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Methods for Improving Neuroplasticity and Memory Function in the Aging or Compromised Brain
Abstract
The role of neuroplasticity, or the brain’s ability to modify neural processes as a result of environmental changes, is crucial to normal memory functioning. Furthermore, this capacity of the central nervous system to adapt is essential for healthy aging and for recovery following trauma or disease states. In this chapter, we identify the synaptic and structural mechanisms that drive plasticity, as well as describe the purported processes responsible for short- and long-term memory. We then review the literature regarding the role of neuroplasticity in the aging brain and in recovery following various types of injury (e.g., traumatic brain injury and stroke). Particular focus is placed on the implications of lifestyle factors, such as diet, exercise, and environmental enrichment, and formal cognitive training or rehabilitation strategies as potential methods for facilitating neuroplasticity and maintaining healthy memory functioning.
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The mammalian hippocampus is crucial for episodic memory formation and transiently retains information for about 3-4 weeks in adult mice and longer in humans. Although neuroscientists widely believe that neural synapses are elemental sites of information storage, there has been no direct evidence that hippocampal synapses persist for time intervals commensurate with the duration of hippocampal-dependent memory. Here we tested the prediction that the lifetimes of hippocampal synapses match the longevity of hippocampal memory. By using time-lapse two-photon microendoscopy in the CA1 hippocampal area of live mice, we monitored the turnover dynamics of the pyramidal neurons' basal dendritic spines, postsynaptic structures whose turnover dynamics are thought to reflect those of excitatory synaptic connections. Strikingly, CA1 spine turnover dynamics differed sharply from those seen previously in the neocortex. Mathematical modelling revealed that the data best matched kinetic models with a single population of spines with a mean lifetime of approximately 1-2 weeks. This implies ∼100% turnover in ∼2-3 times this interval, a near full erasure of the synaptic connectivity pattern. Although N-methyl-d-aspartate (NMDA) receptor blockade stabilizes spines in the neocortex, in CA1 it transiently increased the rate of spine loss and thus lowered spine density. These results reveal that adult neocortical and hippocampal pyramidal neurons have divergent patterns of spine regulation and quantitatively support the idea that the transience of hippocampal-dependent memory directly reflects the turnover dynamics of hippocampal synapses.
The influence of music on the human brain has been recently investigated in numerous studies. Several investigations have shown that structural and functional cerebral neuroplastic processes emerge as a result of long-term musical training, which in turn may produce cognitive differences between musicians and non-musicians. Musicians can be considered ideal cases for studies on brain adaptation, due to their unique and intensive training experiences. This article presents a review of recent findings showing positive effects of musical training on non-musical cognitive abilities, which probably reflect plastic changes in brains of musicians. Treinamento musical, neuroplasticidade e cognição Resumo – A influência da música no cérebro humano tem sido alvo de vários estudos nos últimos anos. Muitos trabalhos têm demonstrado que processos neuroplásticos estruturais e funcionais surgem no cérebro como resultado de treinamento musical prolongado, os quais podem produzir diferenças cognitivas entre músicos e não-músicos. Os músicos podem ser considerados como casos ideais para investigações relacionadas à adaptação cerebral, devido às suas experiências únicas e intensivas de treinamento. Este artigo apresenta uma revisão das recentes descobertas que mostram efeitos positivos do treinamento musical em capacidades cognitivas não-musicais, o que poderia refletir a ocorrência de alterações plásticas nos cérebros de músicos. Palavras-chave: treinamento musical, neuroplasticidade, capacidades cognitivas.
Aerobic exercise may be a catalyst to promote neuroplasticity and recovery following stroke; however, the optimal methods to measure neuroplasticity and the effects of training parameters have not been fully elucidated. We conducted a systematic review and synthesis of clinical trials and studies in animal models to determine (1) the extent to which aerobic exercise influences poststroke markers of neuroplasticity, (2) the optimal parameters of exercise required to induce beneficial effects, and (3) consistent outcomes in animal models that could help inform the design of future trials. Synthesized findings show that forced exercise at moderate to high intensity increases brain-derived neurotrophic factor (BDNF), insulin-like growth factor-I (IGF-I), nerve growth factor (NGF), and synaptogenesis in multiple brain regions. Dendritic branching was most responsive to moderate rather than intense training. Disparity between clinical stroke and stroke models (timing of initiation of exercise, age, gender) and clinically viable methods to measure neuroplasticity are some of the areas that should be addressed in future research.
Memory dysfunction is a common complaint following heart surgery and may be related to a diffuse ischemic state induced by microemboli dislodged during the procedure. Ischemia can induce damage by a number of mechanisms, including oxidative stress. Because pomegranates contain a variety of polyphenols with antioxidant and other potentially beneficial effects, we tested whether supplementation with a pomegranate extract before and after heart surgery could protect against postoperative cognitive dysfunction. Patients undergoing elective coronary artery bypass graft and/or valve surgery were given either 2 g of pomegranate extract (in 2 POMx pills) or placebo (pills containing no pomegranate ingredients) per day from one week before surgery to 6 weeks after surgery. The patients were also administered a battery of neuropsychological tests to assess memory function at 1 week before surgery (baseline), 2 weeks after surgery, and 6 weeks after surgery. The placebo group had significant deficits in postsurgery memory retention, and the pomegranate treatment not only protected against this effect, but also actually improved memory retention performance for up to 6 weeks after surgery as compared to presurgery baseline performance.
