RESUMEN
BACKGROUND: Alzheimer's disease (AD) is the most prevalent dementia, showing higher incidence in women. Besides, lipids play an essential role in brain, and they could be dysregulated in neurodegeneration. Specifically, impaired plasma lipid levels could predict early AD diagnosis. This work aims to identify the main plasma lipids altered in early AD female mouse model and evaluate their relationship with brain lipidome. Also, the possible involvement of the estrous cycle in lipid metabolism has been evaluated. METHODS: Plasma samples of wild-type (n = 10) and APP/PS1 (n = 10) female mice of 5 months of age were collected, processed, and analysed using a lipidomic mass spectrometry-based method. A statistical analysis involving univariate and multivariate approaches was performed to identify significant lipid differences related to AD between groups. Also, cytology tests were conducted to confirm estrous cycle phases. RESULTS: Three hundred thirty lipids were detected in plasma, 18 of them showed significant differences between groups; specifically, some triacylglycerols, cholesteryl esters, lysophosphatidylcholines, phosphatidylcholines, and ether-linked phosphatidylcholines, increased in early AD; while other phosphatidylcholines, phosphatidylethanolamines, ceramides, and ether-linked phosphatidylethanolamines decreased in early AD. A multivariate approach was developed from some lipid variables, showing high diagnostic indexes (70% sensitivity, 90% specificity, 80% accuracy). From brain and plasma lipidome, some significant correlations were observed, mainly in the glycerophospholipid family. Also, some differences were found in both plasma and brain lipids, according to the estrous cycle phase. CONCLUSIONS: Therefore, lipid alterations can be identified in plasma at early AD stages in mice females, with a relationship with brain lipid metabolism for most of the lipid subfamilies, suggesting some lipids as potential AD biomarkers. In addition, the estrous cycle monitoring could be relevant in female studies.
Asunto(s)
Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Encéfalo , Modelos Animales de Enfermedad , Ciclo Estral , Lipidómica , Lípidos , Ratones Transgénicos , Animales , Femenino , Ciclo Estral/fisiología , Ciclo Estral/sangre , Lipidómica/métodos , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/sangre , Precursor de Proteína beta-Amiloide/genética , Lípidos/sangre , Presenilina-1/genética , Ratones , Metabolismo de los Lípidos/fisiología , Ratones Endogámicos C57BLRESUMEN
Background: Alzheimer's disease (AD) is an age-related neurodegenerative disease that is clinically characterized by progressive cognitive decline. Glucagon-like peptide-1 (GLP-1) is a hormone that belongs to the incretin family and is released in response to nutrient intake. It plays a role in maintaining metabolic homeostasis and has been suggested to be involved in maintaining the brain microenvironment. However, the role of GLP-1 in AD pathogenesis has not been fully illustrated. Objective: This study aims to investigate the clinical relevance of GLP-1 in AD and the effects of GLP-1 in amyloid-ß (Aß) metabolism in vitro. Methods: In this study, 39 AD patients and 120 cognitively intact controls were included. Plasma levels of GLP-1 were measured using ELISA. SH-SY5Y cells overexpressing human amyloid precursor protein (APP) were treated with GLP-1. Western blot analysis was used to assess the effects of GLP-1 on the metabolism of Aß. Results: Plasma GLP-1 levels were decreased with aging. Plasma GLP-1 levels were lower in AD patients in comparison with healthy older adults. Plasma GLP-1 levels were positively associated with Mini-Mental State Examination scores but negatively associated with plasma pTau181 levels. GLP-1 dose-dependently increased the area fraction of mitochondrial staining in vitro. Furthermore, GLP-1 dose-dependently promoted the α-cleavage of APP, thus reducing the generation of Aß. Conclusions: GLP-1 has neuroprotective effects in AD, and therefore the decrease in GLP-1 levels during aging might contribute to the development of AD.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Péptido 1 Similar al Glucagón , Humanos , Péptido 1 Similar al Glucagón/sangre , Péptido 1 Similar al Glucagón/metabolismo , Enfermedad de Alzheimer/sangre , Masculino , Anciano , Femenino , Biomarcadores/sangre , Péptidos beta-Amiloides/sangre , Cognición/fisiología , Anciano de 80 o más Años , Precursor de Proteína beta-Amiloide/sangre , Persona de Mediana Edad , Línea Celular Tumoral , Proteínas tau/sangre , Pruebas de Estado Mental y Demencia , Envejecimiento/sangreRESUMEN
Background: Alzheimer's disease (AD) is a devastating neurodegenerative disease without guidelines for early diagnosis or personalized treatment. Previous studies have highlighted a crucial role of increasing phosphorylation levels of the amyloid precursor protein (APP) Tyr682 residue in predicting neuronal deficits in AD patients. However, the lack of a method for the identification and quantification of Tyr682 phosphorylation levels prevents its potential clinical applications. Methods: Here we report a method to identify and quantify APP Tyr682 phosphorylation levels in blood mononuclear cells of AD patients by tandem mass spectrometry (tMS). Results: This method showed excellent sensitivity with detection and quantification limits set respectively at 0.035 and 0.082 ng injected for the phosphorylated peptide and at 0.02 and 0.215 ng injected for the non-phosphorylated peptide. The average levels of both peptides were quantified in transfected HELA cells (2.48 and 3.53 ng/µg of protein, respectively). Preliminary data on 3 AD patients showed quantifiable levels of phosphorylated peptide (0.10-0.15 ng/µg of protein) and below the LOQ level of non-phosphorylated peptide (0.13 ng/µg of protein). Conclusion: This method could allow the identification of patients with increased APP Tyr682 phosphorylation and allow early characterization of molecular changes prior to the appearance of clinical signs.
