Inhibition of EHMT1/2 rescues synaptic damage and motor impairment in a PD mouse model.

Epigenetic dysregulation that leads to alterations in gene expression and is suggested to be one of the key pathophysiological factors of Parkinson's disease (PD). Here, we found that α-synuclein preformed fibrils (PFFs) induced histone H3 dimethylation at lysine 9 (H3K9me2) and increased the euchromatic histone methyltransferases EHMT1 and EHMT2, which were accompanied by neuronal synaptic damage, including loss of synapses and diminished expression levels of synaptic-related proteins. Furthermore, the levels of H3K9me2 at promoters in genes that encode the synaptic-related proteins SNAP25, PSD95, Synapsin 1 and vGLUT1 were increased in primary neurons after PFF treatment, which suggests a linkage between H3K9 dimethylation and synaptic dysfunction. Inhibition of EHMT1/2 with the specific inhibitor A-366 or shRNA suppressed histone methylation and alleviated synaptic damage in primary neurons that were treated with PFFs. In addition, the synaptic damage and motor impairment in mice that were injected with PFFs were repressed by treatment with the EHMT1/2 inhibitor A-366. Thus, our findings reveal the role of histone H3 modification by EHMT1/2 in synaptic damage and motor impairment in a PFF animal model, suggesting the involvement of epigenetic dysregulation in PD pathogenesis.

Mitochondrial dysfunction and oxidative stress contribute to cognitive and motor impairment in FOXP1 syndrome.

FOXP1 syndrome caused by haploinsufficiency of the forkhead box protein P1 (FOXP1) gene is a neurodevelopmental disorder that manifests motor dysfunction, intellectual disability, autism, and language impairment. In this study, we used a Foxp1+/- mouse model to address whether cognitive and motor deficits in FOXP1 syndrome are associated with mitochondrial dysfunction and oxidative stress. Here, we show that genes with a role in mitochondrial biogenesis and dynamics (e.g., Foxo1, Pgc-1α, Tfam, Opa1, and Drp1) were dysregulated in the striatum of Foxp1+/- mice at different postnatal stages. Furthermore, these animals exhibit a reduced mitochondrial membrane potential and complex I activity, as well as decreased expression of the antioxidants superoxide dismutase 2 (Sod2) and glutathione (GSH), resulting in increased oxidative stress and lipid peroxidation. These features can explain the reduced neurite branching, learning and memory, endurance, and motor coordination that we observed in these animals. Taken together, we provide strong evidence of mitochondrial dysfunction in Foxp1+/- mice, suggesting that insufficient energy supply and excessive oxidative stress underlie the cognitive and motor impairment in FOXP1 deficiency.

Cerebral Palsy and Motor Impairment After Extreme Prematurity: Prediction of Diagnoses at Ages 2 and 10 Years.

OBJECTIVE: To identify perinatal factors in children born extremely preterm (EP) that were associated with motor impairment (MI) at 2 and 10 years of age and develop a predictive algorithm to estimate the risk of MI during childhood. STUDY DESIGN: Participants of the Extremely Low Gestational Age Newborns Study (ELGANS) were classified as: no MI, MI only at 2 years, MI only at 10 years, and MI at both 2 and 10 years, based on a standardized neurological examination at 2 and the Gross Motor Function Classification System (GMFCS) at 10 years of age. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to develop the final predictive model. RESULTS: Of the 849 study participants, 64 (7.5%) had a diagnosis of MI at both 2 and 10 years and 63 (7.4%) had a diagnosis of MI at 1 visit but not the other. Of 22 total risk factors queried, 4 variables most reliably and accurately predicted MI: gestational age, weight z-score growth trajectory during neonatal intensive care unit (NICU) stay, ventriculomegaly, and cerebral echolucency on head ultrasound. By selecting probability thresholds of 3.5% and 7.0% at ages 2 and 10, respectively, likelihood of developing MI can be predicted with a sensitivity and specificity of 71.2%/72.1% at age 2 and 70.7%/70.7% at age 10. CONCLUSION: In our cohort, the diagnosis of MI at 2 years did not always predict a diagnosis of MI at 10 years. Specific risk factors are predictive of MI and can estimate an individual infant's risk at NICU discharge of MI at age 10 years.