This study explores the effective outcomes of a structured cognitive stimulation treatment to improve cognition and behavioral symptoms in people with dementia (PWDs), using a randomized controlled clinical trial.
THIRTY PWDS WERE DIVIDED INTO THREE GROUPS: experimental (treated with cognitive stimulation), placebo (treated with occupational therapy), and control (continuing with the usual activities of the nursing home). Assessment, at baseline and after a period of 8 weeks, was performed using the Clinical Dementia Rating Scale, activities of daily living, Mini-Mental State Examination, Esame Neuropsicologico Breve 2, Geriatric Depression Scale and Behavioral Pathology in Alzheimer's Disease Scale.
Only the experimental group improved its performance in cognitive tests (p < 0.05) and showed a significant decrease in behavioral symptoms (p < 0.01) after the treatment.
The results suggest that a cognitive stimulation treatment for PWDs would improve not only their cognition, but also behavioral symptoms.
It remains unsettled whether human language relies exclusively on innately privileged brain structure in the left hemisphere or is more flexibly shaped through experiences, which induce neuroplastic changes in potentially relevant neural circuits. Here we show that learning of second language (L2) vocabulary and its cessation can induce bidirectional changes in the mirror-reverse of the traditional language areas. A cross-sectional study identified that gray matter volume in the inferior frontal gyrus pars opercularis (IFGop) and connectivity of the IFGop with the caudate nucleus and the superior temporal gyrus/supramarginal (STG/SMG), predominantly in the right hemisphere, were positively correlated with L2 vocabulary competence. We then implemented a cohort study involving 16 weeks of L2 training in university students. Brain structure before training did not predict the later gain in L2 ability. However, training intervention did increase IFGop volume and reorganization of white matter including the IFGop-caudate and IFGop-STG/SMG pathways in the right hemisphere. These "positive" plastic changes were correlated with the gain in L2 ability in the trained group but were not observed in the control group. We propose that the right hemispheric network can be reorganized into language-related areas through use-dependent plasticity in young adults, reflecting a repertoire of flexible reorganization of the neural substrates responding to linguistic experiences.
Metabolic syndrome has become an epidemic and poses tremendous burden on the health system. People with metabolic syndrome are more likely to experience cognitive decline. As obesity and sedentary lifestyles become more common, the development of early prevention strategies is critical. In this study, we explore the potential beneficial effects of a combinatory polyphenol preparation composed of grape seed extract, Concord purple grape juice extract, and resveratrol, referred to as standardized grape polyphenol preparation (SGP), on peripheral as well as brain dysfunction induced by metabolic syndrome.
We found dietary fat content had minimal effect on absorption of metabolites of major polyphenols derived from SGP. Using a diet-induced animal model of metabolic syndrome (DIM), we found that brain functional connectivity and synaptic plasticity are compromised in the DIM mice. Treatment with SGP not only prevented peripheral metabolic abnormality but also improved brain synaptic plasticity.
Our study demonstrated that SGP, comprised of multiple bioavailable and bioactive components targeting a wide range of metabolic syndrome related pathological features, provides greater global protection against peripheral and central nervous system dysfunctions and can be potentially developed as a novel prevention/treatment for improving brain connectivity and synaptic plasticity important for learning and memory.
Twenty years ago, the prevalent view in Psychology was that although learning and the formation of new memories are lifelong occurrences, the neural changes associated with these events were all in the existing receptors. No new neural hardware, from synapses to neurons, was thought to appear after a protracted period early in life. In the past 20years, another view has supplanted this one, showing that although the juvenile period is especially suited to neuroplastic adaptation, there is hard neuroplastic change later in life as well. We review a selection of evidence for this view from both animal and human models, showing how it reflects three principles of neuroplasticity: (1) earlier and later experience-induced changes to neuroarchitecture differ in degree more so than in type; (2) the types of experiences that lead to neuroplastic change narrow with age; and (3) differences in the amenability of neural circuitry to change result from basic differences in neuroarchitecture and neuroenvironment in different phases of development.
The literature examining the relationship between cardiorespiratory fitness and the brain in older adults has increased rapidly, with 30 of 34 studies published since 2008. Here we review cross-sectional and exercise intervention studies in older adults examining the relationship between cardiorespiratory fitness and brain structure and function, typically assessed using Magnetic Resonance Imaging (MRI). Studies of patients with Alzheimer's disease are discussed when available. The structural MRI studies revealed a consistent positive relationship between cardiorespiratory fitness and brain volume in cortical regions including anterior cingulate, lateral prefrontal, and lateral parietal cortex. Support for a positive relationship between cardiorespiratory fitness and medial temporal lobe volume was less consistent, although evident when a region-of-interest approach was implemented. In fMRI studies, cardiorespiratory fitness in older adults was associated with activation in similar regions as those identified in the structural studies, including anterior cingulate, lateral prefrontal, and lateral parietal cortex, despite heterogeneity among the functional tasks implemented. This comprehensive review highlights the overlap in brain regions showing a positive relationship with cardiorespiratory fitness in both structural and functional imaging modalities. The findings suggest that aerobic exercise and cardiorespiratory fitness contribute to healthy brain aging, although additional studies in Alzheimer's disease are needed.
