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Traumatic brain injuries (TBI) present a major public health challenge, demanding an in-depth understanding of age-specific symptoms and risk factors. Aging not only significantly influences brain function and plasticity but also elevates the risk of hospitalizations and death following TBIs. Repetitive mild TBIs (rmTBI) compound these issues, resulting in cumulative and long-term brain damage in the brain. In this study, we investigate the impact of age on brain network changes and white matter properties following rmTBI by employing a multi-modal approach that integrates resting-state functional magnetic resonance imaging (rsfMRI), graph theory analysis, diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI). Our hypothesis is that the effects of rmTBI are worsened in aged animals, with this group showing more pronounced alterations in brain connectivity and white matter structure. Utilizing the closed-head impact model of engineered rotational acceleration (CHIMERA) model, we conducted rmTBIs or sham (control) procedures on young (2.5-3-months-old) and aged (22-months-old) male and female mice to model high-risk groups. Functional and structural imaging unveiled age-related reductions in communication efficiency between brain regions, while injuries induced opposhigh-risking effects on the small-world index across age groups, influencing network segregation. Functional connectivity analysis also identified alterations in 79 out of 148 brain regions by age, treatment (sham vs. rmTBI), or their interaction. Injuries exerted pronounced effects on sensory integration areas, including insular and motor cortices. Age-related disruptions in white matter integrity were observed, indicating alterations in various diffusion directions (mean diffusivity, radial diffusivity, axial diffusivity, and fractional anisotropy) and density neurite properties (dispersion index, intracellular and isotropic volume fraction). Neuroinflammation, assessed through Iba-1 and GFAP markers, correlated with higher dispersion in the optic tract, suggesting a neuroinflammatory response in injured aged animals compared to sham aged. These findings offer insight into the interplay between age, injuries, and brain connectivity, shedding light on the long-term consequences of rmTBI.
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OBJECTIVES: Blood biomarkers have the potential to transform diagnosis and prognosis for multiple neurological indications. Establishing normative data is a critical benchmark in the analytical validation process. Normative data are important in children as little is known about how brain development may impact potential biomarkers. The objective of this study is to generate pediatric reference intervals (RIs) for serum neurofilament light (NfL), an axonal marker, and glial fibrillary acidic protein (GFAP), an astrocytic marker. METHODS: Serum from healthy children and adolescents aged 1 to <19â¯years were obtained from the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort. Serum NfL (n=300) and GFAP (n=316) were quantified using Simoa technology, and discrete RI (2.5th and 97.5th percentiles) and continuous RI (5th and 95th percentiles) were generated. RESULTS: While there was no association with sex, there was a statistically significant (p<0.0001) negative association between age and serum NfL (Rho -0.400) and GFAP (Rho -0.749). Two statistically significant age partitions were generated for NfL: age 1 to <10â¯years (lower, upper limit; 3.13, 20.6â¯pg/mL) and 10 to <19â¯years (1.82, 7.44â¯pg/mL). For GFAP, three statistically significant age partitions were generated: age 1 to <3.5â¯years (80.4, 601â¯pg/mL); 3.5 to <11â¯years (50.7, 224â¯pg/mL); and 11 to <19â¯years (26.2, 119â¯pg/mL). CONCLUSIONS: Taken together with the literature on adults, NfL and GFAP display U-shaped curves with high levels in infants, decreasing levels during childhood, a plateau during adolescence and early adulthood and increasing levels in seniors. These normative data are expected to inform future pediatric studies on the importance of age on neurological blood biomarkers.
