Central Nervous System Complications Research Articles

Biotypes of Central Nervous System Complications in People Living With Human Immunodeficiency Virus (HIV): National Institute of Mental Health Perspectives on Advancing the Future of HIV Healthcare

Despite effective suppressive antiretroviral therapy, central nervous system (CNS) complications related to human immunodeficiency virus (HIV) remain a significant problem for people with HIV (PWH). Numerous studies have contributed data to define the mechanisms underlying HIV-associated CNS pathophysiology, but causality remains elusive, with no effective therapies to prevent, reduce, or reverse HIV-associated CNS complications. Multiple physiological, clinical, cognitive, behavioral, social, and environmental factors contribute to the observed heterogeneity of adverse CNS outcomes among PWH. The National Institute of Mental Health in collaboration with investigators engaged in research related to HIV associated CNS complications organized a series of meetings to review the state of the science and facilitate the development of biologically based measures to identify the phenotypic heterogeneity of CNS outcomes linked to pathophysiology (biotypes). In this article, we summarize the proceedings of these meetings and explore the precision medicine framework to identify critical factors linked to the etiopathogenesis of CNS outcomes in PWH.

Biotypes of Central Nervous System Complications in People With Human Immunodeficiency Virus: Virology, Immunology, and Neuropathology.

Despite viral suppression with antiretroviral therapy (ART), people with human immunodeficiency virus (HIV) continue to experience central nervous system (CNS) complications, primarily in the form of mild cognitive impairment and mental health disorders (eg, depression, anxiety, other neuropsychiatric problems). The multifactorial pathogenesis and heterogeneity of mechanisms likely underlying CNS complications must be addressed in the development of preventive interventions and effective treatments. The biotyping approach has previously been useful to define phenotypes of other CNS diseases based on underlying mechanisms and could be translated to the field of neuroHIV. The purpose of the Biotype Workshop series, and the Virology, Immunology and Neuropathology Working Group in particular, is to capitalize on current and new technologies and guide future research efforts using the wealth of available immunological, virologic, and neuropathological data collected from people with HIV on and off ART.

Moving Toward Disentangling Heterogeneity in Central Nervous System Complications in People With Human Immunodeficiency Virus

Moving Toward Disentangling Heterogeneity in Central Nervous System Complications in People With Human Immunodeficiency Virus

Microglial priming induced by loss of Mef2C contributes to postoperative cognitive dysfunction in aged mice

Postoperative cognitive dysfunction (POCD) is a common postoperative central nervous system (CNS) complication with a higher occurrence among aged individuals than among young individuals. The aim of this study was to explore the mechanisms by which POCD preferentially affects older individuals. We found here that exploratory laparotomy induced cognitive function decline in aged mice but not in young mice and that this decline was accompanied by inflammatory activation of microglia in the hippocampus. Furthermore, microglial depletion by feeding of a standard diet containing a colony stimulating factor 1 receptor (CSF1R) inhibitor (PLX5622) markedly protected aged mice from POCD. Notably, the expression of myocyte-specific enhancer 2C (Mef2C), an immune checkpoint that limits overactivation of microglia, was downregulated in aged microglia. Knocking down Mef2C induced a microglial priming phenotype in young mice, resulting in postoperative increases in the hippocampal levels of the inflammatory factors IL1-β, IL-6 and TNF-α that could impair cognition; these findings were consistent with the observations in aged mice. In vitro, BV2 cells lacking Mef2C released higher levels of inflammatory cytokines upon stimulation with lipopolysaccharide (LPS, a bacterial toxin) than Mef2C-sufficient cells. Moreover, upregulation of Mef2C in aged mice restrained postoperative microglial activation, attenuating the neuroinflammatory response and cognitive impairment. These results reveal that during aging, loss of Mef2C leads to microglial priming, amplifying postsurgical neuroinflammation and contributing to the vulnerability of elderly patients to POCD. Thus, targeting the immune checkpoint Mef2C in microglia may be a potential strategy for the prevention and treatment of POCD in aged individuals.

