- Email: [email protected]
COGNITIVE IMPAIRMENT AND INFECTIOUS BURDEN IN THE ELDERLY
Arch. Gerontol. Geriatr. Suppl. 9 (2004) 419–423 0167-4943/$ – see front matter # 2004 Elsevier Ireland Ltd. All rights reserved
COGNITIVE IMPAIRMENT AND INFECTIOUS BURDEN IN THE ELDERLY
T.E. STRANDBERG*, K.H. PITKALA, K. LINNAVUORI and R.S. TlLVlS
Department of Medicine, Geriatric Clinic, and Department of Virology, University of Helsinki, PO Box 340, FIN-00029 HUS, Helsinki, Finland *Corresponding author: Phone: +(358-9)-4711;
FAX +(358-9)-4717-4013;
Email: [email protected]
SUMMARY Infectious agents have been suspected as contributing factors to dementia, especially in Alzheimer disease. We intended to test whether viral or bacterial seropositivity is associated with cognitive impairment among home-dwelling elderly. Viral burden (seropositivity for herpes simplex type 1 (HSVI), type 2 (HSV2), or cytomegalovirus (CMV), and bacterial burden (Chlamydia pneumoniae and Mycoplasma pneumoniae) were tested among 383 home-dwelling individuals with vascular disease (mainly coronary heart disease) in the ongoing DEBATE study (mean age 80 years). Mini-mental state examination (MMSE) and its changes were used to define cognitive impairment. At baseline, 0-1, 2, and 3 positive titers toward viruses were found in 48 (12.5 %), 229 (59.8 %), and 106 (27.7 %) individuals, respectively. MMSE points decreased with increasing viral burden (p = 0.03). At baseline, 58 individuals (15.1 %) had cognitive impairment (MMSE < 24 points) which after adjustments was significantly associated with seropositivity for 3 viruses (risk ratio 2.5, 95% confidence interval 1.3 to 4.7). MMSE score decreased in 150 cases (43%) during 12month follow-up. After adjustment for MMSE score at baseline and with 0-1 seropositivities as reference (1.0), the risk ratios were 1.8 (95 % confidence interval 0.9 to 3.6) and 2.3 (95 % confidence interval 1.1 to 5.0) for 2 and 3 seropositivities, respectively. No significant associations were observed between bacterial burden and cognition. Viral burden of herpesvirus and cytomegalovirus was associated with cognitive impairment in home-dwelling elderly. The association may offer a preventable cause of cognitive decline. Keywords: cognitive impairment, infectious burden in the elderly, viral seropositivities
INTRODUCTION Dementias have several possible causes and also inflammatory or infectious factors have been implicated in their pathogenesis (Dickson et al., 1993; Strandberg and Tilvis, 2000; Weiner and Selkoe, 2002). It can be speculated that a chronic infection would maintain inflammation and induce amyloid fibrils in susceptible persons. Of specific microbes, herpesviridae such as herpes simplex virus 1 (HSVI) has been a prime suspect (Jamieson et al.,1991; ltzhaki et al., 1997; Lin et al., 1998, 2002; Dobson and Itzhaki, 1999; Pyles, 2001). Earlier studies have been mostly neuropathological case-control studies, and
420
not adjusted, for example, for educational level. Bacteria, such as Chlamydia pneumoniae, and Mycoplasma pneumoniae have been associated with the pathogenesis of atherosclerotic vascular diseases whereas data in Alzheimer disease have been conflicting (Balin et al., 1998; Gieffers et al., 2000). In the present study, we have investigated the relationships between systemic microbial burden (serum antibodies) and cognitive function in a sample of elderly persons with vascular diseases, retrieved from the community. PATIENTS AND METHODS From a random community sample (n = 4821) in Helsinki, Finland, who were born between 1904 and 1925, we have randomized 400 home-dwelling individuals with cardio vascular diseases to a multifactorial prevention study (Drugs and Evidence -Based medicine in The Elderly (DEBATE) study, (Strandberg et al., 2001, 2003). Only inclusion criteria for the DEBATE study were the presence of atherosclerotic disease, home dwelling, and informed consent. Participants were not included or excluded on basis of past or present infections. In DEBATE, cognition is evaluated yearly with the mini-mental state examination (MMSE) (Folstein et al., 1975; Tombaug and Mclntyre, 1992) as well as the clinical dementia rating (CDR), where a score >0 implicates possible or definite dementia. MMSE score below 24 points was taken to indicate cognitive impairment. In the present study, we adjusted results for age and education, and therefore a fixed MMSE score and proportion below 24 points was used in cross-sectional studies. Decrease of MMSE score (MMSE points at baseline minus MMSE points at one year) was used as the endpoint in the prospective part of the study. All tests at baseline and after one year were performed by the same nurse, trained to use the test battery. Microbial antibody assays for HSVI and HSV2, cytomegalovirus (CMV), C. pneumoniae and M. pneumoniae were performed at the Department of Virology of the Helsinki University Central Hospital by testing the presence of immunoglobulin G (lgG)-antibodies against these microbes by technicians blinded to the cognitive data of the patients. The results are presented in a qualitative negative/positive scale. Viral burden was defined as the number of seropositivities toward HSVl , HSV2 and CMV divided in 3 categories (0 to 1, 2, or 3). Bacterial burden was defined as seropositivities toward C. pneumoniae and M. pneumoniae divided in 3 categories (0, 1, or 2). Statistical analyses were performed with the NCSS statistical program (www.ncss.com).