In a multicenter European approach, the efficacy of the AIXTENT computerized training programs for intensity aspects (alertness and vigilance) and selectivity aspects (selective and divided attention) of attention was studied in 33 patients with brain damage of vascular and traumatic etiology. Each patient received training in one of two most impaired of the four attention domains. Control tests were performed by means of a standardized computerized attention test battery (TAP) comprising tests for the four attention functions. Assessment was carried out at the beginning and at the end of a four week baseline period and after the training period of 14 one-hour sessions. At the end of the baseline phase, there was only slight but significant improvement for the most complex attention function, divided attention (number of omissions). After the training, there were significant specific training effects for both intensity aspects (alertness and vigilance) and also for the number of omissions in the divided attention task. The application of inferential single case procedures revealed a high number of significant improvements in individual cases after specific training of alertness and vigilance problems. On the other hand, a non specific training addressing selectivity aspects of attention lead either to improvement or deterioration of alertness and vigilance performance. The results corroborate the findings of former studies with the same training instrument but in patients with different lesion etiologies.
In the brains of adult vertebrates, including humans, neurogenesis occurs in restricted niches where it maintains cellular turnover and cognitive plasticity. In virtually all species, however, aging is associated with a significant decline in adult neurogenesis. Moreover, an acceleration of neurogenic defects is observed in models of Alzheimer's disease and other neurodegenerative diseases, suggesting an involvement in aging- and disease-associated cognitive deficits. To gain insights into when, how and why adult neurogenesis decreases in the aging brain, we critically reviewed the scientific literature on aging of the rodent subventricular zone, the neurogenic niche of the adult forebrain. Our analysis revealed that deficits in the neurogenic pathway are largely established by middle age, but that there remains striking ambiguity in the underlying mechanisms, especially at the level of stem and progenitor cells. We identify and discuss several challenging issues that have contributed to these key gaps in our current knowledge. In the future, addressing these issues should help untangle the interactions between neurogenesis, aging and aging-associated diseases.
Recent studies suggest that working memory training may benefit older adults; however, findings regarding training and transfer effects are mixed. The current study aimed to investigate the effects of a process-based training intervention in a diverse sample of older adults and explored possible moderators of training and transfer effects. For that purpose, 80 older adults (65-95 years) were assigned either to a training group that worked on visuospatial, verbal, and executive working memory tasks for 9 sessions over 3 weeks or to a control group. Performance on trained and transfer tasks was assessed in all participants before and after the training period, as well as at a 9-month follow-up. Analyses revealed significant training effects in all 3 training tasks in trained participants relative to controls, as well as near transfer to a verbal working memory task and far transfer to a fluid intelligence task. Encouragingly, all training effects and the transfer effect to verbal working memory were stable at the 9-month follow-up session. Further analyses revealed that training gains were predicted by baseline performance in training tasks and (to a lesser degree) by age. Gains in transfer tasks were predicted by age and by the amount of improvement in the trained tasks. These findings suggest that cognitive plasticity is preserved over a large range of old age and that even a rather short training regime can lead to (partly specific) training and transfer effects. However, baseline performance, age, and training gains moderate the amount of plasticity. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
Cerebral aging is a complex and heterogenous process related to a large variety of molecular changes involving multiple neuronal networks, due to alterations of neurons (synapses, axons, dendrites, etc), particularly affecting strategically important regions, such as hippocampus and prefrontal areas. A substantial proportion of nondemented, cognitively unimpaired elderly subjects show at least mild to moderate, and rarely even severe, Alzheimer-related lesions, probably representing asymptomatic preclinical Alzheimer's disease, and/or mixed pathologies. While the substrate of resilience to cognitive decline in the presence of abundant pathologies has been unclear, recent research has strengthened the concept of cognitive or brain reserve, based on neuroplasticity or the ability of the brain to manage or counteract age-related changes or pathologies by reorganizing its structure, connections, and functions via complex molecular pathways and mechanisms that are becoming increasingly better understood. Part of neuroplasticity is adult neurogenesis in specific areas of the brain, in particular the hippocampal formation important for memory function, the decline of which is common even in “healthy” aging. To obtain further insights into the mechanisms of brain plasticity and adult neurogenesis, as the basis for prevention and potential therapeutic options, is a major challenge of modern neurosciences.
