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BACKGROUND: Chronically dysregulated neuroinflammation has been implicated in neurodegenerative dementias, with separate studies reporting increased brain levels of inflammatory mediators and gliosis in Alzheimer's disease (AD) as well as in Lewy body dementias (LBD). However, it is unclear whether the nature and extent of neuroinflammatory responses in LBD are comparable to those in AD. In this study, we performed head-to-head measurements of a panel of cytokines in the post-mortem neocortex of AD versus the two major clinical subtypes of LBD, namely, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). METHODS: Post-mortem tissues from the mid-temporal cortex (Brodmann area 21) of a cohort of neuropathologically well-defined AD, PDD and DLB patients were processed and measured for a comprehensive range of cytokines (IL-1α, IL-1Ra, IL-8, IL-10, IL-12p70, IL-13, IFN-γ, GM-CSF and FGF-2) using a multiplex immunoassay platform. Associations between inflammation markers and neuropathological measures of neuritic plaques, neurofibrillary tangles as well as Lewy bodies were also performed. RESULTS: We found IL-1α, IFN-γ, GM-CSF and IL-13 to be elevated in the mid-temporal cortex of AD patients. In contrast, none of the measured cytokines were significantly altered in either DLB or PDD. Similar cytokine changes were observed in two other neocortical areas of AD patients. Furthermore, increases of IL-1α, IFN-γ, GM-CSF, IL-10 and IL-13 associated with moderate-to-severe neurofibrillary tangle burden, but not with neuritic plaques or Lewy bodies. Our findings of elevated neocortical pro- and anti-inflammatory cytokines in AD, but not in DLB or PDD, suggest that neuroinflammatory responses are strongly linked to neurofibrillary tangle burden, which is higher in AD compared to LBD. In conclusion, neuroinflammation may not play a prominent role in the pathophysiology of late-stage LBD.
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Enfermedad de Alzheimer , Demencia , Neocórtex , Enfermedad de Parkinson , Humanos , Citocinas , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Interleucina-10 , Interleucina-13 , Enfermedades Neuroinflamatorias , Placa AmiloideRESUMEN
Chronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long-term cognitive impairment and memory loss. Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate its effect on the innate immune response-particularly the inflammasome signaling pathway. Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their downstream products (IL-1ß and IL-18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Polarized glial-cell activation, white-matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 knockout mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis, and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioral and cognitive deficits following BCAS. Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD.
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Disfunción Cognitiva , Demencia Vascular , Sustancia Blanca , Animales , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Inflamasomas/metabolismo , Ratones , Ratones Endogámicos C57BL , Sustancia Blanca/metabolismoRESUMEN
Background and Purpose: Cardiac biomarkers, NT-proBNP (N-terminal probrain natriuretic peptide), hs-cTnT (high-sensitivity-cardiac troponin T), and GDF-15 (growth differentiation factor-15) have been proposed as important biomarkers of early vascular pathology. However, little is known of the longitudinal associations of these cardiac biomarkers with cerebrovascular disease and clinical events. We examine the association of blood-based cardiac biomarkers (NT-proBNP, hs-cTnT, and GDF-15) with cognitive decline, incident cerebrovascular disease, vascular events, and mortality. Methods: Four hundred thirty-four memory-clinic patients provided blood samples at baseline, underwent 3 annual neuropsychological assessments and brain magnetic resonance imaging scans at baseline and follow-up. NT-proBNP and hs-cTnT concentrations were measured by electrochemiluminescence immunoassay and GDF-15 by quantitative sandwich immunoassay. Baseline and follow-up magnetic resonance imagings were graded for white matter hyperintensities, lacunes, cerebral microbleeds, cortical infarcts, and intracranial stenosis. Data on incident vascular events and mortality were obtained. Results: Patients with higher levels of NT-proBNP, hs-cTnT, and GDF-15 showed greater decline in memory domain. Additionally, hs-cTnT was associated with decline in global cognition, executive function, and visuomotor speed. Higher levels of NT-proBNP were associated with incident cerebral microbleeds and hs-cTnT with incident cortical infarcts. During a mean follow-up of 3 years, 26 (5.9%) patients died and 35 (8.1%) developed vascular events. Patients with higher levels of NTpro-BNP and hs-cTnT were at increased risk of vascular events whereas those with higher levels of NT-proBNP and GDF-15 were at risk of mortality. Conclusions: Higher levels of blood-based cardiac biomarkers were associated with decline in memory and risk of vascular events and mortality. Moreover, NT-proBNP and hs-cTnT were associated with incident cerebral microbleeds and cortical infarcts. Thus, these biomarkers are potentially useful in identifying patients at risk of adverse vascular events and death.
