Abstract
As the average lifespan continues to climb because of advances in medical care, there is a greater need to understand the factors that contribute to quality of life in the elderly. The capacity to live independently is highly significant in this regard, but is compromised by cognitive dysfunction. Aging is associated with decreases in cognitive function, including impairments in episodic memory and executive functioning. The prefrontal cortex appears to be particularly vulnerable to the effects of advancing age. Although the mechanism of age-related cognitive decline is not yet known, age-related inflammatory changes are likely to play a role. New insights from preclinical and clinical research may give rise to novel therapeutics which may have efficacy in slowing or preventing cognitive decline with advancing age.
Keywords: aging, cognitive dysfunction, elderly, inflammation, quality of life
Introduction
The world's population is rapidly aging and age-related disease constitutes a growing proportion of healthcare burden. The segment of the population that is 85 or older is growing faster than any other age group and is projected to account for 4.3% of the US population by 2050 [Merck Institute of Aging & Health et al. 2007]. These changes in the population have led to a growing realization that measures must be taken to ensure a high quality of life in addition to increased longevity. Foremost among factors that determine quality of life is the ability to live independently [Bowling, 2005], and cognitive functioning is particularly important in this regard [Desai et al. 2010]. The biological basis of age-related cognitive decline is not currently known with certainty, in part because aging in humans is associated with numerous age-related disease conditions that complicate the attribution of causality. For this reason, insights gained from animal models are important because causality can be established with greater certainty. A growing body of preclinical and clinical literature suggests that age-related inflammatory changes may contribute to cognitive changes.
Our goal here is to review evidence that aging is associated with relatively selective deficits in cognition that contribute to disability in the elderly, and that neuroinflammation is an important factor contributing to age-related cognitive decline. We base these conclusions on research findings drawn from the clinical literature as well as research performed using animal models. Although our focus is on cognitive decline associated with normal aging, we discuss evidence that the effects of inflammation on cognition are further exaggerated in pathological disease states such as in neurodegenerative diseases. Finally, we review some possibilities for intervening to reduce age-related neuroinflammation in the hope of slowing or preventing age-related cognitive decline. Because of the importance cognition plays in one's ability to live independently, reducing the impact of inflammation on cognition during aging is likely to significantly impact on the quality of life of older persons.
Normal aging is associated with declines in memory and executive function
In normal human aging, certain facets of cognition seem to be affected more than others. Here we review evidence that aging primarily affects episodic memory and executive functioning while leaving other aspects of cognition relatively intact. We discuss the role of inflammation in these age-related changes in cognition in subsequent sections below.
Memory is not a unitary construct and distinct components of memory are affected by aging differently [Nilsson, 2003]. Explicit memory includes episodic memory, which involves the conscious recall of events and experiences, and semantic memory, which involves the conscious recall of facts and information [Tulving, 1987]. Episodic memory is affected by aging much more than semantic memory. The Betula study, a 10-year longitudinal project examining memory and health in 1000 people between the ages of 35 and 80 years, showed a striking decrease in episodic memory performance as people age [Nilsson et al. 1997], which is consistent with results from other studies [Birren et al. 2006]. These changes are likely because of age-related dysfunction of the hippocampus and the cortex, since explicit memory is largely encoded in the hippocampus, though other brain regions, such as various neocortical areas, are also thought to be involved [Grady et al. 2003].
Difficulties with free recall and temporal ordering in elderly people have been shown to be associated with deficits in encoding and retrieval of information [Daum et al. 1996]. The frontal lobes play an important role in the encoding of information [Fletcher et al. 1998; Dolan and Fletcher, 1997]. Functional magnetic resonance imaging studies have correlated poor episodic memory performance in older people with reductions in left frontal lobe activation during the initial encoding of a memory [Stebbins et al. 2002]. Therefore, older people may benefit from the use of encoding strategies and cues, which result in increases in left frontal lobe activation and improved memory performance [Logan et al. 2002]. The frontal lobe is also involved in the filtration of irrelevant information that would otherwise interfere with the encoding of pertinent information [Lustig et al. 2001]. Episodic memory capacity in particular relies on successful inhibition of irrelevant and interfering information [Craik and Salthouse, 2007]. In addition, free recall of information seems to depend on prefrontal function, although cued recall and recognition do not [Mesulam, 2000; Jetter et al. 1986]. It is possible that the age-related sensitivity of episodic memory in comparison to semantic memory is due in part to the greater demand on prefrontal functioning during the encoding of transitory events such as autobiographical events (episodic memory) compared with the encoding of public, noncontextual facts (semantic memory). Semantic memory is not as significantly affected by aging. In the Betula study, there were no observable differences in tests of vocabulary between 35-year-old people and 50-year-old people. In addition, after controlling for level of education, there were no age-related declines in general knowledge among people younger than 75 years [Nilsson et al. 1997]. Similarly, the Berlin Aging Study, a 6-year longitudinal project exploring the intellectual abilities of elderly people, showed that while factors such as perceptual speed, episodic memory, and fluency declined with age, other factors such as knowledge (measured by vocabulary) remained relatively stable and intact [Singer et al. 2003].
Some studies have, in fact, demonstrated improvements in semantic memory with age, despite losses in episodic memory performance. One study tested individuals of various ages on knowledge of events occurring from the 1930s to the 1990s, and showed that general knowledge about such historical facts (which required semantic memory) was found to be positively correlated with age [Schacter Daniel, 1987]. Another study revealed that older people had a better recall of facts (semantic details), despite having a poorer recall of thoughts and feelings (episodic details), relative to younger people [St Jacques and Levine, 2007]. Thus, semantic memory remains relatively spared by normal aging and performance may, in fact, increase with age.
Implicit memory, much like semantic memory, also remains relatively stable with age [Ackerman and Rolfhus, 1999]. However, unlike the semantic and episodic components of explicit memory, implicit memory involves information that is utilized without conscious awareness. An important type of implicit memory is procedural memory which involves unconscious, experience-dependent learning of how to perform specific tasks, such as riding a bike. In animal models it has been shown that, after adjusting for differences in baseline and gross motor abilities, there are no significant implicit memory changes associated with advancing age [Churchill et al. 2003].
Implicit memory is mediated by regions of the brain such as the basal ganglia and cerebellum [Hikosaka et al. 2002]. People with damage to the striatum (such as patients with advanced Parkinson's disease) exhibit evidence of impaired learning of novel movements and difficulties acquiring visuomotor skills [Laforce and Doyon, 2002]. People with bilateral striatal damage also have difficulties acquiring new stimulus-response motor associations [Laforce and Doyon, 2001]. These regions are, however, relatively spared by normal aging.
Executive function is also affected by aging. Executive function can be defined as the set of capacities involved in planning, mental flexibility, inhibiting inappropriate actions, attending to relevant sensory information, and ignoring irrelevant sensory information [Stuss and Benson, 1986]. Executive dysfunction is an important component of many neurodegenerative diseases such as Alzheimer's disease (AD) [Swanberg et al. 2004], Parkinson's disease [Zgaljardic et al. 2006], frontotemporal dementia [Kertesz, 2006], and other neuropsychiatric conditions (e.g. schizophrenia [Green, 2006]). Within executive function, attention, or the ability to focus on relevant sensory input and ignore irrelevant sensory input, is of particular interest to this discussion.
Attention, like other components of executive function, is dependent on the prefrontal cortex (PFC), which plays many important roles in cognition and has numerous subregions with specialized functions [Fuster, 1997]. A recent comprehensive review of the literature on attention argues for a fundamental role of working memory, top-down sensitivity control, competitive selection, and automatic bottom-up filtering for salient stimuli, with important roles for PFC and posterior parietal cortex in the former three processes [Knudsen, 2007]. It has been argued that the decline of attention with aging is related to inadequate inhibitory processes rather than deficiencies in activation [Hasher and Zacks, 1988]. As such, memory-impaired adults are more likely to experience difficulty ignoring task-irrelevant inputs and suppressing knowledge that is no longer applicable. In tests of selective attention, patients with prefrontal lesions are less able to ignore irrelevant information than healthy controls [Chao and Knight, 1997]. In addition, it appears that older adults are more vulnerable to distractors than younger adults. This idea is supported by brain-imaging studies that show that older people exhibit more cortical activation compared with younger people when presented with task-irrelevant information, while cortical activity is similar in both age groups when task-relevant information is presented [Gazzaley et al. 2005]. In contrast, sustained attention, which is the ability to maintain attention over a period of time, is relatively stable with age [Berardi et al. 2001]. When measuring sustained attention using a high-speed digit discrimination task, researchers found no age-related differences in sustained attention capacity among young, middle-aged, and elderly people [Berardi et al. 2001].
Given the evidence for decreased PFC function with advancing age, it is not surprising that neuroimaging and neuroanatomical studies have identified structural changes in the PFC with advancing age in a number of mammalian species. For example, aging is correlated with a thinning of layer I of area 46 in monkeys [Peters et al. 1998]. A recent study examined the effects of aging on layer III pyramidal neurons in the dorsolateral PFC of rhesus monkeys [Dumitriu et al. 2010]. The authors determined that aging was associated with a loss of dendritic spines, especially small and thin spines, and a reduction in axospinous synapses. Synapse density and spine morphology were found to correlate with acquisition and performance on the delayed non-matching-to-sample test. Similarly, another study [Erraji-Benchekroun et al. 2005] demonstrated a disorganization of ‘microcolumns’ in area 46 of the PFC of monkeys which was highly correlated with declines in spatial working memory and recognition memory. In addition to these changes in gray matter, aging is also associated with alterations in frontal white matter. For example, diffusion tensor imaging has demonstrated a selective disruption of frontal cortical circuitry with aging in humans [Pfefferbaum et al. 2005].
It is possible that the declines in episodic memory and attention are not due solely to age-related area-specific deficiencies within the brain, but that global reductions in brain efficiency also contribute. This view suggests that aging people experience cognitive decline because of ‘global brain aging’ in addition to area-specific degradation [Rabbitt and Lowe, 2000]. This concept of ‘global brain aging’ informs the processing speed theory of cognitive aging, which suggests that there is an age-related decrease in the speed and efficiency of processing throughout the brain. More specifically, cognitive performance is reduced because the required cognitive operations cannot be executed in the necessary amount of time and because of a reduced ability to process multiple concepts simultaneously [Salthouse, 1996]. Thus, aging may lead to a global reduction in processing efficiency, which may also contribute to the observed age-related declines in both episodic memory and attention that are described above.
Overall, normal aging is associated with relatively selective declines in episodic memory and in executive function, while both semantic and implicit memories are relatively spared. Because episodic memory requires frontal lobe activity for encoding and retrieval, frontal lobe dysfunction appears to play a particularly important role in cognitive decline with normal aging. It is important to note that age-related cognitive decline has important implications for elderly people because cognition is strongly predictive of disability [McGuire et al. 2006; Dodge et al. 2005] and decline in executive functioning seems especially important in this regard [Johnson et al. 2007; Royall et al. 2005; Cahn-Weiner et al. 2002].
Age-related cognitive decline is due in part to age-related increases in inflammation
The notion that neuroinflammation leads to a decline in cognitive function is supported by the association between markers of inflammation and several pathological conditions, such as AD, Parkinson's disease, and mild cognitive impairment (MCI). Postmortem examinations of people with late-stage AD, for example, have revealed that beta-amyloid plaques, one of the defining characteristics of AD, are frequently colocalized with a variety of inflammatory factors, including proinflammatory cytokines, acute phase proteins, complement factors, and activated microglia [Eikelenboom et al. 2006; Eikelenboom and van Gool, 2004]. Neuroinflammation within the diseased brain does not appear to be widespread, however, because it is restricted to regions of the brain that are particularly affected by AD [McGeer and McGeer, 2002]. Additionally, as discussed in more detail below, there is some evidence that the risk of AD is reduced in people who have a history of nonsteroidal anti-inflammatory drug (NSAID) use [Wyss-Coray, 2006; Tuppo and Arias, 2005; Lukiw and Bazan, 2000]. Likewise, polymorphisms in several inflammatory factors appear to serve as risk factors for the development of AD [Eikelenboom et al. 2002; Lukiw and Bazan, 2000].