421
RESULTS Antibodies were available of 383 individuals (96 % of total population; mean age 80 years, 65 % women, 42 % with education more than primary school). 82 % and 37 % had a history of coronary heart disease or stroke.18 % had type 2 diabetes. Median MMSE score at baseline was 27 points, and 58 individuals
(15.1 %) had MMSE points below 24.
Seropositivity for both herpesviruses was significantly more common among individuals with cognitive decline. At baseline, 0-1, 2, and 3 positive titers toward viruses were found in 48 (12.5%), 229 (59.8 %), and 106 (27.7%) individuals, respectively. Positive titers toward 0, 1 and 2 bacteria were found in 79 (20.6 %), 182 (47.5 %), and 122 (31.9 %), respectively. Cognitive status was significantly associated with viral, but not with bacterial burden at baseline. There was a statistically significant (p = 0.03) graded impairment of MMSE points (squared values adjusted for age, sex and education). Increasing viral burden was significantly associated with cognitive impairment (MMSE score < 24). Abnormal CDR score (0.5 or higher) was seen increasingly with increasing viral burden (in 4.9%, 16.2% and 26.9 %; p = 0.008). In logistic regression analyses after adjustment for cardiovascular risk factors, age, and education, seropositivity for 3 viruses was significantly associated with cognitive impairment at baseline and after one year when 348 individuals were re-tested for MMSE (Table I). No significant associations were found with bacterial burden. The type of vascular disease of the subjects did not affect the results. Table I VIRAL BURDEN AND COGNITIVE IMPAIRMENT IN 383 HOME-DWELLING ELDERLY WITH VASCULAR DISEASES Seropositivities for HSV1, HSV2 and CMV
Less than 3, n = 277 3 seropositivities, n = 106
Risk ratio (95 % confidence interval) of cognitive impairment Baseline, 58/383 Univariate Adjusted 1.0 (reference) 1.0 3.2 2.5 (1.8-5.7) (1.3-4.7)
At 12 months, 58/348 Univariate Adjusted 1.0 1.0 2.6 2.3 (1.4-4.6) (1.2-4.6)
Cognitive impairment was defined as MMSE score below 24 points. Data were adjusted for age, education, body mass index, log transformed blood glucose, and log transformed CRP. After 12 months, MMSE examination could be repeated in 348 individuals (91% of the baseline sample) of whom 58 individuals (16.7%) had a MMSE score < 24. During one year, the mean change of MMSE (MMSE at baseline minus MMSE at one year) was 0.42 points (±SD = 2.07). Overall, MMSE was decreased in 150 individuals (43.1% of 348).