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Trastornos Cerebrovasculares/sangre , Disfunción Cognitiva/sangre , Factor 15 de Diferenciación de Crecimiento/sangre , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Troponina T/sangre , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Trastornos Cerebrovasculares/diagnóstico por imagen , Trastornos Cerebrovasculares/psicología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/psicología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Factores de RiesgoRESUMEN
Discovery and development of clinically useful biomarkers for Alzheimer's disease (AD) and related dementias have been the focus of recent research efforts. While cerebrospinal fluid and positron emission tomography or MRI-based neuroimaging markers have made the in vivo detection of AD pathology and its consequences possible, the high cost and invasiveness have limited their widespread use in the clinical setting. On the other hand, advances in potentially more accessible blood-based biomarkers had been impeded by lack of sensitivity in detecting changes in markers of the hallmarks of AD, including amyloid-ß (Aß) peptides and phosphorylated tau (P-tau). More recently, however, emerging technologies with superior sensitivity and specificity for measuring Aß and P-tau have reported high concordances with AD severity. In this focused review, we describe several emerging technologies, including immunoprecipitation-mass spectrometry (IP-MS), single molecule array and Meso Scale Discovery immunoassay platforms, and appraise the current literature arising from their use to identify plaques, tangles and other AD-associated pathology. While there is potential clinical utility in adopting these technologies, we also highlight the further studies needed to establish Aß and P-tau as blood-based biomarkers for AD, including validation with existing large sample sets, new independent cohorts from diverse backgrounds as well as population-based longitudinal studies. In conclusion, the availability of sensitive and reliable measurements of Aß peptides and P-tau species in blood holds promise for the diagnosis, prognosis and outcome assessments in clinical trials for AD.
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Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/sangre , Proteínas tau/sangre , Enfermedad de Alzheimer/sangre , Biomarcadores/sangre , Humanos , FosforilaciónRESUMEN
INTRODUCTION: There is increasing evidence that phosphorylated tau (P-tau181) is a specific biomarker for Alzheimer's disease (AD) pathology, but its potential utility in non-White patient cohorts and patients with concomitant cerebrovascular disease (CeVD) is unknown. METHODS: Single molecule array (Simoa) measurements of plasma P-tau181, total tau, amyloid beta (Aß)40 and Aß42, as well as derived ratios were correlated with neuroimaging modalities indicating brain amyloid (Aß+), hippocampal atrophy, and CeVD in a Singapore-based cohort of non-cognitively impaired (NCI; n = 43), cognitively impaired no dementia (CIND; n = 91), AD (n = 44), and vascular dementia (VaD; n = 22) subjects. RESULTS: P-tau181/Aß42 ratio showed the highest area under the curve (AUC) for Aß+ (AUC = 0.889) and for discriminating between AD Aß+ and VaD Aß- subjects (AUC = 0.903). In addition, P-tau181/Aß42 ratio was associated with hippocampal atrophy. None of the biomarkers was associated with CeVD. DISCUSSION: Plasma P-tau181/Aß42 ratio may be a noninvasive means of identifying AD with elevated brain amyloid in populations with concomitant CeVD.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides/sangre , Pueblo Asiatico/estadística & datos numéricos , Trastornos Cerebrovasculares/complicaciones , Fragmentos de Péptidos/sangre , Proteínas tau/sangre , Anciano , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/patología , Atrofia/patología , Biomarcadores/sangre , Encéfalo/patología , Disfunción Cognitiva/patología , Estudios de Cohortes , Hipocampo/patología , Humanos , Fosforilación , Tomografía de Emisión de Positrones , SingapurRESUMEN
Lipids comprise an exceptionally diverse class of bioactive macromolecules. While quantitatively abundant lipid species serve fundamental roles in cell structure and energy metabolism, thousands of structurally-distinct, quantitatively minor species may serve as important regulators of cellular processes. Historically, a complete understanding of the biological roles of these lipids has been limited by a lack of sensitive, discriminating analytical techniques. The class of sphingolipids alone, for example, is known to consist of over 600 different confirmed species, but is likely to include tens of thousands of metabolites with potential biological significance. Advances in mass spectrometry (MS) have improved the throughput and discrimination of lipid analysis, allowing for the determination of detailed lipid profiles in large cohorts of clinical samples. Databases emerging from these studies will provide a rich resource for the identification of novel biomarkers and for the discovery of potential drug targets, analogous to that of existing genomics databases. In this review, we will provide an overview of the field of sphingolipidomics, and will discuss some of the challenges and considerations facing the generation of robust lipidomics databases.
