Showing papers on "Aging brain published in 2002"

Neurophysiological correlates of age-related changes in human motor function

Abstract: Background: There are well-defined and characteristic age-related deficits in motor abilities that may reflect structural and chemical changes in the aging brain. Objective: To delineate age-related changes in the physiology of brain systems subserving simple motor behavior. Methods: Ten strongly right-handed young ( 50 years of age) subjects with no evidence of cognitive or motor deficits participated in the study. Whole-brain functional imaging was performed on a 1.5-T MRI scanner using a spiral pulse sequence while the subjects performed a visually paced “button-press” motor task with their dominant right hand alternating with a rest state. Results: Although the groups did not differ in accuracy, there was an increase in reaction time in the elderly subjects (mean score ± SD, young subjects = 547 ± 97 ms, elderly subjects = 794 ± 280 ms, p right), and contralateral cerebellum of the elderly subjects. Conclusions: The results of this study show that elderly subjects recruit additional cortical and subcortical areas even for the performance of a simple motor task. These changes may represent compensatory mechanisms invoked by the aging brain, such as reorganization and redistribution of functional networks to compensate for age-related structural and neurochemical changes.

Comparison of Automated and Manual MRI Volumetry of Hippocampus in Normal Aging and Dementia

Abstract: Several neurodegenerative and psychiatric disorders, including Alzheimer’s disease (AD) and schizophrenia show hippocampal atrophy on magnetic resonance imaging (MRI) (1,2). Most studies have used manual tracing of the hippocampus to determine volume changes; however, this approach requires extensive rater training and has a potential risk of rater bias. High-dimensional brain warping algorithms were developed that can be used to automatically mask the hippocampus on MRI data (3–5). Although such algorithms reduce to a large extent dependency on raters, automated marking can be more variable than manual procedures because of computational errors due to image noise, which compromise the reliability of the measurements. This could particularly be a problem for MRI studies of aging brain and dementia, because image contrast is often reduced with older brains. Therefore, the aim of this study was to compare the ability of automated and manual hippocampal volumetry in differentiating between normal aging, cognitive impairment (CI) (which could be an early stage of AD), and AD. AD is the most common cause of dementia in the elderly; it is characterized by neuron loss, especially involving the hippocampus (6). In accordance with pathological findings, a number of MRI studies have shown significant atrophy of the hippocampus in patients with AD (1,7,8). Hippocampal volume loss was also found in subjects with CI (9–12) in the absence of clinical symptoms of dementia, and in cognitively normal subjects with genetic risks for AD (13,14). Furthermore, longitudinal studies suggest that hippocampal volume loss predicts cognitive decline (11,15). In this study, differences in hippocampal volumes among cognitively normal, CI, and AD subjects are determined using both manual and automatic procedures.

The aging brain. Changes in the neuronal insulin/insulin receptor signal transduction cascade trigger late-onset sporadic Alzheimer disease (SAD). A mini-review.

Abstract: Aging of the brain has been demonstrated to be the main risk factor for late-onset sporadic AD what is in contrast to early-onset familial AD in which mutations predominante the pathology. Aging of the brain was found to be associated with a multitude of aberrancies from normal in morphological, cellular and molecular terms. Recent findings provide clear evidence that the function of the neuronal insulin/insulin receptor signal transduction cascade is of pivotal significane to maintain normal cerebral blood flow and oxidative energy metabolism, work of the endoplasmatic reticulum/Golgi apparatus and the cell cycle in terminally differentiated neurons no longer in the cell cycle. It has become evident that normal metabolism of both amyloid precursor protein and tau-protein is part of interactive processes controlled by the neuronal I/IR signal transduction cascade. In normal brain aging, the function of this cascade starts to fail compared to normal resulting in adverse effects in CBF/oxidative energy metabolism, work of the endoplasmatic reticulum/Golgi apparatus and cell cycle. The aberrancies may not be drastic, but multifold and permanently existing, inclusive the metabolism of APP and tau-protein. The amount of intraneuronally formed βA4 may increase, and tau-protein may become hyperphosphorylated. These processes as a whole may increase the vulnarability of the aging brain and may facilitate the generatin of late-onset sporadic AD.

Astrocytes in the aging brain.