Distinct Clinical Implications of Patient- Versus Clinician-Rated Motor Symptoms in Parkinson's Disease.

BACKGROUND: Patient-rated motor symptoms (PRMS) and clinician-rated motor symptoms (CRMS) often differ in Parkinson's disease (PD). OBJECTIVE: Our goal was to investigate the determinants and clinical implications of PRMS compared with CRMS in PD. METHODS: This retrospective, observational cohort study analyzed the cross-sectional associations and longitudinal impacts of PRMS as assessed by the Movement Disorders Society-sponsored Unified PD Rating Scale (MDS-UPDRS) part 2, while controlling for CRMS measured by MDS-UPDRS part 3. Longitudinal analyses used Cox proportional hazards models and multiple linear mixed-effects random intercepts/slope models, adjusting for many clinical predictors. We conducted propensity score matching (PSM) to reinforce our analyses' robustness and surface-based morphometry to investigate neural correlates. RESULTS: We enrolled 442 patients with early-stage PD. At baseline, regardless of CRMS, PRMS were associated with the severity of postural instability and gait disturbance (PIGD). Notably, PRMS independently and more accurately predicted faster long-term deterioration in motor function than CRMS (Hoehn and Yahr 4, adjusted hazard ratio per +1 point = 1.19 [95% confidence intervals, 1.08-1.32]), particularly in PIGD (PIGD subscore, ß-interaction = 0.052 [95% confidence intervals, 0.018-0.086]). PSM confirmed these findings' robustness. Surface-based morphometry suggested that enhanced sensory processing was distinctively associated with PRMS. CONCLUSIONS: In early-stage PD, PRMS weighed different aspects of symptoms and more effectively predicted motor deterioration compared to CRMS, with distinctive brain structural characteristics. The superior sensitivity of PRMS to subtle declines in drug-refractory symptoms like PIGD likely underlie our results, highlighting the importance of understanding the differential clinical implications of PRMS to prevent long-term motor deterioration. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Pericyte ablation causes hypoactivity and reactive gliosis in adult mice.

Capillary pericytes are important regulators of cerebral blood flow, blood-brain barrier integrity and neuroinflammation, but can become lost or dysfunctional in disease. The consequences of pericyte loss or dysfunction is extremely difficult to discern when it forms one component of a complex disease process. To evaluate this directly, we examined the effect of adult pericyte loss on mouse voluntary movement and motor function, and physiological responses such as hypoxia, blood-brain barrier (BBB) integrity and glial reactivity. Tamoxifen delivery to Pdgfrß-CreERT2:: Rosa26-DTA transgenic mice was titrated to produce a dose-dependent ablation of pericytes in vivo. 100mg/kg of tamoxifen ablated approximately half of all brain pericytes, while two consecutive daily doses of 300mg/kg tamoxifen ablated >80% of brain pericytes. In the open field test, mice with âˆ¼50% pericyte loss spent more time immobile and travelled half the distance of control mice. Mice with >80% pericyte ablation also slipped more frequently while performing the beam walk task. Our histopathological analyses of the brain revealed that blood vessel density was unchanged, but vessel lumen width was increased. Pericyte-ablated mice also exhibited: mild BBB disruption; increased neuronal hypoxia; astrogliosis and increased IBA1+ immunoreactivity, suggestive of microgliosis and/or macrophage infiltration. Our results highlight the importance of pericytes in the brain, as pericyte loss can directly compromise brain health and induce behavioural alterations in mice.

Neurobrucellosis Presenting with Motor Damage or Hearing Loss, and Use of Steroids are Associated with a Higher Risk of Sequelae or Relapse: A Systematic Review of Individual Participant Data.

