RESUMEN
SEE HANSSON AND GOURAS DOI101093/AWW146 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Although some brain regions such as precuneus and lateral temporo-parietal cortex have been shown to be more vulnerable to Alzheimer's disease than other areas, a mechanism underlying the differential regional vulnerability to Alzheimer's disease remains to be elucidated. Using fluorodeoxyglucose and Pittsburgh compound B positron emission tomography imaging glucose metabolism and amyloid-ß deposition, we tested whether and how life-long changes in glucose metabolism relate to amyloid-ß deposition and Alzheimer's disease-related hypometabolism. Nine healthy young adults (age range: 20-30), 96 cognitively normal older adults (age range: 61-96), and 20 patients with Alzheimer's disease (age range: 50-90) were scanned using fluorodeoxyglucose and Pittsburgh compound B positron emission tomography. Among cognitively normal older subjects, 32 were further classified as amyloid-positive, with 64 as amyloid-negative. To assess the contribution of glucose metabolism to the regional vulnerability to amyloid-ß deposition, we defined the highest and lowest metabolic regions in young adults and examined differences in amyloid deposition between these regions across groups. Two-way analyses of variance were conducted to assess regional differences in age and amyloid-ß-related changes in glucose metabolism. Multiple regressions were applied to examine the association between amyloid-ß deposition and regional glucose metabolism. Both region of interest and whole-brain voxelwise analyses were conducted to complement and confirm the results derived from the other approach. Regional differences in glucose metabolism between the highest and lowest metabolism regions defined in young adults (T = 12.85, P < 0.001) were maintained both in Pittsburgh compound B-negative cognitively normal older subjects (T = 6.66, P < 0.001) and Pittsburgh compound B-positive cognitively normal older subjects (T = 10.62, P < 0.001), but, only the Pittsburgh compound B-positive cognitively normal older subjects group showed significantly higher Pittsburgh compound B retention in the highest compared to the lowest glucose metabolism regions defined in young adults (T = 2.05, P < 0.05). Regional differences in age and amyloid-ß-dependent changes in glucose metabolism were found such that frontal glucose metabolism was reduced with age, while glucose metabolism in the precuneus was maintained across the lifespan (right hemisphere: F = 7.69, P < 0.001; left hemisphere: F = 8.69, P < 0.001). Greater Alzheimer's disease-related hypometabolism was observed in brain regions that showed both age-invariance and amyloid-ß-related increases in glucose metabolism. Our results indicate that although early and life-long regional variation in glucose metabolism relates to the regional vulnerability to amyloid-ß accumulation, Alzheimer's disease-related hypometabolism is more specific to brain regions showing age-invariant glucose metabolism and amyloid-ß-related hypermetabolism.
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Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Compuestos de Anilina , Corteza Cerebral/metabolismo , Fluorodesoxiglucosa F18 , Glucosa/metabolismo , Tomografía de Emisión de Positrones/métodos , Radiofármacos , Tiazoles , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Corteza Cerebral/diagnóstico por imagen , Estudios de Cohortes , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Beta-amyloid (Aß) deposition is one of the hallmarks of Alzheimer's disease (AD). However, it is also present in some cognitively normal elderly adults and may represent a preclinical disease state. While AD patients exhibit disrupted functional connectivity (FC) both within and between resting-state networks, studies of preclinical cases have focused primarily on the default mode network (DMN). The extent to which Aß-related effects occur outside of the DMN and between networks remains unclear. In the present study, we examine how within- and between-network FC are related to both global and regional Aß deposition as measured by [(11)C]PIB-PET in 92 cognitively normal older people. We found that within-network FC changes occurred in multiple networks, including the DMN. Changes of between-network FC were also apparent, suggesting that regions maintaining connections to multiple networks may be particularly susceptible to Aß-induced alterations. Cortical regions showing altered FC clustered in parietal and temporal cortex, areas known to be susceptible to AD pathology. These results likely represent a mix of local network disruption, compensatory reorganization, and impaired control network function. They indicate the presence of Aß-related dysfunction of neural systems in cognitively normal people well before these areas become hypometabolic with the onset of cognitive decline.
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Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Mapeo Encefálico , Encéfalo/metabolismo , Descanso , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Compuestos de Anilina/farmacocinética , Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Isótopos de Carbono/farmacocinética , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Red Nerviosa/diagnóstico por imagen , Oxígeno/sangre , Tomografía de Emisión de Positrones , Análisis de Regresión , Tiazoles/farmacocinética , Adulto JovenRESUMEN
The common and specific involvement of brain networks in clinical variants of Alzheimer's disease (AD) is not well understood. We performed task-free ("resting-state") functional imaging in 60 nonfamilial AD patients, including 20 early-onset AD (age at onset <65 years, amnestic/dysexecutive deficits), 24 logopenic aphasia (language deficits), and 16 posterior cortical atrophy patients (visual deficits), as well as 60 healthy controls. Seed-based connectivity analyses were conducted to assess differences between groups in 3 default mode network (DMN) components (anterior, posterior, and ventral) and 4 additional non-DMN networks: left and right executive-control, language, and higher visual networks. Significant decreases in connectivity were found across AD variants compared with controls in the non-DMN networks. Within the DMN components, patients showed higher connectivity in the anterior DMN, in particular in logopenic aphasia. No significant differences were found for the posterior and ventral DMN. Our findings suggest that loss of functional connectivity is greatest in networks outside the DMN in early-onset and nonamnestic AD variants and may thus be a better biomarker in these patients.
