Development Of Central Nervous System Disease Research Articles

Toxicology and Metabolic Effects of Methanol and Formaldehyde on the Brain, a ReviewA rticle

Background: Methanol is a toxic alcohol for the human body. The molecular biology of methanol metabolites affecting different organs, such as the brain, is under investigation. This systematic review aimed to consider methanol toxic molecular biology, based on the original articles obtained from data banks to figure out recent achievements. Methods: Scientific articles regarding the toxic effects and metabolites of methanol on the central nervous system (CNS) were collected from valid databases and classified based on their validity. Exclusion criteria were articles with duplicates, no available full text, review articles, case reports, and letters. Results: Current metabolic reactions were addressed in the development of CNS diseases, such as optic neuropathy, basal ganglia lesions, and Alzheimer’s disease. However, proteomic investigations introduced new metabolic changes, and serum proteins regarding blood coagulation, vitamin A metabolism, and immune responses were suggested for early detection of toxicity. Conclusion: Besides CNS disorders introduced for methanol toxicity, there is no exact proteomic serum marker to diagnose toxicity soon; however, the interleukin-1 beta system is suggested as a candidate, and more investigation is required to improve its competency.

The function of astrocytes and their role in neurological diseases.

Astrocytes have countless links with neurons. Previously, astrocytes were only considered a scaffold of neurons; in fact, astrocytes perform a variety of functions, including providing support for neuronal structures and energy metabolism, offering isolation and protection and influencing the formation, function and elimination of synapses. Because of these functions, astrocytes play an critical role in central nervous system (CNS) diseases. The regulation of the secretiory factors, receptors, channels and pathways of astrocytes can effectively inhibit the occurrence and development of CNS diseases, such as neuromyelitis optica (NMO), multiple sclerosis, Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease. The expression of aquaporin 4 in AS is directly related to NMO and indirectly involved in the clearance of Aβ and tau proteins in AD. Connexin 43 has a bidirectional effect on glutamate diffusion at different stages of stroke. Interestingly, astrocytes reduce the occurrence of PD through multiple effects such as secretion of related factors, mitochondrial autophagy and aquaporin 4. Therefore, this review is focused on the structure and function of astrocytes and the correlation between astrocytes and CNS diseases and drug treatment to explore the new functions of astrocytes with the astrocytes as the target. This, in turn, would provide a reference for the development of new drugs to protect neurons and promote the recovery of nerve function.

A curated diverse molecular database of blood-brain barrier permeability with chemical descriptors

The highly-selective blood-brain barrier (BBB) prevents neurotoxic substances in blood from crossing into the extracellular fluid of the central nervous system (CNS). As such, the BBB has a close relationship with CNS disease development and treatment, so predicting whether a substance crosses the BBB is a key task in lead discovery for CNS drugs. Machine learning (ML) is a promising strategy for predicting the BBB permeability, but existing studies have been limited by small datasets with limited chemical diversity. To mitigate this issue, we present a large benchmark dataset, B3DB, complied from 50 published resources and categorized based on experimental uncertainty. A subset of the molecules in B3DB has numerical log BB values (1058 compounds), while the whole dataset has categorical (BBB+ or BBB−) BBB permeability labels (7807). The dataset is freely available at https://github.com/theochem/B3DB and https://doi.org/10.6084/m9.figshare.15634230.v3 (version 3). We also provide some physicochemical properties of the molecules. By analyzing these properties, we can demonstrate some physiochemical similarities and differences between BBB+ and BBB− compounds.

Indoxyl sulfate caused behavioral abnormality and neurodegeneration in mice with unilateral nephrectomy.

Chronic Kidney Disease (CKD) and neurodegenerative diseases are aging-related diseases. CKD with declined renal function is associated with an elevation of circulating indoxyl sulfate, a metabolite synthesized by gut microbes. We explored the roles of gut microbial metabolites in linking with Central Nervous System (CNS) diseases by administrating indoxyl sulfate intraperitoneally to male C57BL/6 mice with unilateral nephrectomy. Upon exposure, the accumulation of indoxyl sulfate was noted in the blood, prefrontal cortical tissues, and cerebrospinal fluid. Mice showed behavioral signs of mood disorders and neurodegeneration such as anxiety, depression, and cognitive impairment. Those behavioral changes were accompanied by disturbed neuronal survival, neural stem cell activity, expression of Brain-Derived Neurotrophic Factor, serotonin, corticosterone, and Repressor Element-1 Silencing Transcription Factor, and post-receptor intracellular signaling, as well as upregulated oxidative stress and neuroinflammation. Uremic toxin adsorbent AST-120 improved the above mentioned changes. Intriguingly, intracerebroventricular indoxyl sulfate administration only caused limited alterations in the normal mice and the alterations were reversed by aryl hydrocarbon receptor antagonism. The findings suggest pathogenic roles of indoxyl sulfate in the development of CNS diseases, and highlight gut microbiota as alternative targets for intervention with the aim of slowing down the progression of CKD and decreasing CNS complications.