422
After adjustment for MMSE points at baseline, the decrease of MMSE during one year was associated with viral burden in a stepwise manner (risk ratios 1.0, 1.8 (95 % CI 0.9 to 3.6) and 2.3 (95 % CI 1.1 to 5.0) for 0-1, 2 and 3 viral seropositivities, respectively. No associations were observed with bacterial burden. DISCUSSION In these elderly individuals living in the community and with cardiovascular diseases, viral burden consisting of seropositivity for herpesviruses and cytomegalovirus was significantly associated with cognitive impairment assessed with MMSE or CDR. The association was strong and graded, and independent of age, sex, education and cardiovascular risk factors including C-reactive protein (CRP). The finding was consistent both crosssectionally and during a 12-month follow -up. No association was detected between cognition and bacterial burden of seropositivity for C. pneumoniae and M. pneumoniae. The results support earlier hypotheses that viral infections may be associated with cognitive impairment and con-sequent dementia in old age (Dobson et al., 2003). The results are also biologically plausible because both HSV and CMV have neurotropic properties. Limitations of the study are that all participants had vascular disease, only seropositivity was used to assess viral burden, and rigorous verification of clinical dementia has not yet been performed. However, if these results are verified in other population -based studies, they could open new avenues to prevent dementia with antiviral drugs or possibly vaccinations. REFERENCES Balin, B.J., Gerard, H.C., Arking, E.J., Appelt, D.M., Branigan, P.J., Abrams, J.T., WhittumHudson, J.AQ. and Hudson, A.P. (1998): Identification and localization of Chlamydia pneumoniae in the Alzheimer’s brain. Med. Microbiol. Immunol. (Berl)., 187, 23-42. Dickson, D.W., Lee, S.C., Mattiace, L.A., Yen, S.H. and Brosnan, C. (1993): Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer’s disease. Glia, 7, 75-83. Dobson, C.B. and ltzhaki, R.F. (1999): Herpes simplex virus type 1 and Alzheimer’s disease. Neurobiol. Aging, 20, 457- 465. Dobson, C.B., Wozniak, M.A. and Itzhaki, R.F. (2003): Do infectious agents play a role in dementia? Trends Microbiol., 1, 312-317. Folstein, M.F., Folstein, S.E. and McHugh, P.R. (1975): Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res., 12, 189-198. Gieffers, J., Reusche, E., Solbach, W. and Maass, M. (2000): Failure to detect Chlamydia pneumoniae in brain sections of Alzheimer disease patients. J. Clin. Microbiol., 38, 881-882.
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Itzhaki, R.F., Lin, W.R., Shang, D., Wilcock, G.K., Faragher, B. and Jamieson, G.A. (1997): Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet, 349. 241244. Jamieson, G.A., Maitland, N.J., Wilcock, G.K., Craske, J. and Itzhaki, R.F. (1990): Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains. J. Med. Virol., 33, 224-227. Lin, W.R., Graham, J., MacGowan, S.M., Wilcock, G.K. and Itzhaki, R.F. (1998): Alzheimer’s disease, herpes virus in brain, apolipoprotein E4 and herpes labialis. Alzheimers Rep., 1, 173-178. Lin, W.R., Wozniak, M.A., Cooper, R.J., Wilcock, G.K. and Itzhaki, R.F. (2002a): Herpesviruses in brain and Alzheimer’s disease. J. Pathol., 197, 395-402. Lin, W.R., Wozniak, M.A., Wilcock, G.K. and Itzhaki, R.F. (2002b): Cytomegalovirus is present in a very high proportion of brains from vascular dementia patients. Neurobiol. Dis., 9, 82-87. Pyles, R.B. (2001): The association of herpes simplex virus and Alzheimer’s disease: a potential synthesis of genetic and environmental factors. Herpes, 8, 64-68. Strandberg, T.E. and Tilvis, R.S. (2000): C-reactive protein, cardiovascular risk factors, and mortality in a prospective study in the elderly. Arterioscl. Thromb. Vasc. Biol., 20, 1057-1060. Strandberg, T.E., PitkaIa, K., Bergling, S., Nieminen, M.S. and Tilvis, R.S. (2001): Multifactorial cardiovascular disease prevention in patients aged 75 years and older: a randomized controlled trial. Am. Heart J., 142, 945-951. Strandberg, T.E., Pitkala, K., Linnavuori, K. and Tilvis, R.S. (2003): Impact of viral and bacterial burden on cognitive impairment in elderly persons with cardiovascular diseases. Stroke, 34, 2126-2131. Tombaug, T.N. and Mclntyre, N.J. (1992): The Mini-Mental State Examination: a comprehensive review. J .Am. Geriatr. Soc., 40, 922-935. Weiner, H.L. and Selkoe, D.J. (2002): Inflammation and therapeutic vaccination in CNS diseases. Nature, 420, 879-884.
