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1.
Ann Neurol ; 96(3): 453-459, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38963256

RESUMEN

The life expectancy of people with multiple sclerosis (MS) has increased, yet we have noted that development of a typical Alzheimer disease dementia syndrome is uncommon. We hypothesized that Alzheimer disease pathology is uncommon in MS patients. In 100 MS patients, the rate of amyloid-ß plasma biomarker positivity was approximately half the rate in 300 non-MS controls matched on age, sex, apolipoprotein E proteotype, and cognitive status. Interestingly, most MS patients who did have amyloid-ß pathology had features atypical for MS at diagnosis. These results support that MS is associated with reduced Alzheimer disease risk, and suggest new avenues of research. ANN NEUROL 2024;96:453-459.


Asunto(s)
Péptidos beta-Amiloides , Esclerosis Múltiple , Humanos , Femenino , Masculino , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/sangre , Esclerosis Múltiple/patología , Esclerosis Múltiple/sangre , Persona de Mediana Edad , Adulto , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/sangre , Biomarcadores/sangre , Anciano
2.
Alzheimers Dement ; 20(2): 1214-1224, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37932961

RESUMEN

INTRODUCTION: Incorporating blood-based Alzheimer's disease biomarkers such as tau and amyloid beta (Aß) into screening algorithms may improve screening efficiency. METHODS: Plasma Aß, phosphorylated tau (p-tau)181, and p-tau217 concentration levels from AHEAD 3-45 study participants were measured using mass spectrometry. Tau concentration ratios for each proteoform were calculated to normalize for inter-individual differences. Receiver operating characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by > 20 Centiloids. Mixture of experts analysis assessed the value of including tau concentration ratios into the existing predictive algorithm for amyloid positron emission tomography status. RESULTS: The area under the receiver operating curve (AUC) was 0.87 for Aß42/Aß40, 0.74 for phosphorylated variant p-tau181 ratio (p-tau181/np-tau181), and 0.92 for phosphorylated variant p-tau217 ratio (p-tau217/np-tau217). The Plasma Predicted Centiloid (PPC), a predictive model including p-tau217/np-tau217, Aß42/Aß40, age, and apolipoprotein E improved AUC to 0.95. DISCUSSION: Including plasma p-tau217/np-tau217 along with Aß42/Aß40 in predictive algorithms may streamline screening preclinical individuals into anti-amyloid clinical trials. CLINICALTRIALS: gov Identifier: NCT04468659 HIGHLIGHTS: The addition of plasma phosphorylated variant p-tau217 ratio (p-tau217/np-tau217) significantly improved plasma biomarker algorithms for identifying preclinical amyloid positron emission tomography positivity. Prediction performance at higher NAV Centiloid levels was improved with p-tau217/np-tau217. All models generated for this study are incorporated into the Plasma Predicted Centiloid (PPC) app for public use.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides , Fragmentos de Péptidos , Amiloide , Proteínas tau , Tomografía de Emisión de Positrones , Biomarcadores
3.
Alzheimers Dement ; 20(6): 3827-3838, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38629508

RESUMEN

INTRODUCTION: In trials of amyloid-lowering drugs for Alzheimer's disease (AD), differential eligibility may contribute to under-inclusion of racial and ethnic underrepresented groups. We examined plasma amyloid beta 42/40 and positron emission tomography (PET) amyloid eligibility for the ongoing AHEAD Study preclinical AD program (NCT04468659). METHODS: Univariate logistic regression models were used to examine group differences in plasma and PET amyloid screening eligibility. RESULTS: Of 4905 participants screened at time of analysis, 1724 were plasma eligible to continue in screening: 13.3% Hispanic Black, 24.7% Hispanic White, 20.8% non-Hispanic (NH) Asian, 24.7% NH Black, and 38.9% NH White. Plasma eligibility differed across groups in models controlling for covariates (odds ratio from 1.9 to 4.0 compared to the NH White reference group, P < 0.001). Among plasma eligible participants, PET eligibility did not differ by group. DISCUSSION: These results suggest that prevalence of brain amyloid pathology differed, but that eligibility based on plasma was equally effective across racial and ethnic group members. HIGHLIGHTS: Plasma amyloid eligibility is lower in underrepresented racial and ethnic groups. In plasma eligible adults, positron emission tomography eligibility rates are similar across race and ethnicity. Plasma biomarker tests may be similarly effective across racial and ethnic groups.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Tomografía de Emisión de Positrones , Anciano , Femenino , Humanos , Masculino , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/etnología , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides/sangre , Biomarcadores/sangre , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Etnicidad , Grupos Raciales
4.
Alzheimers Dement ; 20(5): 3179-3192, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38491912