BACKGROUND: Neurobrucellosis presents diverse clinical challenges and risks of long-term complications. OBJECTIVE: We aimed to assess the relationship between the duration of antibiotic therapy, clinical factors, and the outcome of neurobrucellosis with a case report combined with a systematic review of the literature. METHODS: We present a case of a 31 years-old man successfully treated at our Institution. We then searched Ovid MEDLINE, Embase and Scopus for articles that encompassed neurobrucellosis cases, duration of treatment, and outcome. The primary outcome was to assess an association between the duration of treatment and the risk of sequelae or relapses. Univariate, multivariate and sensitivity analysis were carried out to define which variables affect​ed​ the clinical outcome. Quality assessment was performed using a dedicated tool. RESULTS: A total of 123 studies were included, totaling 221 patients. Median duration of treatment was 4 months (IQR 3 - 6), 69% patients recovered without sequelae, 27% had sequelae. Additionally, five patients had a relapse, and 4 patients died. Multivariate analysis found that the duration of treatment, age, and the use of ceftriaxone were not associated with a higher risk of sequelae or relapses. A significant association was found for corticosteroids use (OR 0.39, 95% IC 0.16 - 0.96, p = 0.038), motor impairment (OR 0.29, 95% IC 0.14 - 0.62, p = 0.002), and hearing loss (OR 0.037, 95% IC 0.01 - 0.11, p < 0.001). CONCLUSIONS: This study highlights the variability in clinical presentations and treatment approaches for neurobrucellosis. Patients with factors indicating higher sequelae risk require meticulous follow-up.

Dynamic Reorganization Patterns of Brain Modules after Stroke Reflecting Motor Function.

OBJECTIVE: Advancements in neuroimaging technologies have significantly deepened our understanding of the neural physiopathology associated with stroke. Nevertheless, the majority of studies ignored the characteristics of dynamic changes in brain networks. The relationship between dynamic changes in brain networks and the severity of motor dysfunction after stroke needs further investigation. From the perspective of multilayer network module reconstruction, we aimed to explore the dynamic reorganization of the brain and its relationship with motor function in subcortical stroke patients. METHODS: We recruited 35 healthy individuals and 50 stroke patients with unilateral limb motor dysfunction (further divided into mild-moderate group and severe group). Using dynamic multilayer network modularity analysis, we investigated changes in the dynamic modular reconfiguration of brain networks. Additionally, we assessed longitudinal clinical scale changes in stroke patients. Correlation and regression analyses were employed to explore the relationship between characteristic dynamic indicators and impairment and recovery of motor function, respectively. RESULTS: We observed increased temporal flexibility in the Default Mode Network (DMN) and decreased recruitment of module reconfiguration in the Attention Network (AN), Sensorimotor Network (SMN), and DMN after stroke. We also observed reduced module loyalty following stroke. Additionally, correlation analysis showed that hyper-flexibility of the DMN was associated with better lower limb motor function performance in stroke patients with mild-to-moderate impairment. Regression analysis indicated that increased flexibility within the DMN and decreased recruitment coefficient within the AN may predict good lower limb function prognosis in patients with mild to moderate motor impairment. CONCLUSIONS: Our study revealed more frequent modular reconfiguration and hyperactive interaction of brain networks after stroke. Notably, dynamic modular remodeling was closely related to the impairment and recovery of motor function. Understanding the temporal module reconfiguration patterns in multilayer networks after stroke can provide valuable information for more targeted treatments.

Motor behavior induced by bergamot essential oil in experimental tasks is differentially modulated by pretreatment with metabotropic glutamate receptor 2/3 or 5 antagonists.