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Metabolismo de los Lípidos , Metabolómica/métodos , Metabolómica/estadística & datos numéricos , Esfingolípidos/análisis , Cromatografía Liquida , Estudios de Cohortes , Bases de Datos Factuales , Humanos , Espectrometría de Masas , Estructura Molecular , Esfingolípidos/químicaRESUMEN
It has been known for decades that the regulation of sphingolipids (SLs) is essential for the proper function of many cellular processes. However, a complete understanding of these processes has been complicated by the structural diversity of these lipids. A well-characterized metabolic pathway is responsible for homeostatic maintenance of hundreds of distinct SL species. This pathway is perturbed in a number of pathological processes, resulting in derangement of the "sphingolipidome." Recently, advances in mass spectrometry (MS) techniques have made it possible to characterize the sphingolipidome in large-scale clinical studies, allowing for the identification of specific SL molecules that mediate pathological processes and/or may serve as biomarkers. This manuscript provides an overview of the functions of SLs, and reviews previous studies that have used MS techniques to identify changes to the sphingolipidome in non-metabolic diseases.
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Metabolismo de los Lípidos , Redes y Vías Metabólicas , Metabolómica/métodos , Esfingolípidos/análisis , Cromatografía Liquida , Estudios de Cohortes , Humanos , Espectrometría de Masas , Neoplasias/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Esfingolípidos/metabolismoRESUMEN
Alzheimer's disease (AD) is the leading cause of dementia in old age and is characterized by the accumulation of ß-amyloid plaques and neurofibrillary tangles (NFT). Recent studies suggest that Fyn tyrosine kinase forms part of a toxic triad with ß-amyloid and tau in the disease process. However, it is not known whether Fyn is associated with the pathological features of AD in an isoform-specific manner. In this study, we identified selective up-regulation of the alternative-spliced FynT isoform with no change in FynB in the AD neocortex. Furthermore, gene ontology term enrichment analyses and cell type-specific localization of FynT immunoreactivity suggest that FynT up-regulation was associated with neurofibrillary degeneration and reactive astrogliosis. Interestingly, significantly increased FynT in NFT-bearing neurons was concomitant to decreased FynB immunoreactivity, suggesting an involvement of alternative splicing in NFT formation. Furthermore, cultured cells of astrocytic origin have higher FynT to FynB ratio compared to those of neuronal origin. Lastly, primary rat mixed neuron-astrocyte cultures treated with Aß25-35 showed selective up-regulation of FynT expression in activated astrocytes. Our findings point to an isoform-specific role of FynT in modulating neurofibrillary degeneration and reactive astrogliosis in AD. Fyn kinase is known to interact with ß-amyloid and tau, and contributes to Alzheimer's disease pathogenesis. In this study, it is shown that the alternatively spliced FynT isoform is specifically up-regulated in the AD neocortex, with no change in FynB isoform. The increased FynT correlated with markers of neurofibrillary degeneration and reactive astrogliosis. In primary mixed cultures, treatment with amyloid peptides specifically up-regulated FynT in activated astrocytes. This study points to altered alternative splicing as a potential pathogenic mechanism in AD.