Central nervous system metastases in breast cancer: the impact of age on patterns of development and outcome.

The purpose of this study is to explore differences in the pattern and outcome of central nervous system (CNS) involvement in breast cancer by age at diagnosis. A retrospective database of a tertiary cancer center yielded 174 consecutive patients with breast cancer who were diagnosed with CNS metastases in 2006-2019. Data on histopathology, characteristics of CNS involvement, treatments, and survival (at three time points during the disease course) were compared between patients aged ≤ 45 and > 45years. Pearson Chi-square or Fisher exact test and Kaplan-Meier survival curves with log-rank test were used for statistical analyses. Study population was divided according to age at diagnosis of breast cancer. 65 patients were ≤ 45years old and 109 patients > 45years old. The younger group was characterized by longer median overall survival (117.1months vs 88months, p = 0.017) and longer interval between breast cancer diagnosis to development of CNS metastases (97.4months vs 75.9months, p = 0.026). Median survival after development of CNS disease was not significantly different (18.7months vs 11.1months, p = 0.341), although it was significantly longer in younger patients within the subgroup of patients with triple-negative disease (22.5 vs 7.9months, p = 0.033). There were no between-group differences in number, location, and clinical presentation of CNS metastases or in systemic and CNS-directed treatment approaches. While the presentation of CNS involvement was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival, and for the subgroups of triple-negative patients, younger age at breast cancer diagnosis was associated with longer survival after diagnosis of CNS disease.

The Gut-Microglia Connection: Implications for Central Nervous System Diseases

The importance of the gut microbiome in central nervous system (CNS) diseases has long been recognized; however, research into this connection is limited, in part, owing to a lack of convincing mechanisms because the brain is a distant target of the gut. Previous studies on the brain revealed that most of the CNS diseases affected by the gut microbiome are closely associated with microglial dysfunction. Microglia, the major CNS-resident macrophages, are crucial for the immune response of the CNS against infection and injury, as well as for brain development and function. However, the current understanding of the mechanisms controlling the maturation and function of microglia is obscure, especially regarding the extrinsic factors affecting microglial function during the developmental process. The gut microflora has been shown to significantly influence microglia from before birth until adulthood, and the metabolites generated by the microbiota regulate the inflammation response mediated by microglia in the CNS; this inspired our hypothesis that microglia act as a critical mediator between the gut microbiome and CNS diseases. Herein, we highlight and discuss current findings that show the influence of host microbiome, as a crucial extrinsic factor, on microglia within the CNS. In addition, we summarize the CNS diseases associated with both the host microbiome and microglia and explore the potential pathways by which the gut bacteria influence the pathogenesis of CNS diseases. Our work is thus a comprehensive theoretical foundation for studies on the gut-microglia connection in the development of CNS diseases; and provides great potential for researchers to target pathways associated with the gut-microglia connection and overcome CNS diseases.

A Functionally Defined In Vivo Astrocyte Population Identified by c-Fos Activation in a Mouse Model of Multiple Sclerosis Modulated by S1P Signaling: Immediate-Early Astrocytes (ieAstrocytes)

Astrocytes have prominent roles in central nervous system (CNS) function and disease, with subpopulations defined primarily by morphologies and molecular markers often determined in cell culture. Here, we identify an in vivo astrocyte subpopulation termed immediate-early astrocytes (ieAstrocytes) that is defined by functional c-Fos activation during CNS disease development. An unbiased screen for CNS cells showing c-Fos activation during experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (MS), was developed by using inducible, TetTag c-Fos reporter mice that label activated cells with a temporally stable, nuclear green fluorescent protein (GFP). Four-dimensional (3D over time) c-Fos activation maps in the spinal cord were produced by combining tissue clearing (iDISCO) and confocal microscopy that identified onset and expansion of GFP+ cell populations during EAE. More than 95% of the GFP+ cells showed glial fibrillary acidic protein (GFAP) immunoreactivity-in contrast to absent or rare labeling of neurons, microglia, and infiltrating immune cells-which constituted ieAstrocytes that linearly increased in number with progression of EAE. ieAstrocyte formation was reduced by either astrocyte-specific genetic removal of sphingosine 1-phosphate receptor 1 (S1P1) or pharmacological inhibition by fingolimod (FTY720), an FDA-approved MS medicine that can functionally antagonize S1P1. ieAstrocytes thus represent a functionally defined subset of disease-linked astrocytes that are the first and predominant CNS cell population activated during EAE, and that track with disease severity in vivo. Their reduction by a disease-modifying agent supports their therapeutic relevance to MS and potentially other neuroinflammatory and neurodegenerative diseases.

