I strongly recommend because I entirely agree with the introductory remarks of Professors McCully and de la Torre. The authors clearly show, that the accumulated knowledge indicate that chronic infection and consequent chronic inflammation and tissue damage can be the cause of many chronic inflammatory disorders, including Alzheimer's disease. These devastating chronic inflammatory disorders can be prevented. This knowledge is based on the observations of thousands of researchers of the last and present century.
Prompt action is needed if we want to stop the suffering of millions. This is an obligation for all of us. Those who have made substantial contribution to this domain should be helped and their research financially supported as based on their accumulated knowledge we might go ahead faster.
Borrelia burgdorferi alone cannot be the cause of Alzheimer's disease . The title of our initial article published 22 years ago clearly expressed: Alzheimer's disease - A spirochetosis? and not Alzheimer's disease a neuroborreliosis? We have stated that spirochetes of the order Spirochaetales - and not Borrelia burgdorferi alone play a role in Alzheimer's disease. This is a very important point to take in consideration in future research. The following discussion shows it well.
It is related to the article of O’Day DH, Catalano A (2014). A lack of correlation between the incidence of Lyme disease and deaths due to Alzheimer’s disease. J Alzheimers Dis42, 115-118.
I am writing this letter in reference to the recent paper by Danton and Catalano . I have read with interest their investigation based on the anticipation that “If the biological agent Borrelia burgdorferi that causes LD (Lyme disease) also causes AD (Alzheimer’s disease), then areas with the highest levels of LD should have significantly higher numbers of deaths due to AD compared to low LD areas.” To compare AD populations suffering from Lyme neuroborreliosis in endemic and non-endemic areas would be the right approach to obtain an answer to the question raised by the authors. From1993 it was emphasized, that Borrelia burgdorferi alone cannot explain all AD cases, as the incidence of Lyme disease, and particularly of Lyme dementia, compared to AD is very low. The authors noticed that various types of spirochetes were suggested to play a role in AD and to consider this point in their investigation would be critical [2,3]. These various spirochetes, including the highly prevalent periodontal pathogen Treponemes were detected in more than 90% of AD cases [4,5]. It is therefore expected that in both endemic and non-endemic LD areas, AD caused by other spirochetes can strongly overlap the small proportion of AD cases caused by Borrelia burgdorferi alone. Consequently, the present study cannot prove or exclude the involvement of Borrelia burgdorferi in AD. It is also important to consider that only about 10-15% of Lyme patients and generally only those who are untreated or insufficiently treated will develop dementia caused by Borrelia burgdorferi. Therefore, to simply compare the incidence of Lyme disease with that of AD may further render the interpretation of the results difficult. The authors also state that “The relationship between LD and AD has also been supported by analysis of existing data using Koch’s and Hill’s Postulates . What is lacking to fulfill these postulates is the isolation of functional entities (e.g., B. burgdorferi) followed by proof of their ability to induce AD-related events in tissue culture cells.”
The isolation of spirochetes from AD brains [1,6,7] and exposure of mammalian primary cell and organotypic cultures to spirochetes were shown to reproduce lesions similar to the pathological and biological hallmarks of AD . The re-isolation of spirochetes (Borrelia burgdorferi) from cell cultures infected by B31 reference strain and those cultivated from AD brains, all induced lesions similar to AD, they revealed to be virulent, invaded neurons and glial cells, and caused nuclear fragmentation, which were all previously documented . But independently of these observations, it is noteworthy that Koch himself acknowledged that the application of his four postulates to establish causality should be used as guidelines and not as definite postulates . Indeed, like Treponema pallidum, several other bacteria and viruses cannot be grown in pure culture and consequently cannot be re-isolated. Despite of this, the causal relationship between Treponema pallidum and syphilitic dementia is established. In order to address the limitations of Koch’s postulates, Hill introduced his new criteria for causality . Hill’s nine postulates do not require the isolation of the microorganisms in pure culture or their re-isolation from infected cell cultures.
This letter is guided with the best intention to openly discuss this newly emerging field of AD research in order not to stop but to help and encourage further investigations in this direction. An infectious etiology of AD was first proposed a century ago and it was never discarded. Leading AD researchers [12,13] about three decades ago claimed that an infectious etiology of AD is a real possibility and cannot be disregarded. To further consider the involvement of various types of spirochetes and co-infections with various bacteria, including Chlamydia pneumoniae , Porphyromonas gingivalis , and various viruses, like herpes simplex virus type 1 (HSV-1) , in AD is critical, particularly as these microorganisms were also detected in various other chronic inflammatory disorders, which are associated with AD.