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Enfermedad de Alzheimer/patología , Corteza Prefrontal/enzimología , Isoformas de Proteínas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Péptidos beta-Amiloides/farmacología , Animales , Células Cultivadas , Técnicas de Cocultivo , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/metabolismo , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fragmentos de Péptidos/farmacología , Corteza Prefrontal/patología , Isoformas de Proteínas/genética , Proteínas Tirosina Quinasas/genética , Ratas , Regulación hacia Arriba/fisiologíaRESUMEN
BACKGROUND: Andrographolide is the major labdane diterpenoid originally isolated from Andrographis paniculata and has been shown to have anti-inflammatory and antioxidative effects. However, there is a dearth of studies on the potential therapeutic utility of andrographolide in neuroinflammatory conditions. Here, we aimed to investigate the mechanisms underlying andrographolide's effect on the expression of anti-inflammatory and antioxidant heme oxygenase-1 (HO-1) in primary astrocytes. METHODS: Measurements of the effects of andrograholide on antioxidant HO-1 and its transcription factor, Nrf2, include gene expression, protein turnover, and activation of putative signaling regulators. RESULTS: Andrographolide potently activated Nrf2 and also upregulated HO-1 expression in primary astrocytes. Andrographolide's effects on Nrf2 seemed to be biphasic, with acute (within 1 h) reductions in Nrf2 ubiquitination efficiency and turnover rate, followed by upregulation of Nrf2 mRNA between 8 and 24 h. The acute regulation of Nrf2 by andrographolide seemed to be independent of Keap1 and partly mediated by p38 MAPK and ERK signaling. CONCLUSIONS: These data provide further insights into the mechanisms underlying andrographolide's effects on astrocyte-mediated antioxidant, and anti-inflammatory responses and support the further assessment of andrographolide as a potential therapeutic for neurological conditions in which oxidative stress and neuroinflammation are implicated.
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BACKGROUND: Andrographolide is the major bioactive compound isolated from Andrographis paniculata, a native South Asian herb used medicinally for its anti-inflammatory properties. In this study, we aimed to assess andrographolide's potential utility as an anti-neuroinflammatory therapeutic. METHODS: The effects of andrographolide on lipopolysaccharide (LPS)-induced chemokine up-regulation both in mouse cortex and in cultured primary astrocytes were measured, including cytokine profiling, gene expression, and, in cultured astrocytes, activation of putative signaling regulators. RESULTS: Orally administered andrographolide significantly attenuated mouse cortical chemokine levels from the C-C and C-X-C subfamilies. Similarly, andrographolide abrogated a range of LPS-induced chemokines as well as tumor necrosis factor (TNF)-α in astrocytes. In astrocytes, the inhibitory actions of andrographolide on chemokine and TNF-α up-regulation appeared to be mediated by nuclear factor-κB (NF-κB) or c-Jun N-terminal kinase (JNK) activation. CONCLUSIONS: These results suggest that andrographolide may be useful as a therapeutic for neuroinflammatory diseases, especially those characterized by chemokine dysregulation.
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Antiinflamatorios/farmacología , Astrocitos/efectos de los fármacos , Corteza Cerebral/citología , Quimiocinas CXC/metabolismo , Diterpenos/farmacología , Regulación hacia Arriba/efectos de los fármacos , Análisis de Varianza , Animales , Supervivencia Celular/efectos de los fármacos , Quimiocinas CXC/genética , Relación Dosis-Respuesta a Droga , Lipopolisacáridos/farmacología , MAP Quinasa Quinasa 4/metabolismo , Ratones , FN-kappa B/metabolismo , RatasRESUMEN
Dementia is a major public health burden characterized by impaired cognition and loss of function. There are limited treatment options due to inadequate understanding of its pathophysiology and underlying causative mechanisms. Discovery-driven iTRAQ-based quantitative proteomics techniques were applied on frozen brain samples to profile the proteome from vascular dementia (VaD) and age-matched nondementia controls to elucidate the perturbed pathways contributing to pathophysiology of VaD. The iTRAQ quantitative data revealed significant up-regulation of protein-l-isoaspartate O-methyltransferase and sodium-potassium transporting ATPase, while post-translational modification analysis suggested deamidation of catalytic and regulatory subunits of sodium-potassium transporting ATPase. Spontaneous protein deamidation of labile asparagines, generating abnormal l-isoaspartyl residues, is associated with cell aging and dementia due to Alzheimer's disease and may be a cause of neurodegeneration. As ion channel proteins play important roles in cellular signaling processes, alterations in their function by deamidation may lead to perturbations in membrane excitability and neuronal function. Structural modeling of sodium-potassium transporting ATPase revealed the close proximity of these deamidated residues to the catalytic site during E2P confirmation. The deamidated residues may disrupt electrostatic interaction during E1 phosphorylation, which may affect ion transport and signal transduction. Our findings suggest impaired regulation and compromised activity of ion channel proteins contribute to the pathophysiology of VaD.