RESUMEN

BACKGROUND: With the availability of disease-modifying therapies for Alzheimer's disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment. METHODS: High-throughput, mass spectrometry-based assays were used to measure %p-tau217 and amyloid beta (Aß)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET. RESULTS: The area under the receiver operating characteristic curve (AUC-ROC) for %p-tau217 (0.94) was statistically significantly higher than that for p-tau217 concentration (0.91). The AUC-ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status. DISCUSSION: The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET.


Asunto(s)
Algoritmos , Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Encéfalo , Espectrometría de Masas , Fragmentos de Péptidos , Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Péptidos beta-Amiloides/sangre , Femenino , Masculino , Proteínas tau/sangre , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/diagnóstico por imagen , Anciano , Fragmentos de Péptidos/sangre , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Biomarcadores/sangre , Persona de Mediana Edad , Anciano de 80 o más Años , Curva ROC
5.
Clin Infect Dis ; 76(10): 1776-1783, 2023 05 24.
Artículo en Inglés | MEDLINE | ID: mdl-36610788

RESUMEN

BACKGROUND: As people with human immunodeficiency virus (HIV) (PWH) age, it remains unclear whether they are at higher risk for age-related neurodegenerative disorders-for example, Alzheimer disease (AD)-and, if so, how to differentiate HIV-associated neurocognitive impairment from AD. We examined a clinically available blood biomarker test for AD (plasma amyloid-ß [Aß] 42/Aß40 ratio) in PWH who were cognitively normal (PWH_CN) or cognitively impaired (PWH_CI) and people without HIV (PWoH) who were cognitively normal (PWoH_CN) or had symptomatic AD (PWoH_AD). METHODS: A total of 66 PWH (age >40 years) (HIV RNA <50 copies/mL) and 195 PWoH provided blood samples, underwent magnetic resonance imaging, and completed a neuropsychological battery or clinical dementia rating scale. Participants were categorized by impairment (PWH_CN, n = 43; PWH_CI, n = 23; PWoH_CN, n = 138; PWoH_AD, n = 57). Plasma Aß42 and Aß40 concentrations were obtained using a liquid chromatography-tandem mass spectrometry method to calculate the PrecivityAD amyloid probability score (APS). The APS incorporates age and apolipoprotein E proteotype into a risk score for brain amyloidosis. Plasma Aß42/Aß40 ratios and APSs were compared between groups and assessed for relationships with hippocampal volumes or cognition and HIV clinical characteristics (PWH only). RESULTS: The plasma Aß42/Aß40 ratio was significantly lower, and the APS higher, in PWoH_AD than in other groups. A lower Aß42/Aß40 ratio and higher APS was associated with smaller hippocampal volumes for PWoH_AD. The Aß42/Aß40 ratio and APS were not associated with cognition or HIV clinical measures for PWH. CONCLUSIONS: The plasma Aß42/Aß40 ratio can serve as a screening tool for AD and may help differentiate effects of HIV from AD within PWH, but larger studies with older PWH are needed.


Asunto(s)
Infecciones por VIH , VIH , Humanos , Anciano , Adulto , Factores de Riesgo , Péptidos beta-Amiloides , Infecciones por VIH/complicaciones
6.
Clin Infect Dis ; 69(7): 1165-1172, 2019 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-30535188