We do not possess a targeted therapy for AD. If AD is caused by spirochetal infection associated with other bacteria and viruses, this might bring new hope for all patients who are suffering from AD and for all those who have concerns about the relationship between LD, periodontal pathogen spirochetes, and AD, as syphilitic dementia was almost eradicated by the use of penicillin. As we have an example in the history of medicine that chronic spirochetal infection can cause dementia and reproduce the pathological hallmarks of AD, including amyloid-β deposition , prompt action is needed to promote this research not only by the neuroscience community but also by governmental health authorities as AD might be prevented.
Judith Miklossy, Director, Prevention Alzheimer International Foundation, International Alzheimer Research Center, Martigny-Croix, Switzerland
References:  O’Day DH, Catalano A (2014) A lack of correlation between the incidence of Lyme disease and deaths due to Alzheimer’s disease. J Alzheimers Dis42, 115-118.  Miklossy J (1993) Alzheimer's disease--a spirochetosis? Neuroreport4, 841-848.  Riviere GR, Riviere KH, Smith KS (2002) Molecular and immunological evidence of oral Treponema in the human brain and their association with Alzheimer's disease. Oral Microbiol Immunol17, 113-118.  Miklossy J (2011) Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria. J Neuroinflammation8, 90. Ref  of the authors.  Miklossy J (2011) Emerging roles of pathogens in Alzheimer disease. Expert Rev Mol Med13, e30.  MacDonald AB, Miranda JM (1987) Concurrent neocortical borreliosis and Alzheimer's disease. Hum Pathol18, 759-761.  Miklossy J, Khalili K, Gern L, Ericson RL, Darekar P, Bolle L, Hurlimann J, Paster BJ (2004) Borrelia burgdorferi persists in the brain in chronic Lyme neuroborreliosis and may be associated with Alzheimer disease. J Alzheimers Dis6, 1-11.  Miklossy J, Kis A, Radenovic A, Miller L, Forro L, Martins R, Reiss K, Darbinian N, Darekar P, Mihaly L, Khalili K (2006) Beta-amyloid deposition and Alzheimer’s type changes induced by Borrelia spirochetes. Neurobiol Aging27, 228-236.  Miklossy J, Kasas S, Zurn AD, McCall S, Yu S, McGeer PL (2008) Persisting atypical and cystic forms of Borrelia burgdorferi and local inflammation in Lyme neuroborreliosis. J Neuroinflammation5, 40.  Koch R (1893) Ueber den augenblicklichen Stand der bakteriologischen Cholera Diagnose. J Hyg Inf14, 319-333.  Hill AB (1965) The environment and disease: association or causation? Proc R Soc Med58, 295-300.  Wisniewsky HM (1978) Possible viral etiology of neurofibrillary changes and neuritic plaques. In Alzheimer’s Disease: Senile Dementia and Related Disorders (Aging, Vol 7), Katzman R, Terry RD, Bick KL, eds. Raven Press, New York, pp. 555-557.  Khachaturian ZS (1985) Diagnosis of Alzheimer’s disease. Arch Neurol42, 1097-1105.  Balin BJ, Hudson AP (2014) Etiology and pathogenesis of late-onset Alzheimer's disease. Curr Allergy Asthma Rep14, 417.  Poole S, Singhrao SK, Chukkapalli S, Rivera M, Velsko I, Kesavalu L, Crean S (2014) Active invasion of Porphyromonas gingivalis and infection-induced complement activation in ApoE-/- mice brains. J Alzheimers Dis, doi: 10.3233/JAD-140315.  Itzhaki RF, Dobson CB, Shipley SJ, Wozniak MA (2004) The role of viruses and of APOE in dementia. Ann N Y Acad Sci1019, 15-18.  Miklossy J, Rosemberg S, McGeer PL (2006) Beta amyloid deposition in the atrophic form of general paresis. In Alzheimer’s Disease: New advances. Proceedings of the 10th International Congress on Alzheimer’s Disease (ICAD). Iqbal K, Winblad B, Avila J, eds. Medimond, International Proceedings, pp. 429-433.