The purpose of this study was to quantitatively combine and examine the results of studies pertaining to physical activity and cognition in children. Studies meeting the inclusion criteria were coded based on design and descriptive characteristics, subject characteristics, activity characteristics, and cognitive assessment method. Effect sizes (ESs) were calculated for each study and an overall ES and average ESs relative to moderator variables were then calculated. ESs (n = 125) from 44 studies were included in the analysis. The overall ES was 0.32 (SD = 0.27), which was significantly different from zero. Significant moderator variables included publication status, subject age, and type of cognitive assessment. As a result of this statistical review of the literature, it is concluded that there is a significant positive relationship between physical activity and cognitive functioning in children.
During aging, sensorimotor, cognitive and physical performance decline, but can improve by training and exercise indicating that age-related changes are treatable. Dancing is increasingly used as an intervention because it combines many diverse features making it a promising neuroplasticity-inducing tool. We here investigated the effects of a 6-month dance class (1 h/week) on a group of healthy elderly individuals compared to a matched control group (CG). We performed a broad assessment covering cognition, intelligence, attention, reaction time, motor, tactile, and postural performance, as well as subjective well-being and cardio-respiratory performance. After 6 months, in the CG no changes, or further degradation of performance was found. In the dance group, beneficial effects were found for dance-related parameters such as posture and reaction times, but also for cognitive, tactile, motor performance, and subjective well-being. These effects developed without alterations in the cardio-respiratory performance. Correlation of baseline performance with the improvement following intervention revealed that those individuals, who benefitted most from the intervention, were those who showed the lowest performance prior to the intervention. Our findings corroborate previous observations that dancing evokes widespread positive effects. The pre-post design used in the present study implies that the efficacy of dance is most likely not based on a selection bias of particularly gifted individuals. The lack of changes of cardio-respiratory fitness indicates that even moderate levels of physical activity can in combination with rich sensorimotor, cognitive, social, and emotional challenges act to ameliorate a wide spectrum of age-related decline.
Conducted 2 studies, involving a total of 460 adults between 18 and 87 yrs of age, to determine which of several hypothesized processing components was most responsible for age-related declines in working memory functioning. Significant negative correlations between age and measures of working memory (i.e., from –.39 to –.52) were found in both studies, and these relations were substantially attenuated by partialing measures hypothesized to reflect storage capacity, processing efficiency, coordination effectiveness, and simple comparison speed. Because the greatest attenuation of the age relations occurred with measures of simple processing speed, it was suggested that many of the age differences in working memory may be mediated by age-related reductions in the speed of executing elementary operations. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Information about the temporal and spatial context of events has been postulated by Hasher and Zacks in 1979 to accumulate in memory via processes that are relatively unaffected by subject variables like age and ability, or task variables such as instructions or practice. These "automatic" processes have been distinguished from "effortful" processes, which are affected by these variables. To evaluate these predictions, we tested memory for temporal order and spatial position in groups of young adults recovering from traumatic brain injuries, normal elderly, and normal young adults, using a design that allowed examination of the effects of practice and instructions. Our results indicate that both traumatic brain injury and aging reduce performance on tasks tapping retention of temporal and spatial information if the subject is asked for a relatively precise estimate of the requested information. These effects tend to disappear when estimation tasks are designed, or errors are analyzed, in a way that allows subjects full credit for only partial information about an item's temporospatial context of presentation. The presence of these task and analysis effects that can eliminate existing differences, calls for reevaluation of those studies in which Hasher and Zacks' criteria for automaticity were satisfied.
(C) Lippincott-Raven Publishers.
A systematic review to examine the efficacy of computer-based cognitive interventions for cognitively healthy older adults was conducted. Studies were included if they met the following criteria: average sample age of at least 55 years at time of training; participants did not have Alzheimer's disease or mild cognitive impairment; and the study measured cognitive outcomes as a result of training. Theoretical articles, review articles, and book chapters that did not include original data were excluded. We identified 151 studies published between 1984 and 2011, of which 38 met inclusion criteria and were further classified into three groups by the type of computerized program used: classic cognitive training tasks, neuropsychological software, and video games. Reported pre-post training effect sizes for intervention groups ranged from 0.06 to 6.32 for classic cognitive training interventions, 0.19 to 7.14 for neuropsychological software interventions, and 0.09 to 1.70 for video game interventions. Most studies reported older adults did not need to be technologically savvy in order to successfully complete or benefit from training. Overall, findings are comparable or better than those from reviews of more traditional, paper-and-pencil cognitive training approaches suggesting that computerized training is an effective, less labor intensive alternative.
Experiential factors shape the neural circuits underlying social and emotional behavior from the prenatal period to the end of life. These factors include both incidental influences, such as early adversity, and intentional influences that can be produced in humans through specific interventions designed to promote prosocial behavior and well-being. Here we review important extant evidence in animal models and humans. Although the precise mechanisms of plasticity are still not fully understood, moderate to severe stress appears to increase the growth of several sectors of the amygdala, whereas the effects in the hippocampus and prefrontal cortex tend to be opposite. Structural and functional changes in the brain have been observed with cognitive therapy and certain forms of meditation and lead to the suggestion that well-being and other prosocial characteristics might be enhanced through training.