COGNITIVE IMPAIRMENT AND INFECTIOUS BURDEN IN THE ELDERLY
T.E. STRANDBERG*, K.H. PITKALA, K. LINNAVUORI and R.S. TlLVlS
Department of Medicine, Geriatric Clinic, and Department of Virology, University of Helsinki, PO Box 340, FIN-00029 HUS, Helsinki, Finland *Corresponding author: Phone: +(358-9)-4711;
FAX +(358-9)-4717-4013;
Email: [email protected]
SUMMARY Infectious agents have been suspected as contributing factors to dementia, especially in Alzheimer disease. We intended to test whether viral or bacterial seropositivity is associated with cognitive impairment among home-dwelling elderly. Viral burden (seropositivity for herpes simplex type 1 (HSVI), type 2 (HSV2), or cytomegalovirus (CMV), and bacterial burden (Chlamydia pneumoniae and Mycoplasma pneumoniae) were tested among 383 home-dwelling individuals with vascular disease (mainly coronary heart disease) in the ongoing DEBATE study (mean age 80 years). Mini-mental state examination (MMSE) and its changes were used to define cognitive impairment. At baseline, 0-1, 2, and 3 positive titers toward viruses were found in 48 (12.5 %), 229 (59.8 %), and 106 (27.7 %) individuals, respectively. MMSE points decreased with increasing viral burden (p = 0.03). At baseline, 58 individuals (15.1 %) had cognitive impairment (MMSE < 24 points) which after adjustments was significantly associated with seropositivity for 3 viruses (risk ratio 2.5, 95% confidence interval 1.3 to 4.7). MMSE score decreased in 150 cases (43%) during 12month follow-up. After adjustment for MMSE score at baseline and with 0-1 seropositivities as reference (1.0), the risk ratios were 1.8 (95 % confidence interval 0.9 to 3.6) and 2.3 (95 % confidence interval 1.1 to 5.0) for 2 and 3 seropositivities, respectively. No significant associations were observed between bacterial burden and cognition. Viral burden of herpesvirus and cytomegalovirus was associated with cognitive impairment in home-dwelling elderly. The association may offer a preventable cause of cognitive decline. Keywords: cognitive impairment, infectious burden in the elderly, viral seropositivities
INTRODUCTION Dementias have several possible causes and also inflammatory or infectious factors have been implicated in their pathogenesis (Dickson et al., 1993; Strandberg and Tilvis, 2000; Weiner and Selkoe, 2002). It can be speculated that a chronic infection would maintain inflammation and induce amyloid fibrils in susceptible persons. Of specific microbes, herpesviridae such as herpes simplex virus 1 (HSVI) has been a prime suspect (Jamieson et al.,1991; ltzhaki et al., 1997; Lin et al., 1998, 2002; Dobson and Itzhaki, 1999; Pyles, 2001). Earlier studies have been mostly neuropathological case-control studies, and
420
not adjusted, for example, for educational level. Bacteria, such as Chlamydia pneumoniae, and Mycoplasma pneumoniae have been associated with the pathogenesis of atherosclerotic vascular diseases whereas data in Alzheimer disease have been conflicting (Balin et al., 1998; Gieffers et al., 2000). In the present study, we have investigated the relationships between systemic microbial burden (serum antibodies) and cognitive function in a sample of elderly persons with vascular diseases, retrieved from the community. PATIENTS AND METHODS From a random community sample (n = 4821) in Helsinki, Finland, who were born between 1904 and 1925, we have randomized 400 home-dwelling individuals with cardio vascular diseases to a multifactorial prevention study (Drugs and Evidence -Based medicine in The Elderly (DEBATE) study, (Strandberg et al., 2001, 2003). Only inclusion criteria for the DEBATE study were the presence of atherosclerotic disease, home dwelling, and informed consent. Participants were not included or excluded on basis of past or present infections. In DEBATE, cognition is evaluated yearly with the mini-mental state examination (MMSE) (Folstein et al., 1975; Tombaug and Mclntyre, 1992) as well as the clinical dementia rating (CDR), where a score >0 implicates possible or definite dementia. MMSE score below 24 points was taken to indicate cognitive impairment. In the present study, we adjusted results for age and education, and therefore a fixed MMSE score and proportion below 24 points was used in cross-sectional studies. Decrease of MMSE score (MMSE points at baseline minus MMSE points at one year) was used as the endpoint in the prospective part of the study. All tests at baseline and after one year were performed by the same nurse, trained to use the test battery. Microbial antibody assays for HSVI and HSV2, cytomegalovirus (CMV), C. pneumoniae and M. pneumoniae were performed at the Department of Virology of the Helsinki University Central Hospital by testing the presence of immunoglobulin G (lgG)-antibodies against these microbes by technicians blinded to the cognitive data of the patients. The results are presented in a qualitative negative/positive scale. Viral burden was defined as the number of seropositivities toward HSVl , HSV2 and CMV divided in 3 categories (0 to 1, 2, or 3). Bacterial burden was defined as seropositivities toward C. pneumoniae and M. pneumoniae divided in 3 categories (0, 1, or 2). Statistical analyses were performed with the NCSS statistical program (www.ncss.com).