Asunto(s)
Precursor de Proteína beta-Amiloide/sangre , Leucocitos Mononucleares/metabolismo , Fosfoproteínas/metabolismo , Espectrometría de Masas en Tándem , Tirosina/metabolismo , Secuencia de Aminoácidos , Precursor de Proteína beta-Amiloide/química , Calibración , Línea Celular , Humanos , Fosforilación , Reproducibilidad de los ResultadosRESUMEN
Serum biomarkers are associated with hemorrhagic transformation and brain edema after cerebral infarction. However, whether serum biomarkers predict hemorrhagic transformation in large vessel occlusion stroke even after mechanical thrombectomy, which has become widely used, remains uncertain. In this prospective study, we enrolled patients with large vessel occlusion stroke in the anterior circulation. We analyzed 91 patients with serum samples obtained on admission. The levels of matrix metalloproteinase-9 (MMP-9), amyloid precursor protein (APP) 770, endothelin-1, S100B, and claudin-5 were measured. We examined the association between serum biomarkers and hemorrhagic transformation within one week. Fifty-four patients underwent mechanical thrombectomy, and 17 patients developed relevant hemorrhagic transformation (rHT, defined as hemorrhagic changes ≥ hemorrhagic infarction type 2). Neither MMP-9 (no rHT: 46 ± 48 vs. rHT: 15 ± 4 ng/mL, P = 0.30), APP770 (80 ± 31 vs. 85 ± 8 ng/mL, P = 0.53), endothelin-1 (7.0 ± 25.7 vs. 2.0 ± 2.1 pg/mL, P = 0.42), S100B (13 ± 42 vs. 12 ± 15 pg/mL, P = 0.97), nor claudin-5 (1.7 ± 2.3 vs. 1.9 ± 1.5 ng/mL, P = 0.68) levels on admission were associated with subsequent rHT. When limited to patients who underwent mechanical thrombectomy, the level of claudin-5 was higher in patients with rHT than in those without (1.2 ± 1.0 vs. 2.1 ± 1.7 ng/mL, P = 0.0181). APP770 levels were marginally higher in patients with a midline shift ≥ 5 mm than in those without (79 ± 29 vs. 97 ± 41 ng/mL, P = 0.084). The predictive role of serum biomarkers has to be reexamined in the mechanical thrombectomy era because some previously reported serum biomarkers may not predict hemorrhagic transformation, whereas the level of APP770 may be useful for predicting brain edema.