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Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Encéfalo/fisiopatología , Variación Genética , Red Nerviosa/fisiopatología , Vías Nerviosas/fisiopatología , Anciano , Enfermedad de Alzheimer/patología , Afasia , Atrofia , Corteza Cerebral/patología , Función Ejecutiva/fisiología , Neuroimagen Funcional , Humanos , Lenguaje , Imagen por Resonancia Magnética , Persona de Mediana Edad , Percepción VisualRESUMEN
Amyloid-ß, a hallmark of Alzheimer's disease, begins accumulating up to two decades before the onset of dementia, and can be detected in vivo applying amyloid-ß positron emission tomography tracers such as carbon-11-labelled Pittsburgh compound-B. A variety of thresholds have been applied in the literature to define Pittsburgh compound-B positron emission tomography positivity, but the ability of these thresholds to detect early amyloid-ß deposition is unknown, and validation studies comparing Pittsburgh compound-B thresholds to post-mortem amyloid burden are lacking. In this study we first derived thresholds for amyloid positron emission tomography positivity using Pittsburgh compound-B positron emission tomography in 154 cognitively normal older adults with four complementary approaches: (i) reference values from a young control group aged between 20 and 30 years; (ii) a Gaussian mixture model that assigned each subject a probability of being amyloid-ß-positive or amyloid-ß-negative based on Pittsburgh compound-B index uptake; (iii) a k-means cluster approach that clustered subjects into amyloid-ß-positive or amyloid-ß-negative based on Pittsburgh compound-B uptake in different brain regions (features); and (iv) an iterative voxel-based analysis that further explored the spatial pattern of early amyloid-ß positron emission tomography signal. Next, we tested the sensitivity and specificity of the derived thresholds in 50 individuals who underwent Pittsburgh compound-B positron emission tomography during life and brain autopsy (mean time positron emission tomography to autopsy 3.1 ± 1.8 years). Amyloid at autopsy was classified using Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria, unadjusted for age. The analytic approaches yielded low thresholds (standard uptake value ratiolow = 1.21, distribution volume ratiolow = 1.08) that represent the earliest detectable Pittsburgh compound-B signal, as well as high thresholds (standard uptake value ratiohigh = 1.40, distribution volume ratiohigh = 1.20) that are more conservative in defining Pittsburgh compound-B positron emission tomography positivity. In voxel-wise contrasts, elevated Pittsburgh compound-B retention was first noted in the medial frontal cortex, then the precuneus, lateral frontal and parietal lobes, and finally the lateral temporal lobe. When compared to post-mortem amyloid burden, low proposed thresholds were more sensitive than high thresholds (sensitivities: distribution volume ratiolow 81.0%, standard uptake value ratiolow 83.3%; distribution volume ratiohigh 61.9%, standard uptake value ratiohigh 62.5%) for CERAD moderate-to-frequent neuritic plaques, with similar specificity (distribution volume ratiolow 95.8%; standard uptake value ratiolow, distribution volume ratiohigh and standard uptake value ratiohigh 100.0%). A receiver operator characteristic analysis identified optimal distribution volume ratio (1.06) and standard uptake value ratio (1.20) thresholds that were nearly identical to the a priori distribution volume ratiolow and standard uptake value ratiolow. In summary, we found that frequently applied thresholds for Pittsburgh compound-B positivity (typically at or above distribution volume ratiohigh and standard uptake value ratiohigh) are overly stringent in defining amyloid positivity. Lower thresholds in this study resulted in higher sensitivity while not compromising specificity.
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Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides/análisis , Compuestos de Anilina , Tomografía de Emisión de Positrones/normas , Radiofármacos , Tiazoles , Anciano , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Masculino , Valores de Referencia , Adulto JovenRESUMEN
BACKGROUND: The aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI). METHODS: Magnetic resonance imaging, F-18 fluorodeoxyglucose positron emission tomography markers, and Alzheimer's Disease Assessment Scale-cognitive subscale were compared in terms of effect size and statistical power over different follow-up periods in 2 MCI groups, selected from Alzheimer's Disease Neuroimaging Initiative data set based on cerebrospinal fluid (abnormal cerebrospinal fluid Aß1-42 concentration-ABETA+) or magnetic resonance imaging evidence of Alzheimer disease (positivity to hippocampal atrophy-HIPPO+). Biomarkers progression was modeled through mixed effect models. Scaled slope was chosen as measure of effect size. Biomarkers power was estimated using simulation algorithms. RESULTS: Seventy-four ABETA+ and 51 HIPPO+ MCI patients were included in the study. Imaging biomarkers of neurodegeneration, especially MR measurements, showed highest performance. For all biomarkers and both MCI groups, power increased with increasing follow-up time, irrespective of biomarker assessment frequency. CONCLUSION: These findings provide information about biomarker enrichment and outcome measurements that could be employed to reduce MCI patient samples and treatment duration in future clinical trials.
