White matter hyperintensities burden in the frontal regions is positively correlated to the freezing of gait in Parkinson’s disease

ObjectivePrevious studies have reported that white matter hyperintensities (WMHs) are associated with freezing of gait (FOG), but it is not clear whether their distribution areas have correlations with FOG in Parkinson’s disease (PD) and the potential influencing factors about WMHs.MethodsTwo hundred and forty-six patients with PD who underwent brain MRI were included. Participants were divided into PD with FOG (n = 111) and PD without FOG (n = 135) groups. Scheltens score was used to assess the WMHs burden in the areas of deep white matter hyperintensities (DWMHs), periventricular hyperintensities (PVHs), basal ganglia hyperintensities (BGHs), and infratentorial foci of hyperintensities (ITF). Whole brain WMHs volume was evaluated by automatic segmentation. Binary logistic regression was used to evaluate relationships between WMHs and FOG. The common cerebrovascular risk factors that may affect WMHs were evaluated by mediation analysis.ResultsThere were no statistical differences between PD with and without FOG groups in whole brain WMHs volume, total Scheltens score, BGHs, and ITF. Binary logistic regression showed that the total scores of DWMHs (OR = 1.094; 95% CI, 1.001, 1.195; p = 0.047), sum scores of PVHs and DWMHs (OR = 1.080; 95% CI, 1.003, 1.164; p = 0.042), especially the DWMHs in frontal (OR = 1.263; 95% CI, 1.060, 1.505 p = 0.009), and PVHs in frontal caps (OR = 2.699; 95% CI, 1.337, 5.450; p = 0.006) were associated with FOG. Age, hypertension, and serum alkaline phosphatase (ALP) are positively correlated with scores of DWMHs in frontal and PVHs in frontal caps.ConclusionThese results indicate that WMHs distribution areas especially in the frontal of DWMHs and PVHs play a role in PD patients with FOG

Using histogram analysis of the intrinsic brain activity mapping to identify essential tremor

BackgroundEssential tremor (ET) is one of the most common movement disorders. Histogram analysis based on brain intrinsic activity imaging is a promising way to identify ET patients from healthy controls (HCs) and further explore the spontaneous brain activity change mechanisms and build the potential diagnostic biomarker in ET patients.MethodsThe histogram features based on the Resting-state functional magnetic resonance imaging (Rs-fMRI) data were extracted from 133 ET patients and 135 well-matched HCs as the input features. Then, a two-sample t-test, the mutual information, and the least absolute shrinkage and selection operator methods were applied to reduce the feature dimensionality. Support vector machine (SVM), logistic regression (LR), random forest (RF), and k-nearest neighbor (KNN) were used to differentiate ET and HCs, and classification performance of the established models was evaluated by the mean area under the curve (AUC). Moreover, correlation analysis was carried out between the selected histogram features and clinical tremor characteristics.ResultsEach classifier achieved a good classification performance in training and testing sets. The mean accuracy and area under the curve (AUC) of SVM, LR, RF, and KNN in the testing set were 92.62%, 0.948; 92.01%, 0.942; 93.88%, 0.941; and 92.27%, 0.939, respectively. The most power-discriminative features were mainly located in the cerebello-thalamo-motor and non-motor cortical pathways. Correlation analysis showed that there were two histogram features negatively and one positively correlated with tremor severity.ConclusionOur findings demonstrated that the histogram analysis of the amplitude of low-frequency fluctuation (ALFF) images with multiple machine learning algorithms could identify ET patients from HCs and help to understand the spontaneous brain activity pathogenesis mechanisms in ET patients

Cerebrospinal fluid GFAP is a predictive biomarker for conversion to dementia and Alzheimer’s disease-associated biomarkers alterations among de novo Parkinson’s disease patients: a prospective cohort study

Abstract Background Dementia is a prevalent non-motor manifestation among individuals with advanced Parkinson’s disease (PD). Glial fibrillary acidic protein (GFAP) is an inflammatory marker derived from astrocytes. Research has demonstrated the potential of plasma GFAP to forecast the progression to dementia in PD patients with mild cognitive impairment (PD–MCI). However, the predictive role of cerebrospinal fluid (CSF) GFAP on future cognitive transformation and alterations in Alzheimer’s disease (AD)-associated CSF biomarkers in newly diagnosed PD patients has not been investigated. Methods 210 de novo PD patients from the Parkinson’s Progression Markers Initiative were recruited. Cognitive progression in PD participants was evaluated using Cox regression. Cross-sectional and longitudinal associations between baseline CSF GFAP and cognitive function and AD-related CSF biomarkers were evaluated using multiple linear regression and generalized linear mixed model. Results At baseline, the mean age of PD participants was 60.85 ± 9.78 years, including 142 patients with normal cognition (PD–NC) and 68 PD–MCI patients. The average follow-up time was 6.42 ± 1.69 years. A positive correlation was observed between baseline CSF GFAP and age (β = 0.918, p < 0.001). There was no statistically significant difference in baseline CSF GFAP levels between PD–NC and PD–MCI groups. Higher baseline CSF GFAP predicted greater global cognitive decline over time in early PD patients (Montreal Cognitive Assessment, β = − 0.013, p = 0.014). Furthermore, Cox regression showed that high baseline CSF GFAP levels were associated with a high risk of developing dementia over an 8-year period in the PD–NC group (adjusted HR = 3.070, 95% CI 1.119–8.418, p = 0.029). In addition, the baseline CSF GFAP was positively correlated with the longitudinal changes of not only CSF α-synuclein (β = 0.313, p < 0.001), but also CSF biomarkers associated with AD, namely, amyloid-β 42 (β = 0.147, p = 0.034), total tau (β = 0.337, p < 0.001) and phosphorylated tau (β = 0.408, p < 0.001). Conclusions CSF GFAP may be a valuable prognostic tool that can predict the severity and progression of cognitive deterioration, accompanied with longitudinal changes in AD-associated pathological markers in early PD

