Showing papers on "Aging brain published in 2005"
TL;DR: Evidence of oxidative stress in aging brain, some of the most important neurodegenerative diseases, and in two common and highly disabling vascular pathologies--stroke and cardiac failure are reviewed.
633 citations
TL;DR: Exposure to lead and monitored the lifetime expression of the APP gene suggested that environmental influences occurring during brain development predetermined the expression and regulation of APP later in life, potentially altering the course of amyloidogenesis.
Abstract: The fetal basis of adult disease (FeBAD) hypothesis states that many adult diseases have a fetal origin. According to FeBAD, injury or environmental influences occurring at critical periods of organ development could result in “programmatic” changes via alterations in gene expression or gene imprinting that may result in functional deficits that become apparent later in life. Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by excessive deposits of aggregated β-amyloid (Aβ) peptides, which are snippets of the β-amyloid precursor protein (APP). The predominately sporadic nature of AD suggests that the environment must play a role in neurodegeneration. To examine latent responses to an environmental agent, we exposed rodents to lead and monitored the lifetime expression of the APP gene. We observed that APP mRNA expression was transiently induced in neonates, but exhibited a delayed overexpression 20 months after exposure to Pb had ceased. This upregulation in APP mRNA expression was commensurate with a rise in activity of the transcription factor Sp1, one of the regulators of the APP gene. Furthermore, the increase in APP gene expression in old age was accompanied by an elevation in APP and its amyloidogenic Aβ product. In contrast, APP expression, Sp1 activity, as well as APP and Aβ protein levels were unresponsive to Pb exposure during old age. These data suggested that environmental influences occurring during brain development predetermined the expression and regulation of APP later in life, potentially altering the course of amyloidogenesis.
341 citations
TL;DR: A larger waist-hip ratio may be related to neurodegenerative, vascular, or metabolic processes that affect brain structures underlying cognitive decline and dementia.
Abstract: Background Central adiposity as an indicator of visceral fat is linked to vascular and metabolic factors that in turn are related to cognitive decline and dementia. Objective To determine whether larger waist-hip ratio (WHR) is associated with structural brain changes that underlie cognitive decline and dementia. Design Cross-sectional analysis of an epidemiologic cohort study of cognitive and functional decline (Sacramento Area Latino Study on Aging). Setting California Central Valley. Participants A total of 112 individuals selected from an ongoing cohort study of 1789 older Latino individuals. Baseline anthropomorphic measures (WHR) and measurements of fasting blood glucose, cholesterol, and insulin levels and blood pressure were obtained. Main Outcome Measures Baseline magnetic resonance images were analyzed quantitatively to determine the hippocampal volumes in the right and left hemispheres and rated for the percentage of white matter hyperintensities. Results Greater WHR ( P = .02) and older age ( P P = .02 and P = .001, respectively). A 1-SD increase in WHR was associated with a 0.2-SD decrease in hippocampal volume and a 27% increase in white matter hyperintensities. These relationships were not affected by adjustment for body mass index, total cholesterol, fasting blood glucose, and insulin levels or systolic blood pressure in the models. Conclusion A larger WHR may be related to neurodegenerative, vascular, or metabolic processes that affect brain structures underlying cognitive decline and dementia.
286 citations
TL;DR: In rodents, long-term growth hormone/IGF-1 replacement improves learning and memory in aged rats and offers valuable insight into the influence of growth hormone and IGF-1 on neuronal events in the aged mammal.
239 citations
01 Jan 2005
192 citations
TL;DR: A 60% increase in the amount of more acidic isoforms of GFAP was observed in AD and these isoforms were both phosphorylated and N-glycosylated, while more basic isoforms exhibited no quantitative differences between post-mortem AD and control brains.
118 citations
TL;DR: Advances in in-vivo imaging methods are providing the tools for identifying different trajectories of neurocognitive aging, and knowledge about these brain changes may promote opportunities for treatment.
Abstract: Purpose of review Recent research has revealed that the population of older adults is composed not only of individuals who are either healthy or have an age-related disease, most commonly Alzheimer's disease, but also individuals with mild cognitive impairment who are at-risk for or already in the prodromal stage of Alzheimer's disease. These variations in cognitive aging can be related to their neural bases via structural and functional neuroimaging methods. Recent findings Healthy aging appears to primarily affect a frontal-striatal system that undergirds executive control of cognition, while minimally affecting medial temporal lobe structures. Functional imaging studies suggest that enhanced prefrontal engagement may offer compensatory plasticity that minimizes age-related cognitive losses. Mild cognitive impairment appears to affect the entorhinal cortex in particular, with functional consequences in other brain regions. Alzheimer's disease is characterized by severe hippocampal injury, although early-stage Alzheimer's disease may relatively spare some cortical regions. Summary Advances in in-vivo imaging methods are providing the tools for identifying different trajectories of neurocognitive aging, and knowledge about these brain changes may promote opportunities for treatment.
95 citations
Journal Article•
TL;DR: Several reports support the concept that flavonoid intake inhibits certain biochemical processes of brain aging, and might thus prevent to some extent the decline of cognitive functions with aging as well as the development or the course of neurodegenerative diseases.
Abstract: Like in all other organs, the functional capacity of the human brain deteriorates over time. Pathological events such as oxidative stress, due to the elevated release of free radicals and reactive oxygen or nitrogen species, the subsequently enhanced oxidative modification of lipids, protein, and nucleic acids, and the modulation of apoptotic signaling pathways contribute to loss of brain function. The identification of neuroprotective food components is one strategy to facilitate healthy brain aging. Flavonoids were shown to activate key enzymes in mitochondrial respiration and to protect neuronal cells by acting as antioxidants, thus breaking the vicious cycle of oxidative stress and tissue damage. Furthermore, recent data indicate a favorable effect of flavonoids on neuro-inflammatory events. Whereas most of these effects have been shown in vitro, limited data in vivo are available, suggesting a rather low penetration of flavonoids into the brain. Nevertheless, several reports support the concept that flavonoid intake inhibits certain biochemical processes of brain aging, and might thus prevent to some extent the decline of cognitive functions with aging as well as the development or the course of neurodegenerative diseases. However, more data are needed to assess the true impact of flavonoids on brain aging.
92 citations
TL;DR: Observed signs of oxidative stress and neuropathological aging in brains from 400-d-old Igf1-/- and wild-type (WT) mice indicate that IGF-I has a major role in regulating tau phosphorylation in the aging brain, whereas its role in promoting or preventing oxidative stress remains uncertain.
Abstract: IGF action has been implicated in the promotion of oxidative stress and aging in invertebrate and murine models. However, some in vitro models suggest that IGF-I specifically prevents neuronal oxidative damage. To investigate whether IGF-I promotes or retards brain aging, we evaluated signs of oxidative stress and neuropathological aging in brains from 400-d-old Igf1-/- and wild-type (WT) mice. Lipofuscin pigment accumulation reflects oxidative stress and aging, but we found no difference in lipofuscin deposition in Igf1-/- and WT brains. Likewise, there was no apparent difference in accumulation of nitrotyrosine residues in Igf1-/- and WT brains, except for layer IV/V of the cerebral cortex, where these proteins were about 20% higher in the Igf1-/- brain (P = 0.03). We found no difference in the levels of oxidative stress-related enzymes, neuronal nitric oxide synthase, inducible nitric oxide synthase, and superoxide dismutase in Igf1-/- and WT brains. Tau is a microtubule-associated protein that causes the formation of neurofibrillary tangles and senile plaques as it becomes hyperphosphorylated in the aging brain. Tau phosphorylation was dramatically increased on two specific residues, Ser-396 and Ser-202, both glycogen synthase kinases target sites implicated in neurodegeneration. These observations indicate that IGF-I has a major role in regulating tau phosphorylation in the aging brain, whereas its role in promoting or preventing oxidative stress remains uncertain.
91 citations
TL;DR: Evidence for the developmental basis of neurodegeneration is presented and mechanisms that may explain how perturbations during development can have long-term or delayed consequences in the aging brain are discussed.
Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose clinical manifestations appear in old age. The hallmark pathological features of AD (amyloid plaques and associated proteins) are present in normal aging indivduals, suggesting that AD may result from the acceleration of normal age-related processes in the brain. The sporadic nature of most AD cases strongly argues for an environmental link that may drive AD pathogenesis; however, it is unclear when this environmental stress may occur. Therefore it is important to identify an environmental trigger(s) and to pinpoint the period during which such factors pose the greatest risk. Recently, we reported that developmental exposure of rats to the xenobiotic metal lead (Pb) resulted in a delayed overexpression (20 months later) of the amyloid precursor protein (APP) and its amyloidogenic Abeta product. Similarly, aged monkeys exposed to Pb as infants also responded in the same way. These data suggest that environmental influences occurring during brain development predetermine the expression and regulation of APP later in life, potentially influencing the course of amyloidogenesis, and argue for both an environmental trigger and a developmental origin of AD. In this review, we present evidence for the developmental basis of neurodegeneration and discuss mechanisms that may explain how perturbations during development can have long-term or delayed consequences in the aging brain.
76 citations
01 Jan 2005
TL;DR: Since approximately half of the elderly population exhibits only negligible brain alterations, MR imaging may facilitate the distinction between usual (no neurologic dysfunction) and successful (no brain or vascular changes) aging.
Abstract: A thorough knowledge of the normal changes that occur in the brain with age is critical before abnormal findings are analyzed. Magnetic resonance (MR) imaging improves the ability to distinguish normal and abnormal findings in the brain. The major changes that may occur in elderly individuals without neurologic deficits include enlargement of the ventricles, cortical sulci, and vermian subarachnoid spaces; multifocal areas of hyperintensity in the white matter and basal ganglia; a progressive prominence of hypointensity on T2-weighted images of the putamen, almost equal to that of the globus pallidus; an increase in the oxygen extraction ratio with normal or mildly decreased neuron metabolism; arteriosclerosis in large and small arteries and amyloid angiopathy in leptomeningeal cortical vessels; and decreased dopamine receptor binding in the corpus striatum. Since approximately half of the elderly population exhibits only negligible brain alterations, MR imaging may facilitate the distinction between usual (no neurologic dysfunction) and successful (no brain or vascular changes) aging.
TL;DR: A clinical model, “the cognitive reserve hypothesis,” proposes that both increased brain volume and enhanced cognitive ability may contribute to healthy brain aging, reducing the likelihood of developing dementia.
Abstract: Compared to other primates, humans live a long time and have large brains. Recent theories of the evolution of human life history stages (grandmother hypothesis, intergenerational transfer of information) lend credence to the notion that selection for increased life span and menopause has occurred in hominid evolution, despite the reduction in the force of natural selection operating on older, especially post-reproductive, individuals. Theories that posit the importance (in an inclusive fitness sense) of the survival of older individuals require them to maintain a reasonably high level of cognitive function (e.g., memory, communication). Patterns of brain aging and factors associated with healthy brain aging should be relevant to this issue. Recent neuroimaging research suggests that, in healthy aging, human brain volume (gray and white matter) is well-maintained until at least 60 years of age; cognitive function also shows only nonsignificant declines at this age. The maintenance of brain volume and cognitive performance is consistent with the idea of a significant post- or late-reproductive life history stage. A clinical model, "the cognitive reserve hypothesis," proposes that both increased brain volume and enhanced cognitive ability may contribute to healthy brain aging, reducing the likelihood of developing dementia. Selection for increased brain size and increased cognitive ability in hominid evolution may therefore have been important in selection for increased lifespan in the context of intergenerational social support networks.
TL;DR: These findings imply that the role of neurogenesis might change between youth and old age, and that further work is needed to understand the potential benefits and liabilities that new neurons may afford an aging brain.
Abstract: A reduction in the ability to generate new neurons in the brain has been suggested to contribute to cognitive decline with advanced age. In an outbred model strain of Long-Evans rats, cognitive performance as a function of age is variable in assessments of hippocampal-dependent spatial memory. Recent research indicates that greater hippocampal neurogenesis accompanies diminished cognitive abilities in older Long-Evans rats. These findings imply that the role of neurogenesis might change between youth and old age, and that further work is needed to understand the potential benefits and liabilities that new neurons may afford an aging brain.
TL;DR: It is proposed that certain cholinesterase inhibitors and the NMDA partial antagonist memantine, which are FDA‐approved drugs for AD and useful to boost central nervous system functioning, can be made more effective by their combination with melatonin or other neuroprotectants.
Abstract: The aging brain shows selective neurochemical changes involving several neural cell populations. Increased brain metal levels have been associated with normal aging and a variety of diseases, including Alzheimer's disease (AD). Melatonin levels are decreased in aging, particularly in AD subjects. The loss of melatonin, which is synthesized by the pineal gland, together with the degeneration of cholinergic neurons of the basal forebrain and the deposition of aggregated proteins, such as the amyloid beta peptides (Abeta), are believed to contribute to the development of cognitive symptoms of dementia. Aging and its variants, such as AD, should be viewed as the result of multiple "hits," including alterations in the levels of Abeta, metals, cholinesterase enzymes, and neuronal gene expression. Herein, we present evidence in support of this theory, based on several studies. We discuss melatonin's neuroprotective function, which plays an important role in aging, prolongation of life span, and health in the aged individual. It interacts with metals and, in some cases, neutralizes their toxic effects. Dietary supplementation of melatonin restores its age-related loss. In mice, an elevated brain melatonin significantly reduced levels of potentially toxic Abeta peptides. Thus, compensation of melatonin loss in aging by dietary supplementation could well be beneficial in terms of reducing metal-induced toxicity, lipid peroxidation, and losses in cholinergic signaling. We propose that certain cholinesterase inhibitors and the NMDA partial antagonist memantine, which are FDA-approved drugs for AD and useful to boost central nervous system functioning, can be made more effective by their combination with melatonin or other neuroprotectants. Herein, we highlight studies elucidating the role of the amyloid pathway, metals, melatonin, and the cholinergic system in the context of aging and AD. Finally, melatonin is present in edible plants and walnuts, and consuming foodstuffs containing melatonin would be beneficial by enhancing the antioxidative capacity of the organisms.
TL;DR: The results suggest that the odor evoked response of the brain is significantly reduced in amplitude and delayed in its latency in normally aging persons and dramatically more delayed in Alzheimer’s patients, confirming the importance of considering a central origin for the olfactory loss associated with aging and AD.
Abstract: More than 14 million Americans over 50 suffer from smell impairment (Murphy et al., 2002). In a series of studies we have sought the underlying cortical substrates of olfactory loss with aging. We used psychophysical, neuropsychological, event related potentials (ERPs) and functional magnetic resonance imaging (fMRI) techniques to address the problem. Psychophysical investigations have revealed significant losses in olfactory threshold sensitivity, odor identification and odor memory. These impairments are significantly worse in patients with neurodegenerative diseases such as Alzheimer’s disease (AD) (Murphy, 2002). The earliest lesions of AD are in the mesial temporal regions of the brain critical to olfactory processing, thus the potential exists for reflection of incipient disease in olfactory tasks. The investigation of olfactory function in aging and AD is of basic science interest and may contribute to the development of more sensitive diagnostic batteries for AD (Murphy, 2002). ERPs provide real-time temporal information about the brain’s response to odor stimulation. We have used this technique to investigate brain response over the lifespan in the normally aging brain (Murphy et al., 2000) and in patients with neurodegenerative diseases such as Alzheimer’s disease (Morgan and Murphy, 2002). The results suggest that the odor evoked response of the brain is significantly reduced in amplitude and delayed in its latency in normally aging persons and dramatically more delayed in Alzheimer’s patients. These results confirm the importance of considering a central origin for the olfactory loss associated with aging and AD. fMRI is a powerful tool for investigation of brain structure and of functional activation in specific regions of interest (ROIs). We have used fMRI to investigate the cortical substrate of olfactory impairment in the elderly. The fMRI data were analyzed with individual, group and ROI analyses. Results are described in Cerf-Ducastel and Murphy (2003), Ferdon and Murphy (2003) and Wiser et al. (2000). Older adults showed less activation in important olfactory ROIs: entorhinal cortex, amygdala, insula and piriform cortex. Cerebellar activation was lower in areas Crus I and II. A number of approaches have been taken to achieve an understanding of integrated brain activity. Functional connectivity involves correlation between fMRI activity in two brain regions during performance of a task. The technique permits testing the hypothesis that interacting brain regions, rather than isolated regions of interest, are the cortical substrate for performance. We have approached functional connectivity with more than one analysis strategy. Calhoun-Haney et al. (2004) used the seed voxel method to examine correlations between individual voxels in hippocampus and in ROIs for olfactory processing during an olfactory task. A number of investigators have conducted connectivity analysis on regional brain activation using correlational methods (Horwitz, 1989). Here we aimed to identify significant correlations in fMRI activation among ROIs for olfactory tasks and to test the hypothesis that the pattern of correlations among these regions is significantly impacted by aging. Activity was correlated separately for young adults, older adults and AD patients.
TL;DR: The goal of these studies is to apply functional genomics and proteomics approaches to aging research to develop new tools to assess age in cell- and tissue-specific manners in order to develop aging biomarkers for pharmacotherapeutic interventions and disease prevention.
TL;DR: Overall, the two tasks activate diverse regions within the frontal, temporal and occipital lobes of the brain, including areas that show age-related structural changes, proving their usefulness in the longitudinal assessment of brain function in the elderly.
TL;DR: Dietary n−3 FA may not oppose the physiological decrease in brain plasmalogen levels during aging and α-LNA appears to be equally as potent as preformed DHA at replacing DHA in the brain of the authors' rat model.
Abstract: The aging brain undergoes modifications in the lipid composition of cell membranes and especially in plasmalogens. These phospholipids represent between one-half and twothirds of the ethanolamine phospholipids in the brain. They are known to facilitate membrane fusion and act as endogenous antioxidants. During normal aging and in some pathological conditions, plasmalogen and DHA levels fall. In this context, we aimed to evaluate the influence of n−3 FA intake on plasmalogens in the brain during aging. Littermates from two generations of n−3-deficient rats were fed an n−3-deficient diet or an equilibrated diet containing either α-linolenic acid alone (α-LNA) or with two doses of DHA (0.3 or 0.6% w/w). After weaning, 9 mon of diet, or 21 mon of diet, plasmalogen levels were assessed, and the sn-2 substitutions of plasmenylethanolamines were analyzed in the cortex, striatum, and hippocampus. Our results showed that plasmalogen contents were not influenced by the diet. Plasmalogen levels were significantly decreased in aged rats compared with adults, whereas DHA levels increased in the hippocampus and remained stable in the cortex and striatum. DHA levels were significantly and similarly increased in total phospholipids and especially in plasmenylethanolamines after 9 mon of diet containing α-LNA alone or combined with DHA. This study showed that each structure sustained specific age-induced modifications. Dietary n−3 FA may not oppose the physiological decrease in brain plasmalogen levels during aging. Moreover, α-LNA appears to be equally as potent as preformed DHA at replacing DHA in the brain of our rat model.
TL;DR: It is suggested that hormone replacement therapy may either reduce or delay the onset of age related diseases like Alzheimer’s, Parkinson's and other neurological disorders.
Abstract: Aging of the normal brain is accompanied by changes in its structure, function, and metabolism. There are significant gender differences in aging brain. Most of these changes increase during menopausal condition in females when the level of estradiol and progesterone are decreased. The objective of this study was to determine the effect of estradiol and progesterone (separate as well as combined) hormones in neuronal tissues from naturally menopausal rats of different age groups. Results show decreased activity of Acetylcholine esterase (AChE) whereas the level of lipid peroxidation increased with age, and after the hormone treatments both AChE activity and level of lipid peroxidation returned to control values. The deposition of lipofuscin, a pigment that accumulated intraneuronally in brain and other tissues and is considered a marker of aging, was increased with aging and the hormone treatment decreased this deposition. The present study clearly shows reduction in risk factors associated with aging in the murine model system by hormone treatments, namely estrogen and progesterone by increasing the activity of acetylcholine esterase and decreasing the levels of lipid peroxidation and lipofuscin deposition in different parts of aging brain. This study suggests that hormone replacement therapy may either reduce or delay the onset of age related diseases like Alzheimer's, Parkinson's and other neurological disorders.
TL;DR: Findings from long-term treatment with the Ca2+-blocker nimodipine, or from housing animals under enriched environmental conditions to ameliorate aging effects were described, suggesting that age-related changes can be reversed by short periods of training and stimulation schedules even if they have developed.
Abstract: Aging comprises many physiological modifications, including structural and metabolic changes, yet little is known about how aging affects the way in which neurons process and integrate sensory information from the environments. Here the framework of “modified use” as a determinant of cortical reorganization was applied for the investigation of age-related modifications of cortical maps and processing, and of associated changes of behavior. The age-related changes of walking behavior in rats were contrasted with the parallel changes of sensorimotor processing developing at the cortical level. Based on the regional specificity of these changes attempts are made to separate age-related changes arising as a consequence of degeneration from a result of adaptable processes following reduced use at high age. Finally, findings from long-term treatment with the Ca2+-blocker nimodipine, or from housing animals under enriched environmental conditions to ameliorate aging effects were described. Combined, these results show the general treatability of age-related changes. The data imply that age-related changes can be reversed by short periods of training and stimulation schedules even if they have developed. Clearly, the development of specific measures to delay aging processes and to rehabilitate aged brains depends on future progress in understanding mechanisms and effects of aging.
TL;DR: ICH causes more severe brain swelling and neurological deficits in aged rats and Clarification of the mechanisms of brain injury after ICH in the aging brain should help develop new therapeutic strategies for hemorrhagic brain injury.
Abstract: Age is an important factor affecting oxidative stress and plasticity after brain injury. The present study investigated the effects of aging on brain injury after intracerebral hemorrhage (ICH). Aging (18- month) and young (3-month) male Sprague-Dawley rats received an intracerebral infusion of 100-µl autologous blood. Age-related changes in brain edema and neurological deficits were examined and heat shock protein 27 (HSP27) and heat shock protein 32 (HSP32) levels were determined by Western blotting. Perihematomal brain swelling was more severe in aged rats compared to young rats at three days after ICH (P < 0.05). The behavioral tests used were forelimb placing test and forelimb use asymmetry test. There were more severe neurological deficits and a slower recovery in aged rats compared to those in young rats after ICH (P < 0.05). In addition, perihematomal HSP27 and HSP32 protein levels were higher (p < 0.05) in aged rats. In conclusion, ICH causes more severe brain swelling and neurological deficits in aged rats. Clarification of the mechanisms of brain injury after ICH in the aging brain should help develop new therapeutic strategies for hemorrhagic brain injury.
TL;DR: It is indicated that cytochrome oxidase activity is regulated regionally in the brain, as well as focally, and that differences in regional regulation may contribute to variation in CO activity among individuals, which was greater in young and old rats than in middle-aged animals.