Dry Powder Inhaler with the technical and practical obstacles, and forthcoming platform strategies.

A Dry Powder Inhaler (DPI) is a technique as well as a device used to inhale formulation which is in the form of dry powder, and is inhaled through the nose or mouth. It was developed for the purpose of treating conditions like chronic obstructive pulmonary disease (COPD), Asthma, and even cystic fibrosis etc. The aim of the review is to discuss the different methods of preparation of dry powders along with the characterization of DPI. Here we present the outline of different methods like supercritical fluid extraction (SCF), spray drying, and milling. The review focussed on various devices including single and multi-dose devices used in the DPI. It also highlights on recent advances in the DPI including nano particulate system, siRNA-based medication, liposomes, and pro-liposomes based delivery. In COVID-19 silver nanoparticles-based DPIs provide very prominent results in the infected lungs. Moreover, this review states that the AI-based DPI development provides and improvement in the bioavailability and effectiveness of the drug along with the role of artificial neural networks (ANN). The study also showed that nasally administered drugs (nose to brain) can easily cross the blood-brain barrier (BBB) and enter the central nervous system (CNS) through the olfactory and trigeminal pathway which provides effective CNS concentrations at lower dosage. It is suggested that DPIs not only target respiratory complications but also treat CNS complications too. This review provides support and guides the researcher in the recent development and evaluation of DPI.

Central and Peripheral Nervous System Complications of Vasculitis Syndromes from Pathology to Bedside: Part 2-Peripheral Nervous System.

Peripheral nervous system vasculitides (PNSV) are a heterogeneous group of disorders with a clinical subset that may differ in prognosis and therapy. We provide a comprehensive update on the clinical assessment, diagnosis, complications, treatment, and follow-up of PNSV. Progress in neuroimaging, molecular testing, and peripheral nerve biopsy has improved clinical assessment and decision-making of PNSV, also providing novel insights on how to prevent misdiagnosis and increase diagnostic certainty. Advances in imaging techniques, allowing to clearly display the vessel walls, have also enhanced the possibility to differentiate inflammatory from non-inflammatory vascular lesions, while recent histopathology data have identified the main morphological criteria for more accurate diagnosis and differential diagnoses. Overall, the identification of peculiar morphological findings tends to improve diagnostic accuracy by defining a clearer boundary between systemic and non-systemic neuropathies. Therefore, the definition of epineurium vessel wall damage, type of vascular lesion, characterization of lymphocyte populations, antibodies, and inflammatory factors, as well as the identification of direct nerve damage or degeneration, are the common goals for pathologists and clinicians, who will both benefit for data integration and findings translation. Nevertheless, to date, treatment is still largely empiric and, in some cases, unsatisfactory, thus often precluding precise prognostic prediction. In this context, new diagnostic techniques and multidisciplinary management will be essential in the proper diagnosis and prompt management of PNSV, as highlighted in the present review. Thirty to fifty percent of all patients with vasculitis have signs of polyneuropathy. Neuropathies associated with systemic vasculitis are best managed according to the guidelines of the underlying disease because appropriate workup and initiation of treatment can reduce morbidity. Steroids, or in severe or progressive cases, cyclophosphamide pulse therapy is the standard therapy in non-systemic vasculitic neuropathies. Some patients need long-term immunosuppression. The use of novel technologies for high-throughput genotyping will permit to determine the genetic influence of related phenotypes in patients with PNSV.

Immunotherapy associated central nervous system complications in primary brain tumors.

Advances clarifying the genetics and function of the immune system within the central nervous system (CNS) and brain tumor microenvironment have led to increasing momentum and number of clinical trials using immunotherapy for primary brain tumors. While neurological complications of immunotherapy in extra-cranial malignancies is well described, the CNS toxicities of immunotherapy in patients with primary brain tumors with their own unique physiology and challenges are burgeoning. This review highlights the emerging and unique CNS complications associated with immunotherapy including checkpoint inhibitors, oncolytic viruses, adoptive cell transfer/chimeric antigen receptor (CAR) T cell and vaccines for primary brain tumors, as well as reviews modalities that have been currently employed or are undergoing investigation for treatment of such toxicities.

