RESUMEN

INTRODUCTION: We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases. METHODS: A mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative. RESULTS: PVS was significantly associated with sEF (c = -0.125 ± 0.054, 95% bootstrap confidence interval [CI] [-0.2309, -0.0189], p = 0.021). This effect was mediated by both GFAP and WMH. DISCUSSION: In this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia. HIGHLIGHTS: Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease. Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury. PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration. PVS's effect on executive function was mediated by GFAP and white matter disease.

Asunto(s)

Biomarcadores , Función Ejecutiva , Proteína Ácida Fibrilar de la Glía , Sistema Glinfático , Imagen por Resonancia Magnética , Enfermedades Neurodegenerativas , Sustancia Blanca , Humanos , Proteína Ácida Fibrilar de la Glía/sangre , Femenino , Masculino , Anciano , Función Ejecutiva/fisiología , Enfermedades Neurodegenerativas/sangre , Biomarcadores/sangre , Sistema Glinfático/patología , Sistema Glinfático/diagnóstico por imagen , Sustancia Blanca/patología , Sustancia Blanca/diagnóstico por imagen , Disfunción Cognitiva/sangre , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/patología , Demencia Frontotemporal/sangre , Demencia Frontotemporal/patología , Demencia Frontotemporal/diagnóstico por imagen , Trastornos Cerebrovasculares/sangre , Trastornos Cerebrovasculares/diagnóstico por imagen , Trastornos Cerebrovasculares/patología , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Estudios de Cohortes , Persona de Mediana Edad

RESUMEN

INTRODUCTION: Donanemab is an amyloid-targeting therapy that specifically targets brain amyloid plaques. The objective of these analyses was to characterize the relationship of donanemab exposure with plasma biomarkers and clinical efficacy through modeling. METHODS: Data for the analyses were from participants with Alzheimer's disease from the phase 1 and TRAILBLAZER-ALZ studies. Indirect-response models were used to fit plasma phosphorylated tau 217 (p-tau217) and plasma glial fibrillated acidic protein (GFAP) data over time. Disease-progression models were developed using pharmacokinetic/pharmacodynamic modeling. RESULTS: The plasma p-tau217 and plasma GFAP models adequately predicted the change over time, with donanemab resulting in decreased plasma p-tau217 and plasma GFAP concentrations. The disease-progression models confirmed that donanemab significantly reduced the rate of clinical decline. Simulations revealed that donanemab slowed disease progression irrespective of baseline tau positron emission tomography (PET) level within the evaluated population. DISCUSSION: The disease-progression models show a clear treatment effect of donanemab on clinical efficacy regardless of baseline disease severity.

RESUMEN

INTRODUCTION: Traumatic brain injury (TBI) is a major public health concern in the U.S. Recommendations for patients admitted in the emergency department (ED) to receive head computed tomography (CT) scan are currently guided by various clinical decision rules. OBJECTIVE: To compare how a blood biomarker approach compares with clinical decision rules in terms of predicting a positive head CT in adult patients suspected of TBI. METHODS: We retrospectively identified patients transported to our emergency department and underwent a noncontrast head CT due to suspicion of TBI and who had blood samples available. Published thresholds for serum and plasma glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1), and serum S100ß were used to make CT recommendations. These blood biomarker-based recommendations were compared to those achieved under widely used clinical head CT decision rules (Canadian, New Orleans, NEXUS II, and ACEP Clinical Policy). RESULTS: Our study included 463 patients, of which 122 (26.3%) had one or more abnormalities presenting on head CT. Individual blood biomarkers achieved high negative predictive value (NPV) for abnormal head CT findings (88%-98%), although positive predictive value (PPV) was consistently low (25%-42%). A composite biomarker-based decision rule (GFAP+UCH-L1)'s NPV of 100% and PPV of 29% were comparable or better than those achieved under the clinical decision rules. CONCLUSION: Blood biomarkers perform at least as well as clinical rules in terms of selecting TBI patients for head CT and may be easier to implement in the clinical setting. A prospective study is necessary to validate this approach.

Asunto(s)

Lesiones Traumáticas del Encéfalo , Reglas de Decisión Clínica , Adulto , Humanos , Estudios Prospectivos , Estudios Retrospectivos , Ubiquitina Tiolesterasa , Canadá , Biomarcadores , Tomografía Computarizada por Rayos X

RESUMEN

Introduction: Plasma glial fibrillary acidic protein (GFAP) may be associated with amyloid burden, neurodegeneration, and stroke but its specificity for Alzheimer's disease (AD) in the general population is unclear. We examined associations of plasma GFAP with amyloid and tau positron emission tomography (PET), cortical thickness, white matter hyperintensities (WMH), and cerebral microbleeds (CMBs). Methods: The study included 200 individuals from the Mayo Clinic Study of Aging who underwent amyloid and tau PET and magnetic resonance imaging and had plasma GFAP concurrently assayed; multiple linear regression and hurdle model analyses were used to investigate associations controlling for age and sex. Results: GFAP was associated with amyloid and tau PET in multivariable models. After adjusting for amyloid, the association with tau PET was no longer significant. GFAP was associated with cortical thickness, WMH, and lobar CMBs only among those who were amyloid-positive. Discussion: This cross-sectional analysis demonstrates the utility of GFAP as a plasma biomarker for AD-related pathologies.