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Filamentos Intermediários , Soro , Adulto , Adolescente , Humanos , Criança , Proteína Glial Fibrilar Ácida , Prognóstico , Biomarcadores , Proteínas de NeurofilamentosRESUMO
BACKGROUND: Central nervous system (CNS) injury following initiation of veno-venous extracorporeal membrane oxygenation (VV-ECMO) is common. An acute decrease in partial pressure of arterial carbon dioxide (PaCO2) following VV-ECMO initiation has been suggested as an etiological factor, but the challenges of diagnosing CNS injuries has made discerning a relationship between PaCO2 and CNS injury difficult. METHODS: We conducted a prospective cohort study of adult patients undergoing VV-ECMO for acute respiratory failure. Arterial blood gas measurements were obtained prior to initiation of VV-ECMO, and at every 2-4 h for the first 24 h. Neuroimaging was conducted within the first 7-14 days in patients who were suspected of having neurological injury or unable to be examined because of sedation. We collected blood biospecimens to measure brain biomarkers [neurofilament light (NF-L); glial fibrillary acidic protein (GFAP); and phosphorylated-tau 181] in the first 7 days following initiation of VV-ECMO. We assessed the relationship between both PaCO2 over the first 24 h and brain biomarkers with CNS injury using mixed methods linear regression. Finally, we explored the effects of absolute change of PaCO2 on serum levels of neurological biomarkers by separate mixed methods linear regression for each biomarker using three PaCO2 exposures hypothesized to result in CNS injury. RESULTS: In our cohort, 12 of 59 (20%) patients had overt CNS injury identified on head computed tomography. The PaCO2 decrease with VV-ECMO initiation was steeper in patients who developed a CNS injury (- 0.32%, 95% confidence interval - 0.25 to - 0.39) compared with those without (- 0.18%, 95% confidence interval - 0.14 to - 0.21, P interaction < 0.001). The mean concentration of NF-L increased over time and was higher in those with a CNS injury (464 [739]) compared with those without (127 [257]; P = 0.001). GFAP was higher in those with a CNS injury (4278 [11,653] pg/ml) compared with those without (116 [108] pg/ml; P < 0.001). The mean NF-L, GFAP, and tau over time in patients stratified by the three thresholds of absolute change of PaCO2 showed no differences and had no significant interaction for time. CONCLUSIONS: Although rapid decreases in PaCO2 following initiation of VV-ECMO were slightly greater in patients who had CNS injuries versus those without, data overlap and absence of relationships between PaCO2 and brain biomarkers suggests other pathophysiologic variables are likely at play.
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INTRODUCTION: This study investigates the effect of apolipoprotein E (APOE) genotype on neurology plasma biomarkers in cognitively healthy Super-Seniors. METHODS: Three hundred seventy plasma specimens from Super-Senior participants ≥ 85 years old, who have never been diagnosed with dementia, cancer, diabetes, cardiovascular, or major pulmonary disease, were analyzed on the Quanterix Simoa HD-X analyzer using commercial Neurology 4-plex E and phosphorylated tau (p-tau)181 assays. RESULTS: Eighty (22%) participants were APOE ε4 carriers and 290 (73%) were non-carriers. No significant differences were found between APOE ε4 carriers and non-carriers regarding age, sex, or Mini-Mental State Examination scores. In APOE ε4 carriers, plasma amyloid beta 42/40 was lower and p-tau181 and glial fibrillary acidic protein were higher compared to non-APOE ε4 carriers. After adjusting for demographic variables, p-tau181 was the only biomarker to remain significantly associated with APOE ε4 carrier status. DISCUSSION: APOE ε4 genotype modifies plasma p-tau181 concentration in seniors resilient to age-related clinical disease, suggesting that some Super-Seniors may have Alzheimer's disease pathology without progressing to cognitive decline. HIGHLIGHTS: Healthy seniors enable identification of associations that may be masked by disease. Plasma phosphorylated tau (p-tau)181 concentrations associate with apolipoprotein E (APOE) ε4 carriership in healthy seniors. APOE should be accounted for when interpreting p-tau181, regardless of disease.
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Apolipoproteína E4 , Biomarcadores , Proteínas tau , Humanos , Feminino , Masculino , Proteínas tau/sangue , Apolipoproteína E4/genética , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Genótipo , Heterozigoto , Doença de Alzheimer/sangue , Doença de Alzheimer/genética , FosforilaçãoRESUMO
Hypoxic ischaemic brain injury after resuscitation from cardiac arrest is associated with dismal clinical outcomes. To date, most clinical interventions have been geared towards the restoration of cerebral oxygen delivery after resuscitation; however, outcomes in clinical trials are disappointing. Therefore, alternative disease mechanism(s) are likely to be at play, of which the response of the innate immune system to sterile injured tissue in vivo after reperfusion has garnered significant interest. The innate immune system is composed of three pillars: (i) cytokines and signalling molecules; (ii) leucocyte migration and activation; and (iii) the complement cascade. In animal models of hypoxic ischaemic brain injury, pro-inflammatory cytokines are central to propagation of the response of the innate immune system to cerebral ischaemia-reperfusion. In particular, interleukin-1 beta and downstream signalling can result in direct neural injury that culminates in cell death, termed pyroptosis. Leucocyte chemotaxis and activation are central to the in vivo response to cerebral ischaemia-reperfusion. Both parenchymal microglial activation and possible infiltration of peripherally circulating monocytes might account for exacerbation of an immunopathological response in humans. Finally, activation of the complement cascade intersects with multiple aspects of the innate immune response by facilitating leucocyte activation, further cytokine release and endothelial activation. To date, large studies of immunomodulatory therapies have not been conducted; however, lessons learned from historical studies using therapeutic hypothermia in humans suggest that quelling an immunopathological response might be efficacious. Future work should delineate the precise pathways involved in vivo in humans to target specific signalling molecules.
