RESUMEN
We used volumetric MRI and analysis of areas under receiver operating characteristic (ROC) curves to directly compare the extent of hippocampus-amygdala formation (HAF) and corpus callosum atrophy in patients with Alzheimer's disease (AD) in different clinical stages of dementia. Based on neuropathological studies, we hypothesized that HAF atrophy, representing allocortical neuronal degeneration, would precede atrophy of corpus callosum, representing loss of neocortical association neurons, in early AD. HAF and corpus callosum sizes were significantly reduced in 27 AD patients (37% and 16%, respectively) compared to 28 healthy controls. In mildly- and moderately-demented AD patients, the ROC derived index of atrophy was greater for HAF volume than for total corpus callosum area. The index of atrophy of posterior corpus callosum was not significantly different from HAF at mild, moderate or severe stages of dementia. In conclusion, these findings suggest a characteristic regional pattern of allocortical and neocortical neurodegeneraton in AD. Our data indicate that neuronal loss in parietotemporal cortex (represented by atrophy of corpus callosum splenium) may occur simultaneously with allocortical neurodegeneration in mild AD. Moreover, ROC analysis may provide a statistical framework to determine atrophy patterns of different brain structures in neurodegenerative diseases in vivo.
Asunto(s)
Enfermedad de Alzheimer/patología , Cuerpo Calloso/patología , Hipocampo/patología , Degeneración Nerviosa/fisiopatología , Anciano , Anciano de 80 o más Años , Amígdala del Cerebelo/patología , Análisis de Varianza , Área Bajo la Curva , Atrofia/patología , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Análisis por Apareamiento , Persona de Mediana Edad , Neocórtex/patología , Degeneración Nerviosa/patología , Pruebas Neuropsicológicas , Curva ROC , Valores de Referencia , Índice de Severidad de la EnfermedadRESUMEN
cDNA microarrays provide an efficient method to analyze gene expression patterns in thousands of genes in parallel. In some cases, large unfocused collections of cDNAs have been used in hybridization studies, in others small logically defined collections of tissue specific arrays have been used. Here we describe the bioinformatic selection of 1152 named human cDNAs specifically designed for neuroscience applications, arrayed on nylon membranes at high density. cDNAs were chosen which represent all the major cellular types of the brain including; neurons, astrocytes, microglia, and oligodendrocytes. Gene families chosen include cell type specific markers, ion-channels, transporters, receptors, and cell adhesion molecules among many others. These arrays were used with region specific samples from human brain to determine MRNA expression profiles for each region. Used with 33p labeled complex probes, this is a low cost, highly sensitive approach for tbc investigator to focus on tissue specific genes of interest where samples of limiting amounts of RNA are used. This selected set of brain-relevant cDNAs should be widely useful in the analysis of gene expression patterns from brain tissues as well as neural cell lines.
Asunto(s)
Encéfalo/fisiología , Neuronas/fisiología , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Encéfalo/citología , Expresión Génica , Humanos , Radioisótopos de FósforoRESUMEN
OBJECTIVE: To determine whether the size of the corpus callosum is related to the extent of white matter pathology in patients with AD and age-matched healthy control subjects. METHODS: White matter hyperintensity load and corpus callosum size were compared between 20 clinically diagnosed AD patients and 21 age-matched healthy control subjects. We investigated the effect of age and disease severity on corpus callosum size and white matter hyperintensity, in addition to the relation between corpus callosum areas and white matter hyperintensity load. RESULTS: We found significant regional atrophy of the corpus callosum in AD when compared with control subjects, although the groups did not differ in their white matter hyperintensity load. We further showed a region-specific correlation between corpus callosum size and white matter hyperintensity in the control group but not in AD patients. In the AD group, corpus callosum size correlated with age and dementia severity, whereas white matter hyperintensity correlated only with age. CONCLUSION: Corpus callosum atrophy in AD can occur independent of white matter degeneration, likely reflecting specific AD pathology in projecting neurons.
