Impact of the COVID-19 pandemic on acute stroke care: An analysis of the 24-month data from a comprehensive stroke center in Shanghai, China.

INTRODUCTION: Whether the coronavirus disease-2019 (COVID-19) pandemic is associated with a long-term negative impact on acute stroke care remains uncertain. This study aims to compare the timing of key aspects of stroke codes between patients before and after the COVID-19 pandemic. METHODS: This retrospective cohort study was conducted at an academic hospital in Shanghai, China and included all adult patients with acute ischemic stroke hospitalized via the emergency department (ED) stroke pathway during the 24 months since the COVID-19 outbreak (COVID-19: January 1, 2020-December 31, 2021). The comparison cohort included patients with ED stroke pathway visits and hospitalizations during the same period (pre-COVID-19: January 1, 2018-December 31, 2019). We compared critical time points of prehospital and intrahospital acute stroke care between patients during the COVID-19 era and patients during the pre-COVID-19 era using t test, χ2 , and Mann-Whitney U test where appropriate. RESULTS: A total of 1194 acute ischemic stroke cases were enrolled, including 606 patients in COVID-19 and 588 patients in pre-COVID-19. During the COVID-19 pandemic, the median onset-to-hospital time was about 108 min longer compared with the same period of pre-COVID-19 (300 vs 192 min, p = 0.01). Accordingly, the median onset-to-needle time was 169 min in COVID-19 and 113 min in pre-COVID-19 (p = 0.0001), and the proportion of patients with onset-to-hospital time within 4.5 h was lower (292/606 [48.2%] vs 328/558 [58.8%], p = 0.0003) during the pandemic period. Furthermore, the median door-to-inpatient admission and door-to-inpatient rehabilitation times increased from 28 to 37 h and from 3 to 4 days (p = 0.014 and 0.0001). CONCLUSIONS: During the 24 months of COVID-19, a prolongation of stroke onset to hospital arrival and to intravenous rt-PA administration times were noted. Meanwhile, acute stroke patients needed to stay in the ED for a longer time before hospitalization. Educational system support and process optimization should be pursued in order to acquire timely delivery of stroke care during the pandemic.

Blood BMP6 Associated with Cognitive Performance and Alzheimer's Disease Diagnosis: A Longitudinal Study of Elders.

BACKGROUND: Bone morphogenetic protein (BMP) plays important roles in the pathology of Alzheimer's disease (AD). OBJECTIVE: We sought blood BMP6 involved in the processes underlying cognitive decline and detected them in association with AD. METHODS: A total of 309 participants in Shanghai Mental Health Center (SMHC) and 547 participants in Alzheimer's disease Neuroimaging Initiative (ADNI) cohort were included. Blood BMP6 and cognitive functions were measured in all subjects of both cohorts at baseline, and in 482 subjects of ADNI cohort after one year. A total of 300 subjects in ADNI cohort were detected cerebrospinal fluid (CSF) tau biomarker, and 244 received 1-year follow-up. RESULTS: AD patients had lower levels of blood BMP6 compared to normal controls, and BMP6 was positively associated with cognitive functions. Longitudinal BMP6 combing with APOE genotype could distinguish probable AD from normal controls. The influence of blood BMP6 on cognition was modulated by tau pathology. CONCLUSION: Blood BMP6 was associated with cognitive performance and identified as a potential predictor for probable AD.

Using a new HSPC senescence model in vitro to explore the mechanism of cellular memory in aging HSPCs.

BACKGROUND: Age-associated changes attenuate human blood system functionality through the aging of hematopoietic stem and progenitor cells (HSPCs), manifested in human populations an increase in myeloproliferative disease and even leukemia; therefore, study on HSPC senescence bears great significance to treat hematopoietic-associated disease. Furthermore, the mechanism of HSPC aging is lacking, especially the cellular memory mechanism. Here, we not only reported a new HSPC senescence model in vitro, but also propose and verify the cellular memory mechanism of HSPC aging of the Polycomb/Trithorax system. METHODS: HSPCs (Lin-c-kit+ cells) were isolated and purified by magnetic cell sorting (MACS). The proportions and cell cycle distribution of cells were determined by flow cytometry; senescence-related ß-galactosidase assay, transmission electron microscope (TEM), and colony-forming unit (CFU)-mix assay were detected for identification of the old HSPC model. Proteomic tests and RNA-seq were applied to analyze differential pathways and genes in the model cells. qPCR, Western blot (WB), and chromatin immunoprecipitation PCR (CHIP-PCR) were used to detect the gene expression of cell memory-related proteins. Knockdown of cell memory-related key genes was performed with shRNA interference. RESULTS: In the model old HSPCs, ß-gal activity, cell cycle, colony-forming ability, aging-related cell morphology, and metabolic pathway were significantly changed compared to the young HSPCs. Furthermore, we found the model HSPCs have more obvious aging manifestations than those of natural mice, and IL3 is the major factor contributing to HSPC aging in the model. We also observed dramatic changes in the expression level of PRC/TrxG complexes. After further exploring the downstream molecules of PRC/TrxG complexes, we found that Uhrf1 and TopII played critical roles in HSPC aging based on the HSPC senescence model. CONCLUSIONS: These findings proposed a new HSPC senescence model in vitro which we forecasted could be used to preliminary screen the drugs of the HSPC aging-related hemopathy and suggested cellular memory mechanism of HSPC aging.

