Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 14.176
Filtrar
1.
Life Sci ; 264: 118627, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33169684

RESUMO

Gut microbiota represents a diverse and dynamic population of microorganisms harboring the gastrointestinal tract, which influences the host health and disease. Gut microbiota communicates with the brain and vice versa through complex bidirectional communication systems - the gut-brain axis, which integrates the peripheral intestinal function with emotional and cognitive brain centers via neuro-immuno-endocrine mediators. Aging alters the gut microbial population, which not only leads to gastrointestinal disturbances but also causes central nervous system (CNS) disorders such as dementia. Alzheimer's disease (AD) is the most common form of dementia affecting the older person, characterized by beta-amyloid (Aß) plaques and neurofibrillary tangles leading to the cognitive deficit and memory impairment. Multiple experimental and clinical studies revealed the role of gut microbiota in host cognition, and its dysbiosis associated with aging leads to neurodegeneration. Gut microbial dysbiosis leads to the secretion of amyloid and lipopolysaccharides (LPS), which disturbs the gastrointestinal permeability and blood-brain barrier. Thereby modulates the inflammatory signaling pathway promoting neuroinflammation, neuronal injury, and ultimately leading to neuronal death in AD. A recent study revealed the antimicrobial property of Aß peptide as an innate immune response against pathogenic microbes. Another study showed that bacterial amyloid shares molecular mimicry with Aß peptide, which elicits misfolding and aggregation of Aß peptide, it's seeding, and propagation through the gut-brain axis followed by microglial cell activation. As aging together with poor diet and gut-derived inflammatory response due to dysbiosis contributes to the pathogenesis of AD, modification of gut microbial composition by uptake of probiotic-rich food can act as a preventive/therapeutic option for AD. The objective of the present review is to summarize the recent findings on the role of gut microbiota in the development of AD. Understanding the relationship between gut microbiota and CNS will help identify novel therapeutic strategies, especially probiotic-based supplementation, for the treatment of AD.


Assuntos
Doença de Alzheimer/microbiologia , Doença de Alzheimer/fisiopatologia , Encéfalo/fisiopatologia , Microbioma Gastrointestinal , Probióticos/uso terapêutico , Envelhecimento , Doença de Alzheimer/tratamento farmacológico , Amiloide/química , Precursor de Proteína beta-Amiloide/genética , Animais , Barreira Hematoencefálica , Sistema Nervoso Central , Humanos , Mucosa Intestinal/patologia , Lipopolissacarídeos/química , Camundongos , Camundongos Transgênicos , Permeabilidade , Ratos
2.
BMC Bioinformatics ; 21(Suppl 21): 496, 2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33371874

RESUMO

BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, typically characterized by memory loss followed by progressive cognitive decline and functional impairment. Many clinical trials of potential therapies for AD have failed, and there is currently no approved disease-modifying treatment. Biomarkers for early detection and mechanistic understanding of disease course are critical for drug development and clinical trials. Amyloid has been the focus of most biomarker research. Here, we developed a deep learning-based framework to identify informative features for AD classification using tau positron emission tomography (PET) scans. RESULTS: The 3D convolutional neural network (CNN)-based classification model of AD from cognitively normal (CN) yielded an average accuracy of 90.8% based on five-fold cross-validation. The LRP model identified the brain regions in tau PET images that contributed most to the AD classification from CN. The top identified regions included the hippocampus, parahippocampus, thalamus, and fusiform. The layer-wise relevance propagation (LRP) results were consistent with those from the voxel-wise analysis in SPM12, showing significant focal AD associated regional tau deposition in the bilateral temporal lobes including the entorhinal cortex. The AD probability scores calculated by the classifier were correlated with brain tau deposition in the medial temporal lobe in MCI participants (r = 0.43 for early MCI and r = 0.49 for late MCI). CONCLUSION: A deep learning framework combining 3D CNN and LRP algorithms can be used with tau PET images to identify informative features for AD classification and may have application for early detection during prodromal stages of AD.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Aprendizado Profundo , Processamento de Imagem Assistida por Computador/métodos , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo , Idoso , Doença de Alzheimer/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Cognição , Progressão da Doença , Diagnóstico Precoce , Feminino , Humanos , Masculino
4.
Science ; 370(6512): 50-56, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33004510

