**2. Chlamydial infection and cerebrovascular disease**

At present, cerebrovascular diseases constitute an important public health problem because of the associated mortality and functional losses in the acute and chronic period. According to studies conducted in the USA, 500,000 new or recurrent stroke cases are observed every year [35]. Approximately 80–85% of these are cases of ischemic stroke [36, 37].

Although studies have identified many etiological factors for stroke, none of these factors can be identified in approximately 40% of cases. The number of patients with no detectable risk factors is increasing, especially in the patient population under 45 years of age [38]. The research, identification, and (if possible) treatment of potential risk factors have become a priority in order to reduce the incidence and consequences of the disease [35, 39, 40].

Many researchers have suggested that viruses play a role in the development of atherosclerosis and have shown that these pathogens are closely linked to the rapidly progressive CAD that develops in heart transplant recipients [41–45].

The main infectious agents implicated are *C. pneumoniae*, cytomegalovirus, *Helicobacter pylori*, *Streptococcus mutans*, *Porphyromonas gingivalis*, *Actinobacillus*, and *Prevotella intermedia*. Although there are a few publications in the literature on the role of *C. pneumoniae* in ischemic cerebrovascular diseases, the number of studies on this subject is steadily increasing [46–57].

Çalık et al. investigated the presence of *C. pneumoniae* antibodies in patients and healthy controls and did not detect IgM positivity, an indicator of acute *C. pneumoniae* infection, in either group. Both IgA and IgG antibodies were more common in the patient group, with IgG antibodies detected in 37 (74%) of patients and 28 (56%) of controls, and IgA antibodies detected in 31 (62%) of patients and 16 (32%) of controls. However, the difference was statistically significant only for IgA antibodies (P < 0.01). Chronic persistent *C. pneumoniae* infection was not present in any of the

controls but was detected in eight patients (16%). Findings of atherosclerosis in the carotid and vertebral arteries were statistically more frequent in the patient group. When they compared patients with and without atherosclerosis on Doppler ultrasound, those with atherosclerosis showed higher rates of *C. pneumoniae* IgG and IgA positivity, higher mean titers of these antibodies, and more frequent chronic persistent infection. However, the differences were not statistically significant [41].

Studies have generally shown that IgA antibodies are associated with ischemic cerebrovascular disease while IgG antibodies are not [49, 50, 53].

In a study by Cook et al., acute *C. pneumoniae* infection or reinfection was found to be associated with ischemic cerebrovascular disease [55].

IgG positivity is an indicator of a previous infection and can remain positive for years [11]. However, IgA antibodies have a very short half-life of 5–6 days on average. Therefore, IgA antibodies are useful in determining persistent and active carrier status. Based on observations, anti-*Chlamydia* IgA antibodies become positive (titer of 1/16 or higher) early in primary chlamydial infections, and the titer increases 2–4 times within 20–40 days, even if the patient is treated. This elevated titer rapidly decreases to former values after treatment [58]. However, infection status can be ascertained by simultaneously determining IgG and IgM antibody status. The presence of IgM antibodies is a definitive indicator of acute infection. In chronic or re-infection, IgM antibodies do not rise at all or are positive at very low titers. Thus, IgM negativity and IgA positivity (≥1/32) accompanied by IgG positivity (≥1/128) indicate chronic or re-infection [11, 53, 56, 59].

Acute *C. pneumoniae* infection was not detected in any of the patients included in the study by Çalık et al. [41]. Similarly, Elkind et al. reported not detecting IgM antibodies in any of the patients in their ischemic stroke study [53].

Although criteria have been established for the diagnosis of chronic persistent infection, a positive IgA titer is an indirect indicator that the causative pathogen is present in the body [60].

Studies have emphasized the relationship between *C. pneumoniae* infections and atherosclerosis, focusing mostly on the coronary and carotid arteries [17, 46, 51, 61].

Schmidt et al. reported that *C. pneumoniae* seropositivity was associated with an increase in intima media thickness in the main carotid arteries [51]. Grayston et al. demonstrated the presence of *C. pneumoniae* in endarterectomy specimens by PCR and immunocytochemistry and concluded that *C. pneumoniae* infections may cause atherosclerosis or play a role in its pathogenesis [62]. The findings support that *C. pneumoniae* infections may be a strong risk factor for atherosclerosis and related vascular diseases [41]. However, the mechanism underlying this relationship has not been elucidated. Different mechanisms have been described in relation to the contribution of infections in the formation or emergence of atherosclerotic diseases. Infections have both direct and indirect effects on the vasculature. The main direct effects are endothelial cell destruction or dysfunction, smooth muscle cell proliferation, and local inflammation. Indirect effects include chronic systemic inflammation, cross-immunoreactivity of antibodies against the pathogen with host tissues, and the impact of the host response to the pathogen on known atherosclerotic risk factors.

*C. pneumoniae* can infect various types of cells. Among the cells it infects are endothelial cells, vascular smooth muscle cells, and macrophages, all of which have important roles in the pathogenesis of atherosclerosis. Changes in the function and structure of these cells are an expected result of direct invasion by the pathogen [41]. Indeed, many studies have demonstrated the presence of *C. pneumoniae* in vascular endothelium affected by atherosclerosis [62, 63]. In addition to local vessel wall

#### *Chlamydia Infection's Role in Neurological Diseases DOI: http://dx.doi.org/10.5772/intechopen.110842*

invasion and destruction, *C. pneumoniae* induces a procoagulant state by causing tumor necrosis factor (TNF) and interleukin (IL)-2 release and affecting lipoprotein levels and tissue factors because of its lipopolysaccharide cell wall components [50, 62]. Hsp60, one of the antigens in the protein structure of *C. pneumoniae*, can trigger atherogenesis indirectly through certain immunological mechanisms [64]. The effects of chronic *C. pneumoniae* infection on blood clotting factors have also been demonstrated. Toss et al. determined that chronic persistent *C. pneumoniae* infection was associated with increased serum fibrinogen levels but were unable to explain the mechanism behind this increase [65].

*C. pneumoniae* infections were also reported to have a number of effects on the blood lipid profile, which has an important role in the development of atherosclerosis [64]. In their study including 1053 patients, Laurila et al. showed that individuals with *C. pneumoniae* IgG antibody titer values of 1/128 and above had higher serum triglyceride levels and lower HDL/total cholesterol ratio compared to individuals with lower antibody titers [66]. The host response to the lipopolysaccharides in the structure of *C. pneumoniae* found in the atherosclerotic region alters the synthesis of certain cytokines. These cytokines cause a complex set of changes in the serum lipid profile [64].

In summary, evidence pointing to the relationship between *C. pneumoniae* and atherosclerosis is as follows: (a) sero-epidemiological studies have demonstrated its association with atherosclerotic diseases (CAD, ischemic cardiovascular disease, and carotid atherosclerosis); (b) the pathogen has been demonstrated in atherosclerotic lesions; and (c) several small clinical studies have shown the benefits of using antiinflammatory antibiotics in the secondary prevention in patients with CAD [52]. If the possible relationship between infections and vascular occlusive diseases such as ischemic cardiovascular disease and CAD is confirmed, adding antibiotics to treatment protocols for stroke and coronary events may help prevent ischemic events [50].
