Real-world effectiveness and safety of recombinant human endostatin plus PD-1 inhibitors and chemotherapy as first-line treatment for EGFR/ALK-negative, advanced or metastatic non-small cell lung cancer.

BACKGROUND: This study aimed to evaluate the effectiveness and safety of recombinant human endostatin (Rh-endostatin) plus programmed cell death 1 (PD-1) inhibitors and chemotherapy as first-line treatment for advanced or metastatic non-small cell lung cancer (NSCLC) in a real-world setting. METHODS: This was a retrospective study on patients with EGFR/ALK-negative, advanced or metastatic NSCLC. Patients received Rh-endostatin plus PD-1 inhibitors and chemotherapy every three weeks for 4 to 6 cycles. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. RESULTS: A total of 68 patients were included in this retrospective analysis. As of data cutoff (December 13, 2022), the median follow-up of 21.4 months (interquartile range [IQR], 8.3-44.4 months). The median PFS and OS was 22.0 (95% confidence interval [CI]: 16.6-27.4) and 31.0 months (95% CI: 23.4-not evaluable [NE]), respectively. The ORR was 72.06% (95% CI: 59.85-82.27%), and DCR was 95.59% (95% CI: 87.64-99.08%). Patients with stage IIIB/IIIC NSCLC had significantly longer median PFS (23.4 vs. 13.2 months), longer median OS (not reached vs. 18.0 months), and higher ORR (89.2% vs. 51.6%) than those with stage IV NSCLC (all p ≤ 0.001). The ORR was higher in patients with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%) than in those with low PD-L1 expression or positive PD-L1 expression (75% vs. 50%, p = 0.025). All patients experienced treatment-related adverse events (TRAEs), and ≥ grade 3 TRAEs occurred in 16 (23.53%) patients. CONCLUSIONS: Rh-endostatin combined with PD-1 inhibitors plus chemotherapy as first-line treatment yielded favorable effectiveness with a manageable profile in patients with advanced or metastatic NSCLC, representing a promising treatment modality.

Dulaglutide Improves Gliosis and Suppresses Apoptosis/Autophagy Through the PI3K/Akt/mTOR Signaling Pathway in Vascular Dementia Rats.

Dulaglutide is a new type of hypoglycemic agent that agonizes glucagon-like peptide-1 receptor (GLP-1RA). It can be concluded from previous studies that a GLP-1RA can reduce apoptosis and regulate autophagy in the nervous system, while related research on dulaglutide in vascular dementia (VD) has not been reported. In our study, the VD rat model was established by bilateral carotid artery occlusion, and the results of the Morris water maze test (MWM) and open-field test showed that the application of dulaglutide could effectively reduce the cognitive decline of VD rats without changing the behavior in the open-field test, which was used to assess an anxiety-like phenotype. We applied HE staining and immunofluorescence labeling to show that dulaglutide treatment significantly alleviated neuronal damage in the hippocampal region of VD rats, and reduced microglial and astrocyte proliferation. Western blot results showed that dulaglutide reduced VD-induced neuronal apoptosis (BCL2/BAX, c-caspase3) and autophagy (P62, LC3B, Beclin-1), and upregulated phosphorylation of PI3K/Akt/mTOR signaling pathway. KEGG pathway analysis of RNA-Sequence results showed that the differentially expressed genes in the dulaglutide treatment group were significantly enriched in the mTOR signaling pathway, and the repressor of mTOR, Deptor, was down-regulated. In conclusion, this study suggested that dulaglutide may alleviate learning and memory impairment and neuron damage in VD rats by attenuating apoptosis, regulating autophagy, and activating the PI3K/Akt/mTOR signaling pathway in neurons, which may make it a promising candidate for the simultaneous treatment of VD and diabetes.

Edaravone Dexborneol Alleviates Neuroinflammation by Reducing Neuroglial Cell Proliferation and Suppresses Neuronal Apoptosis/Autophagy in Vascular Dementia Rats.

