Judith Miklossy

Microbes and Alzheimer's Disease

We are researchers and clinicians working on Alzheimer’s disease (AD) or related topics, and we write to express our concern that one particular aspect of the disease has been neglected, even thoug ...

Borrelia burgdorferi persists in the brain in chronic lyme neuroborreliosis and may be associated with Alzheimer disease

The cause, or causes, of the vast majority of Alzheimers disease cases are unknown. A number of contributing factors have been postulated, including infection. It has long been known that the spirochete Treponema pallidum, which is the infective agent for syphilis, can in its late stages cause dementia, chronic inflammation, cortical atrophy and amyloid deposition. Spirochetes of unidentified types and strains have previously been observed in the blood, CSF and brain of 14 AD patients tested and absent in 13 controls. In three of these AD cases spirochetes were grown in a medium selective for Borrelia burgdorferi. In the present study, the phylogenetic analysis of these spirochetes was made. Positive identification of the agent as Borrelia burgdorferi sensu stricto was based on genetic and molecular analyses. Borrelia antigens and genes were co-localized with beta-amyloid deposits in these AD cases. The data indicate that Borrelia burgdorferi may persist in the brain and be associated with amyloid plaques in AD. They suggest that these spirochetes, perhaps in an analogous fashion to Treponema pallidum, may contribute to dementia, cortical atrophy and amyloid deposition. Further in vitro and in vivo studies may bring more insight into the potential role of spirochetes in AD.

Interferon Regulatory Factor 4 Is Involved in Epstein-Barr Virus-Mediated Transformation of Human B Lymphocytes

ABSTRACT Epstein-Barr virus (EBV) infection is associated with many human malignancies. In vitro, EBV transforms primary B lymphocytes into continuously growing lymphoblastoid cell lines. EBV latent membrane protein 1 (LMP-1) is required for EBV transformation processes. Interferon regulatory factor 4 (IRF-4) is a transcription factor and has oncogenic potential. We find that high levels of IRF-4 are associated with EBV transformation of human primary B cells in vitro and with EBV type III latency in which LMP-1 is expressed. We show that EBV LMP-1 stimulates IRF-4 expression in B lymphocytes. The stimulation of IRF-4 by LMP-1 requires signaling from LMP-1 and involves cellular NF-κB. The growth of EBV-transformed cells is inhibited when IRF-4 is specifically down-regulated. We further demonstrate that IRF-4 knockdown cells have lower proliferation but higher apoptotic rates than control cells. Finally, IRF-4 is expressed in significant numbers of specimens of primary central nervous system (CNS) lymphomas (12/27 [44.4%]), an EBV-associated malignancy. The association between the expression levels of LMP-1 and IRF-4 is statistically significant (P = 0.011) in these CNS lymphomas. Our data suggest that IRF-4 may be a critical factor in EBV transformation and a useful target in the therapy of EBV-mediated neoplasia.

Interferon Regulatory Factor 7 Is Associated with Epstein-Barr Virus-Transformed Central Nervous System Lymphoma and Has Oncogenic Properties

ABSTRACT Interferon regulatory factor 7 (IRF-7) is implicated in the regulation of Epstein-Barr virus (EBV) latency. EBV transforms primary B cells, and the major EBV oncoprotein, latent membrane protein 1 (LMP-1), is required for the process. LMP-1 both induces the expression of IRF-7 and activates the IRF-7 protein by phosphorylation and nuclear translocation. Here we report that the expression of IRF-7 is increased in EBV-immortalized B lymphocytes compared with that in primary B cells. IRF-7 was phosphorylated and predominantly localized in the nucleus in the immortalized cells. The expression of IRF-7 was detected in 19 of 27 specimens of primary lymphomas of the human central nervous system by immunohistochemical analysis. The association between LMP-1 and IRF-7 was statistically highly significant for these specimens. An appreciable amount of the IRF-7 expressed in lymphoma cells was localized in the nucleus. Furthermore, IRF-7 promoted the anchorage-independent growth of NIH 3T3 cells. LMP-1 and IRF-7 showed additive effects on the growth transformation of NIH 3T3 cells. IRF-7-expressing NIH 3T3 cells formed tumors in athymic mice. Thus, IRF-7 has oncogenic properties and, along with LMP-1, may mediate or potentiate the EBV transformation process in the pathogenesis of EBV-associated lymphomas.