08/13/2014 - Answer by O’Day and Catalano In their paper, O’Day and Catalano discuss both the existence of spirochaete-induced dementia and the extensive work by Miklossy and others on the potential role of Borrelia burgforeri—the bacterial perpetrator in Lyme disease (LD)—in Alzheimer’s disease (AD) . That said, it is clear that the incidence of deaths due to AD is in fact lower, not higher, in areas of high LD compared to those areas where LD occurrence is low or essentially non-existent. While extensive circumstantial evidence has suggested the opposite, the results of O’Day and Catalano thus argue strongly that the two diseases, LD and AD, are not linked. In the long run, we hope that improved reporting of both LD and AD cases, including deaths due to AD, will allow others to validate this conclusion.
Danton H. O’Daya,b,* and Andrew Catalanoc
aDepartment of Biology, University of Toronto at Mississauga, Mississauga, Ontario, Canada bDepartment of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada cDepartment of Chemistry, City College of New York, New York, New York, USA *Correspondence to: Danton H O’Day: firstname.lastname@example.org
Reference:  O’Day DH, Catalano A (2014) A lack of correlation between the incidence of Lyme disease and deaths due to Alzheimer’s disease. J Alzheimers Dis42, 115-118.
Response Our second response to O’Day and Catalano comments on 08/17/2014 - 13:39
I would like to thank the opportunity given by the editorial board of JAD for such open discussions. As I did not get an answer with respect to a relevant comment of my letter, I felt that some further clarifications might be helpful for future research.
In the study of O’Day and Catalano , there is no evidence whether the AD patients analyzed had a positive serology for LD or not. In addition, considering the number of deaths due to AD does not mean that all these patients suffered from definite AD, as neuropathological confirmation of definite AD is necessary. Furthermore, there is no evidence whether the LD patients included in the study have dementia or not. Comparing in this way the incidence of deaths due to AD, in areas of high or low LD cannot exclude the involvement of Borrelia burgdorferi in AD, even if the number of AD cases is higher in non-endemic LD areas. AD populations suffering from LD should be compared in LD endemic and non-endemic areas. Even in such conditions, other highly prevalent spirochetes involved in AD may mask the results.
A recent European study by Blanc et al. , considering the positive serology of Borrelia burgdorferi in a large demented population, obtained results that are opposite to those of O’Day and Catalano. They found 20 among 1,594 demented patients with positive Borrelia burgdorferi antibody index (AI), indicating that these patients suffered from Lyme neuroborreliosis. They concluded that Lyme dementia exists and that a small percentage of neurodegenerative dementia is associated with Lyme neuroborreliosis. Seven cases with positive AI were clinically diagnosed with AD (3 of them were associated with Lewy body dementia). Two AD cases (one with AD/Lewy body dementia) were neuropathologically confirmed. As spirochetal infection can lead to dementia, sometimes several decades following the primary infection, further prospective studies and pathological confirmation might give important results.
These observations, taken together with all those previous observations showing that Borrelia burgdorferi was cultivated from the brains of AD patients suffering from Lyme neuroborreliosis and that Borrelia specific antigens and DNA were co-localized with AD-type lesions, clearly indicate that Borrelia burgdorferi is implicated in a small percentage of AD cases. We have an example in the history of medicine that another chronic spirochetal infection can cause dementia and reproduce the pathological and biological hallmarks defining AD, including amyloid-β deposition. Therefore, it is important to follow research in this direction and consider that various types of spirochetes and other co-infecting bacteria and viruses are involved in AD.
With respect to the analysis of the involvement of Borrelia burgdorferi in AD, improved reporting of LD cases suffering from dementia and AD cases with positive serology for Borrelia burgdorferi will further help research in this direction. For this, testing AD patients for Borrelia burgdorferi and considering dementia as one of the tertiary manifestations of late Lyme neuroborreliosis is necessary. That AD-type dementia might be stopped and/or prevented would only give hope to AD and LD patients and to all the medical and neuroscience community.
Judith Miklossy, Director, Prevention Alzheimer International Foundation, International Alzheimer Research Center, Martigny-Croix, Switzerland
References  O’Day DH, Catalano A (2014) A lack of correlation between the incidence of Lyme disease and deaths due to Alzheimer’s disease. J Alzheimers Dis42, 115-118.  Blanc F, Philippi N, Cretin B, Kleitz C, Berly L, Jung B, Kremer S, Namer IJ, Sellal F, Jaulhac B, de Seze J (2014) Lyme neuroborreliosis and dementia. J Alzheimers Dis41, 1087-1093.
