Is inflammation driving cognitive decline in the elderly?
2011; Future Medicine; Volume: 7; Issue: 4 Linguagem: Inglês
10.2217/ahe.11.39
ISSN1745-5103
AutoresBrianne M. Bettcher, Joel H. Kramer,
Tópico(s)Neurological Disorders and Treatments
ResumoAging HealthVol. 7, No. 4 EditorialFree AccessIs inflammation driving cognitive decline in the elderly?Brianne Magouirk Bettcher & Joel H KramerBrianne Magouirk Bettcher† Author for correspondenceUniversity of California, San Francisco, Department of Neurology, Memory & Aging Center, 350 Parnassus Avenue, Suite 905, San Francisco, CA 94143, USA. & Joel H KramerUniversity of California, San Francisco, Department of Neurology, Memory & Aging Center, 350 Parnassus Avenue, Suite 905, San Francisco, CA 94143, USA. Published Online:12 Aug 2011https://doi.org/10.2217/ahe.11.39AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: cognitive declinecytokinesinflammationneurodegenerative diseaseA proposed immune mechanism that drives and potentially exacerbates cognitive decline in older adults has received considerable attention in the past decade, spawning an inflammatory hypothesis of cognitive aging and neurodegeneration [1]. Considering that inflammation has been implicated in a wide array of geriatric conditions, it is important to consider whether dysregulated immune responses are the primary cause of cognitive decline or are ancillary responses to underlying degenerative processes.In nonpathological states, inflammatory processes represent a normal response to infection that is critical for initiating tissue repair and maintaining homeostatic function [2]. However, as we age, our immune system undergoes a systemic recasting, rendering functional changes in immune cells and leaving smaller numbers of naive T-cells to ward off pathogens. The net yield of these changes is a dysregulated immune system, characterized by vulnerabilities to both suppression and overactivation of the immune system. Importantly, while inflammation is crucial to staving off infection, sustained inflammatory responses are damaging and even neurotoxic to brain cells. Converging evidence indicates that many older adults are susceptible to sustained inflammatory responses, as indexed by low-grade elevations of cytokines in the blood and cerebrospinal fluid; however, the mechanism and degree of impact on cognition remains unclear.Specifically, recent findings suggest that sustained inflammation may confer risk for accelerated cognitive decline and may even herald early stages of a neurodegenerative disease in older adults. In the context of cognitive testing, inflammation has primarily been implicated in impaired memory performance [3,4] and executive dysfunction [5,6], although isolated reports have also associated elevations in inflammatory cytokines with visuospatial functioning [3]. In line with neuropsychological results, structural imaging studies suggest that elevated or detectable levels of inflammation are associated with smaller hippocampi [7], reduced total brain volume [8] and lower white matter integrity [9]. However, particularly integral to the discussion is the relationship between inflammatory markers and cognition over time, as mild elevations in inflammatory markers may reflect underlying, progressive neuropathological changes rather than nondegenerative decline. Recent studies have demonstrated a relationship between IL-6, a pro-inflammatory cytokine, and decline in recognition memory, executive functions [5] and processing speed [10], but also suggest additional moderating factors, including APOE4 allele status [11] and the presence of metabolic syndrome [12]. Furthermore, elevated plasma markers of inflammation may also confer risk for later development of dementia [13] and have been demonstrated to predict conversion from mild cognitive impairment to Alzheimer's disease [14]. Collectively, these reports suggest a role for inflammation in both cross-sectional and longitudinal decline in cognitive performance; however, it is important to highlight that other studies have yielded no association with cognitive decline [15–17], suggesting that the relationship between inflammation and cognition might be tenuous or, more likely, might reflect multiple etiologies.In evaluating the controversy surrounding the putative role of inflammation in cognitive decline, the source of debate seems to stem less from a question of whether inflammation affects cognitive function, but rather points to questions of how, when and to what degree these processes might relate to clinical deterioration. Although these are inter-related concerns, the question of 'how' hones in on the issue of causality, as the inverse relationship between inflammation and cognition has frequently been interpreted as evidence for inflammatory pathogenesis in decline. However, the correlation is not necessarily tantamount to causality, as inflammation might play many mechanistic roles in decline. In addition to precipitating cognitive decline, if inflammation occurs in conjunction with a neurodegenerative disease, then its role might be reactionary in nature; thus, elevated inflammatory markers might be epiphenomena of neurodegeneration or may even reflect early attempts for the immune system to productively clear abnormal protein aggregation. In contrast to this potentially positive role in decline, there is also evidence suggesting that inflammation may exacerbate an underlying process, resulting in more rapid progression of the disease [18]. Precipitating, exacerbating and reactionary roles of