While it is not yet known whether neuroinflammatory events precede disease states or are a direct consequence of the damage that occurs with ensuing pathology, beta-amyloid plaques appear to act in a proinflammatory fashion [Halliday et al. 2000; Tuppo and Arias, 2005]. It is not surprising then, that several groups agree that it is likely that neuroinflammatory events initiate or even aid in the progression of AD [Heneka and O'Banion, 2007; Bales et al. 2000]. Indeed, as discussed in more detail below, inflammatory factors have been identified as a potential target in the treatment of AD [Heneka and O'Banion, 2007; McGeer and McGeer, 2003, 2002; Moore and O'Banion, 2002; Rogers et al. 1996]. Nevertheless, it is difficult to establish whether the cognitive decline observed in cases of pathology (e.g. patients with AD) is caused by inflammatory events or other aspects of the progressing disease. To address this issue, nonpathological neuroinflammation must also be explored.
To date, a link between nonpathological neuroinflammation and cognitive impairment has been established in a variety of species, including pigeons [Holden et al. 2008], rodents [Barrientos et al. 2009, 2006; Wan et al. 2007; Gemma et al. 2005; Heyser et al. 1997], and humans [Hilsabeck et al. 2010; van den Kommer et al. 2010; Magaki et al. 2007; Dik et al. 2005].
Inflammation, especially within the central nervous system (CNS), leads to impairments in a variety of cognitive domains, including learning [Hein et al. 2010; Terrando et al. 2010; Barrientos et al. 2009, 2006], memory [Frank et al. 2010; Hirshler et al. 2010; Abraham and Johnson, 2009; Wang et al. 2009] and attention [Holden et al. 2008]. For example, mutant mice overexpressing the proinflammatory cytokine interleukin (IL)-1 [Moore et al. 2009], and rats given chronic ventricular administration of lipopolysaccharide (LPS) [Rosi et al. 2006], a potent activator of innate immunity, are significantly impaired in spatial working memory tasks. Microarray analyses of cortical tissue obtained from mice given a single intracerebroventricular injection of LPS revealed that, in addition to enrichment for inflammation-related genes, neuroinflammation leads to a significant reduction in genes known to be involved in learning and memory [Bonow et al. 2009]. That being said, neuroinflammation may lead to cognitive and behavioral changes via multiple mechanisms including regulation of gene expression [Bonow et al. 2009; Godbout et al. 2005], alterations in neuronal function [Motoki et al. 2009; van Gassen et al. 2005], reduced neurogenesis [Bachstetter et al. 2009; Koo and Duman, 2008; Aalami et al. 2003; Monje et al. 2003; Vallieres et al. 2002] and impaired long-term potentiation [Min et al. 2009; Lewitus et al. 2007; Griffin et al. 2006; Lynch et al. 2004; Hauss-Wegrzyniak et al. 2002; Kelly et al. 2001, 2003; Murray and Lynch, 1998].
Peripheral inflammation is also capable of producing cognitive dysfunction [Buchanan et al. 2008; Tonelli and Postolache, 2005; Reichenberg et al. 2001] and markers of inflammation, such as peripheral cytokines, have been associated with lower cognitive performance [Hilsabeck et al. 2010; Rothenburg et al. 2010; Gimeno et al. 2008; Rafnsson et al. 2007]. Like central administration, systemic LPS has been found to produce deficits in working memory in rodents [Murray et al. 2010; Zhang et al. 2009]. In humans, a connection between peripheral inflammation and cognitive dysfunction has been demonstrated repeatedly in people experiencing acute infection [Elison et al. 2008; Wratten, 2008; Logan et al. 2002; Reichenberg et al. 2001] and recent surgical procedures [Xie et al. 2009; Beloosesky et al. 2007; Gao et al. 2005]. In addition, immune-related impairments in cognitive performance have served as a major hypothesis for the development of a variety of neurodegenerative diseases and dementias [e.g. Cerejeira et al. 2010; McNaull et al. 2010; Morales et al. 2010; Murray et al. 2010; de Rooij et al. 2007; Vaccarino et al. 2007].
The effects of peripheral immune activation, however, still occur in direct association with increases in inflammation within the CNS [Buchanan et al. 2008]. While it is plausible that inflammatory agents or molecules penetrate the CNS to produce direct effects on behavior and cognition, the brain was initially believed to be immunologically privileged, protected from such occurrences by the blood-brain barrier. However, during situations involving the breakdown of the blood-brain barrier [Cunningham et al. 2009; Serres et al. 2009; McColl et al. 2008], sepsis [Semmler et al. 2008; Wratten, 2008; Reichenberg et al. 2001], or chronic repeated stress [Munhoz et al. 2008, 2006], peripheral inflammation leads to increases in proinflammatory cytokine expression within the brain parenchyma and, potentially, cognitive decline [Popescu et al. 2009]. Regardless, whether by direct signaling of inflammatory molecules within the CNS, or by alternative means, peripheral inflammation has been shown to be a potent regulator of neurocognition [Cerejeira et al. 2010; Richwine et al. 2009; Myers et al. 2008; Meyers et al. 2005].
As discussed in the previous section, normal aging is associated with relatively selective declines in episodic memory and executive functioning, with a relative sparing of semantic and implicit memory. If inflammation is responsible for these cognitive changes one would expect that inflammation would be associated with declines in episodic memory and executive functioning more than semantic and implicit memory. Although information is limited, some studies have provided some insight into this question. Marsland and colleagues [Marsland et al. 2006] examined serum IL-6 in a cohort of healthy people aged 30-54 years in relation to cognition. IL-6 levels were inversely related to performance on tests of auditory memory and attention/working memory and executive function but not with word list recall, verbal paired associates, mental control, faces, family pictures, or digit span tests. Schram and colleagues examined the association between serum C-reactive protein (CRP), IL-6, and alpha1-antichymotrypsin and cognition based on data from two large studies [Schram et al. 2007]. The authors found that CRP and IL-6 were associated with worse global cognition [Mini Mental Status Exam scores (MMSE)] and executive function in one study, and that IL-6 levels were associated with steeper declines in performance on a picture memory test in the other study. Hoth and colleagues studied the association between peripheral inflammation and cognition in patients with cardiac disease [Hoth et al. 2008]. CRP levels were found to be associated with declines in attention-executive-psychomotor performance but not language, episodic memory, or visuospatial performance. Associations between genetic variation in IL-1 beta-converting enzyme (ICE) and IL-1beta levels and cognition were recently demonstrated [Trompet et al. 2008]. ICE variants that predicted lower serum IL-1beta levels were associated with better executive functioning, but associations with episodic memory were not significant. Serum levels of CRP have been found to be associated with reduced fractional anisotropy in the frontal lobes, corona radiata, and the corpus callosum by diffusion tensor magnetic resonance imaging, as well as with decreased executive functioning [Wersching et al. 2010]. Not all studies have found an association between inflammation and executive function. For example, Noble and colleagues studied associations between CRP levels and cross-sectional cognitive performance [Noble et al. 2010]. People with the highest CRP levels had higher rates of episodic memory impairment and visuospatial impairment but not executive or language impairment.
Although the results of such studies are not entirely consistent, possibly because of differences in assessment methods and differences in the subject populations studied, there is strong evidence for a role of inflammation in decreased executive functioning as well as episodic memory. Selective effects of inflammation on particular cognitive domains could be due to at least two mechanisms which are not mutually exclusive. First, it is possible that neuroinflammation may not uniformly affect the brain. This view is supported by evidence that inflammatory cytokines are not expressed uniformly in the mammalian brain. For example, Lemke and colleagues examined IL-6 expression in the rat brain using antibody-based as well as in situ hybridization methods and found that IL-6 mRNA and protein are enriched in the hippocampus and cortex, with much stronger expression in neurons than astrocytes or microglia [Lemke et al. 1998]. The IL-6 receptor in the mouse is most highly expressed in the olfactory bulb, retrohippocampal region, and hippocampus, with lower expression in the cortex, striatum, and other regions. IL-1beta is expressed at low levels in the mouse brain with highest levels in the thalamus, hypothalamus, striatum, and brainstem with somewhat lower levels in the cortex, and even lower levels in the hippocampus. Tumor necrosis factor (TNF)-alpha is expressed most strongly in the olfactory bulbs, ventral striatum, and pallidum, with more intermediate expression in the hippocampus and cortex (http://mouse.brain-map.org). Therefore, it is possible that the distribution of inflammatory cytokine expression is partially responsible for the differential effects of inflammation on certain cognitive domains, but other factors must also play a role. For example, it is also possible that certain brain regions are more vulnerable to the effects of inflammation than other brain regions, and this possibility will require further research to assess.
It is interesting to note that one recent study [Grigoleit et al. 2010] tested the effects of LPS administration on healthy humans. The authors tested 12 healthy men before and after the intravenous administration of 0.4 ng/kg LPS. Although the injections caused transient (<4h) fever, elevated neutrophils, and elevated IL-6, IL-10, and TNF-alpha levels, no changes in episodic memory performance or performance on the Stroop Color Word task were noted. Therefore, it is likely that chronically elevated cytokine levels are required to affect cognition.
Age-related increases in inflammation linking deficits in cognition and physical function
Whereas inflammation has been linked to cognitive dysfunction in older people, it also has been found to be associated with physical function in this population. Because of the link between cytokines and several disabling conditions, including cerebrovascular disease [Vila et al. 2000; Kostulas et al. 1998] and coronary heart disease [Tracy et al. 1997; Biasucci et al. 1996], it has been hypothesized that inflammation is a pathophysiological mechanism leading to decline in physical function among older people. Increasing serum levels of IL-6 have been found to be associated, cross sectionally, with disability in basic activities of daily living (ADLs) [Cohen et al. 1997]. Similarly, an analysis of four studies of older people with differing comorbidities found that increasing serum levels of both IL-6 and CRP, but not TNF-alpha, were negatively associated with performance-based mobility function, such as longer time to complete a 4 m walk and lower grip strength [Brinkley et al. 2009]. These associations were largely independent of factors such as age, race, and body composition, and were generally consistent among various chronic diseases such as chronic obstructive pulmonary disease and congestive heart failure [Brinkley et al. 2009]. Increased IL-6 has also been found to be associated with incident self-reported ADL disability [Ferrucci et al. 1999] and mobility disability in longitudinal studies of older people [Brinkley et al. 2009; Penninx et al. 2004; Ferrucci et al. 1999], with the study by Penninx and colleagues also indicating that participants with increased serum levels of CRP and TNF-alpha were more likely to report mobility disability at the 4-year follow-up assessment [Brinkley et al. 2009; Penninx et al. 2004; Ferrucci et al. 1999]. Participants having high levels of all three of these markers showed a particularly high incidence of self-reported mobility disability, with associations persisting even after people with cardiovascular disease were excluded, thereby indicating that the relationship between inflammation and subsequent mobility function is independent of cardiovascular disease [Penninx et al. 2004]. Inconsistencies across studies in the assessment of multiple inflammatory markers, evaluation of physical function (e.g. self report versus performance based), as well as differing follow-up periods, pose challenges in summarizing the findings of these studies. However, these inconsistencies also indicate opportunities for future research.
In addition to being associated with impairments in cognition and physical function, inflammation also may play a role in contributing to increased depressive symptoms in older people. Because depression is also associated with cognitive impairment and disability, the effects of inflammation on depressive symptoms may mediate some of the effects of inflammation on cognition and disability. Cross-sectional [Bremmer, et al. 2008; Penninx et al. 2003; Dentino et al. 1999] and longitudinal studies [Stewart et al. 2009] indicate that increased serum levels of IL-6 are associated with depression in older people. Studies evaluating the relationship between CRP and depression, however, report inconsistent relationships; two report a positive association [Stewart et al. 2009; Penninx et al. 2003] and two report no association [Bremmer et al. 2008; Ladwig et al. 2005]. Like the studies evaluating the association between inflammation and physical function, the methodological discrepancies across these studies, such as differences in study design and whether or not the investigators are evaluating depressive symptoms or major depression, hinder researchers' ability to draw conclusions about the association between inflammatory markers and depression, in general.
Importantly, however, because impairments in cognition, physical function, and mood are common in older people, are risk factors for each other [Yogev-Seligmann et al. 2008; Johnson et al. 2007; Yanagita et al. 2006; Wilson et al. 2004; Sheridan et al. 2003; Lockwood et al. 2002; Penninx et al. 2000], and have repeatedly been shown to have profound deleterious effects on everyday functioning [Inzitari et al. 2006; Studenski et al. 2006; Raji et al. 2004; Stuck et al. 1999], it has been postulated that inflammation may be the underlying mechanism largely responsible for the widely reported associations between deficits in cognition, physical function, and mood in older people.
