations are necessary for PD patients who underwent DBS.