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CitationGPTRetr200

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Abstract of the paper: Sphingosine 1-phosphate (S1P), a lysophospholipid, has gained relevance to multiple sclerosis through the discovery of FTY720 (fingolimod), recently approved as an oral treatment for relapsing forms of multiple sclerosis. Its mechanism of action is thought to be immunological through an active phosphorylated metabolite, FTY720-P, that resembles S1P and alters lymphocyte trafficking through receptor subtype S1P(1). However, previously reported expression and in vitro studies of S1P receptors suggested that direct CNS effects of FTY720 might theoretically occur through receptor modulation on neurons and glia. To identify CNS cells functionally contributing to FTY720 activity, genetic approaches were combined with cellular and molecular analyses. These studies relied on the functional assessment, based on clinical score, of conditional null mouse mutants lacking S1P(1) in CNS cell lineages and challenged by experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. All conditional null mutants displayed WT lymphocyte trafficking that responded normally to FTY720. In marked contrast, EAE was attenuated and FTY720 efficacy was lost in CNS mutants lacking S1P(1) on GFAP-expressing astrocytes but not on neurons. In situ hybridization studies confirmed that astrocyte loss of S1P(1) was the key alteration in functionally affected mutants. Reductions in EAE clinical scores were paralleled by reductions in demyelination, axonal loss, and astrogliosis. Receptor rescue and pharmacological experiments supported the loss of S1P(1) on astrocytes through functional antagonism by FTY720-P as a primary FTY720 mechanism. These data identify nonimmunological CNS mechanisms of FTY720 efficacy and implicate S1P signaling pathways within the CNS as targets for multiple sclerosis therapies.

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CitationGPTRetr201

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: Sphingosine-1-Phosphate Receptors in the Central Nervous and Immune Systems. Abstract of the paper: Sphingosine-1-phosphate receptor (S1PR) modulators have entered clinical practice as immune-modulators for the treatment of multiple sclerosis (MS). Pharmacologic modulation of S1PR expression on lymphocytes inhibits these cells capacity to respond to the S1P gradient within regional lymph nodes (LNs) (and thymus) that promotes their exit into peripheral circulation. The resultant peripheral blood restricted lymphopenia is considered to underlie the capacity of S1PR modulators to reduce new inflammatory lesion formation in MS in the absence of global immune suppression. These modulators also regulate entry of selective lymphocyte populations and dendritic cells (DCs) into LNs and modulate sphingosine-1-phosphate (S1P) cell signaling networks that govern the generation of specific cell subsets within LNs. S1PR modulators that access the CNS can also have functional effects within this compartment since S1PRs are expressed by cells comprising the blood brain barrier (BBB) and by those within the parenchyma, including neurons, astrocytes, oligodendrocytes and microglia. Absence of S1P1 receptor (S1PR1) on astrocytes reduces disease severity in experimental autoimmune encephalomyelitis (EAE). Even under conditions that inhibit cell responses to the natural ligand, S1PR modulators can continue to induce active signaling responses; such responses may be relevant for promoting neuroprotection and augmenting tissue repair within the CNS.

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CitationGPTRetr202

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: The immune modulator FTY720 targets sphingosine 1-phosphate receptors. Abstract of the paper: Immunosuppressant drugs such as cyclosporin have allowed widespread organ transplantation, but their utility remains limited by toxicities, and they are ineffective in chronic management of autoimmune diseases such as multiple sclerosis. In contrast, the immune modulating drug FTY720 is efficacious in a variety of transplant and autoimmune models without inducing a generalized immunosuppressed state and is effective in human kidney transplantation. FTY720 elicits a lymphopenia resulting from a reversible redistribution of lymphocytes from circulation to secondary lymphoid tissues by unknown mechanisms. Using FTY720 and several analogs, we show now that FTY720 is phosphorylated by sphingosine kinase; the phosphorylated compound is a potent agonist at four sphingosine 1-phosphate receptors and represents the therapeutic principle in a rodent model of multiple sclerosis. Our results suggest that FTY720, after phosphorylation, acts through sphingosine 1-phosphate signaling pathways to modulate chemotactic responses and lymphocyte trafficking.

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CitationGPTRetr203

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Abstract of the paper: Blood lymphocyte numbers, essential for the development of efficient immune responses, are maintained by recirculation through secondary lymphoid organs. We show that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolite of the immunosuppressive agent FTY720. Both species were high-affinity agonists of at least four of the five S1P receptors. These agonists produce lymphopenia in blood and thoracic duct lymph by sequestration of lymphocytes in lymph nodes, but not spleen. S1P receptor agonists induced emptying of lymphoid sinuses by retention of lymphocytes on the abluminal side of sinus-lining endothelium and inhibition of egress into lymph. Inhibition of lymphocyte recirculation by activation of S1P receptors may result in therapeutically useful immunosuppression.

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CitationGPTRetr204

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: Fingolimod phosphate promotes the neuroprotective effects of microglia. Abstract of the paper: Fingolimod phosphate (FTY720) is a sphingosine 1-phosphate (S1P) receptor agonist that is being used as a new oral drug for multiple sclerosis. FTY720 prevents lymphocytes from moving out of the lymphoid organs and inhibits autoreactive lymphocytes from infiltrating the central nervous system. Whether FTY720 directly affects microglia-the innate immune cells of the central nervous system-is unclear. Here we show that FTY720 binds S1P1 receptors to downregulate activated microglial production of such pro-inflammatory cytokines as tumor necrosis factor-α, interleukin-1β, and interleukin-6. FTY720 also upregulates microglial production of brain-derived neurotrophic factor and glial cell-derived neurotrophic factor. These results suggested that FTY720 directly promotes the neuroprotective effects of microglia. Therefore, FTY720 may be a potent therapeutic agent for not only multiple sclerosis but also other neurologic diseases associated with microglial activation.

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CitationGPTRetr205

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: Brain sphingosine-1-phosphate receptors: implication for FTY720 in the treatment of multiple sclerosis. Abstract of the paper: Multiple sclerosis (MS) is an autoimmune, neurological disability with unknown etiology. The current therapies available for MS work by an immunomodulatory action, preventing T-cell- and macrophage-mediated destruction of brain-resident oligodendrocytes and axonal loss. Recently, FTY720 (fingolimod) was shown to significantly reduce relapse rates in MS patients and is currently in Phase III clinical trials. This drug attenuates trafficking of harmful T cells entering the brain by regulating sphingosine-1-phosphate (S1P) receptors. Here, we outline the direct roles that S1P receptors play in the central nervous system (CNS) and discuss additional modalities by which FTY720 may provide direct neuroprotection in MS.

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CitationGPTRetr206

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Abstract of the paper: Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfill two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.

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CitationGPTRetr207

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy. Abstract of the paper: Alzheimer's disease (AD) is the most prevalent cause of dementia1. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy2,3. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain4, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aβ by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.

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CitationGPTRetr208

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: S1P1 receptor subtype inhibits demyelination and regulates chemokine release in cerebellar slice cultures. Abstract of the paper: Sphingosine-1-phosphate receptors (S1PRs) are drug targets for the compound FTY720, which is the first oral therapy developed for treatment of relapsing-remitting multiple sclerosis. S1PRs play a variety of functional roles in the differentiation, proliferation, survival and/or migration of neurons and glia. In this study, rat organotypic cerebellar slice cultures were used to assess whether S1PRs play a role in demyelination induced by lysolecithin (LPC). The data demonstrated that FTY720 and SEW2871 (a S1P1R-specific agonist) inhibited LPC-induced demyelination as assessed by myelin basic protein (MBP) immunofluorescence. Treatment with both drugs for 48 h also induced an increase in S1P1R expression in astrocytes. Moreover, FTY720 and SEW2871 inhibited the release of several chemokines in conditions of LPC-induced demyelination, including LIX (CXCL5), MIP-1alpha, and MIP-3alpha. Taken together, the data suggest that activation of S1P1Rs prevents LPC-induced demyelination via a mechanism involving a reduction of chemotactic chemokine release. The study supports the concept that FTY720 attenuates demyelination by not only preventing S1PR-mediated T cell migration into the CNS but also by limiting cytokine communication between cells of the immune system and the CNS.

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CitationGPTRetr209

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Abstract of the paper: Sphingolipids are a class of biologically active lipids that have a role in multiple biological processes including inflammation. Sphingolipids exert their functions by direct signaling or through signaling by their specific receptors. Phosphorylated FTY720 (FTY720P) is a sphingosine 1-phosphate (S1P) analogue that is currently in trial for treatment of multiple sclerosis (MS), which targets all S1P receptors but S1P(2). To date, however, it remains unknown whether FTY720P may exert direct anti-inflammatory effects within the central nervous system (CNS), because data concerning S1P receptor expression and regulation under pathological conditions in the human brain are lacking. To investigate potential regulation of S1P receptors in the human brain during MS, we performed immunohistochemical analysis of S1P receptor 1 and 3 expression in well-characterized MS lesions. A strong increase in S1P receptor 1 and 3 expression on reactive astrocytes was detected in active and chronic inactive MS lesions. In addition, we treated primary cultures of human astrocytes with the proinflammatory cytokine tumor necrosis factor-alpha to identify the regulation of S1P(1/3) on astrocytes under pathological conditions. Importantly, we demonstrate that FTY720P exerts an anti-inflammatory action on human astrocytes by limiting secretion of proinflammatory cytokines. Our data demonstrate that reactive astrocytes in MS lesions and cultured under proinflammatory conditions strongly enhance expression of S1P receptors 1 and 3. Results from this study indicate that astrocytes may act as a yet-unknown target within the CNS for the anti-inflammatory effects observed after FTY720P administration in the treatment of MS.

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CitationGPTRetr210

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: Sphingosine 1-phosphate receptors regulate TLR4-induced CXCL5 release from astrocytes and microglia. Abstract of the paper: Sphingosine 1-phosphate receptors (S1PR) are G protein-coupled and compose a family with five subtypes, S1P1R-S1P5R. The drug Gilenya® (Novartis, Basel, Switzerland) (Fingolimod; FTY720) targets S1PRs and was the first oral therapy for patients with relapsing-remitting multiple sclerosis (MS). The phosphorylated form of FTY720 (pFTY720) binds S1PRs causing initial agonism, then subsequent receptor internalization and functional antagonism. Internalization of S1P1R attenuates sphingosine 1-phosphate (S1P)-mediated egress of lymphocytes from lymph nodes, limiting aberrant immune function in MS. pFTY720 also exerts direct actions on neurons and glial cells which express S1PRs. In this study, we investigated the regulation of pro-inflammatory chemokine release by S1PRs in enriched astrocytes and microglial cultures. Astrocytes and microglia were stimulated with lipopolysaccharide (LPS) and increases in C-X-C motif chemokine 5 (CXCL5), also known as LIX (lipopolysaccharide-induced CXC chemokine) expression were quantified. Results showed that pFTY720 attenuated LPS-induced CXCL5 (LIX) protein release from astrocytes, as did the S1P1R selective agonist, SEW2871. In addition, pFTY720 blocked messenger ribonucleic acid (mRNA) transcription of the chemokines, (i) CXCL5/LIX, (ii) C-X-C motif chemokine 10 (CXCL10) also known as interferon gamma-induced protein 10 (IP10) and (iii) chemokine (C-C motif) ligand 2 (CCL2) also known as monocyte chemoattractant protein 1 (MCP1). Interestingly, inhibition of sphingosine kinase attenuated LPS-induced increases in mRNA levels of all three chemokines, suggesting that LPS-TLR4 (Toll-like receptor 4) signalling may enhance chemokine expression via S1P-S1PR transactivation. Lastly, these observations were not limited to astrocytes since we also found that pFTY720 attenuated LPS-induced release of CXCL5 from microglia. These data highlight a role for S1PR signalling in regulating the levels of chemokines in glial cells and support the notion that pFTY720 efficacy in multiple sclerosis may involve the direct modulation of astrocytes and microglia.

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CitationGPTRetr211

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Abstract of the paper: Fingolimod (FTY720) is a first-in-class orally bioavailable compound that has shown efficacy in advanced clinical trials for the treatment of multiple sclerosis (MS). In vivo, fingolimod is phosphorylated to form fingolimod-phosphate, which resembles naturally occurring sphingosine 1-phosphate (S1P), an extracellular lipid mediator whose major effects are mediated by cognate G protein-coupled receptors. There are at least 5 S1P receptor subtypes, known as S1P subtypes 1-5 (S1P1-5), 4 of which bind fingolimod-phosphate. These receptors are expressed on a wide range of cells that are involved in many biological processes relevant to MS. S1P1 plays a key role in the immune system, regulating lymphocyte egress from lymphoid tissues into the circulation. Fingolimod-phosphate initially activates lymphocyte S1P1 via high-affinity receptor binding yet subsequently induces S1P1 down-regulation that prevents lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the central nervous system (CNS). S1P receptors are also expressed by many CNS cell types and have been shown to influence cell proliferation, morphology, and migration. Fingolimod crosses the blood-brain barrier and may therefore have direct CNS effects, distinguishing it from immunologically targeted MS therapies. Prophylactic administration of fingolimod to animals with experimental autoimmune encephalitis (EAE), a model of MS, completely prevents development of EAE features, whereas therapeutic administration significantly reduces clinical severity of EAE. Therapeutic efficacy observed in animal studies has been substantiated in phase 2 and 3 trials involving patients with relapsing or relapsing-remitting MS.

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CitationGPTRetr212

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: Meningeal lymphatics clear erythrocytes that arise from subarachnoid hemorrhage. Abstract of the paper: Extravasated erythrocytes in cerebrospinal fluid (CSF) critically contribute to the pathogenesis of subarachnoid hemorrhage (SAH). Meningeal lymphatics have been reported to drain macromolecules and immune cells from CSF into cervical lymph nodes (CLNs). However, whether meningeal lymphatics are involved in clearing extravasated erythrocytes in CSF after SAH remains unclear. Here we show that a markedly higher number of erythrocytes are accumulated in the lymphatics of CLNs and meningeal lymphatics after SAH. When the meningeal lymphatics are depleted in a mouse model of SAH, the degree of erythrocyte aggregation in CLNs is significantly lower, while the associated neuroinflammation and the neurologic deficits are dramatically exacerbated. In addition, during SAH lymph flow is increased but without significant lymphangiogenesis and lymphangiectasia. Taken together, this work demonstrates that the meningeal lymphatics drain extravasated erythrocytes from CSF into CLNs after SAH, while suggesting that modulating this draining may offer therapeutic approaches to alleviate SAH severity.