Bergamot essential oil shows anxiolytic-relaxant effects devoid of sedative action and motor impairment typical of benzodiazepines. Considering the potential for clinical of these effects, it is important to understand the underlying mechanisms of the phytocomplex. Modulation of glutamate group I and II metabotropic receptors is involved in stress and anxiety disorders, in cognition and emotions and increases locomotor activity and wakefulness. Interestingly, early data indicate that bergamot essential oil modulates glutamatergic transmission in specific manifestations of the central nervous system. The aim of this work is to investigate if selective antagonists of metabotropic glutamate 2/3 and 5 receptors affect behavioral parameters modulated by the phytocomplex. Male Wistar rats were used to measure behavioral parameters to correlate anxiety and motor activity using elevated plus maze (EPM), open field (OF), and rotarod tasks. Bergamot essential oil increases in EPM the time spent in open/closed arms and reduces total number of entries. The essential oil also increases immobility in EPM and OF and not affect motor coordination in rotarod. Pretreatment with the metabotropic glutamate antagonists does not affect the time spent in open/close arms, however, differently affects motor behavior measured after administration of phytocomplex. Particularly, glutamate 2/3 antagonist reverts immobility and glutamate 5 antagonist potentiates this parameter induced by the phytocomplex. Our data show that modulation of both metabotropic glutamate receptors is likely involved in some of behavioral effects of bergamot essential oil.

High-Fat Diet-Induced Blood-Brain Barrier Dysfunction: Impact on Allodynia and Motor Coordination in Rats.

The associations among increased pain sensitivity, obesity, and systemic inflammation have not been described as related to BBB dysfunctions. To analyze the metabolic, behavioral, and inflammatory effects of a high-fat diet (HFD) and ultrastructural modifications in brain regions, we used an in vivo experimental model. Adult male Wistar rats were randomly assigned to one of two conditions, an ad libitum control group or an HFD (60%)-fed group, for eight weeks. At the end of the protocol, glucose and insulin tolerance tests were performed. Additionally, we analyzed the response to a normally innocuous mechanical stimulus and changes in motor coordination. At the end of the protocol, HFD-fed rats presented increased HOMA-IR and metabolic syndrome (MetS) prevalence. HFD-fed rats also developed an increased nociceptive response to mechanical stimuli and neurological injury, resulting in impaired motor function. Hypothalamus and cerebellum neurons from HFD-fed rats presented with nuclear swelling, an absence of nucleoli, and karyolysis. These results reveal that HFD consumption affects vital brain structures such as the cerebellum, hippocampus, and hypothalamus. This, in turn, could be producing neuronal damage, impairing cellular communication, and consequently altering motricity and pain sensitivity. Although direct evidence of a causal link between BBB dysfunction and sensory-motor changes was not observed, understanding the association uncovered in this study could lead to targeted therapeutic strategies.

Somatosensory evoked potentials amplitude is enhanced after non-invasive brain stimulation in chronic ischemic stroke: Preliminary results from a randomised control trial.

OBJECTIVE: To investigate the effects of transcranial electrical and magnetic non-invasive brain stimulation (NIBS) protocols on somatosensory evoked potential (SEP) in chronic ischemic stroke. METHODS: 33 patients were randomly assigned to one of the four treatment groups of the transcranial direct current stimulation (tDCS) and/or repetitive transcranial magnetic stimulation (rTMS) protocol. SEP parameters were recorded before and after ten days of the treatment session. All the statistical analyses were carried out using SPSS version 19. RESULTS: It was found that there is a statistically significant improvement in the N20-P22 mean amplitude after treatment sessions in all groups except the group where tDCS and rTMS groups were sham. On paired t-tests, the difference betweeen post and pre-stimulation SEP amplitudes for the real tDCS and real rTMS coupled group was 1.045 ± 0.732 (p value = 0.005). For sham tDCS+real rTMS group, 1.05 ± 0.96 (P = 0.04); for real tDCS+sham rTMS 0.543 ± 0.332 (P = 0.01) and for double sham stimulation, 0.204 ± 0.648 (P =  0.4) respectively CONCLUSION: In ischemic stroke patients, either or coupled true transcranial tDCS and rTMS was found to be safe and significantly enhanced the amplitude of cortical somatosensory potentials when combined with standard physiotherapy, in the interim analysis of an ongoing randomised controlled trial. CLINICAL TRIAL REGISTRY OF INDIA: CTRI/2019/11/022009 SIGNIFICANCE: The results of this research indicates the importance of RCTs in developing robust improved NIBS protocols coupled to physiotherapy to enhance the sensory-motor functional recovery following ischemic stroke.