Abstract: Astrocytes have traditionally been viewed as passive supportive cells, which were primarily responsible for maintaining an optimal environment for electrical neuronal activity. Recent studies have, however, demonstrated that the activity of nerve cells can be modulated by astrocytes, in that neurons are recruited into astrocyte-initiated and propagated calcium waves, both in vitro and in situ. By this means, propagated shifts in cytosolic calcium within the astrocytic syncytium may regulate neuronal response and firing thresholds. In turn, astrocytes are actively modulated by neuronal activity, and the existence of astrocyte–neuron signaling loops has been established in several areas of the brain. As a result of these findings, it is now recognized that astrocytes play an active role in brain function, particularly within the highly coupled astrocytic syncytium of the neocortex and the hippocampus. The mechanisms by which calcium signaling is propagated and how it is evoked are the focus of intense research activity. It is known that gap junctions and the connexins, their constituent proteins, together with the local cytoskeleton, the calcium buffer capacity, and calcium waves triggered by purinergic transmitters, all cooperate to modulate astrocytic signaling to neighboring cells in young animals. What changes do astrocytes and their signaling machinery undergo during the aging process? This is a question of paramount importance; altered astrocytic dynamics in the aged brain may alter synaptic efficacy and neuronal survival and perhaps contribute to the cognitive decline observed during aging. In this review, we analyze our current understanding of astrocytic function during aging by reexamining the mechanisms by which astrocytes contribute to neuronal function and survival in normal brain and the changes they undergo in the aged brain.

Calcium Dysregulation in the Aging Brain

Abstract: The idea that age-related cognitive decline is associated with disruption of calcium (Ca2+) homeostasis has been investigated over the past two decades. Much of this work has focused on the hippocampus because hippocampal-dependent memory is age sensitive. It is now well established that Ca(2+)-dependent processes such as susceptibility to neurotoxicity, the afterhyperpolarization amplitude, induction of synaptic plasticity, and long-term potentiation and long-term depression are altered with age. Recent work has identified changes in Ca2+ signaling pathways that may underlie the development of these biological markers of aging. This review considers recent findings concerning interactions between the various Ca(2+)-dependent processes, with special emphasis on the role of altered Ca2+ regulation and disruption of Ca2+ signaling pathways in mediating the expression of biological and behavioral markers of brain aging.

DNA microarray analysis of the aging brain.

Abstract: To examine molecular events associated with brain aging and its retardation by caloric restriction (CR), we have employed high-density oligonucleotide arrays providing data on 6347 genes to define transcriptional patterns in two brain regions (cerebellum and neocortex). Male C57BL/6 mice were either fed normally or subjected to CR. To investigate aging, 5 month (young adult) and 30 month-old normally fed mice were compared. To study CR, 30 month-old control and CR mice were compared. In both brain regions, aging resulted in a gene expression profile suggestive of a marked inflammatory response, oxidative stress and reduced neuronal plasticity and neurotrophic support. In the brain, CR selectively attenuated the age-associated induction of genes encoding inflammatory and stress responses. In addition to providing an improved understanding of the aging process, the use of DNA microarrays generates panels of hundreds of transcriptional biomarkers of molecular aging, providing a new tool to measure biological age on a tissue-specific basis. These studies suggest that genomic approaches may be useful in understanding the molecular basis of the aging process in experimental animals.

Cerebrovascular Disease Is a Major Factor in the Failure of Elimination of Aβ from the Aging Human Brain

Abstract: Alzheimer's disease (AD) is characterized by the intracellular deposition of ubiquitinated tau and by the extracellular accumulation of soluble, insoluble, and fibrillary Abeta. Previous studies suggest that Abeta is normally eliminated from the brain along perivascular pathways that may become blocked in the aging brain, resulting in cerebral amyloid angiopathy. As age is a major risk factor for AD and for cerebrovascular disease (CVD), we test the hypothesis that CVD inhibits the elimination of Abeta from the aging human brain. Sections from 100 aged and AD brains were stained for Abeta by immunohistochemistry and by reticulin and Masson trichrome techniques. Early deposition of Abeta in brain parenchyma was related to individual arterial territories in the cortex. In areas of more extensive accumulation of Abeta, there was an inverse relationship between capillary amyloid angiopathy and plaques of Abeta. Thus, arterial territories with extensive capillary amyloid angiopathy were devoid of Abeta plaques, whereas in areas with abundant diffuse plaques there was no capillary amyloid angiopathy. Serial sections showed that cortical arteries feeding capillary beds with Abeta angiopathy were occluded by thrombus. We conclude that CVD inhibits the elimination of Abeta along capillary walls and changes the distribution of Abeta in the cerebral cortex. Loss of pulsations in thrombosed or arteriosclerotic arteries may thus abolish the motive force necessary for the drainage of Abeta and inhibit the elimination of Abeta. Therapies to increase elimination of Abeta in AD need to consider the effects of CVD on the elimination of Abeta from the aging human brain.

Glucocorticoids stimulate inflammatory 5-lipoxygenase gene expression and protein translocation in the brain.