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Demencia Vascular/metabolismo , Modelos Moleculares , Proteína D-Aspartato-L-Isoaspartato Metiltransferasa/metabolismo , Proteómica/métodos , Transducción de Señal/fisiología , Proteínas Cotransportadoras de Sodio-Fosfato/metabolismo , Amidas/metabolismo , Cromatografía Liquida , Biología Computacional , Humanos , Fosforilación , Electricidad Estática , Espectrometría de Masas en Tándem , Reino UnidoRESUMEN
Dementia with Lewy bodies and Parkinson's disease dementia are different clinical phenotypes of Lewy body dementias differentiated by the temporal relationship between parkinsonism and dementia onset. At present, it is unclear whether the glutamatergic system is affected in these disorders. In this study, we measured α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA subunits in the postmortem neocortex of a cohort of prospectively studied Lewy body dementia cases, as well as age-matched controls by immunoblotting. We found losses of GluA2/3/4 immunoreactivities in Lewy body dementias which correlated with higher pre-death Hoehn and Yahr scores and with longer Parkinson's disease duration before dementia onset, but not with dementia severity, cortical Lewy body burden, or amyloid plaque and neurofibrillary tangle burden. Our study suggests that GluA2/3/4 losses may be a neurochemical marker of motor disability in Lewy body dementias.
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Enfermedad por Cuerpos de Lewy/metabolismo , Destreza Motora/fisiología , Neocórtex/metabolismo , Subunidades de Proteína/metabolismo , Receptores AMPA/metabolismo , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/patología , Enfermedad por Cuerpos de Lewy/fisiopatología , Masculino , Neocórtex/patología , Neocórtex/fisiopatología , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Placa Amiloide/metabolismo , Placa Amiloide/patología , Placa Amiloide/fisiopatología , Índice de Severidad de la EnfermedadRESUMEN
Intermittent fasting (IF), a dietary pattern alternating between eating and fasting periods within a 24-hour cycle, has garnered recognition for its potential to enhance both healthspan and lifespan in animal models and humans. It also shows promise in alleviating age-related diseases, including neurodegeneration. Vascular cognitive impairment (VCI) spans a severity range from mild cognitive deficits to severe cognitive deficits and loss of function in vascular dementia. Chronic cerebral hypoperfusion has emerged as a significant contributor to VCI, instigating vascular pathologies such as microbleeds, blood-brain barrier dysfunction, neuronal loss, and white matter lesions. Preclinical studies in rodents strongly suggest that IF has the potential to attenuate pathological mechanisms, including excitotoxicity, oxidative stress, inflammation, and cell death pathways in VCI models. Hence, this supports evaluating IF in clinical trials for both existing and at-risk VCI patients. This review compiles existing data supporting IF's potential in treating VCI-related vascular and neuronal pathologies, emphasizing the mechanisms by which IF may mitigate these issues. Hence providing a comprehensive overview of the available data supporting IF's potential in treating VCI by emphasizing the underlying mechanisms that make IF a promising intervention for VCI.
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Age-associated cerebral small vessel disease (CSVD) represents a clinically heterogenous condition, arising from diverse microvascular mechanisms. These lead to chronic cerebrovascular dysfunction and carry a substantial risk of subsequent stroke and vascular cognitive impairment in aging populations. Owing to advances in neuroimaging, in vivo visualization of cerebral vasculature abnormities and detection of CSVD, including lacunes, microinfarcts, microbleeds and white matter lesions, is now possible, but remains a resource-, skills- and time-intensive approach. As a result, there has been a recent proliferation of blood-based biomarker studies for CSVD aimed at developing accessible screening tools for early detection and risk stratification. However, a good understanding of the pathophysiological processes underpinning CSVD is needed to identify and assess clinically useful biomarkers. Here, we provide an overview of processes associated with CSVD pathogenesis, including endothelial injury and dysfunction, neuroinflammation, oxidative stress, perivascular neuronal damage as well as cardiovascular dysfunction. Then, we review clinical studies of the key biomolecules involved in the aforementioned processes. Lastly, we outline future trends and directions for CSVD biomarker discovery and clinical validation.
