Circulating antibodies to Helicobacter pylori are associated with biomarkers of neurodegeneration in cognitively intact adults.

Helicobacter pylori (H. pylori) infection confers risk for Alzheimer's Disease (AD), with the mechanisms unknown. Infections are linked to the etiology of AD partly through modulating the humoral immunity post-infection. This study found increased plasma levels of tTau and pTau181 in H. Pylori infected individuals with intact cognition. Plasma antibodies to H. pylori were positively associated with Aß40, Aß42, tTau, and pTau181, adjusting for age, sex, education level, BMI, ApoE ε4 genotype, hypertension, diabetes mellitus, and hypercholesteremia. This study presents novel insights into the relationship between H. pylori infection and AD from an autoimmune perspective.

Artery diameter ratio after recanalization in endovascular therapy for acute ischemic stroke: a new predictor of clinical outcomes.

PURPOSE: This study aimed to investigate the relationship between the artery diameter ratio (ADR) after recanalization and clinical outcomes. METHODS: Patients with middle cerebral artery occlusion confirmed by DSA from 1 January 2018, to 31 December 2019, were retrospectively analyzed. All patients confirmed TICI grade 2b or 3. The ADR was calculated as M2 segment diameter/M1 segment diameter. Multivariate regression analysis was used to describe clinical outcomes of two groups (ADR < 0.6 and ≥ 0.6). ROC curves were used to compare different models and find the best cutoff. RESULTS: A total of 143 patients were included in the study, including 77 males and 66 females, with an average age of 67.79 ± 12 years. The NIHSS at discharge was significantly higher in the ADR < 0.6 group than another group (mean, 16.37 vs. 6.19, P < 0.001). At 90 days, the cases of functional independence was significantly less in the ADR < 0.6 group (20.97% vs. 83.95%, OR 0.05, 95% CI 0.02-0.12, P < 0.001). The ADR < 0.6 group had a higher incidence of cerebral edema (P = 0.027) and sICH (P = 0.038). The ADR had the strongest power to distinguish mRS > 2 (AUC = 0.851) and DC (AUC = 0.805), and the best cutoff value are 0.6 (specificity 85.19%, sensitivity 75.81%) and 0.58 (specificity 65.96%, sensitivity 100%), respectively. CONCLUSION: The low ADR is associated with poor outcomes. The decrease in ADR may be an indirect manifestation of the loss of cerebrovascular autoregulation.

Effects of Oral Antiplatelet Agents and Tirofiban on Functional Outcomes of Patients with Non-Disabling Minor Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Over half of patients with acute ischemic stroke present with minor neurologic deficits. We investigated the effects of oral antiplatelet agents vs. tirofiban, a highly selective GP IIb/IIIa antiplatelet drug, on functional outcomes of stroke patients with non-disabling neurologic deficits. METHODS: This retrospective study analyzed data of 125 patients with minor stroke who had National Institutes of Health Stroke Scale (NIHSS) scores of 5 or less within 6 hours of stroke symptom onset between January 2010 and June 2018. All patients were selected from the Department of Neurology at the Third Affiliated Hospital of Army Medical University. There were 54 cases in each group after propensity score matching, in which patients received oral antiplatelet agents (n = 64) and tirofiban (n = 61). Safety outcomes were assessed by incident intracranial hemorrhage, systemic bleeding and death. Efficacy outcomes were assessed using the NIHSS score at 24 hrs, 7 days or at discharge, and clinical deterioration. The modified rankin scale (mRs) was assessed at 90 days. RESULTS: No significant differences were found in the incidence of intracranial hemorrhage, systemic bleeding or death between groups (P>0.05). Although neurological function improved significantly in both groups, NIHSS scores were lower in the tirofiban group compared with those in the oral antiplatelet agents group at 24 hrs (1 versus 3, P = 0.000), 7 days or at discharge (0 versus 2, P = 0.000). The clinical deterioration rate was higher in the oral antiplatelet agents group than in the tirofiban group, but without significance (16.7% versus 5.6%, P = 0.126). Functional outcomes (mRs = 0) were more favorable in the tirofiban group than in the oral antiplatelet agents group (66.7% vs. 44.4%; adjusted odds ratio 3.32; 95% CI: 1.38-7.99; P = 0. 008). CONCLUSION: Intravenous tirofiban seems to be safe and effective with more favorable functional outcomes than oral antiplatelet agents, suggesting that tirofiban is a viable treatment choice for selected patients with non-disabling minor acute ischemic stroke.