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CitationGPTRetr213

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Abstract of the paper: Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that is critically involved in the embryonic development of the cardiovascular and central nervous systems. In the adult, S1P can produce cytoskeletal re-arrangements in many cell types to regulate immune cell trafficking, vascular homeostasis and cell communication in the central nervous system. S1P is contained in body fluids and tissues at different concentrations, and excessive production of the pleiotropic mediator at inflammatory sites may participate in various pathological conditions. Gene deletion studies and reverse pharmacology (techniques aiming to identify both ligands and function of receptors) provided evidence that many effects of S1P are mediated via five G-protein-coupled S1P receptor subtypes, and novel therapeutic strategies based on interaction with these receptors are being initiated. The prototype S1P receptor modulator, FTY720 (fingolimod), targets four of the five S1P receptor subtypes and may act at several levels to modulate lymphocyte trafficking via lymphocytic and endothelial S1P1 and, perhaps, other inflammatory processes through additional S1P receptor subtypes. A recently completed Phase II clinical trial suggested that the drug may provide an effective treatment of relapsing-remitting multiple sclerosis. FTY720 is currently being evaluated in larger-scale, longer-term, Phase III studies. This review provides an overview on S1P activities and S1P receptor function in health and disease, and summarizes the clinical experience with FTY720 in transplantation and multiple sclerosis.

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CitationGPTRetr214

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: Sphingosine 1-phosphate (S1P): Physiology and the effects of S1P receptor modulation. Abstract of the paper: Sphingosine 1-phosphate (S1P) and 5 specific high-affinity S1P receptor (S1PR) subtypes, S1P(1-5), have important regulatory functions in normal physiology and disease processes, particularly involving the immune, central nervous, and cardiovascular systems. Within the immune system, downmodulation of S1P(1) prevents the egress of B and T cells from lymph nodes (LN) into the lymphatic circulation. This is especially relevant in certain autoimmune diseases, including multiple sclerosis (MS), in which demyelination and brain atrophy occur due to the presence of autoreactive lymphocytes within the CNS. Accordingly, S1P(1)-directed pharmacologic interventions that aim to retain these autoreactive lymphocytes in the LN and thus prevent their recirculation and subsequent infiltration into the CNS have been investigated as a means of preventing disease progression in patients with MS. Fingolimod (FTY720), a structural analog of sphingosine, is phosphorylated in vivo into fingolimod phosphate by sphingosine kinase-2. Fingolimod phosphate, which binds to S1PRs, has been shown to modulate the activity of S1P(1) in patients with MS and to reduce immune cell infiltration into the CNS, consistent with its previously established effects in animal models of the disease. Preclinical studies also suggest that fingolimod has beneficial effects within the CNS that are independent of its immune cell trafficking activity. This review highlights the normal physiologic processes modulated by S1P and S1PRs, and the therapeutic effects of S1PR modulation in the immune, central nervous, and cardiovascular systems.

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CitationGPTRetr215

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: Sphingosine-1-Phosphate (S1P) and S1P Signaling Pathway: Therapeutic Targets in Autoimmunity and Inflammation. Abstract of the paper: Sphingosine-1-phosphate (S1P) and S1P receptors (S1PR) are ubiquitously expressed. S1P-S1PR signaling has been well characterized in immune trafficking and activation in innate and adaptive immune systems. However, the full extent of its involvement in the pathogenesis of autoimmune diseases is not well understood. FTY720 (fingolimod), a non-selective S1PR modulator, significantly decreased annualized relapse rates in relapsing-remitting multiple sclerosis (MS). FTY720, which primarily targets S1P receptor 1 as a functional antagonist, arrests lymphocyte egress from secondary lymphoid tissues and reduces neuroinflammation in the central nervous system (CNS). Recent studies suggest that FTY720 also decreases astrogliosis and promotes oligodendrocyte differentiation within the CNS and may have therapeutic benefit to prevent brain atrophy. Since S1P signaling is involved in multiple immune functions, therapies targeting S1P axis may be applicable to treat autoimmune diseases other than MS. Currently, over a dozen selective S1PR and S1P pathway modulators with potentially superior therapeutic efficacy and better side-effect profiles are in the pipeline of drug development. Furthermore, newly characterized molecules such as apolipoprotein M (ApoM) (S1P chaperon) and SPNS2 (S1P transporter) are also potential targets for treatment of autoimmune diseases. Finally, the application of therapies targeting S1P and S1P signaling pathways may be expanded to treat several other immune-mediated disorders (such as post-infectious diseases, post-stroke and post-stroke dementia) and inflammatory conditions beyond their application in primary autoimmune diseases.

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CitationGPTRetr216

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: Sphingomimetic multiple sclerosis drug FTY720 activates vesicular synaptobrevin and augments neuroendocrine secretion. Abstract of the paper: Neurotransmission and secretion of hormones involve a sequence of protein/lipid interactions with lipid turnover impacting on vesicle trafficking and ultimately fusion of secretory vesicles with the plasma membrane. We previously demonstrated that sphingosine, a sphingolipid metabolite, promotes formation of the SNARE complex required for membrane fusion and also increases the rate of exocytosis in isolated nerve terminals, neuromuscular junctions, neuroendocrine cells and in hippocampal neurons. Recently a fungi-derived sphingosine homologue, FTY720, has been approved for treatment of multiple sclerosis. In its non-phosphorylated form FTY720 accumulates in the central nervous system, reaching high levels which could affect neuronal function. Considering close structural similarity of sphingosine and FTY720 we investigated whether FTY720 has an effect on regulated exocytosis. Our data demonstrate that FTY720 can activate vesicular synaptobrevin for SNARE complex formation and enhance exocytosis in neuroendocrine cells and neurons.

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CitationGPTRetr217

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: Functional antagonism of sphingosine-1-phosphate receptor 1 prevents cuprizone-induced demyelination. Abstract of the paper: Recent evidence suggests that the oral drug Fingolimod (FTY720) for relapsing-remitting multiple sclerosis (MS) may act directly on the central nervous system (CNS) and modulate disease pathogenesis and progression in experimental models of MS. However, the specific subtype of sphingosine-1-phosphate (S1P) receptors that mediates the effect of FTY720 on the CNS cells has not been fully elucidated. Here, we report that S1P receptor 1 (S1PR1) is elevated in reactive astrocytes in an autoimmunity independent mouse model of MS and that selective S1PR1 modulation is sufficient to ameliorate the loss of oligodendrocytes and demyelination. The non-selective S1PR modulator, FTY720, or a short-lived S1PR1-specific modulator, CYM5442, was administered daily to mice while on cuprizone diet. Both FTY720- and CYM5422-treated mice displayed a significant reduction in oligodendrocyte apoptosis and astrocyte and microglial activation in comparison to vehicle-treated groups, which was associated with decreased production of proinflammatory mediators and down-regulation of astrocytic S1PR1 protein. Interestingly, S1PR1 modulation during the early phase of cuprizone intoxication was required to suppress oligodendrocyte death and consequent demyelination as drug treatment from 10 days after the initiation of cuprizone feeding was no longer effective. CYM5442 treatment during the brief cuprizone exposure significantly prevented Il-1β, Il-6, Cxcl10, and Cxcl3 induction, resulting in suppression of subsequent reactive gliosis and demyelination. Our study identifies functional antagonism of S1PR1 as a major mechanism for the protective effect of FTY720 in the cuprizone model and suggests pathogenic contributions of astrocyte S1PR1 signaling in primary demyelination and its potential as a therapeutic target for CNS inflammation.