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BACKGROUND: Preservation of brain health has emerged as a leading public health priority for the aging world population. Advances in neurovascular biology have revealed an intricate relationship among brain cells, meninges, and the hematic and lymphatic vasculature (the neurovasculome) that is highly relevant to the maintenance of cognitive function. In this scientific statement, a multidisciplinary team of experts examines these advances, assesses their relevance to brain health and disease, identifies knowledge gaps, and provides future directions. METHODS: Authors with relevant expertise were selected in accordance with the American Heart Association conflict-of-interest management policy. They were assigned topics pertaining to their areas of expertise, reviewed the literature, and summarized the available data. RESULTS: The neurovasculome, composed of extracranial, intracranial, and meningeal vessels, as well as lymphatics and associated cells, subserves critical homeostatic functions vital for brain health. These include delivering O2 and nutrients through blood flow and regulating immune trafficking, as well as clearing pathogenic proteins through perivascular spaces and dural lymphatics. Single-cell omics technologies have unveiled an unprecedented molecular heterogeneity in the cellular components of the neurovasculome and have identified novel reciprocal interactions with brain cells. The evidence suggests a previously unappreciated diversity of the pathogenic mechanisms by which disruption of the neurovasculome contributes to cognitive dysfunction in neurovascular and neurodegenerative diseases, providing new opportunities for the prevention, recognition, and treatment of these conditions. CONCLUSIONS: These advances shed new light on the symbiotic relationship between the brain and its vessels and promise to provide new diagnostic and therapeutic approaches for brain disorders associated with cognitive dysfunction.
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Disfunção Cognitiva , Acidente Vascular Cerebral , Estados Unidos , Humanos , American Heart Association , Acidente Vascular Cerebral/terapia , Encéfalo , CogniçãoRESUMO
[Figure: see text].
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Parada Cardíaca/complicações , Hipóxia-Isquemia Encefálica/sangue , Neuroglia/metabolismo , Adulto , Biomarcadores/sangue , Proteína Glial Fibrilar Ácida/sangue , Humanos , Hipóxia-Isquemia Encefálica/etiologia , Hipóxia-Isquemia Encefálica/patologia , Interleucina-6/metabolismo , Masculino , Proteínas de Neurofilamentos/sangue , Neuroglia/patologia , Fosfopiruvato Hidratase/sangue , Ubiquitina Tiolesterase/sangue , Proteínas tau/sangueRESUMO
BACKGROUND: Prognostication is very important to clinicians and families during the early management of severe traumatic brain injury (sTBI), however, there are no gold standard biomarkers to determine prognosis in sTBI. As has been demonstrated in several diseases, early measurement of serum metabolomic profiles can be used as sensitive and specific biomarkers to predict outcomes. METHODS: We prospectively enrolled 59 adults with sTBI (Glasgow coma scale, GCS ≤ 8) in a multicenter Canadian TBI (CanTBI) study. Serum samples were drawn for metabolomic profiling on the 1st and 4th days following injury. The Glasgow outcome scale extended (GOSE) was collected at 3- and 12-months post-injury. Targeted direct infusion liquid chromatography-tandem mass spectrometry (DI/LC-MS/MS) and untargeted proton nuclear magnetic resonance spectroscopy (1H-NMR) were used to profile serum metabolites. Multivariate analysis was used to determine the association between serum metabolomics and GOSE, dichotomized into favorable (GOSE 5-8) and unfavorable (GOSE 1-4), outcomes. RESULTS: Serum metabolic profiles on days 1 and 4 post-injury were highly predictive (Q2 > 0.4-0.5) and highly accurate (AUC > 0.99) to predict GOSE outcome at 3- and 12-months post-injury and mortality at 3 months. The metabolic profiles on day 4 were more predictive (Q2 > 0.55) than those measured on day 1 post-injury. Unfavorable outcomes were associated with considerable metabolite changes from day 1 to day 4 compared to favorable outcomes. Increased lysophosphatidylcholines, acylcarnitines, energy-related metabolites (glucose, lactate), aromatic amino acids, and glutamate were associated with poor outcomes and mortality. DISCUSSION: Metabolomic profiles were strongly associated with the prognosis of GOSE outcome at 3 and 12 months and mortality