RESUMO

Sleep is evolutionarily conserved across all species, and impaired sleep is a common trait of the diseased brain. Sleep quality decreases as we age, and disruption of the regular sleep architecture is a frequent antecedent to the onset of dementia in neurodegenerative diseases. The glymphatic system, which clears the brain of protein waste products, is mostly active during sleep. Yet the glymphatic system degrades with age, suggesting a causal relationship between sleep disturbance and symptomatic progression in the neurodegenerative dementias. The ties that bind sleep, aging, glymphatic clearance, and protein aggregation have shed new light on the pathogenesis of a broad range of neurodegenerative diseases, for which glymphatic failure may constitute a therapeutically targetable final common pathway.


Assuntos
Doença de Alzheimer/etiologia , Sistema Glinfático/fisiopatologia , Transtornos do Sono-Vigília/complicações , Sono , Envelhecimento , Doença de Alzheimer/fisiopatologia , Animais , Aquaporina 4/genética , Doenças Cardiovasculares/etiologia , Humanos , Sistema Linfático/fisiopatologia , Camundongos , Polimorfismo Genético , Proteínas Priônicas/metabolismo , Agregados Proteicos , Transtornos do Sono-Vigília/fisiopatologia
5.
Neurology ; 95(20): e2816-e2830, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33004608

RESUMO

OBJECTIVE: To investigate the types of errors produced in a picture naming task by patients with neurodegenerative dementia due to different etiologies and their neural correlates. METHODS: The same standardized picture naming test was administered to a consecutive sample of patients (n = 148) who had been studied with [18F] FDG-PET. The errors were analyzed in 3 categories (visual, semantic, and phonologic). The PET data were analyzed using an optimized single-subject procedure, and the statistical parametric mapping multiple regression design was used to explore the correlation between each type of error and brain hypometabolism in the whole group. Metabolic connectivity analyses were run at the group level on 7 left hemisphere cortical areas corresponding to an a priori defined naming network. RESULTS: Semantic errors were predominant in most patients, independent of clinical diagnosis. In the whole group analysis, visual errors correlated with hypometabolism in the right inferior occipital lobe and in the left middle occipital lobe. Semantic errors correlated with hypometabolism in the left fusiform gyrus, the inferior and middle temporal gyri, and the temporal pole. Phonologic errors were associated with hypometabolism in the left superior and middle temporal gyri. Both positive (occipital-posterior fusiform) and negative (anterior fusiform gyrus and the superior anterior temporal lobe) connectivity changes were associated with semantic errors. CONCLUSIONS: Naming errors reflect the dysfunction of separate stages of the naming process and are specific markers for different patterns of brain involvement. These correlations are not limited to primary progressive aphasia but extend to other neurodegenerative dementias.


Assuntos
Conectoma , Demência , Idioma , Doenças Neurodegenerativas , Lobo Occipital , Tomografia por Emissão de Pósitrons , Lobo Temporal , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Afasia Primária Progressiva/diagnóstico por imagem , Afasia Primária Progressiva/metabolismo , Afasia Primária Progressiva/fisiopatologia , Demência/diagnóstico por imagem , Demência/metabolismo , Demência/fisiopatologia , Feminino , Fluordesoxiglucose F18 , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/metabolismo , Demência Frontotemporal/fisiopatologia , Humanos , Masculino , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Lobo Occipital/diagnóstico por imagem , Lobo Occipital/metabolismo , Lobo Occipital/fisiopatologia , Reconhecimento Visual de Modelos/fisiologia , Estudos Retrospectivos , Semântica , Fala/fisiologia , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/metabolismo , Paralisia Supranuclear Progressiva/fisiopatologia , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/metabolismo , Lobo Temporal/fisiopatologia
7.
Sci Rep ; 10(1): 16396, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009473