RESUMEN

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors have pleotropic anti-inflammatory and immune regulatory effects in addition to glucoregulation. We evaluated inflammation and immune markers in suppressed human immunodeficiency virus (HIV) infection during treatment with the DPP-4 inhibitor sitagliptin. METHODS: Virologically suppressed adults with HIV without diabetes on stable antiretroviral therapy (ART) with ≥100/µL CD4 cells were randomized to 16 weeks of sitagliptin 100 mg/day vs placebo in a multicenter trial. The primary endpoint was the change in plasma soluble CD14 (sCD14) from baseline to week 15-16. RESULTS: Ninety participants were randomized, and 42 from each arm were included in per-protocol analyses. Participants were 45% non-Hispanic white, 38% non-Hispanic black, and 15% Hispanic, with a median age of 51 years; 83% were male; and the median CD4 count was 602 cells/µL. At week 15-16, there was no difference in sCD14 change between the 2 arms (P = .69). Relative to placebo, the sitagliptin arm had 47% greater decline in CXCL10 (95% confidence interval, -57% to -35%) at week 15 (P < .001). There were no significant between-arm differences in other soluble biomarkers, total CD4 and CD8 counts, or markers of lymphocyte or monocyte activation. Sitagliptin was well tolerated. CONCLUSIONS: Sixteen weeks of sitagliptin had no effect on sCD14 levels in virologically suppressed participants with HIV. CXCL10, a chemokine involved in atherogenesis that predicts non-AIDS events during ART, declined markedly with sitagliptin. This suggests that DPP-4 inhibition has the potential to reduce cardiovascular morbidity in treated HIV infection. CLINICAL TRIALS REGISTRATION: NCT01426438.


Asunto(s)
Antiinflamatorios/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH/efectos de los fármacos , Factores Inmunológicos/uso terapéutico , Fosfato de Sitagliptina/uso terapéutico , Adulto , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Terapia Antirretroviral Altamente Activa , Biomarcadores , Recuento de Linfocito CD4 , Femenino , VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversos , Masculino , Persona de Mediana Edad , Fosfato de Sitagliptina/administración & dosificación , Fosfato de Sitagliptina/efectos adversos , Resultado del Tratamiento , Carga Viral
7.
Ann Neurol ; 78(3): 439-53, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26040676

RESUMEN

OBJECTIVE: Age is the single greatest risk factor for Alzheimer's disease (AD), with the incidence doubling every 5 years after age 65. However, our understanding of the mechanistic relationship between increasing age and the risk for AD is currently limited. We therefore sought to determine the relationship between age, amyloidosis, and amyloid-beta (Aß) kinetics in the central nervous system (CNS) of humans. METHODS: Aß kinetics were analyzed in 112 participants and compared to the ages of participants and the amount of amyloid deposition. RESULTS: We found a highly significant correlation between increasing age and slowed Aß turnover rates (2.5-fold longer half-life over five decades of age). In addition, we found independent effects on Aß42 kinetics specifically in participants with amyloid deposition. Amyloidosis was associated with a higher (>50%) irreversible loss of soluble Aß42 and a 10-fold higher Aß42 reversible exchange rate. INTERPRETATION: These findings reveal a mechanistic link between human aging and the risk of amyloidosis, which may be owing to a dramatic slowing of Aß turnover, increasing the likelihood of protein misfolding that leads to deposition. Alterations in Aß kinetics associated with aging and amyloidosis suggest opportunities for diagnostic and therapeutic strategies. More generally, this study provides an example of how changes in protein turnover kinetics can be used to detect physiological and pathophysiological changes and may be applicable to other proteinopathies.


Asunto(s)
Envejecimiento/metabolismo , Péptidos beta-Amiloides/metabolismo , Amiloidosis/metabolismo , Sistema Nervioso Central/metabolismo , Fragmentos de Péptidos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/patología , Amiloidosis/patología , Sistema Nervioso Central/patología , Femenino , Humanos , Cinética , Masculino , Persona de Mediana Edad
8.
Curr HIV/AIDS Rep ; 13(6): 340-348, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27549318

RESUMEN

Frailty is a critical aging-related syndrome marked by diminished physiologic reserve and heightened vulnerability to stressors, predisposing to major adverse clinical outcomes, including hospitalization, institutionalization, disability, and death in the general population of older adults. As the proportion of older adults living with HIV increases in the era of antiretroviral therapy, frailty is increasingly recognized to be of significant clinical and public health relevance to the HIV-infected population. This article reviews current knowledge on the epidemiology and biology of frailty and its potential role as a target for reducing disparities in outcomes in HIV; conceptual frameworks and current approaches to frailty measurement; existing data on frailty interventions; and important areas for future research focus necessary to develop and advance effective strategies to prevent or ameliorate frailty and its marked adverse consequences among people living with HIV.