following sTBI in adults. The metabolic phenotypes on day 4 post-injury were more predictive and significant for predicting the sTBI outcome compared to the day 1 sample. This may reflect the larger contribution of secondary brain injury (day 4) to sTBI outcome. Patients with unfavorable outcomes demonstrated more metabolite changes from day 1 to day 4 post-injury. These findings highlighted increased concentration of neurobiomarkers such as N-acetylaspartate (NAA) and tyrosine, decreased concentrations of ketone bodies, and decreased urea cycle metabolites on day 4 presenting potential metabolites to predict the outcome. The current findings strongly support the use of serum metabolomics, that are shown to be better than clinical data, in determining prognosis in adults with sTBI in the early days post-injury. Our findings, however, require validation in a larger cohort of adults with sTBI to be used for clinical practice.
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Lesões Encefálicas Traumáticas , Espectrometria de Massas em Tandem , Humanos , Escala de Resultado de Glasgow , Cromatografia Líquida , Canadá , Lesões Encefálicas Traumáticas/complicações , Metabolômica , Ácido LácticoRESUMO
Traumatic brain injury (TBI) is an established risk factor for neurodegenerative diseases. In this study, we used the Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA) to investigate the effects of a single high-energy TBI in rTg4510 mice, a mouse model of tauopathy. Fifteen male rTg4510 mice (4 mo) were impacted at 4.0 J using interfaced CHIMERA and were compared to sham controls. Immediately after injury, the TBI mice showed significant mortality (7/15; 47%) and a prolonged duration of loss of the righting reflex. At 2 mo post-injury, surviving mice displayed significant microgliosis (Iba1) and axonal injury (Neurosilver). Western blotting indicated a reduced p-GSK-3ß (S9):GSK-3ß ratio in TBI mice, suggesting chronic activation of tau kinase. Although longitudinal analysis of plasma total tau suggested that TBI accelerates the appearance of tau in the circulation, there were no significant differences in brain total or p-tau levels, nor did we observe evidence of enhanced neurodegeneration in TBI mice compared to sham mice. In summary, we showed that a single high-energy head impact induces chronic white matter injury and altered GSK-3ß activity without an apparent change in post-injury tauopathy in rTg4510 mice.
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Lesões Encefálicas Traumáticas , Traumatismos Cranianos Fechados , Tauopatias , Camundongos , Masculino , Animais , Glicogênio Sintase Quinase 3 beta/genética , Lesões Encefálicas Traumáticas/genética , Encéfalo/metabolismo , Tauopatias/genética , Modelos Animais de Doenças , Aceleração , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Mechanisms underlying the SARS-CoV-2-triggered hyperacute thrombo-inflammatory response that causes multi-organ damage in coronavirus disease 2019 (COVID-19) are poorly understood. Several lines of evidence implicate overactivation of complement. To delineate the involvement of complement in COVID-19, we prospectively studied 25 ICU-hospitalized patients for up to 21 days. Complement biomarkers in patient sera and healthy controls were quantified by enzyme-linked immunosorbent assays. Correlations with respiratory function and mortality were analyzed. Activation of complement via the classical/lectin pathways was variably increased. Strikingly, all patients had increased activation of the alternative pathway (AP) with elevated levels of activation fragments, Ba and Bb. This was associated with a reduction of the AP negative regulator, factor (F) H. Correspondingly, terminal pathway biomarkers of complement activation, C5a and sC5b-9, were significantly elevated in all COVID-19 patient sera. C5a and AP constituents Ba and Bb, were significantly associated with hypoxemia. Ba and FD at the time of ICU admission were strong independent predictors of mortality in the following 30 days. Levels of all complement activation markers were sustained throughout the patients' ICU stays, contrasting with the varying serum levels of IL-6, C-reactive protein, and ferritin. Severely ill COVID-19 patients have increased and persistent activation of complement, mediated strongly via the AP. Complement activation biomarkers may be valuable measures of severity of lung disease and the risk of mortality. Large-scale studies will reveal the relevance of these findings to thrombo-inflammation in acute and post-acute COVID-19.