Asunto(s)
Enfermedad de Alzheimer/patología , Encéfalo/anatomía & histología , Encéfalo/patología , Cuerpo Calloso/anatomía & histología , Cuerpo Calloso/patología , Anciano , Anciano de 80 o más Años , Lóbulo Frontal/anatomía & histología , Lóbulo Frontal/patología , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Neuronas/citología , Neuronas/patología , Valores de Referencia , Análisis de RegresiónRESUMEN
OBJECTIVE: To determine whether the hypometabolism observed in PET images of patients with Alzheimer's disease (AD) is due entirely to brain atrophy. BACKGROUND: Reduced brain glucose metabolism in AD patients measured using PET has been reported by numerous authors. Actual glucose metabolic values in AD may be reduced artificially because of brain atrophy, which accentuates the partial volume effect (PVE) on data collected by PET. METHODS: Using segmented MR images, we corrected regional cerebral metabolic rates for glucose for PVEs to evaluate the effect of atrophy on uncorrected values for brain metabolism in AD patients and healthy control subjects. RESULTS: Global glucose metabolism was reduced significantly before and after correction in AD patients compared with controls. Before PVE correction, glucose metabolic values in patients were lower than in control subjects in the inferior parietal, frontal, and lateral temporal cortex; in the posterior cingulate; and in the precuneus. These reductions remained significantly lower after PVE correction, although in the posterior cingulate the difference in metabolism between AD patients and control subjects lessened. Regional glucose metabolism of these areas with PVE correction was lower in moderately-severely demented patients than in mildly demented patients. CONCLUSION: Reduced glucose metabolism measured by PET in AD is not simply an artifact due to an increase in CSF space induced by atrophy, but reflects a true metabolic reduction per gram of tissue.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Glucosa/metabolismo , Anciano , Enfermedad de Alzheimer/diagnóstico , Atrofia , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Valores de Referencia , Distribución Tisular , Tomografía Computarizada de EmisiónRESUMEN
BACKGROUND: Pathological studies in Alzheimer disease indicate the specific loss of layer III and V large pyramidal neurons in association cortex. These neurons give rise to long corticocortical connections within and between the cerebral hemispheres. OBJECTIVE: To evaluate the corpus callosum as an in vivo marker for cortical neuronal loss. METHOD: Using a new imaging technique, we measured region-specific corpus callosum atrophy in patients with Alzheimer disease and correlated the changes with neuropsychological functioning. Total cross-sectional area of the corpus callosum and areas of 5 callosal subregions were measured on midsagittal magnetic resonance imaging scans of 14 patients with Alzheimer disease (mean age, 64.4 years; Mini-Mental State Examination score, 11.4) and 22 healthy age- and sex-matched control subjects (mean age, 66.6 years; Mini-Mental State Examination score, 29.8). All subjects had minimal white matter changes. RESULTS: The total callosal area was significantly reduced in the patients with Alzheimer disease, with the greatest changes in the rostrum and splenium and relative sparing of the callosal body. Regional callosal atrophy correlated significantly with cognitive impairment in the patients with Alzheimer disease, but not with age or the white matter hyperintensities score. CONCLUSIONS: Callosal atrophy in patients with Alzheimer disease with only minimal white matter changes may indicate loss of callosal efferent neurons in corresponding regions of the cortex. Because these neurons are a subset of corticocortical projecting neurons, region-specific callosal atrophy may serve as a marker of progressive neocortical disconnection in Alzheimer disease.
Asunto(s)
Enfermedad de Alzheimer/patología , Cuerpo Calloso/patología , Neuronas Eferentes/patología , Células Piramidales/patología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Atrofia/patología , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/etiología , Femenino , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Índice de Severidad de la EnfermedadRESUMEN
We describe a computationally straightforward post-hoc statistical method of correcting spatially dependent image pixel intensity nonuniformity based on differences in local tissue intensity distributions. Pixel intensity domains for the various tissues of the composite image are identified and compared to the distributions of local samples. The nonuniformity correction is calculated as the difference of the local sample median from the composite sample median for the tissue class most represented by the sample. The median was chosen to reduce the effecters on determining the sample statistic and to allow a sample size small enough to accurately estimate the spatial variance of the image intensity nonuniformity. The method was designed for application to two-dimensional images. Simulations were used to estimate optimal conditions of local histogram kernel size and to test the accuracy of the method under known spatially dependent nonuniformities. The method was also applied to correct a phantom image and cerebral MRIs from 15 healthy subjects. Results show that the method accurately models simulated spatially dependent image intensity differences. Further analysis of clinical MR data showed that the variance of pixel intensities within the cerebral MRI slices and the variance of slice volumes within individuals were significantly reduced after nonuniformity correction. Improved brain-cerebrospinal fluid segmentation was also obtained. The method significantly reduced the variance of slice volumes within individuals, whether it was applied to the native images or images edited to remove nonbrain tissues. This statistical method was well behaved under the assumptions and the images tested. The general utility of the method was not determined, but conditions for testing the method under a variety of imaging sequences is discussed. We believe that this algorithm can serve as a method for improving MR image segmentation for clinical and research applications.