A closer look at ping-pong gaze: an observational study and literature review.

BACKGROUND: Little is known about ping-pong gaze (PPG) outside of individual case reports. We aimed to describe PPG through an observational study and literature review. METHODS: Consecutive patients with PPG at Shanghai General Hospital (SGH) from February 2016 to March 2018 were enrolled. A literature review through March 2018 was conducted. RESULTS: Of the 14 patients with PPG in SGH, the median age was 60 years and 12 were males. The median Glasgow coma scale score was 7.5. The cycle of the PPG ranged from 1.5 to 6.5 s. The leading three etiologies were acute ischemic stroke in five patients, post-seizure state in three patients, and hypoxic-ischemic encephalopathy in two patients. A total of 88.9% (8/9) of the patients with consistent whole-field PPG had similar bilateral hemispheric damage, whereas 80.0% (4/5) of the patients with PPG in the hemifield had unilateral or extremely asymmetric bilateral hemispheric damage. The hemifiled side was the same side as the sole/dominant hemispheric lesion. The final clinical outcomes were neurologic remission for seven patients, vegetative state for one patient, and death for six patients. CONCLUSIONS: PPG is a sign with localizing value that suggests hemispheric damage and asymmetric PPG might help to predict lateralization of the lesions. Acute ischemic stroke is the most common cause of PPG. Etiology and initial outcome are likely important prognostic factors of PPG.

Targeted disruption of supraspinal motor circuitry reveals a distributed network underlying Restless Legs Syndrome (RLS)-like movements in the rat.

In this study we uncovered, through targeted ablation, a potential role for corticospinal, cerebello-rubro-spinal, and hypothalamic A11 dopaminergic systems in the development of restless legs syndrome (RLS)-like movements during sleep. Targeted lesions in select basal ganglia (BG) structures also revealed a major role for nigrostriatal dopamine, the striatum, and the external globus pallidus (GPe) in regulating RLS-like movements, in particular pallidocortical projections from the GPe to the motor cortex. We further showed that pramipexiole, a dopamine agonist used to treat human RLS, reduced RLS-like movements. Taken together, our data show that BG-cortico-spinal, cerebello-rubro-spinal and A11 descending projections all contribute to the suppression of motor activity during sleep and sleep-wake transitions, and that disruption of these circuit nodes produces RLS-like movements. Taken together with findings from recent genomic studies in humans, our findings provide additional support for the concept that the anatomic and genetic etiological bases of RLS are diverse.

Ventral medullary control of rapid eye movement sleep and atonia.

Discrete populations of neurons at multiple levels of the brainstem control rapid eye movement (REM) sleep and the accompanying loss of postural muscle tone, or atonia. The specific contributions of these brainstem cell populations to REM sleep control remains incompletely understood. Here we show in rats that viral vector-based lesions of the ventromedial medulla at a level rostral to the inferior olive (pSOM) produced violent myoclonic twitches and abnormal electromyographic spikes, but not complete loss of tonic atonia, during REM sleep. Motor tone during non-REM (NREM) sleep was unaffected in these same animals. Acute chemogenetic activation of pSOM neurons in rats robustly and selectively suppressed REM sleep but not NREM sleep. Similar lesions targeting the more rostral ventromedial medulla (RVM) did not affect sleep or atonia, while chemogenetic stimulation of the RVM produced wakefulness and reduced sleep. Finally, selective activation of vesicular GABA transporter (VGAT) pSOM neurons in mice produced complete suppression of REM sleep whereas their loss increased EMG spikes during REM sleep. These results reveal a key contribution of the pSOM and specifically the VGAT+ neurons in this region in REM sleep and motor control.

Movement deficits and neuronal loss in basal ganglia in TRPC1 deficient mice.

Transient receptor potential cation (TRPC) channel proteins are abundantly expressed in brain. However, the functions of these TRPC proteins such as TRPC1 are largely unclear. In this study, we reported that TRPC1 deficiency caused movement disorder as measured by swimming test, modified open field test and sunflower seeds eating test. Immunofluorescent staining showed significant loss of both NeuN-positive cells and tyrosine hydroxylase (TH) -positive cells in the caudate putamen (CPu), the external globus pallidus (GPe), and the substantia nigra pars reticulata (SNr) in 5-month-old TRPC1 knockout mice (TRPC1-/-) compared to the wild type (WT) mice. TUNEL staining further revealed that TUNEL-positive cells were significantly increased in the CPu, GPe, and SNr of TRPC1-/- mice. Taken together, these data suggests that TRPC1 is involved in the control of motor function by inhibiting the apoptosis of neuronal cells of basal ganglia.

