Interaction between neurons and microglia in healthy and disease states.

Working memory (WM) is the ability to transiently maintain and manipulate internal representations beyond its external availability to the senses. This process is thought to support high level cognitive abilities and been shown to be strongly predictive of individual intelligence and reasoning abilities. While early models of WM have relied on a modular perspective of brain functioning, more recent evidence suggests that cognitive functions emerge from the interactions of multiple brain regions to generate large-scale networks. Here we will review the current research on functional connectivity of WM processes to highlight the critical role played by neural interactions in healthy and pathological brain states. Recent findings demonstrate that WM abilities are not determined solely by local brain activity, but also rely on the functional coupling of neocortical-hippocampal regions to support WM processes. Although the hippocampus has long been held to be important for long-term declarative memory, recent evidence suggests that the hippocampus may also be necessary to coordinate disparate cortical regions supporting the periodic reactivation of internal representations in WM. Furthermore, recent brain imaging studies using connectivity measures, have shown that changes in cortico-limbic interactions can be useful to characterize WM impairments observed in different neuropathological conditions. Recent advances in electrophysiological and neuroimaging techniques to model network activity has led to important insights into how neocortical and hippocampal regions support WM processes and how disruptions along this network can lead to the memory impairments commonly reported in many neuropathological populations.

Inflammation is a hallmark of different central nervous system (CNS) pathologies. It has been linked to neurodegenerative disorders as well as primary and metastatic brain tumors. Microglia, the brain-resident immune cells, are emerging as a central player in regulating key pathways in CNS inflammation. Recent insights into neuroinflammation indicate that blood-borne immune cells represent an additional critical cellular component in mediating CNS inflammation. The lack of experimental systems that allow for discrimination between brain-resident and recruited myeloid cells has previously halted functional analysis of microglia and their blood-borne counterparts in brain malignancies. However, recent conceptual and technological advances, such as the generation of lineage tracing models and the identification of cell type-specific markers provide unprecedented opportunities to study the cellular functions of microglia and macrophages by functional interference. The use of different “omic” strategies as well as imaging techniques has significantly increased our knowledge of disease-associated gene signatures and effector functions under pathological conditions. In this review, recent developments in evaluating functions of brain-resident and recruited myeloid cells in neurodegenerative disorders and brain cancers will be discussed and unique or shared cellular traits of microglia and macrophages in different CNS disorders will be highlighted. Insight from these studies will shape our understanding of disease- and cell-type-specific effector functions of microglia or macrophages and will open new avenues for therapeutic intervention that target aberrant functions of myeloid cells in CNS pathologies.

There is some controversy about the value of fetal MRI in prenatal diagnosis, and most of the studies examine its accuracy in central nervous system (CNS) pathology. The objective of this retrospective study was to assess the diagnostic accuracy and usefulness of fetal MRI in the prenatal diagnosis of central nervous system (CNS) pathology and non-CNS pathology. Patients referred to the Radiology Department between 2007 and 2018 for a fetal MRI after detection of an anomaly in the fetal ultrasound, a high-risk pregnancy, or an inconclusive fetal ultrasound (n = 623) were included in the study. Postnatal diagnosis was used to assess the diagnostic accuracy of MRI. Fetal MRI was considered to provide additional information over fetal ultrasound when findings of the fetal MRI were not detected in the fetal ultrasound or when established a pathological condition that was not detected in the fetal ultrasound. Fetal MRI provided useful information for the perinatal management and prognosis over fetal ultrasound when findings of the fetal MRI changed the postnatal prognosis, leaded to the decision to legally terminate the pregnancy, changed prenatal or postnatal follow-up, or helped in the planning of prenatal or postnatal treatment. Fetal MRI offered an accurate diagnosis in 97% of cases (compared to 90.4% of fetal ultrasound; p < 0.001). Concordance between fetal ultrasound and fetal MRI was 92.1%. Fetal MRI provided additional information over fetal ultrasound in 23.1% of cases. In 11.6% of cases, the information was useful for the perinatal management and prognosis. In 45 cases (7.2%), fetal MRI was the only accurate diagnosis. In conclusion, fetal MRI has a superior diagnostic accuracy, especially in CNS pathology, and provides additional useful information in CNS, thoracic, and abdominal pathology.