More and more evidence shows that the pathological mechanism of vascular dementia (VD) is closely related to oxidative stress injury, cell apoptosis, autophagy, inflammatory response, excitatory amino acid toxicity, synaptic plasticity change, calcium overload, and other processes. Edaravone dexborneol (EDB) is a new type of neuroprotective agent that can improve the neurological damage caused by an ischemic stroke. Previous studies showed that EDB has effects on synergistic antioxidants and induces anti-apoptotic responses. However, it remains unclear whether EDB can affect apoptosis and autophagy by activating the PI3K/Akt/mTOR signaling pathway and its impact on the neuroglial cells. In this study, we established the VD model of rats by bilateral carotid artery occlusion to explore the neuroprotective effect of EDB and its mechanism. Morris Water Maze test was applied to assess the cognitive function of rats. H&E and TUNEL staining were applied to observe the cellular structure of the hippocampus. Immunofluorescence labeling was used to observe the proliferation of astrocytes and microglia. ELISA was applied to examine the levels of TNF-α, IL-1ß and IL-6, and RT-PCR was applied to examine their mRNA expression levels. Western blotting was applied to examine apoptosis-related proteins (Bax, Bcl-2, Caspase-3), autophagy-related proteins (Beclin-1, P62, LC3B), PI3K/Akt/mTOR signaling pathway proteins and their phosphorylation levels. The results indicated that EDB ameliorates learning and memory in rats subjected to the VD model, alleviates neuroinflammatory response by reducing the proliferation of the neuroglial cell and inhibits apoptosis and autophagy, which may be mediated by the PI3K/Akt/mTOR signaling pathway.

Effects of motor imagery based brain-computer interface on upper limb function and attention in stroke patients with hemiplegia: a randomized controlled trial.

BACKGROUND: Seeking positive and comprehensive rehabilitation methods after stroke is an urgent problem to be solved, which is very important to improve the dysfunction of stroke. The aim of this study was to investigate the effects of motor imagery-based brain-computer interface training (MI-BCI) on upper limb function and attention in stroke patients with hemiplegia. METHODS: Sixty stroke patients with impairment of upper extremity function and decreased attention were randomly assigned to the control group (CR group) or the experimental group (BCI group) in a 1:1 ratio. Patients in the CR group received conventional rehabilitation. Patients in the BCI group received 20 min of MI-BCI training five times a week for 3 weeks (15 sessions) in addition to conventional rehabilitation. The primary outcome measures were the changes in Fugl-Meyer Motor Function Assessment of Upper Extremities (FMA-UE) and Attention Network Test (ANT) from baseline to 3 weeks. RESULTS: About 93% of the patients completed the allocated training. Compared with the CR group, among those in the BCI group, FMA-UE was increased by 8.0 points (95%CI, 5.0 to 10.0; P < 0.001). Alert network response time (32.4ms; 95%CI, 58.4 to 85.6; P < 0.001), orienting network response (5.6ms; 95%CI, 29.8 to 55.8; P = 0.010), and corrects number (8.0; 95%CI, 17.0 to 28.0; P < 0.001) also increased in the BCI group compared with the CR group. Additionally, the executive control network response time (- 105.9ms; 95%CI, - 68.3 to - 23.6; P = 0.002), the total average response time (- 244.8ms; 95%CI, - 155.8 to - 66.2; P = 0.002), and total time (- 122.0ms; 95%CI, - 80.0 to - 35.0; P = 0.001) were reduced in the BCI group compared with the CR group. CONCLUSION: MI-BCI combined with conventional rehabilitation training could better enhance upper limb motor function and attention in stroke patients. This training method may be feasible and suitable for individuals with stroke. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry with Portal Number ChiCTR2100050430(27/08/2021).

Effects of repetitive transcranial magnetic stimulation combined with music therapy in non-fluent aphasia after stroke: A randomised controlled study.