Asunto(s)
Envejecimiento , Anciano Frágil , Infecciones por VIH/complicaciones , Infecciones por VIH/terapia , Anciano , Humanos
9.
J Neurosci ; 34(24): 8336-46, 2014 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-24920637

RESUMEN

BACE, a ß-secretase, is an attractive potential disease-modifying therapeutic strategy for Alzheimer's disease (AD) as it results directly in the decrease of amyloid precursor protein (APP) processing through the ß-secretase pathway and a lowering of CNS amyloid-ß (Aß) levels. The interaction of the ß-secretase and α-secretase pathway-mediated processing of APP in the rhesus monkey (nonhuman primate; NHP) CNS is not understood. We hypothesized that CNS inhibition of BACE would result in decreased newly generated Aß and soluble APPß (sAPPß), with increased newly generated sAPPα. A stable isotope labeling kinetics experiment in NHPs was performed with a (13)C6-leucine infusion protocol to evaluate effects of BACE inhibition on CNS APP processing by measuring the kinetics of sAPPα, sAPPß, and Aß in CSF. Each NHP received a low, medium, or high dose of MBI-5 (BACE inhibitor) or vehicle in a four-way crossover design. CSF sAPPα, sAPPß, and Aß were measured by ELISA and newly incorporated label following immunoprecipitation and liquid chromatography-mass spectrometry. Concentrations, kinetics, and amount of newly generated APP fragments were calculated. sAPPß and sAPPα kinetics were similar, but both significantly slower than Aß. BACE inhibition resulted in decreased labeled sAPPß and Aß in CSF, without observable changes in labeled CSF sAPPα. ELISA concentrations of sAPPß and Aß both decreased and sAPPα increased. sAPPα increased by ELISA, with no difference by labeled sAPPα kinetics indicating increases in product may be due to APP shunting from the ß-secretase to the α-secretase pathway. These results provide a quantitative understanding of pharmacodynamic effects of BACE inhibition on NHP CNS, which can inform about target development.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Sistema Nervioso Central/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Isótopos de Carbono/metabolismo , Línea Celular Tumoral , Sistema Nervioso Central/efectos de los fármacos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Humanos , Inmunoprecipitación , Leucina/metabolismo , Macaca mulatta , Espectrometría de Masas , Neuroblastoma , Fragmentos de Péptidos , Transfección
10.
Appl Environ Microbiol ; 80(11): 3375-83, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24657858

RESUMEN

Anaerobic digesters rely on the diversity and distribution of parallel metabolic pathways mediated by complex syntrophic microbial communities to maintain robust and optimal performance. Using mesophilic swine waste digesters, we experimented with increased ammonia loading to induce a shift from aceticlastic methanogenesis to an alternative acetate-consuming pathway of syntrophic acetate oxidation. In comparison with control digesters, we observed shifts in bacterial 16S rRNA gene content and in functional gene repertoires over the course of the digesters' 3-year operating period. During the first year, under identical startup conditions, all bioreactors mirrored each other closely in terms of bacterial phylotype content, phylogenetic structure, and evenness. When we perturbed the digesters by increasing the ammonia concentration or temperature, the distribution of bacterial phylotypes became more uneven, followed by a return to more even communities once syntrophic acetate oxidation had allowed the experimental bioreactors to regain stable operation. The emergence of syntrophic acetate oxidation coincided with a partial shift from aceticlastic to hydrogenotrophic methanogens. Our 16S rRNA gene analysis also revealed that acetate-fed enrichment experiments resulted in communities that did not represent the bioreactor community. Analysis of shotgun sequencing of community DNA suggests that syntrophic acetate oxidation was carried out by a heterogeneous community rather than by a specific keystone population with representatives of enriched cultures with this metabolic capacity.