The aimof the investigation was to study neuropsychic manifestations (NPM) of systemic lupus erythematosus (SLE) in the Kyrgyz cohort of patients.Material and methods.The prospective study included 460 patients with a reliable diagnosis of SLE, verified according to the diagnostic criteria ACR (1997) and SLICC (2012), observed in the clinic of the Academician M. Mirrakhimov National Center of Cardiology and Therapy from january 2012 to december 2017. Signs of nervous system damage were revealed in 103 (22.39%) of 460 patients with SLE. Classification criteria of ACR (1999) were used to assess neuropsychic manifestations of SLE, which were diagnosed by the psychiatrist according to ICD-10. Cognitive disorders were detected by a psychologist using a specific test Mini-Mental State Examination (MMSE; mini-scheme study of the mental state of the patient).Results and discussion.Various signs of NPM SLE were revealed in 103 (22.39%) of 460 patients with SLE. Groups of patients with and without NPM SLE at the beginning of the study were comparable in age, time from the appearance of the first signs of SLE to the verification of the diagnosis and the value of the SLEDAI-2K index (p&gt;0.05). Acute variant of SLE course was significantly associated with NPM SLE. The acute course of SLE was observed in 56 (54.38%) of the 103 patients with NPM SLE and 109 (30.53%) of the 357 patients without NPM SLE [odds ratio (OR) 2.71, 95% confidence interval (CI) of 1.73–4.24; p&lt;0.001]. Subacute and chronic course of the disease was diagnosed in a similar number of patients with NPM SLE – 24 (23.30%) and without NSAIDS – 23 (23.33%) (OR 5.75 95% CI 3.54–9.34; p&lt;0.001). In the majority of patients the central nervous system (CNS) lesions prevailed. It was present in 71 (68.93%) patients, peripheral nervous system (PNS) pathology was less frequent and revealed in 32 (31.07%) of 103 cases, and 4 (3.88%) patients had combined CNS and PNS lesions. One manifestation of NPM SLE was detected in 37 (52.11%) patients, two – in 15 (21.13%), three – in 14 (19.72%) and four – in 5 (7.04%) of 71 patients with CNS lesions. According to the criteria of ACR (1999) in 103 patients 155 different NPM SLE were diagnosed: CNS disorders – in 123 (79.35%) and PNS pathology – in 32 (20.65%). The frequency of focal and diffuse CNS disorders was 61.79% and 38.21%, respectively. Cerebrovascular disease (CVD) was diagnosed most frequently – in 33 (43.42%) of the 76 cases of focal neuropsychiatric CNS disorders. Clinical manifestations of CVD were mainly characterized by discirculatory encephalopathy – in 30 (90.91%), less often – by ischemic stroke in the middle cerebral artery basin on the left – in 2 (6.06%) and transient ischemic attack – in 1 (3.03%) of 33 CVD cases. One manifestation was present in 52.11% of patients with CNS pathology. In other cases, there were more symptoms of its damage. Among the 47 diffuse lesions, neuropsychic disorders of the psychosis type prevailed, the main manifestations of which were visual and auditory hallucinations – in 34 (72.34%) patients.Conclusion.NPM SLE was identified in 22.39% of patients. Acute variant of SLE and very high activity was associated with NPM SLE. The risk of NPM SLE developing in very high activity of SLE was increased by 5.75 times. In the vast majority of cases in Kyrgyz patients there was CNS involvement (68.93%), twice less – PNS damage (31.07%), combined lesion of PNS and CNS was noted less frequently (3.88%). 47.89% of patients had more than one manifestation of NPM SLE. In most patients with diffuse NPM SLE, psychosis was observed in the form of visual and auditory hallucinations (72.34%), and focal ones were presented by CVD (43.42%), usually in the form of discirculatory encephalopathy (90.91%).

BackgroundThe role of the extracranial venous system in the pathology of central nervous system (CNS) disorders and aging is largely unknown. It is acknowledged that the development of the venous system is subject to many variations and that these variations do not necessarily represent pathological findings. The idea has been changing with regards to the extracranial venous system.DiscussionA range of extracranial venous abnormalities have recently been reported, which could be classified as structural/morphological, hemodynamic/functional and those determined only by the composite criteria and use of multimodal imaging. The presence of these abnormalities usually disrupts normal blood flow and is associated with the development of prominent collateral circulation. The etiology of these abnormalities may be related to embryologic developmental arrest, aging or other comorbidities. Several CNS disorders have been linked to the presence and severity of jugular venous reflux. Another composite criteria-based vascular condition named chronic cerebrospinal venous insufficiency (CCSVI) was recently introduced. CCSVI is characterized by abnormalities of the main extracranial cerebrospinal venous outflow routes that may interfere with normal venous outflow.SummaryAdditional research is needed to better define the role of the extracranial venous system in relation to CNS disorders and aging. The use of endovascular treatment for the correction of these extracranial venous abnormalities should be discouraged, until potential benefit is demonstrated in properly-designed, blinded, randomized and controlled clinical trials.Please see related editorial: http://www.biomedcentral.com/1741-7015/11/259.

