Neurological diseases & Chlamydophila pneumoniae

Alzheimer's disease

The 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 was investigated using serology [Renvoize, Awad & Hambling, 1987], although no relationship was found. However, in 1998, Balin et al., reported that they were able to find C. pneumoniae DNA in the brains of 17 out of 19 persons with sporadic Alzheimer's disease, but in only 1 out of 19 controls. Chlamydial RNA gene transcripts were detected, indicating that the Chlamydiae were metabolically active. C. pneumoniae was also isolated by culture from tissue homogenates of the two specimens that afforded enough tissue on which to make the attempt. Immunohistology indicated that the Chlamydiae were primarily located in diseased areas of the Alzheimer brain in glial cells , perivascular macrophages and intravascular monocytes. The same lead group of investigators [MacIntyre et al., 2003] reported that C. pneumoniae infection in vitro stimulates the migration of monocytes across the blood brain barrier and that C. pneumoniae infection of human brain microvascular endothelial cells resulted in increased expression of the zonula adherens proteins beta-catenin , N- and VE- cadherin , and decreased expression of the tight junctional protein occludin [MacIntyre et al., 2002]. This provides a plausible mechanism by which C. pneumoniae might cross the blood brain barrier to promote inflammation within the central nervous system.

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 Asmall beta, Greek 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 Asmall beta, Greek 1–42 was observed in pyramidal neurons, something also observed in the entorhinal cortex of Alzheimer's disease brains. However silver staining (Gallyas) and immunohistology for tau protein failed to demonstrate the significant neurofibrillary tangle pathology characteristic of Alzheimer's disease in humans; perhaps the amount of time post-infection was insufficient or perhaps aged animals are needed for tangle formation following a chlamydial or infectious trigger.

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].

Comments

The 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).

For

Against

Direct Direct
C. pneumoniae found by microscopy and PCR in a high proportion of the brains
of AD patients versus controls & associated with more severe pathology.
C. pneumoniae
also cultured from AD brain & RNA transcripts detected. Balin et al., 1998. Failure of others to demonstrate same might be due to methodology, sampling error, absence of standardized techniques.
Five other studies have failed to confirm this: Gieffers et al., 2000; Loeb et al., 2004; Nochlin et al., 1999; Ring & Lyons, 2000; Taylor et al., 2002 including a study using samples from same patients as Balin et al., 1998. However 'Absence of Evidence' is not same as 'Evidence of Absence': Itzhaki et al., 2004.
Two preliminary studies reported at meetings also found C. pneumoniae in AD brain versus controls: Mahoney et al., 2000; Ossewarde et al., 2000. Two years later these preliminary reports not yet substantiated by formal peer reviewed publication.
C. pneumoniae is a respiratory pathogen, giving direct access to brain via the nasal olfactory pathway. Some of the earliest pathology in AD is in olfactory
and entorhinal cortices. C. pneumoniae detected in 2 AD cases in olfactory neuroepithelium [Hudson et al., 2000].
Same investigators; independent studies needed. Not a peer reviewed formal publication.
C. pneumoniae detected in olfactory bulbs of infected mice 1 - 3 months post intranasal infection with increasing number of amyloid plaques but no neurofibrillar tangle pathology [Little et al., 2004]. Important work but mouse model not yet replicated by independent investigators. None of amyloid tangle pathology associated with human AD.
Circumstantial / Indirect Circumstantial / Indirect
Seroprevalence of C. pneumoniae increases in old age. This is the cumulative acquisition of long lived IgG antibody; confuses prevalence with incidence.
C. pneumoniae known to persist in monocytes. In vitro promotes transmigration of monocytes across blood-brain barrier by upregulation of ICAM-1, VCAM-1 etc., McIntyre et al., 2003. Alters junctional complex proteins of human brain vascular endothelia to promote invasion: McIntyre et al., 2002. So what? These studies did not compare role of C. pneumoniae with other bacteria. It is likely other bacteria can do this too.
C. pneumoniae known to be able to cause chronic persisting infection.
Chlamydial LPS stimulates proinflammatory cytokines [see: LPS]. E. coli LPS injected into brains of rats
caused induction of amyloid precursor protein : Itzhaki et al., 2004.
This is hypothetical.
Koch's postulates not appropriate for chronic infective disease, see: Chronic infections: Conclusions. Koch's postulates to establish causal aetiology of a disease not demonstrated.
Evidence for the involvement of C. pneumoniae in other chronic neurological conditions, e.g. Other chronic infections Evidence for other neurological diseases similarly uncertain.
Oral Doxycycline and rifampin treatment over 3 months had a beneficial effect on cognitive function in Alzheimer's Disease patients versus controls. No difference in C. pneumoniae infection rate between patients and controls, therefore modest effect not due to C. pneumoniae.

[MEW] August 2004

NEXT: Cutaneous T cell lymphoma

References

Balin, 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 [Acrobat]

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 [Acrobat]

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. Full article [Acrobat]

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 Ageing16, 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 [Acrobat]

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 [Acrobat]

Taylor, G. S., Vipond, I. B., Paul, I. D., Matthews, S., Wilcock, G. K. & Caul, EO. (2002). ArchiveRestrictedDocsInfectionsTaylor%20GS,%20Vipond%20IB,%20Paul%20ID,%20Matthews%20S,%20Wilcock%20GK,%20Caul%20EO. 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].

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Topic revision: r7 - 2011-04-06 - SanderO
 
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