Risk Factors for Mortality in Severe Fever with Thrombocytopenia Syndrome Patients with Central Nervous System Complications.

BACKGROUND Severe fever with thrombocytopenia syndrome (SFTS) is a zoonotic viral hemorrhagic fever caused by the SFTS virus (SFTSV), which is a newly identified tick-borne bunyavirus, recently named Dabie bandavirus. In rural China, SFTSV or Dabie bandavirus is commonly transmitted by Haemaphysalis longicornis, the Asian longhorned tick. In recent years, SFTS has been of great concern due to its high morbidity and mortality. The present study investigated the risk factors for mortality in patients with SFTS complicated by central nervous system involvement. MATERIAL AND METHODS We studied 69 SFTS patients hospitalized between 2013 and 2020. We analyzed the laboratory test results and clinical data through univariate and multivariate regression. RESULTS Neurological complications occurred in 59 patients in the survival group and 10 in the mortality group. No significant gender difference was found between the 2 groups. No significant difference was found in age, hospitalization duration, or occurrence of encephalitis between the 2 groups. The mean duration of hospitalization and course of the disease in the mortality group were significantly shorter than those in the survival group (P<0.01). The mean values of platelet count, potassium, and sodium in the mortality group were significantly lower, while the mean values of aspartate aminotransferase, lactic dehydrogenase, creatine kinase-MB (CK-MB) and procalcitonin were higher than those in the survival group. Low platelet count and high CK-MB were independent risk factors for mortality in patients. For each unit increase in platelet count, the risk of mortality decreased by 24.2%, and for each unit increase in CK-MB, the probability of mortality increased by 118.6%. CONCLUSIONS Decreased platelets and increased CK-MB were independent risk factors for mortality in encephalitis patients. SFTS patients with encephalitis should be monitored for changes in these 2 indicators.

TaVNS Alleviates Sevoflurane-Induced Cognitive Dysfunction in Aged Rats Via Activating Basal Forebrain Cholinergic Neurons.

Postoperative cognitive dysfunction (POCD) is a common complication of central nervous system after anesthesia or surgery. Sevoflurane, an inhalation anesthetic, may inhibit cholinergic pathway that induce neuronal death and neuroinflammation, ultimately leading to POCD. Transauricular vagus nerve stimulation (taVNS) has neuroprotective effects in POCD rats, but the mechanisms related to cholinergic system have not been revealed. Sprague-Dawley rats were anesthetized with sevoflurane to construct the POCD model. The immunotoxin 192-IgG-saporin (192-sap) selectively lesioned cholinergic neurons in the basal forebrain, which is the major source of cholinergic projections to hippocampus. After lesion, rats received 5 days of taVNS treatment (30min per day) starting 24h before anesthesia. Open field test and Morris water maze were used to test the cognitive function. In this study, rats exposed to sevoflurane exhibited cognitive impairment that was attenuated by taVNS. In addition, taVNS treatment activated cholinergic system in the basal forebrain and hippocampus, and downregulated the expression of apoptosis- and necroptosis-related proteins, such as cleaved Caspase-3 and p-MLKL, in the hippocampus. Meanwhile, the activation of Iba1+ microglial by sevoflurane was reduced by taVNS. 192-sap blocked the cholinergic system activation in the basal forebrain and hippocampus and inhibited taVNS-mediated neuroprotection and anti-inflammation effects in the hippocampus. Generally, our study indicated that taVNS might alleviate sevoflurane-induced hippocampal neuronal apoptosis, necroptosis and microglial activation though activating cholinergic system in the basal forebrain.

Transcranial near-infrared laser improves postoperative neurocognitive disorder in aged mice via SIRT3/AMPK/Nrf2 pathway.

