This is an interesting clinical study assessing the effects of acute systemic inflammatory events (associated with increased circulating levels of TNF) on long-term cognitive decline in a prospective cohort study of individuals with Alzheimer disease. It raises a set of questions regarding the role of peripheral inflammation on progressive neuronal dysfunction in AD and possibly other neurodegenerative diseases.

First, as the authors state, the role of systemic inflammation in the progression of neurodegeneration is supported by studies in animals models of AD (Cunningham et al., 2005; Kitazawa et al., 2005; Qiao et al., 2001; Sheng et al., 2003); similar findings have also been reported for PD (Frank-Cannon et al., 2008;   Read more

This is an interesting clinical study assessing the effects of acute systemic inflammatory events (associated with increased circulating levels of TNF) on long-term cognitive decline in a prospective cohort study of individuals with Alzheimer disease. It raises a set of questions regarding the role of peripheral inflammation on progressive neuronal dysfunction in AD and possibly other neurodegenerative diseases.

First, as the authors state, the role of systemic inflammation in the progression of neurodegeneration is supported by studies in animals models of AD (Cunningham et al., 2005; Kitazawa et al., 2005; Qiao et al., 2001; Sheng et al., 2003); similar findings have also been reported for PD (Frank-Cannon et al., 2008; Crews et al, 2007; Monahan et al, 2008). The extrapolation to human disease will be harder to establish, but is likely to be valid given that a number of chronic low-grade inflammatory conditions cited by the authors (atherosclerosis, diabetes, obesity) increase chronic systemic levels of TNF and are also risk factors for AD.

This study demonstrates a correlation between circulating levels of soluble TNF and a decline in cognitive performance. Whether TNF itself is causative or merely a surrogate biomarker, the elevated levels of TNF and other inflammatory cytokines (as per Wyss-Coray’s “communicome,” (Ray et al., 2007) are likely to increase peripheral immune traffic into the CNS. Although the role of the peripheral immune system in neuro-inflammatory responses in the CNS remain controversial, it is reasonable to think that as the blood-brain-barrier becomes more permeable with aging, recruitment of peripheral immune cells will increase and may become dysregulated in chronic neurodegenerative diseases. As such, acute systemic inflammatory conditions would be expected to increase peripheral immune traffic, in part aided by the increased levels of circulating cytokines such as TNF.

Furthermore, it is interesting to speculate that as long as the primary factors or triggers that cause sporadic AD (or other neurodegenerative diseases without a clear genetic cause) are unknown, an attractive hypothesis is that adult-onset chronic systemic diseases characterized by inflammation (such as arthritis, atherosclerosis, metabolic disorder, obesity, and type 2 diabetes) may be the culprit. The causality here will be difficult to establish but merits investigation. In fact, it is noteworthy that the subjects in the Holmes et al. study had a history of chronic conditions associated with increased peripheral inflammation (hypertension, hypercholesterolemia, and type 2 diabetes).

As the authors point out: “If systemic inflammation has different CNS consequences depending on relative activation state of the central innate immune system, reducing systemic inflammatory/TNF levels may prove beneficial to AD.” In direct relevance to the recent active immunization trials, identification of individuals with a heightened immune system and elevated TNF levels may be critical prior to immunotherapy.

View all comments by Malu G. Tansey

This paper is thought provoking. A number of past studies have shown elevated circulating levels of pro-inflammatory cytokines, including TNFα, in AD patients. However, that body of literature is controversial due to failure to consistently reproduce such results and validity issues stemming from low subject numbers. The current study asks a related, but different, question, namely: are acute systemic inflammatory events correlated with the rate of cognitive decline in AD? Strikingly, the authors find that acute inflammatory events associated with elevated circulating TNFα correlate with a twofold increase in the rate of cognitive decline over six months of follow-up, as measured by ADAS-cog scores. When the authors conducted an analysis of high versus low baseline TNFα levels, they found that AD patients in the former group had a fourfold increase in rate of cognitive decline over a six-month period. By comparison, subjects in the latter group showed stable ADAS-cog scores without evidence of cognitive decline.

These data provide powerful evidence—from 300 community-based...  Read more

This paper is thought provoking. A number of past studies have shown elevated circulating levels of pro-inflammatory cytokines, including TNFα, in AD patients. However, that body of literature is controversial due to failure to consistently reproduce such results and validity issues stemming from low subject numbers. The current study asks a related, but different, question, namely: are acute systemic inflammatory events correlated with the rate of cognitive decline in AD? Strikingly, the authors find that acute inflammatory events associated with elevated circulating TNFα correlate with a twofold increase in the rate of cognitive decline over six months of follow-up, as measured by ADAS-cog scores. When the authors conducted an analysis of high versus low baseline TNFα levels, they found that AD patients in the former group had a fourfold increase in rate of cognitive decline over a six-month period. By comparison, subjects in the latter group showed stable ADAS-cog scores without evidence of cognitive decline.

These data provide powerful evidence—from 300 community-based AD patients—that systemic inflammation associates with exacerbated cognitive decline in AD. These results dovetail with more than 25 epidemiologic studies that show as much as 50 percent reduced risk for AD associated with use of non-steroidal anti-inflammatory drugs. While these prior results have typically been interpreted as NSAIDs having a direct effect on the CNS, the current findings by Holmes et al. raise the intriguing possibility that NSAIDs may exert their protective effect(s) via suppressing peripheral inflammation.

View all comments by Terrence Town