Faculty Bibliography

Glucocorticoids are known to play a role in the regulation of peripheral glucose mobilization and metabolism. Although several animal studies have shown that hippocampal glucose metabolism is reduced acutely and chronically by the action of corticosterone and that excess glucocorticoids are harmful to hippocampal neurons, little is known about the central effects of glucocorticoids in the human. In this study we examined the brain glucose utilization (CMRglu) response to hydrocortisone (cortisol) in seven normal elderly and eight Alzheimer's disease (AD) patients. On 2 separate days, immediately after the administration of a bolus of either 35 mg hydrocortisone or placebo, we administered 2-deoxy-2-[18F]fluoro-D-glucose. After a 35-min radiotracer uptake period, positron emission tomography (PET) images were collected. PET CMRglu images were analyzed using two methods: an image transformation that allowed analyses across cases on a voxel by voxel basis, and an anatomically based region of interest method that used coregistered magnetic resonance imaging scans. Both image analysis methods yielded similar results, identifying relative to placebo, a specific hippocampal CMRglu reduction in response to the hydrocortisone challenge that was restricted to the normal group. The region of interest technique showed CMRglu reductions of 16% and 12% in the right and left hippocampi, respectively. Blood collected during the PET scans showed, for the normal group, a rise in plasma glucose levels, starting approximately 25 min after hydrocortisone administration. The AD group did not show this effect. Baseline cortisol was elevated in the AD group, but the clearance of hydrocortisone was not different between the groups. In conclusion, these data show that among normal individuals in the presence of a pharmacological dose of cortisol, the glucose utilization of the hippocampus is specifically reduced, and serum glucose levels increase. Based in part on other studies, we offer the interpretation that glucocorticoid-mediated regulation of glucose transport is altered in AD, and this may underlie both the hippocampal insensitivity to cortisol and the failure in these patients to mount a peripheral glucose response. As our findings could reflect an altered state of the AD patients, we interpret our results as preliminary with respect to evidence for metabolic abnormalities in AD. The results suggest the continued study of the hydrocortisone challenge as a test of hippocampal responsivity

Our goal was to ascertain the involvement of the temporal lobe in the preclinical (not yet diagnosable) stages of dementia of the Alzheimer's type (DAT) by using MRI-derived volumes. We assessed anatomical subdivisions of the temporal lobe on three groups of carefully screened age- and education-matched elderly individuals: 27 normal elderly (NL), 22 individuals with minimal cognitive impairment (MCI), who did not fulfill DAT criteria but were regarded at high risk for future DAT, and 27 DAT individuals. We found hippocampal volume reductions of 14% for the MCI and 22% for the DAT group compared to the NL group. Utilizing regression analyses and after accounting for gender head size-age, generalized atrophy (CSF), and other temporal lobe subvolumes, the hippocampal volume separated NL from MCI individuals, correctly classifying 74%. For NL and MCI groups combined the hippocampal volume was the only temporal lobe subvolume related to delayed recall memory performance. When contrasting MCI and DAT individuals, the fusiform gyrus volume uniquely improved the ability of the hippocampal volume to separate MCI from DAT individuals from 74 to 80%. Our cross-sectional data suggest that, within the temporal lobe, specific hippocampal volume reductions separated the group at risk for DAT from the normal group. By the time impairments are sufficient to allow a diagnosis of DAT to be made, in addition to the medial temporal lobe volume reductions, the lateral temporal lobe is also showing volume reductions, most saliently involving the fusiform gyrus

We used CT and MR to examine the frequency of occurrence of hippocampal formation atrophy (HA) in a research clinic population of 130 normal elderly, 72 nondemented patients with very mild memory and cognitive impairments (MCI), 73 mild Alzheimer's disease (AD) patients, and 130 patients with moderate to severe AD. HA was found in 29% of the normal elderly group and its frequency of occurrence was strongly related to increasing age. For normal elderly 60-75 years of age, 15% had HA: the proportion rose to 48% in subjects 76-90 years of age. Among the three groups of impaired patients, the frequencies of HA ranged from 78% in the MCI patients to 96% in the advanced AD group. Unlike the normal elderly group, the percentages were not related to age. In both the normal elderly group and MCI group disproportionately more males than females had HA. After controlling for learning and the effects of generalized brain changes as reflected in ventricular size, only in the normal group was HA associated with reduced delayed verbal recall performance. Follow-up examinations for 15 individuals with baseline HA. 4 who at entry were MCI and 11 probable AD, yielded clinical and neuropathologic diagnoses of AD in all cases. The results of the present study indicate that hippocampal formation atrophy is associated with memory and cognitive impairments. Further longitudinal and neuropathologic work is required to validate the relationship between hippocampal formation atrophy and AD