A scoping review of AAC interventions for children and young adults with simultaneous visual and motor impairments: Clinical and research Implications.

Individuals with multiple disabilities are among the most challenging to serve and AAC teams often lack direction in determining effective interventions. The purpose of this scoping review was to summarize the research evidence on AAC interventions for individuals with complex communication needs and simultaneous motor, and visual impairments as part of their multiple disabilities; to consider implications for practice; and to determine gaps and directions for future research. A total of 27 studies were identified and reviewed, involving 55 unique participants with multiple disabilities. Most studies focused on direct intervention to increase requesting or choice-making, with little focus on social communication. Only two studies focused on training communication partners. Results indicated that AAC interventions can be highly effective to increase communication for individuals with multiple disabilities. However, there is an urgent need for increased rigor and more detailed participant information in future AAC intervention research with this population. Future research should investigate AAC intervention to improve social communication and increase language development, not just expression of needs and wants. Future research should focus on the needs of individuals with multiple disabilities from culturally and linguistically diverse backgrounds and on implementation of AAC within natural environments.

Diabetic Encephalopathy: Role of Oxidative and Nitrosative Factors in Type 2 Diabetes.

Diabetes mellitus is a set of complex metabolic disorders characterized by chronic hyperglycaemic condition due to defective insulin secretion (Type 1) and action (Type 2), which leads to serious micro and macro-vascular damage, inflammation, oxidative and nitrosative stress and a deranged energy homeostasis due to imbalance in the glucose and lipid metabolism. Moreover, patient with diabetes mellitus often showed the nervous system disorders known as diabetic encephalopathy. The precise pathological mechanism of diabetic encephalopathy by which it effects the central nervous system directly or indirectly causing the cognitive and motor impairment, is not completely understood. However, it has been speculated that like other extracerebellar tissues, oxidative and nitrosative stress may play significant role in the pathogenesis of diabetic encephalopathy. Therefore, the present review aimed to explain the possible association of the oxidative and nitrosative stress caused by the chronic hyperglycaemic condition with the central nervous system complications of the type 2 diabetes mellitus induced diabetic encephalopathy.

Fading of brain network fingerprint in Parkinson's disease predicts motor clinical impairment.

The clinical connectome fingerprint (CCF) was recently introduced as a way to assess brain dynamics. It is an approach able to recognize individuals, based on the brain network. It showed its applicability providing network features used to predict the cognitive decline in preclinical Alzheimer's disease. In this article, we explore the performance of CCF in 47 Parkinson's disease (PD) patients and 47 healthy controls, under the hypothesis that patients would show reduced identifiability as compared to controls, and that such reduction could be used to predict motor impairment. We used source-reconstructed magnetoencephalography signals to build two functional connectomes for 47 patients with PD and 47 healthy controls. Then, exploiting the two connectomes per individual, we investigated the identifiability characteristics of each subject in each group. We observed reduced identifiability in patients compared to healthy individuals in the beta band. Furthermore, we found that the reduction in identifiability was proportional to the motor impairment, assessed through the Unified Parkinson's Disease Rating Scale, and, interestingly, able to predict it (at the subject level), through a cross-validated regression model. Along with previous evidence, this article shows that CCF captures disrupted dynamics in neurodegenerative diseases and is particularly effective in predicting motor clinical impairment in PD.

Progressive motor impairment from "critical" demyelinating lesions of the cervicomedullary junction.