Increasing evidence shows the positive effect of physical activity (PA) on maintaining cognitive function. Both processes seem intrinsically linked to each other. The most likely mechanism is a reciprocal stimulation of neuroplasticity. Based on extensive experimental work on animals and humans, the concept of an enriched environment, including PA and challenging cognitive tasks, has provided the basis to systematically assess possible interventions for successful aging. I will use recent findings on brain mechanisms associated with PA and its effects on higher cognitive function at a systems and molecular level to demonstrate the need to design effective interventions. Such interventions should be designed to take advantage of the presumed compensatory mechanisms of elderly individuals, thereby limiting functional decline in higher cognitive performance in aging people. My review of the most recent relevant publications concerning this topic supports the notion that it is a promising approach to provide cognitive training and PA in conjunction, since the combination may generate synergistic beneficial changes than either one individually. Multimodal training programs should therefore be tested. However, at present there is insufficient evidence to conclude that multimodal interventions are superior to isolated cognitive or physical exercise interventions, since major studies addressing this topic are lacking. These studies are needed to conclusively prove that both strategies will positively interact when used in combined interventions. Finally the use of modern technology for these interventions will be discussed.
This chapter presents an overview of cognitive training, including classroom-based programs, peer-led courses, computerized brain fitness tools, and apps for smart phones. The chapter also discusses the relevance of these programs for various populations, including normal aging, mild cognitive impairment (MCI), and persons with dementia (e.g., Alzheimer’s disease), along with the transferability and long-term impact of these training modalities.
Stress is an adaptive response to demands of the environment and thus essential for survival. Exposure to stress triggers hypothalamic-pituitary-adrenocortical (HPA) axis activation and associated neurochemical reactions, following glucocorticoid release from the adrenal glands, accompanied by rapid physiological responses. Stimulation of this pathway results in the activation of specific brain regions, including hippocampus, amygdala and prefrontal cortex which are enriched with glucocorticoid receptors (GRs). Recent findings indicate that the activation of GRs mediates the regulation of the brain-derived neurotrophic factor (BDNF). BDNF is crucial for neural plasticity, as it promotes cellular growth and synaptic changes. Hence stress-induced activation of these pathways leads to neuroplastic changes, including the formation of long-lasting memories of the experiences. As a consequence, organisms can learn from stressful events and respond in an adaptive manner to similar demands in the future. Whereas an optimal stress level leads to enhancement of memory performance, the exposure to extreme, traumatic or chronic stressors is a risk factor for psychopathologies which are associated with memory impairment and cognitive deficits such as post traumatic stress disorder (PTSD). In this review article, we will outline the implications of stress exposure on memory formation involving the role of glucocorticoids and BDNF. Within this context, potential adverse effects of neuroplastic alterations will be discussed using the example of PTSD.
The brain has an extraordinary ability to functionally and physically change or reconfigure its structure in response to environmental stimulus, cognitive demand, or behavioral experience. This property, known as neuroplasticity, has been examined extensively in many domains. But how does neuroplasticity occur in the brain as a function of an individual's experience with a second language? It is not until recently that we have gained some understanding of this question by examining the anatomical changes as well as functional neural patterns that are induced by the learning and use of multiple languages. In this article we review emerging evidence regarding how structural neuroplasticity occurs in the brain as a result of one’s bilingual experience. Our review aims at identifying the processes and mechanisms that drive experience-dependent anatomical changes, and integrating structural imaging data with current knowledge of functional neural plasticity of language and other cognitive skills. The evidence reviewed so far portrays a picture that is highly consistent with structural neuroplasticity observed for other domains: second language experience-induced brain changes, including increased gray matter density and white matter integrity, can be found in children, young adults, and the elderly; can occur rapidly with short-term language learning or training; and are sensitive to age, age of acquisition, proficiency or performance level, language-specific characteristics, and individual differences. We conclude with a theoretical perspective on neuroplasticity in language and bilingualism, and point to future directions for research.
This study was set up to evaluate the efficacy of a memory training programme in a group of stroke patients. Berg, Koning-Haanstra, and Deelman (1991) developed a training procedure which successfully improved the memory performance of a group of closed head injury patients. The training programme consists of six simple memory strategies, which are applied to daily memory problems that are selected with the patient. Two groups of stroke patients with demonstrable memory deficits were randomly assigned to the training programme or a non-specific training programme involving repetitive practice on memory tasks. After a four week training period retesting showed a significant improvement of the trained memory skills, but there was no improvement on control memory tasks. Subjective ratings of everyday memory functioning did not differ between the two groups.