It is however impossible to definitively establish causality from the epidemiologic studies. As noted above, inflammation is associated with many disease states which may affect physical functioning independently of inflammation. True experimental designs are for the most part impractical and unethical in humans, with the study of Grigoleit and colleagues reviewed above, as one notable exception [Grigoleit et al. 2010]. Therefore, animal models are essential for determining whether inflammation can in fact cause cognitive impairment and disability. As reviewed in the previous section, it is clear from preclinical research that inflammatory insults are sufficient to cause cognitive and behavioral impairment. Although the precise contribution of inflammation to age-related disability remains unclear, when the existing body of clinical and preclinical data is considered together it is evident that inflammation is likely to be an important contributor to disability in the elderly.
Aging and inflammation: Mechanism
Normal aging is thought to include some aspects of inflammation. The aging brain, for example, is said to be in a state of transition from relative immunocompetence and surveillance, to one of primed immune activation [Dilger and Johnson, 2008; Sparkman and Johnson, 2008]. Microarray analysis has found that inflammatory genes account for the vast majority of those that are upregulated in the aging brain [Godbout et al. 2005; Prolla, 2002]. Additionally, changes are observed in the activation of a variety of immune-related cells. Microglia, for example, the major immune cells of the CNS, switch from a state of relative quiescence to one of activation in which they exhibit an increase in their expression of many inflammatory markers [Deng et al. 2010; Njie et al. 2010; von Bernhardi et al. 2010; Miller and Streit, 2007; Conde and Streit, 2006]. Microglia, particularly when activated, are the primary source of proinflammatory cyto-kines within the brain [e.g. ILs, interferons (IFNs), and chemokines]. While increases in proinflammatory cytokines are often observed during times of infection, these same factors are found to be upregulated as a function of increasing age, in the absence of any overt signs or symptoms of illness [Campuzano et al. 2009; Dilger and Johnson, 2008; Sparkman and Johnson, 2008]. IL-1, IL-6 and IFN-alpha for example, have all been found to be greater in the brains of old-aged mice and rats compared with adults [Campuzano et al. 2009; Sparkman and Johnson, 2008]. Additionally, primed and activated microglia residing in the aging brain often show an exaggerated response to infection and stress [Dilger and Johnson, 2008; Henry et al. 2008; Rosczyk et al. 2008; Godbout et al. 2005; Kelly et al. 2003].
Peripheral markers of inflammation are also elevated in elderly people. Normally low under nonpathological conditions, serum levels of proinflammatory cytokines, such as the ILs and IFN-gamma, have been found to be elevated in aging humans [Zhu et al. 2009; Pietschmann et al. 2003] and animals [Campuzano et al. 2009; Sparkman and Johnson, 2008]. In addition, evidence of peripheral inflammation serves as a risk factor for the development of age-related neurodegenerative disease [Tan and Seshadri, 2010; Tan et al. 2007; McRae et al. 1993] and may play a primary role in the etiology or progression of age-associated pathologies [McNaull et al. 2010; Morales et al. 2010; Tan et al. 2010; Holmes et al. 2009; Pompl et al. 2003]. In general, elderly people are far more sensitive to mild inflammatory insults, such as those associated with surgical procedures [Aalami et al. 2003]. Indeed, increasing age is the primary risk factor for the development of postoperative cognitive dysfunction, memory deficits that persist from days to months following even mild surgical procedures [Ramaiah and Lam, 2009; Rasmussen, 2006]. Given the evidence of greater basal inflammation and the morphological changes observed in neuroimmune cells, it is not surprising that aging people are increasingly sensitive to insults or perturbations and often experience cognitive and behavioral consequences to infection and stress that are larger, more robust and more prolonged than in adults.
Considering the already established links between aging and cognitive decline, aging and inflammation, and inflammation and cognitive dysfunction, it is not surprising that increasing age has been shown to exacerbate the effects of neuroinflammation on cognition and, likewise, inflammation may worsen the effects of aging on cognitive decline. As mentioned previously, aging organisms are more sensitive to the consequences of mild insults, inflammation and perturbations [Ramaiah and Lam, 2009; Aalami et al. 2003; Kelly et al. 2003]. The inflammatory response to chronic mild repeated stress, for example, is exaggerated in old-aged mice compared with adult mice [Buchanan et al. 2008]. Elderly people are at an increased risk for the development of postoperative cognitive dysfunction, which is likely mediated through inflammation-related events [Xie et al. 2009]. Likewise, LPS administration augments the cognitive deficits observed in diseased animals [Cunningham et al. 2009], and may speed the progression of age-related degenerative disorders [Vaccarino et al. 2007].
Inflammation as a therapeutic target
As reviewed above, neuroinflammation clearly does occur with advancing age in the brain. Because there is evidence that inflammation may cause cognitive decline, a number of efforts have focused on reducing inflammation in an effort to prevent or treat cognitive decline associated with normal aging as well as neurodegenerative disease. Here we review the major classes of pharmaceuticals that have been studied with respect to neuroinflammation, with a focus on AD and MCI. Because the literature on these drugs is very large, we focus here on the proposed mechanism of action of these agents as well as a selected review of the clinical findings obtained to date.
Because of the long availability of NSAIDs, inhibitors of cyclooxegenase 1 and 2 (COX1 and 2), this class of compounds has been extensively studied. At a cellular level, membrane phospholipids are converted to arachidonic acid by phospholipase A2. Arachidonic acid is then converted to the prostaglandins (PG) PGG2 and PGH2 by cyclooxygenases and PGH2 is then converted to a variety of prostaglandins and thromboxane A2. In humans, the cyclooxygenases are coded by the genes PTGS1 (COX1) and PTGS2 (COX2). Both enzymes are expressed in the brain, although there are regional and cell-type specific differences in expression that have been reported. In autopsy specimens, COX1 was found to be highly expressed in microglia and weakly expressed in neurons, whereas COX2 was undetectable in control brains but highly expressed in neurons and microglia after an acute ischemic event [Hoth et al. 2008]. COX3 is a splice variant of COX1 and is expressed particularly in endothelium, such as the major arteries and microvasculature of the rat brain [Noble et al. 2010]. The expression of COX1 in the mouse brain is particularly high in the medulla, cortex, pallidum, cerebellum, and hippocampus, whereas COX2 is highest in the hippocampus followed by the cerebellum, olfactory bulbs, retrohippocampal region, and cortex (http://mouse.brain-map.org). PGE2 is a particularly important product of COX and exerts its effects by interaction with a family of PGE receptors (PTGER1—PTGER4) which are coupled to Gq, Gs, Gi/Go, and Gs class G proteins, respectively [Grigoleit et al. 2010]. COX inhibitors reduce PGE2 levels, and because PGE2 is capable of increasing IL-1beta levels, the levels of this important inflammatory mediator are reduced by COX inhibitors. NSAIDS have certain effects that are independent of their ability to inhibit COX. For example, NSAIDS can reduce the levels of reactive oxygen species (ROS), inhibit NF-kappaB, and activate peroxisome proliferator activated receptor (PPAR) gamma [Grigoleit et al. 2010].
COX inhibitors have been found to have efficacy in relation to normal aging in preclinical models. In the rat, celecoxib administered at 12 months of age was found to reduce age-related increases in IL-1beta, TNF-alpha and PGE2 in the hippocampus, and to reduce circulating corticosterone levels at 16 and 22 months of age [Trompet et al. 2008]. Interestingly, the authors found that when the drug was started at 18 months of age, after the inflammatory changes had already developed, no differences in inflammatory cytokine levels were noted at 22 months, suggesting that the drug must be given prior to the onset of neuroinflammation. Drug treatment also improved Morris water maze performance at 16, but not 22 months of age. Another group [Schram et al. 2007] administered the COX2 inhibitors nimesulide and rofecoxib and the nonselective COX inhibitor, naproxen, for 15 days to aged (16-month-old) mice and found that the drugs improved passive avoidance performance in aged but not young (3-month-old) mice. Another group [Marsland et al. 2006] studied the effects of 2 months of oral sulindac in aged (18-month-old) rats. The drug was found to reduce age-related alterations in performance on the radial arm maze and contextual fear conditioning relative to young (6-month-old) rats and also reduced age-related increases in hippocampal IL-1beta levels.
NSAIDs have been tested in humans in relation to AD and the results have been controversial [Trepanier and Milgram, 2010; Marsland et al. 2006]. On the one hand, positive evidence for the efficacy of NSAIDS has been demonstrated in some studies. For example, the Rotterdam study [Trompet et al. 2008] involved a cohort of 6989 people who were free of dementia at baseline. People were screened 2–3 years later and again 6–8 years later. AD risk was analyzed in relation to NSAID use, which was estimated from pharmacy records, and the level of NSAID use was inversely related to the risk of developing AD. Similarly, the Baltimore Longitudinal Study of Aging examined AD risk in relation to the use of aspirin and other NSAIDs over a 15-year period in a cohort of 1686 people [Schram et al. 2007]. Longer duration of NSAID use, but not aspirin or acetaminophen use, was associated with a lower risk of developing AD. Not all observational studies have been positive, however. For example, one group examined 2736 dementia-free people for up to 12 years and determined that people using NSAIDs most heavily had the highest incidence of AD [Breitner et al. 2009]. Additionally, studies using randomized controlled trials have been largely negative. As recently reviewed [Imbimbo, 2009], celecoxib and naproxen given over 2 years to patients aged 70 and over with AD risk factors failed to prevent the development of AD and, in fact, increased the incidence of AD (although this was not statistically significant) [Lyketsos et al. 2007]. Results have also been mixed when NSAIDs were studied for MCI. Trials of rofecoxib [Thal et al. 2005], triflusal [Gomez-Isla et al. 2008], and celecoxib [Small et al. 2008] in patients with MCI were inconsistent. The first study was negative, the second study showed a trend toward improved cognition and significantly reduced risk of developing AD, and the later study showed some benefit with regard to executive functioning and language/semantic memory.
Estrogens are another class of agents that have received considerable attention. At a cellular level, estrogens signal through nuclear receptor superfamily receptors coded by the genes ESR1 (ERalpha) and ESR2 (ERbeta). Both genes are subject to extensive alternative splicing. The two receptors have similar affinities for the endogenous estrogen 17beta-estadiol. ERalpha and ERbeta have somewhat distinct distributions in mammalian brain [Hughes et al. 2009]. In the nonhuman primate brain ERalpha immunostaining is present in several amygdaloid and hypothalamic nuclei, lateral septum, nucleus of the stria terminals, subfornical organ, and periaqueductal gray, with sparse staining in the cholinergic basal forebrain [Blurton-Jones et al. 1999]. ERalpha expression has been observed in pyramidal neurons as well as nonpyramidal neurons of the PFC of humans, monkey, and rat [Montague et al. 2008]. A recent quantitative electron microscopy study determined that ERalpha is present within excitatory synapses, and presynaptic expression was correlated with performance on a PFC-dependent task [Wang et al. 2010]. ERbeta distribution in nonhuman primate brain has been examined by in situ hybridization which revealed high expression levels in the preoptic area, para-ventricular nucleus, and ventromedial nucleus of the hypothalamus, the substantia nigra, caudal linear raphe nuclei, dorsal raphe, and pontine nuclei of the midbrain, the dentate gyrus, CA1, CA2, CA3, CA4, and the prosubiculum/subiculum areas of the hippocampus. Expression in the suprachiasmatic region, supraoptic nucleus, arcuate nucleus, and amygdala was less intense [Gundlah et al. 2000]. Estrogen receptors signal by a ‘classical’ route that involves dimerization of the receptor and recruitment of SRC and N-CoR, and by a nonclassical route that involves direct interaction with activator protein-1 (AP1), NFkappaB, and specificity protein-1 (SP-1), as well as extracellular signal-regulated kinase (ERK), AKT, and protein kinase A activation [Hughes et al. 2009]. Estrogens, particularly ERbeta agonists, have been found to have anti-inflammatory effects and reduce expression of IL-1beta and TNF-alpha. ERalpha agonists reduce IL-1beta expression [Hughes et al. 2009].