Intravenous tirofiban therapy for patients with capsular warning syndrome.

Background: Capsular warning syndrome (CWS) is defined as recurrent episodes of transient ischaemic attacks ≥3 times during a short time frame. There is no effective therapy to stop these attacks. We, herein, report our experience of using intravenous tirofiban to treat CWS. Methods: All patients with CWS in our hospital from January 2013 to September 2017 were reviewed. Patients in tirofiban group (T-group) were treated by intravenous tirofiban at 0.4 µg/kg/min for 30 min followed by 0.1-0.15 µg/kg/min infusion. Other treatments (non-T-group) included thrombolytic, oral antiplatelet agents and anticoagulant. Intracerebral haemorrhage (ICH), systematic bleeding, new attacks after treatment, National Institutes of Health Stroke Scale (NIHSS) scores at 24 hours and modified Rankin Scales (mRSs) at 3 months were recorded. Descriptive statistics were used for analysis. Results: Of 23 patients qualified (15 in T-group, 8 in non-T-group), the duration of symptoms ranged from 2 to 100 min before treatments. After treatment, in T-group, four patients (26.7%) had recurrent attacks, and NIHSS scores were 0 in 11 patients (73.3%) at 24 hours. All patients reached a favourable outcome (mRS ≤2 at 3 months. In non-T-group, five patients (62.5%) had new attacks. NIHSS scores were 0 in two patients (25%) at 24 hours. At 3 months, seven patients (87.5%) reached a favourable outcome. Neither ICH nor systematic bleeding or thrombocytopaenia occurred in both groups of patients. Conclusions: Intravenous tirofiban can be a potentially effective and safe therapy to stop early symptomatic fluctuations and shorten the duration of functional deficits in patients with CWS.

Safety and preliminary efficacy of intravenous tirofiban in acute ischemic stroke patient without arterial occlusion on neurovascular imaging studies.

BACKGROUND: There has been no effective treatment for acute ischemic stroke (AIS) patients who presented to the Emergency Department >4.5h without a visible arterial occlusion on the neurovascular imaging studies. In this study, we aimed to investigate whether intravenous antiplatelet agent tirofiban was safe and potentially effective in AIS patients who had no visible arterial occlusion and was outside of treatment window for Alteplase. The goal of this study was to collect preliminary data to plan a future phase II study. METHOD: Twenty-five patients received intravenous tirofiban therapy. The safety outcomes were assessed by the incidence of symptomatic intracerebral hemorrhage (sICH), systematic bleeding and mortality. Efficacy outcomes were evaluated with National Institutes of Health Stroke Scale (NIHSS) score at day 7 (or discharge) and modified Rankin Scale (mRS) at 90days. Outcomes for these patients were compared with a historical age-gender-admission-NIHSS matched cohort treated with aspirin and/or clopidogrel. RESULTS: The rate of intracerebral hemorrhage, systematic bleedings, and death were not found in both groups. At day 7 or discharge, the neurological function improved significantly in both treatment groups. However, the NIHSS score was lower in tirofiban group compared with the control group (2 vs.3, p=0.045). At 3months, more patients in tirofiban group had favorable outcomes (mRS 0-1) compared with control group (84% vs. 52%; adjusted odds ratio: 10.57; 95% CI: 1.54-72.33; p=0.016). CONCLUSIONS: Intravenous tirofiban appears to be safe and potentially effective for the ischemic stroke patients with no artery occlusion on neurovascular imaging studies and being out of the window for thrombolytic therapy. A next logic step is to plan for a phase II study.

Nutritional Deficiency in Early Life Facilitates Aging-Associated Cognitive Decline.

BACKGROUND: Nutrition is important for the fetal developmental programming. Nutritional deficiency in early life could increase the susceptibility to many aging-related disorders including cognitive decline. OBJECTIVE: Our study aims to investigate the effect of early famine exposure on aging-associated cognitive function. METHODS: We recruited 6790 subjects born between 1956 to 1964 during which the Great Chinese Famine occurred (1959-1961). Cognitive function of these subjects were evaluated using the Mini-Mental State Examination (MMSE), the Activities of Daily Living scale (ADL), the Instrumental Activities of Daily Living scale (IADL) and the Clinical Dementia Rating (CDR). RESULTS: Our study identified that early exposure to the famine significantly increased the risk of cognitive impairments in later life, leading to higher prevalence of Mild Cognitive Impairment (MCI) and dementia. We also found the sex and rural-urban differences in this malnutrition-induced effect. Illiteracy, history of stroke or diabetes mellitus are great risk factors to facilitate the cognitive decline. CONCLUSION: These findings demonstrate that exposure to famine during early life including prenatal period and early childhood facilitates aging-associated cognitive deficits.

