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)
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.
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