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Enfermedades de los Pequeños Vasos Cerebrales , Disfunción Cognitiva , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/complicaciones , Neuroimagen/efectos adversos , Biomarcadores , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Concomitant cerebrovascular diseases (CeVD) have been identified as an important determinant of Alzheimer's disease (AD) progression. Development of robust blood-based biomarkers will provide critical tools to evaluate prognosis and potential interventional strategies for AD with CeVD. OBJECTIVE: This study investigated circulating placental growth factor (PlGF), a potent pro-angiogenic factor related to endothelial dysfunction and vascular inflammation, in an Asian memory clinic cohort of non-demented individuals as well as AD, including its associations with neuroimaging markers of CeVD. METHODS: 109 patients with AD, 76 cognitively impaired with no dementia (CIND), and 56 non-cognitively impaired (NCI) were included in this cross-sectional study. All subjects underwent 3T brain magnetic resonance imaging to assess white matter hyperintensities (WMH), lacunes, cortical infarcts, and cerebral microbleeds (CMBs). Serum PlGF concentrations were measured by electrochemiluminescence immunoassays. RESULTS: Serum PlGF was elevated in AD, but not CIND, compared to the NCI controls. Adjusted concentrations of PlGF were associated with AD only in the presence of significant CeVD. Elevated PlGF was significantly associated with higher burden of WMH and with CMBs in AD patients. CONCLUSIONS: Serum PlGF has potential utility as a biomarker for the presence of CeVD, specifically WMH and CMBs, in AD. Further studies are needed to elucidate the underlying pathophysiological mechanisms linking PlGF to CeVD, as well as to further assess PlGF's clinical utility.
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Enfermedad de Alzheimer , Trastornos Cerebrovasculares , Disfunción Cognitiva , Sustancia Blanca , Femenino , Humanos , Enfermedad de Alzheimer/patología , Trastornos Cerebrovasculares/complicaciones , Disfunción Cognitiva/patología , Estudios Transversales , Imagen por Resonancia Magnética/métodos , Factor de Crecimiento Placentario , Sustancia Blanca/patologíaRESUMEN
In the brain, the extracellular matrix (ECM) composition shapes the neuronal microenvironment and can undergo substantial changes with cerebral pathology. Brevican is integral to the formation of the ECM's neuroprotective perineuronal nets (PNNs). Decreased brevican levels were reported in vascular dementia (VaD) but not in Alzheimer's disease (AD). However, the status of brevican in clinical cohorts with high concomitance of AD pathological burden and cerebrovascular disease (CeVD) is unclear. In this study, 32 non-cognitively impaired (NCI), 97 cognitively impaired no dementia (CIND), 46 AD, and 23 VaD participants recruited from memory clinics based in Singapore underwent neuropsychological and neuroimaging assessments, together with measurements of serum brevican. Association analyses were performed between serum brevican and neuroimaging measures of CeVDs, including white matter hyperintensities (WMHs), lacunes, cortical infarcts, and cerebral microbleeds. Using an aggregated score for CeVD burden, only CIND participants showed lower brevican levels with higher CeVD compared to those with lower CeVD burden (p = 0.006). Among the CeVD subtypes assessed, only elevated WMH burden was associated with lower brevican levels (OR = 2.7; 95% CI = 1.3-5.5). Our findings suggest that brevican deficits may play a role in early cerebrovascular damage in participants at risk of developing dementia.
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Enfermedad de Alzheimer , Brevicano , Trastornos Cerebrovasculares , Demencia Vascular , Anciano , Humanos , Biomarcadores , Encéfalo , Brevicano/sangre , Brevicano/química , Trastornos Cerebrovasculares/diagnóstico , Demencia Vascular/diagnósticoRESUMEN
INTRODUCTION: While elevated blood glial fibrillary acidic protein (GFAP) has been associated with brain amyloid pathology, whether this association occurs in populations with high cerebral small vessel disease (CSVD) concomitance remains unclear. METHODS: Using a Singapore-based cohort of cognitively impaired subjects, we assessed associations between plasma GFAP and neuroimaging measures of brain amyloid and CSVD, including white matter hyperintensities (WMH). We also examined the diagnostic performance of plasma GFAP in detecting brain amyloid beta positivity (Aß+). RESULTS: When stratified by WMH status, elevated brain amyloid was associated with higher plasma GFAP only in the WMH- group (ß = 0.383; P < 0.001). The diagnostic performance of plasma GFAP in identifying Aß+ was significantly higher in the WMH- group (area under the curve [AUC] = 0.896) than in the WMH+ group (AUC = 0.712, P = 0.008). DISCUSSION: The biomarker utility of plasma GFAP in detecting brain amyloid pathology is dependent on the severity of concomitant WMH. Highlight: Glial fibrillary acidic protein (GFAP)'s association with brain amyloid is unclear in populations with high cerebral small vessel disease (CSVD).Plasma GFAP was measured in a cohort with CSVD and brain amyloid.Plasma GFAP was better in detecting amyloid in patients with low CSVD versus high CSVD.Biomarker utility of GFAP in detecting brain amyloid depends on the severity of CSVD.