Asunto(s)
Edema Encefálico/diagnóstico , Infarto Cerebral/diagnóstico , Trastornos Cerebrovasculares/diagnóstico , Accidente Cerebrovascular/diagnóstico , Trombectomía/métodos , Anciano , Anciano de 80 o más Años , Precursor de Proteína beta-Amiloide/sangre , Precursor de Proteína beta-Amiloide/genética , Biomarcadores/sangre , Edema Encefálico/genética , Edema Encefálico/patología , Edema Encefálico/cirugía , Infarto Cerebral/genética , Infarto Cerebral/patología , Infarto Cerebral/cirugía , Trastornos Cerebrovasculares/genética , Trastornos Cerebrovasculares/patología , Trastornos Cerebrovasculares/cirugía , Claudina-5/sangre , Claudina-5/genética , Endotelina-1/sangre , Endotelina-1/genética , Femenino , Expresión Génica , Humanos , Masculino , Metaloproteinasa 9 de la Matriz/sangre , Metaloproteinasa 9 de la Matriz/genética , Valor Predictivo de las Pruebas , Estudios Prospectivos , Subunidad beta de la Proteína de Unión al Calcio S100/sangre , Subunidad beta de la Proteína de Unión al Calcio S100/genética , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/cirugíaRESUMEN
Plasma amyloid-beta (Aß) has long been investigated as a blood biomarker candidate for Cerebral Amyloid Angiopathy (CAA), however previous findings have been inconsistent which could be attributed to the use of less sensitive assays. This study investigates plasma Aß alterations between pre-symptomatic Dutch-type hereditary CAA (D-CAA) mutation-carriers (MC) and non-carriers (NC) using two Aß measurement platforms. Seventeen pre-symptomatic members of a D-CAA pedigree were assembled and followed up 3-4 years later (NC = 8; MC = 9). Plasma Aß1-40 and Aß1-42 were cross-sectionally and longitudinally analysed at baseline (T1) and follow-up (T2) and were found to be lower in MCs compared to NCs, cross-sectionally after adjusting for covariates, at both T1(Aß1-40: p = 0.001; Aß1-42: p = 0.0004) and T2 (Aß1-40: p = 0.001; Aß1-42: p = 0.016) employing the Single Molecule Array (Simoa) platform, however no significant differences were observed using the xMAP platform. Further, pairwise longitudinal analyses of plasma Aß1-40 revealed decreased levels in MCs using data from the Simoa platform (p = 0.041) and pairwise longitudinal analyses of plasma Aß1-42 revealed decreased levels in MCs using data from the xMAP platform (p = 0.041). Findings from the Simoa platform suggest that plasma Aß may add value to a panel of biomarkers for the diagnosis of pre-symptomatic CAA, however, further validation studies in larger sample sets are required.
Asunto(s)
Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Angiopatía Amiloide Cerebral Familiar/genética , Fragmentos de Péptidos/genética , Adulto , Péptidos beta-Amiloides/sangre , Precursor de Proteína beta-Amiloide/sangre , Enfermedades Asintomáticas , Biomarcadores/sangre , Angiopatía Amiloide Cerebral Familiar/sangre , Angiopatía Amiloide Cerebral Familiar/diagnóstico , Angiopatía Amiloide Cerebral Familiar/patología , Progresión de la Enfermedad , Femenino , Expresión Génica , Genes Dominantes , Heterocigoto , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mutación , Pruebas Neuropsicológicas , Linaje , Fragmentos de Péptidos/sangreRESUMEN
BACKGROUND: The neuroprotective benefits of combined folic acid and docosahexaenoic acid (DHA) on cognitive function in mild cognitive impairment (MCI) patients are suggested but unconfirmed. OBJECTIVE: To explore the effects of 6-month folic acidâ+âDHA on cognitive function in patients with MCI. METHODS: Our randomized controlled trial (trial number ChiCTR-IOR-16008351) was conducted in Tianjin, China. We divided 160 MCI patients agedâ>â60 years into four regimen groups randomly: folic acid (0.8âmg/day)â+âDHA (800âmg/day), folic acid (0.8âmg/day), DHA (800âmg/day), and placebo, for 6 months. Cognitive function and blood amyloid-ß peptide (Aß) biomarker levels were measured at baseline and 6 months. Cognitive function was also measured at 12 months. RESULTS: A total of 138 patients completed this trial. Folic acid improved the full-scale intelligence quotient (FSIQ), arithmetic, and picture complement scores; DHA improved the FSIQ, information, arithmetic, and digit span scores; folic acidâ+âDHA improved the arithmetic (difference 1.67, 95% CI 1.02 to 2.31) and digital span (1.33, 0.24 to 2.43) scores compared to placebo. At 12 months, all scores declined in the intervention groups. Folic acid and folic acidâ+âDHA increased blood folate (folic acidâ+âDHA: 7.70, 3.81 to 11.59) and S-adenosylmethionine (23.93, 1.86 to 46.00) levels and reduced homocysteine levels (-6.51, -10.57 to -2.45) compared to placebo. DHA lower the Aß40 levels (-40.57, -79.79 to -1.35) compared to placebo (pâ<â0.05), and folic acidâ+âDHA reduced the Aß42 (-95.59, -150.76 to -40.43) and Aß40 levels (-45.75, -84.67 to -6.84) more than DHA (pâ<â0.05). CONCLUSION: Folic acid and DHA improve cognitive function and reduce blood Aß production in MCI patients. Combination therapy may be more beneficial in reducing blood Aß-related biomarkers.