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Enfermedad de Alzheimer/diagnóstico , Encéfalo/diagnóstico por imagen , Cognición , Disfunción Cognitiva/diagnóstico , Hipocampo/patología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Atrofia , Biomarcadores/líquido cefalorraquídeo , Encéfalo/patología , Ensayos Clínicos como Asunto , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/psicología , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Fluorodesoxiglucosa F18 , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Pruebas Neuropsicológicas , Evaluación de Resultado en la Atención de Salud , Fragmentos de Péptidos/líquido cefalorraquídeo , Tomografía de Emisión de Positrones , RadiofármacosRESUMEN
Recruitment of extra neural resources may allow people to maintain normal cognition despite amyloid-ß (Aß) plaques. Previous fMRI studies have reported such hyperactivation, but it is unclear whether increases represent compensation or aberrant overexcitation. We found that older adults with Aß deposition had reduced deactivations in task-negative regions, but increased activation in task-positive regions related to more detailed memory encoding. The association between higher activity and more detailed memories suggests that Aß-related hyperactivation is compensatory.
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Mapeo Encefálico , Encéfalo/metabolismo , Placa Amiloide/metabolismo , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Compuestos de Anilina/farmacocinética , Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Cognición/fisiología , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Memoria/fisiología , Oxígeno/sangre , Tomografía de Emisión de Positrones , Tiazoles/farmacocinética , Adulto JovenRESUMEN
OBJECTIVE: The objective of this study was to define whether vascular risk factors interact with ß-amyloid (Aß) in producing changes in brain structure that could underlie the increased risk of Alzheimer disease (AD). METHODS: Sixty-six cognitively normal and mildly impaired older individuals with a wide range of vascular risk factors were included in this study. The presence of Aß was assessed using [(11)C]Pittsburgh compound B-PET imaging, and cortical thickness was measured using 3-tesla MRI. Vascular risk was measured with the Framingham Coronary Risk Profile Index. RESULTS: Individuals with high levels of vascular risk factors have thinner frontotemporal cortex independent of Aß. These frontotemporal regions are also affected in individuals with Aß deposition, but the latter show additional thinning in parietal cortices. Aß and vascular risk were found to interact in posterior (especially in parietal) brain regions, where Aß has its greatest effect. In this way, the negative effect of Aß in posterior regions is increased by the presence of vascular risk. CONCLUSION: Aß and vascular risk interact to enhance cortical thinning in posterior brain regions that are particularly vulnerable to AD. These findings give insight concerning the mechanisms whereby vascular risk increases the likelihood of developing AD and supports the therapeutic intervention of controlling vascular risk for the prevention of AD.
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Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Encéfalo/patología , Enfermedades Vasculares/complicaciones , Anciano , Anciano de 80 o más Años , Compuestos de Anilina , Encéfalo/diagnóstico por imagen , Distribución de Chi-Cuadrado , Femenino , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Factores de Riesgo , TiazolesRESUMEN
The relationships between clinical phenotype, ß-amyloid (Aß) deposition and neurodegeneration in Alzheimer's disease (AD) are incompletely understood yet have important ramifications for future therapy. The goal of this study was to utilize multimodality positron emission tomography (PET) data from a clinically heterogeneous population of patients with probable AD in order to: (1) identify spatial patterns of Aß deposition measured by ((11)C)-labeled Pittsburgh Compound B (PiB-PET) and glucose metabolism measured by FDG-PET that correlate with specific clinical presentation and (2) explore associations between spatial patterns of Aß deposition and glucose metabolism across the AD population. We included all patients meeting the criteria for probable AD (NIA-AA) who had undergone MRI, PiB and FDG-PET at our center (N = 46, mean age 63.0 ± 7.7, Mini-Mental State Examination 22.0 ± 4.8). Patients were subclassified based on their cognitive profiles into an amnestic/dysexecutive group (AD-memory; n = 27), a language-predominant group (AD-language; n = 10) and a visuospatial-predominant group (AD-visuospatial; n = 9). All patients were required to have evidence of amyloid deposition on PiB-PET. To capture the spatial distribution of Aß deposition and glucose metabolism, we employed parallel independent component analysis (pICA), a method that enables joint analyses of multimodal imaging data. The relationships between PET components and clinical group were examined using a Receiver Operator Characteristic approach, including age, gender, education and apolipoprotein E ε4 allele carrier status as covariates. Results of the first set of analyses independently examining the relationship between components from each modality and clinical group showed three significant components for FDG: a left inferior frontal and temporoparietal component associated with AD-language (area under the curve [AUC] 0.82, p = 0.011), and two components associated with AD-visuospatial (bilateral occipito-parieto-temporal [AUC 0.85, p = 0.009] and right posterior cingulate cortex [PCC]/precuneus and right lateral parietal [AUC 0.69, p = 0.045]). The AD-memory associated component included predominantly bilateral inferior frontal, cuneus and inferior temporal, and right inferior parietal hypometabolism but did not reach significance (AUC 0.65, p = 0.062). None of the PiB components correlated with clinical group. Joint analysis of PiB and FDG with pICA revealed a correlated component pair, in which increased frontal and decreased PCC/precuneus PiB correlated with decreased FDG in the frontal, occipital and temporal regions (partial r = 0.75, p < 0.0001). Using multivariate data analysis, this study reinforced the notion that clinical phenotype in AD is tightly linked to patterns of glucose hypometabolism but not amyloid deposition. These findings are strikingly similar to those of univariate paradigms and provide additional support in favor of specific involvement of the language network, higher-order visual network, and default mode network in clinical variants of AD. The inverse relationship between Aß deposition and glucose metabolism in partially overlapping brain regions suggests that Aß may exert both local and remote effects on brain metabolism. Applying multivariate approaches such as pICA to multimodal imaging data is a promising approach for unraveling the complex relationships between different elements of AD pathophysiology.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Benzotiazoles/farmacocinética , Encéfalo/metabolismo , Fluorodesoxiglucosa F18/farmacocinética , Glucosa/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Compuestos de Anilina , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagen , Interpretación Estadística de Datos , Femenino , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Masculino , Persona de Mediana Edad , Imagen Multimodal/métodos , Tomografía de Emisión de Positrones/métodos , Análisis de Componente Principal , Radiofármacos/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , TiazolesRESUMEN
