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There is a strong association between Alzheimer's disease and type 2 diabetes. Increasing numbner of recent observations show 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 suggest that infection and local inflammation may play an important role in these chronic age related disorders.
The following manuscript shows for the first time that local inflammation and various chronic bacterial infections may play an important role in type 2 diabetes. Chlamydia pneumoniae, Helicobacter pylorii and 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.
http://www.bentham-open.org/pages/content.php?TOPATJ/2008/00000002/00000001/86TOPATJ.SGM
Abstract:
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.
September 2008
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
Appeared in the Journal of Neuroinflammation, (BMC) 2008; 5: 40- website:
http://www.jneuroinflammation.com/content/5/1/40
This work shows the presence and persistence of atypical pleomorphic and cystic forms of Borrelia burgdorferi spirochetes in the brains of three patients with neuropathologically and serologically confirmed Lyme neuroborreliosis. The in vivo observed pleomorphic forms were identical to those induced in vitro.
The persistence of these more resistant spirochete forms and their intracellular location in host cells, including glial cells and neurons, may be one of those factors which explain the long latent stage and the persistence of Borrelia infection. The results also indicate that Borrelia burgdorferi can induce cellular dysfunction and apoptosis.
Abundant HLA-DR activated microglia and reactive astrocytes in the infected brain tissue is indicative of Borrelia induced chronic local inflammation.
The detection and recognition of atypical, cystic and granular forms of Borrelia burgdorferi spirochetes in infected tissues is essential for the diagnosis and the treatment as they can occur in the absence of the typical spiral Borrelia form.
A more prolonged antibiotic therapy in Lyme patients with persistent symptoms is necessary.
THE INVOLVEMENT OF SEVERAL TYPES OF SPIROCHETES SHOULD BE CONSIDERED AND ANALYZED IN ALZHEIMER'S DISEASE!!! BORRELIA BURGDORFERI IS ONE OF THEM. PERIODONTAL ORAL SPIROCHETES (TREPONEMES) ARE HIGHLY PREVALENT IN THE POPULATION AT LARGE AND MAY BE FREQUENT CANDIDATES. INTESTINAL SPIROCHETES MAY ALSO BE INVOLVED. STUDIES CONSIDERING AND ANALYZING THE SEROLOGY AND THE INVOLVEMENT OF BORRELIA BURGDORFERI ALONE (WITHOUT CONSIDERING THE POSSIBLE ROLE OF OTHER SPIROCHETES) .MAY BE DISAPPOINTING. SUCH STUDIES WILL NOT EXCLUDE OR REINFORCE THE INVOLVEMENT OF BORRELIA BURGDORFERI IN ALZHEIMER'S DISEASE.
The goal of an initial work was not to show the involvement of Borrelia burgdorferi in Alzheimer's disease alone but the involvement of several types of spirochetes - of the order Spirochaetales - including Borrelia burgdorferi (Miklossy, 1993). 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 a serologically and pathologically confirmed archival general paretic case, caused by another spirochete (Treponema pallidum) where silver staining for spirochetes revealed the pathology of Alzheimer's disease. At high magnification the regular spiral form typical of Treponema pallidum clearly indicated that the plaques were made up of Treponema spirochetes and correspond to spirochetal masses. In addition it is also characterized by the deposition of beta-amyloid.
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. It was not investigated and Borrelia spirochetes were not cultivated from the brains. To analyze the serology for Borrelia burgdorferi alone in Alzheimer's disease may give the same negative results, particularly in non endemic areas of Lyme disease. Lyme disease is geographically confined and the incidence is low when compared to Alzheimer's disease. It is therefore not surprising that these studies were not able to show the involvement of Borrelia burgdorferi in Alzheimer's disease.
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 of the patients (MacDonald 1987, Miklossy, 1993, Miklossy 1994, 2004)) and/or the patients showed a positive serology for Lyme disease (Miklossy et al., 2004; Miklossy, 2007 ). Those who were analyzing all types of spirochetes or oral Treponemas, which were expected to be the most frequent candidates, showed their presence in more than 90% of the AD brains (Miklossy et al., 1993; Riviere et al, 2004).