THE GOAL OF THIS INTERNATIONAL FOUNDATION IS TO HELP RESEARCH WITHOUT FRONTIERS FOR THE PREVENTION OF ALZHEIMER'S DISEASE AND HELP RESEARCH ON CHRONIC/LATE LYME DISEASE
Dr Judith Miklossy who is the Director of this international foundation and research center is one of the pioneers in this domain of research..
PREVENTION ALZHEIMER FOUNDATION An international foundation registered in Switzerland www.preventionalzheimer.org Director: Judith Miklossy MD, PhD, DsC Address: 1921 Martigny-Croix, CP 16, 1921, Switzerland Tel: + 41 27 722 0652; Cell: + 41 79 207 4442 Would you like to participate and help with donation?
Bank account of the foundation: Banque Cantonale du Valais Rue des Cèdres 8, Sion 1950, Switzerland IBAN: CH71 0076 5001 0105 7880 3 Account number: 101 057 8803 BIC ou SWIFT: BCVSCH2L Clearing number or CB: 765
Actualities from June to December 2012
CHRONIC OR LATE LYME DISEASE
In the framework of an international effort, a special issue with the participation of internationally recognized experts critically and constructively overviewed the clinical and pathological aspects of Lyme neuroborreliosis and showed directions for future practice and research
This special issue gives a framework of an international effort, to critically and constructively overview the clinical and pathological aspects of Lyme neuroborreliosis and show directions for future practice and research. Borrelia burgdorferi in association with tertiary brain lesions were reported by many authors. These observations indicate that similarly to Tre-ponema pallidum, Borrelia burgdorferi infection is directly involved in the late or chronic manifestations of Lyme neuroborreliosis. Chronic or late Lyme neuroborreliosis both refer to tertiary neuroborreliosis, therefore, the use of these terms as different entities is not justified and may lead to confusion.
The issue in the diagnosis and treatment of Lyme neuro-orreliosis is assessed followed by a comprehensive analysis of the involvement of connective tissue and associated clini-cal manifestations. A critical review shows that both the meningovascular and meningoencephalitic forms, which define chronic or late neurosyphilis also occur in Lyme neuroborreliosis. Clinical and pathological confir-mation of these tertiary forms and detection of
A critical assessment of clinical trials will guide the de-sign of future clinical studies and a detailed analysis of vari-ous factors influencing PCR detection of Borrelia specific DNA would be precious to improve the sensitivity of this potentially important diagnostic tool.
An update on the virulence determinants of Borrelia burgdorferi and the pathomechanisms involved in Lyme disease is discussed followed by a review showing the im-portance of co-infections in the diagnosis and treatment of Lyme disease.
Evidence for an infectious origin of various neuro-psychiatric symptoms of tick-borne diseases and various psychiatric disorders are also discussed. The involvement of immune system reactions, chronic inflammation, genetic and environmental factors are also considered. Finally an update on the perspectives on Lyme Borreliosis in Canada closes the special issue.
The majority of authors are internationally recognized neurologists and scientists with extensive experience and complementary expertise in clinical and/or basic research on Lyme disease. The exchange of knowledge at an interna-tional level and between experts in various branches of medicine and in basic research is the way to advance faster in this new, promising and important field of medicine. The aim of this special issue is to contribute to this process. This approach motivated the authors at the annual meeting of the German Borreliosis Society (Deutsche Borreliose-Gesells-chaft, DBG) in 2011 at Wuppertal, Germany to initiate and realize this special issue.
This issue is dedicated to the memory of Mark A. Smith whose untimely death has left a void for those looking to novel ideas to solve chronic diseases.
Whether spirochetes persist in affected host tissues and cause the late/chronic manifestations of neurosyphilis was the subject of long-lasting debate. Detection of a direct link between persisting infection and tertiary manifestations of neurosyphilis.Treponema pallidum in the brains of patients with general paresis established a link between persisting infection and tertiary manifestations of neurosyphilis.
Today, the same question is in the center of debate with respect to Lyme disease. The goal of this review was to compare the established pathological features of neurosyphilis with those available for Lyme neuroborreliosis. If the main tertiary forms of neurosyphilis also occur in Lyme neuroborreliosis and would indicate that the spirochete is responsible for the neuropsychiatric manifestations of late/chronic Lyme neuroborreliosis.