OBJECTIVE: To investigate the associations among ß-amyloid (Aß), cortical thickness, and episodic memory in a cohort of cognitively normal to mildly impaired individuals at increased risk of vascular disease. METHODS: In 67 subjects specifically recruited to span a continuum of cognitive function and vascular risk, we measured brain Aß deposition using [(11)C] Pittsburgh compound B-PET imaging and cortical thickness using MRI. Episodic memory was tested using a standardized composite score of verbal memory, and vascular risk was quantified using the Framingham Coronary Risk Profile index. RESULTS: Increased Aß was associated with cortical thinning, notably in frontoparietal regions. This relationship was strongest in persons with high Aß deposition. Increased Aß was also associated with lower episodic memory performance. Cortical thickness was found to mediate the relationship between Aß and memory performance. While age had a marginal effect on these associations, the relationship between Aß and cortical thickness was eliminated after controlling for vascular risk except when examined in only Pittsburgh compound B-positive subjects, in whom Aß remained associated with thinner cortex in precuneus and occipital lobe. In addition, only the precuneus was found to mediate the relationship between Aß and memory after controlling for vascular risk. CONCLUSION: These results suggest strong links among Aß, cortical thickness, and memory. They highlight that, in individuals without dementia, vascular risk also contributes to cortical thickness and influences the relationships among Aß, cortical thickness, and memory.
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Péptidos beta-Amiloides/metabolismo , Corteza Cerebral/patología , Trastornos del Conocimiento/patología , Disfunción Cognitiva/patología , Memoria Episódica , Anciano , Anciano de 80 o más Años , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Trastornos del Conocimiento/diagnóstico por imagen , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/psicología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/psicología , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , CintigrafíaRESUMEN
ß-Amyloid (Aß), a feature of Alzheimer's disease (AD) pathology, may precede reduced glucose metabolism and gray matter (GM) volume and cognitive decline in patients with AD. Accumulation of Aß, however, has been also reported in cognitively intact older people, although it remains unresolved whether and how Aß deposition, glucose metabolism, and GM volume relate to one another in cognitively normal elderly. Fifty-two cognitively normal older adults underwent Pittsburgh Compound B-positron emission tomography (PIB-PET), [(18)F]fluorodeoxyglucose-PET, and structural magnetic resonance imaging to measure whole-brain amyloid deposition, glucose metabolism, and GM volume, respectively. Covariance patterns of these measures in association with global amyloid burden measured by PIB index were extracted using principal component analysis-based multivariate methods. Higher global amyloid burden was associated with relative increases of amyloid deposition and glucose metabolism and relative decreases of GM volume in brain regions collectively known as the default mode network including the posterior cingulate/precuneus, lateral parietal cortices, and medial frontal cortex. Relative increases of amyloid deposition and glucose metabolism were also noted in the lateral prefrontal cortices, and relative decreases of GM volume were pronounced in hippocampus. The degree of expression of the topographical patterns of the PIB data was further associated with visual memory performance when controlling for age, sex, and education. The present findings suggest that cognitively normal older adults with greater amyloid deposition are relatively hypermetabolic in frontal and parietal brain regions while undergoing GM volume loss in overlapping brain regions.
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Envejecimiento/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Glucosa/metabolismo , Anciano , Anciano de 80 o más Años , Envejecimiento/patología , Cognición , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Tomografía de Emisión de PositronesRESUMEN
Both cognitive aging and ß-amyloid (Aß) deposition, a pathological hallmark of Alzheimer's disease, are associated with structural and cognitive changes in cognitively normal older people. To examine independent effects of age and Aß deposition on cognition and brain structure in aging, 83 cognitively normal older adults underwent structural magnetic resonance imaging scans and neuropsychological tests and were classified as negative (PIB-) or positive (PIB+) for Aß deposition using the radiotracer Pittsburgh compound B (PIB). Weighted composite discriminant scores represented subjects' cognition. Older adults showed age-related gray matter (GM) atrophy across the whole brain regardless of Aß deposition. Amyloid burden within PIB+ subjects, however, was associated with GM atrophy in the frontal, parietal, and temporal cortices. Associations between cognition and volume in PIB- subjects were primarily seen throughout frontal regions and the striatum, while, in PIB+ subjects, these associations were seen in orbital-frontal and hippocampal regions. Furthermore, in PIB- subjects, cognition was related to putaminal volume, but not to hippocampus, while, in PIB+ subjects, cognition was related to hippocampal volume, but not to putamen. These findings highlight differential age and Aß effects on brain structure, indicating effects of age and Aß that operate somewhat independently to affect frontostriatal and medial temporal brain systems.