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CitationGPTRetr218

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. Abstract of the paper: Fingolimod is the first oral disease-modifying therapy approved for relapsing forms of multiple sclerosis (MS). Following phosphorylation in vivo, the active agent, fingolimod phosphate (fingolimod-P), acts as a sphingosine 1-phosphate (S1P) receptor modulator, binding with high affinity to four of the five known S1P receptors (S1P1, S1P3, S1P4 and S1P5). The mechanism of action of fingolimod in MS has primarily been considered as immunomodulatory, whereby fingolimod-P modulates S1P1 on lymphocytes, selectively retaining autoreactive lymphocytes in lymph nodes to reduce damaging infiltration into the central nervous system (CNS). However, emerging evidence indicates that fingolimod has direct effects in the CNS in MS. For example, in the MS animal model of experimental autoimmune encephalomyelitis (EAE), fingolimod is highly efficacious in both a prophylactic and therapeutic setting, yet becomes ineffective in animals selectively deficient for S1P1 on astrocytes, despite maintained normal immunologic receptor expression and functions, and S1P-mediated immune activities. Here we review S1P signaling effects relevant to MS in neural cell types expressing S1P receptors, including astrocytes, oligodendrocytes, neurons, microglia and dendritic cells. The direct effects of fingolimod on these CNS cells observed in preclinical studies are discussed in view of the functional consequences of reducing neurodegenerative processes and promoting myelin preservation and repair. The therapeutic implications of S1P modulation in the CNS are considered in terms of the clinical outcomes of MS, such as reducing MS-related brain atrophy, and other CNS disorders. Additionally, we briefly outline other existing and investigational MS therapies that may also have effects in the CNS.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: preventing the lymphatic drainage of cnsmeningeal derived antigens and trafficking of leukocytes intoout of the cervical lns either by surgical ligation of the afferent lymphatics to the deep cervical lns or resection of the same lns treatment with the sphingosine1phosphate receptor modulator fty720 or deficiency in ccr7 expression have been linked to altered meningeal t cell responses and the development of cognitive deficits Title of the paper: Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. Abstract of the paper: Sphingosine-1-phosphate (S1P) receptors are widely expressed in the central nervous system where they are thought to regulate glia cell function. The phosphorylated version of fingolimod/FTY720 (FTY720P) is active on a broad spectrum of S1P receptors and the parent compound is currently in phase III clinical trials for the treatment of multiple sclerosis. Here, we aimed to identify which cell type(s) and S1P receptor(s) of the central nervous system are targeted by FTY720P. Using calcium imaging in mixed cultures from embryonic rat cortex we show that astrocytes are the major cell type responsive to FTY720P in this assay. In enriched astrocyte cultures, we detect expression of S1P1 and S1P3 receptors and demonstrate that FTY720P activates Gi protein-mediated signaling cascades. We also show that FTY720P as well as the S1P1-selective agonist SEW2871 stimulate astrocyte migration. The data indicate that FTY720P exerts its effects on astrocytes predominantly via the activation of S1P1 receptors, whereas S1P signals through both S1P1 and S1P3 receptors. We suggest that this distinct pharmacological profile of FTY720P, compared with S1P, could play a role in the therapeutic effects of FTY720 in multiple sclerosis.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Post-stroke cognitive impairment: epidemiology, mechanisms and management. Abstract of the paper: Post-stroke cognitive impairment occurs frequently in the patients with stroke. The prevalence of post-stroke cognitive impairment ranges from 20% to 80%, which varies for the difference between the countries, the races, and the diagnostic criteria. The risk of post-stroke cognitive impairment is related to both the demographic factors like age, education and occupation and vascular factors. The underlying mechanisms of post-stroke cognitive impairment are not known in detail. However, the neuroanatomical lesions caused by the stroke on strategic areas such as the hippocampus and the white matter lesions (WMLs), the cerebral microbleeds (CMBs) due to the small cerebrovascular diseases and the mixed AD with stroke, alone or in combination, contribute to the pathogenesis of post-stroke cognitive impairment. The treatment of post-stroke cognitive impairment may benefit not only from the anti-dementia drugs, but also the manage measures on cerebrovascular diseases. In this review, we will describe the epidemiological features and the mechanisms of post-stroke cognitive impairment, and discuss the promising management strategies for these patients.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Vascular Cognitive Impairment. Abstract of the paper: Cerebrovascular disease typically manifests with stroke, cognitive impairment, or both. Vascular cognitive impairment refers to all forms of cognitive disorder associated with cerebrovascular disease, regardless of the specific mechanisms involved. It encompasses the full range of cognitive deficits from mild cognitive impairment to dementia. In principle, any of the multiple causes of clinical stroke can cause vascular cognitive impairment. Recent work further highlights a role of microinfarcts, microhemorrhages, strategic white matter tracts, loss of microstructural tissue integrity, and secondary neurodegeneration. Vascular brain injury results in loss of structural and functional connectivity and, hence, compromise of functional networks within the brain. Vascular cognitive impairment is common both after stroke and in stroke-free individuals presenting to dementia clinics, and vascular pathology frequently coexists with neurodegenerative pathology, resulting in mixed forms of mild cognitive impairment or dementia. Vascular dementia is now recognized as the second most common form of dementia after Alzheimer's disease, and there is increasing awareness that targeting vascular risk may help to prevent dementia, even of the Alzheimer type. Recent advances in neuroimaging, neuropathology, epidemiology, and genetics have led to a deeper understanding of how vascular disease affects cognition. These new findings provide an opportunity for the present reappraisal of vascular cognitive impairment. We further briefly address current therapeutic concepts.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Cognitive Impairment After Ischemic and Hemorrhagic Stroke: A Scientific Statement From the American Heart Association/American Stroke Association. Abstract of the paper: PURPOSE Cognitive impairment is a common consequence of stroke and has direct implications for poststroke functioning and quality of life, including the ability to maintain a job, live independently, sustain interpersonal relationships, and drive a vehicle. In this scientific statement, we critically appraise the literature on the prevalence, diagnosis, and management of poststroke cognitive impairment (PSCI) and provide a framework for clinical care while highlighting gaps that merit further study. METHODS We performed a scoping literature review of randomized controlled clinical trials, prospective and retrospective cohort studies, case-control studies, clinical guidelines, review articles, and editorials on the incidence and prevalence, natural history, diagnosis, and management of PSCI. Scoping reviews determine the scope of a body of literature on a given topic to indicate the volume of literature and the studies currently available and provide an overview of its focus. RESULTS PSCI is common after stroke, especially in the first year, and ranges from mild to severe. Although cognitive impairment is reversible in some cases early after stroke, up to one-third of individuals with stroke develop dementia within 5 years. The pathophysiology is not yet fully elucidated but is likely attributable to an acute stroke precipitating a series of pathological events, often in the setting of preexisting microvascular and neurodegenerative changes. Screening for associated comorbidities and interdisciplinary management are integral components of the care of individuals with PSCI. There is a need for prospective studies evaluating the individual trajectory of PSCI and the role of the acute vascular event in the predisposition for Alzheimer disease and related dementias, as well as high-quality, randomized clinical trials focused on PSCI management.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Cognitive impairment with vascular impairment and degeneration. Abstract of the paper: Ischemic stroke is a leading cause of death and cognitive impairment worldwide. However, the mechanisms of progressive cognitive decline following brain ischemia are not yet certain. Ongoing interest in cerebrovascular diseases research has provided data showing that Alzheimer's proteins and other factors may be involved in the pathogenesis of gradual ischemic brain injury. Thus, both focal and global brain ischemia in rodents produces a stereotyped pattern of selective neuronal degeneration, which is just the same as in Alzheimer's type dementia. Data from animal models and clinical studies of ischemic stroke have demonstrated an increase in expression and processing of amyloid precursor protein (APP) to a neurotoxic form of oligomeric β-amyloid peptide (Aβ) and hyperphosphorylation of tau protein. The authors of this review are using advances in methods and technologies to study cerebrovascular diseases and this review examines the hypothesis that pathological mechanisms common to both brain ischemia and Alzheimer's dementia are contributing to cognitive impairment and brain ischemia-related dementia.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Stroke injury, cognitive impairment and vascular dementia. Abstract of the paper: The global burden of ischaemic strokes is almost 4-fold greater than haemorrhagic strokes. Current evidence suggests that 25-30% of ischaemic stroke survivors develop immediate or delayed vascular cognitive impairment (VCI) or vascular dementia (VaD). Dementia after stroke injury may encompass all types of cognitive disorders. States of cognitive dysfunction before the index stroke are described under the umbrella of pre-stroke dementia, which may entail vascular changes as well as insidious neurodegenerative processes. Risk factors for cognitive impairment and dementia after stroke are multifactorial including older age, family history, genetic variants, low educational status, vascular comorbidities, prior transient ischaemic attack or recurrent stroke and depressive illness. Neuroimaging determinants of dementia after stroke comprise silent brain infarcts, white matter changes, lacunar infarcts and medial temporal lobe atrophy. Until recently, the neuropathology of dementia after stroke was poorly defined. Most of post-stroke dementia is consistent with VaD involving multiple substrates. Microinfarction, microvascular changes related to blood-brain barrier damage, focal neuronal atrophy and low burden of co-existing neurodegenerative pathology appear key substrates of dementia after stroke injury. The elucidation of mechanisms of dementia after stroke injury will enable establishment of effective strategy for symptomatic relief and prevention. Controlling vascular disease risk factors is essential to reduce the burden of cognitive dysfunction after stroke. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: [Cerebral ischemia/infarction - epidemiology, causes and symptoms]. Abstract of the paper: Eight of ten strokes are due to cerebral ischemia, two from cerebal hemorrhage. Stroke is the most common cause of disability, the second commonest cause of dementia and the fourth commonest cause of death in the developed world. The incidence of stroke is 150-200/100.000 individuals/ year. One of every seven individuals suffers from stroke in their lifetime. In this article the epidemiology, risk factors, pathophysiology and symptoms of cerebral ischemia will be reviewed.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Vascular cognitive impairment. Abstract of the paper: Cognitive impairment commonly accompanies clinical syndromes associated with vascular disease of the brain. Because of evolving definitional criteria, however, the frequency of cognitive impairment attributable to cerebrovascular disease is difficult to determine. Dementia occurs in up to one-third of elderly patients with stroke, a subset of whom have Alzheimer's disease (AD) rather than a pure vascular dementia syndrome. In fact, pure vascular dementia has been shown to be uncommon in most large autopsy series. A mixed etiology of AD and cerebrovascular disease is thought to become more common with increasing age, although no clinical criteria for the diagnosis of AD with cerebrovascular disease are currently available. Epidemiological studies have implicated subcortical small-vessel disease as a risk factor for cognitive impairment and dementia, but the cognitive expression and clinical significance of MRI white matter changes in individual patients is difficult to establish. The frequency of specific neuropathologic features of vascular cognitive impairment depends largely on study inclusion criteria. Cerebral meningocortical microangiopathies with distinctive clinicopathological profiles are associated with dementia in both sporadic cases and familial syndromes. In patients with AD, the contribution of amyloid-beta protein to the degree of cognitive impairment has not been clearly defined.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Vascular cognitive impairment. Abstract of the paper: Cerebrovascular disease is the second most common cause of acquired cognitive impairment and dementia and contributes to cognitive decline in the neurodegenerative dementias. The current narrow definitions of vascular dementia should be broadened to recognise the important part cerebrovascular disease plays in several cognitive disorders, including the hereditary vascular dementias, multi-infarct dementia, post-stroke dementia, subcortical ischaemic vascular disease and dementia, mild cognitive impairment, and degenerative dementias (including Alzheimer's disease, frontotemporal dementia, and dementia with Lewy bodies). Here we review the current state of scientific knowledge on the subject of vascular brain burden. Important non-cognitive features include depression, apathy, and psychosis. We propose use of the term vascular cognitive impairment, which is characterised by a specific cognitive profile involving preserved memory with impairments in attentional and executive functioning. Diagnostic criteria have been proposed for some subtypes of vascular cognitive impairment, and there is a pressing need to validate and further refine these. Clinical trials in vascular cognitive impairment are in their infancy but support the value of therapeutic interventions for symptomatic treatment.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Post-stroke cognitive decline: an update and perspectives for clinical research. Abstract of the paper: The close relationship between stroke and dementia is an important health issue. Ischaemic stroke can facilitate the onset of vascular dementia as well as aggravate pre-existing cognitive decline. The onset of cognitive decline may become manifest immediately following the onset of ischaemic stroke, but often there is a delay in the development of cognitive decline after a stroke. This delay can be seen as a therapeutic time window allowing interventions to be applied to preserve cognition following stroke. Both neurodegenerative and vascular mechanisms are activated and probably result in overlapping processes within the neurovascular unit. This review focuses on the incidence and prevalence of cognitive decline following stroke, predisposing stroke aetiologies, pre-stroke decline, imaging factors and biomarkers. Outcomes are discussed in relation to timing of assessment and neuropsychological tests used for evaluation of cognitive decline in ischaemic stroke patients. Including such tests in routine evaluations of stroke patients after some weeks or months is recommended. Finally, an outlook on ongoing and planned intervention trials is added and some recommendations for future research are proposed.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Incidence of dementia after ischemic stroke: results of a longitudinal study. Abstract of the paper: BACKGROUND AND PURPOSE A number of cross-sectional epidemiological studies have reported that one fourth of elderly patients meet criteria for dementia 3 months after ischemic stroke, but few longitudinal studies of the incidence of dementia after stroke have been performed. We conducted the present study to investigate the incidence and clinical predictors of dementia after ischemic stroke. METHODS We administered neurological, neuropsychological, and functional assessments annually to 334 ischemic stroke patients (age, 70.4+/-7.5 years) and 241 stroke-free control subjects (age, 70.6+/-6.5 years), all of whom were nondemented in baseline examinations. We diagnosed incident dementia using modified Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria requiring deficits in memory and > or =2 additional cognitive domains, as well as functional impairment. RESULTS The crude incidence rate of dementia was 8.49 cases per 100 person-years in the stroke cohort and 1.37 cases per 100 person-years in the control cohort. A Cox proportional-hazards analysis found that the relative risk (RR) of incident dementia associated with stroke was 3.83 (95% CI, 2.14 to 6.84), adjusting for demographic variables and baseline Mini-Mental State Examination score. Within the stroke cohort, intercurrent medical illnesses associated with cerebral hypoxia or ischemia were independently related to incident dementia (RR, 4.40; 95% CI, 2.20 to 8.85), adjusting for recurrent stroke, demographic variables, and baseline Mini-Mental State Examination score. CONCLUSIONS The risk of incident dementia is high among patients with ischemic stroke, particularly in association with intercurrent medical illnesses that might cause cerebral hypoxia or ischemia, suggesting that cerebral hypoperfusion may serve as a basis for some cases of dementia after stroke.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Prevalence of poststroke cognitive impairment: South London Stroke Register 1995-2010. Abstract of the paper: BACKGROUND AND PURPOSE Stroke is a common long-term condition with an increasing incidence as the population ages. This study evaluates temporal changes in the prevalence of cognitive impairment after first-ever stroke stratified by sociodemography, vascular risk factors, and stroke subtypes, up to 15 years after stroke. METHODS Data were collected between 1995 and 2010 (n=4212) from the community-based South London Stroke Register covering an inner-city multiethnic population of 271 817 inhabitants. Patients were assessed for cognitive function using Abbreviated Mental Test or Mini-Mental State Examination at the onset, 3 months, and annually thereafter. All estimates were age adjusted to the European standard. RESULTS The overall prevalence of cognitive impairment 3 months after stroke and at annual follow-up remained relatively unchanged at 22% (24% [95% CI, 21.2-27.8] at 3 months; 22% [17.4-26.8] at 5 years to 21% [3.6-63.8] at 14 years). In multivariate analyses, the poststroke prevalence ratio of cognitive impairment increased with older age (2% [1-3] for each year of age), ethnicity (2.2 [1.65-2.89]-fold higher among black group) and socioeconomic status (42% [8-86] increased among manual workers). A significant, progressive trend of cognitive impairment was observed among patients with small vessel occlusion and lacunar infarction (average annual percentage change: 10% [7.9-12.8] and 2% [0.3-2.7], respectively, up to 5 years after stroke). CONCLUSIONS The prevalence of cognitive impairment after stroke remains persistently high over time, with variations being predominantly explained by sociodemographic characteristics. Given population growth and ageing demographics, effective preventive strategies and poststroke surveillance are needed to manage survivors with cognitive impairment.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Cognitive impairment and stroke in elderly patients. Abstract of the paper: We reviewed current knowledge about the interaction between stroke and vascular risk factors and the development of cognitive impairment and dementia. Stroke is increasingly recognized as an important cause of cognitive problems and has been implicated in the development of both Alzheimer's disease and vascular dementia. The prevalence of cognitive impairment after stroke is high, and their combined effects significantly increase the cost of care and health resource utilization, with reflections on hospital readmissions and increased mortality rates. There is also substantial evidence that vascular risk factors (such as hypertension, diabetes, obesity, dyslipidemia, and tobacco smoking) are independently associated with an increased risk of cognitive decline and dementia. Thus, a successful management of these factors, as well as optimal acute stroke management, might have a great impact on the development of cognitive impairment. Notwithstanding, the pathological link between cognitive impairment, stroke, and vascular risk factors is complex and still partially unclear so that further studies are needed to better elucidate the boundaries of this relationship. Many specific pharmacological treatments, including anticholinergic drugs and antihypertensive medications, and nonpharmacological approaches, such as diet, cognitive rehabilitation, and physical activity, have been studied for patients with vascular cognitive impairment, but the optimal care is still far away. Meanwhile, according to the most recent knowledge, optimal stroke care should also include cognitive assessment in the short and long term, and great efforts should be oriented toward a multidisciplinary approach, including quality-of-life assessment and support of caregivers.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Mild cognitive impairment. Abstract of the paper: Mild cognitive impairment is a syndrome defined as cognitive decline greater than expected for an individual's age and education level but that does not interfere notably with activities of daily life. Prevalence in population-based epidemiological studies ranges from 3% to 19% in adults older than 65 years. Some people with mild cognitive impairment seem to remain stable or return to normal over time, but more than half progress to dementia within 5 years. Mild cognitive impairment can thus be regarded as a risk state for dementia, and its identification could lead to secondary prevention by controlling risk factors such as systolic hypertension. The amnestic subtype of mild cognitive impairment has a high risk of progression to Alzheimer's disease, and it could constitute a prodromal stage of this disorder. Other definitions and subtypes of mild cognitive impairment need to be studied as potential prodromes of Alzheimer's disease and other types of dementia.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Post-Stroke Cognitive Impairment and Dementia. Abstract of the paper: Poststroke cognitive impairment and dementia (PSCID) is a major source of morbidity and mortality after stroke worldwide. PSCID occurs as a consequence of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. Cognitive impairment and dementia manifesting after a clinical stroke is categorized as vascular even in people with comorbid neurodegenerative pathology, which is common in elderly individuals and can contribute to the clinical expression of PSCID. Manifestations of cerebral small vessel disease, such as covert brain infarcts, white matter lesions, microbleeds, and cortical microinfarcts, are also common in patients with stroke and likewise contribute to cognitive outcomes. Although studies of PSCID historically varied in the approach to timing and methods of diagnosis, most of them demonstrate that older age, lower educational status, socioeconomic disparities, premorbid cognitive or functional decline, life-course exposure to vascular risk factors, and a history of prior stroke increase risk of PSCID. Stroke characteristics, in particular stroke severity, lesion volume, lesion location, multiplicity and recurrence, also influence PSCID risk. Understanding the complex interaction between an acute stroke event and preexisting brain pathology remains a priority and will be critical for developing strategies for personalized prediction, prevention, targeted interventions, and rehabilitation. Current challenges in the field relate to a lack of harmonization of definition and classification of PSCID, timing of diagnosis, approaches to neurocognitive assessment, and duration of follow-up after stroke. However, evolving knowledge on pathophysiology, neuroimaging, and biomarkers offers potential for clinical applications and may inform clinical trials. Preventing stroke and PSCID remains a cornerstone of any strategy to achieve optimal brain health. We summarize recent developments in the field and discuss future directions closing with a call for action to systematically include cognitive outcome assessment into any clinical studies of poststroke outcome.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Dementia, stroke, and vascular risk factors; a review. Abstract of the paper: Interest in dementia has increased over the past few decades. Stroke is an important cause of cognitive problems. The term vascular cognitive impairment is now used to describe dementia attributed to stroke or deep white matter lesions detected on imaging. Although vascular cognitive impairment is increasingly diagnosed, Alzheimer's disease remains the most common dementia worldwide. The relationship between Alzheimer's disease and vascular cognitive impairment is unclear, although there exists significant overlap, which prompts physicians to consider them opposite ends of a disease spectrum, rather than separate entities. There is also substantial evidence that stroke risk factors such as hypertension, diabetes; lipid disorders, etc. are independently associated with an increased risk of Alzheimer's disease and vascular cognitive impairment. Evidence suggests that these risk factors have a cumulative effect on Alzheimer's disease development but not on vascular cognitive impairment. This is more marked in Alzheimer's disease patients in the presence of the ε4 allelic variant of apolipoprotein E. How these risk factors increase the risk of dementia is largely unknown. Physicians must be aware that stroke causes dementia; that vascular risk factors appear to be independent risk factors in developing dementia, and that poststroke care must include cognitive assessment.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Cognitive impairment and risk of stroke: a systematic review and meta-analysis of prospective cohort studies. Abstract of the paper: BACKGROUND AND PURPOSE Cognitive impairment is linked to vascular risk factors and brain vascular pathologies. Several studies have tested whether subjects with cognitive impairment have higher risk for stroke. The aim of this study was to systematically review available evidence on the association between cognitive impairment and risk of stroke to obtain precise effect estimates of the association and to identify which cognitive domains associate most with incident stroke. METHODS PubMed, EMBASE, and Web of Science were searched from January 1, 1980, to October 1, 2013, without language restriction. Only prospective cohort studies were included. From each study, data on the association between cognitive impairment and stroke estimated with hazard ratios or relative risks with 95% confidence interval (CI) were extracted. For each study, risk of stroke per SD lower performance in various cognitive tests was calculated. RESULTS Twelve studies were included, comprising 82,899 participants of whom 3043 had an incident stroke. The pooled relative risk per SD lower global cognitive performance was 1.19 (95% CI, 1.12-1.27). Each SD lower score in executive function or attention was associated with 1.14-fold (95% CI, 1.06-1.24) higher risk of stroke. Lower scores in memory were associated with 1.07-fold (95% CI, 1.02-1.12) higher risk of stroke, and lower scores in language were associated with 1.08-fold (95% CI, 1.02-1.16) higher risk of stroke. CONCLUSIONS Cognitive impairment is associated with higher risk of stroke. The associations were not significantly different for executive function, memory, and language.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Progressive impairment on neuropsychological tasks in a longitudinal study of preclinical Alzheimer's disease. Abstract of the paper: Previous research suggests that patients with Alzheimer's disease exhibit cognitive impairment in the years preceding a clinical diagnosis. Memory impairments are particularly pronounced, but the relative degree to which other cognitive functions are impaired and the speed with which they decline during the preclinical years remains unclear. The authors report a detailed neuropsychological evaluation of 11 patients over the course of 3 years up to and including the 1st year of nonnormal diagnosis. The results suggest that performance falls off rapidly in all areas of cognitive functioning but that abilities thought to be subserved by the medial and lateral temporal lobes (episodic and semantic memory, respectively) appear to be substantially more impaired than those abilities thought to be subserved by the frontal lobes.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: 1H MRS in stroke patients with and without cognitive impairment. Abstract of the paper: The pathophysiological basis of cognitive impairment in patients with cerebrovascular disease (CVD) is not well understood, particularly in relation to the role of non-infarction ischemic change and associated Alzheimer-type pathology. We used single voxel 1H MRS to determine the differences in brain neurometabolites in non-infarcted frontal white matter and occipito-parietal gray matter of 48 stroke patients with or without cognitive impairment and 60 elderly controls. The results showed that there were no significant neurometabolite differences between the stroke cohort and healthy elderly controls, but there was a difference in NAA/H2O between the stroke patients that had cognitive impairment (vascular dementia (VaD) and vascular cognitive impairment (VCI)) compared with those patients with no impairment. This was significant in the occipito-parietal gray matter, but not in the frontal white matter, although the results were in the same direction for the latter. This suggests that cognitive impairment in stroke patients may be related to cortical neuronal dysfunction rather than purely subcortical change. Moreover, cortical regions not obviously infarcted may have dysfunctional neurons, the pathophysiological basis for which needs further study.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Atherosclerotic risk factors, vascular cognitive impairment, and Alzheimer disease. Abstract of the paper: The involvement of vascular factors in Alzheimer dementia was first appreciated over 100 years ago. Recently, significant advances in our understanding of these brain-vascular relationships have taken place. Vascular cognitive impairment is now recognized as a distinct group of interrelated vascular-based neurological insults that can accumulate and lead to dementia. Importantly, the pathology of vascular cognitive impairment extends far beyond brain destruction wrought by major stroke. Other subtle changes may also arise that contribute to vascular cognitive impairment and dementia, including subclinical stroke, white-matter changes such as hyperintensities and lipohyalinosis, small lacunar infarcts, cerebral hypoperfusion, and compromise of the blood-brain barrier. In this review we critically examine the emerging body of evidence that relates atherosclerotic risk factors, brain functioning, and Alzheimer disease.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: ischemiarelated cognitive impairment ranges from mild to severe occurring in about 3570 of survivors oneyear poststroke with higher rates seen soon poststroke Title of the paper: Predictors of reversible mild cognitive impairment after stroke: a 2-year follow-up study. Abstract of the paper: UNLABELLED Many studies have investigated mild cognitive impairment (MCI) in the context of prodromal dementia, but few have investigated recovery from MCI. The aim of this study was to determine the prevalence of reversible MCI after stroke and to identify factors related to recovery. METHODS One hundred and eighteen patients with a first ever cerebral stroke were followed up for 2 years. Neuropsychological assessment was performed at 1, 6, 12, and 24 months poststroke. Possible predictors of reversible MCI were demographic variables, baseline MMSE scores, presence of stroke risk factors, and CT variables. Poststroke MCI was diagnosed when there was a deficit in at least one cognitive domain, without their being demented. Recovery was considered when MCI was no longer present. RESULTS Twenty-four (20.3%) patients were classified as having permanent reversible MCI and were compared with patients without recovery. Most patients recovered from MCI between the first and second assessments (19.7% versus 13.1% and 2.0% later on). Higher baseline MMSE scores and female sex were independent predictors of recovery (OR(High MMSE)=9.9; OR(female sex)=2.8). Neither stroke-related risk factors nor CT variables were predictors of favorable outcome. CONCLUSION About 20% of patients with poststroke MCI recover from MCI. Higher MMSE scores at baseline and female sex are independent predictors of this recovery.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: Amyloid beta-peptide and amyloid pathology are central to the oxidative stress and inflammatory cascades under which Alzheimer's disease brain exists. Abstract of the paper: Alzheimer's disease (AD) brain is characterized by excess deposition of amyloid beta-peptide (Abeta), particularly the 42-amino acid peptide [Abeta(1-42)] and by extensive oxidative stress. Several sources of the oxidative stress and inflammatory cascades are likely, including that induced by advanced glycation end products, microglial activation, and by Abeta(1-42) and its sequelae. This review briefly examines each of these sources of oxidative stress and inflammation in AD brain and discusses their potential roles in the clinical progression of AD dementia.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: Amyloid beta-peptide [1-42]-associated free radical-induced oxidative stress and neurodegeneration in Alzheimer's disease brain: mechanisms and consequences. Abstract of the paper: In addition to synapse loss, neurofibrillary tangles, and neurodegeneration, oxidative stress and amyloid beta-peptide [Abeta] deposition are hallmarks of Alzheimer's disease [AD] brain. Our laboratory coupled these two characteristics of AD into a comprehensive model to account for the synapse loss and neurodegeneration in AD brain. This model combines much of the extant studies on AD and is based on oxidative stress associated with amyloid beta-peptide. This review presents evidence in support of this model and provides insight into the molecular basis of this devastating dementing disorder.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. Abstract of the paper: Increased awareness for a role of oxidative stress in the pathogenesis of Alzheimer's disease has highlighted the issue of whether oxidative damage is a fundamental step in the pathogenesis or instead results from disease-associated pathology. In vitro experiments support both possibilities: Oxidative stress increases amyloid-beta production, and, conversely, amyloid-beta increases oxidative damage. To address the relationship between amyloid-beta and oxidative stress in vivo, we examined, using an array of oxidative markers, transgenic mice that overexpress amyloid-beta precursor protein and, as in Alzheimer's disease, develop characteristic amyloid-beta deposits within the brain parenchyma. Transgenic animals show the same type of oxidative damage that is found in Alzheimer's disease, and it is important that this damage directly correlates with the presence of amyloid-beta deposits. The significance of these studies is twofold. First, they provide evidence that amyloid-beta and oxidative damage are inextricably linked in vivo. Second, they support the use of transgenic animals for the development of antioxidant therapeutic strategies.