The substantial amounts of data available in the literature show that the major forms of late/chronic Lyme neuroborreliosis (meningovascular and meningoencephalitis) are clinically and pathologically confirmed. Borrelia burgdorferi was detected in association with tertiary brain lesions and cultivated from the affected brain or cerebrospinal fluid. The accumulated data also indicate that Borrelia burgdorferi is able to evade from destruction by the host immune reactions, persist in host tissues and sustain chronic infection and inflammation. These observations represent evidences that Borrelia burgdorfei in an analogous way to Treponema pallidum is responsible for the chronic/late manifestations of Lyme neuroborreliosis.
Late Lyme neuroborreliosis is accepted by all existing guidelines in Europe, US and Canada. The terms chronic and late are synonymous and both define tertiary neurosyphilis or tertiary Lyme neuroborreliosis. The use of chronic and late Lyme neuroborreliosis as different entities is inaccurate and can be confusing. Further pathological investigations and the detection of spirochetes in infected tissues and body fluids are strongly needed.
August - September 2011
Increasing amount of data indicate that spirochetes are involved in the pathogenesis of Alzheimer's disease. Here we review historic and new data related to the involvement of spirochetes in Alzheimer's disease. All positive and negative data are included. The goal was to critically analyze the association and causality between spirochetes and Alzheimer's disease, based on the substantial amount of data available and on established objective criteria of Koch and Hill
F1000 evaluation: "An infectious origin of Alzheimer'sdisease has been suggested for many decades. In a wonderfully synthetic review, a convincing role for neurospirochetesis made. This review opens a new perspective on the pathogenesis of Alzheimer's and other neurodegenerative diseases."
It is established that chronic spirochetal infection can cause slowly progressive dementia, brain atrophy and amyloid deposition in late neurosyphilis. Recently it has been suggested that various types of spirochetes, in an analogous way to Treponema pallidum, could cause dementia and may be involved in the pathogenesis of Alzheimer’s disease (AD). Here, we review all data available in the literature on the detection of spirochetes in AD and critically analyze the association and causal relationship between spirochetes and AD following established criteria of Koch and Hill. The results show a statistically significant association between spirochetes and AD (P = 1.5 x 10-17, OR = 20, 95% CI = 8-60, N = 247). When neutral techniques recognizing all types of spirochetes were used, or the highly prevalent periodontal pathogen Treponemas were analyzed, spirochetes were observed in the brain in more than 90% of AD cases. Borrelia burgdorferi was detected in the brain in 25.3% of AD cases analyzed and was 13 times more frequent in AD compared to controls. Periodontal pathogen Treponemas (T. pectinovorum, T. amylovorum, T. lecithinolyticum, T. maltophilum, T. medium, T. socranskii) and Borrelia burgdorferi were detected using species specific PCR and antibodies. Importantly, co-infection with several spirochetes occurs in AD.The pathological and biological hallmarks of AD were reproduced in vitro. The analysis of reviewed data following Koch’s and Hill’s postulates shows a probable causal relationship between neurospirochetosis and AD. Persisting inflammation and amyloid deposition initiated and sustained by chronic spirochetal infection form together with the various hypotheses suggested to play a role in the pathogenesis of AD a comprehensive entity.As suggested by Hill, once the probability of a causal relationship is established prompt action is needed. Support and attention should be given to this field of AD research. Spirochetal infection occurs years or decades before the manifestation of dementia. As adequate antibiotic and anti-inflammatory therapies are available, as in syphilis, one might prevent and eradicate dementia.
In this review all pathogens (bacteria and viruses) were considered. All positive and negative data were included. In addition to the critical review of available data, the molecular mechanisms involved in chronic slowly progressive infectious dementia and suggestions for future investigations are included.
Chronic spirochetal infection can cause slowly progressive dementia, cortical atrophy and amyloid deposition in the atrophic form of general paresis. There is a statistically significant association between various types of spirochete (including the periodontal pathogens Treponemas and Borrelia burgdorferi), Chlamydophyla pneumoniae, herpes simplex virus type-1 (HSV-1) IgM levels and Alzheimer disease (AD). Although there is no significant difference between the frequency of HSV-1 in AD cases and age-matched controls, the number of ApoE4 HSV-1 carriers with AD is reported to be significantly higher compared with disease occurrence in noncarriers. Exposure of mammalian neuronal and glial cells and organotypic cultures to spirochetes reproduces the biological and pathological hallmarks of AD. Senile-plaque-like beta amyloid (Aβ) deposits are also observed in mice following inhalation of C. pneumoniae in vivo, and Aβ accumulation and phosphorylation of tau is induced in neurons by HSV-1 in vitro and in vivo. Specific bacterial ligands, and bacterial and viral DNA and RNA all increase the expression of proinflammatory molecules, and activate the innate and adaptive immune systems. Evasion of pathogens from destruction by the host immune reactions leads to persistent infection, chronic inflammation, neuronal destruction and Aβ deposition. Aβ has been shown to be a pore-forming antimicrobial peptide, indicating that Aβ accumulation might be a response to infection. Global attention and action is needed to support this emerging field of research because dementia might be prevented by combined antibiotic/antiviral and anti-inflammatory therapy.