Postoperative neurocognitive disorder (PND) is a common central nervous system (CNS) complication that might increase the morbidity and mortality of elderly patients after anesthesia/surgery. Neuroinflammation, oxidative stress, and synaptic dysfunction are closely related to cognitive dysfunction, an important clinical feature of PND. Transcranial near-infrared laser (TNIL) is regarded as an effective treatment for cognitive-related diseases by improving mitochondrial function and alleviating neuroinflammation and oxidative stress damage. Aged male C57BL/6 mice underwent a carotid artery exposure procedure under isoflurane anesthesia. We treated PND-aged mice for three consecutive days (4 h post-operation, 1-laser) with 810 nm continuous wave (CW) laser 18 J/cm2 at 120 mW/cm2. The post-treatment evaluation included behavioral tests, RTq-PCR, immunofluorescence, and Western blot. The results demonstrated that TNIL improved PND and the levels of synaptic function-associated proteins such as post-synaptic density protein 95 (PSD95), synaptophysin (SYP), and brain-derived neurotrophic factor (BDNF). Besides, neuroinflammatory cytokine levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β as well as microglia activation and oxidative stress damage were attenuated after TNIL treatment in aged mice with PND. Further investigation suggested that TNIL relieved oxidative stress response by activating the SIRT3/AMPK/Nrf2 pathway. Transcranial near-infrared laser improved cognitive impairment in aged mice with PND, which may be a promising therapeutic for PND.

Imaging findings in a case of leptomeningeal myelomatosis, a rare but critical central nervous system complication of multiple myeloma.

Leptomeningeal myelomatosis is a rare complication of multiple myeloma (<1% of the patients). There was an increase in the incidence of leptomeningeal myelomatosis during the last decade; the prognosis of leptomeningeal myelomatosis remains poor, (overall median survival from the time of diagnosis of 2months). We discuss a rare case of a monoclonal gammopathy evolving into multiple myeloma and finally into a rapidly progressing leptomeningeal disease. A 76year-old woman in hematologic follow-up for advanced stage multiple myeloma in sixth-line treatment had an episode of generalized tonic-clonic seizure with sphincter release followed by altered state of consciousness. The unenhanced head CT scan showed a mild enlargement of the ventricular system without intra-axial or extra-axial hemorrhages nor significant changes in brain parenchyma. The subsequent contrast-enhanced brain MRI revealed a widespread nodular leptomeningeal enhancement characterized by contrast-enhancement of the pia mater extended into the subarachnoid spaces of the sulci and cisterns, involving supra- and sub-tentorial regions and the statoacoustic nerve in the inner ear canal bilaterally. The fluid-attenuated inversion recovery MRI images demonstrated an abnormally elevated signal within the sulci in the parieto-occipital regions. The radiological diagnosis of leptomeningeal myelomatosis was made. The patient died 4 days after the examination. In patients with long-lasting multiple myeloma and onset of neurological signs or symptoms, a contrast-enhanced brain MRI should be performed to assess the actual burden of central nervous system involvement in leptomeningeal myelomatosis; CT may provide a clue to the diagnosis when progressive enlargement of the ventricles over time is noted.

Prognostic Value of Cardiac and Noncardiac Biomarkers in Infective Endocarditis: A Prospective Cross-sectional Study