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COVID-19 , Biomarcadores , Ativação do Complemento , Mortalidade Hospitalar , Humanos , Hipóxia , SARS-CoV-2RESUMO
Mild traumatic brain injuries are typically caused by nonpenetrating head impacts that accelerate the skull and result in deformation of the brain within the skull. The shear and compressive strains caused by these deformations damage neural and vascular structures and impair their function. Accurate head acceleration measurements are necessary to define the nature of the insult to the brain. A novel murine head tracking system was developed to improve the accuracy and efficiency of kinematic measurements obtained with high-speed videography. A three-dimensional (3D)-printed marker carrier was designed for rigid fixation to the upper jaw and incisors with an elastic strap around the snout. The system was evaluated by impacting cadaveric mice with the closed head impact model of engineered rotational acceleration (CHIMERA) system using an energy of 0.7 J (5.29 m/s). We compared the performance of the head-marker system to the previously used skin-tracking method and documented significant improvements in measurement repeatability (aggregate coefficient of variation (CV) within raters from 15.8 to 1.5 and between raters from 15.5 to 1.5), agreement (aggregate percentage error from 24.9 to 8.7), and temporal response (aggregate temporal curve agreement from 0.668 to 0.941). Additionally, the new system allows for automated software tracking, which dramatically decreases the analysis time required (74% reduction). This novel head tracking system for mice offers an efficient, reliable, and real-time method to measure head kinematics during high-speed impacts using CHIMERA or other rodent or small mammal head impact models.
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Concussão Encefálica , Aceleração , Fenômenos Biomecânicos , RotaçãoRESUMO
Vascular contributions to cognitive impairment and dementia (VCID) are characterized by the aging neurovascular unit being confronted with and failing to cope with biological insults due to systemic and cerebral vascular disease, proteinopathy including Alzheimer's biology, metabolic disease, or immune response, resulting in cognitive decline. This report summarizes the discussion and recommendations from a working group convened by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke to evaluate the state of the field in VCID research, identify research priorities, and foster collaborations. As discussed in this report, advances in understanding the biological mechanisms of VCID across the wide spectrum of pathologies, chronic systemic comorbidities, and other risk factors may lead to potential prevention and new treatment strategies to decrease the burden of dementia. Better understanding of the social determinants of health that affect risks for both vascular disease and VCID could provide insight into strategies to reduce racial and ethnic disparities in VCID.
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Encéfalo/fisiopatologia , Transtornos Cerebrovasculares/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Demência Vascular/fisiopatologia , Educação , Envelhecimento/fisiologia , Biomarcadores , Humanos , National Heart, Lung, and Blood Institute (U.S.) , National Institute of Neurological Disorders and Stroke (USA) , Estados UnidosRESUMO
PURPOSE OF REVIEW: We review current knowledge regarding HDL and Alzheimer's disease, focusing on HDL's vasoprotective functions and potential as a biomarker and therapeutic target for the vascular contributions of Alzheimer's disease. RECENT FINDINGS: Many epidemiological studies have observed that circulating HDL levels associate with decreased Alzheimer's disease risk. However, it is now understood that the functions of HDL may be more informative than levels of HDL cholesterol (HDL-C). Animal model studies demonstrate that HDL protects against memory deficits, neuroinflammation, and cerebral amyloid angiopathy (CAA). In-vitro studies using state-of-the-art 3D models of the human blood-brain barrier (BBB) confirm that HDL reduces vascular Aß accumulation and attenuates Aß-induced endothelial inflammation. Although HDL-based therapeutics have not been tested in clinical trials for Alzheimer's disease , several HDL formulations are in advanced phase clinical trials for coronary artery disease and atherosclerosis and could be leveraged toward Alzheimer's disease . SUMMARY: Evidence from human studies, animal models, and bioengineered arteries supports the hypothesis that HDL protects against cerebrovascular dysfunction in Alzheimer's disease. Assays of HDL functions relevant to Alzheimer's disease may be desirable biomarkers of cerebrovascular health. HDL-based therapeutics may also be of interest for Alzheimer's disease, using stand-alone or combination therapy approaches.