Amyloid beta, which is the most important biological marker of Alzheimer's disease, revealed to be an anttimicrobial peptide (AMP) following an excellent team work between several Universities such as Mass. General Institute for Neurodegenerative Disease and Dept. of Neurology, Boston University School of Medicine, Beth Israel Deaconess Medical Center, Uppsala University, Uppsala, Sweden and Boston University, Boston, MA.
September 2008 Diabetes type 2 - similarities to Alzheimer's disease
There is a strong association between Alzheimer's disease and type 2 diabetes. Recent observations show a seroprevalance of various infectious agents in type 2 diabetes. The association of periodontal disorders, which are polybacterial disorders, with Alzheimer's disease and type 2 diabetes suggests that infection and local inflammation can play an important role in these chronic age related disorders.
The following manuscript shows for the first time that d various chronic bacterial infections and local inflammation can play an important role in type 2 diabetes. Chlamydia pneumoniae, Helicobacter pylorii and spirochetes (probably, as in Alzheimer's disease, various types of spirochetes, including periodontal and intestinal spirochetes ) are amoung the candidate pathogens. Antibiotics together with antiinflammatory drugs may slow down and prevent the disease.
Miklossy J, Martins RN, Darbinian N, Khalili K, McGeer PL. Type 2 diabetes: Local inflammation and direct effect of bacterial toxic products. Open Pathol J, 2008, 2: 86-95.
It has been known for almost a century that amyloidosis is frequently associated with chronic bacterial infection. Islet amyloid deposit is characteristic of type 2 diabetes. Periodontal disease, which is predominantly caused by several Gram negative bacteria, is a risk factor for type 2 diabetes. The goal of the study was to explore whether bacteria or their toxic components may play a role in type 2 diabetes. The pancreas in 22 autopsy cases were analyzed for the presence of lipopolysaccharide (LPS), bacterial peptidoglycan (BPG) and local inflammatory processes. Ten of the cases had clinically diagnosed type 2 diabetes, and 12 were age matched controls. The results of an immunohistochemical analysis showed the presence of LPS and BPG in association with islet amyloid deposits in all the 10 diabetic cases as well as in 3 controls with clinically silent amyloid deposits. Chlamydia pneumoniae and Helicobacter pylori specific antigens were detected in the affected islets in a subset of diabetic patients. Clumps of HLA-DR positive activated macrophages, abundant immunoreactivity to the activated complement components C3d, C4d and C5b-9, the terminal attack complex, and a moderate numbers of T4 and particularly of T8 lymphocytes were present in the pancreas of all diabetic cases. These results suggest that bacteria or their slowly degradable remnants may initiate and sustain chronic inflammation in the pancreas and therefore play a role in the pathogenesis of type 2 diabetes. They also indicate that local immune responses, including activation of the classical complement pathway are important in the pathogenesis of type 2 diabetes. There may also be some involvement of the adaptive immune system. Further investigations are essential since a parallel use of antibacterial and antiinflammatory drugs may prevent or slow down the disease progression.
Miklossy J, Kasas S, Zurn AD, McCall S, Yu S, McGeer PL. Persisting atypical and cystic forms of Borrelia burgdorferi and local inflammation in Lyme neuroborreliosis Journal of Neuroinflammation, 2008; 5: 40 (open access, highly accessed)
This work shows the presence and persistence of atypical pleomorphic and cystic forms of Borrelia burgdorferi in the brains of three patients with neuropathologically and serologically confirmed Lyme neuroborreliosis. Borrelia burgdorferi was also cultivated from the brains of these patients. The in vivo observed pleomorphic forms of Borrelia spirochetes were identical to those induced in vitro.