ABSTRACTIntroduction: Adverse immune activation contributes to many central nervous system (CNS) disorders. All main CNS cell types express toll-like receptor 4 (TLR 4). This receptor is critical for a myriad of immune functions such as cytokine secretion and phagocytic activity of microglia; however, imbalances in TLR 4 activation can contribute to the progression of neurodegenerative diseases.Areas covered: We considered available evidence implicating TLR 4 activation in the following CNS pathologies: Alzheimer’s disease, Parkinson’s disease, ischemic stroke, traumatic brain injury, multiple sclerosis, multiple systems atrophy, and Huntington’s disease. We reviewed studies reporting effects of TLR 4-specific antagonists and agonists in models of peripheral and CNS diseases from the perspective of possible future use of TLR 4 ligands in CNS disorders.Expert opinion: TLR 4-specific antagonists could suppress neuroinflammation by reducing overproduction of inflammatory mediators; however, they may interfere with protein clearance mechanisms and myelination. Agonists that specifically activate myeloid differentiation primary-response protein 88 (MyD88)-independent pathway of TLR 4 signaling could facilitate beneficial glial phagocytic activity with limited activity as inducers of proinflammatory mediators. Deciphering the disease stage-specific involvement of TLR 4 in CNS pathologies is crucial for the future clinical development of TLR 4 agonists and antagonists.

The pharmacokinetic parameters, safety, and tolerability of OptiMARK (gadoversetamide injection), a gadolinium-based magnetic resonance imaging (MRI) contrast agent, were evaluated in 163 subjects with either central nervous system (CNS) or liver pathology with and without renal insufficiency, for which a contrast-enhanced MRI was indicated. A multicenter, double-blind, randomized, placebo-controlled, parallel-group design was used in which subjects received 0.1, 0.3, or 0.5 mmol/kg of OptiMARK or placebo intravenously. Samples were analyzed for total gadolinium by inductively coupled plasma/mass spectrometry. Gadolinium pharmacokinetics were affected by renal impairment: area under the curve, half-life, and steady-state distribution volume significantly increased with declining renal function, while total body clearance decreased. In subjects with normal renal function, neither age, gender, nor liver versus CNS pathology altered gadolinium pharmacokinetics. No clinically significant changes from baseline were noted in vital signs, laboratory measures, electrocardiograms, or physical examinations. OptiMARK is safe and well-tolerated following a single intravenous injection in subjects with either liver or CNS pathology despite a prolonged elimination half-life in subjects with renal impairment.

Alpha-mannosidosis (AM) (OMIM 248500) is a rare lysosomal storage disease. The understanding of the central nervous system (CNS) pathology is limited. This study is the first describing the CNS pathology and the correlation between the CNS pathology and intellectual disabilities in human AM. Thirty-four patients, aged 6-35 years, with AM were included. Data from 13 healthy controls were included in the analysis of the magnetic resonance spectroscopy (MRS). Measurements of CNS neurodegeneration biomarkers in cerebrospinal fluid (CSF), CSF-oligosaccharides, and performance of cerebral magnetic resonance imaging (MRI) and MRS were carried out. On MRI, 5 of 10 patients had occipital white matter (WM) signal abnormalities, and 6 of 10 patients had age-inappropriate myelination. MRS demonstrated significantly elevated mannose complex in gray matter and WM. We found elevated concentrations of tau-protein, glial fibrillary acidic protein and neurofilament light protein in 97 patients, 74% and 41% of CSF samples, respectively. A negative correlation between CSF-biomarkers and cognitive function and CSF-oligosaccharides and cognitive function was found. The combination of MRS/MRI changes, elevated concentrations of CSF-biomarkers and CSF-oligosaccharides suggests gliosis and reduced myelination, as part of the CNS pathology in AM. Our data demonstrate early neuropathological changes, which may be taken into consideration when planning initiation of treatment.