BACKGROUND: Progressive motor impairment anatomically associated with a "critical" lesion has been described in primary demyelinating disease. Most "critical" lesions occur within the spinal cord. OBJECTIVE: To describe the clinical and radiological features of "critical" lesions of the cervicomedullary junction (CMJ). METHODS: Observational study on people presenting with a CMJ lesion associated with primary demyelinating disease-related progressive motor impairment. Clinical data were extracted by chart review. Brain and spinal cord magnetic resonance images were reviewed to characterize the CMJ lesion and determine additional demyelination burden. RESULTS: Forty-one people were included: 29 (71%) had progression from onset and 12 (29%) had a relapse onset (secondary progressive) course. Most had progressive hemiparesis (21 (51%)) or progressive quadriparesis (15 (37%)) with a median Expanded Disability Status Scale (EDSS) of 5.5 (2.0-8.5) at last follow-up. No "critical" CMJ lesion enhanced; most were bilateral (25 (61%)). Brain magnetic resonance images were otherwise normal in 16 (39%) or with a restricted demyelination burden in 15 (37%). Cervical and thoracic cord MRIs were without additional lesions in 25 (61%) and 22/37 (59%), respectively. CONCLUSION: CMJ "critical" lesions can correlate with progressive motor impairment even with few or no additional magnetic resonance imaging (MRI) lesions. Lesion location is an important determinant of progressive motor impairment in demyelinating disease.

How does joint impairment affect the functional capacity of the lower limb in early haemophilia-related arthropathy?

INTRODUCTION: The impact of joint damage on functional capacity in patients with mild haemophilia (PwMH) has yet to be well studied. The primary aim of this study was to investigate the effect of joint impairment on the functional capacity of the lower limb in PwMH. The secondary aim was to identify physical predictors of lower limb functional capacity. METHOD: Forty-nine PwMH were evaluated. Dynamic balance was assessed using Time Up and Go (TUG). Thirty-second sit-to-stand (30-STS) and 60-second-STS (60-STS) were used to assess muscle power and endurance, respectively. Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) was used to assess joint damage. PwMH were divided based on HEAD-US: with joint damage (≥3 points) and without or with very low joint damage (0-2 points). Univariate ANOVA and multiple regression analyses were performed to identify differences in functional capacity and potential physical predictors. RESULTS: Only 30-STS showed significant differences between groups (p = .002). TUG and 60-STS were primarily explained by age (r2  = .21 and r2  = .44, respectively), while for 30-STS, age combined with joint damage and pain level explains 54% of the variance. CONCLUSION: Our findings indicate that the 30-STS is useful for assessing functional deterioration in people with early-stage haemophilia-related arthropathy. Our results also indicate that joint damage, combined with ageing and pain, may impact 30-STS outcomes in PwMH. Furthermore, our findings show that the loss in TUG and 60-STS performance in PwMH is related to ageing.

Association between Baseline NIHSS Limb Motor Score and Functional Recovery after Stroke: Analysis Based on a Multicountry Dataset.

INTRODUCTION: Motor skills are the domains most often affected by stroke, but a comprehensive assessment of motor function is often impractical in the acute setting. It could be useful to have a brief simple tool allowing the stratification of patients at the time of inclusion in clinical studies. Hence, our primary objective was to evaluate whether the baseline NIH Stroke Scale limb motor score (b-NIHSS-LMS), obtained by summing the four motor items 5a to 6b of the NIHSS, is associated with functional recovery assessed by the modified Rankin Score (mRS). A secondary objective was to apply this new tool in the context of a clinical trial. METHODS: The analysed population considered for this research included subjects from a large published, double-blind, multicentre trial, randomised to receive either a combination of various herbal and non-herbal components (MLC601) or placebo, administered within 72 h after an acute ischaemic stroke of intermediate severity (defined by baseline NIH Stroke Scale [b-NIHSS] score of 8-14). Associations between b-NIHSS-LMS and favourable outcome, i.e., mRS 0-1 at month 3, were evaluated using logistic regression adjusted for baseline covariates and study treatment. RESULTS: The analysis included 533 subjects with an acute ischaemic stroke of intermediate severity assessed at month 3. Analyses showed that b-NIHSS-LMS was independently associated with a favourable outcome (OR 0.84; 95% confidence interval 0.76-0.92; p < 0.0003) at 3 months. Furthermore, in the clinical study considered, a selection of patients based upon a sufficient level of motor impairment at study entry (b-NIHSS-LMS ≥3) would result in the detection of a more pronounced and longer-lasting treatment effect. Indeed, ORs of treatment effect versus placebo in the selected subgroup (b-NIHSS-LMS ≥3) were statistically significant from months 3-24. DISCUSSION/CONCLUSIONS: As an independent association between b-NIHSS-LMS and functional recovery after an acute ischaemic stroke of intermediate severity was established in this study, we suggest that the b-NIHSS-LMS can be used as a stratification factor in large clinical trials to define a target population with poststroke motor impairments.