Asunto(s)
Cognición/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Ácidos Docosahexaenoicos/farmacología , Ácido Fólico/farmacología , Anciano , Péptidos beta-Amiloides/sangre , Precursor de Proteína beta-Amiloide/sangre , Biomarcadores/sangre , Disfunción Cognitiva/sangre , Disfunción Cognitiva/psicología , Ácidos Docosahexaenoicos/uso terapéutico , Método Doble Ciego , Femenino , Ácido Fólico/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fragmentos de Péptidos/sangreRESUMEN
The number of patients with Alzheimer's Disease (AD) and other types of dementia disorders has drastically increased over the last decades. AD is a complex progressive neurodegenerative disease affecting about 14 million patients in Europe and the United States. The hallmarks of this disease are neurotic plaques consist of the Amyloid-ß peptide (Aß) and neurofibrillary tangles (NFTs) formed of hyperphosphorylated Tau protein (pTau). Currently, four CSF biomarkers: Amyloid beta 42 (Aß42), Aß42/40 ratio, Tau protein, and Tau phosphorylated at threonine 181 (pTau181) have been indicated as core neurochemical AD biomarkers. However, the identification of additional fluid biomarkers, useful in the prognosis, risk stratification, and monitoring of drug response is sorely needed to better understand the complex heterogeneity of AD pathology as well as to improve diagnosis of patients with the disease. Several novel biomarkers have been extensively investigated, and their utility must be proved and eventually integrated into guidelines for use in clinical practice. This paper presents the research and development of CSF and blood biomarkers for AD as well as their potential clinical significance. Upper panel: Aß peptides are released from transmembrane Amyloid Precursor Protein (APP) under physiological conditions (blue arrow). In AD, however, pathologic accumulation of Aß monomers leads to their accumulation in plaques (red arrow). This is reflected in decreased concentration of Aß1-42 and decreased Aß42/40 concentration ratio in the CSF. Lower panel: Phosphorylated Tau molecules maintain axonal structures; hyperphosphorylation of Tau (red arrow) in AD leads to degeneration of axons, and release of pTau molecules, which then accumulate in neurofibrillary tangles. This process is reflected by increased concentrations of Tau and pTau in the CSF.
Asunto(s)
Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/sangre , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Proteínas Morfogenéticas Óseas/sangre , Proteínas Morfogenéticas Óseas/líquido cefalorraquídeo , Proteínas Morfogenéticas Óseas/metabolismo , Humanos , Proteínas tau/sangre , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/metabolismoRESUMEN
INTRODUCTION: In mice there might be an association between sleep deprivation and amyloid ß plasma levels. Hence, we examined whether amyloid plasma levels are associated with sleep duration or fragmentation in 17 psychiatrists on-call. METHODS: Amyloid ß (Aß)42, Aß40, and soluble amyloid precursor protein ß (sAPP-ß) plasma concentrations were measured at the beginning and end of 90 on-call nights, and analyzed using generalized linear models. RESULTS: In on-call nights, a 10.7% reduction of Aß42 was revealed overnight. Every single short sleep interruption diminished this reduction by 5.4%, as well as every pg/mL of sAPP-ß by 1.2%, each copy of APOE ε4 by 10.6%, and each year of professional experience by 3.0%. DISCUSSION: The extent of sleep fragmentation diminishes the physiological overnight reduction of Aß42 but not Aß40 plasma levels in the same direction as the enzyme for Aß42 production, the genetic risk factor for Alzheimer's disease (AD), and on-call experience. Might on-call duty and sleep fragmentation in general alter the risk for AD?
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Psiquiatría , Privación de Sueño/fisiopatología , Adulto , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/sangre , Precursor de Proteína beta-Amiloide/sangre , Apolipoproteína E4/genética , Femenino , Humanos , MasculinoRESUMEN
Background Down syndrome (DS) is a common chromosomal disease resulting in neurodegeneration. Cognitive competence has been assessed among adults with DS using various methods because DS patients have a tendency to develop Alzheimer's disease (AD) after middle age. However, research describing cognitive assessments in DS children is not as many as in DS adults, let alone with regard to performed analyses to determine factors that predict cognitive assessments. In this study, we evaluated the Gesell Developmental Schedules (GDS) scores and their associations with the relevant biochemical indicators and demographic factors in DS children. Methods All the subjects underwent GDS testing. The plasma amyloid-ß (Aß) peptide and serum vitamin A (VA) values were measured with enzyme-linked immunosorbent assay and high-performance liquid chromatography, and in the meanwhile, the demographic information of the subjects was collected. Results Forty-six DS children were recruited for this study. The GDS scores of children with DS were lower than those in children without DS. The plasma Aß40 and Aß42 levels were negatively associated with the GDS scores. Moreover, the GDS scores of the non-VA deficiency (NVAD) group were significantly higher than those of the VA deficiency (VAD) group. Certain demographic characteristics, such as the paternal labor intensity and paternal educational status, were relevant factors with regard to the GDS scores of the DS children. Conclusions This study determined that DS children exhibited abnormal GDS scores which indicated developmental delay of children with DS; the levels of plasma Aß40, Aß42 and serum VA were influential biochemical indicators and the paternal labor intensity and educational status were related demographic factors.