The extracranial venous system is complex and variable between individuals. Until recently, these variations were acknowledged as developmental variants and were not considered pathological findings. However, in the last decade, the presence and severity of uni- or bi-lateral jugular venous reflux (JVR) was linked to several central nervous system (CNS) disorders such as transient global amnesia, transient monocular blindness, cough headache, primary exertional headache and, most recently, to Alzheimer's disease. The most recent introduction of a composite criteria-based vascular condition named chronic cerebrospinal venous insufficiency (CCSVI), which was originally linked to multiple sclerosis, increased the interest in better understanding the role of the extracranial venous system in the pathophysiology of CNS disorders. The ultimate cause-consequence relationship between these conditions and CNS disorders has not been firmly established and further research is needed. The purpose of this article collection in BMC Medicine and BMC Neurology is to synthesize current concepts and most recent findings concerning the evaluation, etiology, pathophysiology and clinical relevance of the potential involvement of the extracranial venous system in the pathology of multiple CNS disorders and in aging.Please see related debate: http://www.biomedcentral.com/1741-7015/11/260.

The medicolegal autopsy is part of a death investigation that determines the cause and manner of death and the extent of the testing performed is variable and is directed by the specifics of a particular case. Published studies disagree on the value of routine examination of microscopic sections of internal organs in forensic cases and no studies have specifically reviewed the utility of routine neuropathology microscopic sections. We reviewed the Miami-Dade County Medical Examiner Department and Mayo Clinic computer databases to determine whether routine brain histology is of value in medicolegal autopsies and the impact on the cause and manner of death. Consecutive cases from each institution were analyzed to determine whether the microscopic neuropathological findings revealed a previously unrecognized disease, changed the cause or manner of death, or significantly impacted the death investigation. In the cases in which the immediate cause of death was attributable to central nervous system (CNS) pathology, the cause of death was readily apparent from the gross brain examination. If CNS pathology was the proximate cause of death, contributed significantly to the death, or was a significant part of the death investigation, full appreciation of the neuropathology required microscopic examination and often additional special/immunostains. We conclude that microscopic brain examination is needed in selected medicolegal autopsies to exclude and/or diagnose underlying disease processes, particularly if the gross examination doesn't reveal an obvious explanation of the CNS pathology or the clinical history suggests underlying neuropathology.

Astrogliosis, a cellular reaction with specific structural and functional characteristics, represents a remarkably homotypic response of astrocytes to all kinds of central nervous system (CNS) pathologies. Astrocytes play diverse functions in the brain, both harmful and beneficial. Mounting evidence indicates that astrogliosis is an underlying component of a diverse range of diseases and associated neuropathologies. The mechanisms that lead to astrogliosis are not fully understood, nevertheless, damaged neurons have long been reported to induce astrogliosis and astrogliosis has been used as an index for underlying neuronal damage. As the predominant source of proinflammatory factors in the CNS, microglia are readily activated under certain pathological conditions. An increasing body of evidence suggests that release of cytokines and other soluble products by activated microglia can significantly influence the subsequent development of astrogliosis and scar formation in CNS. It is well known that damaged neurons activate microglia very quickly, therefore, it is possible that activated microglia contribute factors/mediators through which damaged neuron induce astrogliosis. The hypothesis that activated microglia initiate and maintain astrogliosis suggests that suppression of microglial overactivation might effectively attenuate reactive astrogliosis. Development of targeted anti-microglial activation therapies might slow or halt the progression of astrogliosis and, therefore, help achieve a more beneficial environment in various CNS pathologies.

Electrocardiographic (ECG) abnormalities, as well as rhythm changes associated with the central nervous system (CNS) pathology, have been known for decades. They have been reported commonly in patients with subarachnoid and intracerebral haemorrhages, but also in a variety of other CNS disorders such as CNS infections, tumours, traumas and neurosurgical procedures. An elevated intracranial pressure has also been suggested as a potential cause of neurogenic ECG abnormalities. However, it is interesting that there is still no published data describing ECG changes in patients with hypertensive encephalopathy. We report the case of a 9 year-old boy presenting with loss of consciousness, systemic arterial hypertension, and generalised seizures. A 12-lead ECG obtained at admission revealed sinus bradycardia and non-specific ECG repolarisation changes, together with markedly prolonged QTc interval (QTc of 0.60 s) (Fig. 1). Since the cerebrogenic ECG changes due to hypertensive encephalopathy had not previously been described, a reasonable doubt that a child could have a primary myocardial electric (a likely aetiology or comorbid condition for this patient’s presentation) made us unable to make a correct initial diagnosis. After the definitive diagnosis of hypertensive encephalopathy had been established in the next few hours (Fig. 2), the actual aetiology of such ECG changes was revealed to us. Serial ECG tracings over the next few days, eventually becoming normal on the 5th day of hospitalisation (Fig. 3), finally ruled out primary long QT syndrome as a possible pathologic condition in our patient, and pointed to a ‘cerebrogenic’ origin of the noted electrophysiological changes. It is possible that these could have been responsible (prolongation of QT interval and possible cerebrogenic cardiac arrhythmias) for the loss of consciousness and convulsions in our patient. Although increased intracranial pressure might potentially explain sinus bradycardia, systemic hypertension as well as cardiac repolarisation changes in our patient, computed tomography scan of a head showing ischaemic brain damage in left occipitally cortico-subcortical region, strongly supported a different etiopathogenesis for such ECG alterations. This is coincident with the results of a few studies showing that the incidence of ECG abnormalities in patients with sub arachnoid haemorrhage or brain tumours does not increase noticeably in a group of patients with elevated intracranial pressure, compared to those patients without elevated intracranial pressure. Since a primary or secondary prolonged QT interval is frequently considered as a major risk determinant for cardiac arrhythmias and mortality, it is of great importance to clarify the real aetiology of similar ECG changes as a potential differential diagnostic clue and clinical hallmarks in all children suspected of having CNS disorder. Our case highlights the importance of interpreting changes in the ECG as a potential differential diagnostic clinical tool in all children suspected of having CNS disorder. To the best of our knowledge, a similar clinical presentation has not been described before in the literature.