If we would like to analyze the involvement of Treponema pallidum in dementia in a population with negative serology for Treponema pallidum we would never succeed, despite that it has been known from a century that they can cause dementia. If we would like to analyze the involvement of Treponema pallidum in analyzing the serology of Treponema pallidum in a population with dementia, depending on the number of cases analyzed we would not find positive results or we would find only a few cases with positive serology.
To consider the involvement of Borrelia burgdorferi in Alzheimer patients who have a positive serology for Borrelia burgdorferi is essential. There are examples of AD patients with a positive serology for Borrelia burgdorferi who improved following antibiotic treatment.
It was always known that spirochetes co-infect with other bacteria. Therefore, to consider co-infecting pathogens which may play a role in Alzheimer's disease is also important.
The accumulated old historic and new observations and the fact that Alois Alzheimer himself discussed the possibility that microorgansisms may play a role in the formation of senile plaques in AD indicate that it is our duty with respect to the patients to consider that infectious agents may play a role in Alzheimer's disease. Today, to support this emerging field of research is essential, particularly, as adequate therapy would be available.
JULY 2008
A new volume "Dementia" of the prestigious Handbook of Clinical Neurology: Vol 89 (3rd series)
Series Editors: Aminoff, Boller and Swaab, Elsevier
Editors: Charles Duyckaerts (Lab de Neuropath R Escourolle, Paris, France) and
Irene Litvan (Raymond Lee Lebby Professor of Parkinson Disease Research, Department of Neurology, University of Louisville School of Medicine, Louisville, KY, USA)
Website order: http://www.ingentaconnect.com/search/article?title=SYPHILIS&title_type=tka&year_from=1998&year_to=2008&database=0&pageSize=20&index=33
In chapters 71 (Ricardo Nitrini: Clinical and therapeutic aspects of dementia in syphilis and Lyme disease) and 72 (Miklossy J. Biology and neuropathology of dementia in syphilis and Lyme disease) the clinical, pathological and biological aspects of syphilis and Lyme disease are discussed.
In chapter 72 the neuropathology and biology of late neurosyphilis and late neuroborreliosis are described. Evidences are presented that chronic Lyme neuroborreliosis exists. The pathological changes of tertiary Lyme neuroborreliosis (parenchymal Lyme neuroborreliosis) are strikingly similar to those occurring in tertiary neurosyphilis.
Dementia and stroke as a consequence of Treponema or Borrelia infections occur in the tertiary or late stages of these spirochetal diseases.
In meningovascular neurosyphilis and neuroborreliosis the leptomeninges and leptomeningeal arteries are involved leading to Heubner's arteritis, arterial thrombosis with secondary cerebral infarct (indirect parenchymal involvement). When Treponema or Borrelia spirochetes invade the nervous tissue (direct parenchymal involvement) there is a meningo-encephalitis or encephalitis. With respect to the direct parenchymal involvement two different forms are distinguished. In the infiltrative form there is a severe lymphoplasmacytic infiltration and in the atrophic form, a poor or absent lymphoplasmacytic infiltration, but severe microgliosis, neuronal loss and cortical atrophy are present. The pathology of both, the infiltrative and atrophic forms were documented in neurosyphilis and in Lyme neuroborreliosis.
The cases with chronic Lyme disease, illustrated in the chapter, were published in per reviewed, internationally recognized medical journals. Some of them more than 15 years ago. Chronic Lyme neuroborreliosis was confirmed by clinical, pathological and serological examinations and the spirochetes, their antigens or their genes were detected in the tertiary lesions. Improvement of chronic neurosyphilis and neuroborreliosis following antibiotic treatment was repeatedly reported in both, syphilis and Lyme disease. Syphilis was virtually eradicated by the use of Penicillin, indicating that by the use of combined antibiotic therapy we can also eradicate Lyme disease.
Newer approaches to the treatment of Lyme disease should take into account the frequent co-infections with other pathogens and the need for a more prolonged combination therapy also in patients with various persistent symptoms, including cognitive decline or progressive stroke.