Macaque species susceptibility to simian immunodeficiency virus: increased incidence of SIV central nervous system disease in pigtailed macaques versus rhesus macaques.

Immune pressure exerted by MHC class I-restricted cytotoxic T cells drives the development of viral escape mutations, thereby regulating HIV disease progression. Nonetheless, the relationship between host immunity and HIV central nervous system (CNS) disease remains poorly understood. The simian immunodeficiency virus (SIV) macaque model recapitulates key features of HIV infection including development of AIDS and CNS disease. To investigate cell-mediated immunity regulating SIV CNS disease progression, we compared the incidence of SIV encephalitis and the influence of MHC class I allele expression on the development of CNS disease in rhesus macaques (Macaca mulatta) versus pigtailed macaques (Macaca nemestrina). After inoculation with the immunosuppressive swarm SIV/DeltaB670 and the neurovirulent molecular clone SIV/17E-Fr, pigtailed macaques progressed more rapidly to AIDS, had higher plasma and cerebrospinal fluid (CSF) viral loads, and were more likely to progress to SIV-associated encephalitis (SIVE) compared to rhesus macaques. In addition, MHC class I alleles were neuroprotective in both species (Mamu-A*001 in rhesus macaques and Mane-A1*084:01:01 in pigtailed macaques); animals expressing these alleles were less likely to develop SIV encephalitis and correspondingly had lower viral replication in the brain. Species-specific differences in susceptibility to SIV disease demonstrated that cell mediated immune responses are critical to SIV CNS disease progression.

Abstract P6-11-10: Central nervous system metastases in breast cancer: Impact of tumour sub-type and outcome from current treatments

Abstract Background: The use of more effective systemic therapies in the management of metastatic breast cancer has led to increased response rates, progression-free survival and overall survival. The incidence of central nervous system (CNS) metastases has become an increasingly important area of unmet need. It is important to identify tumour-related factors which may predict for CNS occurrence and assess the efficacy of treatments in current use. Methods: Consecutive patients (pts) with breast cancer (BC) seen at 2 institutions following establishment of breast cancer databases were included: January 2000 (institution A) and January 2003 (institution B) to December 2012. Patient demographic data, tumour pathology and systemic treatment given were reviewed in those patients who developed CNS metastases. Multivariate analysis of factors impacting on overall survival in this patient population will be performed. Results: Over the study period, 4751 pts with a median age of 52.7 yrs were seen, where 86.4% and 13.6% of pts presented with early and metastatic disease, respectively. In the entire population, 77% of tumours were hormone receptor positive, 21% HER2 positive, and 15% triple negative. Overall, 228 (4.8%) pts had CNS metastases with a median age of 48.9 yrs. CNS involvement was present at the time of first metastatic recurrence in 27% of pts who had CNS metastases. The proportion of pts developing CNS metastases according to tumour subtypes were: 48% hormone receptor positive, 36% Her2 positive, and 20% triple negative. Median time from diagnosis to development of CNS metastases (excluding pts with CNS involvement at the time of first metastatic disease) was 48.9 (4.7-248 months, m). The median time to development of CNS recurrence was 61m, 43m, 23m respectively, according to tumour subtype. CNS disease was parenchymal only, leptomeningeal only or both in 78%, 9%, 13% respectively. Pts who died from BC, had a median overall survival from initial BC diagnosis of 53.6m, whereas median overall survival from CNS metastases was 4.8 m. The impact of whole brain radiation with or without stereotactic therapy, surgical resection of brain metastases and type of systemic therapy administered following development of CNS disease on overall survival will be presented. Discussion: CNS metastases occurred in up to 5% of breast cancer pts seen at two large cancer centres. Despite improvements in overall survival of metastatic BC pts with the use of more effective systemic treatments, the prognosis following CNS involvement remains extremely poor. Until specific interventions are available to manage CNS metastases in pts with breast cancer, it remains important to assess outcomes from current standard treatment in these pts. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-10.