Background and Aims: Infective endocarditis (IE) is associated with several morbidities and high rate of mortality. Predicting these morbidities can be helpful in managing patients and can prevent possible complications, result from IE. In this study, we aimed to evaluate the association between C-reactive protein (CRP), N-terminal pro brain natriuretic peptide (BNP), monocyte to high density lipoprotein (HDL) ratio Charlson comorbidity index, and European System for Cardiac Operative Risk Evaluation (Euro SCORE) in complicated cases of IE. Materials and Methods: This prospective study was conducted on a referral center from January 2017 to December 2020. Patients with definite or possible diagnosis of IE based on the modified Duke criteria were included in this study. Demographic information and serum levels of N-terminal pro BNP, D-Dimer, CRP were evaluated in patients. In addition, we used Charlson comorbidity index and The Euro SCORE for subjective assessment. Results: One hundred and four patients (64 males, median age: 58) included in the final analysis. Intracardiac involvement, central nervous system (CNS) complications and systemic complications were observed in nine patients (9.7%), 16 patients (15.4%), and eight patients (7.7%) respectively. The mortality rate was 14.4%. D-dimer (P = 0.008), pro-BNP (P = 0.008), and Charlson criteria (P = 0.012) were higher in patients with systematic complications. In addition, NT pro-BNP was significantly associated with CNS complications (P = 0.04) and D-Dimer level was significantly associated with in-hospital mortality (P = 0.008). Conclusion: Serum biomarkers such as pro-BNP and D-dimer, and comorbidity indices can be used for risk stratification of patients with IE. The level of pro-BNP is significantly associated with CNS complications and the level of D-dimer is significantly with mortality in patients with IE.

Neuroimmunological renal function for zinc(Ⅱ) induced CKD prevention and modulatory progression

Zinc (Ⅱ) supplementation (30 mg/day) should become likely therapeutic chronic kidney disease (CKD) prevention implications with immense importance of CKD-associated immunological and neurological complications of central nervous system (CNS) disorder and peripheral nervous system (PNS) condition. Zinc induced neuro immunological inhibitive CKD progression with Stage 2～3A, 3B, zinc supplementation may be beneficial for nutritional status in CKD children and adolescents, and zinc could reduce urinary protein excretion composed of albumin and/or minimize proteinuria excretion in proteinuric CKD. In CKD 4～5 stage, risk of cardiovascular disease (CVD) become higher that zinc supplementation of 25 mg/day in zinc homeostasis has a beneficial effect for CVD in vascular dysfunction, in which zinc induced CKD Stage 5 (eGFR < 15) is involved that zinc is actively bound to several proteins that the decrease of circulating zinc levels in CKD is becoming zinc-deficiency with advanced stage CKD and ESRD in CKD. Zinc 15 mg/day and Selenium 50–70 μg/day that are recommended may be thought to prevent ESRD stage. Zinc induced NAD (P)H oxidase (Nox) activation occurring ROS generation in CKD cell involves assembly that ROS include the superoxide anion (O2•–), hydrogen peroxide (H2O2), and hydroxyl radicals (OH•) in the kidney. Zinc(Ⅱ) ions-binding protein molecular mechanism is involved that Zn2+ ions induced binding ligands of such as albumin, a-macroglobulin and transferrin in several proteins had been found on the binding specificity by Zn2+ ions-centered tetrahedral geometric coordination, in which causing zinc-activated serine, histidine and aspartate hydrogen residues enhance renal function activity and resulting inhibition of CKD progression proceeds.

Central nervous system complications after allogeneic hematopoietic stem cell transplantation: focusing on viral encephalitis and leukoencephalopathy

同種造血幹細胞移植後にはウイルス，真菌，原虫などによる多彩な感染症，脳血管障害，免疫介在性の病態，代謝異常，薬剤，腫瘍浸潤など様々な病態が中枢神経系合併症の原因となる。国内ではHHV-6Bは中枢神経系合併症の主要な原因である。特に臍帯血移植患者において移植後2～6週目に中枢神経系症状をきたした場合はHHV-6B脳炎を疑う。発症早期における精神状態の変化を見落とさず治療を開始することが予後の改善に繋がると考えられる。可逆性後頭葉白質脳症症候群はカルシニューリン阻害薬による血管内皮細胞障害を主たる原因として，前処置，免疫学的活性化，感染症や高血圧などが発症を促進する。免疫抑制剤の中止により神経症状の改善が期待されるが，GVHDの悪化を高率にきたす。移植後中枢神経系感染症は様々な病原体が原因となり，診断が困難な場合が少なくない。次世代シークエンシングなどによる網羅的解析の実用化が期待される。

Orofacial Dyskinesia and Intractable Hiccups in a Patient with Varicella-Zoster Virus Encephalomyelitis.