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CitationGPTRetr243

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: Abeta aggregation and possible implications in Alzheimer's disease pathogenesis. Abstract of the paper: Amyloid beta protein (Abeta) has been associated with Alzheimer's disease (AD) because it is a major component of the extracellular plaque found in AD brains. Increased Abeta levels correlate with the cognitive decline observed in AD. Sporadic AD cases are thought to be chiefly associated with lack of Abeta clearance from the brain, unlike familial AD which shows increased Abeta production. Abeta aggregation leading to deposition is an essential event in AD. However, the factors involved in Abeta aggregation and accumulation in sporadic AD have not been completely characterized. This review summarizes studies that have examined the factors that affect Abeta aggregation and toxicity. By necessity these are studies that are performed with recombinant-derived or chemically synthesized Abeta. The studies therefore are not done in animals but in cell culture, which includes neuronal cells, other mammalian cells and, in some cases, non-mammalian cells that also appear susceptible to Abeta toxicity. An understanding of Abeta oligomerization may lead to better strategies to prevent AD.

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CitationGPTRetr244

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: β-amyloid and Oxidative Stress: Perspectives in Drug Development. Abstract of the paper: Alzheimer's Disease (AD) is a slow-developing neurodegenerative disorder in which the main pathogenic role has been assigned to β-amyloid protein (Aβ) that accumulates in extracellular plaques. The mechanism of action of Aβ has been deeply analyzed and several membrane structures have been identified as potential mediators of its effect. The ability of Aβ to modify neuronal activity, receptor expression, signaling pathways, mitochondrial function, and involvement of glial cells have been analyzed. In addition, extensive literature deals with the involvement of oxidative stress in Aβ effects. Herein we focus more specifically on the reciprocal regulation of Aβ, that causes oxidative stress, that favors Aβ aggregation and toxicity and negatively affects the peptide clearance. Analysis of this strict interaction may offer novel opportunities for therapeutic intervention. Both common and new molecules endowed with antioxidant properties deserve attention in this regard.

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CitationGPTRetr245

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: Amyloid beta-peptide(1-42) contributes to the oxidative stress and neurodegeneration found in Alzheimer disease brain. Abstract of the paper: Oxidative stress is extensive in Alzheimer disease (AD) brain. Amyloid beta-peptide (1-42) has been shown to induce oxidative stress and neurotoxicity in vitro and in vivo. Genetic mutations that result in increased production of Abeta1-42 from amyloid precursor protein are associated with an early onset and accelerated pathology of AD. Consequently, Abeta1-42 has been proposed to play a central role in the pathogenesis of AD as a mediator of oxidative stress. In this review, we discuss the role of Abeta1-42 in the lipid peroxidation and protein oxidation evident in AD brain and the implications of such oxidative stress for the function of various proteins that we have identified as specifically oxidized in AD brain compared to control, using proteomics methods. Additionally, we discuss the critical role of methionine 35 in the oxidative stress and neurotoxic properties exhibited by Abeta1-42.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: Oxidative stress and the amyloid beta peptide in Alzheimer's disease. Abstract of the paper: Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer's disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ) in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the production of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ). The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding molecule (proteins, lipids, …). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding molecules in terms of oxidative damage. In addition, the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS production are discussed, along with both in vitro and in vivo oxidation of the Aβ peptide, at the molecular level.

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CitationGPTRetr247

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: Generation of reactive oxygen species by beta amyloid fibrils and oligomers involves different intra/extracellular pathways. Abstract of the paper: A neuropathological characteristic of Alzheimer's disease is the extracellular accumulation of amyloid beta peptide (Abeta) in neuritic plaques. Recent evidences suggested that soluble Abeta oligomers are the predominant neurotoxic species for neurons. Thus, considerable attention has been paid to discriminate the cytotoxic pathways of Abeta pre-fibrillar aggregates and mature fibrils. We showed that the mechanisms by which Abeta oligomers and fibrils generated reactive oxygen species differ in terms of site of production and kinetics, suggesting the involvement of different intra/extracellular pathways.

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CitationGPTRetr248

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: Oxidative stress and β-amyloid protein in Alzheimer's disease. Abstract of the paper: Oxidative stress has been proposed to be an important factor in the pathogenesis of Alzheimer's disease (AD) and contributed to β-amyloid (Aβ) generation. Interaction between oxidative stress and neuro-inflammation leads to Aβ generation. AD is associated with an increase in blood-brain barrier (BBB) permeability due to tight junction involvement. Oxidative stress decreases the expression of low-density lipoprotein receptor-related protein 1 and up-regulates receptor for advanced glycation end products in BBB and increases the BBB permeability, which could potentially lead to increased deposition of Aβ within AD brain. Apoptosis takes place in the pathogenesis of AD, and oxidative stress contributes to apoptosis through both extrinsic pathway and intrinsic pathway. Oxidative stress-induced apoptosis may be a potential factor to Aβ generation. Aβ generation requires two sequential cleavages of APP, with the two proteolytic enzymes: β-secretase and γ-secretase. Oxidative damage up-regulates Aβ via inducing activity of β- and γ-secretases. In this review, we will focus on the mechanism and pathway that oxidative stress contributes to Aβ generation.