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In recent decades, mass spectrometry-based lipidomics has provided a fertile environment for scientific investigations of biochemical and mechanistic processes in biological systems. Notably, this approach has been used to characterize physiological and pathological processes relevant to the central nervous system by identifying changes in the sphingolipid content in the brain, cerebral spinal fluid, and blood plasma. However, despite a preponderance of studies identifying correlations between specific lipids and disease progression, this powerful resource has not yet substantively translated into clinically useful diagnostic assays. Part of this gap may be explained by insufficient depth of the lipidomic profiles in many studies, by lab-to-lab inconsistencies in methodology, and a lack of absolute quantification. These issues limit the identification of specific molecular species and the harmonization of results across independent studies. In this chapter, we contextualize these issues with recent reports identifying correlations between brain lipids and neurological diseases, and we describe the workflow our group has optimized for analysis of the blood plasma sphingolipidome, adapted to the characterization of the human brain tissue.
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Encéfalo , Lipidómica , Humanos , Espectrometría de Masas/métodos , Esfingolípidos , Flujo de TrabajoRESUMEN
BACKGROUND: The lysosomal protease cathepsin D (catD) has been reported to be upregulated in postmortem Alzheimer's disease (AD) cortex, where it colocalized with neurofibrillary tangles and correlated with levels of phosphorylated tau, suggesting pathophysiological links between catD and neurodegeneration. In contrast, studies of serum catD in AD have yielded conflicting results, and potential associations between baseline serum catD and functional outcomes of patients are at present unknown. OBJECTIVE: We aimed to examine the status of serum catD in a Singapore-based longitudinal study of dementia and investigate catD associations with functional and cognitive decline. METHODS: 35 subjects with no cognitive impairment, 40 patients with cognitive impairment no dementia and 34 with AD dementia underwent annual neuropsychological assessments (mean follow-up=4.3 years), as well as collection of baseline serum for catD measurements by ELISA. RESULTS: Higher serum catD at baseline was associated with AD clinical diagnosis (odds ratios [OR]: 10.0; 95% confidence interval [CI]: 1.02-97.95) as well as with cortical atrophy. Furthermore, higher catD was associated with global cognitive and functional decline (OR: 9.94; 95% CI: 1.02-97.34). CONCLUSION: The associations of serum catD with AD dementia as well as atrophy provide further support for the proposed links between catD and neurodegeneration, as well as for the assessment of serum catD as a prognostic biomarker predicting global cognitive and functional decline in larger studies.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Estudios Longitudinales , Catepsina D , Disfunción Cognitiva/psicología , Biomarcadores , AtrofiaRESUMEN
BACKGROUND: Neuroinflammation has been postulated to play an important role in cognitive impairment, cognitive decline, and dementia. Inflammatory biomarkers such as interleukin-6 (IL-6) and IL-8 are found to be associated with the neuro-inflammatory process and worse cognitive function. However, it is unknown whether these interleukins are associated with long-term cognitive function. OBJECTIVE: To investigate the association of baseline IL-6 and IL-8 with cognitive function at baseline as well as its association with cognitive decline over five-year follow-up. METHODS: 387 patients were recruited from an ongoing memory clinic-based study who underwent comprehensive physical, medical, neuropsychological and blood assessments together with brain MRI. IL-6 and IL-8 were measured using LUMINEX assays. The National Institute of Neurological Disorders and Stroke-Canadian Stroke Network neuropsychological battery was used to assess cognitive decline across multiple domains. RESULTS: Among the 387 (mean ageâ=â72.9 years and 53.7% males) participants, 322 had at least two follow-up assessments and were included in the longitudinal analysis. Negative linear trend associations were found between tertiles of IL-8 with baseline global cognition (p-trend<â0.001), attention (p-trendâ=â0.005), executive function (p-trend<â0.001), and visuospatial function (p-trendâ=â0.002) domains. No association was found between baseline IL-8 and cognitive decline. IL-6 was not associated with both baseline and follow-up cognition. CONCLUSION: IL-8 was associated with worse cognition especially in attention, executive function, and visuospatial function, suggesting the role of neuroinflammation in cognitive impairment. Hence, blood inflammatory biomarkers may be useful indicators in identifying patients at risk of cognitive impairment and warrant consideration for inclusion in treatment trials.