Diane Teichberg

Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer's disease

Objective To determine whether the hypometabolism observed in PET images of patients with Alzheimers 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.

Method for quantification of brain, ventricular, and subarachnoid CSF volumes from MR images

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.

Volumetric magnetic resonance imaging in men with dementia of the Alzheimer type: Correlations with disease severity

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.

Regional pattern of hippocampus and corpus callosum atrophy in Alzheimer’s disease in relation to dementia severity: evidence for early neocortical degeneration

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 Alzheimers 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.

Longitudinal changes in lateral ventricular volume in Datients with dementia of the Alzheimer type

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. The rate of total lateral ventricular enlargement very early in the course of Alzheimers disease is significantly less than the rate of ventricular enlargement is after the onset of nonmemory cognitive deficits but is stable for all other degrees of dementia severity, suggesting a biphasic process. Although not diagnostic for the disease early in its course, longitudinal CT measures can still provide a reliable and independent measure of disease progression in patients with DAT.

Discriminant analysis of MRI measures as a method to determine the presence of dementia of the Alzheimer type

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.

Dissociation between corpus callosum atrophy and white matter pathology in Alzheimer's disease

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.

Differentially Expressed Genes in MHC-Compatible Rat Strains That Are Susceptible or Resistant to Experimental Autoimmune Uveitis

PURPOSE Experimental autoimmune uveitis (EAU) is an established model for immune-mediated human uveitis. Although several genes from major histocompatibility complex (MHC) loci have been shown to play a role in uveitis, little is known about the role of non-MHC genes in the pathogenesis of EAU. Several non-MHC genes have been implicated in the pathogenesis of various autoimmune diseases. The primary objective of this study was to identify the non-MHC genes involved in the pathogenesis of EAU, to identify potential drug targets and possibly to target their protein products for immunotherapy. METHODS EAU was induced in the susceptible (Lewis; LEW) or resistant (Fischer 344; F344) rats that have identical MHC class II haplotype. Draining lymph node cells were obtained during the innate and adaptive phase of the immune response, and the pattern of gene expression was evaluated using microarray technology. Differentially expressed genes were validated at mRNA and protein levels using various methods. RESULTS Susceptibility to EAU was associated with an increased expression of numerous non-MHC genes such as Th1-type cytokines and chemokines, antiapoptotic factors, hormones, and neurotransmitters and a downregulation of selected adhesion molecules. In this study a combined genetic-genomic approach was used to identify different patterns of gene expression associated with the sensitization and effector phase of EAU pathogenesis. CONCLUSIONS The data demonstrate that the differential expression of several non-MHC genes is associated with the mechanism of uveitis.