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Neurological diseases & Chlamydophila pneumoniaeAlzheimer's diseaseThe proportion of people surviving to old age,
and thus the number affected by the diseases of old age, is increasing. One in
five people over the age of 80 are affected by Alzheimer's Disease [Dobson et
al., 2003; Robinson et al., 2004]. As long ago as 1987, a possible association of
chlamydiae and
other infectious agents with Alzheimer's disease
Two abstracts [Mahony et al., 2000; Ossewaarde et al., 2000] are often cited in support of the Balin study, but, as pointed out by Robinson et al., 2004, two years later neither have been published in peer reviewed formal papers. On the other hand, a number of other studies have failed to confirm any association between Alzheimer's disease and C. pneumoniae infection [Gieffers et al., 2000; Nochlin et al., 1999; Ring & Lyons, 2000; Taylor et al., 2002]. In this respect, the study by Taylor et al., 2002 is of particular concern because, although it involved very experienced investigators, they failed to detect C. pneumoniae in 19 samples from 10 of the brain specimens included in the original Balin study despite the use of PCR primers against the same C. pneumoniae genes. As Robinson et al., 2004 point out: "Since PCR is a capricious technique, it might be argued that these results are ‘false negatives’ and that a positive result carries more weight than a negative one. This argument cannot be entirely dismissed, but it does overlook the fact that C. pneumoniae has been independently reported to be associated with multiple sclerosis and atherosclerosis despite similar methodological discrepancies and conflicting results between research groups. In both cases, the number of published studies confirming an association are far fewer than those in which no association was observed, leading most chlamydiologists to hold a guarded opinion as to whether this association is causal, contributory, or merely coincidental", a view with which this reviewer concurs. The fact that viable chlamydiae were associated with Alzheimer's disease in the Balin study might mean that the C. pneumoniae infection has to be acute and active rather than persistent. However the simultaneous occurrence of such an event exclusively in 17 of the 19 patients in the Balin study is difficult to explain. It has been suggested that C. pneumoniae may be neurotropic and involved in a number of neuro-inflammatory conditions including multiple sclerosis, Guillain-Barre syndrome [Haidl et al., 1992], stroke, meningoencephalomyeltis [Guglielminotti et al., 2000], and acute disseminated encephalomyelitis [Gieffers et al., 2001]. Whether C. pneumoniae is simply sequestered in neurological tissues or takes an active part in generating disease is unclear from these studies. Possible role of Tumour necrosis factor. Bruunsgaard et al., 2002, noting that plasma levels of tumour necrosis factor (TNF)-alpha increase with age, particularly in dementia and atherosclerosis in centenarians, explored the hypothesis that this might be due to associated C. pneumoniae infection. In a group of 126 Danish centenarians they found no association between C. pneumoniae-specific IgA antibody and TNF-alpha. Furthermore in this small group no associations were found between antibodies to C. pneumoniae and dementia or cardiovascular diseases. They considered that, although TNF-alpha is likely to be involved in the pathogenesis of atherosclerosis and dementia, there was no evidence that this was due to C. pneumoniae infection. Animal model of C. pneumoniae Alzheimer's Disease The Balin group of investigators have developed a mouse model of C. pneumoniae-induced disease to explore the role of this organism in Alzheimer's disease. Normal, young mice do not develop the characteristic pathology of Alzheimer's disease. Thus, they are a suitable host for analyzing whether infection leads to pathological changes in the brain. Normal, three month-old, female BALB/c mice were inoculated intranasally with an isolate of C. pneumoniae obtained from an Alzheimer's disease brain. Intranasal inoculation was used to mimic the putative olfactory route of respiratory C. pneumoniae infection to the brain. Mice were killed at 1, 2, and 3 months post-infection and representative areas of the brain and olfactory bulbs were analyzed for the presence of C. pneumoniae, inflammation, and Alzheimer's disease pathology, particularly amyloid plaques and neurofibrillary tangles.C. pneumoniae was demonstrated by light microscopy and electron
microscopy of the olfactory bulbs of animals 1–3 months post-infection [Little