Asunto(s)
Péptidos beta-Amiloides/sangre , Precursor de Proteína beta-Amiloide/sangre , Apolipoproteínas E/sangre , Biomarcadores/sangre , Discapacidades del Desarrollo/diagnóstico , Síndrome de Down/complicaciones , Niño , Preescolar , Discapacidades del Desarrollo/sangre , Discapacidades del Desarrollo/etiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , PronósticoRESUMEN
OBJECTIVE: To compare the therapeutic effect of electroacupuncture (EA) combined with donepezil hydrochloride and donepezil hydrochloride alone on improving learning-memory ability in patients with Alzheimer's disease (AD), and to explore its action mechanism. METHODS: Sixty patients of AD were randomly divided into an observation group and a control group, 30 cases in each group. The patients in the observation group were treated with EA at governor vessel (GV) combined with donepezil hydrochloride. EA was applied at Baihui (GV 20) and Fengfu (GV 16) with dilatational wave (10 Hz/50 Hz of frequency, 0.5 to 5.0 mA of intensity), and the needles were kept for 40 min, EA was given once a day; the donepezil hydrochloride tablet was taken orally, 5 mg, once a day, and after 4 weeks the dosage might be increased to 10 mg per day according to the specific situation. All the treatment was given for 8 weeks. The patients in the control group were only treated with donepezil hydrochloride with the identical procedure as the observation group. The Montreal cognitive assessment (MoCA) and Alzheimer's disease assessment scale cognitive part (ADAS-Cog) were evaluated before and after treatment; P300 (latency and amplitude of N2 and P3) was detected by EEG/ERP system brain event related potential instrument, and amyloid precursor protein (APP) and ß-amyloid protein 1-42 (Aß1-42) were detected by ELISA. RESULTS: Compared before treatment, the MoCA scores were increased after treatment in the two groups (P<0.05), and the MoCA score in the observation group was higher than that in the control group (P<0.05). Compared before treatment, the ADAS-Cog scores were decreased after treatment in the two groups (P<0.05), and the ADAS-Cog score in the observation group was lower than that in the control group (P<0.05). Compared before treatment, the latency of N2 and P3 was shortened and the amplitude was increased after treatment in the two groups (P<0.05); after treatment, the latency of N2 and P3 in the observation group was shorter than that in the control group and the amplitude was higher than that in the control group (P<0.05). Compared before treatment, the serum levels of APP and Aß1-42 were lower after treatment in the two groups (P<0.05), and the serum levels of APP and Aß1-42 in the observation group were lower than those in the control group (P<0.05). CONCLUSION: EA at Baihui (GV 20) and Fengfu (GV 6) combined with donepezil hydrochloride can effectively reduce the serum levels of APP and Aß1-42 and improve the scores of MoCA and ADAS-Cog and the levels of N2 and P3 of P300 in AD patients, which has superior effect to donepezil hydrochloride alone in improving the learning-memory of AD patients.
Asunto(s)
Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides/sangre , Precursor de Proteína beta-Amiloide/sangre , Electroacupuntura , Aprendizaje , Memoria , Fragmentos de Péptidos/sangre , Enfermedad de Alzheimer/sangre , Cognición , Donepezilo/uso terapéutico , HumanosRESUMEN
Cognitive dysfunction is common among people with schizophrenia. The molecular substrates underlying this remain poorly understood. To address this, we analyzed changes in amyloid precursor protein (APP) in platelets of people with acute schizophrenia (n=24) and control subjects (n=20) by ECL-immunoblotting. APP bands corresponding to molecular masses of â¼130, â¼110 and â¼100 kDa, and the APP ratio (APPr: highest APP molecular mass vs lowest APP molecular mass bands) were quantified. The intensity of 130 kDa-APP and the APPr were significantly reduced in schizophrenia patients compared to control subjects. The age-associated decreases in the 130 kDa, â¼110 kDa proteins and APPr were present in patients, but not controls. Our results confirm peripheral APP metabolism is altered in people with schizophrenia. Further work is now warranted on a larger sample of diseased subjects with detailed cognitive assessment to determine the APP role in cognitive processing in schizophrenia, how it is related to severity and disease progression, as well as outcomes.