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Envejecimiento/patología , Enfermedad de Alzheimer/patología , Encéfalo/patología , Cognición , Sustancia Gris/patología , Placa Amiloide/patología , Anciano , Envejecimiento/psicología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides , Apolipoproteína E4/genética , Atrofia/patología , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Pruebas Neuropsicológicas , Tamaño de los Órganos , Análisis de Componente Principal , Análisis de RegresiónRESUMEN
A potential mechanism that enables intellectual preservation in cognitively normal elderly that harbor beta-amyloid (Aß) pathology is heightened cerebral glucose metabolism. To investigate cross-sectional inter-relationships between Aß, glucose metabolism, and cognition, 81 subjects (mean age: 75 ± 7 years) underwent [(11)C]Pittsburgh Compound-B and [(18)F]fluorodeoxyglucose positron emission tomography scans and neuropsychological testing. They were divided into low-Aß (n = 53), intermediate-Aß (n = 13) and high-Aß (n = 15) groups as defined by their global cortical [(11)C]PIB retention. Glucose metabolism was assessed using a MetaROI mask that covers metabolically critical regions in Alzheimer's disease (AD) (i.e., posterior cingulate and bilateral angular and inferior temporal gyri). Previously validated factor scores for verbal and visual episodic memory, semantic memory, working memory, and executive functioning were used to evaluate cognitive performances. Greater Aß deposition in the precuneus was associated with higher metabolic activity (at trend level) and lower visual episodic memory scores. Glucose metabolism did not correlate with cognition across all subjects. However, heightened metabolic activity was associated with better verbal episodic memory performance in subjects with elevated amyloid levels. This preliminary study suggests that neural compensation, as a manifestation of brain reserve, enables elderly supposedly on the path to AD, at least temporarily, to preserve cognitive function.
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Encéfalo/fisiología , Memoria Episódica , Placa Amiloide/fisiopatología , Percepción del Habla/fisiología , Anciano , Encéfalo/diagnóstico por imagen , Estudios Transversales , Función Ejecutiva/fisiología , Femenino , Fluorodesoxiglucosa F18 , Glucosa/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Memoria a Corto Plazo/fisiología , Pruebas Neuropsicológicas , Placa Amiloide/diagnóstico por imagen , Tomografía de Emisión de Positrones , Radiofármacos , Semántica , Percepción Visual/fisiologíaRESUMEN
BACKGROUND: Apolipoprotein E ε4 (ApoE4) has been associated with an increased risk of Alzheimer's disease (AD), amyloid deposition and hypometabolism. ApoE4 is less prevalent in non-amnestic AD variants suggesting a direct effect on the clinical phenotype. However, the impact of ApoE4 on amyloid burden and glucose metabolism across different clinical AD syndromes is not well understood. We aimed to assess the relationship between amyloid deposition, glucose metabolism and ApoE4 genotype in a clinically heterogeneous population of AD patients. METHODS: 52 patients with probable AD (National Institute on Aging-Alzheimer's Association) underwent [(11)C]Pittsburgh compound B (PIB) and [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) scans. All patients had positive PIB-PET scans. 23 were ApoE4 positive (ApoE4+) (14 heterozygous and 9 homozygous) and 29 were ApoE4 negative (ApoE4-). Groups consisted of language-variant AD, visual-variant AD and AD patients with amnestic and dysexecutive deficits. 52 healthy controls were included for comparison. FDG and PIB uptake was compared between groups on a voxel-wise basis and in regions of interest. RESULTS: While PIB patterns were diffuse in both patient groups, ApoE4- patients showed higher PIB uptake than ApoE4+ patients across the cortex. Higher PIB uptake in ApoE4- patients was particularly significant in right lateral frontotemporal regions. In contrast, similar patterns of hypometabolism relative to controls were found in both patient groups, mainly involving lateral temporoparietal cortex, precuneus, posterior cingulate cortex and middle frontal gyrus. Comparing patient groups, ApoE4+ subjects showed greater hypometabolism in bilateral medial temporal and right lateral temporal regions, and ApoE4- patients showed greater hypometabolism in cortical areas, including supplementary motor cortex and superior frontal gyrus. CONCLUSIONS: ApoE4+ AD patients showed lower global amyloid burden and greater medial temporal hypometabolism compared with matched ApoE4- patients. These findings suggest that ApoE4 may increase susceptibility to molecular pathology and modulate the anatomic pattern of neurodegeneration in AD.