Even in the doubt of tuberculosis it is obligatory to treat patients with "tritherapy" for 6 months. It should be an example for the future treatment of Lyme disease. Such treatment, in analogy to tuberculosis and syphilis will substantially prevent extensive healthcare costs in the future.
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For the first time in a special issue of the Journal of Alzheimer's Disease (JAD) historic and new obervations are reviewed whicg clearly show that infectious agents are implicated in the pathogenesis of Alzheimer's disease.
Chronic inflammation and Amyloidogenesis in Alzheimer’s Disease: The Emerging Role of Infection. Guest Editors: Judith Miklossy and Ralph Martins
http://www.j-alz.com/issues/13/vol13-4.html
Press release (IOS Press)
http://www.sciencedaily.com/releases/2008/05/
"Researchers Explore the Emerging Role of Infection in Alzheimer’s Disease
May 22, 2008, Amsterdam – A number of chronic diseases are in fact caused by one or more infectious agents. For example, stomach ulcers are caused by Helicobacter pylori, chronic lung disease in newborns and chronic asthma in adults are both caused by Mycoplasmas and Chlamydia pneumonia, while some other pathogens have been associated with atherosclerosis. The realization that pathogens can produce slowly progressive chronic diseases has opened new lines of research into Alzheimer’s disease.
In a special issue of the Journal of Alzheimer’s Disease published May 2008, guest editors Judith Miklossy, from The University of British Columbia, and Ralph N. Martins, from Edith Cowan University and Hollywood Private Hospital, Perth, Western Australia, and a group of experts explore this exciting topic.
Alzheimer’s disease (AD), the most frequent cause of dementia, is a form of amyloidosis. It has been known for a century that dementia, brain atrophy and amyloidosis can be caused by chronic bacterial infections, namely by Treponema pallidum in the atrophic form of general paresis in syphilis. Bacteria and viruses are powerful stimulators of inflammation. It was suggested by Alois Alzheimer and his colleagues a century ago that microorganisms may be contributors in the generation of senile plaques in AD.
The fact that pathogens may suppress, subvert or evade host defenses and establish chronic or latent infection has received little attention in the past. During infection, active oxygen and nitrogen species generated by inflammatory cells may cause DNA damage, induce apoptosis, and modulate enzyme activities and gene expression. Depending upon the biology of the pathogen and the host defense mechanisms the organism can persist in the infected tissues and cause chronic inflammation and amyloid deposition. The outcome of infection is as much determined by the genetic predisposition of the patient as by the virulence and biology of the infecting agent. Environmental factors and nutrition are critical determinants of disease expression as well.
In this special issue a series of reviews draws attention to both historic and recent observations related to this emerging field of AD research. The first review shows the importance of chronic inflammation in AD, followed by three articles presenting evidence on the involvement of spirochetes, Chlamydia pneumoniae and Herpes simplex virus type 1 in AD. These are followed by a review of amyloid proteins, which occur in many cellular forms in Eukaryotes and Prokaryotes.
The link between several viral and bacterial infections and the most significant genetic factor for AD, APOE ε4, is discussed in the next review. The link between excessive or misplaced iron and a variety of neurodegenerative diseases and infection is reviewed in the final article.
According to Miklossy and Martins, “The historic and new observations reviewed in this special issue clearly show that high priority should be given for further research in this field as it may have major implications for public health, treatment, and prevention as adequate anti-bacterial and anti-viral drugs are available. Treatment of a bacterial infection and associated viral infection may result in regression and, if started early, prevention of disease. The impact on reducing healthcare costs would be substantial.”
Reviews of the special issue of JAD (abstracts)
Claudia Schwab and Patrick L. McGeer
Inflammatory Aspects of Alzheimer Disease and Other Neurodegenerative Disorders
Alzheimer and a number of other neurodegenerative diseases are characterized by the presence of reactive microglia and reactive astrocytes in association with the lesions. The classic view that microglia exist primarily in either a resting or activated state needs to be broadened in view of recent results. Resting microglia are in constant activity sampling their surround. Activated microglia may be pro-inflammatory, releasing inflammatory cytokines and other inflammatory mediators, or anti-inflammatory, promoting the healing process. There is evidence that microglial phagocytosis is more powerful in the anti-inflammatory state. Activated astrocytes also have pro-inflammatory and anti-inflammatory properties. In the pro-inflammatory state they release inflammatory cytokines. In the anti-inflammVolume 13, Number 4, IN PRESS - atory state they release various growth factors. In AD and other neurodegenerative diseases, both microglia and astrocytes are in a pro-inflammatory state. From a therapeutic point of view it is desirable to find methods of tipping the balance towards an anti-inflammatory state for both types of glia.