Synaptosome microRNAs: emerging synapse players in aging and Alzheimer’s disease

Lipocalin-2, a neutrophil gelatinase-associated lipocalin, is a 25-kDa secreted protein implicated in a broad range of inflammatory diseases affecting the brain and periphery. It is a pleotropic protein expressed by various immune and nonimmune cells throughout the body. Importantly, the surge in lipocalin-2 levels in disease states has been associated with a myriad of undesirable effects, further exacerbating the ongoing pathological processes. In the brain, glial cells are the principal source of lipocalin-2, which plays a definitive role in determining their functional phenotypes. In different central nervous system pathologies, an increased expression of glial lipocalin-2 has been linked to neurotoxicity. Lipocalin-2 mediates a crosstalk between central and peripheral immune cells under neuroinflammatory conditions. One intriguing aspect is that elevated lipocalin-2 levels in peripheral disorders, such as cancer, metabolic conditions, and liver diseases, potentially incite an inflammatory activation of glial cells while disrupting neuronal functions. This review comprehensively summarizes the influence of lipocalin-2 on the exacerbation of neuroinflammation by regulating various cellular processes. Additionally, this review explores lipocalin-2 as a mediator of neuroimmune crosstalk in various central nervous system pathologies and highlights the role of lipocalin-2 in carrying inflammatory signals along the neuroimmune axis.

Systemic infection and/or inflammation has been related with an increased risk of brain abscesses, cerebrovascular disease, cognitive impairment and other pathological states of the brain. Therefore, it is plausible, that a chronic infection and inflammation disease, such as periodontitis, may affect the central nervous system (CNS). Chronic periodontal disease is a condition that causes breakdown of the supporting tissues of the teeth, alveolar bone and soft tissues. Chronic periodontitis is a multifactorial disease caused by dental plaque composed of pathogenic bacteria that triggers the immune response in susceptible hosts. Oral pathogenic bacteria is a source of chronic infection that can induce local and peripheral production of pro-inflammatory cytokines such as IL-1s, IL-6 and TNF- , inflammatory mediators, as well as bacterial products such as lipopolysaccaride endotoxin. Viruses, such as herpes and Epstein-Barr, can also be found in periodontal pockets. It is well established that oral pathogenic microorganisms may cause systemic infection by transient or persistent bacteremia, disseminating within the body, and infiltrate distal sites and organs. It has been proposed that in vulnerable populations and under certain circumstances, bacterial and viral infections may enter the brain from the bloodstream. Once in the brain, infectious pathogens and inflammatory products may compromise vascular integrity. Thus, the potential role of the pathogenesis of chronic periodontitis in the development and progression of cerebral infection and inflammation can have a link. There is no direct evidence that determines whether oral diseases have a causal association with CNS pathologies, nonetheless there are several reports that have found oral periodontal pathogens lodged in the brain. Both inflammatory states may just share a casual connection with common risk factors and complex multifactorial etiologies. However, the possibility that pathogenic oral microorganisms disseminate to the bloodstream and reach the brain, initiating or exacerbating existing cerebral lesions, cannot be disregarded. In addition, not only periodontal pathogens may be involved in invading the brain, but also, the pro-inflammatory factors induced systemically by periodontitis, may play a role in CNS pathologies. This oral systemic link will be discussed in this paper.