Ac-YVAD-CMK Decreases Blood-Brain Barrier Degradation by Inhibiting Caspase-1 Activation of Interleukin-1β in Intracerebral Hemorrhage Mouse Model

Among many proinflammatory cytokines, interleukin-1β (IL-1β) is considered a key mediator of neuronal injury. However, in order to become activated, it must be processed and cleaved by a caspase-1 enzyme. In this study, we tested the neuroprotective effect of Ac-YVAD-CMK, a known selective caspase-1 inhibitor, in a mouse model of intracerebral hemorrhage (ICH). Sixty-six adult male CD-1 mice were subjected to collagenase-induced ICH. Ac-YVAD-CMK or vehicle was administered into the left lateral ventricle 20 min before ICH modeling. Brain edema and neurological functions were assessed at 24 and 72 h after the surgery. Expression of IL-1β, phosphorylated JNK, tight junction protein zona occludens 1 (ZO-1), and matrix metalloproteinase-9 (MMP-9) were measured by Western blot along with MMP-9 activity measured by zymography at 24 h after ICH. At 24 h after ICH, Ac-YVAD-CMK treatment significantly reduced brain edema and improved neurological functions. The neuroprotection was associated with downregulation of IL-1β, JNK, MMP-9, and an inhibition of ZO-1 degradation in brain. We conclude that Ac-YVAD-CMK protects the brain against ICH-induced injury, and the neuroprotective effect may result from anti-inflammation-induced blood-brain barrier protection

Different Alterations of Cerebral Regional Homogeneity in Early-Onset and Late-Onset Parkinson's Disease

AbstractObjective: Early-onset Parkinson’s disease (EOPD) is distinct from late-onset PD (LOPD) as it relates to the clinical profile and response to medication. The objective is to investigate whether characteristics of spontaneous brain activity in the resting state are associated with the age of disease onset. Methods: We assessed the correlation between neural activity and age-at-onset in a sample of 39 PD patients (18 EOPD and 21 LOPD) and 37 age-matched normal control subjects. Regional homogeneity (ReHo) approaches were employed using ANOVA with two factors: PD and age.Results: In the comparisons between LOPD and EOPD, EOPD revealed lower ReHo values in the right putamen gyrus and higher ReHo values in the left superior frontal gyrus. Compared with age-matched control subjects, EOPD exhibited lower ReHo values in the right putamen and higher ReHo values in the left inferior temporal gyrus; however, LOPD showed lower ReHo values in the right putamen and left insula. The ReHo values were negatively correlated with the UPDRS total scores in the right putamen in LOPD, but a correlation between the ReHo value and UPDRS score was not detected in EOPD. Conclusions: Our findings support the notion that age at onset is associated with the distribution of cerebral regional homogeneity in the resting state and suggest that disproportionate putamen alterations are more prominent in patients with a younger age of onset

Altered spontaneous brain activity in patients with Parkinson's disease accompanied by depressive symptoms, as revealed by regional homogeneity and functional connectivity in the prefrontal-limbic system.

As patients with Parkinson's disease (PD) are at high risk for comorbid depression, it is hypothesized that these two diseases are sharing common pathogenic pathways. Using regional homogeneity (ReHo) and functional connectivity approaches, we characterized human regional brain activity at resting state to examine specific brain networks in patients with PD and those with PD and depression (PDD). This study comprised 41 PD human patients and 25 normal human subjects. The patients completed the Hamilton Depression Rating Scale and were further divided into two groups: patients with depressive symptoms and non-depressed PD patients (nD-PD). Compared with the non-depressed patients, those with depressive symptoms exhibited significantly increased regional activity in the left middle frontal gyrus and right inferior frontal gyrus, and decreased ReHo in the left amygdala and bilateral lingual gyrus. Brain network connectivity analysis revealed decreased functional connectivity within the prefrontal-limbic system and increased functional connectivity in the prefrontal cortex and lingual gyrus in PDD compared with the nD-PD group. In summary, the findings showed regional brain activity alterations and disruption of the mood regulation network in PDD patients. The pathogenesis of PDD may be attributed to abnormal neural activity in multiple brain regions

Short-term sleep deprivation stimulates hippocampal neurogenesis in rats following global cerebral ischemia/reperfusion.