RESUMO

Alzheimer Disease (AD) is a pathology suffered by millions of people worldwide and it has a great social and economic impact. Previous studies reported a relationship between alterations in different amino acids and derivatives involved in neurotransmission systems and cognitive impairment. Therefore, in this study the neurotransmission impairment associated to early AD has been evaluated. For this purpose, different amino acids and derivatives were determined in saliva samples from AD patients and healthy subjects, by means of an analytical method based on chromatography coupled to tandem mass spectrometry. Results showed statistically significant differences in salivary levels for the compounds myo-inositol, creatine and acetylcholine; and other compounds (myo-inositol, glutamine, creatine, acetylcholine) showed significant correlations with some cognitive tests scores. Therefore, these compounds were included in a multivariate analysis and the corresponding diagnosis model showed promising indices (AUC 0.806, sensitivity 61%, specificity 92%). In conclusion, some amino acids and derivatives involved in neurotransmission impairment could be potential biomarkers in early and non-invasive AD detection.


Assuntos
Doença de Alzheimer/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Transmissão Sináptica/fisiologia , Acetilcolina/metabolismo , Idoso , Doença de Alzheimer/metabolismo , Aminoácidos/metabolismo , Biomarcadores/metabolismo , Disfunção Cognitiva/metabolismo , Creatina/metabolismo , Feminino , Humanos , Inositol/metabolismo , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade
8.
Sci Rep ; 10(1): 18517, 2020 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-33116184

RESUMO

Alzheimer's disease (AD), the most prevalent form of dementia, is a progressive and devastating neurodegenerative condition for which there are no effective treatments. Understanding the molecular pathology of AD during disease progression may identify new ways to reduce neuronal damage. Here, we present a longitudinal study tracking dynamic proteomic alterations in the brains of an inducible Drosophila melanogaster model of AD expressing the Arctic mutant Aß42 gene. We identified 3093 proteins from flies that were induced to express Aß42 and age-matched healthy controls using label-free quantitative ion-mobility data independent analysis mass spectrometry. Of these, 228 proteins were significantly altered by Aß42 accumulation and were enriched for AD-associated processes. Network analyses further revealed that these proteins have distinct hub and bottleneck properties in the brain protein interaction network, suggesting that several may have significant effects on brain function. Our unbiased analysis provides useful insights into the key processes governing the progression of amyloid toxicity and forms a basis for further functional analyses in model organisms and translation to mammalian systems.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Fragmentos de Peptídeos/metabolismo , Mapas de Interação de Proteínas/fisiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/fisiologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Estudos Longitudinais , Neurônios/metabolismo , Fragmentos de Peptídeos/fisiologia , Proteômica/métodos
9.
Life Sci ; 263: 118591, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33069735

RESUMO

Inflammation is a physiological response to injury, stimulating tissue repair and regeneration. However, the presence of peculiar individual conditions can negatively perturb the resolution phase eventually leading to a state of low-grade systemic chronic inflammation, characterized by tissue and organ damages and increased susceptibility to non-communicable disease. Marine n-3 polyunsaturated fatty acids (n-3 PUFAs), mainly eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), are able to influence many aspects of this process. Experiments performed in various animal models of obesity, Alzheimer's disease and multiple sclerosis have demonstrated that n-3 PUFAs can modulate the basic mechanisms as well as the disease progression. This review describes the available data from experimental studies to the clinical trials.


Assuntos
Ácidos Graxos Ômega-3/uso terapêutico , Inflamação/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Animais , Organismos Aquáticos/química , Progressão da Doença , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/uso terapêutico , Humanos , Inflamação/fisiopatologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/fisiopatologia , Obesidade/tratamento farmacológico , Obesidade/fisiopatologia
10.
J Appl Physiol (1985) ; 129(6): 1413-1421, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33031017