421
RESULTS Antibodies were available of 383 individuals (96 % of total population; mean age 80 years, 65 % women, 42 % with education more than primary school). 82 % and 37 % had a history of coronary heart disease or stroke.18 % had type 2 diabetes. Median MMSE score at baseline was 27 points, and 58 individuals
(15.1 %) had MMSE points below 24.
Seropositivity for both herpesviruses was significantly more common among individuals with cognitive decline. At baseline, 0-1, 2, and 3 positive titers toward viruses were found in 48 (12.5%), 229 (59.8 %), and 106 (27.7%) individuals, respectively. Positive titers toward 0, 1 and 2 bacteria were found in 79 (20.6 %), 182 (47.5 %), and 122 (31.9 %), respectively. Cognitive status was significantly associated with viral, but not with bacterial burden at baseline. There was a statistically significant (p = 0.03) graded impairment of MMSE points (squared values adjusted for age, sex and education). Increasing viral burden was significantly associated with cognitive impairment (MMSE score < 24). Abnormal CDR score (0.5 or higher) was seen increasingly with increasing viral burden (in 4.9%, 16.2% and 26.9 %; p = 0.008). In logistic regression analyses after adjustment for cardiovascular risk factors, age, and education, seropositivity for 3 viruses was significantly associated with cognitive impairment at baseline and after one year when 348 individuals were re-tested for MMSE (Table I). No significant associations were found with bacterial burden. The type of vascular disease of the subjects did not affect the results. Table I VIRAL BURDEN AND COGNITIVE IMPAIRMENT IN 383 HOME-DWELLING ELDERLY WITH VASCULAR DISEASES Seropositivities for HSV1, HSV2 and CMV
Less than 3, n = 277 3 seropositivities, n = 106
Risk ratio (95 % confidence interval) of cognitive impairment Baseline, 58/383 Univariate Adjusted 1.0 (reference) 1.0 3.2 2.5 (1.8-5.7) (1.3-4.7)
At 12 months, 58/348 Univariate Adjusted 1.0 1.0 2.6 2.3 (1.4-4.6) (1.2-4.6)
Cognitive impairment was defined as MMSE score below 24 points. Data were adjusted for age, education, body mass index, log transformed blood glucose, and log transformed CRP. After 12 months, MMSE examination could be repeated in 348 individuals (91% of the baseline sample) of whom 58 individuals (16.7%) had a MMSE score < 24. During one year, the mean change of MMSE (MMSE at baseline minus MMSE at one year) was 0.42 points (±SD = 2.07). Overall, MMSE was decreased in 150 individuals (43.1% of 348).