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Doença de Alzheimer/metabolismo , Lipoproteínas HDL/metabolismo , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Animais , Comorbidade , Humanos , Resistência VascularRESUMO
Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.
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Doença de Alzheimer/fisiopatologia , Biomarcadores , Doenças Vasculares/fisiopatologia , Substância Branca/patologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/metabolismo , Encéfalo/patologia , Circulação Cerebrovascular/fisiologia , Humanos , National Institute on Aging (U.S.) , Estados UnidosRESUMO
High-density lipoproteins (HDL) are known to have vasoprotective functions in peripheral arteries and many of these functions extend to brain-derived endothelial cells. Importantly, several novel brain-relevant HDL functions have been discovered using brain endothelial cells and in 3D bioengineered human arteries. The cerebrovascular benefits of HDL in healthy humans may partly explain epidemiological evidence suggesting a protective association of circulating HDL levels against Alzheimer's Disease (AD) risk. As several methods exist to prepare HDL from plasma, here we compared cerebrovascular functions relevant to AD using HDL isolated by density gradient ultracentrifugation relative to apoB-depleted plasma prepared by polyethylene-glycol precipitation, a common high-throughput method to evaluate HDL cholesterol efflux capacity in clinical biospecimens. We found that apoB-depleted plasma was functionally equivalent to HDL isolated by ultracentrifugation in terms of its ability to reduce vascular Aß accumulation, suppress TNFα-induced vascular inflammation and delay Aß fibrillization. However, only HDL isolated by ultracentrifugation was able to suppress Aß-induced vascular inflammation, improve Aß clearance, and induce endothelial nitric oxide production.
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Doença de Alzheimer/sangue , Doença de Alzheimer/metabolismo , Apolipoproteínas B/deficiência , Lipoproteínas HDL/sangue , Lipoproteínas HDL/metabolismo , Plasma/metabolismo , Adulto , Peptídeos beta-Amiloides/metabolismo , Bioengenharia , Barreira Hematoencefálica/metabolismo , Células Cultivadas , Angiopatia Amiloide Cerebral/sangue , Angiopatia Amiloide Cerebral/metabolismo , Células Endoteliais/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Inflamação/sangue , Inflamação/metabolismo , Masculino , Monócitos/citologia , Monócitos/metabolismo , Óxido Nítrico/metabolismo , Adulto JovemRESUMO
apoE is the primary lipid carrier within the CNS and the strongest genetic risk factor for late onset Alzheimer's disease (AD). apoE is primarily lipidated via ABCA1, and both are under transcriptional regulation by the nuclear liver X receptor (LXR). Considerable evidence from genetic (using ABCA1 overexpression) and pharmacological (using synthetic LXR agonists) studies in AD mouse models suggests that increased levels of lipidated apoE can improve cognitive performance and, in some strains, can reduce amyloid burden. However, direct synthetic LXR ligands have hepatotoxic side effects that limit their clinical use. Here, we describe a set of small molecules, previously annotated as antagonists of the purinergic receptor, P2X7, which enhance ABCA1 expression and activity as well as apoE secretion, and are not direct LXR ligands. Furthermore, P2X7 is not required for these molecules to induce ABCA1 upregulation and apoE secretion, demonstrating that the ABCA1 and apoE effects are mechanistically independent of P2X7 inhibition. Hence, we have identified novel dual activity compounds that upregulate ABCA1 across multiple CNS cell types, including human astrocytes, pericytes, and microglia, through an indirect LXR mechanism and that also independently inhibit P2X7 receptor activity.
