I. Old, historic data confirming our initial observations

That slowly progressive dementia, cortical atrophy can be caused by chronic spirochetal infection of the brain is well established.

When cortical brain sections of a patient suffering from syphilitic dementia were used as positive controls for the detection of spirochetes, it was surprising, that the accumulation of Treponema pallida showed the pathology of Alzheimer’s disease. The accumulation of spirochetes in masses or colonies, and the individual spirochetes were indistinguishable from senile plaques and curly fibers. Neurofibrillary tangles were also present. This observation was the starting point of our hypothesis that similarly to Treponema pallidum, several types of spirochetes might also cause slowly progressive dementia, brain atrophy and reproduce the pathological hallmarks of Alzheimer’s disease. 

Following this first observation we revisited the historic literature of syphilis, to see, whether old, historic descriptions and illustrations may show that Treponema pallidum is able to reproduce the pathological hallmarks of Alzheimer’s disease. 

The results showed that more that 100 manuscripts and/or illustrations show the accumulation of spirochetes in colonies, masses or balls in the cerebral cortex, which morphologically are indistinguishable from senile plaques. The local amyloid deposition revealed to be, as in Alzheimer’s disease, beta amyloid. Individual disseminated spirochetes cannot be distinguished from curly fibers of Alzheimer’s disease, strongly suggesting that curly fibers may correspond to individual spirochetes. 

These historic observations represent not only an important support for our studies, but clearly indicate that it is our obligation to investigate whether various types of spirochetes alone or together or with other associated bacteria and viruses may play a role in Alzheimer’s disease. It is particularly important, as to find the cause of Alzheimer’s disease is urgently needed.

We can say that we have an example in the history of medicine that chronic spirochetal infection causes dementia and reproduces the clinical and pathological hallmarks of Alzheimer’s disease.

Therefore historic data confirms our first observation and motivated us to investigate during the last 20 years whether various types of spirochetes can cause slowly progressive dementia and reproduce the pathological and biological hallmarks of Alzheimer’s disease.

II. Confirmation and reproduction of our results by other laboratories 

 1. With respect to amyloid as an integral part of bacteria and spirochetes (Miklossy, 1993):

Ultrastructural study of anti-APP immunostained Alzheimer brain sections revealed coiled elements in the cerebral cortex whose morphology was compatible with that of spirochetes. Reference strains of Borrelia burgdorferi (strain B31) and Treponema pallidum (Nichols strain) as well as spirochetes isolated from the brains of Alzheimer’s patients showed a positive immunoreaction, using monoclonal antibody against APP (Miklossy, 1993). In an additional case with concurrent Alzheimer’s disease and Lyme disease, the location of Borrelia burgdorferi antigens in the cerebral cortex was similar to that of APP and Ab. These observations suggested that amyloid may be an integral part of spirochetes and thus may be the source of the excess of Ab deposited in the brain in Alzheimer’s disease. These observations suggested that spirochetes might synthesize their own APP or APP-like protein.

Based on these initial observations we suggested that amyloidogenic protein may be an integral part of spirochetes (Miklossy, 1993, 1994a, Miklossy et al., 1996, 1998, 2006, 2008) and play a role in amyloidogenesis in Alzheimer disease.

Increasing number of recent observations show that various bacteria contain amyloidogenic proteins (Jarrett and Lansbury1992; Chapman et al., 2002; Maury, 2009; Hammer et al., 2008; Epstein and Chapman, 2008; Jordal et al., 2009). That spirochetes, namely Borrelia burgdorferi, contains amyloidogenic protein was reinforced by the observations of Ohnishi et al., (2000, 2001) who demonstrated that a beta-hairpin peptide, termed BH(9-10), derived from a single-layer beta-sheet of Borrelia OspA assembles into amyloid fibrils, which are similar to human amyloid deposits. More recent observations definitely indicate, that the presence of amyloid in bacteria, is rather a rule than an exception; that amyloid proteins are produced by various Gram-positive and Gram-negative bacteria and that they constitute a previously overlooked integral part of their cellular envelope (Jordal et al., 2009). Their morphology, tinctorial properties, their resistance to proteinase K and their beta-sheet secondary structure are all characteristic features of amyloid. 