Abstract: In the brain, the expression of 5-lipoxygenase (5-LO), the enzyme responsible for the synthesis of inflammatory leukotrienes, increases during aging. Antiinflammatory drugs are currently being evaluated for the treatment of aging-associated neurodegenerative diseases such as Alzheimer's disease. Although generally considered antiinflammatory, glucocorticoids, whose production also increases during aging, are not particularly effective in this disease. In human monocytes, 5-LO mRNA content increases on exposure to the synthetic glucocorticoid dexamethasone, which prompted us to hypothesize that glucocorticoids might increase 5-LO expression in the brain as well. We treated rats for 10 days either with corticosterone (implanted subcutaneously) or with dexamethasone (injected daily); they were killed on day 10 after pellet implantation or 24 h after the 10th dexamethasone injection. We found increased levels of 5-LO mRNA and protein in hippocampus and cerebellum of glucocorticoid-treated rats; 5-LO-activating protein (FLAP) mRNA content was not affected. Using western immunobloting, we also observed the concurrent translocation of 5-LO protein from cytosol to membrane, an indication of its activation. Thus, glucocorticoid-mediated up-regulation of the neuronal 5-LO pathway may contribute to rendering an aging brain vulnerable to degeneration.

Effect of aging on brain energy-metabolism.

Abstract: The aging process involves morphological and functional changes in cerebral vasculature and deterioration of mitochondrial number and function. Furthermore, slow oscillations of cerebral blood flow and oxidative metabolism occur in animals under different pathological conditions such as ischemia. The aim of this study was to evaluate the effect of aging on energy-metabolism of the rat brain during anoxia and normoxia and to further investigate the occurrence of oscillations under normoxia in the aging brain. Simultaneous hemodynamical (CBF), biochemical (NADH/NAD ratio) and electrical activity from the cerebral cortex were measured by means of a multiparametric assembly (MPA) system. Exposure of adult rats to anoxia (100% N2) resulted in a 36±2% elevation of NADH. Furthermore, exposure of the aged group to anoxia caused NADH elevation as low as 9.6±4% (P<0.05). The changes in the NADH levels were followed by an increase in CBF. In addition, during the normoxic periods, hemodynamic oscillations were recorded in the old animals. This study suggests that the structural and functional changes that occur in vessels in the aging brain cause disability of cerebromicrovessels to optimally deliver nutrients and oxygen to the brain, affecting the mitochondrial ability to respond to anoxia. Furthermore, this study supports the approach that the hemodynamic oscillations are related to the development of a pathological state and are not a normal cerebral function.

Intraneuronal amyloid precursor protein (APP) and appearance of extracellular β‐amyloid peptide (aβ) in the brain of aging kokanee salmon

Abstract: Antibodies to human amyloid precursor protein (APP(695)) and beta-amyloid peptide (A beta(1-42)) were used to determine timing of amyloidosis in the brain of kokanee salmon (Oncorhynchus nerka kennerlyi) in one of four reproductive stages: immature (IM), maturing (MA), sexually mature (SM), and spawning (SP), representing a range of aging from somatically mature but sexually immature to spawning and somatic senescence. In IM fish, immunoreactive (ir) intracellular APP occurred in 18 of 23 brain regions. During sexual maturation and aging, the number of neurons expressing APP increased in 11 of these APP-ir regions. A beta-ir was absent in IM fish, present in seven regions in MA fish, moderately abundant in 15 regions in SM fish, and was most abundant in all brain regions of SP fish exhibiting A beta-ir. Intracellular APP-ir was observed in brain regions involved in sensory integration, olfaction, vision, stress responses, reproduction, and coordination. Intra- and extracellular A beta(1-42) immunoreactivity (A beta-ir) was present in all APP-ir regions except the nucleus lateralis tuberis (hypothalamus) and Purkinje cells (cerebellum). APP-ir and A beta deposition increase during aging. APP-ir is present in IM fish; A beta-ir usually appears first in MA or SM fish and increases in SM fish as does APP-ir. Extracellular A beta deposition dramatically increases between SM and SP stages (1-2 weeks) in all fish, indicating an extremely rapid and synchronized process. Rapid senescence observed in pacific salmon could make them a useful model to investigate timing of amyloidosis and neurodegeneration during brain aging.