Brian J. Balin, C. Scott Little, Christine J. Hammond, Denah M. Appelt, Judith A. Whittum-Hudson, Hervé C. Gérard, Alan P. Hudson
Chlamydophila pneumoniae and the etiology of late-onset Alzheimer’s disease
Sporadic, late-onset Alzheimer’s disease (LOAD) is a non-familial, progressive neurodegenerative disease that is now the most common and severe form of dementia in the elderly. That dementia is a direct result of neuronal damage and loss associated with accumulations of abnormal protein deposits in the brain. Great strides have been made in the past 20 years with regard to understanding the pathological entities that arise in the AD brain, both for familial AD (~5% of all cases) and LOAD (~95% of all cases). The neuropathology observed includes: neuritic senile plaques (NSPs), neurofibrillary tangles (NFTs), neuropil threads (NPs), and often deposits of cerebrovascular amyloid. Genetic, biochemical, and immunological analyses have provided a relatively detailed knowledge of these entities, but our understanding of the “trigger” events leading to the many cascades resulting in this pathology and neurodegeneration is still quite limited. For this reason, the etiology of AD, in particular LOAD, has remained elusive. However, a number of recent and ongoing studies have implicated infection in the etiology and pathogenesis of LOAD. This review focuses specifically on infection with Chlamydophila (Chlamydia) pneumoniae in LOAD and how this infection may function as a “trigger or initiator” in the pathogenesis of this disease.
Judith Miklossy
Chronic inflammation and amyloidogenesis in Alzheimer's disease – role of spirochetes
Alzheimer's disease (AD) is associated with dementia, brain atrophy and the aggregation and accumulation of a cortical amyloid-β peptide (Aβ). Chronic bacterial infections are frequently associated with amyloid deposition. Bacteria or their toxic components are powerful inflammatory stimulators and are amyloidogenic. It had been known from a century that the spirochete Treponema pallidum can cause dementia in the atrophic form of general paresis where. It is noteworthy that the pathological hallmarks of this atrophic form are similar to those of AD. Recent observations showed that bacteria, including spirochetes contain amyloidogenic proteins and also that Aβ deposition and tau phosphorylation can be induced in vitro or in vivo following exposure to bacteria or LPS. Bacteria or their poorly degradable debris are powerful inflammatory cytokine inducers, activate complement, affect vascular permeability, generate nitric oxide and free radicals, induce apoptosis and are amyloidogenic. All these processes are involved in the pathogenesis of AD. Old and new observations, reviewed here, indicate that to consider the possibility that bacteria, including several types of spirochetes highly prevalent in the population at large or their persisting debris may initiate cascade of events leading to chronic inflammation and amyloid deposition in AD is important, as appropriate antibacterial and antiinflammatory therapy would be available to prevent dementia.
Ruth F. Itzhaki and Matthew A. Wozniak
Herpes Simplex Virus Type 1 in Alzheimer’s disease: The Enemy Within
Alzheimer's disease is a modern scourge and is likely to become increasingly so in the future, with increasing longevity. The disease has been investigated for over one hundred years yet the causes of the disease and of the neuropathological characteristics seen in AD brain are still completely unknown. Evidence for a major causative role of a common virus, herpes simplex virus type 1 (HSV1), acting in combination with a genetic factor – the type 4 allele of the apolipoprotein gene, a known susceptibility factor – is presented here. The characteristics of the virus, some of which make it an especially likely candidate for this role, are described, as are the many precedents for the action of a genetic factor modulating outcome of infection. Various possible ways in which HSV1 might lead to development of AD, such as its up-regulation of various enzymes and in particular certain kinases, its effect on the cell cycle, on autophagy, and its inflammatory and oxidative effects are discussed also. It is concluded that there is strong evidence that the virus is indeed a major factor in AD and therefore there is a strong case for appropriate treatment, and possibly for prevention in the future.