Abstract P6-11-12: CNS metastases in breast cancer: A comparison report

Abstract Background: Breast cancer is one of the most common causes of central nervous system (CNS) metastases, with 25-34% of patients experiencing brain metastases. Typically, CNS metastasis is associated with a dismal survival largely due to the inability of chemotherapeutic and biologic agents to cross the blood-brain barrier. In the last 5 to 7 years the management of CNS metastases utilizing targeted therapies, stereotactic radiation, and craniotomy have all shown to improve survival. We reviewed and analyzed data for CNS metastastic breast cancer treated at City of Hope (COH), a tertiary cancer center in California, in two cohorts between 2000-2005 and 2006-2011 to compare their survival. Methods/Results: A retrospective, comparative, correlational chart review was performed. Data from 172 women diagnosed with CNS metastases between 2000 and 2011 at COH, was evaluated. There were 47 patients in 2000-2005 and 125 patients in 2006-2011. The sample consisted of Caucasians (49.7%), Hispanics (26.1%), Asians (16.8%), and African Americans (7.4%). The median age at CNS diagnosis was 53 years old (24-87). Of these patients 38.2% were Her2neu positive, 30.6% ER/PR positive, and 21.4% triple negative (TN). In this cohort, the median survival for all patients with brain metastases is 5 months (0.03-85.6 months). The survival with brain metastasis among Her2neu positive, TN, and ER/PR positive is significantly different (8 months, 2.5 months, and, 5.3 months, respectively, p<0.0295). Limited sample size prevented the relatively substantial difference in patients with with Her2+ versus Her2- from reaching significance (median survival 8months vs 3.8 months respectively, p<0.0939). The median survival for patients diagnosed and treated in 2006-2011 is statistically significantly worse than those in 2000-20005 (4.4 months and 7 months, respectively, p = 0.0042). Most patients received treatment for brain metastases with one or more therapies, including whole brain radiation, stereotactic radiation, craniotomy, and intrathecal chemotherapy. Most of the patients who received chemotherapy, craniotomy, and/or stereotactic radiation were in the 2006-2011 group (100%, 82.5%, and 72.6%, respectively).There was also a shift in the incidence of patients with TN, her2neu positive, and ER/PR positive disease in the 2006-2011 as compared to 2000-2005 (24% vs 14.6%, p<0.004; 40% vs 31.3%, p<0.000; 31.2% vs 29.2%, p 0.033, respectively). Conclusion: The results of our study showed that despite the new therapies there was no change in survival for brain metastasis in breast cancer. In this single institution report, this may be in part due to an increase number of patients with TN and Her2neu positive CNS disease, better data collection, or due to better systemic control. We also noted an increase in the number of patients with brain metastases, which may be attributed to the increase in the number of patients presenting with metastatic breast cancer at COH for consideration of investigational therapies. Further studies aimed to determine why there is a shift in the tumor biology, as well as, to characterize risk factors for development of CNS disease and to develop new treatment strategies are warranted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-12.

HIV-associated central nervous system diseases in the recent combination antiretroviral therapy era

Data describing the incidence and survival of HIV-related central nervous system diseases (CNS-D) in recent years are sparse. Between 1996 and 2007, adult subjects without previous CNS-D within a large UK cohort were included (n=30,954). CNS-D were HIV encephalopathy (HIVe), progressive multifocal leucoencephalopathy (PML), cerebral toxoplasmosis (TOXO) and cryptococcal meningitis (CRYP). Associations between demographic, clinical and laboratory parameters with incidence and survival of CNS-D were evaluated using Poisson regression analysis and Kaplan-Meier techniques. Six hundred and thirteen new CNS-D occurred in 574 subjects (HIVe:187, PML:113, TOXO:184, CRYP:129). Incidence of all CNS-D declined from 13.1 per 1000 PY in 1996/1997 to 1.0 per 1000 PY in 2006/2007 (P=0.0001). Current CD4+ cell count below 200 cells/ul and plasma HIV RNA above 100,000 copies/ml were independently associated with the development of CNS-D. Calendar year 1996/1997, older age, prior AIDS diagnosis and PML diagnosis were significantly associated with shorter survival. An ongoing decline in the incidence of CNS-D has been observed in very recent years. Mortality following such a diagnosis remains high.

Brain-reactive lymphocytotoxic antibodies in the serum of patients with systemic lupus erythematosus.

Homogenized tissue from the frontal cortex of normal human brains obtained at postmortem examination was used to absorb lymphocytotoxic antibody from the serum of six patients with systemic lupus erythematosus (SLE). Four absorptions of all of the SLE sera with equal volumes of homogenized brain tissue at 4 degrees C depleted their cytotoxic capacity more than 90%. Three of the six sera, however, retained some lymphocytotoxicity despite extensive brain absorption. Absorbed lymphocytotoxic antibodies were eluted from brain tissue absorbents at 37 degrees C. Cytotoxicity of the brain eluates was blocked by antibodies to human IgM (mu-chain specific) but not anti-IgG. The unabsorbed SLE sera, brain-absorbed sera, and brain eluates were equally cytotoxic to T (thymus-derived) and B (bone marrow-derived) cells fractionated from normal human peripheral blood lymphocytes. Thus, the lymphocytotoxic antibodies in SLE serum exhibit no preference for circulating human T cells. An analysis of the clinical records of 40 patients with SLE whose serum cytotoxic capacity had been determined revealed that circulating lymphocytotoxicity is greater in sera of patients with central nervous system (CNS) manifestations than in other SLE patients. This observation suggests a possible role for brain-reactive lymphocytotoxic antibodies in the development of CNS disease in SLE.