BACKGROUND: Although existing studies have shown that both repetitive transcranial magnetic stimulation (rTMS) and music therapy have advantages in the treatment of non-fluent aphasia, the efficacy of the combination of these two methods remains to be investigated. AIMS: To investigate the clinical efficacy of low-frequency rTMS combined with music therapy on language function and depression in patients with non-fluent aphasia after stroke. METHODS & PROCEDURES: A single-blind parallel randomised controlled trial was conducted. Sixty patients (mean duration = 93.78 days) with non-fluent aphasia after stroke were randomly divided into a traditional therapy group (n = 20), a music therapy group (n = 20) and a combined therapy group (n = 20, 1 Hz). The language function and depression were evaluated before and 3 weeks after treatment with the Chinese version of the Western Aphasia Battery scale, Boston Diagnostic Aphasia Examination scale and Stroke Aphasic Depression Questionnaire Hospital Version scale. OUTCOMES & RESULTS: The combined therapy group was significantly better in all outcomes than the traditional therapy group and was significantly better in depression than the music therapy group. The music therapy group was significantly better in repetition and depression than the traditional therapy group. Language improvement was positively correlated with depression improvement. For adverse events, only two patients in the combined therapy group showed slight dizziness during rTMS treatment and their symptoms improved after rest. CONCLUSIONS & IMPLICATIONS: Our preliminary randomised controlled study indicates that low-frequency rTMS combined with music therapy is feasible and safe in improving language function and depression in non-fluent aphasia patients after stroke. WHAT THIS PAPER ADDS: What is already known on this subject Repetitive transcranial magnetic stimulation (rTMS) and music therapy respectively have advantages in the treatment of non-fluent aphasia after stroke, but whether the combination of the two methods is more effective is still unknown. What this paper adds to the existing knowledge This is one of the first randomised control trials to investigate whether the clinical efficacy of low-frequency rTMS combined music therapy for non-fluent aphasia is better. The findings show that low-frequency rTMS combined music therapy is superior to traditional therapy in spontaneous speech, auditory comprehension, repetition, naming, aphasia quotient, functional language level and depression, and superior to music therapy in depression, while music therapy is superior to traditional therapy in repetition and depression. What are the potential or actual clinical implications of this work? Low-frequency rTMS combined music therapy may be a better method for treatment of non-fluent aphasia.

Past Exposure to Cigarette Smoke Aggravates Cognitive Impairment in a Rat Model of Vascular Dementia via Neuroinflammation.

Smoking is a risk factor for dementia. Cognitive function can be partially restored after quitting smoking, but still lower than never smoked group. The underlying mechanisms still remain unclear. The effects of smoking cessation combined with cerebral chronic hypoperfusion (CCH) on cognitive function have never been described. Here, we established a cigarette smoking cessation model, a CCH model, and a cigarette smoking cessation plus CCH model. We investigated cognitive function in these models and the mechanisms of the neuroinflammation, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3(NLRP3)/cysteine aspartate-specific proteinase (caspase-1)/interleukin- 1ß (IL-1ß) pathway, and eucaryotic initiation factor 2α (eIF2α) /autophagy pathway. We used morris water maze (MWM) and novel object recognition (NOR) test to evaluate cognitive function in rats. Nissl staining was performed to observe cell morphology in the hippocampal CA1 area. A neuroinflammatory marker (glial fibrillary acidic protein, GFAP) was assessed by Western blot analysis and immunohistochemistry staining. IL-1ß levels were detected by ELISA. The protein levels of NLRP3/caspase-1/ IL-1ß and eIF2α/autophagy pathway were evaluated by Western blot analysis. LC3 was assessed by immunofluorescence staining. CCH can affect cognitive function by influencing neuroinflammation, NLRP3/caspase-1/IL-1ß pathway, and eIF2α/autophagy pathway. Past exposure to cigarette smoke can also affect cognitive function by influencing neuroinflammation and NLRP3/caspase-1/IL-1ß pathway, which may be induced by smoking and may not be alleviated after smoking cessation. Past exposure to cigarette smoke does not influence autophagy, which may be increased by smoking and then decrease to normal levels after smoking cessation. Past exposure to smoking can further aggravate cognitive impairment and neuroinflammation in VaD animals: cognitive impairment induced by CCH via neuroinflammation, NLRP3/caspase-1/IL-1ß, and eIF2α/autophagy pathway and cognitive impairment induced by past exposure to cigarette smoke via neuroinflammation and NLRP3/caspase-1/IL-1ß pathway. The combined group had the worst cognitive impairment because of harmful reasons.

Bilateral fornix infarction presented with acute amnesia: case report.