2. With respect to spirochetes detected in the brain in Alzheimer’s disease 

In our initial paper we concluded that several types of spirochetes (from the order Spirochaetales) can be involved in Alzheimer’s disease and that the characterizations of these spirochetes is needed. “Knowing the genus and species of these spirochetes would indicate the source, the mode of transmission, and the site of primary infection” (Miklossy, 1993, 1994 a, b).

“We would like to strengthen that we do not interpret the present observations and those published earlier in that all AD cases are the late manifestation of Lyme borreliosis. ….The incidence of AD, which affects a large proportion of the aged population, is higher that the population at risk for developing AD due to Lyme neuroborreliosis. Spirochetes, in general, have a high meningo- and neurotropism; therefore, other spirochetes, e.g., oral spirochetes, intestinal spirochetes and those so-called commensal spirochetes, may all be considered as possible candidates to develop tertiary neurospirochetosis in the form of AD. “ (Miklossy et al., 1995). 

Our initial observations confirmed previous observations made by the pioneer work of MacDonald and Miranda, (1987) and MacDonald (1989), who have first shown the presence of Borrelia burgdorferi specific antigens in the brains of two Alzheimer’s patients and cultivated this spirochete from the brain in BSK medium. We have confirmed their observation in several additional works reported from 1993 until 2006 (www.miklossy.ch see our contribution) and we concluded that Borrelia burgdorferi is one of the various types of spirochetes, which is involved in Alzheimer’s disease.

Papolla et al., (1989) were not able to observe Borrelia burgdorferi in 6 AD patients analyzed but they have suggested that another spirochetes not detected by their methods might play a role in AD.
Later Meer-Scherrer et al. (2006) showed Borrelia burgdorferi by PCR in a patient suffering from concurrent Alzheimer’s disease and Lyme disease.

In the two other studies where B burgdorferi was not detected in the brain, evidence is lacking whether the analyzed AD patients suffered from Lyme neuroborrelisosis (Gutacker et al.,1998; Marques et al., 2000). We cannot expect to detect B. burgdorferi in the brains of AD patients who have no Lyme neuroborreliosis. An example is the analysis of the involvement of T. pallidum in syphilitic dementia. If we would like to demonstrate the involvement of T. pallidum in dementia in a population without syphilis, we cannot succeed, despite the established fact that this spirochete can cause dementia. In order to study the involvement of B. burgdorferi in AD, the analysis of AD patients suffering from Lyme disease is necessary.

Similarly, due to the low incidence of Lyme dementia compared to AD, the analysis of the seroprevalence of Borrelia burgdorferi alone may be disappointing (Gutacker et al., 1998; Galbussera et al., 2008). In such studies, where the Alzheimer’s patients analyzed do not suffer from Lyme disease, it is difficult to prove the involvement of Borrelia burgdorferi in AD. In addition, these studies cannot exclude the involvement of other spirochetes.
They rather confirm our initial studies that several types of spirochetes and not Borrelia burgdorferi alone can cause Alzheimer’s disease. 

Our initial study, which concluded that several types of spirochetes are involved in Alzheimer’s disease was reproduced and confirmed by Riviere et al, (2002). It is noteworthy, that we have found spirochetes in all Alzheimer’s cases analyzed and we have always used control cases without any Alzheimer’s types changes. As oral spirochetes are important periodontal pathogens and are highly predominant in the population at large we indeed expected that they might play a role in a high percentage of Alzheimer cases.