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CitationGPTRetr249

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: Formation of the 42-mer Amyloid β Radical and the Therapeutic Role of Superoxide Dismutase in Alzheimer's Disease. Abstract of the paper: Oxidative stress is closely involved in age-related diseases and ageing itself. There is evidence of the leading contribution of oxidative damage to neurodegenerative disease, in contrast to other diseases where oxidative stress plays a secondary role. The 42-mer amyloid β (Aβ42) peptide is thought to be a culprit in the pathogenesis of Alzheimer's disease (AD). Aβ42 aggregates form the oligomeric assembly and show neurotoxicity, causing synaptic dysfunction. Aβ42 also induces tissue oxidation (DNA/RNA, proteins, and lipids) through trace metals (Cu, Zn, and Fe), which can be protected by antioxidant enzymes, vitamin C, and vitamin E. Superoxide dismutase catalyzes the conversion of toxic superoxide radical to less reactive hydrogen peroxide, contributing to protection from AD. Here we review the involvement of oxidative stress in AD progression induced from an imbalance between the radical formation of Aβ42 itself together with unique turn structure at positions Glu22 and Asp23 and several defense systems.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: Amyloid-β production: major link between oxidative stress and BACE1. Abstract of the paper: Sequential endoproteolytic cleavages operated by the γ-secretase and the β-secretase (BACE1) on the β-amyloid precursor protein result in the production of the β-amyloid (Aβ) species, with two C-terminal variants, at residue 40 or at residue 42. Accumulation in brain tissue of aggregates of Aβ42 is the major pathogenetic event in Alzheimer's disease (AD). The causes of Aβ accumulation in the common sporadic form of AD are not completely understood, but they are likely to include oxidative stress (OS). Data reviewed here shed light on how Aβ generation, oxidative stress, and secretase functions are intimately related in sporadic AD. According to our hypothesis, in sporadic AD, OS resulted from several cellular insults such as aging, hypoxia, hyperglycemia, and hypercholesterolemia-that are well-known risk factors for AD development-can determine a primary induction of γ-secretase and BACE1. The loop proceeds with the generation of Aβ42 and its signaling to BACE1 transcription.

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CitationGPTRetr251

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: Roles of amyloid beta-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer's disease and mild cognitive impairment. Abstract of the paper: Oxidative stress has been implicated to play a crucial role in the pathogenesis of a number of diseases, including neurodegenerative disorders, cancer, and ischemia, just to name a few. Alzheimer disease (AD) is an age-related neurodegenerative disorder that is recognized as the most common form of dementia. AD is histopathologically characterized by the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles, the presence of oligomers of amyloid beta-peptide (Abeta), and synapse loss. In this review we discuss the role of Abeta in the pathogenesis of AD and also the use of redox proteomics to identify oxidatively modified brain proteins in AD and mild cognitive impairment. In addition, redox proteomics studies in in vivo models of AD centered around human Abeta(1-42) are discussed.

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CitationGPTRetr252

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: Amyloid-beta aggregation. Abstract of the paper: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the growing population of elderly people. A hallmark of AD is the accumulation of plaques in the brain of AD patients. The plaques predominantly consist of aggregates of amyloid-beta (Abeta), a peptide of 39-42 amino acids generated in vivo by specific, proteolytic cleavage of the amyloid precursor protein. There is a growing body of evidence that Abeta aggregates are ordered oligomers and the cause rather than a product of AD. The analysis of the assembly pathway of Abeta in vitro and biochemical characterization of Abeta deposits isolated from AD brains indicate that Abeta oligomerization occurs via distinct intermediates, including oligomers of 3-50 Abeta monomers, annular oligomers, protofibrils, fibrils and plaques. Of these, the most toxic species appear to be small Abeta oligomers. This article reviews the current knowledge of the mechanism of Abeta assembly in vivo and in vitro, as well as the influence of inherited amino acid replacements in Abeta and experimental conditions on Abeta aggregation. Challenges regarding the reproducible handling of the Abeta peptide for in vitro assembly studies are discussed.

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CitationGPTRetr253

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: Alzheimer disease and the role of free radicals in the pathogenesis of the disease. Abstract of the paper: Oxidative stress occurs early in the progression of Alzheimer disease, significantly before the development of the pathologic hallmarks, neurofibrillary tangles and senile plaques. All classes of macromolecules (sugar, lipids, proteins, and nucleic acids) are affected by oxidative stress leading, inevitably, to neuronal dysfunction. Extensive data from the literature support the notion that mitochondrial and metal abnormalities are key sources of oxidative stress in Alzheimer disease. Furthermore, it has been suggested that in the initial stages of the development of Alzheimer disease, amyloid-beta deposition and hyperphosphorylated tau function as compensatory responses to ensure that neuronal cells do not succumb to oxidative damage. However, during the progression of the disease, the antioxidant activity of both agents is either overwhelmed or, according to others, evolves into pro-oxidant activity resulting in the exacerbation of reactive species production.

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CitationGPTRetr254

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease. Abstract of the paper: Amyloidogenesis has been implicated in a broad spectrum of diseases in which amyloid protein is invariably misfolded and deposited in cells and organs. Alzheimer's disease is one of the most devastating ailments among amyloidogenesis induced dementia. The amyloid beta (Aβ) peptide derived from amyloid precursor protein (APP) is misfolded and deposited as plaques in the brain, which are said to be the hallmark of Alzheimer's disease. In normal brains physiological concentration of the Aβ peptide has been indicated to be involved in modulating neurogenesis and synaptic plasticity. However, excess Aβ production, its aggregation and deposition deleteriously affect a large number of biologically important pathways leading to neuronal cell death. Targeting Aβ production, Aβ aggregation or its clearance from the brain has been an active area of research for preventing or curing AD. Our Feature Article intends to detail the aggregation mechanism, the physiological role of the Aβ peptide, elaborate its toxic effects, and outline the different classes of molecules designed in the last two years to inhibit amyloidogenic APP processing, Aβ oligomerization or fibrillogenesis and to modulate different pathways for active clearance of Aβ from the brain.

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CitationGPTRetr255

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: [Oxidative stress, beta-amyloide peptide and Alzheimer's disease]. Abstract of the paper: Alzheimer's disease, the leading cause of dementia in the elderly is characterized by the presence in the brain of senile plaques formed of insoluble fibrillar deposits of beta-amyloid peptide. This peptide is normally produced in a monomeric soluble form and it is present in low concentrations in the blood and spinal fluid. At physiological concentrations, this peptide is a neurotrophic and neuroprotector factor; nevertheless, with aging and particularly in Alzheimer's disease this peptide accumulates, favors the formation of insoluble fibrils and causes neurotoxicity. beta-Amyloid peptide toxicity has been associated with the generation of free radicals that in turn promote lipid peroxidation and protein oxidation. Through the recognition of specific receptors such as the scavenger receptor, the beta-amyloid peptide becomes internalized in the form of aggregates. Independently of the way the peptide enters the cell, it generates oxidative stress that eventually triggers a state of neurotoxicity and cell death. Recent studies in our laboratory have shown the effect caused by an extracellular oxidative stress upon the internalization of the scavenger receptor. We have also demonstrated that the process of protein translation of molecules implicated in the mechanism of endocytosis through the scavenger receptor, such as the case of beta-adaptin, is arrested in microglial cells treated with beta-amyloid.

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CitationGPTRetr256

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: Amyloid beta-peptide is produced by cultured cells during normal metabolism. Abstract of the paper: Alzheimer's disease is characterized by the extracellular deposition in the brain and its blood vessels of insoluble aggregates of the amyloid beta-peptide (A beta), a fragment, of about 40 amino acids in length, of the integral membrane protein beta-amyloid precursor protein (beta-APP). The mechanism of extracellular accumulation of A beta in brain is unknown and no simple in vitro or in vivo model systems that produce extracellular A beta have been described. We report here the unexpected identification of the 4K (M(r) 4,000) A beta and a truncated form of A beta (approximately 3K) in media from cultures of primary cells and untransfected and beta-APP-transfected cell lines grown under normal conditions. These peptides were immunoprecipitated readily from culture medium by A beta-specific antibodies and their identities confirmed by sequencing. The concept that pathological processes are responsible for the production of A beta must not be reassessed in light of the observation that A beta is produced in soluble form in vitro and in vivo during normal cellular metabolism. Further, these findings provide the basis for using simple cell culture systems to identify drugs that block the formation or release of A beta, the primary protein constituent of the senile plaques of Alzheimer's disease.

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CitationGPTRetr257

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: Oligomerization of Alzheimer's beta-amyloid within processes and synapses of cultured neurons and brain. Abstract of the paper: Multiple lines of evidence implicate beta-amyloid (Abeta) in the pathogenesis of Alzheimer's disease (AD), but the mechanisms whereby Abeta is involved remain unclear. Addition of Abeta to the extracellular space can be neurotoxic. Intraneuronal Abeta42 accumulation is also associated with neurodegeneration. We reported previously that in Tg2576 amyloid precursor protein mutant transgenic mice, brain Abeta42 localized by immunoelectron microscopy to, and accumulated with aging in, the outer membranes of multivesicular bodies, especially in neuronal processes and synaptic compartments. We now demonstrate that primary neurons from Tg2576 mice recapitulate the in vivo localization and accumulation of Abeta42 with time in culture. Furthermore, we demonstrate that Abeta42 aggregates into oligomers within endosomal vesicles and along microtubules of neuronal processes, both in Tg2576 neurons with time in culture and in Tg2576 and human AD brain. These Abeta42 oligomer accumulations are associated with pathological alterations within processes and synaptic compartments in Tg2576 mouse and human AD brains.

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CitationGPTRetr258

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: The toxic conformation of the 42-residue amyloid beta peptide and its relevance to oxidative stress in Alzheimer's disease. Abstract of the paper: Senile plaques in the brain of patients with Alzheimer's disease mainly consist of aggregates of amyloid beta peptides (Abeta42, Abeta40). Abeta42 is more neurotoxic than Abeta40. This review describes recent findings from a structural analysis of Abeta42 aggregates and discusses their relevance to neurotoxicity through the formation of radicals.

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CitationGPTRetr259

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: the excessive deposition of extracellular aβ is often not accompanied by ad Title of the paper: Deciphering an interplay of proteins associated with amyloid β 1-42 peptide and molecular mechanisms of Alzheimer's disease. Abstract of the paper: Extracellular and intracellular accumulation of amyloid beta 1-42 peptide in different states of aggregation has been involved in the development and progression of Alzheimer's disease. However, the precise mechanisms involved in amyloid beta peptide neurotoxicity have not been fully understood. There exists a wide variety of studies demonstrating the binding of amyloid beta peptide to a great variety of macromolecules and that such associations affect the cellular functions. This type of association involves proteins and receptors anchored to the plasma membrane of neurons or immune cells of the central nervous system as well as intracellular proteins that can alter intracellular transport, activate signaling pathways or affect proper mitochondrial function. In this review, we present some examples of such associations and the role played by these interactions, which are generally involved in the pathological progression of Alzheimer's disease.

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CitationGPTRetr260

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents. Abstract of the paper: The Mitogen Activated Protein Kinase (MAPK) signaling plays a critical role in the outcome and the sensitivity to anticancer therapies. Activated MAPK can transmit extracellular signals to regulate cell growth, proliferation, differentiation, migration, apoptosis and so on. Apoptosis as well as macroautophagy (hereafter referred to as autophagy) can be induced by extracellular stimuli such the treatment of chemotherapeutic agents, resulting in different cell response to these drugs. However, the molecular mechanisms mediating these two cellular processes remain largely unknown. Recently, several studies provide new insights into p38 and JNK MAPK pathways function in the control of the balance of autophagy and apoptosis in response to genotoxic stress. Our increased understanding of the role of p38 and JNK MAPK pathways in regulating the balance of autophagy and apoptosis will hopefully provide prospective strategies for cancer therapy.

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CitationGPTRetr261

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: p38(MAPK): stress responses from molecular mechanisms to therapeutics. Abstract of the paper: The p38(MAPK) protein kinases affect a variety of intracellular responses, with well-recognized roles in inflammation, cell-cycle regulation, cell death, development, differentiation, senescence and tumorigenesis. In this review, we examine the regulatory and effector components of this pathway, focusing on their emerging roles in biological processes involved in different pathologies. We summarize how this pathway has been exploited for the development of therapeutics and discuss the potential obstacles of targeting this promiscuous protein kinase pathway for the treatment of different diseases. Furthermore, we discuss how the p38(MAPK) pathway might be best exploited for the development of more effective therapeutics with minimal side effects in a range of specific disease settings.

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CitationGPTRetr262

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: Mitogen-activated protein kinases in apoptosis regulation. Abstract of the paper: Cells are continuously exposed to a variety of environmental stresses and have to decide 'to be or not to be' depending on the types and strength of stress. Among the many signaling pathways that respond to stress, mitogen-activated protein kinase (MAPK) family members are crucial for the maintenance of cells. Three subfamilies of MAPKs have been identified: extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38-MAPKs. It has been originally shown that ERKs are important for cell survival, whereas JNKs and p38-MAPKs were deemed stress responsive and thus involved in apoptosis. However, the regulation of apoptosis by MAPKs is more complex than initially thought and often controversial. In this review, we discuss MAPKs in apoptosis regulation with attention to mouse genetic models and critically point out the multiple roles of MAPKs.

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CitationGPTRetr263

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: Compromised MAPK signaling in human diseases: an update. Abstract of the paper: The mitogen-activated protein kinases (MAPKs) in mammals include c-Jun NH2-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK). These enzymes are serine-threonine protein kinases that regulate various cellular activities including proliferation, differentiation, apoptosis or survival, inflammation, and innate immunity. The compromised MAPK signaling pathways contribute to the pathology of diverse human diseases including cancer and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The JNK and p38 MAPK signaling pathways are activated by various types of cellular stress such as oxidative, genotoxic, and osmotic stress as well as by proinflammatory cytokines such as tumor necrosis factor-α and interleukin 1β. The Ras-Raf-MEK-ERK signaling pathway plays a key role in cancer development through the stimulation of cell proliferation and metastasis. The p38 MAPK pathway contributes to neuroinflammation mediated by glial cells including microglia and astrocytes, and it has also been associated with anticancer drug resistance in colon and liver cancer. We here summarize recent research on the roles of MAPK signaling pathways in human diseases, with a focus on cancer and neurodegenerative conditions.