A protective effect of estrogen use with respect to risk for AD is supported by a number of observational studies. For example, Baldereschi and colleagues studied 2816 women aged 65-84 years and found a higher frequency of estrogen use among nonpatients than among patients with AD [Baldereschi et al. 1998]. The results of randomized trials, however, have been less positive. One randomized, placebo-controlled, cross-over study tested 12 weeks of estrogen versus placebo in 43 men with MCI and noted a benefit only for the men randomized to placebo followed by estrogen [Sherwin et al. 2009]. The Women's Health Initiative Memory Study determined the effects of estrogen plus progestin on the incidence of dementia and MCI in 4532 postmenopausal women without dementia who were aged 65 and older. The authors noted increased risk in the patients receiving estrogen and progestin [Shumaker et al. 2003]. Estrogens have also been tested in several randomized controlled trials for AD. In one study, 120 women with AD were randomized to 1 year of estrogen or placebo and no group differences were noted [Mulnard et al. 2000]. Similarly, Henderson and colleagues randomized 42 women with AD to estrogen versus placebo for 16 weeks and no differences were detected [Henderson et al. 2000].
Endocannabinoids are lipids which interact with cannabinoid receptors including CB1 (coded by the gene CNR1) and CB2 (coded by the gene CNR2) which couple to Gi/Go class G proteins. Whereas CB1 receptors are widely expressed in brain, CB2 receptors are expressed on immune cells, including T cells, macrophages, B cells, and microglial cells [Wolf et al. 2008]. The anti-inflammatory effects of cannabinoids are mediated mainly by activation of CB2 receptors. Activation of CB2 receptors inhibits the expression of proinflammatory cytokines such as TNF-alpha, IL-1beta, IL-6, and IL-8, and increases the expression of anti-inflammatory cytokines [Wolf et al. 2008]. Although this class of drugs has received attention in preclinical studies, we are not aware of any randomized controlled trials in humans in relation to MCI or AD.
Drugs that act as PPAR agonists have found clinical application mainly in the area of diabetes but have been tested experimentally for efficacy in neuroinflammation. The PPARs are nuclear hormone receptors and are coded by the genes PPARA, PPARB, and PPARG in humans. These receptors regulate gene expression by forming heterodimers with retinoid X receptors (coded by RXRA, RXRB, and RXRG) and interact with PPRE sequences on target genes [Shie et al. 2009]. All of the PPARs are expressed in neurons and astrocytes, and PPARG is the main isoform expressed in microglia. PPARG agonists are capable of inhibiting activated microglia and astrocytes [Storer et al. 2005]. The most potent endogenous ligand is 15d-PGJ2, a derivative of the prostaglandin, PGD2. Most of the experimental work on this system has relied on thiazolidinediones (TZDs; also known as glitazones) [Shie et al. 2009]. In addition, a class of compounds known as heterocyclic thiadiazolidinones (TDZDs) is under development and may have much better CNS permeability than the TZDs and are GSK3beta inhibitors in addition to being PPARG agonists [Shie et al. 2009]. In addition to these compounds, NSAIDS have some ability to activate PPARG. Some data support the use of PPARgamma agonists in AD. For example, Watson and colleagues randomized 30 people with mild AD or amnestic syndrome to 6 months of rosiglitazone or placebo. People receiving rosiglitazone showed improved delayed recall compared with people receiving placebo [Watson et al. 2005].
The activation of microglial cells contributes to increased oxidative stress. A number of studies have examined the ability of drugs with antioxidant properties to interfere with this process. One such drug is resveratrol, a naturally occurring compound found in red wine that is readily available as a dietary supplement. This drug has been found to be neuroprotective in a variety of preclinical studies and has the ability to inhibit microglial activation [Zhang et al. 2010]. The mechanism is thought to involve effects on reduction of ROS, decreased mitogen-activated protein kinase signaling, and activation of the Sirt1 pathway, and the drug is capable of reducing inflammatory cytokine release as well [Zhang et al. 2010].
N-Acetylcysteine (NAC) has seen widespread use in preclinical and clinical studies. It is believed that the thiol group has antioxidant effects and acts as a free radical scavenger. In addition to its US Food and Drug Administration (FDA) approved use in acetaminophen overdose and renal protection, it has proven effective in a wide range of neuropsychiatric conditions [Dean et al. 2010]. Thus far, NAC has not been subjected to any randomized trials for MCI to our knowledge. It has been tested for AD [Adair et al. 2001] in a small study involving 43 people with probable AD. Although no differences were noted at 24 weeks on the primary outcome measures, a trend toward improvement on MMSE scores and figure recall and significant improvements on letter fluency were noted. Similarly, omega-3 fatty acids have received some attention. Omega-3 fatty acids such as eicosapentaenoic acid and docosahexaenoic acid are found in oily fish. Omega-3 fatty acids have been studied as potential treatments for AD with no clear positive effects but further research is needed [Cederholm and Palmblad, 2010].
A large number of pharmaceuticals have been developed to specifically combat neuroinflammation associated with conditions such as multiple sclerosis (MS). Although these drugs have for the most part not been tested for normal aging, AD, or MCI, the pharmacology is of potential importance for these conditions.
IFNs include type I IFNs (IFN-alpha, IFN-beta, and IFN-omega) and type II IFNs (IFN-gamma). IFNs play an important role in host response to viral infection and enhance major histocompatibility complex I (MHC I) and MHC II expression and immunoproteasome activity [Codarri et al. 2010]. Thus far, only the type I IFNs have found clinical application, with IFNalpha used in hepatitis. IFNbeta-1a (Avonex [Biogen Idec, Weston, MA, USA], Rebif [EMD Serono, Inc., Rockland, MA, USA], and CinnoVex [CinnaGen company, Tehran, Iran]) and IFNbeta-1b (Betaseron [Bayer HealthCare Pharmaceuticals, Leverkusen, North Rhine-Westphalia, Germany], Extavia [Novartis, Basel, Switzerland]) are FDA approved for use in MS.
Glucocorticoids such as dexamethasone and methylprednisolone have proven efficacy in MS. Despite powerful anti-inflammatory effects, these drugs are limited by numerous adverse neuropsychiatric effects. Preclinical studies (e.g. Li and colleagues [Li et al. 2010]) show that glucocorticoids worsen outcomes in animal models of AD. Prednisone has been tested in one randomized trial for AD [Aisen et al. 2000] which involved a high dose over 4 weeks followed by a lower dose over 1 year. No differences in cognition were noted between the treatment groups, but prednisone worsened behavioral decline.
Glatiramer acetate (Copaxone) [TEVA Neuroscience, Inc, Kansas City, Missouri, USA] has proven efficacy in relapsing-remitting MS. Although the drug is thought to mimic the myelin basic protein component of myelin, it has been found to have numerous other anti-inflammatory effects. There is some support for the use of this agent in AD based on preclinical models. For example, vaccination of doubly transgenic APP/PS1 mice with amyloid beta-peptide (Abeta) and glatiramer acetate reduced plaque formation and cognitive decline [Butovsky et al. 2006]. A similar report based on Abeta vaccination given along with glatiramer acetate showed clearing of Abeta fibrils.
Many pharmaceutical companies are developing pharmaceuticals known as biologics, which include recombinant antibodies and proteins that may have more highly targeted actions than small molecules. Natalizumab (Tysabri [Biogen Idec, Weston, MA, USA]) is a humanized monoclonal antibody against the cellular adhesion molecule alpha4-integrin. The drug is believed to work by inhibiting the migration of leukocytes into the CNS. Its use is limited primarily by the infrequent occurrence of progressive multifocal leukoencephalopathy [Clifford et al. 2010; Warnke et al. 2010] and has not been tested in AD or MCI. Another important biologic is etanercept, a recombinant molecule consisting of a soluble TNF receptor 2 fused to the Fc portion of IgG1. Although the drug is FDA approved for arthritis and ankylosing spondylitis, some preliminary findings, based on open-label administration, suggest possible efficacy in AD [Tobinick and Gross, 2008a, 2008b; Tobinick, 2007].
In addition to pharmaceuticals, certain lifestyle factors are known to have important roles in inflammation and cognition, and may help to inform future drug development. One of the most replicated findings in the aging field is that caloric restriction slows the rate of aging through, at least in part, a reduction of inflammation in both the periphery and CNS. The results of a landmark 20-year study of caloric restriction in Rhesus macaques were recently published [Colman et al. 2009] featuring 46 males and 30 females randomized to 30% caloric restriction or control. Of the animals that died of age-related causes, 37% of control animals died compared with only 13% of the caloric restriction animals. Improved maintenance of muscle mass, glucose homeostasis, a 50% decline in cancer, and a 50% drop in cardiovascular disease was noted. Within the CNS, caloric restriction led to decreased atrophy of subcortical regions, mid-cingulate cortex, lateral temporal cortex, and right dorsolateral frontal lobe. A recent meta-analysis of caloric restriction and aging in mice [Swindell, 2009] found evidence for an upregulation of numerous immune-related genes such as complement components and CD antigens with aging and a reversal of these changes by caloric restriction. The mechanism of caloric restriction is an area of intense investigation. One important hypothesis involves the mammalian target of rapamycin (mTOR) pathway, which plays an important role in nutrient sensing [Kapahi et al. 2010]. Interestingly, mTOR appears to play an important role in microglial activation in response to cytokines as well as in microglial survival [Dello Russo et al. 2009], suggesting that mTOR inhibitors may have therapeutic value. It is likely that research on the mechanism of caloric restriction will continue to suggest novel therapeutic targets for age-related cognitive decline.
Conclusions
Whereas aging is associated with declines in executive functioning as well as episodic memory, semantic memory is only affected much later in life, and implicit memory appears to be relatively spared. Since prefrontal functioning is likely to be more important for episodic memory than semantic memory and directly mediates executive functioning, it is not surprising that these differences in sensitivity to aging are consistent with a particular sensitivity of prefrontal cortex to aging.
Age-related declines in cognition, especially in executive functioning, significantly affect a person's ability to live independently, along with their overall quality of life. As the population ages, maintaining a high quality of life is a very important objective. The etiology of age-related cognitive decline is not entirely clear, but a model where age-related increases in inflammation lead to decrements in cognition is consistent with the literature, although other mechanisms also likely play a role. Such a model would suggest that aging effects on cognition are not inevitable and are potentially modifiable by reductions in inflammatory signaling. There is some evidence that pharmaceuticals directed against neuroinflammation can affect cognitive changes associated with normal aging as well as neurodegenerative diseases but much more research is needed to develop more effective drugs for this application. In the future, drugs which target CNS inflammation may prove effective in preventing or slowing age-related cognitive decline and promise to increase the quality of life in this growing segment of the population.
Acknowledgement
The authors wish to thank Becky Carlyle for her critical reading of the manuscript.
Footnotes
This work was supported by a grant from the Yale Pepper Center and the NIA (grant numbers AG030004 and AG030970). KB was supported by the NIMH (grant number T32 MH014276).
The authors declare no conflict of interest in preparing this manuscript.
