Ribosomal subunit kinase-2 is required for growth factor-stimulated transcription of the c-Fos gene.

Ribosomal subunit kinases (Rsk) have been implicated in the regulation of transcription by phosphorylating and thereby activating numerous transcription factors, such as c-Fos, cAMP responsive element binding protein (CREB), and nuclear receptors. Here we describe the generation and characterization of immortalized embryonic fibroblast cell lines from mice in which the Rsk-2 gene was disrupted by homologous recombinant gene targeting. Rsk-2-deficient (knockout or KO) cell lines have no detectable Rsk-2 protein, whereas Rsk-1 expression is unaltered as compared with cell lines derived from wild-type control mice. KO cells exhibit a major reduction in platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF)-1-stimulated expression of the immediate-early gene c-Fos. This results primarily from a reduced transcriptional activation of the ternary complex factor Elk-1 and reduced activation of the serum response factor. The reduced Elk-1 activation in KO cells occurs despite normal activation of the mitogen-activated protein kinase pathway and normal PDGF- and IGF-1-stimulated Elk-1 phosphorylation. By contrast, PDGF- and IGF-1-stimulated phosphorylation and transcriptional activation of CREB is unaltered in KO cells. Thus Rsk-2 is required for growth factor-stimulated expression of c-Fos and transcriptional activation of Elk-1 and the serum response factor, but not for activation of CREB or the mitogen-activated protein kinase pathway in response to PDGF and IGF-1 stimulation.

Melanin-concentrating hormone: a functional melanocortin antagonist in the hypothalamus.

Melanin-concentrating hormone (MCH) and alpha-melanocyte-stimulating hormone (alpha-MSH) demonstrate opposite actions on skin coloration in teleost fish. Both peptides are present in the mammalian brain, although their specific physiological roles remain largely unknown. In this study, we examined the interactions between MCH and alpha-MSH after intracerebroventricular administration in rats. MCH increased food intake in a dose-dependent manner and lowered plasma glucocorticoid levels through a mechanism involving ACTH. In contrast, alpha-MSH decreased food intake and increased glucocorticoid levels. MCH, at a twofold molar excess, antagonized both actions of alpha-MSH. alpha-MSH, at a threefold molar excess, blocked the orexigenic properties of MCH. MCH did not block alpha-MSH binding or the ability of alpha-MSH to induce cAMP in cells expressing either the MC3 or MC4 receptor, the principal brain alpha-MSH receptor subtypes. These data suggest that MCH and alpha-MSH exert opposing and antagonistic influences on feeding behavior and the stress response and may function in a coordinate manner to regulate metabolism through a novel mechanism mediated in part by an MCH receptor.

Comparison of positron emission tomography, cognition, and brain volume in Alzheimer's disease with and without severe abnormalities of white matter.