Neurogenesis, a process of generation of new neurons, is reported to be reduced in several neurodegenerative disorders including Alzheimer's disease (AD). Induction of neurogenesis by targeting endogenous neural stem cells (NSC) could be a promising therapeutic approach to such diseases by influencing the brain self-regenerative capacity. Curcumin, a neuroprotective agent, has poor brain bioavailability. Herein, we report that curcumin-encapsulated PLGA nanoparticles (Cur-PLGA-NPs) potently induce NSC proliferation and neuronal differentiation in vitro and in the hippocampus and subventricular zone of adult rats, as compared to uncoated bulk curcumin. Cur-PLGA-NPs induce neurogenesis by internalization into the hippocampal NSC. Cur-PLGA-NPs significantly increase expression of genes involved in cell proliferation (reelin, nestin, and Pax6) and neuronal differentiation (neurogenin, neuroD1, neuregulin, neuroligin, and Stat3). Curcumin nanoparticles increase neuronal differentiation by activating the Wnt/β-catenin pathway, involved in regulation of neurogenesis. These nanoparticles caused enhanced nuclear translocation of β-catenin, decreased GSK-3β levels, and increased promoter activity of the TCF/LEF and cyclin-D1. Pharmacological and siRNA-mediated genetic inhibition of the Wnt pathway blocked neurogenesis-stimulating effects of curcumin. These nanoparticles reverse learning and memory impairments in an amyloid beta induced rat model of AD-like phenotypes, by inducing neurogenesis. In silico molecular docking studies suggest that curcumin interacts with Wif-1, Dkk, and GSK-3β. These results suggest that curcumin nanoparticles induce adult neurogenesis through activation of the canonical Wnt/β-catenin pathway and may offer a therapeutic approach to treating neurodegenerative diseases such as AD, by enhancing a brain self-repair mechanism.
Cognitive impairments, and particularly memory deficits, are a defining feature of the early stages of Alzheimer's disease and vascular dementia. Interventions that target these cognitive deficits and the associated difficulties with activities of daily living are the subject of ever-growing interest. Cognitive training and cognitive rehabilitation are specific forms of non-pharmacological intervention to address cognitive and non-cognitive outcomes. The present review is an abridged version of a Cochrane Review and aims to systematically evaluate the evidence for these forms of intervention in people with mild Alzheimer's disease or vascular dementia. Randomized controlled trials (RCTs), published in English, comparing cognitive rehabilitation or cognitive training interventions with control conditions and reporting relevant outcomes for the person with dementia or the family caregiver (or both), were considered for inclusion. Eleven RCTs reporting cognitive training interventions were included in the review. A large number of measures were used in the different studies, and meta-analysis could be conducted for several primary and secondary outcomes of interest. Several outcomes were not measured in any of the studies. Overall estimates of the treatment effect were calculated by using a fixed-effects model, and statistical heterogeneity was measured by using a standard chi-squared statistic. One RCT of cognitive rehabilitation was identified, allowing the examination of effect sizes, but no meta-analysis could be conducted. Cognitive training was not associated with positive or negative effects in relation to any of the reported outcomes. The overall quality of the trials was low to moderate. The single RCT of cognitive rehabilitation found promising results in relation to some patient and caregiver outcomes and was generally of high quality. The available evidence regarding cognitive training remains limited, and the quality of the evidence needs to improve. However, there is still no indication of any significant benefits from cognitive training. Trial reports indicate that some gains resulting from intervention may not be captured adequately by available standardized outcome measures. The results of the single RCT of cognitive rehabilitation show promise but are preliminary in nature. Further well-designed studies of cognitive training and cognitive rehabilitation are required to provide more definitive evidence. Researchers should describe and classify their interventions appropriately by using the available terminology.
Neurodegenerative diseases pose a significant problem for the healthcare system, doctors, and patients. With an aging population, more and more individuals are developing neurodegenerative diseases and there are few treatment options at the present time. Meditation techniques present an interesting potential adjuvant treatment for patients with neurodegenerative diseases and have the advantage of being inexpensive, and easy to teach and perform. There is increasing research evidence to support the application of meditation techniques to help improve cognition and memory in patients with neurodegenerative diseases. This review discusses the current data on meditation, memory, and attention, and the potential applications of meditation techniques in patients with neurodegenerative diseases.
USING two-site enzyme immunoassays (EIAs), we measured the levels of neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) simultaneously in three brain regions (motor cortex, dentate gyrus and entorhinal cortex) of patients with Alzheimer's disease (AD) and control individuals. Significant differences between the neurotrophin levels of these two groups were found in the different brain regions depending on the neurotrophin. The NGF level in the dentate gyrus of AD patients was higher, whereas the BDNF level in the entorhinal cortex and the NT-3 level in the motor cortex were lower than the corresponding control levels. These results indicate that protein levels of individual neurotrophins in different brain regions are affected differently by AD, and such differential changes may contribute to the complex pathology of AD.
This review presents some of the current research and thinking regarding the neuropsychological features associated with aging and aging-related conditions. In the context of the current longevity revolution, many bider adults are increasingly concerned about their cognitive performance and the risk for cognitive decline. This makes it critically important to understand the neuropsychological profiles of normal aging and the cognitive features of conditions associated with aging, such as age-associated memory impairment, mild cognitive impairment and dementia. There are also several factors that can modify the neuropsychological abilities and outcomes associated with aging, including gender, genetic status, lifestyle issues and education. The authors point to the importance for future research to embrace a fluid or multifactorial approach to neuropsychology, to focus on those factors contributing to healthy cognition and successful aging, and to correlate neuropsychological changes with the results of nueroimaging.