Acute episodes of amnestic syndrome can be a challenging diagnostic problem. Except for nonvascular etiology, thalamic strokes or infarction involving several temporal lobe structures has been reported in earlier cases. The authors report a patient who suddenly developed memory loss without any other focal neurologic deficits. Brain magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) performed 1 day after onset revealed acute infarction involving the bilateral fornix column and the genu of corpus callosum. Because simple fornix infarcts often have no obvious positive neurological signs, most of the related manifestations were provided by family members, are easy to be diagnosed falsely, and missed in clinical areas, we suggest that bilateral fornix infarction should be considered in the diagnosis of an acute onset amnestic syndrome.

Tianzhi granule improves cognition and BPSD of vascular dementia: a randomized controlled trial.

BACKGROUND AND PURPOSE: Tianzhi granule (TZ) is usually used for patients with vascular dementia (VaD) in China. The aim was to assess the effect of TZ by a randomized clinical trial (RCT). METHODS: A 24-week RCT was conducted in 16 centres. Participants were grouped into TZ, donepezil or placebo. The co-primary outcomes were the Vascular Dementia Assessment Scale-cognitive subscale (VADAS-cog) and Clinician's Interview-based Impression of Change-plus caregiver information (CIBIC-plus). RESULTS: A total of 543 patients with mild to moderate VaD were enrolled, of whom 242 took TZ granules, 241 took donepezil, and 60 took placebo. The least-squares mean changes from baseline and 95% CI were 6.20 (5.31, 7.09) (TZ group), 6.53 (5.63, 7.42) (donepezil group) and 3.47 (1.76, 5.19) (placebo group), both TZ and donepezil showed small but significantly improvement compared with placebo group. The percent of improvement on the global impression which was measured by CIBIC-plus was 73.71% in TZ and 58.18% in placebo, there was significant different between TZ and placebo group (P = 0.004). No significant differences were observed between TZ and donepezil. No significant differences of adverse events were found. CONCLUSIONS: TZ and donepezil could bring symptomatic benefit for mild to moderate VaD. Trial registration The protocol had retrospectively registered at clinical trial.gov, Unique identifier: NCT02453932, date of registration: May 27, 2015; https://www.clinicaltrials.gov/ct2/show/NCT02453932?term=NCT02453932&rank=1.

Estrogen Exerts Neuroprotective Effects in Vascular Dementia Rats by Suppressing Autophagy and Activating the Wnt/ß-Catenin Signaling Pathway.

Vascular dementia (VD) is a clinical syndrome of acquired cognitive dysfunction caused by various cerebrovascular factors. Estrogen is a steroid hormone involved in promoting neuronal survival and in regulating many signaling pathways. However, the mechanism by which it confers neuroprotective effects in VD remains unclear. Here, we aimed to investigate the effect of estrogen on neuronal injury and cognitive impairment in VD rats. Adult female rats were randomly divided into four groups (sham, model, estrogen early and estrogen later treatment) and received sham surgery or bilateral ovariectomy and permanent occlusion of bilateral common carotid arteries (BCCAO). The early treatment group received daily intraperitoneal injections of 17ß-estradiol (100 µg/kg/day) for 8 weeks starting the day after BCCAO. The later treatment group was administered the same starting 1 week after BCCAO. Learning and memory functions were assessed using the Morris water maze. Morphological changes within the hippocampal CA1 region were observed by hematoxylin/eosin staining and electron microscopy. Expression of proteins associated with autophagy and signaling were detected by immunohistochemical staining and Western blot. We found that estrogen significantly alleviated cognitive damage and neuronal injury and reduced the expression of Beclin1 and LC3B, indicating a suppression of autophagy. Moreover, estrogen enhanced expression of ß-catenin and Cyclin D1, while reducing glycogen synthase kinase 3ß, suggesting activation of Wnt/ß-catenin signaling. These results indicate that estrogen ameliorates learning and memory deficiencies in VD rats, and that this neuroprotective effect may be explained by the suppression of autophagy and activation of Wnt/ß-catenin signaling.