True

CitationGPTRetr264

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. Abstract of the paper: The generic mitogen-activated protein kinases (MAPK) signaling pathway is shared by four distinct cascades, including the extracellular signal-related kinases (ERK1/2), Jun amino-terminal kinases (JNK1/2/3), p38-MAPK and ERK5. Mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) pathway is reported to be associated with the cell proliferation, differentiation, migration, senescence and apoptosis. The literatures were searched extensively and this review was performed to review the role of MAPK/ERK signaling pathway in cell proliferation, differentiation, migration, senescence and apoptosis.

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CitationGPTRetr265

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: Pathological roles of MAPK signaling pathways in human diseases. Abstract of the paper: The mammalian family of mitogen-activated protein kinases (MAPKs) includes extracellular signal-regulated kinase (ERK), p38, and c-Jun NH(2)-terminal kinase (JNK), with each MAPK signaling pathway consisting of at least three components, a MAPK kinase kinase (MAP3K), a MAPK kinase (MAP2K), and a MAPK. The MAPK pathways are activated by diverse extracellular and intracellular stimuli including peptide growth factors, cytokines, hormones, and various cellular stressors such as oxidative stress and endoplasmic reticulum stress. These signaling pathways regulate a variety of cellular activities including proliferation, differentiation, survival, and death. Deviation from the strict control of MAPK signaling pathways has been implicated in the development of many human diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and various types of cancers. Persistent activation of the JNK or p38 signaling pathways has been suggested to mediate neuronal apoptosis in AD, PD, and ALS, whereas the ERK signaling pathway plays a key role in several steps of tumorigenesis including cancer cell proliferation, migration, and invasion. In this review, we summarize recent findings on the roles of MAPK signaling pathways in human disorders, focusing on cancer and neurodegenerative diseases including AD, PD, and ALS.

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CitationGPTRetr266

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: The complexity of mitogen-activated protein kinases (MAPKs) made simple. Abstract of the paper: The mitogen-activated protein kinase (MAPK) pathways are known to be involved in various processes of growth, differentiation and cell death. In spite of their ubiquitous presence and seemingly enormous cross-talk with each other, their action is very specific. This review deals with various aspects of the three different MAPK pathways (ERK, p38 and JNK) and how their specificity is brought about.

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CitationGPTRetr267

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: p38 MAP-kinases pathway regulation, function and role in human diseases. Abstract of the paper: Mammalian p38 mitogen-activated protein kinases (MAPKs) are activated by a wide range of cellular stresses as well as in response to inflammatory cytokines. There are four members of the p38MAPK family (p38alpha, p38beta, p38gamma and p38delta) which are about 60% identical in their amino acid sequence but differ in their expression patterns, substrate specificities and sensitivities to chemical inhibitors such as SB203580. A large body of evidences indicates that p38MAPK activity is critical for normal immune and inflammatory response. The p38MAPK pathway is a key regulator of pro-inflammatory cytokines biosynthesis at the transcriptional and translational levels, which makes different components of this pathway potential targets for the treatment of autoimmune and inflammatory diseases. However, recent studies have shed light on the broad effect of p38MAPK activation in the control of many other aspects of the physiology of the cell, such as control of cell cycle or cytoskeleton remodelling. Here we focus on these emergent roles of p38MAPKs and their implication in different pathologies.

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CitationGPTRetr268

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: Reactive oxygen species in the activation of MAP kinases. Abstract of the paper: There are three well-defined subgroups of mitogen-activated protein kinases (MAPKs): the extracellular signal-regulated kinases (ERKs), the c-Jun N-terminal kinases (JNKs), and the p38 MAPKs. Three subgroups of MAPKs are involved in both cell growth and cell death, and the tight regulation of these pathways, therefore, is paramount in determining cell fate. MAPK pathways have been shown to be activated not only by receptor ligand interactions but also by different stressors placed on the cell. MAPK phosphatases (MKPs) dephosphorylate and deactivate MAPKs. Reactive oxygen species (ROS), such as hydrogen peroxide, have been reported to activate ERKs, JNKs, and p38 MAPKs, but the mechanisms by which ROS can activate these kinases are unclear. Oxidative modifications of MAPK signaling proteins and inactivation and/or degradation of MKPs may provide the plausible mechanisms for activation of MAPK pathways by ROS, which will be reviewed in this chapter.

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CitationGPTRetr269

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: Activation and signaling of the p38 MAP kinase pathway. Abstract of the paper: The family members of the mitogen-activated protein (MAP) kinases mediate a wide variety of cellular behaviors in response to extracellular stimuli. One of the four main sub-groups, the p38 group of MAP kinases, serve as a nexus for signal transduction and play a vital role in numerous biological processes. In this review, we highlight the known characteristics and components of the p38 pathway along with the mechanism and consequences of p38 activation. We focus on the role of p38 as a signal transduction mediator and examine the evidence linking p38 to inflammation, cell cycle, cell death, development, cell differentiation, senescence and tumorigenesis in specific cell types. Upstream and downstream components of p38 are described and questions remaining to be answered are posed. Finally, we propose several directions for future research on p38.

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CitationGPTRetr270

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: Mitogen-activated protein kinases in innate immunity. Abstract of the paper: Following pathogen infection or tissue damage, the stimulation of pattern recognition receptors on the cell surface and in the cytoplasm of innate immune cells activates members of each of the major mitogen-activated protein kinase (MAPK) subfamilies--the extracellular signal-regulated kinase (ERK), p38 and Jun N-terminal kinase (JNK) subfamilies. In conjunction with the activation of nuclear factor-κB and interferon-regulatory factor transcription factors, MAPK activation induces the expression of multiple genes that together regulate the inflammatory response. In this Review, we discuss our current knowledge about the regulation and the function of MAPKs in innate immunity, as well as the importance of negative feedback loops in limiting MAPK activity to prevent host tissue damage. We also examine how pathogens have evolved complex mechanisms to manipulate MAPK activation to increase their virulence. Finally, we consider the potential of the pharmacological targeting of MAPK pathways to treat autoimmune and inflammatory diseases.

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CitationGPTRetr271

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Abstract of the paper: Multicellular organisms have three well-characterized subfamilies of mitogen-activated protein kinases (MAPKs) that control a vast array of physiological processes. These enzymes are regulated by a characteristic phosphorelay system in which a series of three protein kinases phosphorylate and activate one another. The extracellular signal-regulated kinases (ERKs) function in the control of cell division, and inhibitors of these enzymes are being explored as anticancer agents. The c-Jun amino-terminal kinases (JNKs) are critical regulators of transcription, and JNK inhibitors may be effective in control of rheumatoid arthritis. The p38 MAPKs are activated by inflammatory cytokines and environmental stresses and may contribute to diseases like asthma and autoimmunity.

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CitationGPTRetr272

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: Signal integration by JNK and p38 MAPK pathways in cancer development. Abstract of the paper: Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) family members function in a cell context-specific and cell type-specific manner to integrate signals that affect proliferation, differentiation, survival and migration. Consistent with the importance of these events in tumorigenesis, JNK and p38 MAPK signalling is associated with cancers in humans and mice. Studies in mouse models have been essential to better understand how these MAPKs control cancer development, and these models are expected to provide new strategies for the design of improved therapeutic approaches. In this Review we highlight the recent progress made in defining the functions of the JNK and p38 MAPK pathways in different cancers.

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CitationGPTRetr273

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: Differential regulation and properties of MAPKs. Abstract of the paper: Mitogen-activated protein kinases (MAPKs) regulate diverse cellular programs including embryogenesis, proliferation, differentiation and apoptosis based on cues derived from the cell surface and the metabolic state and environment of the cell. In mammals, there are more than a dozen MAPK genes. The best known are the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK(1-3)) and p38(alpha, beta, gamma and delta) families. ERK3, ERK5 and ERK7 are other MAPKs that have distinct regulation and functions. MAPK cascades consist of a core of three protein kinases. Despite the apparently simple architecture of this pathway, these enzymes are capable of responding to a bewildering number of stimuli to produce exquisitely specific cellular outcomes. These responses depend on the kinetics of their activation and inactivation, the subcellular localization of the kinases, the complexes in which they act, and the availability of substrates. Fine-tuning of cascade activity can occur through modulatory inputs to cascade component from the primary kinases to the scaffolding accessory proteins. Here, we describe some of the properties of the three major MAPK pathways and discuss how these properties govern pathway regulation and activity.

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CitationGPTRetr274

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: Regulation of JNK and p38 MAPK in the immune system: signal integration, propagation and termination. Abstract of the paper: Stress-activated MAP kinases (MAPKs), comprised of JNK and p38, play prominent roles in the innate and adaptive immune systems. Activation of MAPKs is mediated by a three-tiered kinase module comprised of MAPK kinase kinases (MAP3Ks), MAPK kinases (MAP2Ks) and MAPKs through sequential protein phosphorylation. Activated MAPKs, in turn, phosphorylate transcription factors and other targets to regulate gene transcription and immune responses. Recent studies have provided new insight into the upstream and downstream components of the MAPK pathway that facilitate the activation and propagation of MAPK signaling in immune responses. Moreover, MAPK activity is negatively regulated by MAPK phosphatases (MKPs), a group of dual-specificity phosphatases that dephosphorylate and inactivate the MAPKs. Here we discuss the recent advances in our understanding of these regulatory processes in MAPK signaling with a focus on their impacts on immune function.

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CitationGPTRetr275

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: Novel strategies for inhibition of the p38 MAPK pathway. Abstract of the paper: The p38 subgroup of the mitogen-activated protein kinase superfamily has four isoforms: p38alpha, p38beta, p38delta and p38gamma. Whereas p38alpha is involved in inflammation, proliferation, differentiation and apoptosis, the biological functions of p38beta, p38delta and p38gamma are not understood completely. Many p38alpha inhibitors with diverse chemical structures and modes of protein interaction have been designed on the basis of their ability to compete with ATP for binding to p38alpha. Although some of these inhibitors show anti-inflammatory effects in animal models, they have repeatedly failed in clinical trials, highlighting the need for better approaches to inhibitor design. Here, we discuss alternative strategies that might lead to better p38 inhibitors, including non-ATP-competitive inhibitors and inhibitors that are targeted to other components of the signaling pathway.

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CitationGPTRetr276

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: MAP kinase signalling pathways in cancer. Abstract of the paper: Cancer can be perceived as a disease of communication between and within cells. The aberrations are pleiotropic, but mitogen-activated protein kinase (MAPK) pathways feature prominently. Here, we discuss recent findings and hypotheses on the role of MAPK pathways in cancer. Cancerous mutations in MAPK pathways are frequently mostly affecting Ras and B-Raf in the extracellular signal-regulated kinase pathway. Stress-activated pathways, such as Jun N-terminal kinase and p38, largely seem to counteract malignant transformation. The balance and integration between these signals may widely vary in different tumours, but are important for the outcome and the sensitivity to drug therapy.

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CitationGPTRetr277

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Abstract of the paper: An abundance of scientific literature exists demonstrating that oxidative stress influences the MAPK signaling pathways. This review summarizes these findings for the ERK, JNK, p38, and BMK1 pathways. For each of these different MAPK signaling pathways, the following is reviewed: the proteins involved in the signaling pathways, how oxidative stress can activate cellular signaling via these pathways, the types of oxidative stress that are known to induce activation of the different pathways, and the specific cell types in which oxidants induce MAPK responses. In addition, the functional outcome of oxidative stress-induced activation of these pathways is discussed. The purpose of this review is to provide the reader with an overall understanding and appreciation of oxidative stress-induced MAPK signaling.

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CitationGPTRetr278

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: MAP kinase pathways. Abstract of the paper: MAP kinases are activated within protein kinase cascades that regulate cell proliferation, differentiation, and death. In mammals, MAP kinases are grouped into three families: ERKs, JNKs, and p38/SAPKs.

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CitationGPTRetr279

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: broadly speaking we can assert that erk12mediated pathways are activated by growth factors and stimulate cell proliferation migration differentiation and survival 159162 while p38 and jnk are activated by stress factors such as oxidative stress or inflammation and are therefore responsible for inflammatory and stress responses autophagy and apoptosis although they can also participate in cell differentiation Title of the paper: Mitogen-Activated Protein Kinases and Reactive Oxygen Species: How Can ROS Activate MAPK Pathways? Abstract of the paper: Mitogen-activated protein kinases (MAPKs) are serine-threonine protein kinases that play the major role in signal transduction from the cell surface to the nucleus. MAPKs, which consist of growth factor-regulated extracellular signal-related kinases (ERKs), and the stress-activated MAPKs, c-jun NH(2)-terminal kinases (JNKs) and p38 MAPKs, are part of a three-kinase signaling module composed of the MAPK, an MAPK kinase (MAP2K) and an MAPK kinase (MAP3K). MAP3Ks phosphorylate MAP2Ks, which in turn activate MAPKs. MAPK phosphatases (MKPs), which recognize the TXY amino acid motif present in MAPKs, dephosphorylate and deactivate MAPKs. MAPK pathways are known to be influenced not only by receptor ligand interactions, but also by different stressors placed on the cell. One type of stress that induces potential activation of MAPK pathways is the oxidative stress caused by reactive oxygen species (ROS). Generally, increased ROS production in a cell leads to the activation of ERKs, JNKs, or p38 MAPKs, but the mechanisms by which ROS can activate these kinases are unclear. Oxidative modifications of MAPK signaling proteins and inactivation and/or degradation of MKPs may provide the plausible mechanisms for activation of MAPK pathways by ROS, which will be reviewed in this paper.