Diet - brain connections : impact on memory, mood, aging and disease

Abstract: Preface. 1. Prenatal Choline Supplementation Modifies Brain Development: Improved Cognition and Neuroprotection C. Williams, E. Mohler. 2. Diet and Mood D. Benton. 3. Dietary Fatty Acids and Cognitive Function S. Kalmijn. 4. Dietary Antioxidants and Synaptic Plasticity: Cellular and Molecular Mechanisms M. Lynch. 5. Increasing Brain Healthspan by Dietary Restriction M.P. Mattson, J. Lee. 6. Caloric Restriction Versus a Diet High in Antioxidants: Are They Equipotent in Altering or Reversing the Course of Aging? G. Casadesus, et al. 7. Dietary Folate, B Vitamins and The Brain: The Homocysteine Connection M.P. Mattson, et al. 8. Molecular Actions of Gingko Biloba Extract In Vivo and In Vitro: Global gene expression profiles reveal multiple molecular targets K. Gohil, L. Packer. 9. Creatine and Gingko Biloba Use in Sports and Health: A Knowledge Utilization Approach J.D. Geiger, et al. 10. Acetyl-L-Carnite in Mood, Aging and Disease J.W. Pettegrew, et al. 11. Effects of Phytoestrogens on Brain Chemistry, Structure and Cognition Yuanlong Pan. 12. Dietary Neurotoxins L.G. Costa, et al. 13. Dietary Anti-oxidants and the Risk for Brain Disease: The Hypothesis and Epidemiologic Evidence L.J. Launer. 14. Copper, Zinc and Alzheimer's Disease A.L. Friedlich, et al. 15. Ethanol Effects on Aging Brain J. Rintala, P. Jaatinen. Index.

Interactive report Age-related changes in GluR2 and NMDAR1 glutamate receptor subunit protein immunoreactivity in corticocortically projecting

Abstract: A distinct subpopulation of neurons forming long corticocortical projections in the association neocortex is highly vulnerable to the degenerative process in Alzheimer's disease. However, the degree to which age-related molecular and morphologic alterations of identifiable neuronal populations reflects early cellular degeneration leading to functional deficits has not yet been fully investigated in the aging brain. We performed an immunohistochemical analysis of neurons forming short and long corticocortical projections in young and old monkeys using antibodies to the GluR2 and NMDAR1 glutamate receptor subunit proteins. Projection neurons differed in their expression of these receptor subunits, as GluR2 was less prevalent than NMDAR1 among retrogradely labeled neurons. Long and short corticocortical pathways in old animals demonstrated a considerable decrease in the proportions of projection neurons containing GluR2 and NMDAR1, an observation that was particularly consistent in the case of GluR2. No age-related differences were observed in distribution of neurofilament protein in either type of projection neurons. These data suggest that cortical neurons furnishing long and short corticocortical projections display consistent neurochemical changes during aging and that a differential decrease in cellular expression of glutamate receptor subunit proteins occurs. The fact that in aging these neurons have lower levels of GluR2 than in young individuals, but comparatively higher levels of NMDAR1 than GluR2, may render them prone to calcium-mediated excitotoxicity, which in humans may be related to the selective vulnerability of such neurons during the course of Alzheimer's disease. Also, it is apparent that age-related neuronal changes are quite subtle and involve subcellular components of the cortical circuits rather than major morphologic alterations. © 2002 Elsevier Science B.V. All rights reserved.

Effects of Estrogens and Thyroid Hormone on Development and Aging of Astrocytes and Oligodendrocytes

Abstract: The regulatory role of hormones and growth factors on glial cell development has been demonstrated in several studies (1–3) Hormones also influence the aging of glial cells and their role in the aging brain (4) In early reports, the gliosis that occurred in the brain of aged animals consisted primarily of astrocytes and oligodendrocytes and was interpreted as a compensatory response to the diminishing structural integrity and functional competence of neurons and their increasing pathology (5,6) The stimulatory effects of thyroid hormones on development and adult function of glial cells are numerous and well established (4,7) Endocrine-glia interactions may support normal function of neurons and repair damage of central nervous system (CNS) regions The current view is that neurons may regenerate not only during development but also in adulthood, and not only in laboratory animals but also in humans (8-10) The “post-developmental” CNS may not be “as hostile an environment for the regeneration of neuronal networks as once believed” (10) and it may be induced to regenerate by internal influences (8) As glial cells are an important component of the neuronal microenvironment, they may represent a key factor for CNS repair after injury or in prevention and treatment of neurodegenerative diseases

Ethanol Effects on Aging Brain

Abstract: Research on the acute and chronic effects of ethanol in the aging brain is becoming increasingly important, because the number of people reaching old age is growing dramatically. While the deleterious effects of chronic, heavy ethanol consumption on the brain of middle-aged (male) persons are fairly well-characterized, the effects of ethanol consumption on the brain in aged individuals deserve to be more thoroughly clarified. This review will summarize available data on the effects of ethanol on the aging brain, in terms of structural changes and structure-function relationships. The relevance of these changes to cognition and dementia will be discussed together with the potential strategies to prevent and treat the harmful consequences of ethanol in the aging brain.