The human brain adapts to changing demands by altering its functional and structural properties ("neuroplasticity") which results in learning and acquiring skills. Convergent evidence from both human and animal studies suggests that physical activity facilitates neuroplasticity of certain brain structures and as a result cognitive functions. Animal studies have identified an enhancement of neurogenesis, synaptogenesis, angiogenesis and the release of neurotrophins as neural mechanisms mediating beneficial cognitive effects of physical exercise. This review summarizes behavioral consequences and neural correlates at the system level following physical exercise interventions in humans of different ages. The results suggest that physical exercise may trigger processes facilitating neuroplasticity and, thereby, enhances an individual's capacity to respond to new demands with behavioral adaptations. Indeed, some recent studies have suggested that combining physical and cognitive training might result in a mutual enhancement of both interventions. Moreover, new data suggest that to maintain the neuro-cognitive benefits induced by physical exercise, an increase in the cardiovascular fitness level must be maintained.
The increasing life expectancy in the populations of rich countries raises the pressing question of how the elderly can maintain their cognitive function. Cognitive decline is characterised by the loss of short-term memory due to a progressive impairment of the underlying brain cell processes. Age-related brain damage has many causes, some of which may be influenced by diet. An optimal diet may therefore be a practical way of delaying the onset of age-related cognitive decline. Nutritional investigations indicate that the ω-3 poyunsaturated fatty acid (PUFA) content of western diets is too low to provide the brain with an optimal supply of docosahexaenoic acid (DHA), the main ω-3 PUFA in cell membranes. Insufficient brain DHA has been associated with memory impairment, emotional disturbances and altered brain processes in rodents. Human studies suggest that an adequate dietary intake of ω-3 PUFA can slow the age-related cognitive decline and may also protect against the risk of senile dementia. However, despite the many studies in this domain, the beneficial impact of ω-3 PUFA on brain function has only recently been linked to specific mechanisms.
Objectives:
To examine the effects of cognitive stimulation (mahjong) and physical exercise (tai chi [TC]) on cognitive performance in persons with dementia.
Design:
Cluster-randomized open-label controlled design.
Setting:
Nursing homes.
Participants:
One hundred ten residents, most of whom were cholinesterase-inhibitor naive. Inclusion criteria were Mini-Mental State Examination (MMSE) = 10-24 and suffering from at least very mild dementia (Clinical Dementia Rating ≥ 0.5). Exclusion criteria were being bedbound, audio/visual impairment, regular activity participation before study, or contraindications for physical or group activities.
Interventions:
Homes were randomized into three conditions (mahjong, TC, and simple handicrafts [control]). Activities were conducted three times weekly for 12 weeks.
Measurements:
Primary outcome was MMSE. Secondary outcomes were immediate/delayed recall, categorical fluency, and digit span. Various biological risk factors, including apolipoprotein E ε4 allele, were included as covariates. Measures were collected at 0 (baseline), 3 (posttreatment), 6, and 9 months.
Results:
Intent-to-treat analyses were performed using mixed-effects regression. Mahjong's effect varied by time for MMSE, delayed recall, and forward digit span. TC had similar effects but not for delayed recall. The typical pattern was that control participants deteriorated while mahjong and TC participants maintained their abilities over time, leading to enlarged treatment effects as time progressed. By 9 months, mahjong and TC differed from control by 4.5 points (95% confidence interval: 2.0-6.9; d = 0.48) and 3.7 points (95% confidence interval: 1.4-6.0; d = 0.40), respectively, on MMSE. No treatment effects were observed for immediate recall and backward digit span.
Conclusions:
Mahjong and TC can preserve functioning or delay decline in certain cognitive domains, even in those with significant cognitive impairment.
The influence of adult foreign-language acquisition on human brain organization is poorly understood. We studied cortical thickness and hippocampal volumes of conscript interpreters before and after three months of intense language studies. Results revealed increases in hippocampus volume and in cortical thickness of the left middle frontal gyrus, inferior frontal gyrus, and superior temporal gyrus for interpreters relative to controls. The right hippocampus and the left superior temporal gyrus were structurally more malleable in interpreters acquiring higher proficiency in the foreign language. Interpreters struggling relatively more to master the language displayed larger gray matter increases in the middle frontal gyrus. These findings confirm structural changes in brain regions known to serve language functions during foreign-language acquisition.