References
- Aalami O.O., Fang T.D., Song H.M., Nacamuli R.P. (2003) Physiological features of aging persons. Arch Surg 138: 1068–1076 [DOI] [PubMed] [Google Scholar]
- Abraham J., Johnson R.W. (2009) Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice. Rejuvenation Res 12: 445–453 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ackerman P.L., Rolfhus E.L. (1999) The locus of adult intelligence: Knowledge, abilities, and nonability traits. Psychol Aging 14: 314–330 [DOI] [PubMed] [Google Scholar]
- Adair J.C., Knoefel J.E., Morgan N. (2001) Controlled trial of N-acetylcysteine for patients with probable Alzheimer's disease. Neurology 57: 1515–1517 [DOI] [PubMed] [Google Scholar]
- Aisen P.S., Davis K.L., Berg J.D., Schafer K., Campbell K., Thomas R.G., et al. (2000) A randomized controlled trial of prednisone in Alzheimer's disease. Alzheimer's Disease Cooperative Study. Neurology 54: 588–593 [DOI] [PubMed] [Google Scholar]
- Bachstetter A.D., Morganti J.M., Jernberg J., Schlunk A., Mitchell S.H., Brewster K.W., et al. (2009) Fractalkine and CX(3)CR1 regulate hippocampal neurogenesis in adult and aged rats. Neurobiol Aging 15 December [Epub ahead of print]. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Baldereschi M., Di Carlo A., Lepore V., Bracco L., Maggi S., Grigoletto F., et al. (1998) Estrogen-replacement therapy and Alzheimer's disease in the Italian Longitudinal Study on Aging. Neurology 50: 996–1002 [DOI] [PubMed] [Google Scholar]
- Bales K.R., Du Y., Holtzman D., Cordell B., Paul S.M. (2000) Neuroinflammation and Alzheimer's disease: Critical roles for cytokine/Abetainduced glial activation, NF-kappaB, and apolipoprotein E. Neurobiol Aging 21: 427–432, discussion 451-423. [DOI] [PubMed] [Google Scholar]
- Barrientos R.M., Frank M.G., Hein A.M., Higgins E.A., Watkins L.R., Rudy J.W., et al. (2009) Time course of hippocampal IL-1 beta and memory consolidation impairments in aging rats following peripheral infection. Brain Behav Immun 23: 46–54 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Barrientos R.M., Higgins E.A., Biedenkapp J.C., Sprunger D.B., Wright-Hardesty K.J., Watkins L.R., et al. (2006) Peripheral infection and aging interact to impair hippocampal memory consolidation. Neurobiol Aging 27: 723–732 [DOI] [PubMed] [Google Scholar]
- Beloosesky Y., Hendel D., Weiss A., Hershkovitz A., Grinblat J., Pirotsky A., et al. (2007) Cytokines and C-reactive protein production in hip-fracture-operated elderly patients. J Gerontol A Biol Sci Med Sci 62: 420–426 [DOI] [PubMed] [Google Scholar]
- Berardi A., Parasuraman R., Haxby J.V. (2001) Overall vigilance and sustained attention decrements in healthy aging. Exp Aging Res 27: 19–39 [DOI] [PubMed] [Google Scholar]
- Biasucci L.M., Vitelli A., Liuzzo G., Altamura S., Caligiuri G., Monaco C., et al. (1996) Elevated levels of interleukin-6 in unstable angina. Circulation 94: 874–877 [DOI] [PubMed] [Google Scholar]
- Birren J.E., Schaie K.W., Abeles R.P., Gatz M., Salthouse T.A. (2006) Handbook of the Psychology of Aging, 6th edn, Elsevier Academic Press: Amsterdam, Boston, p. xxi [Google Scholar]
- Blurton-Jones M.M., Roberts J.A., Tuszynski M.H. (1999) Estrogen receptor immunoreactivity in the adult primate brain: Neuronal distribution and association with p75, trkA, and choline acetyltransferase. J Comp Neurol 405: 529–542 [PubMed] [Google Scholar]
- Bonow R.H., Aid S., Zhang Y., Becker K.G., Bosetti F. (2009) The brain expression of genes involved in inflammatory response, the ribosome, and learning and memory is altered by centrally injected lipopolysaccharide in mice. Pharmacogenomics J 9: 116–126 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bowling A. (2005) Ageing Well: Quality of Life in Old Age, Open University Press: Maidenhead, New York, p. ix [Google Scholar]
- Bremmer M.A., Beekman A.T., Deeg D.J., Penninx B.W., Dik M.G., Hack C.E., et al. (2008) Inflammatory markers in late-life depression: Results from a population-based study. J Affect Disord 106: 249–255 [DOI] [PubMed] [Google Scholar]
- Breitner J.C., Haneuse S.J., Walker R., Dublin S., Crane P.K., Gray S.L., et al. (2009) Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort. Neurology 72: 1899–1905 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brinkley T.E., Leng X., Miller M.E., Kitzman D.W., Pahor M., Berry M.J., et al. (2009) Chronic inflammation is associated with low physical function in older adults across multiple comorbidities. J Gerontol A Biol Sci Med Sci 64: 455–461 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Buchanan J.B., Sparkman N.L., Chen J., Johnson R.W. (2008) Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice. Psychoneuroendocrinology 33: 755–765 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Butovsky O., Koronyo-Hamaoui M., Kunis G., Ophir E., Landa G., Cohen H., et al. (2006) Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulinlike growth factor 1. Proc Natl Acad Sci USA 103: 11784–11789 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cahn-Weiner D.A., Boyle P.A., Malloy P.F. (2002) Tests of executive function predict instrumental activities of daily living in community-dwelling older individuals. Appl Neuropsychol 9: 187–191 [DOI] [PubMed] [Google Scholar]
- Campuzano O., Castillo-Ruiz M.M., Acarin L., Castellano B., Gonzalez B. (2009) Increased levels of proinflammatory cytokines in the aged rat brain attenuate injury-induced cytokine response after excitotoxic damage. J Neurosci Res 87: 2484–2497 [DOI] [PubMed] [Google Scholar]
- Cederholm T., Palmblad J. (2010) Are omega-3 fatty acids options for prevention and treatment of cognitive decline and dementia? Curr Opin Clin Nutr Metab Care 13: 150–155 [DOI] [PubMed] [Google Scholar]
- Cerejeira J., Firmino H., Vaz-Serra A., Mukaetova-Ladinska E.B. (2010) The neuroinflammatory hypothesis of delirium. Acta Neuropathol 119: 737–754 [DOI] [PubMed] [Google Scholar]
- Chao L.L., Knight R.T. (1997) Prefrontal deficits in attention and inhibitory control with aging. Cereb Cortex 7: 63–69 [DOI] [PubMed] [Google Scholar]
- Churchill J.D., Stanis J.J., Press C., Kushelev M., Greenough W.T. (2003) Is procedural memory relatively spared from age effects? Neurobiol Aging 24: 883–892 [DOI] [PubMed] [Google Scholar]
- Clifford D.B., De Luca A., Simpson D.M., Arendt G., Giovannoni G., Nath A. (2010) Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: Lessons from 28 cases. Lancet Neurol 9: 438–446 [DOI] [PubMed] [Google Scholar]
- Codarri L., Fontana A., Becher B. (2010) Cytokine networks in multiple sclerosis: Lost in translation. Curr Opin Neurol 23: 205–211 [DOI] [PubMed] [Google Scholar]
- Cohen H.J., Pieper C.F., Harris T., Rao K.M., Currie M.S. (1997) The association of plasma IL-6 levels with functional disability in community-dwelling elderly. J Gerontol A Biol Sci Med Sci 52: M201–M208 [DOI] [PubMed] [Google Scholar]
- Colman R.J., Anderson R.M., Johnson S.C., Kastman E.K., Kosmatka K.J., Beasley T.M., et al. (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325: 201–204 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Conde J.R., Streit W.J. (2006) Microglia in the aging brain. J Neuropathol Exp Neurol 65: 199–203 [DOI] [PubMed] [Google Scholar]
- Craik F.I.M., Salthouse T.A. (2007) The Handbook of Aging and Cognition, 3rd edn, New York: Psychology Press [Google Scholar]
- Cunningham C., Campion S., Lunnon K., Murray C.L., Woods J.F., Deacon R.M., et al. (2009) Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry 65: 304–312 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Daum I., Graber S., Schugens M.M., Mayes A.R. (1996) Memory dysfunction of the frontal type in normal ageing. Neuroreport 7: 2625–2628 [DOI] [PubMed] [Google Scholar]
- de Rooij S.E., van Munster B.C., Korevaar J.C., Levi M. (2007) Cytokines and acute phase response in delirium. J Psychosom Res 62: 521–525 [DOI] [PubMed] [Google Scholar]
- Dean O., Giorlando F., Berk M. (2010) N-acetylcysteine in psychiatry: Current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci 35: 100057. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dello Russo C., Lisi L., Tringali G., Navarra P. (2009) Involvement of mTOR kinase in cytokinedependent microglial activation and cell proliferation. Biochem Pharmacol 78: 1242–1251 [DOI] [PubMed] [Google Scholar]
- Deng X.H., Bertini G., Palomba M., Xu Y.Z., Bonaconsa M., Nygard M., et al. (2010) Glial transcripts and immune-challenged glia in the suprachiasmatic nucleus of young and aged mice. Chronobiol Int 27: 742–767 [DOI] [PubMed] [Google Scholar]
- Dentino A.N., Pieper C.F., Rao M.K., Currie M.S., Harris T., Blazer D.G., et al. (1999) Association of interleukin-6 and other biologic variables with depression in older people living in the community. J Am Geriatr Soc 47: 6–11 [DOI] [PubMed] [Google Scholar]
- Desai A.K., Grossberg G.T., Chibnall J.T. (2010) Healthy brain aging: A road map. Clin Geriatr Med 26: 1–16 [DOI] [PubMed] [Google Scholar]
- Dik M.G., Jonker C., Hack C.E., Smit J.H., Comijs H.C., Eikelenboom P. (2005) Serum inflammatory proteins and cognitive decline in older persons. Neurology 64: 1371–1377 [DOI] [PubMed] [Google Scholar]
- Dilger R.N., Johnson R.W. (2008) Aging, microglial cell priming, and the discordant central inflammatory response to signals from the peripheral immune system. J Leukoc Biol 84: 932–939 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dodge H.H., Kadowaki T., Hayakawa T., Yamakawa M., Sekikawa A., Ueshima H. (2005) Cognitive impairment as a strong predictor of incident disability in specific ADL-IADL tasks among community-dwelling elders: The Azuchi Study. Gerontologist 45: 222–230 [DOI] [PubMed] [Google Scholar]
- Dolan R.J., Fletcher P.C. (1997) Dissociating prefrontal and hippocampal function in episodic memory encoding. Nature 388: 582–585 [DOI] [PubMed] [Google Scholar]
- Dumitriu D., Hao J., Hara Y., Kaufmann J., Janssen W.G., Lou W., et al. (2010) Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment. J Neurosci 30: 7507–7515 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Eikelenboom P., Hoogendijk W.J., Jonker C., van Tilburg W. (2002) Immunological mechanisms and the spectrum of psychiatric syndromes in Alzheimer's disease. J Psychiatr Res 36: 269–280 [DOI] [PubMed] [Google Scholar]
- Eikelenboom P., van Gool W.A. (2004) Neuroinflammatory perspectives on the two faces of Alzheimer's disease. J Neural Transm 111: 281–294 [DOI] [PubMed] [Google Scholar]
- Eikelenboom P., Veerhuis R., Scheper W., Rozemuller A.J., van Gool W.A., Hoozemans J.J. (2006) The significance of neuroinflammation in understanding Alzheimer's disease. J Neural Transm 113: 1685–1695 [DOI] [PubMed] [Google Scholar]
- Elison S., Shears D., Nadel S., Sahakian B., Garralda M.E. (2008) Neuropsychological function in children following admission to paediatric intensive care: A pilot investigation. Intensive Care Med 34: 1289–1293 [DOI] [PubMed] [Google Scholar]
- Erraji-Benchekroun L., Underwood M.D., Arango V., Galfalvy H., Pavlidis P., Smyrniotopoulos P., et al. (2005) Molecular aging in human prefrontal cortex is selective and continuous throughout adult life. Biol Psychiatry 57: 549–558 [DOI] [PubMed] [Google Scholar]
- Ferrucci L., Harris T.B., Guralnik J.M., Tracy R.P., Corti M.C., Cohen H.J., et al. (1999) Serum IL-6 level and the development of disability in older persons. J Am Geriatr Soc 47: 639–646 [DOI] [PubMed] [Google Scholar]
- Fletcher P.C., Shallice T., Dolan R.J. (1998) The functional roles of prefrontal cortex in episodic memory. I. Encoding. Brain 121: 1239–1248 [DOI] [PubMed] [Google Scholar]