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Transportador 1 de Cassete de Ligação de ATP/agonistas , Apolipoproteínas E/agonistas , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Adamantano/análogos & derivados , Adamantano/química , Adamantano/farmacologia , Animais , Apolipoproteínas E/metabolismo , Aziridinas/química , Aziridinas/farmacologia , Benzamidas/química , Benzamidas/farmacologia , Células Cultivadas , Humanos , Camundongos , Camundongos Knockout , Estrutura Molecular , Naftoquinonas/química , Naftoquinonas/farmacologia , Antagonistas do Receptor Purinérgico P2X/química , Receptores Purinérgicos P2X7/deficiência , Bibliotecas de Moléculas Pequenas/química , Sulfonamidas/química , Sulfonamidas/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
INTRODUCTION: In recent years, there has been growing discussion to better understand the pathophysiological mechanisms of traumatic brain injury and post-traumatic stress disorder and how they may be linked to an increased risk of neurodegenerative diseases including Alzheimer's disease in veterans. METHODS: Building on that discussion, and subsequent to a special issue of Alzheimer's & Dementia published in June 2014, which focused on military risk factors, the Alzheimer's Association convened a continued discussion of the scientific community on December 1, 2016. RESULTS: During this meeting, participants presented and evaluated progress made since 2012 and identified outstanding knowledge gaps regarding factors that may impact veterans' risk for later life dementia. DISCUSSION: The following is a summary of the invited presentations and moderated discussions of both the review of scientific understanding and identification of gaps to inform further investigations.
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Demência/etiologia , Militares , Veteranos , Animais , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/epidemiologia , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/fisiopatologia , Congressos como Assunto , Demência/epidemiologia , Demência/genética , Demência/fisiopatologia , Humanos , Fatores de RiscoRESUMO
Many lines of evidence suggest a protective role for high-density lipoprotein (HDL) and its major apolipoprotein (apo)A-I in Alzheimer's Disease (AD). HDL/apoA-I particles are produced by the liver and intestine and, in addition to removing excess cholesterol from the body, are increasingly recognized to have vasoprotective functions. Here we tested the ability of reconstituted HDL (rHDL) consisting of human apoA-I reconstituted with soy phosphatidylcholine for its ability to lower amyloid beta (Aß) levels in symptomatic APP/PS1 mice, a well-characterized preclinical model of amyloidosis. Animals were treated intravenously either with four weekly doses (chronic study) or a single dose of 60mg/kg of rHDL (acute study). The major finding of our acute study is that soluble brain Aß40 and Aß42 levels were significantly reduced within 24h of a single dose of rHDL. By contrast, no changes were observed in our chronic study with respect to soluble or deposited Aß levels in animals assessed 7days after the final weekly dose of rHDL, suggesting that beneficial effects diminish as rHDL is cleared from the body. Further, rHDL-treated animals showed no change in amyloid burden, cerebrospinal fluid (CSF) Aß levels, neuroinflammation, or endothelial activation in the chronic study, suggesting that the pathology-modifying effects of rHDL may indeed be acute and may be specific to the soluble Aß pool. That systemic administration of rHDL can acutely modify brain Aß levels provides support for further investigation of the therapeutic potential of apoA-I-based agents for AD. 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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Peptídeos beta-Amiloides/metabolismo , Amiloidose/terapia , Apolipoproteína A-I/uso terapêutico , Encéfalo/metabolismo , Lipoproteínas HDL/uso terapêutico , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/sangue , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/sangue , Amiloidose/sangue , Amiloidose/metabolismo , Amiloidose/patologia , Animais , Apolipoproteína A-I/administração & dosagem , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Lipoproteínas HDL/administração & dosagem , Masculino , Camundongos , Camundongos Transgênicos , Fragmentos de Peptídeos/sangueRESUMO
PURPOSE OF REVIEW: This article evaluates recent experimental and human evidence regarding the involvement of lipids, lipoproteins, and apolipoproteins in neurodegenerative diseases, and reviews the current literature of the effects of cholesterol-lowering treatment on cognition. RECENT FINDINGS: Plasma levels of traditional lipids and lipoproteins are not consistently associated with risk of dementia even though low plasma levels of apolipoprotein E, through unknown mechanisms, robustly predict future dementia. Experimental evidence suggests neuroprotective roles of several brain and cerebrospinal fluid apolipoproteins. Whether plasma levels of apolipoprotein E, or any other apolipoprotein with possible central nervous system and/or blood-brain barrier functions (apolipoproteins J, A-I, A-II, A-IV, D, C-I, and C-III) may become accessible biomarker components that improve risk prediction for dementia together with genetic risk variants and cardiovascular risk factors remains to be determined. SUMMARY: Apolipoproteins with well established functions in peripheral lipid metabolism may play important roles for brain vascular health and Alzheimer's disease pathophysiology. Experimental work on lipids, lipoproteins, and apolipoproteins in the central nervous system together with robust prospective human studies will help to substantiate the drug target potential of these lipid components.