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CitationGPTRetr280

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: Biomarker modeling of Alzheimer's disease using PET-based Braak staging. Abstract of the paper: Gold-standard diagnosis of Alzheimer's disease (AD) relies on histopathological staging systems. Using the topographical information from [18F]MK6240 tau positron-emission tomography (PET), we applied the Braak tau staging system to 324 living individuals. We used PET-based Braak stage to model the trajectories of amyloid-β, phosphorylated tau (pTau) in cerebrospinal fluid (pTau181, pTau217, pTau231 and pTau235) and plasma (pTau181 and pTau231), neurodegeneration and cognitive symptoms. We identified nonlinear AD biomarker trajectories corresponding to the spatial extent of tau-PET, with modest biomarker changes detectable by Braak stage II and significant changes occurring at stages III-IV, followed by plateaus. Early Braak stages were associated with isolated memory impairment, whereas Braak stages V-VI were incompatible with normal cognition. In 159 individuals with follow-up tau-PET, progression beyond stage III took place uniquely in the presence of amyloid-β positivity. Our findings support PET-based Braak staging as a framework to model the natural history of AD and monitor AD severity in living humans.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: Multicenter 18F-PI-2620 PET for In Vivo Braak Staging of Tau Pathology in Alzheimer's Disease. Abstract of the paper: Tau aggregates accumulate in the Alzheimer's disease (AD) brain according to the established Braak staging scheme and spread from transentorhinal over limbic regions to the neocortex. To impact the management of AD patients, an in vivo tool for tau Braak staging is needed. First-generation tau tracers have limited performance in detecting early stages of tau. Therefore, we tested the corresponding capability of the next-generation tau tracer, 18F-PI-2620. We analyzed 18F-PI-2620 multicenter PET data from 37 beta-amyloid-positive AD dementia patients and those from 26 healthy controls. We applied kinetic modeling of the 0-60 min p.i. PET data using MRTM2 with the lower cerebellum as the reference region to extract Braak stage-dependent distribution volume ratios, whereas controls were used to define Braak stage PET positivity thresholds. Stage-dependent PET positivity widely followed the Braak scheme (except Braak stage III) presenting descending frequency of PET positivity from Braak I (43%), II (38%), III (49%), IV (35%), V (30%) to VI (14%). A strictly hierarchical model was met by 64% of AD dementia cases. Nineteen percent showed a hippocampal sparing tauopathy pattern. Thus, we could assign 87% to the six-stage hierarchical Braak model including tauopathy variants. 18F-PI-2620 PET appears to be able to perform Braak tau staging of AD in vivo.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages. Abstract of the paper: SEE THAL AND VANDENBERGHE DOI101093/BRAIN/AWW057 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Post-mortem Braak staging of neurofibrillary tau tangle topographical distribution is one of the core neuropathological criteria for the diagnosis of Alzheimer's disease. The recent development of positron emission tomography tracers targeting neurofibrillary tangles has enabled the distribution of tau pathology to be imaged in living subjects. Methods for extraction of classic Braak staging from in vivo imaging of neurofibrillary tau tangles have not yet been explored. Standardized uptake value ratio images were calculated from 80-100 minute (18)F-AV-1451 (also known as T807) positron emission tomography scans obtained from n = 14 young reference subjects (age 21-39 years, Mini-Mental State Examination 29-30) and n = 173 older test subjects (age 50-95 years) comprising amyloid negative cognitively normal (n = 42), clinically-diagnosed mild cognitive impairment (amyloid positive, n = 47, and amyloid negative, n = 40) and Alzheimer's disease (amyloid positive, n = 28, and amyloid negative, n = 16). We defined seven regions of interest in anterior temporal lobe and occipital lobe sections corresponding closely to those used as decision points in Braak staging. An algorithm based on the Braak histological staging procedure was applied to estimate Braak stages directly from the region of interest profiles in each subject. Quantitative region-based analysis of (18)F-AV-1451 images yielded region of interest and voxel level profiles that mirrored key features of neuropathological tau progression including profiles consistent with Braak stages 0 through VI. A simple set of decision rules enabled plausible Braak stages corresponding to stereotypical progression patterns to be objectively estimated in 149 (86%) of test subjects. An additional 12 (7%) subjects presented with predefined variant profiles (relative sparing of the hippocampus and/or occipital lobe). The estimated Braak stage was significantly associated with amyloid status, diagnostic category and measures of global cognition. In vivo (18)F-AV-1451 positron emission tomography images across the Alzheimer's disease spectrum could be classified into patterns similar to those prescribed by Braak neuropathological staging of tau pathology.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: PET Imaging of Tau Deposition in the Aging Human Brain. Abstract of the paper: Tau pathology is a hallmark of Alzheimer's disease (AD) but also occurs in normal cognitive aging. Using the tau PET agent (18)F-AV-1451, we examined retention patterns in cognitively normal older people in relation to young controls and AD patients. Age and β-amyloid (measured using PiB PET) were differentially associated with tau tracer retention in healthy aging. Older age was related to increased tracer retention in regions of the medial temporal lobe, which predicted worse episodic memory performance. PET detection of tau in other isocortical regions required the presence of cortical β-amyloid and was associated with decline in global cognition. Furthermore, patterns of tracer retention corresponded well with Braak staging of neurofibrillary tau pathology. The present study defined patterns of tau tracer retention in normal aging in relation to age, cognition, and β-amyloid deposition.

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CitationGPTRetr284

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: Striatal amyloid plaque density predicts Braak neurofibrillary stage and clinicopathological Alzheimer's disease: implications for amyloid imaging. Abstract of the paper: Amyloid imaging may revolutionize Alzheimer's disease (AD) research and clinical practice but is critically limited by an inadequate correlation between cerebral cortex amyloid plaques and dementia. Also, amyloid imaging does not indicate the extent of neurofibrillary tangle (NFT) spread throughout the brain. Currently, the presence of dementia as well as a minimal brain load of both plaques and NFTs is required for the diagnosis of AD. Autopsy studies suggest that striatal amyloid plaques may be mainly restricted to subjects in higher Braak NFT stages that meet clinicopathological diagnostic criteria for AD. Striatal plaques, which are readily identified by amyloid imaging, might therefore be used to predict the presence of a higher Braak NFT stage and clinicopathological AD in living subjects. This study determined the sensitivity and specificity of striatal plaques for predicting a higher Braak NFT stage and clinicopathological AD in a postmortem series of 211 elderly subjects. Subjects included 87 clinicopathologically classified as non-demented elderly controls and 124 with AD. A higher striatal plaque density score (moderate or frequent) had 95.8% sensitivity, 75.7% specificity for Braak NFT stage V or VI and 85.6% sensitivity, 86.2% specificity for the presence of dementia and clinicopathological AD (National Institute on Aging - Reagan Institute "intermediate" or "high"). Amyloid imaging of the striatum may be useful as a predictor, in living subjects, of Braak NFT stage and the presence or absence of dementia and clinicopathological AD. Validation of this hypothesis will require autopsy studies of subjects that had amyloid imaging during life.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: 18F-MK-6240 PET for early and late detection of neurofibrillary tangles. Abstract of the paper: Braak stages of tau neurofibrillary tangle accumulation have been incorporated in the criteria for the neuropathological diagnosis of Alzheimer's disease. It is expected that Braak staging using brain imaging can stratify living individuals according to their individual patterns of tau deposition, which may prove crucial for clinical trials and practice. However, previous studies using the first-generation tau PET agents have shown a low sensitivity to detect tau pathology in areas corresponding to early Braak histopathological stages (∼20% of cognitively unimpaired elderly with tau deposition in regions corresponding to Braak I-II), in contrast to ∼80-90% reported in post-mortem cohorts. Here, we tested whether the novel high affinity tau tangles tracer 18F-MK-6240 can better identify individuals in the early stages of tau accumulation. To this end, we studied 301 individuals (30 cognitively unimpaired young, 138 cognitively unimpaired elderly, 67 with mild cognitive impairment, 54 with Alzheimer's disease dementia, and 12 with frontotemporal dementia) with amyloid-β 18F-NAV4694, tau 18F-MK-6240, MRI, and clinical assessments. 18F-MK-6240 standardized uptake value ratio images were acquired at 90-110 min after the tracer injection. 18F-MK-6240 discriminated Alzheimer's disease dementia from mild cognitive impairment and frontotemporal dementia with high accuracy (∼85-100%). 18F-MK-6240 recapitulated topographical patterns consistent with the six hierarchical stages proposed by Braak in 98% of our population. Cognition and amyloid-β status explained most of the Braak stages variance (P < 0.0001, R2 = 0.75). No single region of interest standardized uptake value ratio accurately segregated individuals into the six topographic Braak stages. Sixty-eight per cent of the cognitively unimpaired elderly amyloid-β-positive and 37% of the cognitively unimpaired elderly amyloid-β-negative subjects displayed tau deposition, at least in the transentorhinal cortex (Braak I). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid-β, neurodegeneration, and cognitive impairment (P < 0.0001). 18F-MK-6240 deposition in regions corresponding to Braak IV-VI was associated with the highest prevalence of neurodegeneration, whereas in Braak V-VI regions with the highest prevalence of cognitive impairment. Our results suggest that the hierarchical six-stage Braak model using 18F-MK-6240 imaging provides an index of early and late tau accumulation as well as disease stage in preclinical and symptomatic individuals. Tau PET Braak staging using high affinity tracers has the potential to be incorporated in the diagnosis of living patients with Alzheimer's disease in the near future.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: [F-18]-AV-1451 binding correlates with postmortem neurofibrillary tangle Braak staging. Abstract of the paper: [F-18]-AV-1451, a PET tracer specifically developed to detect brain neurofibrillary tau pathology, has the potential to facilitate accurate diagnosis of Alzheimer's disease (AD), staging of brain tau burden and monitoring disease progression. Recent PET studies show that patients with mild cognitive impairment and AD dementia exhibit significantly higher in vivo [F-18]-AV-1451 retention than cognitively normal controls. Importantly, PET patterns of [F-18]-AV-1451 correlate well with disease severity and seem to match the predicted topographic Braak staging of neurofibrillary tangles (NFTs) in AD, although this awaits confirmation. We studied the correlation of autoradiographic binding patterns of [F-18]-AV-1451 and the stereotypical spatiotemporal pattern of progression of NFTs using legacy postmortem brain samples representing different Braak NFT stages (I-VI). We performed [F-18]-AV-1451 phosphor-screen autoradiography and quantitative tau measurements (stereologically based NFT counts and biochemical analysis of tau pathology) in three brain regions (entorhinal cortex, superior temporal sulcus and visual cortex) in a total of 22 cases: low Braak (I-II, n = 6), intermediate Braak (III-IV, n = 7) and high Braak (V-VI, n = 9). Strong and selective [F-18]-AV-1451 binding was detected in all tangle-containing regions matching precisely the observed pattern of PHF-tau immunostaining across the different Braak stages. As expected, no signal was detected in the white matter or other non-tangle containing regions. Quantification of [F-18]-AV-1451 binding was very significantly correlated with the number of NFTs present in each brain region and with the total tau and phospho-tau content as reported by Western blot and ELISA. [F-18]-AV-1451 is a promising biomarker for in vivo quantification of brain tau burden in AD. Neuroimaging-pathologic studies conducted on postmortem material from individuals imaged while alive are now needed to confirm these observations.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study. Abstract of the paper: BACKGROUND Neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau proteins, are one of the pathologic hallmarks of Alzheimer disease (AD). We aimed to determine whether patterns of gray matter atrophy from antemortem MRI correlate with Braak staging of NFT pathology. METHODS Eighty-three subjects with Braak stage III through VI, a pathologic diagnosis of low- to high-probability AD, and MRI within 4 years of death were identified. Voxel-based morphometry assessed gray matter atrophy in each Braak stage compared with 20 pathologic control subjects (Braak stages 0 through II). RESULTS In pairwise comparisons with Braak stages 0 through II, a graded response was observed across Braak stages V and VI, with more severe and widespread loss identified at Braak stage VI. No regions of loss were identified in Braak stage III or IV compared with Braak stages 0 through II. The lack of findings in Braak stages III and IV could be because Braak stage is based on the presence of any NFT pathology regardless of severity. Actual NFT burden may vary by Braak stage. Therefore, tau burden was assessed in subjects with Braak stages 0 through IV. Those with high tau burden showed greater gray matter loss in medial and lateral temporal lobes than those with low tau burden. CONCLUSIONS Patterns of gray matter loss are associated with neurofibrillary tangle (NFT) pathology, specifically with NFT burden at Braak stages III and IV and with Braak stage itself at higher stages. This validates three-dimensional patterns of atrophy on MRI as an approximate in vivo surrogate indicator of the full brain topographic representation of the neurodegenerative aspect of Alzheimer disease pathology.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: Tau imaging with PET: an overview of challenges, current progress, and future applications. Abstract of the paper: Folded and misfolded tau is common to many neurodegenerative conditions, collectively termed "tauopathies". In recent years, many efforts have contributed toward development of tau imaging agents to allow measurement of tau deposits in vivo using positron emission tomography (PET). The particularities of tau present some unique challenges for the development of tau imaging tracers. Most notably, these pertain to the predominantly intracellular nature of tau aggregations, the existence of six isoforms, multiple post-translational modification, and that tau is usually surrounded by larger concentrations of Aβ plaques. Nevertheless, significant progress has been made towards overcoming these issues and a number of tracers are now undergoing human trials. Once validated, tau imaging with PET will be a useful tool for the differential diagnosis and disease staging, as well as therapeutic trials of AD and non-AD tauopathies.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: Patterns of tau pathology identified with 18 F-MK-6240 PET imaging. Abstract of the paper: INTRODUCTION Positron emission tomography (PET) imaging for neurofibrillary tau allows investigation of the in vivo spatiotemporal progression of Alzheimer's disease (AD) pathology. We evaluated the suitability of 18 F-MK-6240 in a clinical sample and determined the relationships among 18 F-MK-6240 binding, age, cognition, and cerebrospinal fluid (CSF)-based AD biomarkers. METHODS Participants (n = 101, 72 ± 9 years, 52% women) underwent amyloid PET, tau PET, structural T1-weighted magnetic resonance imaging, and neuropsychological evaluation. Twenty-one participants had lumbar puncture for CSF measurement of amyloid beta (Aβ)42 , tau, and phosphorylated tau (p-tau). RESULTS 18 F-MK-6240 recapitulated Braak staging and correlated with CSF tau and p-tau, normalized to Aβ42 . 18 F-MK-6240 negatively correlated with age across Braak regions in amyloid-positive participants, consistent with greater tau pathology in earlier onset AD. Domain-specific, regional patterns of 18 F-MK-6240 binding were associated with reduced memory, executive, and language performance, but only in amyloid-positive participants. DISCUSSION 18 F-MK-6240 can approximate Braak staging across the AD continuum and provide region-dependent insights into biomarker-based AD models.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: Correlations between cortical and subcortical tau pathology. Abstract of the paper: AIM Recent studies indicate that tau pathology in Alzheimer's disease (AD) does not initially manifest in the cerebral cortex but in selected subcortical nuclei, in particular the locus ceruleus (LC). In this study we correlate both olfactory and brainstem tau pathology with neuritic Braak stages. METHODS We examined 239 unselected autopsy cases (57.3% female, 42.7% male; aged 55-102, mean 82.8 ± 9.7 SD years; AD, 44.8%; non-demented controls, 31.8%; Parkinson's disease, 5.0%; dementia with Lewy bodies, 2.5%; AD+Lewy body disease, 15.9%). Neuropathological examination according to standardized methods included immunohistochemistry and semiquantitative assessment of tau lesions in LC, substantia nigra (SN), dorsal motor nucleus of nervus vagus (dmX), and olfactory bulb (OB). RESULTS In Braak stage 0, tau pathology (usually very sparse pretangle material) was seen in the OB in 52.9% and in the SN/LC in 44%. The prevalence of OB and subcortical tau pathology increased with increasing Braak stages and reached 100% in OB, SN and LC and 95.2% in dmX in Braak stage VI, respectively. The severity of tau pathology in OB and subcortical nuclei significantly (P < 0.001) correlated with Braak stages and these correlations remained statistically significant when controlling for concomitant α-synuclein pathology in the respective regions. CONCLUSIONS Our finding of an increase in both prevalence and severity of OB, LC, SN and dmX tau pathology in AD with increasing Braak stages suggests that these regions become increasingly involved during AD progression rather than representing sites initially affected by AD-associated tau pathology.