A 73-year-old Japanese man with diabetic complications presented with involuntary lip movements and long-lasting hiccups after developing zoster rash. Magnetic resonance imaging revealed lesions involving the medial temporal lobe and C1 level of the spinal cord. Varicella-zoster virus (VZV) encephalomyelitis was diagnosed. We considered attributing the orofacial dyskinesia, a very rare symptom of VZV central nervous system (CNS) complications, to the temporal lobe lesion. Although the culprit lesion for the hiccups was unclear, further examinations may have clarified this issue. As immunocompromised patients with herpes zoster may develop CNS complications with a wide variety of symptoms, special care is needed.

Venetoclax Penetrates the Blood Brain Barrier: A Pharmacokinetic Analysis in Pediatric Leukemia Patients.

Infiltration of malignant cells into the central nervous system in hematological malignancies correlates with poor clinical outcomes. Investigations into the penetration of venetoclax into the central nervous system have been limited. We report venetoclax pharmacokinetics in plasma and cerebrospinal fluid samples from a Phase 1 study in pediatric patients with relapsed or refractory malignancies that demonstrate venetoclax ability to cross into the central nervous system. Venetoclax was detected in cerebrospinal fluid (CSF) samples, with concentrations ranging from < 0.1 to 26 ng/mL (mean, 3.6 ng/mL) and a plasma:CSF ratio ranging from 44 to 1559 (mean, 385). Plasma:CSF ratios were comparable among patients with AML and ALL and no clear trend was observed in the ratios over the course of treatment. Moreover, improvement in central nervous system (CNS) involvement status was observed in patients who had measurable concentrations of venetoclax in the CSF. CNS resolution was observed for up to six months while on treatment. These findings highlight the potential role of venetoclax and provide the opportunity to further investigate its utility in improving clinical outcomes for patients with CNS complications.

COVID-19 in a Newborn Caught on Magnetic Resonance Imaging: A Case Report

The Coronavirus Disease 2019 (COVID-19) remains a global public health threat. It is generally believed that children, especially neonates, are relatively spared from the disastrous effects of COVID-19 compared to adults. Most symptomatic children experience only mild respiratory and gastrointestinal symptoms. Central Nervous System (CNS) complications in COVID-19 are unusual in children and neonates. In this report, the authors present the case of a five-day-old COVID-19 positive neonate who presented with convulsions and tachypnoea. Magnetic Resonance Imaging (MRI) findings suggested a cytotoxic oedematous pattern. This child made a complete recovery after receiving appropriate management. There is limited data available regarding COVID-19 in neonates, and only a few similar cases of neonatal involvement have been described in the literature. The aim of this report is to highlight the unusual imaging manifestations of COVID-19 in a neonate.

Is Anosmia-Ageusia in COVID-19 Patients Associated with Neuro-Philic Virus Mutant and Mild Respiratory Involvement?

Introduction and Objective: In COVID-19, sudden onset anosmia-ageusia can be observed in patients, regardless of other rhinologic symptoms or prominent nasal symptoms. In our clinical follow-ups, it has drawn our attention that patients presenting with anosmia-ageusia have milder pulmonary symptoms and milder progression. It was thought that this group of patients were infected with neurosensitive SARS-CoV-2 and the study was planned based on this hypothesis. We present our results to contribute to the literature because our study may be a practical screening approach in patient follow-up, may provide predictions of disease progression, and isolation period can be determined. Materials and Methods: The study was conducted in March 2020, by interviewing recorded patients via phone. Patients’ anosmia-ageusia characteristics, hospitalizations, and recorded Thoracic Computed Tomography (CT) reports were evaluated. The reports were analyzed by a single physician and CT positivity was reported and grouped as mild, moderate and severe. Results: A total of 1438 patients were included in the study. Of the patients, 47.8% were male and 52.0% were male, while the mean age was 44.33 ∓ 16.01 years. In terms of educational levels, patients were found to be elementary (25.6%) and high school (20.7%) graduates at most. Discussion and Conclusion: Hospitalization rates of patients presenting with anosmia-ageusia were lower and their disease progression were milder. We suggest that there are mainly neuro- or pulmonary-sensitive variants of the virus. This characteristic is of great importance for the long-term follow-up of these patients and predictions of complications. Patients presenting with a sudden development of anosmia-ageusia should be considered as positive patients. Quarantine and isolation periods should be extended in these patients, keeping in mind the prolonged RT-PCR positivity as well. Besides, it should be noted that these patients are more likely to develop central nervous system complications and they should be followed up.