In their important work Riviere and collaborators (2002) have shown the presence of 6 different oral spirochetes namely, Treponema denticola, Treponema socranskii, Treponema pectinovorum, Treponema amylovorum, Treponema lecithinolyticum, Treponema maltophilum and Treponema medium, in the brain of Alzheimer’s patients. They were found in more than 93% of AD cases analyzed. They have also shown that several types of spirochetes can infect together, indicating the importance to look for the involvement of several types of spirochetes in the pathogenesis of Alzheimer’s disease.

Riviere et al., (2002) have also found Borrelia burgdorferi specific DNA in 5 of 16 (31.25%) AD cases analyzed. This confirmed previous data of Alan MacDonald and Miranda, 1987, MacDonald, 1989 that Borrelia burgdorferi is involved in the pathogenesis of AD and our observations showing that Borrelia burgdorferi is one of the various spirochetes involved in Alzheimer’s disease (3 of 14 (21.3%) Alzheimer’s cases analyzed (Miklossy, 1993; Miklossy et al., 2004). 

McLaughlin et al., (1999) have found spirochetes in the blood in one of 22 clinically diagnosed AD patients (Table 1). The authors suggested that the spirochete observed could correspond to oral Treponema spirochetes, which further reinforced our view that several types of spirochetes are involved in Alzheimer’s disease. The spirochete illustrated by the authors corresponds to a regular vegetative form and it is not clear, whether the atypical, pleomorphic spirochete forms common in blood and infected tissues were considered in this study. 

It has been reported that oral treponemes can represent up to 50% of the detectable flora in subgingival plaque from diseased sites. The human periodontal pocket harbors a highly diverse treponeme population. Near 60 diverse Treponema species were identified in subgingival pockets in human periodontal diseases (Paster 2000, Paster and Dewhirst 2000) These observations strongly support the findings of Miklossy, 1993 and Riviere et al., 2002, that several types of spirochetes are involved in Alzheimer’s disease.

The high number of excellent studies showing an association between periodontal disorders and Alzheimer’s disease represent further support for our observations (e.g. Kamer et al., 2008; 2009). 

Following the pioneer work of Riviere at al., (1991, 1992) several periodontal spirochetes, previously considered as commensal spirochetes revealed to be invasive. Adherence to host tissues is a critical first step in establishing a bacterial infection. Treponema denticola and other periodontal pathogen Treponemes adhere to host cells and to matrix proteins in vitro. (Riviere et al., 1991 a, b, 1992; Thomas, 1996; Sela et al., 2001). « The picture that begins to emerge is similar to that for binding of Treponema pallidum to host cells » (Thomas, 1996). 

Furthermore, it was shown that Treponema denticola has not only high pathogenicity but disseminate in vivo, in experimental animal, to distant organs, including the brain (Foschi et al., 2006). This further shows the potential importance of these periodontal pathogen spirochete in oral and linked systemic conditions, including the central nervous system.

All these observations strongly support our results showing that various types of spirochetes can be involved in Alzheimer’s disease. They further indicate that periodontal pathogen spirochetes can behave like Treponema pallidum and cause dementia and reproduce the pathological and biological hallmarks of Alzheimer’s disease. 

3. Further data from many laboratories supporting and reproducing the results that spirochetes can cause dementia 

The main symptomatology of the atrophic form of Lyme meningoencephalitis, as in syphilis, is cognitive decline. The occurrence of dementia and subacute presenile dementia in Lyme disease was reported by many authors (MacDonald 1986; Reik et al. 1986; MacDonald and Miranda 1987; Dupuis 1988; Miklossy 1993, 1994; Miklossy et al., 1994; Fallon, 1994; Pennekamp and Jaques, 1994; Schaeffer et al., 1994; Waniek et al., 1995; Juchnowicz et al., 2002; Miklossy 2004; Almeida and Lautenschlager 2005; Miklossy, 2011) and cerebral atrophy was documented by neuroradiology (Aasly and Nilsen, 1990; Tarasow et al., 2001).