Asunto(s)
Acetatos/metabolismo , Amoníaco/metabolismo , Bacterias/clasificación , Bacterias/metabolismo , Reactores Biológicos/microbiología , Biota/efectos de los fármacos , Animales , Análisis por Conglomerados , ADN Bacteriano/química , ADN Bacteriano/genética , ADN Ribosómico/química , ADN Ribosómico/genética , Heces/microbiología , Hidrógeno/metabolismo , Metano/metabolismo , Datos de Secuencia Molecular , Oxidación-Reducción , Filogenia , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN , Porcinos
11.
Blood ; 120(7): 1422-31, 2012 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-22786879

RESUMEN

TLR agonists initiate a rapid activation program in dendritic cells (DCs) that requires support from metabolic and bioenergetic resources. We found previously that TLR signaling promotes aerobic glycolysis and a decline in oxidative phosphorylation (OXHPOS) and that glucose restriction prevents activation and leads to premature cell death. However, it remained unclear why the decrease in OXPHOS occurs under these circumstances. Using real-time metabolic flux analysis, in the present study, we show that mitochondrial activity is lost progressively after activation by TLR agonists in inflammatory blood monocyte-derived DCs that express inducible NO synthase. We found that this is because of inhibition of OXPHOS by NO and that the switch to glycolysis is a survival response that serves to maintain ATP levels when OXPHOS is inhibited. Our data identify NO as a profound metabolic regulator in inflammatory monocyte-derived DCs.


Asunto(s)
Células Dendríticas/metabolismo , Células Dendríticas/patología , Glucólisis , Inflamación/patología , Óxido Nítrico/biosíntesis , Adenosina Trifosfato/metabolismo , Animales , Muerte Celular/efectos de los fármacos , Respiración de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Células Dendríticas/enzimología , Glucólisis/efectos de los fármacos , Inflamación/enzimología , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Modelos Inmunológicos , Monocitos/patología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Factores de Tiempo , Receptores Toll-Like/metabolismo
12.
Proc Natl Acad Sci U S A ; 108(10): 4158-63, 2011 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-21368115

RESUMEN

Anaerobic digestion is the most successful bioenergy technology worldwide with, at its core, undefined microbial communities that have poorly understood dynamics. Here, we investigated the relationships of bacterial community structure (>400,000 16S rRNA gene sequences for 112 samples) with function (i.e., bioreactor performance) and environment (i.e., operating conditions) in a yearlong monthly time series of nine full-scale bioreactor facilities treating brewery wastewater (>20,000 measurements). Each of the nine facilities had a unique community structure with an unprecedented level of stability. Using machine learning, we identified a small subset of operational taxonomic units (OTUs; 145 out of 4,962), which predicted the location of the facility of origin for almost every sample (96.4% accuracy). Of these 145 OTUs, syntrophic bacteria were systematically overrepresented, demonstrating that syntrophs rebounded following disturbances. This indicates that resilience, rather than dynamic competition, played an important role in maintaining the necessary syntrophic populations. In addition, we explained the observed phylogenetic differences between all samples on the basis of a subset of environmental gradients (using constrained ordination) and found stronger relationships between community structure and its function rather than its environment. These relationships were strongest for two performance variables--methanogenic activity and substrate removal efficiency--both of which were also affected by microbial ecology because these variables were correlated with community evenness (at any given time) and variability in phylogenetic structure (over time), respectively. Thus, we quantified relationships between community structure and function, which opens the door to engineer communities with superior functions.


Asunto(s)
Microbiología , Metabolismo Energético , Filogenia
13.
Diagnostics (Basel) ; 14(16)2024 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-39202226