Asunto(s)
Precursor de Proteína beta-Amiloide/sangre , Plaquetas/metabolismo , Esquizofrenia/sangre , Esquizofrenia/diagnóstico , Adolescente , Adulto , Biomarcadores/sangre , Estudios de Cohortes , Femenino , Humanos , Masculino , Proyectos Piloto , Recuento de Plaquetas/métodos , Adulto JovenRESUMEN
INTRODUCTION: Beta-amyloid is considered to be a pathophysiological marker in Alzheimer's disease (AD). Soluble amyloid precursor proteins (sAPPs) -α (sAPPα) and -ß (sAPPß), which are the byproducts of non-amyloidogenic and amyloidogenic process of APP, respectively, have been repeatedly observed in the cerebrospinal fluids (CSF) of AD patients. The present study focused on the determination of sAPP levels in peripheral blood. METHODS: The plasma protein levels of sAPPα and sAPPß were measured with ELISA. Plasma from 52 AD patients, 98 amnestic mild cognitive impairment (MCI) patients, and 114 cognitively normal controls were compared. RESULTS: The plasma level of sAPPß was significantly increased in AD patients than in cognitively healthy controls. However, no significant change in plasma sAPPα was observed among the three groups. Furthermore, the plasma sAPPß levels significantly correlated with cognitive assessment scales, such as clinical dementia rating (CDR), and mini-mental status examination (MMSE). Interestingly, sAPPα and sAPPß had a positive correlation with each other in blood plasma, similar to previous studies on CSF sAPP. This correlation was stronger in the MCI and AD groups than in the cognitively healthy controls. CONCLUSIONS: These results suggest that individuals with elevated plasma sAPPß levels are at an increased risk of AD; elevation in these levels may reflect the progression of disease.
Asunto(s)
Enfermedad de Alzheimer/sangre , Precursor de Proteína beta-Amiloide/sangre , Disfunción Cognitiva/sangre , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Fragmentos de Péptidos/sangreRESUMEN
To identify whether platelet amyloid-ß protein precursor (AßPP) ratio, phosphorylated-tau (P-tau) 231, P-tau181, and serine 396 and 404 (Ser396/404) phosphorylated tau are potential peripheral indicators for early Alzheimer's disease (AD). Forty-three amnesic mild cognitive impairment (aMCI) patients and 45 normal controls were recruited. Peripheral venous blood was drawn and platelets were collected and evaluated for potential indicators by Western blot analysis. Subsequent meta-analysis was completed on these selected indicators. In platelets of aMCI patients, the AßPP ratio level was significantly lower and levels of P-tau231 and Ser396/404 phosphorylated tau were significantly higher. Moreover, in aMCI patients, a negative correlation was observed between platelet P-tau231 level and the Trail Making Tests A score, and it was found that higher platelet P-tau231 levels significantly associated with a worse performance of information processing speed. Furthermore, values of the area under the curve of platelet P-tau231 and Ser396/404 phosphorylated tau were 0.624 and 0.657, respectively. Finally, a meta-analysis indicated platelet AßPP ratio level was significantly lower in MCI cohorts. In conclusion, platelets of aMCI subjects showed a lower AßPP ratio and higher levels of P-tau231 and Ser396/404 phosphorylated tau when compared to normal controls, which may be critical in identifying early AD.
Asunto(s)
Enfermedad de Alzheimer/sangre , Precursor de Proteína beta-Amiloide/sangre , Proteínas tau/sangre , Anciano , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Biomarcadores/sangre , Plaquetas/metabolismo , Estudios de Casos y Controles , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/psicología , Diagnóstico Precoz , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fosforilación , Proteínas tau/químicaRESUMEN
AIM: Obesity contributes to the development of mild cognitive impairment, but the potential role of normal weight obesity in this disease has not been explored in humans. The aim of the study was to reveal the relationship between normal weight obesity and mild cognitive impairment in elderly individuals. METHODS: This study consisted of 360 patients with amnestic mild cognitive impairment and 360 cognitively normal controls. Normal weight obesity was defined as having metabolic syndrome but a normal weight. Metabolic health meant having no metabolic syndrome. Reverse transcription quantitative real-time polymerase chain reaction was adopted to measure the messenger RNA expression of four cognitive-related genes (amyloid precursor protein, cyclic adenosine monophosphate-responsive element-binding protein 1, sortilin-related receptor 1, and synapsin I) in peripheral blood mononuclear cells. RESULTS: Normal weight obesity was related to a higher risk of amnestic mild cognitive impairment (odds ratio = 3.14, 95% confidence interval: 2.13-4.60). In the patients, the expression of each gene in the peripheral blood mononuclear cells was linearly related to Mini-Mental State Examination and Montreal Cognitive Assessment scores (P < 0.05). The expression of these genes in the patients with metabolic health deviated from the normal levels found in the controls (P < 0.05), and the deviations were more significant in the patients with normal weight obesity (P < 0.05). CONCLUSION: Normal weight obesity may be a potential risk factor for amnestic mild cognitive impairment in elderly. This relationship was reflected in the abnormal expression of several cognitive-related genes in peripheral blood mononuclear cells.