- Frank M.G., Barrientos R.M., Hein A.M., Biedenkapp J.C., Watkins L.R., Maier S.F. (2010) IL-1RA blocks E. coli-induced suppression of Arc and long-term memory in aged F344xBN F1 rats. Brain Behav Immun 24: 254–262 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fuster J.M. (1997) The Prefrontal Cortex: Anatomy, Physiology, and Neuropsychology of the Frontal Lobe, 3rd edn, Lippincott-Raven: Philadelphia, p. xvi [Google Scholar]
- Gao L., Taha R., Gauvin D., Othmen L.B., Wang Y., Blaise G. (2005) Postoperative cognitive dysfunction after cardiac surgery. Chest 128: 3664–3670 [DOI] [PubMed] [Google Scholar]
- Gazzaley A., Cooney J.W., Rissman J., D'Esposito M. (2005) Top-down suppression deficit underlies working memory impairment in normal aging. Nat Neurosci 8: 1298–1300 [DOI] [PubMed] [Google Scholar]
- Gemma C., Fister M., Hudson C., Bickford P.C. (2005) Improvement of memory for context by inhibition of caspase-1 in aged rats. Eur J Neurosci 22: 1751–1756 [DOI] [PubMed] [Google Scholar]
- Gimeno D., Marmot M.G., Singh-Manoux A. (2008) Inflammatory markers and cognitive function in middle-aged adults: The Whitehall II study. Psychoneuroendocrinology 33: 1322–1334 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Godbout J.P., Chen J., Abraham J., Richwine A.F., Berg B.M., Kelley K.W., et al. (2005) Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J 19: 1329–1331 [DOI] [PubMed] [Google Scholar]
- Gomez-Isla T., Blesa R., Boada M., Clarimon J., Del Ser T., Domenech G., et al. (2008) A randomized, double-blind, placebo controlled-trial of triflusal in mild cognitive impairment: The TRIMCI study. Alzheimer Dis Assoc Disord 22: 21–29 [DOI] [PubMed] [Google Scholar]
- Grady C.L., McIntosh A.R., Craik F.I. (2003) Age-related differences in the functional connectivity of the hippocampus during memory encoding. Hippocampus 13: 572–586 [DOI] [PubMed] [Google Scholar]
- Green M.F. (2006) Cognitive impairment and functional outcome in schizophrenia and bipolar disorder. J Clin Psychiatry 67 (Suppl 9): 3–8; discussion 36-42. [PubMed] [Google Scholar]
- Griffin R., Nally R., Nolan Y., McCartney Y., Linden J., Lynch M.A. (2006) The age-related attenuation in long-term potentiation is associated with microglial activation. J Neurochem 99: 1263–1272 [DOI] [PubMed] [Google Scholar]
- Grigoleit J.S., Oberbeck J.R., Lichte P., Kobbe P., Wolf O.T., Montag T., et al. (2010) Lipopolysaccharide-induced experimental immune activation does not impair memory functions in humans. Neurobiol Learn Mem 94: 561–567 [DOI] [PubMed] [Google Scholar]
- Gundlah C., Kohama S.G., Mirkes S.J., Garyfallou V.T., Urbanski H.F., Bethea C.L. (2000) Distribution of estrogen receptor beta (ERbeta) mRNA in hypothalamus, midbrain and temporal lobe of spayed macaque: Continued expression with hormone replacement. Brain Res Mol Brain Res 76: 191–204 [DOI] [PubMed] [Google Scholar]
- Halliday G., Robinson S.R., Shepherd C., Kril J. (2000) Alzheimer's disease and inflammation: A review of cellular and therapeutic mechanisms. Clin Exp Pharmacol Physiol 27: 1–8 [DOI] [PubMed] [Google Scholar]
- Hasher L., Zacks R.T. (1988) Working memory, comprehension, and aging: A review and a new view, In: The Psychology of Learning and Motivation, Bower G.H. (ed.), Academic Press: New York, Vol. 22, pp. 193–225 [Google Scholar]
- Hauss-Wegrzyniak B., Lynch M.A., Vraniak P.D., Wenk G.L. (2002) Chronic brain inflammation results in cell loss in the entorhinal cortex and impaired LTP in perforant path-granule cell synapses. Exp Neurol 176: 336–341 [DOI] [PubMed] [Google Scholar]
- Hein A.M., Stasko M.R., Matousek S.B., Scott-McKean J.J., Maier S.F., Olschowka J.A., et al. (2010) Sustained hippocampal IL-1beta overexpression impairs contextual and spatial memory in transgenic mice. Brain Behav Immun 24: 243–253 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Henderson V.W., Paganini-Hill A., Miller B.L., Elble R.J., Reyes P.F., Shoupe D., et al. (2000) Estrogen for Alzheimer's disease in women: Randomized, double-blind, placebo-controlled trial. Neurology 54: 295–301 [DOI] [PubMed] [Google Scholar]
- Heneka M.T., O'Banion M.K. (2007) Inflammatory processes in Alzheimer's disease. J Neuroimmunol 184: 69–91 [DOI] [PubMed] [Google Scholar]
- Henry C.J., Huang Y., Wynne A., Hanke M., Himler J., Bailey M.T., et al. (2008) Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflammation 5: 15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heyser C.J., Masliah E., Samimi A., Campbell I.L., Gold L.H. (1997) Progressive decline in avoidance learning paralleled by inflammatory neurodegeneration in transgenic mice expressing interleukin 6 in the brain. Proc Natl Acad Sci USA 94: 1500–1505 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hikosaka O., Nakamura K., Sakai K., Nakahara H. (2002) Central mechanisms of motor skill learning. Curr Opin Neurobiol 12: 217–222 [DOI] [PubMed] [Google Scholar]
- Hilsabeck R.C., Anstead G.M., Webb A.L., Hoyumpa A., Ingmundson P., Holliday S., et al. (2010) Cognitive efficiency is associated with endogenous cytokine levels in patients with chronic hepatitis C. J Neuroimmunol 221: 53–61 [DOI] [PubMed] [Google Scholar]
- Hirshler Y.K., Polat U., Biegon A. (2010) Intracranial electrode implantation produces regional neuroinflammation and memory deficits in rats. Exp Neurol 222: 42–50 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Holden J.M., Meyers-Manor J.E., Overmier J.B., Gahtan E., Sweeney W., Miller H. (2008) Lipopolysaccharide-induced immune activation impairs attention but has little effect on short-term working memory. Behav Brain Res 194: 138–145 [DOI] [PubMed] [Google Scholar]
- Holmes C., Cunningham C., Zotova E., Woolford J., Dean C., Kerr S., et al. (2009) Systemic inflammation and disease progression in Alzheimer disease. Neurology 73: 768–774 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hoth K.F., Haley A.P., Gunstad J., Paul R.H., Poppas A., Jefferson A.L., et al. (2008) Elevated C-reactive protein is related to cognitive decline in older adults with cardiovascular disease. J Am Geriatr Soc 56: 1898–1903 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hughes Z.A., Liu F., Marquis K., Muniz L., Pangalos M.N., Ring R.H., et al. (2009) Estrogen receptor neurobiology and its potential for translation into broad spectrum therapeutics for CNS disorders. Curr Mol Pharmacol 2: 215–236 [DOI] [PubMed] [Google Scholar]
- Imbimbo B.P. (2009) An update on the efficacy of non-steroidal anti-inflammatory drugs in Alzheimer's disease. Expert Opin Investig Drugs 18: 1147–1168 [DOI] [PubMed] [Google Scholar]
- Inzitari M., Carlo A., Baldereschi M., Pracucci G., Maggi S., Gandolfo C., et al. (2006) Risk and predictors of motor-performance decline in a normally functioning population-based sample of elderly subjects: The Italian Longitudinal Study on Aging. JAm Geriatr Soc 54: 318–324 [DOI] [PubMed] [Google Scholar]
- Jetter W., Poser U., Freeman R.B., Jr, Markowitsch H.J. (1986) A verbal long term memory deficit in frontal lobe damaged patients. Cortex 22: 229–242 [DOI] [PubMed] [Google Scholar]
- Johnson J.K., Lui L.-Y., Yaffe K. (2007) Executive function, more than global cognition, predicts functional decline and mortality in elderly women. J Gerontol A Biol Sci Med Sci 62: 1134–1141 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kapahi P., Chen D., Rogers A.N., Katewa S.D., Li P.W., Thomas E.L., et al. (2010) With TOR, less is more: A key role for the conserved nutrient-sensing TOR pathway in aging. Cell Metab 11: 453–465 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kelly A., Lynch A., Vereker E., Nolan Y., Queenan P., Whittaker E., et al. (2001) The anti-inflammatory cytokine, interleukin (IL)-10, blocks the inhibitory effect of IL-1 beta on long term potentiation. A role for JNK. J Biol Chem 276: 45564–45572 [DOI] [PubMed] [Google Scholar]
- Kelly A., Vereker E., Nolan Y., Brady M., Barry C., Loscher C.E., et al. (2003) Activation of p38 plays a pivotal role in the inhibitory effect of lipopolysaccharide and interleukin-1 beta on long term potentiation in rat dentate gyrus. J Biol Chem 278: 19453–19462 [DOI] [PubMed] [Google Scholar]
- Kertesz A. (2006) Progress in clinical neurosciences: Frontotemporal dementia-pick's disease. Can J Neurol Sci 33: 141–148 [DOI] [PubMed] [Google Scholar]
- Knudsen E.I. (2007) Fundamental components of attention. Annu Rev Neurosci 30: 57–78 [DOI] [PubMed] [Google Scholar]
- Koo J.W., Duman R.S. (2008) IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci USA 105: 751–756 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kostulas N., Kivisakk P., Huang Y., Matusevicius D., Kostulas V., Link H. (1998) Ischemic stroke is associated with a systemic increase of blood mononuclear cells expressing interleukin-8 mRNA. Stroke 29: 462–466 [DOI] [PubMed] [Google Scholar]
- Ladwig K.H., Marten-Mittag B., Lowel H., Doring A., Koenig W. (2005) C-reactive protein, depressed mood, and the prediction of coronary heart disease in initially healthy men: Results from the Monica-Kora Augsburg Cohort Study 1984-1998. Eur Heart J 26: 2537–2542 [DOI] [PubMed] [Google Scholar]
- Laforce R., Jr, Doyon J. (2001) Distinct contribution of the striatum and cerebellum to motor learning. Brain Cogn 45: 189–211 [DOI] [PubMed] [Google Scholar]
- Laforce R., Jr, Doyon J. (2002) Differential role for the striatum and cerebellum in response to novel movements using a motor learning paradigm. Neuropsychologia 40: 512–517 [DOI] [PubMed] [Google Scholar]
- Lemke R., Hartig W., Rossner S., Bigl V., Schliebs R. (1998) Interleukin-6 is not expressed in activated microglia and in reactive astrocytes in response to lesion of rat basal forebrain cholinergic system as demonstrated by combined in situ hybridization and immunocytochemistry. J Neurosci Res 51: 223–236 [DOI] [PubMed] [Google Scholar]
- Lewitus G.M., Zhu J., Xiong H., Hallworth R., Kipnis J. (2007) CD4(+)CD25(-) effector T-cells inhibit hippocampal long-term potentiation in vitro. Eur J Neurosci 26: 1399–1406 [DOI] [PubMed] [Google Scholar]
- Li W.Z., Li W.P., Yao Y.Y., Zhang W., Yin Y.Y., Wu G.C., et al. (2010) Glucocorticoids increase impairments in learning and memory due to elevated amyloid precursor protein expression and neuronal apoptosis in 12-month old mice. Eur J Pharmacol 628: 108–115 [DOI] [PubMed] [Google Scholar]
- Lockwood K.A., Alexopoulos G.S., van Gorp W.G. (2002) Executive dysfunction in geriatric depression. Am J Psychiatry 159: 1119–1126 [DOI] [PubMed] [Google Scholar]
- Logan J.M., Sanders A.L., Snyder A.Z., Morris J.C., Buckner R.L. (2002) Under-recruitment and nonselective recruitment: Dissociable neural mechanisms associated with aging. Neuron 33: 827–840 [DOI] [PubMed] [Google Scholar]
- Lukiw W.J., Bazan N.G. (2000) Neuroinflammatory signaling upregulation in Alzheimer's disease. Neurochem Res 25: 1173–1184 [DOI] [PubMed] [Google Scholar]
- Lustig C., May C.P., Hasher L. (2001) Working memory span and the role of proactive interference. J Exp Psychol Gen 130: 199–207 [DOI] [PubMed] [Google Scholar]
- Lyketsos C.G., Breitner J.C., Green R.C., Martin B.K., Meinert C., Piantadosi S., et al. (2007) Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology 68: 1800–1808 [DOI] [PubMed] [Google Scholar]
- Lynch A.M., Walsh C., Delaney A., Nolan Y., Campbell V.A., Lynch M.A. (2004) Lipopolysaccharide-induced increase in signalling in hippocampus is abrogated by IL-10—a role for IL-1 beta? J Neurochem 88: 635–646 [DOI] [PubMed] [Google Scholar]