RESUMEN

Alzheimer's disease (AD) is a progressive irreversible neurodegenerative disorder that represents a major global public health concern. Traditionally, AD is diagnosed using cerebrospinal fluid biomarker analysis or brain imaging modalities. Recently, less burdensome, more widely available blood biomarker (BBM) assays for amyloid-beta (Aß42/40) and phosphorylated-tau concentrations have been found to accurately identify the presence/absence of brain amyloid plaques and tau tangles and have helped to streamline AD diagnosis. However, few BBMs have been rigorously analytically validated. Herein, we report the analytical validation of a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) multiplex method for quantifying plasma phosphorylated-tau217 (p-tau217) and non-phosphorylated-tau217 (np-tau217) peptide concentrations. We combined the p-tau217/np-tau217 concentrations ratio (%p-tau217) and the previously validated LC-MS/MS multiplex assay for plasma Aß42/40 into a new multianalyte assay with algorithmic analysis (MAAA; PrecivityAD2™ test) that identifies brain amyloid status based on brain amyloid positron emission tomography. We found (a) the %p-tau217 assay is precise, accurate, sensitive, and linear over a wide analytical measurement range, and free from carryover and interference; (b) the pre-analytical specimen collection, processing, storage, and shipping conditions that maintain plasma tau peptide stability; and (c) using the measured analytical imprecision for plasma Aß42/40 and p-tau217/np-tau217 levels in a worst-case scenario model, the PrecivityAD2 test algorithm for amyloid pathology classification changed for only 3.5% of participants from brain amyloid positive to negative, or from negative to positive. The plasma sample preparation and LC-MS/MS methods underlying the PrecivityAD2 test are suitable for use in the clinical laboratory and valid for the test's intended purpose: to aid in the diagnostic evaluation of individuals aged 55 and older with signs or symptoms of mild cognitive impairment or dementia.

14.
J Alzheimers Dis ; 97(3): 1353-1363, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38306056

RESUMEN

BACKGROUND: Alzheimer's disease (AD), the most common cause of dementia, poses a significant global burden. Diagnosis typically involves invasive and costly methods like neuroimaging or cerebrospinal fluid (CSF) biomarker testing of phosphorylated tau (p-tau) and amyloid-ß42/40 (Aß42/40). Such procedures are especially impractical in resource-constrained regions, such as the Democratic Republic of Congo (DRC). Blood-based biomarker testing may provide a more accessible screening opportunity. OBJECTIVE: This study aims to examine if AD-related blood-based biomarkers are associated with cognitive test performance in the Congolese population, where limited research has been conducted. METHODS: In this cross-sectional study of 81 Congolese individuals, cognitive assessments (Alzheimer's Questionnaire (AQ) and Community Screening Interview for Dementia (CSID)) distinguished dementia cases from controls. Blood draws were taken to assess p-tau 181 and Aß42/40 biomarkers. Relationships between the biomarkers and cognitive performance were analyzed using multiple linear regression models. RESULTS: Lower plasma Aß42/40 was significantly associated with lower CSID scores and higher AQ scores, indicative of AD (p < 0.001). These relationships were observed in healthy controls (CSID p = 0.01, AQ p = 0.03), but not in dementia cases. However, p-tau 181 did not exhibit significant associations with either measure. Factors such as age, sex, education, presence of APOEɛ4 allele, did not alter these relationships. CONCLUSIONS: Understanding relationships between AD-related screening tests and blood biomarkers is a step towards utilization of blood-based biomarker tests as a screening tool for AD, especially in resource-limited regions. Further research should be conducted to evaluate blood biomarker test efficacy in larger samples and other populations.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Estudios Transversales , Péptidos beta-Amiloides/líquido cefalorraquídeo , República Democrática del Congo , Proteínas tau/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Pruebas Neuropsicológicas , Fragmentos de Péptidos/líquido cefalorraquídeo , Cognición , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/líquido cefalorraquídeo
15.
Front Neurol ; 15: 1320727, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38601333

RESUMEN

Background: The current study examined the sensitivity of two memory subtests and their corresponding learning slope metrics derived from the African Neuropsychology Battery (ANB) to detect amyloid pathology and APOEε4 status in adults from Kinshasa, the Democratic Republic of the Congo. Methods: 85 participants were classified for the presence of ß-amyloid pathology and based on allelic presence of APOEε4 using Simoa. All participants were screened using CSID and AQ, underwent verbal and visuospatial memory testing from ANB, and provided blood samples for plasma Aß42, Aß40, and APOE proteotype. Pearson correlation, linear and logistic regression were conducted to compare amyloid pathology and APOEε4 status with derived learning scores, including initial learning, raw learning score, learning over trials, and learning ratio. Results: Our sample included 35 amyloid positive and 44 amyloid negative individuals as well as 42 without and 39 with APOEε4. All ROC AUC ranges for the prediction of amyloid pathology based on learning scores were low, ranging between 0.56-0.70 (95% CI ranging from 0.44-0.82). The sensitivity of all the scores ranged between 54.3-88.6, with some learning metrics demonstrating good sensitivity. Regarding APOEε4 prediction, all AUC values ranged between 0.60-0.69, with all sensitivity measures ranging between 53.8-89.7. There were minimal differences in the AUC values across learning slope metrics, largely due to the lack of ceiling effects in this sample. Discussion: This study demonstrates that some ANB memory subtests and learning slope metrics can discriminate those that are normal from those with amyloid pathology and those with and without APOEε4, consistent with findings reported in Western populations.