Asunto(s)
Disfunción Cognitiva/genética , Expresión Génica , Leucocitos Mononucleares , Síndrome Metabólico/genética , Obesidad/genética , ARN Mensajero , Anciano , Anciano de 80 o más Años , Amnesia/complicaciones , Precursor de Proteína beta-Amiloide/sangre , Precursor de Proteína beta-Amiloide/genética , Biomarcadores/sangre , Índice de Masa Corporal , Estudios de Casos y Controles , China/epidemiología , Disfunción Cognitiva/complicaciones , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/sangre , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Femenino , Humanos , Peso Corporal Ideal , Proteínas Relacionadas con Receptor de LDL/sangre , Proteínas Relacionadas con Receptor de LDL/genética , Masculino , Proteínas de Transporte de Membrana/sangre , Proteínas de Transporte de Membrana/genética , Pruebas de Estado Mental y Demencia , Síndrome Metabólico/clasificación , Obesidad/clasificación , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sinapsinas/sangre , Sinapsinas/genéticaRESUMEN
OBJECTIVE: Our study aimed to assess the effect of a 12-month vitamin D supplementation on cognitive function and amyloid beta (Aß)-related biomarkers in subjects with Alzheimer's disease (AD). METHODS : This was a randomised, double-blind, placebo-controlled trial. 210 AD patients were randomly divided into intervention and control groups. Participants received 12-month 800 IU/day of vitamin D or starch granules as placebo. Tests of cognitive performance and Aß-related biomarkers were measured at baseline, 6 months and 12 months. RESULTS : Repeated-measures analysis of variance showed significant improvements in plasma Aß42, APP, BACE1, APPmRNA, BACE1mRNA (p<0.001) levels and information, arithmetic, digit span, vocabulary, block design and picture arrange scores (p<0.05) in the intervention group over the control group. According to mixed-model analysis, vitamin D group had significant increase in full scale IQ during follow-up period (p<0.001). CONCLUSIONS: Daily oral vitamin D supplementation (800 IU/day) for 12 months may improve cognitive function and decrease Aß-related biomarkers in elderly patients with AD. Larger scale longer term randomised trials of vitamin D are needed. TRIAL REGISTRATION NUMBER: ChiCTR-IIR-16009549.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Precursor de Proteína beta-Amiloide/sangre , Cognición/efectos de los fármacos , Suplementos Dietéticos , Vitamina D/uso terapéutico , Vitaminas/uso terapéutico , Anciano , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/psicología , Secretasas de la Proteína Precursora del Amiloide/sangre , Ácido Aspártico Endopeptidasas/sangre , Método Doble Ciego , Femenino , Humanos , Hidroxicolecalciferoles/sangre , Pruebas de Inteligencia , Masculino , Pruebas Neuropsicológicas , Desempeño Psicomotor/efectos de los fármacosRESUMEN
Identification of molecular mechanisms underlying early-stage Alzheimer's disease (AD) is important for the development of new therapies against and diagnosis of AD. In this study, gas chromatography time-of-flight mass spectrometry (GC-TOF-MS)-based metabolomics approach was employed to investigate the metabolic profiles in plasma and brain tissues harvested from 5-month-old APP/PS1 transgenic mice and their wildtype counterparts. Since different brain regions were expected to have their own distinct metabolic signals, four different brain regions, namely cortex, hippocampus, midbrain and cerebellum tissues, were dissected and had their metabolic profiles studied separately. Biochemical assays were also performed on plasma and brain cortex tissue of transgenic mice and wildtype mice, with a focus on mitochondrial health. Amyloid precursor protein and amyloid-ß levels in plasma, brain cortex tissue and mitochondria fractions isolated from brain cortex were measured to assess the amyloid pathology. Our findings include the observation of extensive metabolic alterations in cortex and cerebellum of APP/PS1 mice, but not in their hippocampus, midbrain and plasma. The major pathways affected in cortex and cerebellum of APP/PS1 mice were closely related to impaired energy metabolism and perturbation of amino acid metabolism in these mice. APP/PS1 mice also exhibited higher amyloid-ß40 and amyloid-ß42 in their cortex, accumulation of mitochondria APP in their cortex, and presented an altered oxidative state in their brain. Treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone (PIO) successfully restored the energy metabolism, lowered amyloid-ß levels and afforded the APP/PS1 mice a better antioxidative capacity in their cortex.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Cerebelo/metabolismo , Corteza Cerebral/metabolismo , PPAR gamma/agonistas , Pioglitazona/uso terapéutico , Presenilina-1/metabolismo , Enfermedad de Alzheimer/sangre , Precursor de Proteína beta-Amiloide/sangre , Animales , Catalasa/metabolismo , Citrato (si)-Sintasa/metabolismo , Análisis Discriminante , Modelos Animales de Enfermedad , Femenino , Hipocampo/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Masculino , Metabolómica , Ratones Transgénicos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Pioglitazona/farmacología , Análisis de Componente Principal , Superóxido Dismutasa/metabolismoRESUMEN