RESUMO

The transport of oxygen between blood and tissue is limited by blood's capillary transit time, understood as the time available for diffusion exchange before blood returns to the heart. If all capillaries contribute equally to tissue oxygenation at all times, this physical limitation would render vasodilation and increased blood flow insufficient means to meet increased metabolic demands in the heart, muscle, and other organs. In 1920, Danish physiologist August Krogh was awarded the Nobel Prize in Physiology or Medicine for his mathematical and quantitative, experimental demonstration of a solution to this conceptual problem: capillary recruitment, the active opening of previously closed capillaries to meet metabolic demands. Today, capillary recruitment is still mentioned in textbooks. When we suspect symptoms might represent hypoxia of a vascular origin, however, we search for relevant, flow-limiting conditions in our patients and rarely ascribe hypoxia or hypoxemia to short capillary transit times. This review describes how natural changes in capillary transit-time heterogeneity (CTH) and capillary hematocrit (HCT) across open capillaries during blood flow increases can account for a match of oxygen availability to metabolic demands in normal tissue. CTH and HCT depend on a number of factors: on blood properties, including plasma viscosity, the number, size, and deformability of blood cells, and blood cell interactions with capillary endothelium; on anatomical factors including glycocalyx, endothelial cells, basement membrane, and pericytes that affect the capillary diameter; and on any external compression. The review describes how risk factor- and disease-related changes in CTH and HCT interfere with flow-metabolism coupling and tissue oxygenation and discusses whether such capillary dysfunction contributes to vascular disease pathology.


Assuntos
Capilares/fisiologia , Microcirculação , Modelos Cardiovasculares , Consumo de Oxigênio , Oxigênio/sangue , Doença de Alzheimer/sangue , Doença de Alzheimer/fisiopatologia , Anemia Falciforme/sangue , Anemia Falciforme/fisiopatologia , Animais , Velocidade do Fluxo Sanguíneo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/fisiopatologia , Difusão , Humanos , Hipóxia/sangue , Hipóxia/fisiopatologia , Fluxo Sanguíneo Regional , Fatores de Tempo
11.
Int J Nanomedicine ; 15: 6113-6135, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32884267

RESUMO

The field of nanomedicine is constantly expanding. Since the first work dated in 1999, almost 28 thousand articles have been published, and more and more are published every year: just think that only in the last five years 20,855 have come out (source PUBMED) including original research and reviews. The goal of this review is to present the current knowledge about nanomedicine in Alzheimer's disease, a widespread neurodegenerative disorder in the over 60 population that deeply affects memory and cognition. Thus, after a brief introduction on the pathology and on the state-of-the-art research for NPs passing the BBB, special attention is placed to new targets that can enter the interest of nanoparticle designers and to new promising therapies. The authors performed a literature review limited to the last three years (2017-2020) of available studies with the intention to present only novel formulations or approaches where at least in vitro studies have been performed. This choice was made because, while limiting the sector to nanotechnology applied to Alzheimer, an organic census of all the relevant news is difficult to obtain.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Barreira Hematoencefálica/efeitos dos fármacos , Nanomedicina/métodos , Doença de Alzheimer/fisiopatologia , Animais , Barreira Hematoencefálica/fisiologia , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Humanos , Nanopartículas/administração & dosagem , Nanopartículas/uso terapêutico , Medicina de Precisão , Transplante de Células-Tronco , Nanomedicina Teranóstica/métodos , Terapias em Estudo
12.
PLoS One ; 15(9): e0238690, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915845

RESUMO

BACKGROUND: There is a need for outcome measures with improved responsiveness to changes in pre-dementia populations. Both cognitive and motor function play important roles in neurodegeneration; motor function decline is detectable at early stages of cognitive decline. This proof of principle study used a Pooled Index approach to evaluate improved responsiveness of the predominant outcome measure (ADAS-Cog: Alzheimer's Disease Assessment Scale-Cognitive Subscale) when assessment of motor function is added. METHODS: Candidate Pooled Index variables were selected based on theoretical importance and pairwise correlation coefficients. Kruskal-Wallis and Mann-Whitney U tests assessed baseline discrimination. Standardized response means assessed responsiveness to longitudinal change. RESULTS: Final selected variables for the Pooled Index include gait velocity, dual-task cost of gait velocity, and an ADAS-Cog-Proxy (statistical approximation of the ADAS-Cog using similar cognitive tests). The Pooled Index and ADAS-Cog-Proxy scores had similar ability to discriminate between pre-dementia syndromes. The Pooled Index demonstrated trends of similar or greater responsiveness to longitudinal decline than ADAS-Cog-Proxy scores. CONCLUSION: Adding motor function assessments to the ADAS-Cog may improve responsiveness in pre-dementia populations.