et al., 2004]. Immunohistology showed A Treatment study In Canada, a randomized, triple blinded controlled trial was performed to assess whether oral daily doses of 200mg of doxycycline and 300 mg of rifampin for three months had any beneficial effect over 6 to 12 months on cognitive function in 101 patients with probable Alzheimer's and mild to moderate dementia. There was significantly less decline in the cognitive score at 6 months in the antibiotic group than in the placebo group, (-2.75 points, 95% confidence interval -5.28 to -0.22, p=.034). At 12 months, the difference between groups in the SADAScog was -4.31 points (confidence interval -9.17 to -0.56, p=.079). There were no differences in C. pneumoniae detection using PCR or serology between patient and control groups. It was concluded that therapy with doxycycline and rifampin might have a therapeutic role in these patients but that the mechanism was unlikely to be due to their effect on C. pneumoniae [Loeb et al., 2004]. CommentsThe table below summarizes the arguments for and against a role of C. pneumoniae in Alzheimer's disease. Proponents of the role of C. pneumoniae point out that C. pneumoniae is a common cause of respiratory infection in the community; it has the potential to cause persistent chronic infections and to interfere with host cell biology; it could reach the brain either within circulating monocytes or via the naso-olfactory route; it has been demonstrated in Alzheimer's brain tissue; it can produce some of the pathology of the disease in experimental animal models. It is envisaged that C. pneumoniae may contribute to pathology both directly and as a trigger of inflammatory and degenerative processes in which activated macrophages or macrophage-like cells play a key role. Opponents and those yet to be convinced point out that the key Balin et al 1998 study linking C. pneumoniae with Alzheimer's Disease and the animal model developed by the same group have yet to be independently confirmed. Clearly this is essential for progress in this area. Robinson et al., 2004 in their review concluded that, on balance, the data presently available do not support the hypothesis that Alzheimer's Disease is caused by chronic infiltration of the brain by C. pneumoniae. Mattson 2004 [who from his abstract seems to think that chlamydiae are viruses!] reached a similar conclusion. However it remains entirely possible that C. pneumoniae infections do contribute to the pathogenesis of Alzheimer's Disease in a small proportion of cases, perhaps depending on host genotype. If infection does contribute to the pathogenesis of Alzheimer's Disease, it is likely that a variety of infections may be the trigger. After all, key cytokines like interleukin 1 beta, after crossing the blood brain barrier, have the potential to further activate reactive microglial cells. In this context it is interesting that infection induced increases in interleukin 1beta have been associated with related periods of cognitive decline in Alzheimer's Disease patients [see Robinson et al., 2004 for references]. Table 1. Summary of evidence for and against a role of C. pneumoniae in Alzheimer's Disease (AD).
[MEW] August 2004 NEXT: Mycosis fungoides ReferencesBalin, B. J. & Appelt, D. M. (2001). Role of infection in Alzheimer's disease. Journal of the American Osteopathy Association 101 (12 Suppl) S1 - 6. [Review]. Balin, B. J., Gerard, H. C., Arking, E. J., Appelt, D. M., Branigan,
P. J., Abrams, J. T. et al. (1998). Identification and localization of
Chlamydia pneumoniae in the Alzheimer's brain. Medical Microbiology
and Immunology (Berlin) 18, 23 - 42. Bruunsgaard, H., Ostergaard, L., Andersen-Ranberg, K., Jeune, B. & Pedersen, B. K. (2002). Proinflammatory cytokines, antibodies to Chlamydia pneumoniae and age-associated diseases in Danish centenarians: is there a link? Scandinavian Journal of Infectious Diseases 34, 493 - 499. Dobson, C. B., Wozniak, M. A. & Itzhaki, R. F. (2003). Do infectious agents play a role in dementia? Trends in Microbiology 11, 312 - 316. Gieffers, J., Reusche, E., Solbach, W. & Maass M. (2000). Failure to detect
Chlamydia pneumoniae in brain sections of Alzheimer's disease patients. Journal
of Clinical Microbiology 38, 881 - 882. Full
article Gieffers, J., Pohl, D., Treib, J., Dittmann, R., Stephan, C., Klotz, K., Hanefeld, F., Solbach, W., Haass, A, & Maass, M. (2001). Presence of Chlamydia pneumoniae DNA in the cerebral spinal fluid is a common phenomenon in a variety of neurological diseases and not restricted to multiple sclerosis. Annals of Neurology 49, 585 - 589. Guglielminotti, J., Lellouche, N., Maury, E., Alzieu, M., Guidet, B. & Offenstadt, G. (2000). Severe meningoencephalitis: an unusual manifestation of Chlamydia pneumoniae infection. Clinical Infectious Diseases 30, 209 - 210. [Brief case report of this syndrome occurring after C. pneumoniae infection but not necessarily associated]. Haidl, S., Ivarsson, S., Bjerre, I. & Persson, K. (1992). Guillain-Barre syndrome after Chlamydia pneumoniae infection. New England Journal of Medicine 326, 576 - 577. [Brief case report of this syndrome occurring after C. pneumoniae infection but not necessarily associated]. Hudson, A. P., Gerard, H. C., Whittum-Hudson, J. A., Appelt, D. M. & Balin, B. J. (2000). Chlamydia pneumoniae, APOE genotype and Alzheimer's disease. In: Chlamydia pneumoniae and chronic disease. L'age-Stehr J (ed). Springer Verlag 121 - 136. Itzhaki, R. F., Wozniak, M. A., Appelt, D. M.