Increased apoptosis in the platelets of patients with Alzheimer's disease and amnestic mild cognitive impairment.

OBJECTIVES: Alzheimer's disease (AD), the most common cause of dementia, is a progressive, incurable neurodegenerative disorder. Platelet is a suitable source of human peripheral tissue to study pathological mechanisms occurring in the brain. The present study aims to investigate (1) whether abnormal apoptotic events besides involved in AD within the central neurologic system, could also occur at peripheral platelet level; (2) whether apoptosis at peripheral platelet level starts at the early stage of AD. PATIENTS AND METHODS: Amnestic mild cognitive impairment (MCI), AD, and age-matched healthy individuals were recruited, and each group had 50 person. In the present study, we investigate whether alterations of caspase family and Bcl2 family could be found in the platelets in Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI) patients. The platelet levels of caspase protein and Bcl2 family were analyzed by western blot. RESULTS: The results show that the platelet levels of caspase-3, caspase-9, Bad, and Bax significantly increased in AD and amnestic MCI. The increased apoptosis proteins levels in amnestic MCI were found between AD and normal controls. The anti-apoptosis protein Bcl2 increased in amnestic MCI, while decreased in AD. CONCLUSION: We suggest that increased apoptosis exist in the platelet and might mirror apoptosis within the brain. Abnormal apoptosis may appear in the early of AD, and the ratio between pro- and anti-apoptotic protein levels partially determines the susceptibility of platelet to a death signal. In conclusion, platelet may be a good model to study apoptotic pathways of AD.

LIMK1 is involved in the protective effects of bone morphogenetic protein 6 against amyloid-ß-induced neurotoxicity in rat hippocampal neurons.

Bone morphogenetic protein 6 (BMP6) has neuroprotective effects against various neuronal injuries, but its effect on amyloid-ß (Aß)-induced neurotoxicity remains unclear. We exposed rat hippocampal neurons to different concentrations of Aß25-35 to induce neurotoxicity, and then treated cells with BMP6 to assess the neuroprotective effects. In vivo, we bilaterally injected Aß1-40 into basal forebrain to simulate the neuropathological process of Alzheimer's disease (AD), and explored changes in the expression of BMP6 and LIMK1. Our data demonstrated that BMP6 prevented apoptosis induced by a high dose of Aß25-35, and inhibited rod formation induced by low dose of Aß25-35 in hippocampal neurons. Forebrain injection of Aß1-40 led to a significant downregulation of BMP6, and inactivation of LIMK1 pathway in basal forebrain, whereas the opposite changes were observed in hippocampus. Our results suggest that BMP6 has neuroprotective effects against Aß25-35. The BMP6 and LIMK1 pathways may have different expression patterns at different stages of AD, and be self-regulating via a negative feedback mechanism between different brain regions.

A 14-year-old girl with an unusual combination of incontinentia pigmenti and conversion disorder.

Incontinentia pigmenti is a rare X-linked neurological-skin genetic disease. Some studies have shown that about 30~40% of patients with IP have varying symptoms of eye/central nervous system which are the major causes of disability. Conversion disorder is one of the most common mental diseases in children and may exhibit the single or multiple neurological symptoms. In this paper, we will report a child with new and rare incontinentia pigmenti accompanied by conversion disorder and explore the relationship of this rare combination.

Serum levels of inflammation factors and cognitive performance in amnestic mild cognitive impairment: a Chinese clinical study.

Early diagnosis of Alzheimer's disease (AD) is important for initiating timely therapy to block or slow the rate of disease progression. This study was designed to investigate the potential of inflammation-related biomarkers in peripheral blood to accurately reflect AD onset and progression. Individuals (n=150) with amnestic mild cognitive impairment (aMCI) were divided into two subgroups (low- and high-risk) based on APOEε4 allele carrier status, and administered a battery of neuropsychological tests and tested for serum levels of IL-6, IL-10, TNF-α, and IFN-γ by using specific enzyme-linked immunosorbent assays. Results were compared with those from age-matched healthy controls (n=150). The levels of IL-6 were significantly higher in the aMCI group than in controls (P<0.01). When the aMCI group was stratified by APOEε4 status, significant differences were found between the low- and high-risk groups and controls in the levels of IL-6 and IFN-γ (P<0.01 and P=0.041, respectively). Moreover, the IL-6 level in the low-risk aMCI group was higher than that in the high-risk aMCI group (P=0.028). A weak but significant negative correlation was found between IL-6 and cognitive performance. Taken together, these findings indicate that IL-6, while not useful alone, has potential in combination with other biomarkers to support early diagnosis of aMCI due to its association with the progression of cognitive impairment.