There is compelling evidence for the early involvement of the hippocampal formation in the natural history of Alzheimer's disease (AD). The evidence comes from recent neuropathology, neuropsychology, and neuroimaging studies. AD-type histopathologic changes limited to the hippocampus have been described and may be seen in normal aging subjects. The sites of maximal neuronal loss in the hippocampal formation are in the CA1, subiculum, and entorhinal cortex. Minimally cognitively impaired (MCI) individuals (defined by ratings of functional capacity and psychiatric symptomatology) exhibit a neuropsychological profile that is distinct from that of the unimpaired elderly. Pathologic evidence suggests that most of these cases already have AD brain changes accentuated in the hippocampal region, and our own longitudinal studies reveal that 70% of this group develop dementia within a 4-year period. We have developed a negative-angle axial view designed to cut parallel to the anterior-posterior plane of the hippocampus. Using this modified axial plane of section in conjunction with computed tomography (CT) and magnetic resonance imaging (MRI), we estimated the prevalence of hippocampal atrophy in normal aging and across severity levels of cognitively impaired elderly patients. Longitudinal study shows that hippocampal atrophy is a sensitive and specific predictor of future AD for patients with MCI. MRI volume study of AD patients, controls, and MCI patients shows specific hippocampal volume loss in MCI. We conclude that the atrophic changes associated with early AD can be visualized using qualitative techniques and are readily quantifiable with volumetry. This article is not intended to be comprehensive, but to provide an overview of some of the structural neuroimaging data from our laboratory

Population trends indicate that in the near future the size of the elderly population will increase. This will result in a large increment in the numbers of persons suffering mild to severe levels of cognitive impairment. While considerable efforts continue to be made to explain brain changes associated with Alzheimer disease (AD), little is known of the brain changes in aging without dementia or so-called normal aging. Pathologic studies suggest that the medial temporal lobe is informative in the examination of the early brain changes related to AD. However, pathologic studies only offer a single observation and considerable uncertainty exists regarding the likelihood of progression of disease and the development of dementia. Several structural neuroimaging studies have recently investigated this anatomy and recent reports are encouraging for a medial temporal lobe based diagnosis for age-related cognitive impairments. We will present our findings on the MRI anatomy of the hippocampal formation as well as data bearing on the use of hippocampal formation imaging in the diagnosis of AD and as a predictive marker for future dementia. Our findings suggest an anatomically specific relationship between hippocampal volume and secondary memory performance. Because these observations apply to nondemented and normal elderly subjects, we are encouraged that the anatomy of age-related cognitive impairments can be reliably recognized and possibly put to use in therapeutic studies

CSF levels of 5-hydroxyindolacetic acid (5-HIAA), the serotonin metabolite, were assayed in 10 violent and 10 matched nonviolent patients with schizophrenia. Mean group levels of 5-HIAA in cerebrospinal fluid were found to be nearly identical. Possible explanations, including effects of medications, are discussed

The role of imaging in the evaluation of neurodegenerative disorders is summarized. The primary role of imaging is to exclude potentially treatable disorders such as meningioma, extracerebral hematoma, Wernicke's disease, and hypothyroidism. Atrophic changes dominate in the hippocampal region on Alzheimer's disease versus the anterior, frontal, and temporal lobes in Pick's disease. Signal hypointensity in the putamen on T2-weighted spin-echo images favors poorly drug-responsive Parkinson's disease whereas putaminal hyperintensity is observed with Creutzfeldt-Jacob, Wilson's, and Leigh's diseases. As our population ages, a thorough understanding of imaging findings in a geriatric population assumes an increasing importance