DL-3-n-butylphthalide alleviates vascular cognitive impairment by regulating endoplasmic reticulum stress and the Shh/Ptch1 signaling-pathway in rats.

BACKGROUND: DL-3-n-butylphthalide (NBP) has been approved to be effective in improving cognitive deficits. The aim of the current study was to determine whether NBP protects against cognitive deficits in a rat model of vascular dementia (VD) induced by chronic cerebral hypoperfusion (CCH) by regulating the sonic hedgehog (Shh)/patched1 (Ptch1) pathway and endoplasmic reticulum stress (ERS)-related markers. METHODS: Adult male Sprague-Dawley rats were subjected to permanent bilateral occlusion of the common carotid arteries (2VO) to established the model of VD. These rats were randomly divided into five groups: sham, model, NBP30 (30 mg/kg), NBP 60 (60 mg/kg), and NBP 120 (120 mg/kg) groups. The Morris water maze test was used to assess for cognitive function at 4 weeks after operation. RESULTS: NBP significantly alleviated spatial learning and memory impairment, and inhibited the loss of neurons in the CA1 region of the hippocampus. Western blot analysis and real-time quantitative polymerase chain reaction analysis revealed that plasticity-related synaptic markers and the Shh/Ptch1 pathway significantly increased in the NBP treated groups, while ERS-related markers decreased. CONCLUSION: The results of the current study prove that the Shh/Ptch1 pathway plays an essential role in the model of VD. NBP had protective effects on cognitive impairment induced by CCH. This mechanism was associated with ERS and the Shh/Ptch1 pathway. Meanwhile, the Shh/Ptch1 pathway and ERS may interact with each other.

The cost of Alzheimer's disease in China and re-estimation of costs worldwide.

INTRODUCTION: The socioeconomic costs of Alzheimer's disease (AD) in China and its impact on global economic burden remain uncertain. METHODS: We collected data from 3098 patients with AD in 81 representative centers across China and estimated AD costs for individual patient and total patients in China in 2015. Based on this data, we re-estimated the worldwide costs of AD. RESULTS: The annual socioeconomic cost per patient was US $19,144.36, and total costs were US $167.74 billion in 2015. The annual total costs are predicted to reach US $507.49 billion in 2030 and US $1.89 trillion in 2050. Based on our results, the global estimates of costs for dementia were US $957.56 billion in 2015, and will be US $2.54 trillion in 2030, and US $9.12 trillion in 2050, much more than the predictions by the World Alzheimer Report 2015. DISCUSSION: China bears a heavy burden of AD costs, which greatly change the estimates of AD cost worldwide.

Correlation between antiplatelet therapy in secondary prevention of acute cerebral infarction and cerebral microbleeds: A susceptibility-weighted imaging (SWI) study.

OBJECTIVE: To investigate the clinical significance of antiplatelet aggregation therapy for patients diagnosed with acute cerebral infarction (ACI) complicated with the cerebral microbleeds (CMBs). METHODS: Thirty patients with ACI and 36 patients with intracerebral hemorrhage (ICH) were included in this research. Two groups, studied by susceptibility-weighted imaging (SWI), were compared in terms of the number, location, and severity of CMBs. Then, 30 cases of ACI patients were divided into CMBs sub-group and non-CMBs sub-group. Univariate analysis between these two sub-groups was performed to determine the risk factors regarding the incidence of CMBs. For ACI patients, the number of CMBs before and after applying anti-platelet treatment were compared to examine the impacts of anti-platelet treatment on hemorrhagic transformation. RESULTS: CMBs were found to be more prevalent and severe in ICH patients than in ACI patients. CMBs in patients with ICH were more severe than in patients with ischemic stroke (IS), which indicates that CMBs closely relate to ICH. Hypertension and leukoaraiosis were found to have significant effects on the incidence of CMBs. After anti-platelet treatment, patients with CMBs (≥5) increased the number of CMB, whereas there was no obvious effect on patients with the CMBs less than 5 or no CMBs. CONCLUSIONS: The number of CMBs increased significantly among ACI patients with 5 or more CMBs before the anti-platelet treatment. CMBs are more frequently found in patients with hemorrhagic stroke than in patients with ischemic stroke, and more severe than the latter, which suggests that the clinical impact of higher association between the increase of the number of the CMBs and the hemorrhagic stroke.