422
After adjustment for MMSE points at baseline, the decrease of MMSE during one year was associated with viral burden in a stepwise manner (risk ratios 1.0, 1.8 (95 % CI 0.9 to 3.6) and 2.3 (95 % CI 1.1 to 5.0) for 0-1, 2 and 3 viral seropositivities, respectively. No associations were observed with bacterial burden. DISCUSSION In these elderly individuals living in the community and with cardiovascular diseases, viral burden consisting of seropositivity for herpesviruses and cytomegalovirus was significantly associated with cognitive impairment assessed with MMSE or CDR. The association was strong and graded, and independent of age, sex, education and cardiovascular risk factors including C-reactive protein (CRP). The finding was consistent both crosssectionally and during a 12-month follow -up. No association was detected between cognition and bacterial burden of seropositivity for C. pneumoniae and M. pneumoniae. The results support earlier hypotheses that viral infections may be associated with cognitive impairment and con-sequent dementia in old age (Dobson et al., 2003). The results are also biologically plausible because both HSV and CMV have neurotropic properties. Limitations of the study are that all participants had vascular disease, only seropositivity was used to assess viral burden, and rigorous verification of clinical dementia has not yet been performed. However, if these results are verified in other population -based studies, they could open new avenues to prevent dementia with antiviral drugs or possibly vaccinations. REFERENCES Balin, B.J., Gerard, H.C., Arking, E.J., Appelt, D.M., Branigan, P.J., Abrams, J.T., WhittumHudson, J.AQ. and Hudson, A.P. (1998): Identification and localization of Chlamydia pneumoniae in the Alzheimer’s brain. Med. Microbiol. Immunol. (Berl)., 187, 23-42. Dickson, D.W., Lee, S.C., Mattiace, L.A., Yen, S.H. and Brosnan, C. (1993): Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer’s disease. Glia, 7, 75-83. Dobson, C.B. and ltzhaki, R.F. (1999): Herpes simplex virus type 1 and Alzheimer’s disease. Neurobiol. Aging, 20, 457- 465. Dobson, C.B., Wozniak, M.A. and Itzhaki, R.F. (2003): Do infectious agents play a role in dementia? Trends Microbiol., 1, 312-317. Folstein, M.F., Folstein, S.E. and McHugh, P.R. (1975): Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res., 12, 189-198. Gieffers, J., Reusche, E., Solbach, W. and Maass, M. (2000): Failure to detect Chlamydia pneumoniae in brain sections of Alzheimer disease patients. J. Clin. Microbiol., 38, 881-882.
423
Itzhaki, R.F., Lin, W.R., Shang, D., Wilcock, G.K., Faragher, B. and Jamieson, G.A. (1997): Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet, 349. 241244. Jamieson, G.A., Maitland, N.J., Wilcock, G.K., Craske, J. and Itzhaki, R.F. (1990): Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains. J. Med. Virol., 33, 224-227. Lin, W.R., Graham, J., MacGowan, S.M., Wilcock, G.K. and Itzhaki, R.F. (1998): Alzheimer’s disease, herpes virus in brain, apolipoprotein E4 and herpes labialis. Alzheimers Rep., 1, 173-178. Lin, W.R., Wozniak, M.A., Cooper, R.J., Wilcock, G.K. and Itzhaki, R.F. (2002a): Herpesviruses in brain and Alzheimer’s disease. J. Pathol., 197, 395-402. Lin, W.R., Wozniak, M.A., Wilcock, G.K. and Itzhaki, R.F. (2002b): Cytomegalovirus is present in a very high proportion of brains from vascular dementia patients. Neurobiol. Dis., 9, 82-87. Pyles, R.B. (2001): The association of herpes simplex virus and Alzheimer’s disease: a potential synthesis of genetic and environmental factors. Herpes, 8, 64-68. Strandberg, T.E. and Tilvis, R.S. (2000): C-reactive protein, cardiovascular risk factors, and mortality in a prospective study in the elderly. Arterioscl. Thromb. Vasc. Biol., 20, 1057-1060. Strandberg, T.E., PitkaIa, K., Bergling, S., Nieminen, M.S. and Tilvis, R.S. (2001): Multifactorial cardiovascular disease prevention in patients aged 75 years and older: a randomized controlled trial. Am. Heart J., 142, 945-951. Strandberg, T.E., Pitkala, K., Linnavuori, K. and Tilvis, R.S. (2003): Impact of viral and bacterial burden on cognitive impairment in elderly persons with cardiovascular diseases. Stroke, 34, 2126-2131. Tombaug, T.N. and Mclntyre, N.J. (1992): The Mini-Mental State Examination: a comprehensive review. J .Am. Geriatr. Soc., 40, 922-935. Weiner, H.L. and Selkoe, D.J. (2002): Inflammation and therapeutic vaccination in CNS diseases. Nature, 420, 879-884.