Safety and Preliminary Efficacy of Early Tirofiban Treatment After Alteplase in Acute Ischemic Stroke Patients.

BACKGROUND AND PURPOSE: We investigated whether early initiation of tirofiban, a glycoprotein IIb/IIIa antagonist, is safe, can reduce the risk of reocclusion, and improve outcomes in acute ischemic stroke patients after alteplase. METHODS: Forty-one patients received alteplase followed by intravenous tirofiban infusion for at least 24 hours. The incidence of symptomatic intracranial hemorrhage, systematic bleedings, and death was recorded. The National Institutes of Health stroke scale score was evaluated at 24 hours and at day 7 (or discharge). Modified Rankin scale was assessed at 3 months. Outcomes for these patients were compared with a propensity score-matched historical cohort with alteplase only. RESULTS: The incidence of symptomatic intracranial hemorrhage, death, or systematic bleedings (P=1.00) was not increased in the alteplase/tirofiban group. At 24 hours, fewer patients experienced reocclusion in the alteplase/tirofiban group (2.4% versus 22.0%; P=0.025). At day 7 or discharge, the median National Institutes of Health stroke scale score was significantly lower in the alteplase/tirofiban group (1 versus 6; P=0.002). At 3 months, more patients had favorable outcomes of modified Rankin scale 0 to 1 (70.7% versus 46.2%; P=0.026). CONCLUSIONS: Intravenous tirofiban immediately after alteplase seems to be safe and potentially more effective when compared with alteplase alone for selected stroke patients. CLINICAL TRIAL REGISTRATION: URL: http://www.chictr.org.cn/. Unique identifier: ChiCTR-TRC-14004630.

An N-terminal antibody promotes the transformation of amyloid fibrils into oligomers and enhances the neurotoxicity of amyloid-beta: the dust-raising effect.

BACKGROUND: Senile plaques consisting of amyloid-beta (Aß) are the major pathological hallmark of Alzheimer's disease (AD) and have been the primary therapeutic target. Immunotherapies, which are designed to remove brain Aß deposits, increased levels of soluble Aß and accelerated brain atrophy in some clinical trials, suggesting that the solubilization of Aß deposition might facilitate the formation of more toxic Aß oligomers and enhance neurotoxicity. METHODS: The capacity of antibodies against different epitopes of Aß to disaggregate preformed Aß fibrils was investigated. The co-incubation of antibodies and Aß fibrils was then tested for neurotoxicity both in vitro and in vivo. RESULTS: After the incubation of preformed Aß fibrils with the N-terminal antibody 6E10, the fibrils were decreased, while the oligomers, mostly dimers and trimers, were significantly increased. However, no such effects were observed for antibodies targeting the middle domain (4G8) and C-terminus of Aß (8G7). The co-incubates of preformed Aß fibrils with 6E10 were more neurotoxic, both in vitro and in vivo, than the co-incubates with 4G8 and 8G7. CONCLUSIONS: Our results indicate that the antibody targeting the N-terminus of Aß promoted the transformation of Aß from fibrils into oligomers and increased neurotoxicity. Immunotherapies should take into consideration the enhanced neurotoxicity associated with the solubilization of Aß deposits by antibodies against the Nterminus of Aß.

Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits.

Alzheimer's disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-ß (Aß) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Aß aggregation and attenuating Aß-induced oxidation in vitro. When given before or after the onset of Aß deposition via i.p. injection, Edaravone substantially reduces Aß deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis.

Identification of a novel mutation in the presenilin 1 gene in a Chinese Alzheimer's disease family.