Deep learning prediction of motor performance in stroke individuals using neuroimaging data.

The degree of motor impairment and profile of recovery after stroke are difficult to predict for each individual. Measures obtained from clinical assessments, as well as neurophysiological and neuroimaging techniques have been used as potential biomarkers of motor recovery, with limited accuracy up to date. To address this, the present study aimed to develop a deep learning model based on structural brain images obtained from stroke participants and healthy volunteers. The following inputs were used in a multi-channel 3D convolutional neural network (CNN) model: fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity maps obtained from Diffusion Tensor Imaging (DTI) images, white and gray matter intensity values obtained from Magnetic Resonance Imaging, as well as demographic data (e.g., age, gender). Upper limb motor function was classified into "Poor" and "Good" categories. To assess the performance of the DL model, we compared it to more standard machine learning (ML) classifiers including k-nearest neighbor, support vector machines (SVM), Decision Trees, Random Forests, Ada Boosting, and Naïve Bayes, whereby the inputs of these classifiers were the features taken from the fully connected layer of the CNN model. The highest accuracy and area under the curve values were 0.92 and 0.92 for the 3D-CNN and 0.91 and 0.91 for the SVM, respectively. The multi-channel 3D-CNN with residual blocks and SVM supported by DL was more accurate than traditional ML methods to classify upper limb motor impairment in the stroke population. These results suggest that combining volumetric DTI maps and measures of white and gray matter integrity can improve the prediction of the degree of motor impairment after stroke. Identifying the potential of recovery early on after a stroke could promote the allocation of resources to optimize the functional independence of these individuals and their quality of life.

Potentially inappropriate medications among older patients with Parkinson's disease: a cross-sectional analysis of a national health insurance database in China.

BACKGROUND: With the rapid aging trend of China's population, the issue of drug rational use in older adults has become more and more prominent. Parkinson's disease (PD) is the one of the most common age-related neurodegenerative disorders. Pharmaceutical treatment plays a cardinal role in alleviating motor and non-motor symptoms to improve the quality of life of patients with PD. Patients with PD have complex medical needs yet little is known about the use of potentially inappropriate medications (PIM) among them in China. We quantify the prevalence of PIM use and identify its predictors among older persons with PD in China. METHODS: We conducted a cross-sectional analysis using a national representative database of all medical insurance beneficiaries across China, extracting records of ambulatory visits of older adults with PD between 2015 and 2017. Beneficiaries aged 65 and above were eligible for inclusion. The prevalence of patients exposed to overall PIMs and PIMs related to motor and cognitive impairment was calculated based on Beers Criteria 2015 version. Potential predictors of PIM concerning patients' characteristics were estimated using multivariate logistic regression. RESULTS: A total of 14,452 older adults with PD were included. In total, 8,356 (57.8%) patients received at least one PIM; 2,464 (17.1%) patients received at least one motor-impairing PIM and 6,201 (42.9%) patients received at least one cognition-impairing PIM. The prevalence of overall PIM use was higher in patients of older age group (54.7% [65-74] vs. 59.5% [75-84; OR, 1.22; 95% CI, 1.14-1.31] vs.65.5% [≥ 85; OR, 1.58; 95% CI, 1.38-1.80) and females (61.4% [female] vs. 55.0% [males; OR, 0.77; 95% CI, 0.72-0.82). CONCLUSIONS: Prescribing PIMs for older adults with PD was common in China, especially for females and older age groups, yet younger patients were more inclined to be prescribed with motor or cognition-impaired PIMs. Our findings represent a clear target awaiting multidimensional efforts to promote the rational prescribing of medications for this vulnerable population.