Assuntos
Doença de Alzheimer/fisiopatologia , Cognição/fisiologia , Disfunção Cognitiva/fisiopatologia , Marcha/fisiologia , Idoso , Doença de Alzheimer/epidemiologia , Disfunção Cognitiva/epidemiologia , Demência/epidemiologia , Demência/fisiopatologia , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Índice de Gravidade de Doença , Estatísticas não Paramétricas
13.
Neurology ; 95(23): e3093-e3103, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-32989109

RESUMO

OBJECTIVE: To determine whether vascular risk and Alzheimer disease (AD) biomarkers have independent or synergistic effects on cognitive decline and whether vascular risk is associated with the accumulation of AD pathology as measured by change in biomarkers over time. METHODS: At baseline, participants (n = 168) were cognitively normal and primarily middle-aged (mean 56.4 years, SD 10.9 years) and had both vascular risk factor status and proximal CSF biomarkers available. Baseline vascular risk was quantified with a composite vascular risk score reflecting the presence or absence of hypertension, hypercholesterolemia, diabetes, current smoking, and obesity. CSF biomarkers of ß-amyloid (Aß)1-42, total tau (t-tau), and phosphorylated tau (p-tau) were used to create dichotomous high and low AD biomarker groups (based on Aß1-42 and tau). Linear mixed-effects models were used to examine change in a cognitive composite score (mean follow-up 13.9 years) and change in CSF biomarkers (mean follow-up 4.2 years). RESULTS: There was no evidence of a synergistic relationship between the vascular risk score and CSF AD biomarkers and cognitive decline. Instead, the vascular risk score (estimate -0.022, 95% confidence interval [CI] -0.043 to -0.002, p = 0.03) and AD biomarkers (estimate -0.060, 95% CI -0.096 to -0.024, p = 0.001) were independently and additively associated with cognitive decline. In addition, the vascular risk score was unrelated to levels of or rate of change in CSF Aß1-42, t-tau, or p-tau. CONCLUSIONS: The results of this observational cohort study suggest that vascular risk and biomarkers of AD pathology, when measured in midlife, act along independent pathways and underscore the importance of accounting for multiple risk factors for identifying cognitively normal individuals at the greatest risk of cognitive decline.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Doenças Cardiovasculares , Disfunção Cognitiva , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/fisiopatologia , Biomarcadores/líquido cefalorraquidiano , Doenças Cardiovasculares/líquido cefalorraquidiano , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/fisiopatologia , Diabetes Mellitus/epidemiologia , Feminino , Seguimentos , Humanos , Hipercolesterolemia/epidemiologia , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Fatores de Risco , Fumar/epidemiologia
14.
Life Sci ; 262: 118401, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32926928

RESUMO

AIM: Insulin has a well-established role in cognition, neuronal detoxification and synaptic plasticity. Insulin transduction affect neurotransmitter functions, influence bioenergetics and regulate neuronal survival through regulating glucose energy metabolism and downward pathways. METHODS: A systematic literature review of PubMed, Medline, Bentham, Scopus and EMBASE (Elsevier) databases was carried out with the help of the keywords like "Alzheimer's disease; Hypometabolism; Oxidative stress; energy failure in AD, Insulin; Insulin resistance; Bioenergetics" till June 2020. The review was conducted using the above keywords to collect the latest articles and to understand the nature of the extensive work carried out on insulin resistance and bioenergetic manifestations in Alzheimer's disease. KEY FINDINGS: The article sheds light on insulin resistance mediated hypometabolic state on pathological progression of AD. The disrupted insulin signaling has pathological outcome in form of disturbed glucose homeostasis, altered bioenergetic state which increases build-up of senile plaques (Aß), neurofibrillary tangles (τ), decline in transportation of glucose and activation of inflammatory pathways. The mechanistic link of insulin resistant state with therapeutically explorable potential transduction pathways is the focus of the reviewed work. SIGNIFICANCE: The present work opines that the mechanism by which the insulin resistance mediates dysregulation of bioenergetics and progresses to neurodegenerative state holds the tangible potential to succeed in the development of novel dementia therapies. Further, hypometabolic complications and altered insulin signaling may be explored as a mechanistic relation between bioenergetic deficits and AD.


