RESUMEN
Neuroinflammation is a pathological hallmark of Alzheimer's disease, but its role in cognitive impairment and its course of development during the disease are largely unknown. To address these unknowns, we used positron emission tomography with (11)C-PBR28 to measure translocator protein 18 kDa (TSPO), a putative biomarker for inflammation. Patients with Alzheimer's disease, patients with mild cognitive impairment and older control subjects were also scanned with (11)C-Pittsburgh Compound B to measure amyloid burden. Twenty-nine amyloid-positive patients (19 Alzheimer's, 10 mild cognitive impairment) and 13 amyloid-negative control subjects were studied. The primary goal of this study was to determine whether TSPO binding is elevated in patients with Alzheimer's disease, and the secondary goal was to determine whether TSPO binding correlates with neuropsychological measures, grey matter volume, (11)C-Pittsburgh Compound B binding, or age of onset. Patients with Alzheimer's disease, but not those with mild cognitive impairment, had greater (11)C-PBR28 binding in cortical brain regions than controls. The largest differences were seen in the parietal and temporal cortices, with no difference in subcortical regions or cerebellum. (11)C-PBR28 binding inversely correlated with performance on Folstein Mini-Mental State Examination, Clinical Dementia Rating Scale Sum of Boxes, Logical Memory Immediate (Wechsler Memory Scale Third Edition), Trail Making part B and Block Design (Wechsler Adult Intelligence Scale Third Edition) tasks, with the largest correlations observed in the inferior parietal lobule. (11)C-PBR28 binding also inversely correlated with grey matter volume. Early-onset (<65 years) patients had greater (11)C-PBR28 binding than late-onset patients, and in parietal cortex and striatum (11)C-PBR28 binding correlated with lower age of onset. Partial volume corrected and uncorrected results were generally in agreement; however, the correlation between (11)C-PBR28 and (11)C-Pittsburgh Compound B binding was seen only after partial volume correction. The results suggest that neuroinflammation, indicated by increased (11)C-PBR28 binding to TSPO, occurs after conversion of mild cognitive impairment to Alzheimer's disease and worsens with disease progression. Greater inflammation may contribute to the precipitous disease course typically seen in early-onset patients. (11)C-PBR28 may be useful in longitudinal studies to mark the conversion from mild cognitive impairment or to assess response to experimental treatments of Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Receptores de GABA/metabolismo , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Análisis de Varianza , Compuestos de Anilina/farmacocinética , Encéfalo/patología , Mapeo Encefálico , Trastornos del Conocimiento/diagnóstico por imagen , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Escalas de Valoración Psiquiátrica , Pirimidinas/farmacocinética , Receptores de GABA/genética , Estadística como Asunto , Tiazoles/farmacocinéticaRESUMEN
BACKGROUND: Neuroimaging studies using (18) F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and single photon emission computed tomography (SPECT) have shown that the posterior cingulate cortex (PCC) is the primary and most prominent area of cerebral metabolic and perfusional decrement in early Alzheimer's disease (AD). We carried out the present preliminary study to investigate whether a decline of cerebral blood flow (CBF) in the PCC in early to moderate AD was accompanied with that of cerebral protein synthesis (CPS). METHODS: We carried out both N-isopropyl-p-[123I] iodoamphetamine SPECT (IMP-SPECT) and L-[methyl-11C] methionine positron emission tomography (MET-PET) in eight AD patients with apolipoprotein E epsilon 4 allele in the early to moderate stage. We also carried out IMP-SPECT in eight healthy controls (HC). We located 32 regions of interest (ROI), and values of regional MET or IMP uptakes were averaged in five regions; the frontal lobe (FL), the parietal lobe (PL), the medial temporal lobe (MTL), PCC and the occipital lobe. Furthermore, the values in the FL, PL, MTL and PCC were divided by values in the occipital areas, and normalized values of regional CBF (rCBF) and CPS (rCPS) were calculated. Then, the rCBF in the FL, PL, MTL and PCC were compared between AD and HC. In addition, the rCBF and rCPS were compared in the FL, PL, MTL and PCC of AD. RESULTS: The rCBF in the PCC, but not in the other three regions, was significantly lower in AD than in HC. The rCBF was significantly lower than rCPS in the PCC, but rCBF and rCPS were comparable in the other three regions in AD. CONCLUSIONS: The CBF reduction in the PCC in AD was partly caused by neuronal loss in the PCC and partly supported the hypothesis that CBF reduction in the PCC was a result of functional deafferentation by neural degeneration in areas other than the PCC.