- Magaki S., Mueller C., Dickson C., Kirsch W. (2007) Increased production of inflammatory cytokines in mild cognitive impairment. Exp Gerontol 42: 233–240 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Marsland A.L., Petersen K.L., Sathanoori R., Muldoon M.F., Neumann S.A., Ryan C., et al. (2006) Interleukin-6 covaries inversely with cognitive performance among middle-aged community volunteers. Psychosom Med 68: 895–903 [DOI] [PubMed] [Google Scholar]
- McColl B.W., Rothwell N.J., Allan S.M. (2008) Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice. J Neurosci 28: 9451–9462 [DOI] [PMC free article] [PubMed] [Google Scholar]
- McGeer E.G., McGeer P.L. (2003) Inflammatory processes in Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 27: 741–749 [DOI] [PubMed] [Google Scholar]
- McGeer P.L., McGeer E.G. (2002) Local neuroinflammation and the progression of Alzheimer's disease. J Neurovirol 8: 529–538 [DOI] [PubMed] [Google Scholar]
- McGuire L.C., Ford E.S., Ajani U.A. (2006) Cognitive functioning as a predictor of functional disability in later life. Am J Geriatr Psychiatry 14: 36–42 [DOI] [PubMed] [Google Scholar]
- McNaull B.B., Todd S., McGuinness B., Passmore A.P. (2010) Inflammation and antiinflammatory strategies for Alzheimer's disease - a mini-review. Gerontology 56: 3–14 [DOI] [PubMed] [Google Scholar]
- McRae A., Dahlstrom A., Polinsky R., Ling E.A. (1993) Cerebrospinal fluid microglial antibodies: Potential diagnostic markers for immune mechanisms in Alzheimer's disease. Behav Brain Res 57: 225–234 [DOI] [PubMed] [Google Scholar]
- Merck Institute of Aging & Health, Gerontological Society of America and Merck Company Foundation (2007) The state of aging and health in America, Washington, DC: Merck Institute of Aging & Health, p. v [Google Scholar]
- Mesulam M.M. (2000) Principles of Behavioral and Cognitive Neurology, 2nd edn, Oxford, New York: Oxford University Press, p. xviii [Google Scholar]
- Meyers C.A., Albitar M., Estey E. (2005) Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer 104: 788–793 [DOI] [PubMed] [Google Scholar]
- Miller K.R., Streit W.J. (2007) The effects of aging, injury and disease on microglial function: A case for cellular senescence. Neuron Glia Biol 3: 245–253 [DOI] [PubMed] [Google Scholar]
- Min S.S., Quan H.Y., Ma J., Han J.S., Jeon B.H., Seol G.H. (2009) Chronic brain inflammation impairs two forms of long-term potentiation in the rat hippocampal CA1 area. Neurosci Lett 456: 20–24 [DOI] [PubMed] [Google Scholar]
- Monje M.L., Toda H., Palmer T.D. (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302: 1760–1765 [DOI] [PubMed] [Google Scholar]
- Montague D., Weickert C.S., Tomaskovic-Crook E., Rothmond D.A., Kleinman J.E., Rubinow D.R. (2008) Oestrogen receptor alpha localisation in the prefrontal cortex of three mammalian species. J Neuroendocrinol 20: 893–903 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moore A.H., O'Banion M.K. (2002) Neuroinflammation and anti-inflammatory therapy for Alzheimer's disease. Adv Drug Deliv Rev 54: 1627–1656 [DOI] [PubMed] [Google Scholar]
- Moore A.H., Wu M., Shaftel S.S., Graham K.A., O'Banion M.K. (2009) Sustained expression of interleukin-1beta in mouse hippocampus impairs spatial memory. Neuroscience 164: 1484–1495 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Morales I., Farias G., Maccioni R.B. (2010) Neuroimmunomodulation in the pathogenesis of Alzheimer's disease. Neuroimmunomodulation 17: 202–204 [DOI] [PubMed] [Google Scholar]
- Motoki K., Kishi H., Hori E., Tajiri K., Nishijo H., Muraguchi A. (2009) The direct excitatory effect of IL-1beta on cerebellar Purkinje cell. Biochem Biophys Res Commun 379: 665–668 [DOI] [PubMed] [Google Scholar]
- Mulnard R.A., Cotman C.W., Kawas C., van Dyck C.H., Sano M., Doody R., et al. (2000) Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: A randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA 283: 1007–1015 [DOI] [PubMed] [Google Scholar]
- Munhoz C.D., Garcia-Bueno B., Madrigal J.L., Lepsch L.B., Scavone C., Leza J.C. (2008) Stress-induced neuroinflammation: Mechanisms and new pharmacological targets. Braz J Med Biol Res 41: 1037–1046 [DOI] [PubMed] [Google Scholar]
- Munhoz C.D., Lepsch L.B., Kawamoto E.M., Malta M.B., Lima S. Lde, Avellar M.C., et al. (2006) Chronic unpredictable stress exacerbates lipopolysac-charide-induced activation of nuclear factor-kappaB in the frontal cortex and hippocampus via glucocorticoid secretion. J Neurosci 26: 3813–3820 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Murray C.A., Lynch M.A. (1998) Evidence that increased hippocampal expression of the cytokine interleukin-1 beta is a common trigger for age- and stress-induced impairments in long-term potentiation. J Neurosci 18:2974–2981 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Murray C., Sanderson D.J., Barkus C., Deacon R.M., Rawlins J.N., Bannerman D.M., et al. (2010) Systemic inflammation induces acute working memory deficits in the primed brain: Relevance for delirium. Neurobiol Aging 12 May [Epub ahead of print]. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Myers J.S., Pierce J., Pazdernik T. (2008) Neurotoxicology of chemotherapy in relation to cytokine release, the blood-brain barrier, and cognitive impairment. Oncol Nurs Forum 35: 916–920 [DOI] [PubMed] [Google Scholar]
- Nilsson L.G. (2003) Memory function in normal aging. Acta Neurol Scand Suppl 179: 7–13 [DOI] [PubMed] [Google Scholar]
- Nilsson L.G., Bäckman L., Erngrund K., Nyberg L., Adolfsson R., Bucht G., et al. (1997) The Betula prospective cohort study: Memory, health, and aging. Aging Neuropsychol Cognition 4: 1–32 [Google Scholar]
- Njie E.G., Boelen E., Stassen F.R., Steinbusch H.W., Borchelt D.R., Streit W.J. (2010) Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol Aging 25 June [Epub ahead of print]. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Noble J.M., Manly J.J., Schupf N., Tang M.X., Mayeux R., Luchsinger J.A. (2010) Association of C-reactive protein with cognitive impairment. Arch Neurol 67: 87–92 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Penninx B.W., Deeg D.J., van Eijk J.T., Beekman A.T., Guralnik J.M. (2000) Changes in depression and physical decline in older adults: A longitudinal perspective. J Affect Disord 61: 1–12 [DOI] [PubMed] [Google Scholar]
- Penninx B.W., Kritchevsky S.B., Newman A.B., Nicklas B.J., Simonsick E.M., Rubin S., et al. (2004) Inflammatory markers and incident mobility limitation in the elderly. Journal of the American Geriatrics Society 52: 1105–1113 [DOI] [PubMed] [Google Scholar]
- Penninx B.W., Kritchevsky S.B., Yaffe K., Newman A.B., Simonsick E.M., Rubin S., et al. (2003) Inflammatory markers and depressed mood in older persons: Results from the health, aging and body composition study. Biol Psychiatry 54: 566–572 [DOI] [PubMed] [Google Scholar]
- Peters A., Sethares C., Moss M.B. (1998) The effects of aging on layer 1 in area 46 of prefrontal cortex in the rhesus monkey. Cereb Cortex 8: 671–684 [DOI] [PubMed] [Google Scholar]
- Pfefferbaum A., Adalsteinsson E., Sullivan E.V. (2005) Frontal circuitry degradation marks healthy adult aging: Evidence from diffusion tensor imaging. Neuroimage 26: 891–899 [DOI] [PubMed] [Google Scholar]
- Pietschmann P., Gollob E., Brosch S., Hahn P., Kudlacek S., Willheim M., et al. (2003) The effect of age and gender on cytokine production by human peripheral blood mononuclear cells and markers of bone metabolism. Exp Gerontol 38: 1119–1127 [DOI] [PubMed] [Google Scholar]
- Pompl P.N., Yemul S., Xiang Z., Ho L., Haroutunian V., Purohit D., et al. (2003) Caspase gene expression in the brain as a function of the clinical progression of Alzheimer disease. Arch Neurol 60: 369–376 [DOI] [PubMed] [Google Scholar]
- Popescu B.O., Toescu E.C., Popescu L.M., Bajenaru O., Muresanu D.F., Schultzberg M., et al. (2009) Blood-brain barrier alterations in ageing and dementia. J Neurol Sci 283: 99–106 [DOI] [PubMed] [Google Scholar]
- Prolla T.A. (2002) DNA microarray analysis of the aging brain. Chem Senses 27: 299–306 [DOI] [PubMed] [Google Scholar]
- Rabbitt P., Lowe C. (2000) Patterns of cognitive ageing. Psychol Res 63: 308–316 [DOI] [PubMed] [Google Scholar]
- Rafnsson S.B., Deary I.J., Smith F.B., Whiteman M.C., Rumley A., Lowe G.D., et al. (2007) Cognitive decline and markers of inflammation and hemostasis: The Edinburgh Artery Study. J Am Geriatr Soc 55: 700–707 [DOI] [PubMed] [Google Scholar]
- Raji M.A., Al Snih S., Ray L.A., Patel K.V., Markides K.S. (2004) Cognitive status and incident disability in older Mexican Americans: Findings from the Hispanic established population for the epidemiological study of the elderly. Ethnicity Dis 14: 26–31 [PubMed] [Google Scholar]
- Ramaiah R., Lam A.M. (2009) Postoperative cognitive dysfunction in the elderly. Anesthesiol Clin 27: 485–496 [DOI] [PubMed] [Google Scholar]
- Rasmussen L.S. (2006) Postoperative cognitive dysfunction: Incidence and prevention. Best Pract Res Clin Anaesthesiol 20: 315–330 [DOI] [PubMed] [Google Scholar]
- Reichenberg A., Yirmiya R., Schuld A., Kraus T., Haack M., Morag A., et al. (2001) Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 58: 445–452 [DOI] [PubMed] [Google Scholar]
- Richwine A.F., Sparkman N.L., Dilger R.N., Buchanan J.B., Johnson R.W. (2009) Cognitive deficits in interleukin-10-deficient mice after peripheral injection of lipopolysaccharide. Brain Behav Immun 23: 794–802 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rogers J., Webster S., Lue L.F., Brachova L., Civin W.H., Emmerling M., et al. (1996) Inflammation and Alzheimer's disease pathogenesis. Neurobiol Aging 17: 681–686 [DOI] [PubMed] [Google Scholar]
- Rosczyk H.A., Sparkman N.L., Johnson R.W. (2008) Neuroinflammation and cognitive function in aged mice following minor surgery. Exp Gerontol 43: 840–846 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rosi S., Vazdarjanova A., Ramirez-Amaya V., Worley P.F., Barnes C.A., Wenk G.L. (2006) Memantine protects against LPS-induced neuroinflammation, restores behaviorally-induced gene expression and spatial learning in the rat. Neuroscience 142: 1303–1315 [DOI] [PubMed] [Google Scholar]
- Rothenburg L.S., Herrmann N., Swardfager W., Black S.E., Tennen G., Kiss A., et al. (2010) The relationship between inflammatory markers and post stroke cognitive impairment. J Geriatr Psychiatry Neurol 23: 199–205 [DOI] [PubMed] [Google Scholar]
- Royall D.R., Palmer R., Chiodo L.K., Polk M.J. (2005) Normal rates of cognitive change in successful aging: The freedom house study. J Int Neuropsychol Soc 11: 899–909 [DOI] [PubMed] [Google Scholar]
- Salthouse T.A. (1996) The processing-speed theory of adult age differences in cognition. Psychol Rev 103: 403–428 [DOI] [PubMed] [Google Scholar]
- Schacter L. Daniel. (1987) Implicit memory: History and current status. J Exp Psychol Learning Memory Cogn 13: 501–518 [Google Scholar]
- Schram M.T., Euser S.M., de Craen A.J., Witteman J.C., Frolich M., Hofman A., et al. (2007) Systemic markers of inflammation and cognitive decline in old age. J Am Geriatr Soc 55: 708–716 [DOI] [PubMed] [Google Scholar]
- Semmler A., Hermann S., Mormann F., Weberpals M., Paxian S.A., Okulla T., et al. (2008) Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism. J Neuroinflammation 5: 38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Serres S., Anthony D.C., Jiang Y., Broom K.A., Campbell S.J., Tyler D.J., et al. (2009) Systemic inflammatory response reactivates immune-mediated lesions in rat brain. J Neurosci 29: 4820–4828 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sheridan P.L., Solomont J., Kowall N., Hausdorff J.M. (2003) Influence of executive function on locomotor function: Divided attention increases gait variability in Alzheimer's disease. J Am Geriatr Soc 51: 1633–1637 [DOI] [PubMed] [Google Scholar]