Assuntos
Doença de Alzheimer/fisiopatologia , Resistência à Insulina , Insulina/metabolismo , Animais , Metabolismo Energético/fisiologia , Glucose/metabolismo , Humanos , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologia
16.
Nat Commun ; 11(1): 4413, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887883

RESUMO

The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovascular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation-dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which prominently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed transcriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.


Assuntos
Envelhecimento/patologia , Barreira Hematoencefálica , Encéfalo/fisiopatologia , Células Endoteliais/metabolismo , Exenatida/farmacologia , Doença de Alzheimer/fisiopatologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/fisiopatologia , Capilares/metabolismo , Células Cultivadas , Humanos , Camundongos , Microglia/efeitos dos fármacos , Doenças Neurodegenerativas/fisiopatologia , Transcriptoma/efeitos dos fármacos
17.
Neurology ; 95(23): e3104-e3116, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-32873693

RESUMO

OBJECTIVE: To determine the ordering of changes in Alzheimer disease (AD) biomarkers among cognitively normal individuals. METHODS: Cross-sectional data, including CSF analytes, molecular imaging of cerebral fibrillar ß-amyloid (Aß) with PET using the [11C] benzothiazole tracer Pittsburgh compound B (PiB), MRI-based brain structures, and clinical/cognitive outcomes harmonized from 8 studies, collectively involving 3,284 cognitively normal individuals 18 to 101 years of age, were analyzed. The age at which each marker exhibited an accelerated change (called the change point) was estimated and compared across the markers. RESULTS: Accelerated changes in CSF Aß1-42 (Aß42) occurred at 48.28 years of age and in Aß42/Aß40 ratio at 46.02 years, followed by PiB mean cortical standardized uptake value ratio (SUVR) with a change point at 54.47 years. CSF total tau (Tau) and tau phosphorylated at threonine 181 (Ptau) had a change point at ≈60 years, similar to those for MRI hippocampal volume and cortical thickness. The change point for a cognitive composite occurred at 62.41 years. The change points for CSF Aß42 and Aß42/Aß40 ratio, albeit not significantly different from that for PiB SUVR, occurred significantly earlier than that for CSF Tau, Ptau, MRI markers, and the cognitive composite. Adjusted analyses confirmed that accelerated changes in CSF Tau, Ptau, MRI markers, and the cognitive composite occurred at ages not significantly different from each other. CONCLUSIONS: Our findings support the hypothesized early changes of amyloid in preclinical AD and suggest that changes in neuronal injury and neurodegeneration markers occur close in time to cognitive decline.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/metabolismo , Córtex Cerebral , Disfunção Cognitiva , Proteínas tau/líquido cefalorraquidiano , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Compostos de Anilina , Biomarcadores/metabolismo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Estudos Transversais , Feminino , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Sintomas Prodrômicos , Tiazóis , Adulto Jovem
18.
J Alzheimers Dis ; 78(2): 479-503, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32955466

RESUMO

Alzheimer's and Parkinson's diseases (AD, PD) have a pediatric and young adult onset in Metropolitan Mexico City (MMC). The SARS-CoV-2 neurotropic RNA virus is triggering neurological complications and deep concern regarding acceleration of neuroinflammatory and neurodegenerative processes already in progress. This review, based on our MMC experience, will discuss two major issues: 1) why residents chronically exposed to air pollution are likely to be more susceptible to SARS-CoV-2 systemic and brain effects and 2) why young people with AD and PD already in progress will accelerate neurodegenerative processes. Secondary mental consequences of social distancing and isolation, fear, financial insecurity, violence, poor health support, and lack of understanding of the complex crisis are expected in MMC residents infected or free of SARS-CoV-2. MMC residents with pre-SARS-CoV-2 accumulation of misfolded proteins diagnostic of AD and PD and metal-rich, magnetic nanoparticles damaging key neural organelles are an ideal host for neurotropic SARS-CoV-2 RNA virus invading the body through the same portals damaged by nanoparticles: nasal olfactory epithelium, the gastrointestinal tract, and the alveolar-capillary portal. We urgently need MMC multicenter retrospective-prospective neurological and psychiatric population follow-up and intervention strategies in place in case of acceleration of neurodegenerative processes, increased risk of suicide, and mental disease worsening. Identification of vulnerable populations and continuous effort to lower air pollution ought to be critical steps.