Icariin Inhibits Overexpression and Aggregation of α-Synuclein in A53T α-Synuclein Transgenic Mice by Regulating Parkin and PLK2.

BACKGROUND: Synucleinopathies, which are major pathological features of Parkinson's disease (PD), are characterized by misfolded aggregates of α-synuclein in the peripheral and central nervous system. Icariin (ICA) is the main active component of Epimedium flavonoids. Our previous study found that ICA decreases α-synuclein expression in APPV717I transgenic mice. METHODS: The aim of the present study was to examine the potential applications and mechanisms of ICA in PD using A53T α-synuclein transgenic (A53T Tg) mice. After 3 months of intragastric ICA administration, rotarod and pole tests were used to assess behavioral changes in A53T Tg mice at 8 and 13 months of age. SH-SY5Y cells over-expressing wild-type α-synuclein were used to further examine the pharmacological effect and underlying mechanism of ICA. Western blotting and immunocytochemistry were used to detect the expression levels of α-synuclein and its related proteins. RESULTS: ICA significantly improved the impaired motor function and coordination in A53T Tg mice. It also decreased the expression, Ser129 phosphorylation, and aggregation of α-synuclein in SH-SY5Y cells transfected with α-synuclein and the striatum of A53T Tg mice. Moreover, ICA increased the expression of parkin, which is associated with the ubiquitin-proteasome system (UPS), and decreased the level of polo-like kinase 2 (PLK2), an enzyme that phosphorylates α-synuclein. CONCLUSIONS: ICA alleviated motor impairments in A53T mice, an effect which may be associated with the decreased phosphorylation and aggregation of α-synuclein through PLK2 and parkin regulation.

Impairments of the ipsilesional upper-extremity in the first 6-months post-stroke.

BACKGROUND: Ipsilesional motor impairments of the arm are common after stroke. Previous studies have suggested that severity of contralesional arm impairment and/or hemisphere of lesion may predict the severity of ipsilesional arm impairments. Historically, these impairments have been assessed using clinical scales, which are less sensitive than robot-based measures of sensorimotor performance. Therefore, the objective of this study was to characterize progression of ipsilesional arm motor impairments using a robot-based assessment of motor function over the first 6-months post-stroke and quantify their relationship to (1) contralesional arm impairment severity and (2) stroke-lesioned hemisphere. METHODS: A total of 106 participants with first-time, unilateral stroke completed a unilateral assessment of arm motor impairment (visually guided reaching task) using the Kinarm Exoskeleton. Participants completed the assessment along with a battery of clinical measures with both ipsilesional and contralesional arms at 1-, 6-, 12-, and 26-weeks post-stroke. RESULTS: Robotic assessment of arm motor function revealed a higher incidence of ipsilesional arm impairment than clinical measures immediately post-stroke. The incidence of ipsilesional arm impairments decreased from 47 to 14% across the study period. Kolmogorov-Smirnov tests revealed that ipsilesional arm impairment severity, as measured by our task, was not related to which hemisphere was lesioned. The severity of ipsilesional arm impairments was variable but displayed moderate significant relationships to contralesional arm impairment severity with some robot-based parameters. CONCLUSIONS: Ipsilesional arm impairments were variable. They displayed relationships of varying strength with contralesional impairments and were not well predicted by lesioned hemisphere. With standard clinical care, 86% of ipsilesional impairments recovered by 6-months post-stroke.