Neal D. Hammer, Xuan Wang, Bryan A. McGuffie, Matthew R. Chapman
Amyloids: Friend or Foe?
Amyloidogenesis is the aggregation of soluble proteins into structurally conserved fibers. Amyloid fibers are distinguished by their resistance to proteinase K, tinctorial properties and β-sheet-rich secondary structure. Amyloid formation is a hallmark of many human diseases including Alzheimer’s, Huntington’s and the prion diseases. Therefore, understanding amyloidogenesis will provide insights into the development of therapeutics that target these debilitating diseases. A new class of ‘functional’ amyloids promises a unique glimpse at how nature has harnessed the amyloid fiber to accomplish important physiological tasks. Functional amyloids are produced by organisms spanning all aspects of cellular life. Herein we review amyloidogenesis, with special attention focused on the similarities and differences between the best characterized disease-associated amyloidogenic protein amyloid-β and the formation of several functional amyloids. The implications of studying functional amyloidogenesis and the strategies organisms employ to limit exposure to toxic intermediates will also be discussed.
Nadezda Urosevic and Ralph N. Martins
Infection and Alzheimer’s disease: The ApoE e4 connection and lipid metabolism
Microorganisms, bacteria and viruses, may infect and cause a range of acute and chronic diseases in humans dependent on the genetic background, age, sex, immune and health status of the host, as well as on the nature, virulence and dose of infectious agent. Late onset Alzheimer’s disease (AD) is a progressive neurodegenerative illness of broad aetiology with a strong genetic component and a significant contribution of age, sex and life style factors. Both infectious diseases and AD are characterised by an increased production of an array of immune mediators, cytokines, chemokines and complement proteins by the host cells as well as by changes in the host lipid metabolism. In this review, we re-examine a dangerous liaison between several viral and bacterial infections and the most significant genetic factor for AD, APOE ε4, and the possible impact of this alliance on AD development. This connection was discussed in the broader context of lipid metabolism and in the light of different capacity of various infectious agents, their toxic lipophilic products and host lipoprotein particles for binding to cell receptor(s).
Angela R. Kamer, Ananda Dasanayeke, Ronald G. Craig, Lidia Glodzik-Sobanska, Miroslow Bry, Mony J. de Leon
Alzheimer’s disease and peripheral infections: The possible contribution from periodontal infections, model and hypothesis
Alzheimer’s disease (AD) affects approximately 4.5 million people in the U.S. and this number will increase as the population ages and the life-span increases. Therefore, of paramount importance is identifying mechanisms and factors that affect the risk of developing AD. The etiology and pathogenic mechanisms for AD have not been defined, although inflammation within the brain is thought to play a role. Consistent with this hypothesis, studies suggest that peripheral infections contribute to the inflammatory state of the central nervous system. Periodontitis is a prevalent, persistent peripheral infection associated with gram negative, anaerobic bacteria that are capable of exhibiting localized and systemic infections in the host. This review offers a hypothetical link between periodontitis and AD and will present possible mechanistic links between periodontitis related inflammation and AD. It will review the pathogenesis of periodontitis and the mechanisms by which periodontal infections may affect the onset and progression of AD. Since periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD.
Eugene D. Weinberg, Judith Miklossy
Iron withholding: a defense against disease
Excessive and misplaced iron promotes an array of neurodegenerative and endocrine diseases as well as cardiomyopathy, arthropathy, neoplasia and infection. Vertebrates maintain an iron withholding defense system designed to prevent accumulation of redox-active (free) iron in sensitive sites and to sequester the metal in innocuous packages. Numerous genetic, behavioral and environmental factors counteract the defense system. Our increasing awareness of the pathologic roles of iron, as well as of the methods for prevention of iron loading coupled with intensified research and development of tissue specific iron chelator drugs, can be expected to yield marked improvements in human health.