& Balin, B. J. (2004).
Infiltration of the brain by pathogens causes Alzheimer's disease.
Neurobiology of Aging 25, 619 - 627. [Review
by key group]
Full article Little, C. S., Hammond, C. J., MacIntyre, A., Balin, B. J. &
Appelt, D. M. (2004).
Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of
BALB/c mice. Neurobiology of Aging 25, 419 -
429. Loeb, M. B., Molloy, D., Smieja, M., Standish, T., Goldsmith, C. H., Mahony
J. et al., (2004).
A randomized, controlled trial
of doxycycline and rifampin for patients with Alzheimer's disease. Journal of
the American Geriatric Society 52, 381 - 387. MacIntyre, A., Abramov, R., Hammond, C. J., Hudson, A. P., Arking, E. J., Little, C. S., Appelt, D. M. & Balin, B. J. (2003). Chlamydia pneumoniae infection promotes the transmigration of monocytes through human brain endothelial cells. Journal of Neuroscience Research 71, 740 - 750. MacIntyre, A., Hammond, C. J., Little, C. S., Appelt, D. M. & Balin, B. J. (2002). Chlamydia pneumoniae infection alters the junctional complex proteins of human brain microvascular endothelial cells. FEMS Microbiology Letters 217, 167 - 172. Mahony, J., Woulfel, J., Munoz, D., Chong, S. & Smieja, M. (2000). Chlamydia pneumoniae in the Alzheimer’s brain—is detection hampered by low copy number? In: Proceedings of 4th Meeting of the European Society for Chlamydia Research, Helsinki, Finland; 2000. p. 299–300. Mattson, M. P. (2004). Infectious agents and age-related neurodegenerative disorders. Ageing Research Reviews 3, 105 - 120. Nochlin, D., Shaw, C. M., Campbell, L. A. & Kuo, C. C. (1999). Failure to detect Chlamydia pneumoniae in brain tissues of Alzheimer's disease. Neurology 53, 1888. Ossewaarde, J. M., Gielis-Proper, S. K., Meijer, A. & Roholl, P. J. M. (2000). Chlamydia pneumoniae antigens are present in the brains of Alzheimer patients, but not the brains of patients with other dementias. In: Saikku P, (ed.) Proceedings of the fourth meeting of the European Society for Chlamydia Research, Helsinki, Finland. p 284. Renvoize, E. B., Awad, I. O. & Hambling, M. H. (1987). A sero-epidemiological study of conventional infectious agents in Alzheimer's disease. Age and Ageing 16, 311 - 314. Ring, R. H. & Lyons, J. M. (2000). Failure to detect
Chlamydia pneumoniae in the late-onset Alzheimer's brain. Journal of Clinical Microbiology
38, 2591 - 2594. Full
article Robinson, S. R., Dobson, C. & Lyons, J. (2004).
Challenges and directions for the pathogen hypothesis of Alzheimer's disease.
Neurobiology of Aging 25, 629 - 637. [Good
review]
Full article Taylor, G. S., Vipond, I. B., Paul, I. D., Matthews, S., Wilcock, G. K. & Caul, EO. (2002). Failure to correlate C. pneumoniae with late onset Alzheimer's disease. Neurology 59, 142 - 143. Yucesan, C. & Sriram, S. (2001). Chlamydia pneumoniae infection of the central nervous system. Current Opinion in Neurology 14, 355 - 359. [Review]. NEXT: Mycosis fungoides |
was investigated
using serology [
1–42 immunoreactive amyloid plaques in increasing numbers from 1 to 3 months
post infection in all areas of the brain but with relatively little
fibrillogenesis or inflammation. The authors concluded that mature amyloid plaque formation
was a consequence of C. pneumoniae infection in this model, though the
mechanism was uncertain. In some regions of the brain, intracellular A
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