Primary Central Nervous System Lymphoma Expressing the Human Neurotropic Polyomavirus, JC Virus, Genome

ABSTRACT B lymphocytes are known as a potential site for latency and reactivation of the human neurotropic polyomavirus, JC virus (JCV). In light of recent studies on the oncogenicity of JCV and the transforming ability of the JCV early protein, T antigen, we investigated the association of JCV with B-cell lymphomas of the central nervous system. Examination of 27 well-characterized clinical specimens by gene amplification and immunohistochemistry revealed the presence of DNA sequences corresponding to the JCV early genome and the late Agnoprotein in 22 samples and the JCV late genome encoding the viral capsid proteins in 8 samples. Expression of T antigen and that of Agnoprotein by immunohistochemistry were each detected in six specimens. No evidence of the production of viral capsid proteins was observed, ruling out productive infection of JCV in the tumor cells. The results from laser capture microdissection verified the presence of JCV T-antigen sequences in tumor cells with positive immunoreactivity to antibodies against the viral proteins T antigen and Agnoprotein. Due to previous reports demonstrating an association of the Epstein-Barr virus (EBV) with transformation of B lymphocytes, EBV DNA sequences and the EBV transforming protein, latent membrane protein 1 (LMP1), were analyzed in parallel. EBV LMP1 DNA sequences were detected in 16 of 23 samples, and LMP1 expression was detected in 16 samples, 5 of which exhibited positive immunoreactivity to JCV proteins. Double labeling demonstrated coexpression of JCV T antigen and EBV LMP1 in the same cells. The detection of the JCV genome in large numbers of B-cell lymphomas and its coexistence with EBV suggest a potential role for JCV in the pathogenesis of primary CNS lymphoma.

Chronic or Late Lyme Neuroborreliosis: Analysis of Evidence Compared to Chronic or Late Neurosyphilis

Whether spirochetes persist in affected host tissues and cause the late/chronic manifestations of neurosyphilis was the subject of long-lasting debate. Detection of Treponema pallidum in the brains of patients with general paresis established a direct 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 Borrelia burgdorferi can be detected in brain lesions 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 burgdorferi 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.

Chronic or late lyme neuroborreliosis: present and future.

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. The issue in the diagnosis and treatment of Lyme neuroorreliosis is assessed followed by a comprehensive analysis of the involvement of connective tissue and associated clinical 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 Borrelia burgdorferi in association with tertiary brain lesions were reported by many authors. These observations indicate that similarly to Treponema 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. A critical assessment of clinical trials will guide the design of future clinical studies and a detailed analysis of various 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 importance 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 international 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.

Role of Microbes in the Development of Alzheimer's Disease: State of the Art - An International Symposium Presented at the 2017 IAGG Congress in San Francisco.

This article reviews research results and ideas presented at a special symposium at the International Association of Gerontology and Geriatrics (IAGG) Congress held in July 2017 in San Francisco. Five researchers presented their results related to infection and Alzheimer’s disease (AD). Prof. Itzhaki presented her work on the role of viruses, specifically HSV-1, in the pathogenesis of AD. She maintains that although it is true that most people harbor HSV-1 infection, either latent or active, nonetheless aspects of herpes infection can play a role in the pathogenesis of AD, based on extensive experimental evidence from AD brains and infected cell cultures. Dr. Miklossy presented research on the high prevalence of bacterial infections that correlate with AD, specifically spirochete infections, which have been known for a century to be a significant cause of dementia (e.g., in syphilis). She demonstrated how spirochetes drive senile plaque formation, which are in fact biofilms. Prof. Balin then described the involvement of brain tissue infection by the Chlamydia pneumoniae bacterium, with its potential to use the innate immune system in its spread, and its initiation of tissue damage characteristic of AD. Prof. Fülöp described the role of AD-associated amyloid beta (Aβ) peptide as an antibacterial, antifungal and antiviral innate immune effector produced in reaction to microorganisms that attack the brain. Prof. Barron put forward the novel hypothesis that, according to her experiments, there is strong sequence-specific binding between the AD-associated Aβ and another ubiquitous and important human innate immune effector, the cathelicidin peptide LL-37. Given this binding, LL-37 expression in the brain will decrease Aβ deposition via formation of non-toxic, soluble Aβ/LL-37 complexes. Therefore, a chronic underexpression of LL-37 could be the factor that simultaneously permits chronic infections in brain tissue and allows for pathological accumulation of Aβ. This first-of-its-kind symposium opened the way for a paradigm shift in studying the pathogenesis of AD, from the “amyloid cascade hypothesis,” which so far has been quite unsuccessful, to a new “infection hypothesis,” or perhaps more broadly, “innate immune system dysregulation hypothesis,” which may well permit and lead to the discovery of new treatments for AD patients.

Suppl 1: Chronic or Late Lyme Neuroborreliosis: Present and Future

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. The issue in the diagnosis and treatment of Lyme neuroorreliosis is assessed followed by a comprehensive analysis of the involvement of connective tissue and associated clinical 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 Borrelia burgdorferi in association with tertiary brain lesions were reported by many authors. These observations indicate that similarly to Treponema 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. A critical assessment of clinical trials will guide the design of future clinical studies and a detailed analysis of various 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 importance 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 international 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.

Editorial: Chronic or late Lyme neuroborreliosis: Present and future

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. The issue in the diagnosis and treatment of Lyme neuroorreliosis is assessed followed by a comprehensive analysis of the involvement of connective tissue and associated clinical 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 Borrelia burgdorferi in association with tertiary brain lesions were reported by many authors. These observations indicate that similarly to Treponema 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. A critical assessment of clinical trials will guide the design of future clinical studies and a detailed analysis of various 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 importance 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 international 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.