16.
PLoS One ; 19(5): e0302998, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38809849

RESUMEN

BACKGROUND: Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. OBJECTIVE: To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. METHODS: This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. CONCLUSION: The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.


Asunto(s)
Enfermedad de Alzheimer , Tiamina , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Tiamina/análogos & derivados , Tiamina/uso terapéutico , Tiamina/administración & dosificación , Tiamina/efectos adversos , Método Doble Ciego , Masculino , Femenino , Anciano , Persona de Mediana Edad , Resultado del Tratamiento , Profármacos/efectos adversos , Profármacos/uso terapéutico , Profármacos/administración & dosificación , Profármacos/farmacocinética
17.
Sleep ; 47(1)2024 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-38011629

RESUMEN

STUDY OBJECTIVES: Given the established racial disparities in both sleep health and dementia risk for African American populations, we assess cross-sectional and longitudinal associations of self-report sleep duration (SRSD) and daytime sleepiness with plasma amyloid beta (Aß) and cognition in an African American (AA) cohort. METHODS: In a cognitively unimpaired sample drawn from the African Americans Fighting Alzheimer's in Midlife (AA-FAiM) study, data on SRSD, Epworth Sleepiness Scale, demographics, and cognitive performance were analyzed. Aß40, Aß42, and the Aß42/40 ratio were quantified from plasma samples. Cross-sectional analyses explored associations between baseline predictors and outcome measures. Linear mixed-effect regression models estimated associations of SRSD and daytime sleepiness with plasma Aß and cognitive performance levels and change over time. RESULTS: One hundred and forty-seven participants comprised the cross-sectional sample. Baseline age was 63.2 ±â€…8.51 years. 69.6% self-identified as female. SRSD was 6.4 ±â€…1.1 hours and 22.4% reported excessive daytime sleepiness. The longitudinal dataset included 57 participants. In fully adjusted models, neither SRSD nor daytime sleepiness is associated with cross-sectional or longitudinal Aß. Associations with level and trajectory of cognitive test performance varied by measure of sleep health. CONCLUSIONS: SRSD was below National Sleep Foundation recommendations and daytime sleepiness was prevalent in this cohort. In the absence of observed associations with plasma Aß, poorer self-reported sleep health broadly predicted poorer cognitive function but not accelerated decline. Future research is necessary to understand and address modifiable sleep mechanisms as they relate to cognitive aging in AA at disproportionate risk for dementia. CLINICAL TRIAL INFORMATION: Not applicable.


Asunto(s)
Demencia , Trastornos de Somnolencia Excesiva , Trastornos del Inicio y del Mantenimiento del Sueño , Anciano , Femenino , Humanos , Persona de Mediana Edad , Péptidos beta-Amiloides , Negro o Afroamericano , Cognición , Estudios Transversales , Trastornos de Somnolencia Excesiva/complicaciones , Duración del Sueño , Masculino
18.
HIV Clin Trials ; 14(6): 303-12, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24334183