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Giro del Cíngulo/irrigación sanguínea , Giro del Cíngulo/metabolismo , Tomografía de Emisión de Positrones , Biosíntesis de Proteínas , Tomografía Computarizada de Emisión de Fotón Único , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Estudios de Casos y Controles , Circulación Cerebrovascular , Femenino , Giro del Cíngulo/diagnóstico por imagen , Humanos , Japón , MasculinoRESUMEN
UNLABELLED: Ten percent of humans lack specific binding of [(11)C]PBR28 to 18 kDa translocator protein (TSPO), a biomarker for inflammation. "Non-binders" have not been reported using another TSPO radioligand, [(11)C]-(R)-PK 11195, despite its use for more than two decades. This study asked two questions: (1) What is the cause of non-binding to PBR28? and (2) Why has this phenomenon not been reported using [(11)C]-(R)-PK 11195? METHODS: Five binders and five non-binders received whole-body imaging with both [(11)C]-(R)-PK 11195 and [(11)C]PBR28. In vitro binding was performed using leukocyte membranes from binders and non-binders and the tritiated versions of the ligand. Rhesus monkeys were imaged with [(11)C]-(R)-PK 11195 at baseline and after blockade of TSPOs. RESULTS: Using [(11)C]PBR28, uptake in all five organs with high densities of TSPO (lung, heart, brain, kidney, and spleen) was 50% to 75% lower in non-binders than in binders. In contrast, [(11)C]-(R)-PK 11195 distinguished binders and non-binders in only heart and lung. For the in vitro assay, [(3)H]PBR28 had more than 10-fold lower affinity to TSPO in non-binders than in binders. The in vivo specific binding of [(11)C]-(R)-PK 11195 in monkey brain was approximately 80-fold lower than that reported for [(11)C]PBR28. CONCLUSIONS: Based on binding of [(3)H]PK 11195 to leukocyte membranes, both binders and non-binders express TSPO. Non-binding to PBR28 is caused by its low affinity for TSPO in non-binders. Non-binding may be differentially expressed in organs of the body. The relatively low in vivo specific binding of [(11)C]-(R)-PK 11195 may have obscured its detection of non-binding in peripheral organs.
Asunto(s)
Acetamidas/farmacocinética , Inflamación/diagnóstico por imagen , Inflamación/metabolismo , Isoquinolinas/farmacocinética , Tomografía de Emisión de Positrones/métodos , Piridinas/farmacocinética , Receptores de GABA/metabolismo , Adulto , Animales , Biomarcadores/metabolismo , Radioisótopos de Carbono/farmacocinética , Femenino , Haplorrinos , Humanos , Masculino , Radiofármacos/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Imagen de Cuerpo Entero/métodosRESUMEN
BACKGROUND/AIMS: We developed an idiopathic normal-pressure hydrocephalus grading scale (iNPHGS) to classify a triad of disorders (cognitive impairment, gait disturbance and urinary disturbance) of iNPH with a wide range of severity. The purpose of this study was to assess the reliability and validity of this scale in 38 patients with iNPH. RESULTS: The interrater reliability of this scale was high. The iNPHGS cognitive domain score significantly correlated with the cognitive test scores, including the Mini-Mental State Examination (MMSE), the gait domain score with the Up and Go Test and Gait Status Scale scores, and the urinary domain score with the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) score. The MMSE, Gait Status Scale and ICIQ-SF scores significantly improved in patients whose iNPHGS scores improved after CSF tapping but not in those whose iNPHGS scores did not improve after CSF tapping. Fourteen of the 38 patients received shunt operations. In these 14 patients, changes in the iNPHGS cognitive and urinary domains after CSF tapping were significantly associated with the changes after the shunt operation.