The subgranule zone of the dentate gyrus in rats has been shown to be proliferative into adulthood and senescence. However, the connectivity of newly generated, identified neurons in the adult has not been definitively described. In the present study, 9 weeks after a series of intraperitoneal injections of 5-bromo-2′-deoxyuridine (BrdU), animals received stereotaxic iontophoretic injections of Fluoro-Gold (FG) into field CA3. Three weeks after FG injections, sections were analyzed for BrdU immunoreactivity (proliferative label), FG retrograde label, and either calbindin-D28k or synaptophysin immunohistochemistry. A large proportion (up to 44%) of BrdU-labeled cells in the dentate gyrus within regions of FG retrograde label incorporated FG. All of the doubly labeled (BrdU-FG) neurons also immunolabeled with the antibody to calbindin-D28k. Many doubly labeled (BrdU-FG) cells were also surrounded in three planes by synaptophysin immunoreactivity. We conclude that newly generated neurons in the dentate gyrus have the correct immunohistochemical profile, send appropriate axonal projections to field CA3, and are surrounded by profiles containing synaptic vesicle proteins. J. Comp. Neurol. 406:449–460, 1999. © 1999 Wiley-Liss, Inc.
Chronic stress occurs in everyday life and induces impaired spatial cognition, neuroendocrine and plasticity abnormalities. A potential therapeutic for these stress related disturbances is curcumin, derived from the curry spice turmeric. Previously we demonstrated that curcumin reversed the chronic stress-induced behavioral deficits in escape from an aversive stimulus, however the mechanism behind its beneficial effects on stress-induced learning defects and associated pathologies are unknown. This study investigated the effects of curcumin on restraint stress-induced spatial learning and memory dysfunction in a water maze task and on measures related neuroendocrine and plasticity changes. The results showed that memory deficits were reversed with curcumin in a dose dependent manner, as were stress-induced increases in serum corticosterone levels. These effects were similar to positive antidepressant imipramine. Additionally, curcumin prevented adverse changes in the dendritic morphology of CA3 pyramidal neurons in the hippocampus, as assessed by the changes in branch points and dendritic length. In primary hippocampal neurons it was shown that curcumin or imipramine protected hippocampal neurons against corticosterone-induced toxicity. Furthermore, the portion of calcium/calmodulin kinase II (CaMKII) that is activated (phosphorylated CaMKII, pCaMKII), and the glutamate receptor sub-type (NMDA2B) expressions were increased in the presence of corticosterone. These effects were also blocked by curcumin or imipramine treatment. Thus, curcumin may be an effective therapeutic for learning and memory disturbances as was seen within these stress models, and its neuroprotective effect was mediated in part by normalizing the corticosterone response, resulting in down-regulating of the pCaMKII and glutamate receptor levels.
Epidemiological studies reveal better cognitive function in physically active individuals. Possible mediators for this effect are neurotrophins, which are up-regulated through physical exercise and induce neuronal growth and synaptogenesis in the animal model. Here we cross-sectionally assessed 75 healthy older individuals for levels of physical activity, aerobic fitness, and memory encoding, as well as neurotrophin levels and cerebral gray matter volume. We found that physical activity, but not cardiovascular fitness, was associated with better memory encoding after controlling for age, sex, education, depression, alcohol consumption, and smoking. Higher levels of physical activity were associated with higher levels of the neurotrophin granulocyte colony stimulating factor (G-CSF) and increased cerebral gray matter volume in prefrontal and cingulate cortex as assessed by magnetic resonance voxel-based morphometry. While mediating factors will need to be further elucidated, these findings indicate that even low-level physical activity exerts beneficial effects on memory functions in older individuals.
This article describes the effects of exercise on neural plasticity after traumatic brain injury (TBI). There is strong evidence that indicates that exercise has neuroprotective effects by activating specific neuronal circuits and increasing molecules that enhance synaptic plasticity. Findings obtained from experimental models of TBI are discussed to support the use of exercise as a rehabilitative tool. These studies indicate that injury characteristics are likely to influence the time window for therapeutic exercise. Results of human and animal studies suggest that premature postconcussive exercise may be deleterious by exacerbating postconcussive symptomatology and disrupting restorative processes. A better understanding of the mechanisms that influence exercise after TBI will contribute to improving guidelines for the return to exercise activities and to the successful use of exercise as a therapeutic tool.
Chronic traumatic encephalopathy (CTE) has been linked to participation in contact sports such as boxing and American football. CTE results in a progressive decline of memory and cognition, as well as depression, suicidal behavior, poor impulse control, aggressiveness, parkinsonism, and, eventually, dementia. In some individuals, it is associated with motor neuron disease, referred to as chronic traumatic encephalomyelopathy, which appears clinically similar to amyotrophic lateral sclerosis. Results of neuropathologic research has shown that CTE may be more common in former contact sports athletes than previously believed. It is believed that repetitive brain trauma, with or possibly without symptomatic concussion, is responsible for neurodegenerative changes highlighted by accumulations of hyperphosphorylated tau and TDP-43 proteins. Given the millions of youth, high school, collegiate, and professional athletes participating in contact sports that involve repetitive brain trauma, as well as military personnel exposed to repeated brain trauma from blast and other injuries in the military, CTE represents an important public health issue. Focused and intensive study of the risk factors and in vivo diagnosis of CTE will potentially allow for methods to prevent and treat these diseases. Research also will provide policy makers with the scientific knowledge to make appropriate guidelines regarding the prevention and treatment of brain trauma in all levels of athletic involvement as well as the military theater.