Cost- and time-effective markers of Alzheimer's disease (AD), reliable and feasible at the population level are urgently needed. Soluble amyloid-ß protein precursor ß (sAßPPß) in plasma has attracted scientific attention as a potential AD biomarker candidate. Here we report that plasma sAßPPß levels in patients with AD dementia and typical for AD cerebrospinal fluid (CSF) biomarker profiles (Nâ=â33) are significantly lower (pâ<â0.01) than those of cognitively healthy elderly individuals without AD (Nâ=â39), while CSF sAßPPß levels did not differ between the studied groups. This provides further evidence for the potential of sAßPPß in plasma as an AD biomarker candidate.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Precursor de Proteína beta-Amiloide/sangre , Demencia/diagnóstico , Anciano , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Demencia/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas tau/líquido cefalorraquídeoRESUMEN
OBJECTIVES: To investigate whether baseline [123I]FP-CIT SPECT and CSF markers can predict cognitive impairment (CI) in PD patients, and provide a profile of those most at risk. METHODS: 262 de novo PD patients from the Parkinson's Progression Markers Initiative database were stratified into two CI groups at the 36-month follow-up: MoCA-defined diagnosis: PD patients who had a MoCA score < 26; neuropsychological test-defined diagnosis: PD patients with MoCA-defined diagnosis and at least two test scores (of six; irrespective of test domain) greater than 1.5 standard deviation below the mean score in healthy controls. Predictive variables of CI were divided into deciles, providing us with ideal cutoff values for each variable. RESULTS: At the 36-month follow-up, 108/262 (41.2%) PD patients had CI as defined by the MoCA, of which 40/108 (37.0%) had neuropsychological test-defined CI. Baseline CSF Aß42 (hazard ratio [HR]: 0.996, confidence interval [CI]: 0.992-0.999, p = 0.025), CSF total tau ([HR]: 1.023, [CI]: 1.002-1.044, p = 0.031) and caudate [123I]FP-CIT SPECT uptake ([HR]: 0.332, [CI]: 0.115-0.960, p = 0.042) were predictors of CI. Patients with reduced CSF Aß42 (< 384.6 pg/mL), increased CSF total tau (> 45.0 pg/mL) and reduced caudate [123I]FP-CIT SPECT uptake (< 1.82) had a 65% risk of developing CI at 36-month follow-up. CONCLUSION: We report a characteristic profile (reduced CSF Aß42, increased CSF total tau and reduced caudate [123I]FP-CIT SPECT uptake) that enables identification of early PD patients at risk of developing CI. These findings confirm previous reports of low CSF Aß42, elevated CSF total tau and reduced dopaminergic integrity being associated with cognitive decline in PD.
Asunto(s)
Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/metabolismo , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/metabolismo , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/sangre , Apolipoproteína A-I/sangre , Núcleo Caudado/diagnóstico por imagen , Trastornos del Conocimiento/diagnóstico por imagen , Factor de Crecimiento Epidérmico/sangre , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Enfermedad de Parkinson/diagnóstico por imagen , Fragmentos de Péptidos/líquido cefalorraquídeo , Valor Predictivo de las Pruebas , Tomografía Computarizada de Emisión de Fotón Único , Tropanos/farmacocinéticaRESUMEN
Background and objective: Deregulation of the expression of amyloid precursor protein (APP) can lead to the development of Alzheimer's disease (AD). Recent studies have shown that many single nucleotide polymorphisms (SNPs) in the 3' untranslated region (UTR) of APP are associated with the development of AD. Since microRNAs (miRNAs) are involved in the regulation of APP expression, we believe that the APP 3'UTR polymorphism may affect the regulation of APP expression in miRNAs. Results: The levels of miR-101-3p, miR-153-3p, miR-144-3p, miR-381-3p, and miR-383-5p in plasma of patients with AD were significantly lower than those in the control group. The APP-534G/A site A allele was a protective factor for AD risk (adjusted odds ratio (OR) = 0.700, 95% confidence interval (95% CI): 0.573-0.840, P<0.001). The APP-369C/G site variation was not associated with AD risk. The APP-118C/A site A allele was a protective factor for AD (adjusted OR = 0.762, 95% CI: 0.639-0.897, P=0.001). The APP-534G/A site mutation affects the regulation of APP protein expression by miR-101-3p, miR-144-3p, miR-153-3p, and miR-381-3p, and the mutation of the APP-118C/A site affects miR-101-3p, miR-144-3p, miR-153-3p, and miR-383-5p regulation of APP expression. Conclusion: APP 3'UTR polymorphisms can affect the regulation of APP expression by miRNAs and thus affect the occurrence of AD.