- Sherwin B.B., Chertkow H., Schipper H., Nasreddine Z. (2009) A randomized controlled trial of estrogen treatment in men with mild cognitive impairment. Neurobiol Aging. [DOI] [PubMed] [Google Scholar]
- Shie F.S., Nivison M., Hsu P.C., Montine T.J. (2009) Modulation of microglial innate immunity in Alzheimer's disease by activation of peroxisome proliferator-activated receptor gamma. Curr Med Chem 16: 643–651 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shumaker S.A., Legault C., Rapp S.R., Thal L., Wallace R.B., Ockene J.K., et al. (2003) Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: The Women's Health Initiative Memory Study: A randomized controlled trial. JAMA 289: 2651–2662 [DOI] [PubMed] [Google Scholar]
- Singer T., Verhaeghen P., Ghisletta P., Lindenberger U., Baltes P.B. (2003) The fate of cognition in very old age: Six-year longitudinal findings in the Berlin Aging Study (BASE). Psychol Aging 18: 318–331 [DOI] [PubMed] [Google Scholar]
- Small G.W., Siddarth P., Silverman D.H., Ercoli L.M., Miller K.J., Lavretsky H., et al. (2008) Cognitive and cerebral metabolic effects of celecoxib versus placebo in people with age-related memory loss: Randomized controlled study. Am J Geriatr Psychiatry 16: 999–1009 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sparkman N.L., Johnson R.W. (2008) Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress. Neuroimmunomodulation 15: 323–330 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stebbins G.T., Carrillo M.C., Dorfman J., Dirksen C., Desmond J.E., Turner D.A., et al. (2002) Aging effects on memory encoding in the frontal lobes. Psychol Aging 17: 44–55 [DOI] [PubMed] [Google Scholar]
- Stewart J.C., Rand K.L., Muldoon M.F., Kamarck T.W. (2009) A prospective evaluation of the directionality of the depression-inflammation relationship. Brain Behav Immun 23: 936–944 [DOI] [PMC free article] [PubMed] [Google Scholar]
- St Jacques P.L., Levine B. (2007) Ageing and autobiographical memory for emotional and neutral events. Memory 15: 129–144 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Storer P.D., Xu J., Chavis J., Drew P.D. (2005) Peroxisome proliferator-activated receptor-gamma agonists inhibit the activation of microglia and astrocytes: Implications for multiple sclerosis. J Neuroimmunol 161: 113–122 [DOI] [PubMed] [Google Scholar]
- Stuck A.E., Walthert J.M., Nikolaus T., Bula C.J., Hohmann C., Beck J.C. (1999) Risk factors for functional status decline in community-living elderly people: A systematic literature review. Soc Sci Med 48: 445–469 [DOI] [PubMed] [Google Scholar]
- Studenski S., Carlson M.C., Fillit H., Greenough W.T., Kramer A., Rebok G.W. (2006) From bedside to bench: Does mental and physical activity promote cognitive vitality in late life? Sci Aging Knowledge Environ 2006: pe21. [DOI] [PubMed] [Google Scholar]
- Stuss D.T., Benson D.F. (1986) The Frontal Lobes, New York: Raven Press [Google Scholar]
- Swanberg M.M., Tractenberg R.E., Mohs R., Thal L.J., Cummings J.L. (2004) Executive dysfunction in Alzheimer disease. Arch Neurol 61: 556–560 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Swindell W.R. (2009) Genes and gene expression modules associated with caloric restriction and aging in the laboratory mouse. BMC Genomics 10: 585. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tan M.G., Chua W.T., Esiri M.M., Smith A.D., Vinters H.V., Lai M.K. (2010) Genome wide profiling of altered gene expression in the neocortex of Alzheimer's disease. J Neurosci Res 88: 1157–1169 [DOI] [PubMed] [Google Scholar]
- Tan Z.S., Beiser A.S., Vasan R.S., Roubenoff R., Dinarello C.A., Harris T.B., et al. (2007) Inflammatory markers and the risk of Alzheimer disease: The Framingham Study. Neurology 68: 1902–1908 [DOI] [PubMed] [Google Scholar]
- Tan Z.S., Seshadri S. (2010) Inflammation in the Alzheimer's disease cascade: Culprit or innocent bystander? Alzheimers Res Ther 2: 6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Terrando N., Fidalgo A. Rei, Vizcaychipi M., Cibelli M., Ma D., Monaco C., et al. (2010) The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction. Crit Care 14: R88. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thal L.J., Ferris S.H., Kirby L., Block G.A., Lines C.R., Yuen E., et al. (2005) A randomized, doubleblind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology 30: 1204–1215 [DOI] [PubMed] [Google Scholar]
- Tobinick E. (2007) Perispinal etanercept for treatment of Alzheimer's disease. Curr Alzheimer Res 4: 550–552 [DOI] [PubMed] [Google Scholar]
- Tobinick E.L., Gross H. (2008a) Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration. J Neuroinflammation 5: 2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tobinick E.L., Gross H. (2008b) Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer's disease. BMC Neurol 8: 27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tonelli L.H., Postolache T.T. (2005) Tumor necrosis factor alpha, interleukin-1 beta, interleukin-6 and major histocompatibility complex molecules in the normal brain and after peripheral immune challenge. Neurol Res 27: 679–684 [DOI] [PubMed] [Google Scholar]
- Tracy R.P., Lemaitre R.N., Psaty B.M., Ives D.G., Evans R.W., Cushman M., et al. (1997) Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol 17: 1121–1127 [DOI] [PubMed] [Google Scholar]
- Trepanier C.H., Milgram N.W. (2010) Neuroinflammation in Alzheimer's disease: Are NSAIDs and selective COX-2 inhibitors the next line of therapy? J Alzheimers Dis 6 August [Epub ahead of print]. [DOI] [PubMed] [Google Scholar]
- Trompet S., de Craen A.J., Slagboom P., Shepherd J., Blauw G.J., Murphy M.B., et al. (2008) Genetic variation in the interleukin-1 beta-converting enzyme associates with cognitive function. The PROSPER study. Brain 131: 1069–1077 [DOI] [PubMed] [Google Scholar]
- Tulving E. (1987) Multiple memory systems and consciousness. Hum Neurobiol 6: 67–80 [PubMed] [Google Scholar]
- Tuppo E.E., Arias H.R. (2005) The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol 37: 289–305 [DOI] [PubMed] [Google Scholar]
- Vaccarino V., Johnson B.D., Sheps D.S., Reis S.E., Kelsey S.F., Bittner V., et al. (2007) Depression, inflammation, and incident cardiovascular disease in women with suspected coronary ischemia: The National Heart, Lung, and Blood Institute-sponsored WISE study. J Am Coll Cardiol 50: 2044–2050 [DOI] [PubMed] [Google Scholar]
- Vallieres L., Campbell I.L., Gage F.H., Sawchenko P.E. (2002) Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 22: 486–492 [DOI] [PMC free article] [PubMed] [Google Scholar]
- van den Kommer T.N., Dik M.G., Comijs H.C., Jonker C., Deeg D.J. (2010) The role of lipoproteins and inflammation in cognitive decline: Do they interact? Neurobiol Aging 29 June [Epub ahead of print]. [DOI] [PubMed] [Google Scholar]
- van Gassen K.L., Netzeband J.G., de Graan P.N., Gruol D.L. (2005) The chemokine CCL2 modulates Ca2+ dynamics and electrophysiological properties of cultured cerebellar Purkinje neurons. Eur J Neurosci 21: 2949–2957 [DOI] [PubMed] [Google Scholar]
- Vila N., Castillo J., Davalos A., Chamorro A. (2000) Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke 31: 2325–2329 [DOI] [PubMed] [Google Scholar]
- von Bernhardi R., Tichauer J.E., Eugenin J. (2010) Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. J Neurochem 112: 1099–1114 [DOI] [PubMed] [Google Scholar]
- Wan Y., Xu J., Ma D., Zeng Y., Cibelli M., Maze M. (2007) Postoperative impairment of cognitive function in rats: A possible role for cytokinemediated inflammation in the hippocampus. Anesthesiology 106: 436–443 [DOI] [PubMed] [Google Scholar]
- Wang A.C., Hara Y., Janssen W.G., Rapp P.R., Morrison J.H. (2010) Synaptic estrogen receptor-alpha levels in prefrontal cortex in female rhesus monkeys and their correlation with cognitive performance. J Neurosci 30: 12770–12776 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wang W.F., Wu S.L., Liou Y.M., Wang A.L., Pawlak C.R., Ho Y.J. (2009) MPTP lesion causes neuroinflammation and deficits in object recognition in Wistar rats. Behav Neurosci 123: 1261–1270 [DOI] [PubMed] [Google Scholar]
- Warnke C., Menge T., Hartung H.P., Racke M.K., Cravens P.D., Bennett J.L., et al. (2010) Natalizumab and progressive multifocal leukoencephalopathy: What are the causal factors and can it be avoided? Arch Neurol 67: 923–930 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Watson G.S., Cholerton B.A., Reger M.A., Baker L.D., Plymate S.R., Asthana S., et al. (2005) Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: A preliminary study. Am J Geriatr Psychiatry 13: 950–958 [DOI] [PubMed] [Google Scholar]
- Wersching H., Duning T., Lohmann H., Mohammadi S., Stehling C., Fobker M., et al. (2010) Serum C-reactive protein is linked to cerebral microstructural integrity and cognitive function. Neurology 74: 1022–1029 [DOI] [PubMed] [Google Scholar]
- Wilson R.S., De Leon C.F. Mendes, Bennett D.A., Bienias J.L., Evans D.A. (2004) Depressive symptoms and cognitive decline in a community population of older persons. J Neurol Neurosurg Psychiatry 75: 126–129 [PMC free article] [PubMed] [Google Scholar]
- Wolf S.A., Tauber S., Ullrich O. (2008) CNS immune surveillance and neuroinflammation: Endocannabinoids keep control. Curr Pharm Des 14: 2266–2278 [DOI] [PubMed] [Google Scholar]
- Wratten M.L. (2008) Therapeutic approaches to reduce systemic inflammation in septic-associated neurologic complications. Eur J Anaesthesiol Suppl 42: 1–7 [DOI] [PubMed] [Google Scholar]
- Wyss-Coray T. (2006) Inflammation in Alzheimer disease: Driving force, bystander or beneficial response? Nat Med 12: 1005–1015 [DOI] [PubMed] [Google Scholar]
- Xie G., Zhang W., Chang Y., Chu Q. (2009) Relationship between perioperative inflammatory response and postoperative cognitive dysfunction in the elderly. Med Hypotheses 73: 402–403 [DOI] [PubMed] [Google Scholar]
- Yanagita M., Willcox B.J., Masaki K.H., Chen R., He Q., Rodriguez B.L., et al. (2006) Disability and depression: Investigating a complex relation using physical performance measures. Am J Geriatr Psychiatry 14: 1060–1068 [DOI] [PubMed] [Google Scholar]
- Yogev-Seligmann G., Hausdorff J.M., Giladi N. (2008) The role of executive function and attention in gait. Move Disord 23: 329–342, quiz 472. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zgaljardic D.J., Borod J.C., Foldi N.S., Mattis P.J., Gordon M.F., Feigin A., et al. (2006) An examination of executive dysfunction associated with frontostriatal circuitry in Parkinson's disease. J Clin Exp Neuropsychol 28: 1127–1144 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhang A., Hao S., Bi J., Bao Y., Zhang X., An L., et al. (2009) Effects of catalpol on mitochondrial function and working memory in mice after lipopolysaccharide-induced acute systemic inflammation. Exp Toxicol Pathol 61: 461–469 [DOI] [PubMed] [Google Scholar]
- Zhang F., Liu J., Shi J.S. (2010) Anti-inflammatory activities of resveratrol in the brain: Role of resveratrol in microglial activation. Eur J Pharmacol 636: 1–7 [DOI] [PubMed] [Google Scholar]
- Zhu S., Patel K.V., Bandinelli S., Ferrucci L., Guralnik J.M. (2009) Predictors of interleukin-6 elevation in older adults. J Am Geriatr Soc 57: 1672–1677 [DOI] [PMC free article] [PubMed] [Google Scholar]