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Enfermedad de Alzheimer/metabolismo , Amiloide/metabolismo , Apolipoproteína E4/metabolismo , Lóbulo Temporal/metabolismo , Anciano , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Compuestos de Anilina , Apolipoproteína E4/fisiología , Encéfalo/patología , Estudios de Casos y Controles , Femenino , Fluorodesoxiglucosa F18 , Glucosa/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Lóbulo Temporal/patología , Lóbulo Temporal/fisiopatología , TiazolesRESUMEN
IMPORTANCE: Criteria for preclinical Alzheimer disease (AD) propose ß-amyloid (Aß) plaques to initiate neurodegeneration within AD-affected regions. However, some cognitively normal older individuals harbor neural injury similar to patients with AD, without concurrent Aß burden. Such findings challenge the proposed sequence and suggest that Aß-independent precursors underlie AD-typical neurodegenerative patterns. OBJECTIVE To examine relationships between Aß and non-Aß factors as well as neurodegeneration within AD regions in cognitively normal older adults. The study quantified neurodegenerative abnormalities using imaging biomarkers and examined cross-sectional relationships with Aß deposition; white matter lesions (WMLs), a marker of cerebrovascular disease; and cognitive functions. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study in a community-based convenience sample of 72 cognitively normal older individuals (mean [SD] age, 74.9 [5.7] years; 48 women; mean [SD] 17.0 [1.9] years of education) of the Berkeley Aging Cohort. INTERVENTION: Each individual underwent a standardized neuropsychological test session, magnetic resonance imaging, and positron emission tomography scanning. MAIN OUTCOMES AND MEASURES: For each individual, 3 AD-sensitive neurodegeneration biomarkers were measured: hippocampal volume, glucose metabolism, and gray matter thickness, the latter 2 sampled from cortical AD-affected regions. To quantify neurodegenerative abnormalities, each biomarker was age adjusted, dichotomized into a normal or abnormal status (using cutoff thresholds derived from an independent AD sample), and summarized into 0, 1, or more than 1 abnormal neurodegenerative biomarker. Degree and topographic patterns of neurodegenerative abnormalities were assessed and their relationships with cognitive functions, WML volume, and Aß deposition (quantified using carbon 11-labeled Pittsburgh compound B positron emission tomography). RESULTS: Of our cognitively normal elderly individuals, 40% (n = 29) displayed at least 1 abnormal neurodegenerative biomarker, 26% (n = 19) of whom had no evidence of elevated Pittsburgh compound B retention. In those people who were classified as having abnormal cortical thickness, degree and topographic specificity of neurodegenerative abnormalities were similar to patients with AD. Accumulation of neurodegenerative abnormalities was related to poor memory and executive functions as well as larger WML volumes but not elevated Pittsburgh compound B retention. CONCLUSIONS AND RELEVANCE: Our study confirms that a substantial proportion of cognitively normal older adults harbor neurodegeneration, without Aß burden. Associations of neurodegenerative abnormalities with cerebrovascular disease and cognitive performance indicate that neurodegenerative pathology can emerge through non-Aß pathways within regions most affected by AD.
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Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico , Trastornos del Conocimiento/etiología , Enfermedades Neurodegenerativas/etiología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Compuestos de Anilina , Biomarcadores/metabolismo , Trastornos del Conocimiento/diagnóstico por imagen , Estudios de Cohortes , Investigación Participativa Basada en la Comunidad , Estudios Transversales , Femenino , Fluorodesoxiglucosa F18 , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Fibras Nerviosas Mielínicas/patología , Enfermedades Neurodegenerativas/diagnóstico por imagen , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Escalas de Valoración Psiquiátrica , TiazolesRESUMEN
Although previous studies have emphasized the vulnerability of the default mode network (DMN) in Alzheimer's disease (AD), little is known about the involvement of other functional networks and their relationship to clinical phenotype. To test whether clinicoanatomic heterogeneity in AD is driven by the involvement of specific networks, network connectivity was assessed in healthy subjects by seeding regions commonly and specifically atrophied in three clinical AD variants: early-onset AD (age at onset, <65 y; memory and executive deficits), logopenic variant primary progressive aphasia (language deficits), and posterior cortical atrophy (visuospatial deficits). Four-millimeter seed regions of interest were used to obtain intrinsic connectivity maps in 131 healthy controls (age, 65.5 ± 3.5 y). Atrophy patterns in independent cohorts of AD variant patients and their correspondence to connectivity networks in controls were also assessed. The connectivity maps of commonly atrophied regions of interest support posterior DMN and precuneus network involvement across AD variants, whereas seeding regions specifically atrophied in each AD variant revealed distinct, syndrome-specific connectivity patterns. Goodness-of-fit analysis of each connectivity map with network templates showed the highest correspondence between the early-onset AD seed connectivity map and anterior salience and right executive-control networks, the logopenic aphasia seed connectivity map and the language network, and the posterior cortical atrophy seed connectivity map and the higher visual network. Connectivity maps derived from controls matched regions commonly and specifically atrophied in the patients. Our findings indicate that the posterior DMN and precuneus network are commonly affected in AD variants, whereas syndrome-specific neurodegenerative patterns are driven by the involvement of specific networks outside the DMN.
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Enfermedad de Alzheimer/psicología , Red Nerviosa , Anciano , Encéfalo/fisiología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia , Análisis y Desempeño de TareasRESUMEN
In many species sexual dimorphisms in brain structures and functions have been documented. In ovine model, we have previously demonstrated that peri-pubertal pharmacological blockade of gonadotropin releasing hormone (GnRH) action increased sex-differences of executive emotional behavior. The structural substrate of this behavioral alteration however is unknown. In this magnetic resonance image (MRI) study on the same animals, we investigated the effects of GnRH agonist (GnRHa) treatment on the volume of total brain, hippocampus and amygdala. In total 41 brains (17 treated; 10 females and 7 males, and 24 controls; 11 females and 13 males) were included in the MRI study. Image acquisition was performed with 3-T MRI scanner. Segmentation of the amygdala and the hippocampus was done by manual tracing and total gray and white matter volumes were estimated by means of automated brain volume segmentation of the individual T2-weighted MRI volumes. Statistical comparisons were performed with general linear models. Highly significant GnRHa treatment effects were found on the volume of left and right amygdala, indicating larger amygdalae in treated animals. Significant sex differences were found for total gray matter and right amygdala, indicating larger volumes in male compared to female animals. Additionally, we observed a significant interaction between sex and treatment on left amygdala volume, indicating stronger effects of treatment in female compared to male animals. The effects of GnRHa treatment on amygdala volumes indicate that increasing GnRH concentration during puberty may have an important impact on normal brain development in mammals. These novel findings substantiate the need for further studies investigating potential neurobiological side effects of GnRHa treatment on the brains of young animals and humans.