Asunto(s)
Hidrocéfalo Normotenso/diagnóstico , Anciano , Anciano de 80 o más Años , Derivaciones del Líquido Cefalorraquídeo , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/epidemiología , Femenino , Humanos , Hidrocéfalo Normotenso/epidemiología , Hidrocéfalo Normotenso/cirugía , Masculino , Persona de Mediana Edad , Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/epidemiología , Pruebas Neuropsicológicas , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Incontinencia Urinaria/diagnóstico , Incontinencia Urinaria/epidemiologíaRESUMEN
In schizophrenic patients, cognitive and behavioral deficits are often associated with frontal lobe dysfunction. By functional neuroimaging studies, abnormalities of the frontal lobe (especially the prefrontal lobe) have been detected in schizophrenic patients. As for morphological changes on neuroimaging, lateral lobe atrophy and enlargement of the lateral ventricles or third ventricle are often reported, but there is no consensus as to whether frontal lobe atrophy is seen more frequently in schizophrenic patients compared with normal controls. The reasons for this disagreement include variations in the precision of measurement on MRI, differences in the methods of MRI among studies, and biases in the subjects being evaluated. Here we present a patient with schizophrenia and frontal lobe atrophy, which was clearly recognized on MRI and showed no progress in the 2 years following its detection. The patient was a 26-year-old woman with a 4.5-year history of schizophrenia when she was referred to us for the treatment of persistent auditory hallucinations and delusions. She showed no neurological findings apart from her psychiatric symptoms. Head MRI showed mild atrophy of the frontal lobe, and the extent of atrophy did not change over the following two years. On resting SPECT 99mTc-HMPAO, hypoperfusion of the bilateral frontal regions was demonstrated. There were no significant findings in the temporal lobe on either MRI or SPECT. She achieved low scores in neuropsychological tests of intelligence, memory, and frontal lobe-associated functions, and showed almost the same degrees of impairment in all of the tests in 2 years of follow-up. The possibility of degenerative diseases, such as young-onset frontotemporal dementia, was ruled out. She had a low intelligence quotient in the WAIS-R and her answers showed the specific pattern which is commonly seen in schizophrenic patients. There is a possibility that hypoperfusion on resting SPECT reflected not only frontal lobe atrophy, but also frontal lobe dysfunction in this patient. Frontal lobe dysfunction in schizophrenics is generally considered to be a secondary effect of meso-limbic system pathology. In this patient, however, the dysfunction seemed to arise from an intrinsic disorder of the frontal lobe, because frontal lobe abnormalities were conspicuous, whereas the temporal lobe was almost normal on both MRI and SPECT.
Asunto(s)
Lóbulo Frontal/patología , Imagen por Resonancia Magnética , Esquizofrenia/patología , Adulto , Atrofia , Circulación Cerebrovascular , Femenino , Estudios de Seguimiento , Lóbulo Frontal/irrigación sanguínea , Lóbulo Frontal/fisiopatología , Humanos , Pruebas Neuropsicológicas , Esquizofrenia/diagnóstico , Esquizofrenia/fisiopatología , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
UNLABELLED: Permeability-glycoprotein (P-gp), an efflux transporter in several organs, acts at the blood-brain barrier to protect the brain from exogenous toxins. P-gp almost completely blocks brain entry of the PET radiotracer (11)C-N-desmethyl-loperamide ((11)C-dLop). We examined the ability of (11)C-dLop to quantify P-gp function in humans after increasing doses of tariquidar, an inhibitor of P-gp. METHODS: Seventeen healthy volunteers had a total of 23 PET scans with (11)C-dLop at baseline and after increasing doses of tariquidar (2, 4, and 6 mg/kg intravenously). A subset of subjects received PET with (15)O-H(2)O to measure cerebral blood flow. Brain uptake of (11)C-dLop was quantified in 2 ways. Without blood data, uptake was measured as area under the time-activity curve in the brain from 10 to 30 min (AUC(10-30)). With arterial blood data, brain uptake was quantified with compartmental modeling to estimate the rates of entry into (K(1)) and efflux from (k(2)) the brain. RESULTS: Brain uptake of radioactivity was negligible at baseline and increased only slightly (approximately 30%) after 2 mg of tariquidar per kilogram. In contrast, 4 and 6 mg of tariquidar per kilogram increased brain uptake 2- and 4-fold, respectively. Greater brain uptake reflected greater brain entry (K(1)), because efflux (k(2)) and cerebral blood flow did not differ between tariquidar-treated and untreated subjects. In the subjects who received the highest dose of tariquidar (and had the highest brain uptake), regional values of K(1) correlated linearly with absolute cerebral blood flow, consistent with high single-pass extraction of (11)C-dLop. AUC(10-30) correlated linearly with K(1). CONCLUSION: P-gp function at the blood-brain barrier in humans can be quantified using PET and (11)C-dLop. A simple measure of brain uptake (AUC(10-30)) may be used as a surrogate of the fully quantified rate constant for brain entry (K(1)) and thereby avoid arterial sampling. However, to dissect the function of P-gp itself, both brain uptake and the influx rate constant must be corrected for radiotracer delivery (blood flow).