This study has identified a gene mutation in a Chinese family with Alzheimer's disease (AD). Family members were screened by a set of medical examinations and neuropsychological tests. Their DNA was extracted from blood cells and sequenced for gene mutation in the amyloid precursor protein (APP), the presenilin 1 (PS1) and the presenilin 2 (PS2) genes. Genetic analysis showed that the AD patients in the family harbored a T to G missense mutation at the position 314 in exon 4 of the PS1 gene, resulting in a change of F105C in amino acid sequence. Clinical manifestation of these patients included memory loss, counting difficulty, personality change, disorientation, dyscalculia, agnosia, aphasia, and apraxia, which was similar to that of the familial AD (FAD) patients harboring other PS1 mutations. We intend to add a novel mutation F105C of the PS1 gene to the pool of FAD mutations. With the current available genetic data, mutations of the PS1 gene account for the majority of gene mutations in Chinese FAD.

The relationship between single nucleotide polymorphisms of the NTRK2 gene and sporadic Alzheimer's disease in the Chinese Han population.

Alzheimer's disease (AD) is characterized by the degeneration of basal forebrain cholinergic neurons, whose survival and function are affected by neurotrophins and their receptors. The impaired signaling pathway of brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) is considered to play an important role in AD pathogenesis. To explore the association of polymorphisms within the NTRK2 gene (encoding TrkB) and sporadic AD (sAD), a case-control study was conducted in a Chinese Han cohort including 216 sAD patients and 244 control participants. Five single nucleotide polymorphisms (SNPs), with four of them within the promoter region and one in intron, were selected and genotyped with a polymerase chain reaction-ligase detection reaction (PCR-LDR) method. No association was revealed between these SNPs or the haplotypes containing four promoter SNPs and the risk of sAD. The results of this study indicate that polymorphisms in the selected regions of the NTRK2 gene are unlikely to confer the susceptibility of sAD in the Chinese Han population.

proNGF inhibits proliferation and oligodendrogenesis of postnatal hippocampal neural stem/progenitor cells through p75NTR in vitro.

Neural stem/progenitor cells (NSCs) proliferate and differentiate under tight regulation by various factors in the stem cell niche. Recent studies have shown that the precursor of nerve growth factor (NGF), proNGF, abounds in the central nervous system (CNS) and that its expression level in the brain is substantially elevated with aging as well as in several types of CNS disorders. In this study, we found for the first time that proNGF inhibited the proliferation of NSCs isolated from postnatal mouse hippocampus and caused cell cycle arrest in the G0/G1 phase without affecting apoptosis. In addition, proNGF reduced the differentiation of NSCs to oligodendrocytes. The effects of proNGF were blocked by the fusion protein of p75 neurotrophin receptor extracellular domain and human IgG Fc fragment (p75NTR/Fc), and by p75NTR knockout, suggesting that proNGF/p75NTR interaction was involved in the effects of proNGF on NSC proliferation and differentiation. proNGF decreased the phosphorylation level of extracellular signal responsive kinase 1/2 (ERK 1/2) in a p75NTR-dependent manner under both self-renewal and differentiation conditions. The inhibition of ERK 1/2 phosphorylation by U0126 significantly reduced the proliferation and oligodendrogenesis of NSCs, indicating that ERK 1/2 inhibition by proNGF partially explains its effects on NSC proliferation and oligodendrogenesis. These results suggest that the proNGF/p75NTR signal plays a key role in the regulation of NSCs' behavior.

No association of SORT1 gene polymorphism with sporadic Alzheimer's disease in the Chinese Han population.

Increasing evidence shows that sortilin (encoded by SORT1 gene), a member of the vacuolar protein sorting 10 family of sorting receptors, can modulate amyloid-ß peptides (Aß) metabolism and clearance, as well as mediate the neurotoxicity of the Aß oligomer and proneurotrophins, thus playing diverse roles in the pathogenesis of Alzheimer's disease. To assess the association between single nucleotide polymorphism (SNP) of the SORT1 gene and sporadic Alzheimer's disease (sAD) in the Chinese Han population, a case-control study was carried out including 220 sAD patients and 245 controls. One tag SNP was selected from the entire SORT1 gene through construction of linkage disequilibrium blocks, and three SNPs located in the vicinity of SORT1 that affect its expression were also selected. The four target SNPs were genotyped using a multiplex PCR-ligase detection reaction method, yielding no significant association between them or haplotypes containing three of them, and the risk of sAD. The results of this study indicate that polymorphisms of the SORT1 gene are unlikely to confer the risk of sAD in the Chinese Han population.