inflammation in cognitive decline are all possible explanations for study findings, and are not mutually exclusive given the mixed profile of CNS inflammation.Consistent with concerns related to causality, it is also important to address the when of the inflammation debate. Considering that many markers and predictors of inflammation (e.g., lifestyle factors, stress and vascular risk) may be mitigated by appropriate therapeutic treatments, identifying the starting point and peak of inflammatory effects on cognition is of great importance. Despite broad-based interest in identifying early perpetrators of decline, little is known about how to ameliorate and potentially circumvent the impact of inflammation on cognitive functioning. While early epidemiological investigations of nonsteroidal anti-inflammatory drugs appeared promising, recent intervention trials have reported relatively lackluster benefits. One proposed explanation for these mixed results is that nonsteroidal anti-inflammatory drugs have been utilized in populations that already shows signs of neurodegeneration and cognitive complaints and thus, their therapeutic application may be too late in the process to truly confer benefit. A more comprehensive understanding of when inflammation exerts its deleterious effects and potentially how to harness its more favorable, disease-fighting mechanisms is crucial to the success of anti-inflammatory therapies.A final, related quandary is the degree to which inflammation affects cognitive decline, as this question queries to the strength and specificity of the relationship. In terms of strength, it is unclear whether the relationship between inflammation and cognition is truly linear or if inflammatory markers confer risk for decline only at high levels. Therefore, while some study results suggest dose effects, others have unearthed associations only when examining upper tertiles of inflammatory markers [16,17]. For example, in a recent longitudinal cohort study of high-functioning older adults, only individuals in the top tertile of IL-6 displayed increased risk of incident declines on a brief, global cognitive measure [17]. These differences may be caused by the inconsistency in laboratory analytes used in studies; however, it could also suggest a threshold effect, such that some cytokines in the inflammatory cascade may affect cognition only at a specific level, whereas other cytokines may exert gradual effects on cognitive function, even at low degrees of elevation. In line with this discussion, the degree to which inflammation affects specific cognitive domains (e.g., memory) remains inconclusive, and is often obscured by the use of global measures of cognitive function or gross composite scores. While preliminary evidence points to an association between inflammation and more severe memory impairments and executive dysfunction, subtle changes in other cognitive domains may also be present. In particular, inflammation-mediated changes in vascular permeability and endothelial functioning [19] might contribute to disproportionate slowing of processing speed and executive dysfunction, rather than visuospatial impairment. As such, investigating the level at which inflammation might interact with cognition, as well as the degree to which inflammation associates with specific cognitive functions, is imperative to our mechanistic understanding of inflammation in older adults.Is inflammation driving cognitive decline in the elderly? Collectively, the evidence suggests that sustained inflammation detrimentally impacts cognitive functioning and likely interacts with neurodegeneration; however, whether inflammation is primarily culpable for these changes or precipitates cognitive decline remains an unanswered question. Our understanding of how inflammation affects cognition and neurodegeneration is still in its infancy, with many questions remaining. Specifically, if inflammation accelerates cognitive decline, what are the neurobiological processes by which this happens? Is the mechanism caused by interruptions in long-term potentiation or even phagocytosis? Is it caused by increased apoptosis or mediated by vascular mechanisms? Rather than focusing solely on diagnostic differences in inflammatory markers or debating whether inflammation is a feature of cognitive deterioration, future studies should prioritize efforts to elucidate the various mechanisms by which inflammation might impact decline. Longitudinal studies are especially vital for investigating the etiology, temporal features and strength of the relationship between inflammation and cognitive functioning. Most importantly, information gleaned from future studies is crucial to solidifying how, when and to what degree anti-inflammatory intervention efforts might mitigate cognitive decline.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Bibliography1 Eikelenboom P, van Exel E, Hoozemans JJM, Veerhuis R, Rozemuller AJM, van Gool WA. 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Pharmacol.78,539–552 (2009).Medline CASGoogle ScholarFiguresReferencesRelatedDetailsCited ByLongitudinal Associations between Physical and Cognitive Performance among Community-Dwelling Older Adults13 April 2015 | PLOS ONE, Vol. 10, No. 4 Vol. 7, No. 4 Metrics History Published online 12 August 2011 Published in print August 2011 Information© Future Medicine LtdKeywordscognitive declinecytokinesinflammationneurodegenerative diseaseFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download
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