Sleep deprivation (SD) plays a complex role in central nervous system (CNS) diseases. Recent studies indicate that short-term SD can affect the extent of ischemic damage. The aim of this study was to investigate whether short-term SD could stimulate hippocampal neurogenesis in a rat model of global cerebral ischemia/reperfusion (GCIR).One hundred Sprague-Dawley rats were randomly divided into Sham, GCIR and short-term SD groups based on different durations of SD; the short-term SD group was randomly divided into three subgroups: the GCIR+6hSD*3d-treated, GCIR+12hSD-treated and GCIR+12hSD*3d-treated groups. The GCIR rat model was induced via the bilateral occlusion of the common carotid arteries and hemorrhagic hypotension. The rats were sleep-deprived starting at 48 h following GCIR. A Morris water maze test was used to assess learning and memory ability; cell proliferation and differentiation were analyzed via 5-bromodeoxyuridine (BrdU) and neuron-specific enolase (NSE), respectively, at 14 and 28 d; the expression of hippocampal BDNF was measured after 7 d.The different durations of short-term SD designed in our experiment exhibited improvement in cognitive function as well as increased hippocampal BDNF expression. Additionally, the short-term SD groups also showed an increased number of BrdU- and BrdU/NSE-positive cells compared with the GCIR group. Of the three short-term SD groups, the GCIR+12hSD*3d-treated group experienced the most substantial beneficial effects.Short-term SD, especially the GCIR+12hSD*3d-treated method, stimulates neurogenesis in the hippocampal dentate gyrus (DG) of rats that undergo GCIR, and BDNF may be an underlying mechanism in this process

Additional file 1 of Cerebrospinal fluid GFAP is a predictive biomarker for conversion to dementia and Alzheimer’s disease-associated biomarkers alterations among de novo Parkinson’s disease patients: a prospective cohort study

Additional file 1: Figure S1. Quantile–Quantile plot of GFAP. Figure S2. CSF GFAP concentration was positively correlated with age. Figure S3. Relationships between Aβ42 and T-tau or P-tau were mediated by baseline CSF GFAP. Figure S4. Relationship between CSF GFAP and longitudinal cognitive decline. Table S1. Number of data-points of longitudinal CSF biomarkers and cognitive assessments. Table S2. Baseline correlation of GFAP with CSF biomarkers and cognitive assessments. Table S3. Effects of baseline GFAP (continuous value) on longitudinal CSF biomarkers and cognitive progression. Table S4. Effects of baseline GFAP on longitudinal CSF biomarkers and cognitive progression in the tertiles. Table S5. Effects of baseline GFAP*time (continuous value) on longitudinal CSF biomarkers and cognitive progression. Table S6. Effects of baseline GFAP*time on longitudinal CSF biomarkers and cognitive progression in the tertiles. Table S7. Progression risk from NC to MCI or dementia or from MCI to dementia. Table S8. Prediction of baseline GFAP and GFAP*time in male and female patients with de novo PD. Table S9. Prediction of baseline GFAP and GFAP*time in de novo PD patients aged < 56 and ≥ 65. Table S10. Prediction of baseline GFAP and GFAP*time in patients with PD–NC and PD–MCI. Table S11. Prediction of baseline GFAP and GFAP*time in new-onset PD patients carrying APOE ε4 or not. Table S12. Prediction of baseline GFAP and GFAP*time in patients with Amyloid-PD and Amyloid + PD

Null Mutation of the Fascin2 Gene by TALEN Leading to Progressive Hearing Loss and Retinal Degeneration in C57BL/6J Mice

Fascin2 (FSCN2) is an actin cross-linking protein that is mainly localized in retinas and in the stereocilia of hair cells. Earlier studies showed that a deletion mutation in human FASCIN2 (FSCN2) gene could cause autosomal dominant retinitis pigmentosa. Recent studies have indicated that a missense mutation in mouse Fscn2 gene (R109H) can contribute to the early onset of hearing loss in DBA/2J mice. To explore the function of the gene, Fscn2 was knocked out using TALEN (transcription activator-like effector nucleases) on the C57BL/6J background. Four mouse strains with deletions of 1, 4, 5, and 41 nucleotides in the target region of Fscn2 were developed. F1 heterozygous (Fscn2+/−) mice carrying the same deletion of 41 nucleotides were mated to generate the Fscn2−/− mice. As a result, the Fscn2−/− mice showed progressive hearing loss, as measured in the elevation of auditory brainstem-response thresholds. The hearing impairment began at age 3 weeks at high-stimulus frequencies and became most severe at age 24 weeks. Moreover, degeneration of hair cells and loss of stereocilia were remarkable in Fscn2−/− mice, as revealed by F-actin staining and scanning electron microscopy. Furthermore, compared to the controls, the Fscn2−/− mice displayed significantly lower electroretinogram amplitudes and thinner retinas at 8, 16, and 24 weeks. These results demonstrate that, in C57BL/6Jmice, Fscn2 is essential for maintaining ear and eye function and that a null mutation of Fscn2 leads to progressive hearing loss and retinal degeneration