Assuntos
Doença de Alzheimer/complicações , Encefalopatias/etiologia , Infecções por Coronavirus/complicações , Poluentes Ambientais/efeitos adversos , Nanopartículas/efeitos adversos , Doença de Parkinson/complicações , Pneumonia Viral/complicações , Adulto , Poluição do Ar/efeitos adversos , Doença de Alzheimer/fisiopatologia , Progressão da Doença , Humanos , Pessoa de Meia-Idade , Pandemias , Doença de Parkinson/fisiopatologia , Suicídio/estatística & dados numéricos , População Urbana
19.
PLoS One ; 15(8): e0235691, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32857763

RESUMO

Exercise exerts a beneficial effect on the major pathological and clinical symptoms associated with Alzheimer's disease in humans and mouse models of the disease. While numerous mechanisms for such benefits from exercise have been proposed, a clear understanding of the causal links remains elusive. Recent studies also suggest that cerebral blood flow in the brain of both Alzheimer's patients and mouse models of the disease is decreased and that the cognitive symptoms can be improved when blood flow is restored. We therefore hypothesized that the mitigating effect of exercise on the development and progression of Alzheimer's disease may be mediated through an increase in the otherwise reduced brain blood flow. To test this idea, we performed a pilot study to examine the impact of three months of voluntary wheel running in a small cohort of ~1-year-old APP/PS1 mice on short-term memory function, brain inflammation, amyloid deposition, and baseline cerebral blood flow. Our findings that exercise led to a trend toward improved spatial short-term memory, reduced brain inflammation, markedly increased neurogenesis in the dentate gyrus, and a reduction in hippocampal amyloid-beta deposits are consistent with other reports on the impact of exercise on the progression of Alzheimer's related symptoms in mouse models. Notably, we did not observe any impact of wheel running on overall baseline blood flow nor on the incidence of non-flowing capillaries, a mechanism we recently identified as one contributing factor to cerebral blood flow deficits in mouse models of Alzheimer's disease. Overall, our findings add to the emerging picture of differential effects of exercise on cognition and blood flow in Alzheimer's disease pathology by showing that capillary stalling is not decreased following exercise.


Assuntos
Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/irrigação sanguínea , Terapia por Exercício , Presenilina-1/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Circulação Cerebrovascular , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Neurogênese , Condicionamento Físico Animal , Projetos Piloto , Presenilina-1/genética , Transgenes
20.
PLoS One ; 15(8): e0236568, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790788

RESUMO

PURPOSE: To evaluate the ability of re-test pattern electroretinogram (RE-PERG), a non-invasive and fast steady-state PERG, to detect inner retinal bioelectric function anomalies in patients with early-onset Alzheimer's disease (AD). METHODS: The study population consisted of 17 patients with AD-related mild cognitive impairment (MCI), 16 patients with vascular dementia (VD)-related MCI, both assessed using the neuropsychological Mini-Mental State Examination (MMSE) and by structural magnetic resonance imaging, and 19 healthy, age-matched normal controls (NC). All participants were visually asymptomatic, had normal or near-normal general cognitive functioning and no or minimal impairments in daily life activities. Visual field (VF) test, optical coherence tomography (OCT) and RE-PERG, sampled in five consecutive blocks of 130 events, were performed. RESULTS: There was no statistically significant difference among the three groups with respect to age, VF parameters (mean and pattern standard deviations) and OCT parameters (ganglion cell complex thickness and retinal nerve fiber layer thickness). The mean amplitude in the RE-PERG was significantly lower, but only weakly in the AD group than in NC (p = 0.1) whereas the intrinsic variability of the 2nd harmonic phase was significantly higher in the AD group than in either the VD or NC group (p<0.001). CONCLUSIONS: RE-PERG is altered in early-stage AD, showing a reduced amplitude with high intrinsic phase variability. It also allows the discrimination of AD from VD. A high intrinsic variability in the PERG signal, determined using RE-PERG, may thus be a new promising test for neurodegenerative diseases.


Assuntos
Doença de Alzheimer/diagnóstico , Eletrorretinografia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/fisiopatologia , Método Duplo-Cego , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Tomografia de Coerência Óptica , Testes de Campo Visual
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA