Showing papers on "Aging brain published in 2008"

The Aging Brain

Abstract: Aging is accompanied by cognitive decline in a major segment of the population and is the primary risk factor for Alzheimer's disease and other prevalent neurodegenerative disorders. Despite this central role in disease pathogenesis and morbidity, the aging of the brain has not been well understood at a molecular level. This review seeks to integrate what is known about age-related cognitive and neuroanatomical changes with recent advances in understanding basic molecular mechanisms that underlie aging. An important issue is how normal brain aging transitions to pathological aging, giving rise to neurodegenerative disorders. Toxic protein aggregates have been identified as potential contributory factors, including amyloid β-protein in Alzheimer's disease, tau in frontotemporal dementia, and α-synuclein in Parkinson's disease. However, current models of pathogenesis do not explain the origin of the common sporadic forms of these diseases or address the critical nexus between aging and disease. This review ...

Training-Induced Brain Structure Changes in the Elderly

Abstract: It has been suggested that learning is associated with a transient and highly selective increase in brain gray matter in healthy young volunteers. It is not clear whether and to what extent the aging brain is still able to exhibit such structural plasticity. We built on our original study, now focusing on healthy senior citizens. We observed that elderly persons were able to learn three-ball cascade juggling, but with less proficiency compared with 20-year-old adolescents. Similar to the young group, gray-matter changes in the older brain related to skill acquisition were observed in area hMT/V5 (middle temporal area of the visual cortex). In addition, elderly volunteers who learned to juggle showed transient increases in gray matter in the hippocampus on the left side and in the nucleus accumbens bilaterally.

Evolution of the Aging Brain Transcriptome and Synaptic Regulation

Abstract: Alzheimer's disease and other neurodegenerative disorders of aging are characterized by clinical and pathological features that are relatively specific to humans. To obtain greater insight into how brain aging has evolved, we compared age-related gene expression changes in the cortex of humans, rhesus macaques, and mice on a genome-wide scale. A small subset of gene expression changes are conserved in all three species, including robust age-dependent upregulation of the neuroprotective gene apolipoprotein D (APOD) and downregulation of the synaptic cAMP signaling gene calcium/calmodulin-dependent protein kinase IV (CAMK4). However, analysis of gene ontology and cell type localization shows that humans and rhesus macaques have diverged from mice due to a dramatic increase in age-dependent repression of neuronal genes. Many of these age-regulated neuronal genes are associated with synaptic function. Notably, genes associated with GABA-ergic inhibitory function are robustly age-downregulated in humans but not in mice at the level of both mRNA and protein. Gene downregulation was not associated with overall neuronal or synaptic loss. Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes.

Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress.

Abstract: The aging brain is characterized by a shift from the homeostatic balance of inflammatory mediators to a proinflammatory state. This increase in neuroinflammation is marked by increased numbers of activated and primed microglia, increased steady-state levels of inflammatory cytokines and decreases in anti-inflammatory molecules. These conditions sensitize the aged brain to produce an exaggerated response to the presence of an immune stimulus in the periphery or following exposure to a stressor. In the brain, proinflammatory cytokines can have profound effects on behavioral and neural processes. As the aged brain is primed to respond to inflammatory stimuli, infection or stress may produce more severe detriments in cognitive function in the aged. Typically after an immune stimulus, aged animals display prolonged sickness behaviors, increased cytokine induction and greater cognitive impairments compared to adults. Additionally, aging can also augment the central response to stressors leading to exaggerated cytokine induction and increased decrements in learning and memory. This alteration in neuroinflammation and resultant sensitization to extrinsic and intrinsic stressors can have considerable effects upon the elderly's recovery and coping during disease and stress.

Cellular stress response: a novel target for chemoprevention and nutritional neuroprotection in aging, neurodegenerative disorders and longevity

Abstract: The predominant molecular symptom of aging is the accumulation of altered gene products. Moreover, several conditions including protein, lipid or glucose oxidation disrupt redox homeostasis and lead to accumulation of unfolded or misfolded proteins in the aging brain. Alzheimer’s and Parkinson’s diseases or Friedreich ataxia are neurological diseases sharing, as a common denominator, production of abnormal proteins, mitochondrial dysfunction and oxidative stress, which contribute to the pathogenesis of these so called “protein conformational diseases”. The central nervous system has evolved the conserved mechanism of unfolded protein response to cope with the accumulation of misfolded proteins. As one of the main intracellular redox systems involved in neuroprotection, the vitagene system is emerging as a neurohormetic potential target for novel cytoprotective interventions. Vitagenes encode for cytoprotective heat shock proteins (Hsp) Hsp70 and heme oxygenase-1, as well as thioredoxin reductase and sirtuins. Nutritional studies show that ageing in animals can be significantly influenced by dietary restriction. Thus, the impact of dietary factors on health and longevity is an increasingly appreciated area of research. Reducing energy intake by controlled caloric restriction or intermittent fasting increases lifespan and protects various tissues against disease. Genetics has revealed that ageing may be controlled by changes in intracellular NAD/NADH ratio regulating sirtuin, a group of proteins linked to aging, metabolism and stress tolerance in several organisms. Recent findings suggest that several phytochemicals exhibit biphasic dose responses on cells with low doses activating signaling pathways that result in increased expression of vitagenes encoding survival proteins, as in the case of the Keap1/Nrf2/ARE pathway activated by curcumin and NAD/NADH-sirtuin-1 activated by resveratrol. Consistently, the neuroprotective roles of dietary antioxidants including curcumin, acetyl-l-carnitine and carnosine have been demonstrated through the activation of these redox-sensitive intracellular pathways. Although the notion that stress proteins are neuroprotective is broadly accepted, still much work needs to be done in order to associate neuroprotection with specific pattern of stress responses. In this review the importance of vitagenes in the cellular stress response and the potential use of dietary antioxidants in the prevention and treatment of neurodegenerative disorders is discussed.

Docosahexaenoic Acid and the Aging Brain

Abstract: The dietary essential PUFA docosahexaenoic acid [DHA; 22:6(n-3)] is a critical contributor to cell structure and function in the nervous system, and deficits in DHA abundance are associated with cognitive decline during aging and in neurodegenerative disease. Recent studies underscore the importance of DHA-derived neuroprotectin D1 (NPD1) in the homeostatic regulation of brain cell survival and repair involving neurotrophic, antiapoptotic and antiinflammatory signaling. Emerging evidence suggests that NPD1 synthesis is activated by growth factors and neurotrophins. Evolving research indicates that NPD1 has important determinant and regulatory interactions with the molecular-genetic mechanisms affecting beta-amyloid precursor protein (betaAPP) and amyloid beta (Abeta) peptide neurobiology. Deficits in DHA or its peroxidation appear to contribute to inflammatory signaling, apoptosis, and neuronal dysfunction in Alzheimer disease (AD), a common and progressive age-related neurological disorder unique to structures and processes of the human brain. This article briefly reviews our current understanding of the interactions of DHA and NPD1 on betaAPP processing and Abeta peptide signaling and how this contributes to oxidative and pathogenic processes characteristic of aging and AD pathology.

Berry fruit supplementation and the aging brain.

Abstract: The onset of age-related neurodegenerative diseases such as Alzheimer's or Parkinson's disease, superimposed on a declining nervous system, could exacerbate the motor and cognitive behavioral deficits that normally occur in senescence. In cases of severe deficits in memory or motor function, hospitalization and/or custodial care would be a likely outcome. This means that unless some way is found to reduce these age-related decrements in neuronal function, health-care costs will continue to rise exponentially. Thus, it is extremely important to explore methods to retard or reverse age-related neuronal deficits, as well as their subsequent behavioral manifestations, to increase healthy aging. In this regard, consumption of diets rich in antioxidants and anti-inflammatory polyphenolics, such as those found in fruits and vegetables, may lower the risk of developing age-related neurodegenerative diseases. Research suggests that the polyphenolic compounds found in berry fruits, such as blueberries and strawberries, may exert their beneficial effects either through their ability to lower oxidative stress and inflammation or directly by altering the signaling involved in neuronal communication, calcium buffering ability, neuroprotective stress shock proteins, plasticity, and stress signaling pathways. These interventions, in turn, may exert protection against age-related deficits in cognitive and motor function. The purpose of this paper is to discuss the benefits of these interventions in rodent models and to describe the putative molecular mechanisms involved in their benefits.

Apolipoprotein D is involved in the mechanisms regulating protection from oxidative stress.

Abstract: Many nervous system pathologies are associated with increased levels of apolipoprotein D (ApoD), a lipocalin also expressed during normal development and aging. An ApoD homologous gene in Drosophila, Glial Lazarillo, regulates resistance to stress, and neurodegeneration in the aging brain. Here we study for the first time the protective potential of ApoD in a vertebrate model organism. Loss of mouse ApoD function increases the sensitivity to oxidative stress and the levels of brain lipid peroxidation, and impairs locomotor and learning abilities. Human ApoD overexpression in the mouse brain produces opposite effects, increasing survival and preventing the raise of brain lipid peroxides after oxidant treatment. These observations, together with its transcriptional up-regulation in the brain upon oxidative insult, identify ApoD as an acute response protein with a protective and therefore beneficial function mediated by the control of peroxidated lipids.

Preservation of neuronal number despite age-related cortical brain atrophy in elderly subjects without Alzheimer disease.

Abstract: Cerebral volume loss has long been associated with normal aging, but whether this is due to aging itself or to age-related diseases, including incipient Alzheimer disease, is uncertain. To understand the changes that occur in the aging brain, we examined the cerebral cortex of 27 normal individuals ranging in age from 56 to 103 years. None fulfilled the criteria for the neuropathologic diagnosis of Alzheimer disease or other neurodegenerative disease. Seventeen of the elderly participants had cognitive testing an average of 6.7 months prior to death. We used quantitative approaches to analyze cortical thickness, neuronal number, and density. Frontal and temporal neocortical regions had clear evidence of cortical thinning with age, but total neuronal numbers in frontal and temporal neocortical regions remained relatively constant during a 50-year age range. These data suggest that loss of neuronal and dendritic architecture, rather than loss of neurons, underlies neocortical volume loss with increasing age in the absence of Alzheimer disease.

Vascular risk factors and Alzheimer’s disease

Abstract: Vascular cognitive impairment risk factors include stroke, hypertension, diabetes and atherosclerosis. In the elderly, vascular risk factors occur in the presence of high levels of amyloid in the aging brain. Stroke alters the clinical expression of a given load of Alzheimer's disease (AD) pathology. Experimentally, large vessel infarcts or small striatal infarcts are larger in the presence of amyloid. Patients with minor cerebral infarcts and moderate AD lesions will develop the clinical manifestations of dementia. Moreover, there is also an association between other vascular risk factors and the clinical expression of cognitive decline and dementia. The risk of AD is increased in subjects with adult-onset diabetes mellitus, hypertension, atherosclerotic disease and atrial fibrillation. Experimentally, small striatal infarcts in the presence of high levels of amyloid in the brain exhibit a progression in infarct size over time with enhanced degree of cognitive impairment, AD-type pathology and neuroinflammation compared with striatal infarcts or high amyloid levels alone.

Neurogenesis in the aging brain.

Abstract: Neurogenesis, or the birth of new neural cells, was thought to occur only in the developing nervous system and a fixed neuronal population in the adult brain was believed to be necessary to maintain the functional stability of adult brain circuitry. However, recent studies have demonstrated that neurogenesis does indeed continue into and throughout adult life in discrete regions of the central nervous systems (CNS) of all mammals, including humans. Although neurogenesis may contribute to the ability of the adult brain to function normally and be induced in response to cerebral diseases for self-repair, this nevertheless declines with advancing age. Understanding the basic biology of neural stem cells and the molecular and cellular regulation mechanisms of neurogenesis in young and aged brain will allow us to modulate cell replacement processes in the adult brain for the maintenance of healthy brain tissues and for repair of disease states in the elderly.

Effect of aging on neurogenesis in the canine brain.

Abstract: An age-dependent decline in hippocampal neurogenesis has been reported in laboratory rodents. Environmental enrichment proved to be a strong trigger of neurogenesis in young and aged laboratory rodents, which are generally kept in facilities with a paucity of environmental stimuli. These data raise the question whether an age-dependent decline in hippocampal cell proliferation and neurogenesis can also be observed in individuals exposed to diversified and varying surroundings. Therefore, we determined rates of canine hippocampal neurogenesis using post-mortem tissue from 37 nonlaboratory dogs that were exposed to a variety of environmental conditions throughout their life. Expression of the neuronal progenitor cell marker doublecortin clearly correlated with age. The analysis of doublecortin-labeled cells in dogs aged > 133 months indicated a 96% drop in the aged canine brain as compared to young adults. Expression of the proliferation marker Ki-67 in the subgranular zone decreased until dogs were aged 85-132 months. In the aging canine brain amyloid-beta peptide deposits have been described that might resemble an early pathophysiological change in the course of human Alzheimer's disease. Comparison of Ki-67 and doublecortin expression in canine brain tissue with or without diffuse plaques revealed no differences. The data indicate that occurrence of diffuse plaques in the aging brain is not sufficient to trigger enhanced proliferation or enhanced neurogenesis such as described in human Alzheimer's disease. In addition, this study gives first proof that an age-dependent decline also dominates hippocampal neurogenesis rates in individuals living in diversified environments.

Diffusion tensor imaging investigations in Alzheimer's disease: the resurgence of white matter compromise in the cortical dysfunction of the aging brain.

Abstract: Diffusion tensor imaging (DTI) is a sophisticated MRI-based neuroimaging technique that enables in vivo quantification of differences in molecular diffusion at the cellular level. Owing to the highly directional architecture of white matter (WM), DTI is providing important clues of the structure and geometric organization of this neural compartment. Since DTI can detect changes even in the case of radiologically “normal” appearing WM, researchers are using the technique for the study of WM integrity at the initial stages of the most common neurodegenerative disorders. Along with a well characterized cortical pathology (neuritic plaques and intracellular neurofibrillary tangles), WM changes have been also demonstrated in Alzheimer’s disease (AD). However, these changes had been for years found nonliable in the onset and progress of AD, basically due to lack of incriminatory evidence. The use of novel tools such as DTI has enabled the anatomical distribution of WM microstructural damage in the prodromal stages of AD to be gauged and determined, granting a long-delayed protagonic role to WM in the natural history of this highly prevalent neurodegenerative condition.

(n-6) and (n-3) Polyunsaturated Fatty Acids and the Aging Brain: Food for Thought

Abstract: Over the last decade, the role of dietary PUFA in growth, development, and cognitive function in the infant has been a topic at numerous national and international meetings. Only recently has the role of PUFA been more seriously examined as they relate to the aging brain. In fact, a search of the literature reveals very few randomized control trials exploring this research area. However, the literature reveals growing mechanistic evidence that cognitive function of the aging brain can be preserved, or loss of function can be diminished with docosahexaenoic acid, a long-chain (n-3) PUFA. Furthermore, no symposia have taken a serious look at the impact of (n-6) PUFA on the brain, in particular arachidonic acid (AA), the most highly concentrated (n-6) PUFA in the brain. This symposium explores the role of AA metabolism in the brain as it relates to neurological mood disorders. To that end, this symposium was designed to highlight the potential effects of dietary PUFA on the adult brain, an important issue given the growing elderly population in this country and the growing problems with neurological disorders (dementia, Alzheimer disease, Parkinson disease, bipolar disorders, etc.).

Emerging concepts of how β-amyloid proteins and pro-inflammatory cytokines might collaborate to produce an 'Alzheimer brain' (Review).

