We agree with Dr. Kamer that periodontitis probably plays an important role in disease progression in AD. Periodontitis is a good example of a peripheral chronic infectious disease known to be associated with the production of systemic pro-inflammatory cytokines including TNFalpha, IL-6 and IL-1beta. [5]
Following our laboratory and clinical findings [1,6] we would hypothesize that periodontitis has a detrimental effect on clinical progression in AD because the degenerating CNS produces an amplified cytokine response to systemic inflammation. However, periodontitis is only one of many chronic systemic inflammatory conditions that would have this effect and AD subjects may have many co-morbid conditions. [1] We believe that raised serum TNFalpha will remain an independent risk factor for cognitive decline even when correcting for specific peripheral biomarkers, in this case positive IgG antibodies, for periodontopathic bacteria. This argument should hold true when examining differences in serum TNFalpha levels and antibody markers in the cross-sectional case control study of AD and normal subjects.[3]
While the reported significant associations between positive IgG antibodies and serum TNFalpha with AD are interesting, it is not possible to assume causality from case control studies. For example, a decline in oral hygiene is a result—rather than a cause—of dementia. [7] Furthermore, not all studies have found evidence of raised serum TNFalpha in AD compared to controls. [8] This might be due to a lack of attention to possible confounders (e.g. cholinesterase inhibitors are associated with reductions in serum TNFalpha[1]) but it may be that what is most important is the central inflammatory response to the systemic inflammatory signal. In addition to further animal studies, we need to conduct longitudinal, cohort studies in humans to address these issues.
We agree that it is important to examine a number of serum inflammatory markers, including both pro- and anti-inflammatory markers. Our focus on TNFalpha does not imply that it is the only inflammatory marker of interest. Blood markers of acute and chronic systemic events are complex. The aged innate immune system is changing in ways that are only just beginning to be documented. [9]
References
5. D’Aiuto F, Parkar M, Andreou G, et al. Periodontitis and systemic inflammation: control of local infection is associated with a reduction in serum inflammatory markers. J Dent Research 2004;83:156-160.
6. Cunningham C, Wilcockson DC, Campion S, et al. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 2005;25:9275-9284.
7. Ship JA. Oral health of patients with Alzheimer’s Disease. J Am Dent Assoc 1992;123:53-58.
8. Ray S, Britschgi M, Herbert C, et al. Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signalling proteins. Nat Med 2007;13:1359-1362.
9. Thiem U, Niklaus D, Sehlhoff B, et al. C-reactive protein, severity of pneumonia and mortality in elderly, hospitalised patients with community-acquired pneumonia. Age Ageing 2009;38:693-697.
Disclosure: Prof. Holmes has received research support from the Alzheimer’s Society, the UK Department of Health, and the Medical Research Council. Dr. Cunningham has received non–industry-sponsored funding for travel and receives research support from the Wellcome Trust; his sister is an employee of Wyeth Pharmaceuticals. Prof. Perry has received honoraria from the Danish Research Council and UCB; and receives research support from the European Union, the Medical Research Council, the Biotechnology and Biological Sciences Research Council, and Wellcome Trust. Ms. Zotova, Ms. Woolford, Ms. Dean, Ms. Kerr, and Mr. Culliford report no disclosures.
We agree with Dr. Kamer that periodontitis probably plays an important role in disease progression in AD. Periodontitis is a good example of a peripheral chronic infectious disease known to be associated with the production of systemic pro-inflammatory cytokines including TNFalpha, IL-6 and IL-1beta. [5]
Following our laboratory and clinical findings [1,6] we would hypothesize that periodontitis has a detrimental effect on clinical progression in AD because the degenerating CNS produces an amplified cytokine response to systemic inflammation. However, periodontitis is only one of many chronic systemic inflammatory conditions that would have this effect and AD subjects may have many co-morbid conditions. [1] We believe that raised serum TNFalpha will remain an independent risk factor for cognitive decline even when correcting for specific peripheral biomarkers, in this case positive IgG antibodies, for periodontopathic bacteria. This argument should hold true when examining differences in serum TNFalpha levels and antibody markers in the cross-sectional case control study of AD and normal subjects.[3]
While the reported significant associations between positive IgG antibodies and serum TNFalpha with AD are interesting, it is not possible to assume causality from case control studies. For example, a decline in oral hygiene is a result—rather than a cause—of dementia. [7] Furthermore, not all studies have found evidence of raised serum TNFalpha in AD compared to controls. [8] This might be due to a lack of attention to possible confounders (e.g. cholinesterase inhibitors are associated with reductions in serum TNFalpha[1]) but it may be that what is most important is the central inflammatory response to the systemic inflammatory signal. In addition to further animal studies, we need to conduct longitudinal, cohort studies in humans to address these issues.
We agree that it is important to examine a number of serum inflammatory markers, including both pro- and anti-inflammatory markers. Our focus on TNFalpha does not imply that it is the only inflammatory marker of interest. Blood markers of acute and chronic systemic events are complex. The aged innate immune system is changing in ways that are only just beginning to be documented. [9]
References
5. D’Aiuto F, Parkar M, Andreou G, et al. Periodontitis and systemic inflammation: control of local infection is associated with a reduction in serum inflammatory markers. J Dent Research 2004;83:156-160.
6. Cunningham C, Wilcockson DC, Campion S, et al. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 2005;25:9275-9284.
7. Ship JA. Oral health of patients with Alzheimer’s Disease. J Am Dent Assoc 1992;123:53-58.
8. Ray S, Britschgi M, Herbert C, et al. Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signalling proteins. Nat Med 2007;13:1359-1362.
9. Thiem U, Niklaus D, Sehlhoff B, et al. C-reactive protein, severity of pneumonia and mortality in elderly, hospitalised patients with community-acquired pneumonia. Age Ageing 2009;38:693-697.
Disclosure: Prof. Holmes has received research support from the Alzheimer’s Society, the UK Department of Health, and the Medical Research Council. Dr. Cunningham has received non–industry-sponsored funding for travel and receives research support from the Wellcome Trust; his sister is an employee of Wyeth Pharmaceuticals. Prof. Perry has received honoraria from the Danish Research Council and UCB; and receives research support from the European Union, the Medical Research Council, the Biotechnology and Biological Sciences Research Council, and Wellcome Trust. Ms. Zotova, Ms. Woolford, Ms. Dean, Ms. Kerr, and Mr. Culliford report no disclosures.