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Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Hormona Liberadora de Gonadotropina/agonistas , Goserelina/farmacología , Imagen por Resonancia Magnética , Maduración Sexual/efectos de los fármacos , Animales , Femenino , Masculino , Neuroimagen/métodos , Tamaño de los Órganos/efectos de los fármacos , Caracteres Sexuales , Maduración Sexual/fisiología , Oveja Doméstica , Factores de TiempoRESUMEN
ß-Amyloid (Aß) plaque deposition and neurodegeneration within temporoparietal and hippocampal regions may indicate increased risk of Alzheimer's disease (AD). This study examined relationships between AD biomarkers of Aß and neurodegeneration as well as cognitive performance in cognitively normal older individuals. Aß burden was quantified in 72 normal older human subjects from the Berkeley Aging Cohort (BAC) using [(11)C] Pittsburgh compound B (PIB) positron emission tomography. In the same individuals, we measured hippocampal volume, as well as glucose metabolism and cortical thickness, which were extracted from a template of cortical AD-affected regions. The three functional and structural biomarkers were merged into a highly AD-sensitive multimodality biomarker reflecting neural integrity. In the normal older individuals, there was no association between elevated PIB uptake and either the single-modality or the multimodality neurodegenerative biomarkers. Lower neural integrity within the AD-affected regions and a control area (the visual cortex) was related to lower scores on memory and executive function tests; the same association was not found with PIB retention. The relationship between cognition and the multimodality AD biomarker was stronger in individuals with the highest PIB uptake. The findings indicate that neurodegeneration occurs within AD regions regardless of Aß deposition and accounts for worse cognition in cognitively normal older people. The impact of neural integrity on cognitive functions is, however, enhanced in the presence of high Aß burden for brain regions that are most affected in AD.
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Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/metabolismo , Amiloide/metabolismo , Biomarcadores/metabolismo , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/etiología , Anciano , Anciano de 80 o más Años , Envejecimiento , Enfermedad de Alzheimer/diagnóstico por imagen , Análisis de Varianza , Compuestos de Anilina , Mapeo Encefálico , Trastornos del Conocimiento/diagnóstico por imagen , Femenino , Fluorodesoxiglucosa F18 , Humanos , Modelos Lineales , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Escala del Estado Mental , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Radioisótopos , Reproducibilidad de los Resultados , TiazolesRESUMEN
IMPORTANCE: ß-Amyloid (Aß) deposition and vascular brain injury (VBI) frequently co-occur and are both associated with cognitive decline in aging. Determining whether a direct relationship exists between them has been challenging. We sought to understand VBI's influence on cognition and clinical impairment, separate from and in conjunction with pathologic changes associated with Alzheimer disease (AD). OBJECTIVE: To examine the relationship between neuroimaging measures of VBI and brain Aß deposition and their associations with cognition. DESIGN AND SETTING: A cross-sectional study in a community- and clinic-based sample recruited for elevated vascular disease risk factors. PARTICIPANTS: Clinically normal (mean age, 77.1 years [N = 30]), cognitively impaired (mean age, 78.0 years [N = 24]), and mildly demented (mean age, 79.8 years [N = 7]) participants. INTERVENTIONS: Magnetic resonance imaging, Aß (Pittsburgh Compound B-positron emission tomographic [PiB-PET]) imaging, and cognitive testing. MAIN OUTCOME MEASURES: Magnetic resonance images were rated for the presence and location of infarct (34 infarct-positive participants, 27 infarct-negative participants) and were used to quantify white matter lesion volume. The PiB-PET uptake ratios were used to create a PiB index by averaging uptake across regions vulnerable to early Aß deposition; PiB positivity (29 PiB-positive participants, 32 PiB-negative participants) was determined from a data-derived threshold. Standardized composite cognitive measures included executive function and verbal and nonverbal memory. RESULTS: Vascular brain injury and Aß were independent in both cognitively normal and impaired participants. Infarction, particularly in cortical and subcortical gray matter, was associated with lower cognitive performance in all domains (P < .05 for all comparisons). Pittsburgh Compound B positivity was neither a significant predictor of cognition nor interacted with VBI. CONCLUSIONS AND RELEVANCE: In this elderly sample with normal cognition to mild dementia, enriched for vascular disease, VBI was more influential than Aß in contemporaneous cognitive function and remained predictive after including the possible influence of Aß. There was no evidence that VBI increases the likelihood of Aß deposition. This finding highlights the importance of VBI in mild cognitive impairment and suggests that the impact of cerebrovascular disease should be considered with respect to defining the etiology of mild cognitive impairment.