Abstract: Three steps lead to the development of full-blown sporadic or late-onset Alzheimer's disease or dementia (AD). In the young brain, amyloid β-(1-42) (Aβ 42) is a normal aggregation-prone protein product of neuronal activity that is kept at a safe low level by proteolysis in neurons and glial cells, and by expulsion across the blood-brain barrier. But clearance declines with advancing age. Step 1: Because of the normal decline with age of the Aβ 42-clearing mechanisms, toxic amyloid-derived diffusible ligands (ADDLs) made of dodecamers of the aggregation-prone Aβ 42 start accumulating. These Aβ 42 dodecamers selectively target the initially huge numbers of excitatory synapses of neurons and cause them to start slowly dropping, which increasingly impairs plasticity and sooner or later starts noticeably affecting memory formation. At a certain point, this increasing loss of synapses induces the neurons to redirect their still-expressed cell cycle proteins from post-mitotic jobs, such as maintaining synapses, to starting a cell cycle and partially or completely replicating DNA without entering mitosis. The resulting aneuploid or tetraploid neurons survive for as long as 6-12 months as quasi-functional 'undead zombies', with developing tangles of hyperphosphorylated τ protein disrupting the vital anterograde axonal transport of mitochondria and other synapse-vital components. Step 2: The hallmark AD plaques appear as Aβ 42 clearance continues to decline and the formation of Aβ 42 non-diffusible fibrils begins in the aging brain. Step 3: A terminal cytokine-driven maelstrom begins in the aging brain when microglia, the brain's professional macrophages, are activated in and around the plaques. They produce pro-inflammatory cytokines, such as IFN-γ, IL-1β and TNF-α. One of these, IFN-γ, causes the astrocytes enwrapping the neuronal synapses to express their β-secretase (BACE1) genes and produce and release Aβ 42, which can kill the closely apposed neurons by binding to their p75NTR receptors, which generate apoptogenic signals. Astrocytes are also stimulated by the same cytokines to turn on their nitric oxide synthase (NOS)-2 genes and start pouring large amounts of nitric oxide (NO) and its cytocidal derivative peroxynitrite (ONOO-) directly out onto the closely apposed neurons.

Neurosonology: a means of evaluating normal aging versus dementia

Abstract: The aging of the population and higher life expectancy have led to an increase in the incidence of cognitive changes and dementia. It is important to differentiate between cognitive changes associated with normal aging and those associated with dementia. Dementia is a syndrome caused by a heterogeneous group of disorders, the most common being Alzheimer’s disease and vascular dementia. While cardiovascular risk factors, such as diabetes mellitus, hypertension, hypercholesterolemia, atrial fibrillation and smoking, are particularly relevant in the development of vascular dementia, they may also play a role in Alzheimer’s disease. The control of these risk factors at an early stage may help to delay the onset and reduce the severity of vasculopathy. Cognitive changes and vasculopathy are correlated with decreased mean blood flow velocities in the main arteries of the brain. Intracranial hemodynamics of the aging brain can sucessfully be assessed by a number of methods, including transcranial Doppler sonogra...

D-aspartate exerts an opposing role upon age-dependent NMDAR-related synaptic plasticity and memory decay

Abstract: In the present study, we demonstrated that D-aspartate acts as an _in vitro_ and _in vivo_ neuromodulatory molecule upon hippocampal NMDAR transmission. Accordingly, we showed that this D-amino acid, widely expressed during embryonic phase, was able to strongly influence hippocampus-related functions at adulthood. Thus, while up-regulated levels of D-aspartate increased LTP and spatial memory in four-month old adult mice, the prolonged deregulation of this molecule in thirteen-month old animals induced a substantial acceleration of age-dependent decay of synaptic plasticity and cognitive functions. Moreover, we highlighted a role for D-aspartate in enhancing NMDAR-dependent synaptic plasticity through an inducible "turn-on/turn-off-like mechanism". Strikingly, we also showed that D-aspartate, when administered to aged mice, strongly rescued their physiological synaptic decay and attenuated their cognitive deterioration. In conclusion, our data suggest a tantalizing hypothesis for which this in-embryo-occurring D-amino acid, might disclose plasticity windows in the aging brain.

Cognition and Aging : Typical Development

Abstract: Declining cognitive functions are a normal and inevitable part of healthy aging. Some changes may stem from global alterations in brain functions, including metabolic changes; others may result from localized decline of specific neural circuits. Current research on cognitive aging aims not only to identify the mechanisms that underlie cognitive change, but also to understand and harness the genetic, experiential and environmental factors that promote the preservation of cognitive abilities. Recent technological advances are leading to new breakthroughs in cognitive aging research, while also posing new challenges to understand the relation between genetic, anatomical, physiological, and cognitive factors and to integrate these levels of analysis. Moreover, the availability of high-resolution neuroimaging methods is revising our perspective on aging and giving way to new ideas about the aging mind and brain. We now know that the aging brain is not simply a depleted and reduced version of the younger brain. Instead, recent cognitive neuroscience evidence points to patterns of preservation and decline, along with functional reorganization and plasticity.