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Longitudinal Inflammation, Cognitive Decline, and Alzheimer's Disease: A Mini‐Review

Published on Oct 1, 2014in Clinical Pharmacology & Therapeutics6.336
· DOI :10.1038/clpt.2014.147
Brianne M. Bettcher21
Estimated H-index: 21
(UCSF: University of California, San Francisco),
Joel H. Kramer89
Estimated H-index: 89
(UCSF: University of California, San Francisco)
Abstract
Inflammation as a potential catalyst for cognitive decline and neurodegenerative disease has generated considerable interest over the past decade, and spawned numerous debates regarding the role of pro-inflammatory regulation in aging adults. Current research suggests that pro-inflammatory markers increase with age 1, display altered profiles in neurodegenerative diseases 2, and correlate with deleterious cognitive outcomes in late life 3, 4. In terms of underlying mechanisms, older adults with higher systemic levels of inflammatory markers have been shown to evidence smaller hippocampi 5 and medial temporal lobes 4 relative to those with low levels of inflammation. Over and above traditional vascular risk factors, recent evidence also suggests that inflammation induces changes in vascular permeability, endothelial function, and microvascular structure, all of which may contribute to the pathogenesis of cerebrovascular disease and affect white matter integrity 6, 7. Although the breadth of evidence suggests that inflammatory processes differentially change with age and disease states, it remains unclear if inflammation plays a fundamental role in defining clinical course. The repeated failure of anti-inflammatory therapy clinical trials brings the influential nature of inflammation into further question, as many trials have shown no effect of non-steroidal anti-inflammatory drug use on incident risk 8 or later development of Alzheimer’s disease 9. In line with this concern, prior reviews have aptly questioned whether pro-inflammatory processes are simply spectators of an already evolving pathophysiology or represent a critical lynchpin in the disease trajectory 10, 11. The vast majority of clinical research, however, has focused on cross-sectional examinations of inflammatory markers, rendering it difficult to determine the chronicity of inflammatory levels, much less to identify dynamic relationships with cognition and clinical function over time. In order to garner a preliminary understanding of how inflammatory markers change and possibly exert negative effects in neurodegenerative disease, longitudinal cohort analyses with multiple inflammatory markers are imperative. This review aims to synthesize recent research on the longitudinal association between inflammation and clinical presentation in older adults at risk for Alzheimer’s disease, and critically outline methodological considerations and unanswered questions for future research. Brief attention will be directed towards studies evaluating the predictive role of baseline inflammation in longitudinal cognitive decline, followed by a focused review of studies that a) incorporate two or more time points of inflammatory markers and b) evaluate cognitive decline or conversion to Alzheimer’s disease. Search terms used to identify studies included combinations of the following three categories: longitudinal [longitudinal or change]; aging [aging, older adult, or Alzheimer’s]; and inflammation [inflammation, inflammatory, cytokine, IL-1, IL-6, CRP, or TNF-alpha]. Of note, ‘cognitive decline’ was typically defined in studies as a decline in global cognitive functioning, but in some studies it was also referred to as declines on specific neuropsychological tests, namely episodic memory consolidation (e.g. delayed recall) and/or executive function measures.
  • References (39)
  • Citations (45)
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References39
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#1Andrea L. Metti (University of Pittsburgh)H-Index: 11
#2Kristine Yaffe (UCSF: University of California, San Francisco)H-Index: 116
Last. Jane A. Cauley (University of Pittsburgh)H-Index: 145
view all 7 authors...
Objectives: To determine the association between interleukin-6 (IL-6), IL-6 soluble receptor (sR), and soluble tumor necrosis factor receptor-1 (sTNF-R1) and cognitive status in the oldest-old women. Design: Twenty-year longitudinal cohort study. Setting: Four clinical sites in the United States. Participants: Women from the Study of Osteoporotic Fractures (N = 905; mean age 88.3 ± 2.8 at cognitive status adjudication). Measurements: At Year 20, cognitive status was adjudicated as normal, mild c...
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#1Thomas A. S. LimaH-Index: 1
#2Amanda L. AdlerH-Index: 1
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Background: circulating measures of inflammatory markers, such as C-reactive protein (CRP) have been associated with an increased risk of future cognitive decline. However, the nature of the relationship among the very old (>75 years) is unclear. Cross-sectional evidence suggests that elevated CRP may even be protective in this age group. This study examines these associations longitudinally. Methods: logistic regression was used to investigate the association between CRP and drop in cognitive p...
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#1Yael Rosenberg-Hasson (Stanford University)H-Index: 11
#2Leo Hansmann (Stanford University)H-Index: 8
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Multiplexed fluorescence or electrochemiluminescence immunoassays of soluble cytokines are commonly performed in the context of human serum or plasma, to look for disease biomarkers and to monitor the immune system in a simple and minimally invasive way. These assays provide challenges due to the complexities of the matrix (serum or plasma) and the presence of many cytokines near the limit of detection of the assay. Here, we compare the readout of matched serum and plasma samples, which are gene...
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Markers of Alzheimer’s disease (AD) are being widely sought with a number of studies suggesting blood measures of inflammatory proteins as putative biomarkers. Here we report findings from a panel of 27 cytokines and related proteins in over 350 subjects with AD, subjects with Mild Cognitive Impairment (MCI) and elderly normal controls where we also have measures of longitudinal change in cognition and baseline neuroimaging measures of atrophy. In this study, we identify five inflammatory protei...
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#1Andrea L. Metti (University of Pittsburgh)H-Index: 11
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SUMMARY Dementia is a huge public health concern today owing to the exponentially increasing number of older adults it affects each year, and there has been a large number of investigators looking at potential biomarkers of dementia. Peripheral inflammatory markers have emerged as one potential class of markers that may be useful in predicting those individuals at a greater risk of developing dementia, or in expounding the underlying mechanisms or pathways of this complex disease. Although some ...
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Chronic inflammation is a key component of aging-related pathologies (1). For example, higher levels of the inflammatory biomarker C-reactive protein (CRP) are associated with increased risk of cardiovascular and non-cardiovascular morbidity and mortality (2,3) as well as dementia, sarcopenia, and osteoporosis (4). Many studies have likewise shown associations of interleukin-6 (IL-6) with aging-related declines in physical and cognitive function, frailty, and increased risk of death in older adu...
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Neuropathological studies have revealed the presence of a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) in Alzheimer's disease (AD) brains. These constituents of innate immunity are involved in several crucial pathogenic events of the underlying pathological cascade in AD, and recent studies have shown that innate immunity is involved in the etiology of late-onset AD. Genome-wide association studies have demonstrated gene lo...
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