RESUMEN
OBJECTIVE: To investigate whether longitudinal declines in cognition are associated with higher fibrillar amyloid-beta (Abeta) deposition in vivo in individuals without dementia. METHOD: [(11)C]PiB images were obtained to measure fibrillar Abeta burden in 57 participants without dementia from the Baltimore Longitudinal Study of Aging. Participants (33 men, 24 women) had a mean (SD) age of 78.7 (6.2) years. Six participants (4 men, 2 women) had mild cognitive impairment defined as Clinical Dementia Rating = 0.5. To measure [(11)C]PiB retention, distribution volume ratios (DVR) for 15 regions of interest were estimated by fitting a simplified reference tissue model to the measured time activity curves. Mixed effects regression was used to predict cognitive trajectories over time using data before and including time of PiB (mean follow-up 10.8 years), with mean cortical DVR, age at baseline, sex, and education as independent predictors. Voxel-based analysis identified local associations. RESULTS: [(11)C]PiB retention was higher in older individuals. Greater declines over time in mental status and verbal learning and memory, but not visual memory, were associated significantly with higher PiB retention. Voxel-based analysis showed significant associations in frontal and lateral temporal regions. CONCLUSIONS: Higher Abeta deposition is associated with greater longitudinal decline in mental status and verbal memory in the preceding years. The differential association for verbal but not visual memory may reflect the greater reliance of verbal word list learning on prefrontal regions, which show early Abeta deposition. Prospective imaging may help distinguish between individuals with evolving neuropathology who develop accelerated cognitive decline vs those with normal aging.
Asunto(s)
Amiloide/metabolismo , Compuestos de Anilina , Trastornos del Conocimiento/diagnóstico por imagen , Trastornos del Conocimiento/metabolismo , Tiazoles , Anciano , Anciano de 80 o más Años , Mapeo Encefálico , Radioisótopos de Carbono , Femenino , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética/métodos , Masculino , Escala del Estado Mental , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones/métodos , Estudios RetrospectivosRESUMEN
In vivo assessment of the beta-sheet proteins deposited in amyloid plaques (A beta peptide) or neurofibrillary tangles (tau protein) presents a target for the development of biological markers for Alzheimer's disease (AD). In an effort to develop in vivo beta-sheet imaging probes, derivatives of thioflavin-T (ThT) were synthesized and evaluated. These compounds lack the positively charged quaternary heterocyclic nitrogen of ThT and are therefore uncharged at physiological pH. They are 600-fold more lipophilic than ThT. These ThT derivatives bind to A beta(1-40) fibrils with higher affinity (Ki = 20.2 nM) than ThT (Ki = 890 nM). The uncharged ThT derivatives stained both plaques and neurofibrillary tangles in post-mortem AD brain, showing some preference for plaque staining. A carbon-11 labeled compound, [N-methyl-11C]6-Me-BTA-1, was prepared, and its brain entry and clearance were studied in Swiss-Webster mice. This compound entered the brain at levels comparable to commonly used neuroreceptor imaging agents (0.223 %ID-kg/g or 7.61 %ID/g at 2 min post-injection) and showed good clearance of free and non-specifically bound radioactivity in normal rodent brain tissue (brain clearance t(1,2) = 20 min). The combination of relatively high affinity for amyloid, specificity for staining plaques and neurofibrillary tangles in post-mortem AD brain, and good brain entry and clearance makes [N-methyl-11C]6-Me-BTA-1 a promising candidate as an in vivo positron emission tomography (PET) beta-sheet imaging agent.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Tiazoles/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Benzotiazoles , Fenómenos Químicos , Química Física , Femenino , Colorantes Fluorescentes , Histocitoquímica , Concentración de Iones de Hidrógeno , Ratones , Unión Proteica , Solubilidad , Espectrometría de Fluorescencia , Tomografía Computarizada de EmisiónRESUMEN
Imaging serotonin-2A (5-HT(2A)) neuroreceptors with positron emission tomography (PET) and [(18)F]altanserin has been the focus of a series of PET studies, as [(18)F]altanserin is one of the most selective 5-HT(2A) antagonist radiotracers. Previous animal studies showed that radiolabeled metabolites (radiometabolites) of [(18)F]altanserin crossed the blood-brain barrier (BBB) to localize nonspecifically in brain, consistent with a constant radioactivity "background." In this work, we evaluated human bolus injection [(18)F]altanserin PET data with detailed consideration of the impact of BBB-permeable metabolites on the specific binding parameters. Data were quantified using either single (parent radiotracer), dual (parent radiotracer and radiometabolites), or no arterial input function(s) (cerebellum as reference tissue input function). A step-gradient high-performance liquid chromatography (HPLC) analysis provided distinct separation of [(18)F]altanserin and four radiolabeled components in plasma. After [(18)F]altanserin injection, the step-gradient data showed that the major BBB-permeable radiometabolites approached constant levels in plasma (>50 min), consistent with a constant metabolite "background." The single-input Logan graphical results were highly correlated with the dual-input results and its bias was fairly constant across regions and subjects, as similarly observed for a nongraphical reference tissue method. The most comprehensive and quantitatively valid analysis for bolus [(18)F]altanserin PET data was the dual-input method that specifically accounted for BBB-permeable metabolites, although the Logan analysis was preferred because it provided a good compromise between validity, sensitivity, and reliability of implementation. Further study is needed to better understand how the cerebellar kinetics of [(18)F]altanserin and its radiometabolites impact the reference tissue measures.
Asunto(s)
Radioisótopos de Flúor/farmacocinética , Ketanserina/análogos & derivados , Ketanserina/farmacocinética , Modelos Biológicos , Receptores de Serotonina/metabolismo , Tomografía Computarizada de Emisión/métodos , Adolescente , Adulto , Anciano , Barrera Hematoencefálica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptor de Serotonina 5-HT2ARESUMEN
Positron emission tomography (PET) has been used to study serotonin 2A (5-HT(2A)) receptor binding in human brain using the 5-HT(2A) antagonist, [(18)F]altanserin. Previous analyses of bolus injection [(18)F]altanserin data provided 5-HT(2A) specific binding measures that were highly correlated with the in vitro distribution of 5-HT(2A) receptors and reflected decreased binding after ketanserin (5-HT(2A) antagonist) administration. These observations were made in the presence of a nonspecific tissue component that was consistent with blood-brain barrier (BBB) passage of radiolabeled metabolites (radiometabolites). In this work, we evaluated the in vivo kinetics of [(18)F]altanserin and two major radiometabolites of [(18)F]altanserin, focusing on the kinetics of free and nonspecifically-bound radioactivity. PET studies were performed in baboons after the bolus injection of [(18)F]altanserin or one of its major radiometabolites, either [(18)F]altanserinol or [(18)F]4-(4-fluorobenzoyl)piperidine, at baseline and after pharmacologic receptor blockade (blocking data). The cerebellar and blocking data were analyzed using either single (parent radiotracer) or dual (parent radiotracer and radiometabolites) input function methods. After bolus injection of either [(18)F]altanserin metabolite, radioactivity crossed the BBB and localized nonspecifically. The radio- metabolites were found to contribute to nonspecific "background" radioactivity that was similar in receptor-poor and receptor-rich regions. After bolus injection in baboons, two of the major radiometabolites of [(18)F]altanserin crossed the BBB and contributed to a fairly uniform background of nonspecific radioactivity. This uniformity suggests that conventional analyses are appropriate for human bolus injection [(18)F]altanserin PET data, although these methods may overestimate [(18)F]altanserin nonspecific binding.