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Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: Memory and mental status correlates of modified Braak staging. Abstract of the paper: We assessed the relationships of performance on memory and mental status tests and neuropathologic stage of Alzheimer's disease as defined by Braak and Braak in 29 patients from a prospective clinicopathologic series. We predicted that memory changes would occur at an earlier Braak stage than mental status changes. Staging was accomplished by matching the topographic distribution of neurofibrillary lesions detected with tau immunocytochemistry to the best fitting diagram published by Braak and Braak. Higher Braak stages were associated with decrements in performance on both memory and mental status tests. As predicted, memory performance declined from stages II to III and mental status did not decline until stages III to IV. The association between memory and Braak stage was unchanged after adjusting for neocortical senile plaques, whereas adjustments for Braak stage eliminated the association between cognitive functioning and amyloid burden. We conclude that Braak staging provides a useful summary of Alzheimer's disease neuropathology, which is associated with both memory and mental status performance.

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CitationGPTRetr292

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: Comparison of multiple tau-PET measures as biomarkers in aging and Alzheimer's disease. Abstract of the paper: The recent development of tau-specific positron emission tomography (PET) tracers enables in vivo quantification of regional tau pathology, one of the key lesions in Alzheimer's disease (AD). Tau PET imaging may become a useful biomarker for clinical diagnosis and tracking of disease progression but there is no consensus yet on how tau PET signal is best quantified. The goal of the current study was to evaluate multiple whole-brain and region-specific approaches to detect clinically relevant tau PET signal. Two independent cohorts of cognitively normal adults and amyloid-positive (Aβ+) patients with mild cognitive impairment (MCI) or AD-dementia underwent [18F]AV-1451 PET. Methods for tau tracer quantification included: (i) in vivo Braak staging, (ii) regional uptake in Braak composite regions, (iii) several whole-brain measures of tracer uptake, (iv) regional uptake in AD-vulnerable voxels, and (v) uptake in a priori defined regions. Receiver operating curves characterized accuracy in distinguishing Aβ- controls from AD/MCI patients and yielded tau positivity cutoffs. Clinical relevance of tau PET measures was assessed by regressions against cognition and MR imaging measures. Key tracer uptake patterns were identified by a factor analysis and voxel-wise contrasts. Braak staging, global and region-specific tau measures yielded similar diagnostic accuracies, which differed between cohorts. While all tau measures were related to amyloid and global cognition, memory and hippocampal/entorhinal volume/thickness were associated with regional tracer retention in the medial temporal lobe. Key regions of tau accumulation included medial temporal and inferior/middle temporal regions, retrosplenial cortex, and banks of the superior temporal sulcus. Our data indicate that whole-brain tau PET measures might be adequate biomarkers to detect AD-related tau pathology. However, regional measures covering AD-vulnerable regions may increase sensitivity to early tau PET signal, atrophy and memory decline.

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CitationGPTRetr293

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: In vivo Patterns of Tau Pathology, Amyloid-β Burden, and Neuronal Dysfunction in Clinical Variants of Alzheimer's Disease. Abstract of the paper: The clinical heterogeneity of Alzheimer's disease is not reflected in the rather diffuse cortical deposition of amyloid-β. We assessed the relationship between clinical symptoms, in vivo tau pathology, amyloid distribution, and hypometabolism in variants of Alzheimer's disease using novel multimodal PET imaging techniques. Tau pathology was primarily observed in brain regions related to clinical symptoms and overlapped with areas of hypometabolism. In contrast, amyloid-β deposition was diffusely distributed over the entire cortex. Tau PET imaging may thus serve as a valuable biomarker for the localization of neuronal injury in vivo and may help to validate atypical subtypes of Alzheimer's disease.

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CitationGPTRetr294

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: Staging of Alzheimer-type pathology: an interrater-intrarater study. Abstract of the paper: The staging method proposed by Braak and Braak is based on the sequential accumulation of neurofibrillary pathology in the cerebral cortex. Unlike the currently used diagnostic criteria for Alzheimer's disease (AD) it does not take into consideration the age of the patients and whether they were demented or not for the establishment of the pathological stage of the disease. To examine the interobserver reliability of the method we performed an inter- and intrarater study using the Braak staging method in 41 brains. The agreement between the examiners and between the diagnoses of the same examiner at different times was almost perfect, the kappa statistics reaching values above 0.90. These findings indicate that the staging, relying on the differential distribution of neuritic pathology in the brain in AD, is a reliable and reproducible method for the description of AD-related pathology. This makes it suitable for brain-banking and research purposes.

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CitationGPTRetr295

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: Correlation of Alzheimer Disease Neuropathologic Staging with Amyloid and Tau Scintigraphic Imaging Biomarkers. Abstract of the paper: PET neuroimaging of amyloid-β (Aβ) provides an in vivo biomarker for pathologic changes associated with Alzheimer disease (AD). Aβ-targeted agents have been approved by the Food and Drug Administration, with additional agents, most notably targeting tau, currently under clinical investigation and one approved in May 2020. These agents, along with nonscintigraphic biomarkers from blood and cerebrospinal fluid, have provided an opportunity to investigate the pathogenesis, prodromal changes, and time course of the disease in living individuals. The current understanding is that the neuropathologic changes of the AD continuum begin up to 25 y before the onset of clinical symptomatology. The opportunities afforded by in vivo biomarkers of AD, whether by serum, cerebrospinal fluid examination or PET, have transformed the design of AD therapeutic trials by shifting focus to the preclinical stages of disease. Future disease-modifying therapies, should they be forthcoming, will rely heavily on the use of approved biomarkers or biomarkers currently under investigation to confirm the presence of target pathology. Understanding the progressive neuropathologic changes that occur in AD-and how scintigraphic findings relate to these changes-will help the interpreting physician to fully appreciate the implications of the scintigraphic findings and provide a basis to interpret the examinations. The recently adopted National Institute on Aging-Alzheimer Association guidelines define postmortem AD neuropathologic changes as a composite score based on 3 elements. These elements are the extent of involvement (spread) by cerebral Aβ based on the progression model defined by the Thal Aβ phases, the extent of involvement (spread) by neurofibrillary tangles (composed of hyperphosphorylated tau proteins) based on the progression model defined by Braak, and the Consortium to Establish a Registry for Alzheimer's Disease score, which describes the density of neuritic plaques based on certain key locations in the neocortex. This paper will review the 3 elements that define the National Institute on Aging-Alzheimer's Association scoring system and discusses current evidence on how these elements relate to findings based on Aβ and tau PET scintigraphy.

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CitationGPTRetr296

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: In vivo tau PET imaging in dementia: Pathophysiology, radiotracer quantification, and a systematic review of clinical findings. Abstract of the paper: In addition to the deposition of β-amyloid plaques, neurofibrillary tangles composed of aggregated hyperphosphorylated tau are one of the pathological hallmarks of Alzheimer's disease and other neurodegenerative disorders. Until now, our understanding about the natural history and topography of tau deposition has only been based on post-mortem and cerebrospinal fluid studies, and evidence continues to implicate tau as a central driver of downstream neurodegenerative processes and cognitive decline. Recently, it has become possible to assess the regional distribution and severity of tau burden in vivo with the development of novel radiotracers for positron emission tomography (PET) imaging. In this article, we provide a comprehensive discussion of tau pathophysiology, its quantification with novel PET radiotracers, as well as a systematic review of tau PET imaging in normal aging and various dementia conditions: mild cognitive impairment, Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy, and Lewy body dementia. We discuss the main findings in relation to group differences, clinical-cognitive correlations of tau PET, and multi-modal relationships among tau PET and other pathological markers. Collectively, the small but growing literature of tau PET has yielded consistent anatomical patterns of tau accumulation that recapitulate post-mortem distribution of neurofibrillary tangles which correlate with cognitive functions and other markers of pathology. In general, AD is characterised by increased tracer retention in the inferior temporal lobe, extending into the frontal and parietal regions in more severe cases. It is also noted that the spatial topography of tau accumulation is markedly distinct to that of amyloid burden in aging and AD. Tau PET imaging has also revealed characteristic spatial patterns among various non-AD tauopathies, supporting its potential role for differential diagnosis. Finally, we propose novel directions for future tau research, including (a) longitudinal imaging in preclinical dementia, (b) multi-modal mapping of tau pathology onto other pathological processes such as neuroinflammation, and (c) the need for more validation studies against post-mortem samples of the same subjects.

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CitationGPTRetr297

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: Widespread tau seeding activity at early Braak stages. Abstract of the paper: Transcellular propagation of tau aggregates may underlie the progression of pathology in Alzheimer's disease (AD) and other tauopathies. Braak staging (B1, B2, B3) is based on phospho-tau accumulation within connected brain regions: entorhinal cortex (B1); hippocampus/limbic system (B2); and frontal and parietal lobes (B3). We previously developed a specific and sensitive assay that uses flow cytometry to quantify tissue seeding activity based on fluorescence resonance energy transfer (FRET) in cells that stably express tau reporter proteins. In a tauopathy mouse model, we have detected seeding activity far in advance of histopathological changes. It remains unknown whether individuals with AD also develop seeding activity prior to accumulation of phospho-tau. We measured tau seeding activity across four brain regions (hippocampus, frontal lobe, parietal lobe, and cerebellum) in 104 fresh-frozen human AD brain samples from all Braak stages. We observed widespread seeding activity, notably in regions predicted to be free of phospho-tau deposition, and in detergent-insoluble fractions that lacked tau detectable by ELISA. Seeding activity correlated positively with Braak stage and negatively with MMSE. Our results are consistent with early transcellular propagation of tau seeds that triggers subsequent development of neuropathology. The FRET-based seeding assay may also complement standard neuropathological classification of tauopathies.

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CitationGPTRetr298

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: "End-stage" neurofibrillary tangle pathology in preclinical Alzheimer's disease: fact or fiction? Abstract of the paper: Among individuals who were cognitively intact before death, autopsies may reveal some Alzheimer's disease-type pathology. The presence of end-stage pathology in cognitively intact persons would support the hypothesis that pathological markers are epiphenomena. We assessed advanced neurofibrillary (Braak stages V and VI) pathology focusing on nondemented individuals. Data from the National Alzheimer's Coordinating Center database (n = 4,690 included initially) and from the Nun Study (n = 526 included initially) were analyzed, with antemortem information about global cognition and careful postmortem studies available from each case. Global cognition (final Mini-Mental State Examination scores (MMSE) and clinical 'dementia' status) was correlated with neuropathology, including the severity of neurofibrillary pathology (Braak stages and neurofibrillary tangle counts in cerebral neocortex). Analyses support three major findings: 1. Braak stage V cases and Braak VI cases are significantly different from each other in terms of associated antemortem cognition; 2. There is an appreciable range of pathology within the category of Braak stage VI based on tangle counts such that brains with the most neurofibrillary tangles in neocortex always had profound antemortem cognitive impairment; and 3. There was no nondemented case with final MMSE score of 30 within a year of life and Braak stage VI pathology. It may be inappropriate to combine Braak stages V and VI cases, particularly in patients with early cognitive dysfunction, since the two pathological stages appear to differ dramatically in terms of both pathological severity and antemortem cognitive status. There is no documented example of truly end-stage neurofibrillary pathology coexisting with intact cognition.

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CitationGPTRetr299

Predict the citation correlation between the following sentence and a biomedical paper represented by the provided title and abstract. Sentence: in vivo observations in these imaging studies have been shown to have significant compatibility with classic braak staging Title of the paper: High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer's and Non-Alzheimer's Disease Tauopathies. Abstract of the paper: A panel of radiochemicals has enabled in vivo positron emission tomography (PET) of tau pathologies in Alzheimer's disease (AD), although sensitive detection of frontotemporal lobar degeneration (FTLD) tau inclusions has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing diverse tau deposits. In vitro assays demonstrated the reactivity of this compound with tau pathologies in AD and FTLD. We could also utilize PM-PBB3 for optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of 18F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant progressive supranuclear palsy (PSP) tau topologies. Notably, the in vivo reactivity of 18F-PM-PBB3 with FTLD tau inclusion was strongly supported by neuropathological examinations of brains derived from Pick's disease, PSP, and corticobasal degeneration patients who underwent PET scans. Finally, visual inspection of 18F-PM-PBB3-PET images was indicated to facilitate individually based identification of diverse clinical phenotypes of FTLD on a neuropathological basis.

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