L-3-n-Butylphthalide Activates Akt/mTOR Signaling, Inhibits Neuronal Apoptosis and Autophagy and Improves Cognitive Impairment in Mice with Repeated Cerebral Ischemia-Reperfusion Injury.

L-3-n-Butylphthalide (L-NBP) exerts neuroprotective effects in animal models of cerebral ischemia, but its potential benefits in repeated cerebral ischemia-reperfusion (RCIR) injury remain unknown. We investigated the effect of L-NBP on cognitive impairment induced by RCIR in mice. Male C57Bl/6 mice received sham surgery or bilateral common carotid artery occlusion (3 times, 20 min each) and were orally administered preoperative L-NBP (30 mg/kg/day, 7 days), postoperative L-NBP (30 or 60 mg/kg/day, 28 days) or postoperative vehicle (28 days). Learning and memory were assessed by the Morris water maze task and step-down passive avoidance test. Nissl staining was used to identify pathologic changes in the hippocampal CA1 region. The expressions of proteins associated with signaling, apoptosis and autophagy were assessed by quantitative PCR and western blot. RCIR induced deficits in learning and memory that were alleviated by preoperative or postoperative L-NBP administration. Pathologic lesions in the hippocampal CA1 region induced by RCIR were less severe in mice treated with L-NBP. Preoperative or postoperative L-NBP administration in mice receiving RCIR promoted hippocampal expression of phospho-Akt and phospho-mTOR (suggesting activation of Akt/mTOR signaling), increased the Bcl-2/Bax ratio (indicating suppression of apoptosis) and reduced the LC3-II/LC3-I ratio (implying inhibition of autophagy). Preoperative or postoperative L-NBP administration also depressed hippocampal levels of beclin-1 mRNA (indicating suppression of autophagy). These findings suggest that the effect of L-NBP to alleviate learning and memory deficits in mice following RCIR may involve activation of Akt/mTOR signaling and regulation of the expressions of proteins related to apoptosis and autophagy.

Cognitive Function and Prognosis of Multimodal Neuroimage-Guided Thrombectomy on Mild to Moderate Anterior Circulation Infarction Patients with Broadened Therapeutic Window: A Prospective Study.

BACKGROUND AND OBJECTIVES: Endovascular mechanical thrombectomy is an important approach for acute ischemic stroke (AIS) treatment. Multimodal neuroimaging methods ideally provide the exact localization, extent, and metabolic activity of target tissues. Post-stroke cognitive impairment has recently been realized to be another major concern except for neurological function impairment. The aim of our study was to carry out a prospective study to compare neurological and cognitive functions after thrombectomy in mild to moderate anterior circulation infarction patients selected by multimodal neuroimaging. METHODS: Ninety patients were recruited from January 2016 to March 2017 consecutively. Neurological function was assessed by NIHSS before thrombectomy, and 6 h, 24 h, 7 days, 90 days after mechanical thrombectomy. Cognitive functions were evaluated by Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and Hachinski Ischemic Scale. RESULTS: Patients who received mechanical thrombectomy had significantly better neurological functions at 6 h (p < 0.001), 24 h (p < 0.001), 7 days (p < 0.001), and 90 days (p < 0.001), as well as cognitive functions evaluated by MoCA (26.23 ± 3.85 vs. 24.62 ± 2.25, p = 0.022, n = 85) and MMSE (26.65 ± 2.77 vs. 25.10 ± 2.36, p = 0.023, n = 85) compared to the standard therapy group. CONCLUSIONS: The current prospective study demonstrated that mechanical thrombectomy can significantly improve neurological and cognitive functions in patients with mild to moderate AIS at broadened therapeutic window under multimodal CT and multimodal MRI imaging.

Cerebral small vessel disease and post-stroke cognitive impairment.