A clinical memory battery for screening for amnestic mild cognitive impairment in an elderly chinese population.

Amnestic mild cognitive impairment (MCI) might be more likely to progress to Alzheimer's disease than single non-memory MCI and multiple domain MCI. After excluding those who did not conform to the inclusion criteria of amnestic MCI or healthy controls, a neuropsychologic battery that included the Mini-Mental State Examination, Clinical Dementia Rating, Chinese version of the Montreal Cognitive Assessment, Instrumental Activities of Daily Living scale and Auditory Verbal Learning Test was performed on 150 amnestic MCI and 150 normal control patients. The Chinese version of the Montreal Cognitive Assessment was measured for its test-retest reliability, sensitivity and specificity. Blood was collected for apolipoprotein E (APOE) genotyping. Compared with the control group, the amnestic MCI group performed significantly worse on all neuropsychological tests, and non-APOE-ε4 carriers in the amnestic MCI group performed better than APOE-ε4 carriers in the amnestic MCI group. The set of neuropsychological tests in our study could distinguish amnestic MCI participants from normal elderly participants accurately. APOE did have a role in amnestic MCI patients, but the magnitude and mechanism of its influence are not fully understood.

Involvement of IRE1α signaling in the hippocampus in patients with mesial temporal lobe epilepsy.

Cumulative evidence suggests that programmed cell death (apoptosis) may contribute to the progressive hippocampal sclerosis seen in patients with refractory mesial temporal lobe epilepsy (MTLE). The endoplasmic reticulum (ER) stress-mediated cell apoptotic pathway has recently emerged as a vital intrinsic pathway, but the molecular mechanisms underlying this process in the epileptic brain remain unclear. We investigated inositol-requiring protein 1α (IRE1α)-mediated ER stress pro-and anti-apoptotic signaling pathways in resected hippocampi from 32 patients with intractable MTLE. Immunoreactivity for the ER stress markers glucose-regulated proteins 78 and 94 was significantly higher in MTLE hippocampi than in controls. The levels of IRE1α, tumor necrosis factor receptor associated factor 2 (TRAF2), apoptosis signal-regulating kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK), which together constitute the IRE1α/TRAF2/ASK1/JNK pro-apoptotic signaling pathway, were significantly upregulated in patients with MTLE. Immunoreactivity for caspase-4, a homologue of caspase-12 that is possibly activated by IRE1α via TRAF2 following ER stress, and caspase-3 which was a downstream effector of caspase-4, were both detected in MTLE tissue samples. In contrast, immunoreactivity for caspase-4 and caspase-3 were low or absent in control samples. Simultaneously, the X-box binding protein 1 (XBP1), a basic leucine zipper (bZIP) family transcription factor downstream of IRE1α which can promote cell survival by upregulation of multiple ER-targeted genes, was also overexpressed and activated in MTLE hippocampi. Our data suggest that chronic epilepsy is associated with ER stress, as well as induction of both IRE1α-mediated pro- and anti-apoptotic signaling pathways.

Preliminary explorations of the role of mitochondrial proteins in refractory epilepsy: some findings from comparative proteomics.

Approximately 20-30% of patients with epilepsy continue to have seizures despite carefully monitored treatment with antiepileptic drugs. The mechanisms that underlie why some patients are responsive and others prove resistant to antiepileptic drugs are poorly understood. Increasing evidence supports a role for altered mitochondrial function in the pathogenesis of epilepsy. To gain greater molecular insight in the pathogenesis of intractable epilepsy, we undertook a global analysis of protein expressions in a pharmacoresistant epileptic model selected by phenytoin in electrical amygdala-kindled rats by using two-dimensional gel electrophoresis coupled with matrix-assisted laser desorption/ionization time of flight (MALDI-TOF-TOF). We identified five increased proteins and 14 decreased proteins including voltage-dependent anion channel 1 (VDAC1) with a 2.82-fold increased level (P < 0.05) and voltage-dependent anion channel 2 (VDAC2) with a 3.97-fold decreased level (P < 0.05) in hippocampus of pharmacoresistant rats. The increased VDAC1 and decreased VDAC2 were confirmed by Western blot analysis and immunohistochemistry. Vascular mitochondria and apoptosis neurons were observed through electron microscopy. Energy contents, the adenine nucleotides, were measured by high-performance liquid chromatography (HPLC). The correlation analyses were carried out between VDAC and the energy charge. These findings indicate that the increase of VDAC1 and the decrease of VDAC2 play an important role during the process and provide new molecular evidence in understanding mechanism of refractory epilepsy.