Asunto(s)
Encéfalo/patología , Aumento de la Imagen/instrumentación , Procesamiento de Imagen Asistido por Computador/instrumentación , Imagen por Resonancia Magnética/instrumentación , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Artefactos , Líquido Cefalorraquídeo/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fantasmas de Imagen , Valores de ReferenciaRESUMEN
Multivariate discriminant analysis of brain volumes obtained from semiautomated magnetic resonance image (MRI) quantification was used in an attempt to identify demented patients very early in the course of the disease. Temporal and posterior frontal brain volumes were quantified from MRIs in a cross-sectional study of 31 male and female patients with dementia of the Alzheimer type (DAT) and 29 age- and sex-matched healthy comparison subjects. Mean scores on the Folstein Mini-Mental State Examination (MMS) were in the mild range for the DAT group (20 +/- 6.6), but patients with moderate and severe dementia were also included (MMS range of entire DAT group = 4-28). Significant mean differences in frontal and temporal lobe brain volumes were found between the DAT group and the age- and sex-matched healthy comparison group, but the sensitivity of any single measure was limited to 87% with a specificity of 83%. Initial multivariate discriminant analysis revealed significant gender differences among the healthy subjects, but not the DAT patients. The large group size allowed for subsequent discriminant analyses to be performed by gender. All healthy subjects and DAT patients were correctly classified by gender-specific discriminant functions. The male discriminant variables included brain volume, age, and temporal lobe measures. Inclusion of age in the male discriminant function accounted for age-related brain atrophy, a finding that may have emerged as a consequence of the broad age range of the male DAT population (50-81 years). The male discriminant function was also successfully applied to an independent group of mildly demented subjects that included patients for whom the diagnosis of dementia was uncertain but verified by follow-up clinical evaluations. Measures of temporal lobe brain matter and temporal lobe cerebrospinal fluid volumes were the significant discriminator variables for the women. Quantitative MRI and multivariate discriminant analysis showed promise in distinguishing the dementing process from healthy aging in a group of 60 subjects. Moreover, while not diagnostic of DAT, the approach appeared to offer additional information about the probability of a diagnosis being later confirmed in patients with very mild dementia for whom the clinical identification of DAT is uncertain.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Imagen por Resonancia Magnética , Adulto , Anciano , Envejecimiento , Enfermedad de Alzheimer/fisiopatología , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Lóbulo Temporal/fisiopatologíaRESUMEN
PURPOSE: To evaluate age-related differences in temporal and supratemporal brain regions in carefully selected, very healthy men 19 to 92 years of age. METHODS: MR quantification of brain regions used image segmentation into cerebrospinal fluid and brain matter based on nonlinear modeling of pixel intensity distributions. RESULTS: There was a significant age-related decrease (approximately 1% per decade) of posterior frontal lobe volume, but not of temporal lobe volume. The mean volume of the right temporal lobe was significantly greater than the left, and this relation did not change with age. CONCLUSION: In very healthy aging, the volume of the temporal lobes remains constant over the age range of human life.
Asunto(s)
Envejecimiento/patología , Imagen por Resonancia Magnética , Lóbulo Temporal/anatomía & histología , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/fisiología , Encéfalo/anatomía & histología , Acueducto del Mesencéfalo/anatomía & histología , Ventrículos Cerebrales/anatomía & histología , Líquido Cefalorraquídeo , Cognición/fisiología , Lóbulo Frontal/anatomía & histología , Humanos , Inteligencia/fisiología , Estudios Longitudinales , Imagen por Resonancia Magnética/métodos , Masculino , Memoria/fisiología , Persona de Mediana Edad , Análisis de RegresiónRESUMEN
Using magnetic resonance imaging (MRI), we measured the volumes of various brain structures and cerebrospinal fluid (CSF) in 19 men with dementia of the Alzheimer type (DAT) and 18 healthy age-matched control men. The mean (+/- S.D) Mini-Mental State exam score (MMSE) of the DAT men was 16 +/- 7; 9 were mildly (MMSE > 20), 5 moderately (MMSE 10-20), and 5 severely (MMSE < 10) demented. Brain and CSF volumes were normalized as a percent of the traced intracranial volume to control for the relation of volumes of cerebral structures to head size, and analyzed statistically. The whole group of DAT subjects had significantly smaller mean cerebral brain matter and temporal lobe volumes (p < 0.05), and significantly larger mean ventricular and temporal lobe peripheral CSF volumes than did controls. Mean volumes of the subcortical nuclei did not differ significantly between groups, and mean volume of temporal lobe brain matter decreased significantly more than whole brain, suggesting regional loss of brain matter in DAT. Mildly demented DAT patients had significantly smaller mean cerebral brain matter and temporal lobe volumes and significantly larger volumes of lateral ventricles, and of temporal lobe peripheral CSF, than did controls. Neuropsychological measures of disease severity in DAT patients were significantly (p < 0.05) and appropriately correlated to volumes of cerebral brain matter and right lateral ventricle. These results suggest that in DAT: (i) significant brain atrophy is present early in the disease process, (ii) brain atrophy correlates with severity of cognitive impairment, and (iii) there is greater involvement of the telencephalic association system than whole brain, and there is relative sparing of the caudate, lenticular and thalamic nuclei.