The persistence of these more resistant spirochete forms and their intracellular location in host cells, (neurons and glial cells) may be one of those factors, which are responsible for the long latent stage of the disease and the persistence of Borrelia infection. The results also indicate that Borrelia burgdorferi can induce cellular dysfunction and apoptosis.
The abundant HLA-DR activated microglia and reactive astrocytes in the infected brain are indicative of Borrelia induced chronic local inflammation. The detection and recognition of atypical, cystic and granular forms of Borrelia burgdorferi in infected tissues is essential for the diagnosis and the treatment of Lyme disease as they can occur in the absence of typical spiral Borrelia form.
These results suggest that in such cases an adequate and more prolonged antibiotic therapy may be necessary.
ALZHEIMER DISEASE - THE ATROPHIC FORM OF LATE NEUROSPIROCHETOSES
THE INVOLVEMENT OF SEVERAL TYPES OF SPIROCHETES SHOULD BE CONSIDERED AND ANALYZED IN ALZHEIMER'S DISEASE! BORRELIA BURGDORFERI IS ONLY ONE OF THEM. PERIODONTAL ORAL TREPONEMA SPIROCHETES ARE HIGHLY PREVALENT IN THE POPULATION AT LARGE AND MAY BE FREQUENT CANDIDATES IN ALZHEIMER'S DISEASE. INTESTINAL SPIROCHETES AND SPIROCHETES OF THE UROGENITAL TRACTS AND VARIOUS OTHER BORRELIA SPIROCHETES MAY ALL BE INVOLVED IN ALZHEIMER DISEASE. THEREFORE STUDIES CONSIDERING AND ANALYZING BORRELIA BURGDORFERI ALONE CAN BE DISAPPOINTING. SUCH STUDIES CANNOT EXCLUDE OR REINFORCE THE INVOLVEMENT OF BORRELIA BURGDORFERI IN ALZHEIMER'S DISEASE.
To analyze the involvement of Borrelia burgdorferi in Alzheimer patients who have a positive serology for Borrelia burgdorferi is essential. If we would like to analyze the involvement of Treponema pallidum in a population with dementia without syphilis we would never succeed, despite that it has been known from a century that this spirochete can cause dementia.
In those studies who failed to show the involvement of Borrelia burgdorferi in Alzheimer's disease, the Alzheimer's patients investigated had no positive serology for Borrelia burgdorferi indicating, these these patients did not suffer from Lyme disease. However in those studies where Borrelia burgdorferi was found to be implicated in Alzheimer's disease, Borrelia spirochetes were cultivated in BSK medium from the brains (MacDonald 1987, Miklossy, 1993, Miklossy 1994, 2004) and/or the patients showed a positive serology for Lyme disease (Miklossy et al., 2004; Miklossy, 2007 ) or a positive PCR for Borrelia burgdorferi (Riviere et al., 2004).
The goal of our initial studies was not to show the involvement of Borrelia burgdorferi alone in Alzheimer's disease but to show that several types of spirochetes of the order Spirochaetales are involved in Alzheimer disease, including Borrelia burgdorferi (Miklossy, 1993-1996, Miklossy et al 1994-2011). The title of the report clearly indicates: Alzheimer's disease - A spirochetosis? and not Alzheimer's disease - A neuroborreliosis? In addition, the hypothesis was based on the observation, that in the brain of a demented patient with atrophic general paresis - used as positive control for the detection of spirochetes - the silver technique for spirochetes revealed the pathology of Alzheimer's disease. At high magnification the regular spiral form and the atypical forms of Treponema pallidum clearly showed that the plaques are made up of Treponema spirochetes and correspond to spirochetal masses. Recently, the local cortical amyloid deposit in the atrophic form of general paresis was characterized and, as in Alzheimer disease, corresponds to beta-amyloid.
Those who were analyzing all types of spirochetes including oral periodontal pathogen Treponemas, which are expected to be frequent candidates (Miklossy, 1993; Riviere et al, 2004) detected spirochetes in more than 90% of the Alzheimer's cases analyzed.
It is known that spirochetes frequently co-infect with other bacteria. Therefore, the consideration of co-infecting pathogens in Alzheimer's disease is also important.
The accumulated old historic and new observations and the fact that Fischer suggested (1907) and Alois Alzheimer and his colleagues cited Fischer's suggestion and stated that Fischer was not able to cultivate the microorgansisms. We should remember that Treponema pallidum cannot be cultivated and maintained in synthetic medium even today.