Moyamoya syndrome in Schimke immuno-osseous dysplasia

Introduction. Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive multisystem disorder associated with biallelic mutations of the SMAR-CAL1 gene. Vascular central nervous system complications in the form of Moyamoya syndrome (MMS) have been reported as a comorbidity in nearly half of the patients clinically presenting with severe migraine-like headaches, transient ischemic attacks (TIA), and ischemic or hemorrhagic infarctions. We present an illustrative case of an infantile form of SIOD with MMS, with a review of the latest diagnostic possibilities, as well as current diagnostic and therapeutic dilemmas in managing SIOD. Case report. We present a female patient with the infantile form of SIOD. The proband was born small for gestational age in the 34th gestation week with characteristic dysmorphic features. Genetic testing found a biallelic, nonsense mutation c.2542G&gt;T in the SMARCAL1 gene. The patient presented early with TIA, seizures, and recurrent ischemic strokes. Magnetic resonance imaging (MRI) confirmed the presence of progressive brain atrophy with bilateral occlusion/stenosis of middle cerebral artery and anterior cerebral artery and a smoke-like collateral vessel appearance consistent with the MMS. At the age of 5 years and 9 months, the patient developed a high fever and cough with unknown cause, with a low erythrocyte and white blood cell count during four weeks, with a poor therapeutic response to antibiotics, transfusion of red blood cells, and granulocyte growth factor. She later died. Conclusion. Patients with SIOD may present progressive cerebral vascular changes and clinical neurologic deterioration early in the course of the disease. In such patients, early diagnosis and preventive revascularization surgery are of paramount importance. In diagnosing MMS, MRI angiography can be an appropriate substitute for standard invasive cerebral angiography.

Microbiome-metabolomics analysis reveals the potential effect of verbascoside in alleviating cognitive impairment in db/db mice.

Cognitive impairment is the main central nervous system complication of diabetes, affecting the quality of life of patients. Herba Cistanche is a homologous plant widely used as a health food and therapeutic drug. Verbascoside, a signature component of Herba Cistanche, has anti-diabetic and neuroprotective effects. However, it is quickly metabolized by the gut microbiota, and the mechanism of its neuroprotection and improvement of learning and memory remains unclear. We investigated the effectiveness and potential mechanisms of verbascoside on cognitive dysfunction in db/db mice using a 16S rRNA microbiome and serum metabolomics approach. We found that 12-week treatment with verbascoside significantly inhibited insulin resistance, reduced blood glucose and lipids, and improved cognitive deficits. In addition, verbascoside increased the gut microbiota diversity, improved intestinal dysbiosis, attenuated intestinal barrier disruption, reduced the levels of inflammatory factors, regulated the expression of the metabolites associated with cognitive function, and enhanced the central insulin sensitivity and hippocampal synaptogenesis signaling. We revealed that verbascoside induced the enrichment of Alistipes, Roseburia, and Intestinimonas in the gut, suppressed the abundance of Escherichia-Shigella, increased the serum levels of gamma-aminobutyric acid, L-glutamic acid, and L-lysine, and decreased taurine expression. Finally, a strong association between gut microbes, serum metabolites, and cognitive performance affected by verbascoside was observed. Our research suggests that alterations in gut microbes/metabolites are involved in the development of diabetic cognitive dysfunction, which is alleviated by verbascoside in the db/db mice through restructuring the gut microbiota composition, ameliorating diabetic metabolic disorders, and attenuating pathological brain damage.