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Encéfalo/patología , Líquido Cefalorraquídeo/fisiología , Imagen por Resonancia Magnética/métodos , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Atrofia , Mapeo Encefálico/métodos , Cefalometría/métodos , Ventrículos Cerebrales/patología , Estudios Transversales , Dominancia Cerebral/fisiología , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Lóbulo Temporal/patologíaRESUMEN
OBJECTIVES: To study phosphorus and glucose metabolism in whole-brain slices of otherwise healthy patients with dementia of the Alzheimer type (DAT) and healthy controls. DESIGN: We used proton nuclear magnetic resonance imaging phosphorus spectroscopy and positron emission tomography to study in vivo brain phosphorus and glucose metabolism. PATIENTS: Whole-brain slice phosphorus metabolism was studied in nine drug free patients with mild to moderately severe dementia of the Alzheimer type (DAT) and in eight age- and sex-matched healthy controls. Mean ages (+/- SD) of the patients and controls were 60 +/- 10 years and 64 +/- 16 years, respectively. Positron emission tomography was used to study cerebral glucose metabolism in seven of the patients with DAT and seven of the healthy controls. RESULTS: Patients with DAT had significant brain glucose hypometabolism compared with controls, but there was no significant group difference in any phosphorus metabolite concentration or ratio in the same volume of brain tissue. Also, within patients with DAT there was no correlation between any phosphorus metabolite concentration or ratio and either severity of dementia or glucose metabolism. CONCLUSIONS: We suggest glucose metabolism is reduced early in DAT (reflecting decreased basal synaptic functioning) and is unrelated to a rate limitation in glucose delivery, abnormal glucose metabolism, or abnormal coupling between oxidation and phosphorylation. Normal or near-normal levels of phosphorus metabolites are maintained in mild, moderate, and severe DAT. Therefore, altered high-energy phosphate levels are not a consequence of reduced glucose metabolism in DAT, and do not play a major role in the pathophysiology of the disorder, at least in whole-brain sections.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Glucosa/metabolismo , Espectroscopía de Resonancia Magnética , Fósforo/metabolismo , Tomografía Computarizada de Emisión , Anciano , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la EnfermedadRESUMEN
We determined the rates of lateral ventricular enlargement and decline in cognitive performance for 11 men and nine women with dementia of the Alzheimer type (DAT), and compared these rates with the same measures obtained for age-matched healthy controls (nine men and eight women). DAT patients, as a group, had only mild cognitive impairment at initial evaluation, and each patient was followed from 9 months to over 7 years with yearly evaluations. Six DAT patients had isolated memory impairment as their only cognitive deficit early in the course of the disease. The rate of total lateral ventricle enlargement (cm3/yr) was significantly different between DAT and healthy controls, and was more specific and sensitive to the diagnosis of DAT than comparison of cross-sectional volumes at final evaluation. The rate of total lateral ventricular enlargement did not differ significantly by patient sex, ventricular size at initial evaluation, age, or degree of cognitive impairment as measured by Mini Mental State Examination scores. However, in the six DAT patients initially found to have isolated memory impairment, the rate of ventricular enlargement during the period of isolated memory impairment was significantly less than the rate of ventricular enlargement after the onset of nonmemory cognitive impairment. The diagnostic power of total lateral ventricular measures made from two CTs separated by 1 year and obtained early in the course of the illness, however, was only 0.33. We conclude that the total lateral ventricular enlargement accompanying DAT is due to continuous, pathologic cell loss, significantly greater than cell loss due to the healthy aging process.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Ventriculografía Cerebral/métodos , Tomografía Computarizada por Rayos X/métodos , Anciano , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Sensibilidad y Especificidad , Factores de TiempoRESUMEN
We describe a simple, rapid, and semiautomated method of MR analysis based on mathematical modeling of MR pixel intensity histograms. The method is shown to be accurate and reliable for regional analysis of brain, central, and subarachnoid CSF volumes. Application of the method to five young and six older subjects revealed significant age-related changes in regional brain volumes whereas no difference was found for traced central CSF volumes or subarachnoid CSF volumes. We conclude that this is a simple method that can be applied to further studies of quantification of brain structure in healthy aging and brain disease.