In cases with slowly progressive dementia and brain atrophy, B. burgdorferi was detected or was cultivated from the brain by various investigators (MacDonald 1986; MacDonald and Miranda, 1987; Duray 1987; Miklossy, 1993, 1994; Miklossy et al., 1994a; Miklossy et al., 2004; MacDonald 2006a,b; Meer-Scherrer et al. 2006). In three patients, with slowly progressive dementia, where Borrelia burgdorferi was cultivated from the brain two had positive CSF serology. The pathological changes and the distribution of spirochetes were identical to those of T. pallidum in the atrophic form of general paresis [Miklossy et al., 2004, 2008].

The main pathological changes consisted of diffuse cortical atrophy with frontotemporal predominance, severe neuron loss and microglial and astrocytic proliferation. The spirochetes were restricted to the cerebral cortex and were numerous. The diagnosis of the atrophic form of Lyme meningoencephlitis is based on the typical clinical and pathological findings, on the positive serology, on the cultivation of Borrelia burgdorferi from the cerebral cortex, and on the identification of species-specific antigens and genes in the brain [Miklossy, 2004]. Positive identification of the cultivated spirochetes as Borrelia burgdorferi was confirmed by phylogenetic analysis of 16SrRNA.  

4. Data with respect to the virulence of periodontal spirochetes

T. denticola  (and other oral treponeme species as well) do indeed adhere both to host cells and to matrix proteins in vitro. This interaction involves proteins or protein-containing moieties on the surfaces of the spirochetes. Strain variability probably exists but is, at present, ill-defined. The picture that begins to emerge is similar to that for binding of T. pallidum  to host cells.

Treponemes represent a large fraction of the bacteria associated with periodontal

disease, and patients have antibodies to Treponema denticola, which speaks to an association (Armitage et al,  1982; Loesche, 1988; Simonson et al,  1988).

Only a fraction of the many oral spirochetes described have been cultivated (DaMeetal,  1993; Loesche, 1993). Although T. denticola and other cultivable oral treponemes undoubtedly possess cytolytic and enzymatic activities. Studies aimed at identifying and cultivating additional oral spirochetes and evaluating their potential pathogenicity, such as those dealing with the "pathogen-related" oral spirochetes (PROS) (Riviere et al., 1991a,b, 1992) should be pursued.

Potential impact on the traitment

It is known that antibiotic therapy is less efficient in chronic neurosyphilis and Lyme neuroborreliosis, however, syphilis was almost eradicated by the use of Penicillin and improvement in neuropsychiatric symptoms or complete recovery of patients suffering from late/chronic neurosyphilis and Lyme neuroborreliosisis was frequently reported.
Regressive evolution of tertiary Lyme neuroborreliosis and improvement or disappearance of neuropsychiatric symptoms in Lyme encephalitis following antibiotic treatment were reported by many authors (Stanek et al. 1996; Kruger et al., 1991; Wilke et al., 2000; Schmutzhard et al., 1995; Roelcke et al., 1992; Deloizy et al., 2000; Brower et al., 1996; van den Bergen et al., 1993; Lebas et al., 2012; Klingebiel et al., pediatrics 2002; Laroche et al., 1999; Zhang et al., 2000; Sparsa et al., 2009; Rey et al., 2010; Weder et al., 1987; Kacinski et al., 2007; De Cauwer et al. 2009; Kawano et al., 2010; Christen and Hanefeld, 1993; Topakian et al., 2008). These observations are also indicative of ongoing infection and point to the necessity of careful consideration of spirochetes in the etiology of stroke, dementia, mood disorders and various other neuropsychiatric symptoms associated with Lyme disease. They also underline the necessity of treatment.

In addition to discuss the confirmation of our observations by others, summarized here, we have also discussed the questions raised by the editorial comment, which accompanied our initial manuscript in 1993. During the last 20 years, the accumulated number of observations derived from our and other laboratories answer the main concerns raised by the editorial comment. You can see these answers in clicking here.

All these data indicate that attention and support should be given to this field of research.



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