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Envejecimiento/patología , Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Lesiones del Sistema Vascular/complicaciones , Anciano , Anciano de 80 o más Años , Compuestos de Anilina , Apolipoproteínas E/genética , Infarto Encefálico/etiología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/genética , Estudios Transversales , Función Ejecutiva , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Memoria , Escala del Estado Mental , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , TiazolesRESUMEN
The factors driving clinical heterogeneity in Alzheimer's disease are not well understood. This study assessed the relationship between amyloid deposition, glucose metabolism and clinical phenotype in Alzheimer's disease, and investigated how these relate to the involvement of functional networks. The study included 17 patients with early-onset Alzheimer's disease (age at onset <65 years), 12 patients with logopenic variant primary progressive aphasia and 13 patients with posterior cortical atrophy [whole Alzheimer's disease group: age = 61.5 years (standard deviation 6.5 years), 55% male]. Thirty healthy control subjects [age = 70.8 (3.3) years, 47% male] were also included. Subjects underwent positron emission tomography with (11)C-labelled Pittsburgh compound B and (18)F-labelled fluorodeoxyglucose. All patients met National Institute on Ageing-Alzheimer's Association criteria for probable Alzheimer's disease and showed evidence of amyloid deposition on (11)C-labelled Pittsburgh compound B positron emission tomography. We hypothesized that hypometabolism patterns would differ across variants, reflecting involvement of specific functional networks, whereas amyloid patterns would be diffuse and similar across variants. We tested these hypotheses using three complimentary approaches: (i) mass-univariate voxel-wise group comparison of (18)F-labelled fluorodeoxyglucose and (11)C-labelled Pittsburgh compound B; (ii) generation of covariance maps across all subjects with Alzheimer's disease from seed regions of interest specifically atrophied in each variant, and comparison of these maps to functional network templates; and (iii) extraction of (11)C-labelled Pittsburgh compound B and (18)F-labelled fluorodeoxyglucose values from functional network templates. Alzheimer's disease clinical groups showed syndrome-specific (18)F-labelled fluorodeoxyglucose patterns, with greater parieto-occipital involvement in posterior cortical atrophy, and asymmetric involvement of left temporoparietal regions in logopenic variant primary progressive aphasia. In contrast, all Alzheimer's disease variants showed diffuse patterns of (11)C-labelled Pittsburgh compound B binding, with posterior cortical atrophy additionally showing elevated uptake in occipital cortex compared with early-onset Alzheimer's disease. The seed region of interest covariance analysis revealed distinct (18)F-labelled fluorodeoxyglucose correlation patterns that greatly overlapped with the right executive-control network for the early-onset Alzheimer's disease region of interest, the left language network for the logopenic variant primary progressive aphasia region of interest, and the higher visual network for the posterior cortical atrophy region of interest. In contrast, (11)C-labelled Pittsburgh compound B covariance maps for each region of interest were diffuse. Finally, (18)F-labelled fluorodeoxyglucose was similarly reduced in all Alzheimer's disease variants in the dorsal and left ventral default mode network, whereas significant differences were found in the right ventral default mode, right executive-control (both lower in early-onset Alzheimer's disease and posterior cortical atrophy than logopenic variant primary progressive aphasia) and higher-order visual network (lower in posterior cortical atrophy than in early-onset Alzheimer's disease and logopenic variant primary progressive aphasia), with a trend towards lower (18)F-labelled fluorodeoxyglucose also found in the left language network in logopenic variant primary progressive aphasia. There were no differences in (11)C-labelled Pittsburgh compound B binding between syndromes in any of the networks. Our data suggest that Alzheimer's disease syndromes are associated with degeneration of specific functional networks, and that fibrillar amyloid-ß deposition explains at most a small amount of the clinico-anatomic heterogeneity in Alzheimer's disease.
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Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Glucosa/metabolismo , Placa Amiloide/patología , Anciano , Enfermedad de Alzheimer/patología , Amiloide/análisis , Femenino , Fluorodesoxiglucosa F18 , Humanos , Interpretación de Imagen Asistida por Computador , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fenotipo , Tomografía de Emisión de Positrones , RadiofármacosRESUMEN
Cognitive flexibility or the ability to change behavior in response to external cues is conceptualized as two processes: one for shifting between perceptual features of objects and another for shifting between the abstract rules governing the selection of these objects. Object and rule shifts are believed to engage distinct anatomical structures and functional processes. Dopamine activity has been associated with cognitive flexibility, but patients with dopaminergic deficits are not impaired on all tasks assessing cognitive flexibility, suggesting that dopamine may have different roles in the shifting of objects and rules. The goals of this study were to identify brain regions supporting object and rule shifts and to examine the role of dopamine in modulating these two forms of cognitive flexibility. Sixteen young, healthy volunteers underwent fMRI while performing a set-shift task designed to differentiate shifting between object features from shifting between abstract task rules. Participants also underwent PET with 6-[¹8F]-fluoro-l-m-tyrosine (FMT), a radiotracer measuring dopamine synthesis capacity. Shifts of abstract rules were not associated with activation in any brain region, and FMT uptake did not correlate with rule shift performance. Shifting between object features deactivated the medial PFC and the posterior cingulate and activated the lateral PFC, posterior parietal areas, and the striatum. FMT signal in the striatum correlated negatively with object shift performance and deactivation in the medial PFC, a component of the default mode network, suggesting that dopamine influences object shifts via modulation of activity in the default mode network.