Cerebral small vessel disease (CSVD) refers to a group of pathological processes with multifarious etiologies that affect the small arteries, arterioles, venules, and capillaries of the brain. Features seen on neuroimaging include white matter hyperintensities, lacunar infarction, cerebral microbleeds, brain atrophy, microinfarcts and enlarged perivascular spaces (EPVS). CSVD gives rise to one in five strokes worldwide and is a leading cause of cognitive impairment and dementia, especially in the elderly. Post-stroke cognitive impairment (PSCI) is one of the most common subtypes of cognitive impairment. The underlying mechanisms of PSCI are not known in detail. A growing body of evidence has been suggesting that CSVD plays an important role in the pathogenesis of PSCI. This article reviews the advances in research on the relationship between CSVD and PSCI.

The effects of DL-3-n-butylphthalide in patients with vascular cognitive impairment without dementia caused by subcortical ischemic small vessel disease: A multicentre, randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Vascular cognitive impairment without dementia is very common among the aged and tends to progress to dementia, but there have been no proper large-scale intervention trials dedicated to it. Vascular cognitive impairment without dementia caused by subcortical ischemic small vessel disease (hereinafter, subcortical Vascular cognitive impairment without dementia) represents a relatively homogeneous disease process and is a suitable target for therapeutic trials investigating Vascular cognitive impairment without dementia. Preclinical trials showed that dl-3-n-butylphthalide (NBP) is effective for cognitive impairment of vascular origin. METHODS: In this randomized, double-blind, placebo-controlled trial, we enrolled patients aged 50-70 years who had a diagnosis of subcortical Vascular cognitive impairment without dementia at 15 academic medical centers in China. Inclusion criteria included a clinical dementia rating ≥0.5 on at least one domain and global score ≤0.5; a mini-mental state examination score ≥20 (primary school) or ≥24 (junior school or above); and brain magnetic resonance imaging consistent with subcortical ischemic small vessel disease. Patients were randomly assigned to NBP 200 mg three times daily or matched placebo (1:1) for 24 weeks according to a computer-generated randomization protocol. All patients and study personnel were masked to treatment assignment. Primary outcome measures were the changes in Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) and clinician's interview-based impression of change plus caregiver input (CIBIC-plus) after 24 weeks. All patients were monitored for adverse events (AEs). Outcome measures were analyzed for both the intention-to-treat (ITT) population and the per protocol population. RESULTS: This study enrolled 281 patients. NBP showed greater effects than placebo on ADAS-cog (NBP change -2.46 vs. placebo -1.39; P = .03; ITT) and CIBIC-plus (80 [57.1%] vs. 59 [42.1%] patients improved; P = .01; ITT). NBP-related AE were uncommon and primarily consisted of mild gastrointestinal symptoms. DISCUSSION: Over the 6-month treatment period, NBP was effective for improving cognitive and global functioning in patients with subcortical vascular cognitive impairment without dementia and exhibited good safety.

Lipoxin A4 methyl ester alleviates vascular cognition impairment by regulating the expression of proteins related to autophagy and ER stress in the rat hippocampus.

Since autophagy and endoplasmic reticulum stress mechanisms are involved in some neurodegenerative and cerebral vascular diseases, we suspected that similar mechanisms might participate in vascular cognitive impairments induced by chronic cerebral hypoperfusion. Lipoxin A4 methyl ester (LXA4 ME) is an inflammation inhibitor that exhibits potent protective effects in experimental stroke models. In an earlier study, we found that LXA4 ME improved cognitive deficit in a rat model of vascular cognitive impairment created using bilateral common carotid artery ligation (BCCAL) and two-vessel occlusion (2VO). In this study, LXA4 ME treatment of 2VO rats improved brain morphological defects. We found that LXA4 ME reduced the expression of some autophagy- and ERS-related factors in the hippocampus of 2VO rats, namely C/EBP homologous protein, beclin1 and the ratio of microtubule-associated protein light chain 3 II (LC3-II) to LC3-I. By contrast, LXA4 ME upregulated the protein expression of phospho-mTOR, total-mTOR, glucose-regulated protein 78 and spliced and unspliced X-box binding protein-1 mRNA. Differential protein regulation by LXA4 ME might underlie its ability to protect cognition after chronic cerebral hypoperfusion.

A Nomogram Including Total Cerebral Small Vessel Disease Burden Score for Predicting Mild Vascular Cognitive Impairment in Patients with Type 2 Diabetes Mellitus.