OBJECTIVES: To examine cerebral metabolism, cognitive performance, and brain volumes in healthy controls and two groups of patients with probable Alzheimer's disease, one group with severe abnormalities of white matter (DAT+) and the other group with none, or minimal abnormalities (DAT-). METHODS: Neuropsychological tests, CT, MRI, quantitative MRI, and PET studies were carried out to allow comparison between the DAT+ and DAT- groups and the healthy controls. RESULTS: Compared with the healthy controls, both demented groups had significantly reduced global and regional cerebral metabolism, significant brain atrophy, and significantly lower scores on neuropsychological testing. The DAT- patient group showed a pattern of parietal-temporal cerebral metabolic reductions and neuropsychological performance deficits typical of Alzheimer's disease. In addition, metabolism in the association neocortex (AD ratio) and measures of neuropsychological task performance were significantly correlated in the DAT- patient group. Comparison of DAT+ with DAT- patients showed a significantly higher ratio of parietal to whole brain glucose utilisation for the DAT+ group. Moreover, when comparing group z score differences from the healthy controls, the DAT+ group had, on average, smaller differences from controls in the frontal, parietal, and temporal regions than did the DAT- group. Discriminant analysis using metabolic ratios of the frontal, parietal, and temporal regions showed cerebral metabolic patterns to be significantly different among the DAT+, the DAT-, and the healthy controls. These differences were due primarily to relatively higher frontal, parietal, and temporal metabolic ratios in the DAT+ group which resulted in discriminant scores for the DAT+ group between the healthy controls and the DAT- group. Group mean scores on tests of neuropsychological performance were not significantly different between the DAT- and DAT+ patients. By contrast with the DAT- group, however, no significant correlations between the AD ratio and any neuropsychological task were seen in the DAT+ group. Multiple regression analysis showed significant between group differences in the relation between the AD ratio and neuropsychological scores on three tasks. The slopes of the relations between the AD ratio and memory scores (memory and freedom from distractability deviation quotient of the Wechsler adult intelligence scale (WMDQ)) also were significantly different for the two groups. CONCLUSIONS: Although multiple causes for abnormalities of white matter exist in patients with Alzheimer's disease, these data suggest that the presence of severe abnormalities of white matter indicate a second pathological process in the DAT+ patients. The DAT- patients showed the parietal-temporal metabolic deficits and correlations between association neocortical metabolism and neuropsychological task performance typical of patients with Alzheimer's disease. By contrast, the DAT+ group had a pattern of cerebral metabolism significantly different from healthy controls and DAT+ patients, as well as no significant correlations between metabolism in the association neocortex and neuropsychological performance. These differences probably reflect the superimposed pathology of the abnormalities of white matter which may exert their affect through disruption of long corticocortical pathways.

The effect of white matter hyperintensity volume on brain structure, cognitive performance, and cerebral metabolism of glucose in 51 healthy adults.

OBJECTIVE: To assess the association of MRI white matter hyperintensities (WMHI) with cognitive performance, cerebral structure, and cerebral metabolism in 51 healthy individuals aged 19 to 91 years without cerebrovascular risk factors. BACKGROUND: Abnormal white matter signals have been associated with brain atrophy, reduced cerebral blood flow, focal neurologic signs, gait disorder, and poorer neuropsychological test performance. Most studies of WMHI, however, include subjects with hypertension or other identifiable causes of cerebrovascular disease that may have an independent effect on brain structure and function. To assess brain changes associated with WMHI independent of cerebrovascular risk factors, we determined WMHI volume, brain volume, cerebral metabolism, and cognitive performance for a group of subjects free of medical illness. Regional cerebral metabolism and cognitive domains were also assessed to evaluate the possible role of frontal lobe dysfunction in subjects with WMHI. DESIGN: Cross-sectional study of 51 very healthy subjects aged 19 to 91 years. METHODS: WMHI, brain, and CSF volumes were determined by MRI segmentation. Neuropsychological tests were employed to assess multiple cognitive domains. Brain metabolism was determined from 18-fluoro-2-deoxy-D-glucose PET. Multivariate relations were tested with stepwise linear regression. Models included the potential confounders of age and education where appropriate. RESULTS: The distribution of WMHI volume was bimodal, with five subjects having WMHI volumes beyond three SDs from the normally distributed population. A WMHI volume of greater than 0.5% of intracranial volume was considered abnormal. Within the multivariate models, WMHI volumes were significantly predictive of increased ventricular volume, reduced brain volume, and reduced cognitive scores. Subjects with greater than 0.5% WMHI volume also had significantly lower frontal lobe metabolism, significantly higher systolic blood pressure, significantly larger ventricular volume, and significantly lower scores on frontal lobe-mediated neuropsychological tests than age-matched controls. CONCLUSION: WMHI volume is associated with structural and functional brain changes even within a group of very healthy individuals. WMHI is associated with poorer frontal lobe cognitive function and, when severe, is accompanied by significantly reduced frontal lobe metabolism. Subjects with large WMHI volumes have significantly higher systolic blood pressure, brain atrophy, reduced cerebral metabolism, and lower scores on tests of frontal lobe function than age-matched controls. Large amounts of WMHI are, therefore, pathologic and may be related to elevated systolic blood pressure even when it is within the normal age-related range.

Lack of age-related differences in temporal lobe volume of very healthy adults.

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.

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.

Longitudinal changes in lateral ventricular volume in patients 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.(ABSTRACT TRUNCATED AT 250 WORDS)