RESUMEN

BACKGROUND: Individuals with HIV infection and peripheral metabolic complications have impaired basal myocardial insulin sensitivity that is related to left ventricular (LV) diastolic dysfunction. It is unknown whether interventions shown to be effective in improving peripheral insulin sensitivity can improve basal myocardial insulin sensitivity and diastolic function in people with HIV and peripheral metabolic complications. OBJECTIVE: In a pilot study, we evaluated whether the peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist pioglitazone or combined endurance and resistance exercise training improves basal myocardial insulin sensitivity and diastolic function in HIV+ adults with peripheral metabolic complications. DESIGN: Twenty-four HIV+ adults with metabolic complications including peripheral insulin resistance were randomly assigned to 4 months of pioglitazone (PIO; 30 mg/d) or supervised, progressive endurance and resistance exercise training (EXS; 90-120 min/d, 3 d/wk). Basal myocardial substrate metabolism was quantified by radioisotope tracer methodology and positron emission tomography (PET) imaging, and LV function was measured by echocardiography. RESULTS: Twenty participants completed the study. Neither PIO nor EXS resulted in a detectable improvement in basal myocardial insulin sensitivity or diastolic function. Post hoc analyses revealed sample sizes of more than 100 participants are needed to detect significant effects of these interventions on basal myocardial insulin sensitivity and function. CONCLUSIONS: PIO or EXS alone did not significantly increase basal myocardial insulin sensitivity or LV diastolic function in HIV+ individuals with peripheral metabolic complications.


Asunto(s)
Ejercicio Físico , Infecciones por VIH/complicaciones , Hipoglucemiantes/uso terapéutico , Miocardio/metabolismo , Tiazolidinedionas/uso terapéutico , Función Ventricular Izquierda/fisiología , Adulto , Femenino , Infecciones por VIH/metabolismo , Infecciones por VIH/fisiopatología , Humanos , Resistencia a la Insulina/fisiología , Masculino , Proyectos Piloto , Pioglitazona , Estudios Prospectivos
19.
Nat Med ; 12(7): 856-61, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16799555

RESUMEN

Certain disease states are characterized by disturbances in production, accumulation or clearance of protein. In Alzheimer disease, accumulation of amyloid-beta (Abeta) in the brain and disease-causing mutations in amyloid precursor protein or in enzymes that produce Abeta indicate dysregulation of production or clearance of Abeta. Whether dysregulation of Abeta synthesis or clearance causes the most common form of Alzheimer disease (sporadic, >99% of cases), however, is not known. Here, we describe a method to determine the production and clearance rates of proteins within the human central nervous system (CNS). We report the first measurements of the fractional production and clearance rates of Abeta in vivo in the human CNS to be 7.6% per hour and 8.3% per hour, respectively. This method may be used to search for novel biomarkers of disease, to assess underlying differences in protein metabolism that contribute to disease and to evaluate treatments in terms of their pharmacodynamic effects on proposed disease-causing pathways.


Asunto(s)
Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Secuencia de Aminoácidos , Péptidos beta-Amiloides/biosíntesis , Biomarcadores/líquido cefalorraquídeo , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Conformación Proteica
20.
medRxiv ; 2023 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-37693503

RESUMEN

Background: Alzheimer's Disease (AD), the most common cause of dementia, poses a significant global burden. Diagnosis typically involves invasive and costly methods like neuroimaging or cerebrospinal fluid (CSF) biomarker testing of phosphorylated tau (p-tau) and amyloid-ß42/40 (Aß42/40). Such procedures are especially impractical in resource-constrained regions, such as the Democratic Republic of Congo (DRC). Blood-based biomarker testing may provide a more accessible screening opportunity. Objective: This study aims to examine if AD-related blood-based biomarkers are associated with cognitive test performance in the Congolese population, where limited research has been conducted. Methods: In this cross-sectional study of 81 Congolese individuals, cognitive assessments (Alzheimer's Questionnaire (AQ) and Community Screening Interview for Dementia (CSID)) distinguished dementia cases from controls. Blood draws were taken to assess p-tau 181 and Aß42/40 biomarkers. Relationships between the biomarkers and cognitive performance were analyzed using multiple linear regression models. Results: Lower plasma Aß42/40 was significantly associated with lower CSID scores and higher AQ scores, indicative of AD (p<0.001). These relationships were observed in healthy controls (CSID p=0.01, AQ p=0.03), but not in dementia cases. However, p-tau 181 did not exhibit significant associations with either measure. Factors such as age, sex, education, presence of APOE e4 allele, did not alter these relationships. Conclusion: Understanding relationships between AD-related screening tests and blood-biomarkers is a step towards utilization of blood-based biomarker tests as a screening tool for AD, especially in resource-limited regions. Further research should be conducted to evaluate blood biomarker test efficacy in larger samples and other populations.

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