Background: Total cerebral small vessel disease (CSVD) burden score is an important predictor of vascular cognitive impairment (VCI). However, few predictive models of VCI in type 2 diabetes mellitus (T2DM) patients have included the total CSVD burden score, especially in the early stage of VCI. Objective: To develop and validate a nomogram that includes the total CSVD burden score to predict mild VCI in patients with T2DM. Methods: A total of 322 eligible participants with T2DM who were divided into mild and normal cognitive groups were enrolled in this retrospective study. Demographic data, laboratory data and imaging markers of CSVD were collected. The total CSVD burden score was calculated by combining the different CSVD markers. Step-backward multivariable logistic regression analysis with the Akaike information criterion was applied to select significant predictors and develop a best-fit predictive nomogram. The performance of the nomogram was assessed in terms of discriminative ability, calibrated ability, and clinical usefulness. Results: The nomogram model consisted of five variables: age, education, hemoglobin A1c level, serum homocysteine level, and total CSVD burden score. A nomogram with these variables showed good discriminative ability (area under the receiver operating characteristic curve was 0.801 in internal verification). In addition, the Hosmer-Lemeshow test (χ2 =9.226, P=0.417) and bootstrap-corrected calibration plot indicated that the nomogram had good calibration. The Brier score of the predictive model was 0.178. Decision curve analysis demonstrated that when the threshold probability ranged between 16% and 98%, the use of the nomogram to predict mild VCI in patients with T2DM provide a greater net benefit. Conclusions: The nomogram, composed of age, education, stroke, HbA1c level, Hcy level, and total CSVD burden score, had good predictive accuracy and may provide clinicians with a practical tool for predicting the risk of mild VCI in T2DM patients.

Atorvastatin Calcium Ameliorates Cognitive Deficits Through the AMPK/Mtor Pathway in Rats with Vascular Dementia.

AIM: In this study, the protective effects of atorvastatin calcium (AC) on nerve cells and cognitive improvement in vivo and in vitro were investigated by establishing cell models and vascular dementia (VD) rat models. BACKGROUND: VD is a neurodegenerative disease characterized by cognitive deficits caused by chronic cerebral hypoperfusion. AC has been studied for its potential to cure VD but its efficacy and underlying mechanism are still unclear. OBJECTIVE: The mechanism of action of AC on cognitive deficits in the early stages of VD is unclear. Here, the 2-vessel occlusion (2-VO) model in vivo and the hypoxia/reoxygenation (H/R) cell model in vitro was established to investigate the function of AC in VD. METHODS: The spatial learning and memory abilities of rats were detected by the Morris method. The IL-6, tumour necrosis factor-α (TNF-α), malondialdehyde (MDA) and superoxide dismutase (SOD) in cell supernatant was tested by ELISA kits. After behavioural experiments, rats were anaesthetized and sacrificed, and their brains were extracted. One part was immediately fixed in 4% paraformaldehyde for H&E, Nissl, and immunohistochemical analyses, and the other was stored in liquid nitrogen. All data were shown as mean ± SD. Statistical comparison between the two groups was performed by Student's t-test. A two-way ANOVA test using GraphPad Prism 7 was applied for escape latency analysis and the swimming speed test. The difference was considered statistically significant at p < 0.05. RESULTS: AC decreased apoptosis, increased autophagy, and alleviated oxidative stress in primary hippocampal neurons. AC regulated autophagy-related proteins in vitro by western blotting. VD mice improved cognitively in the Morris water maze. Spatial probing tests showed that VD animals administered AC had considerably longer swimming times to the platform than VD rats. H&E and Nissl staining showed that AC reduces neuronal damage in VD rats. Western blot and qRT-PCR indicated that AC in VD rats inhibited Bax and promoted LC3-II, Beclin-1, and Bcl-2 in the hippocampus region. AC also improves cognition via the AMPK/mTOR pathway. CONCLUSION: This study found that AC may relieve learning and memory deficits as well as neuronal damage in VD rats by changing the expression of apoptosis/autophagy-related genes and activating the AMPK/mTOR signalling pathway in neurons.