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Historic evidence to support a causal relationship between spirochetal infections and Alzheimer’s disease
Abstract and Figures
Following previous observations a statistically significant association between various types of spirochetes and Alzheimer’s disease (AD) fulfilled Hill’s criteria in favor of a causal relationship. If spirochetal infections can indeed cause AD, the pathological and biological hallmarks of AD should also occur in syphilitic dementia. To answer this question, observations and illustrations on the detection of spirochetes in the atrophic form of general paresis, which is known to be associated with slowly progressive dementia, were reviewed and compared with the characteristic pathology of AD. Historic observations and illustrations published in the first half of the 20th Century indeed confirm that the pathological hallmarks, which define AD, are also present in syphilitic dementia. Cortical spirochetal colonies are made up by innumerable tightly spiraled
Treponema pallidum spirochetes, which are morphologically indistinguishable from senile
plaques, using conventional light microscopy. Local brain amyloidosis also occurs in general paresis and, as in AD, corresponds to amyloid beta. These historic observations enable us to conclude that chronic spirochetal infections can cause dementia and reproduce the defining hallmarks of AD. They represent further evidence in support a causal relationship between various spirochetal infections and AD. They also indicate that local invasion of the brain by these helically shaped bacteria reproduce the filamentous pathology characteristic of AD. Chronic infection by spirochetes, and co-infection with other bacteria and viruses should be included in our current view on the etiology of AD. Prompt action is needed as AD might be prevented.
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... Therefore, it is enormously important to investigate the involvement of pathogens in AD progression to better understand AD pathogenesis and therapeutic intervention. Indeed, several studies have identified the presence of different microbes in the post-mortem brain tissue of AD patients, suggesting they might be involved in AD (Renvoize and Hambling, 1984;Miklossy, 1993Miklossy, , 2011Miklossy, , 2015Itzhaki et al., 1997;Riviere et al., 2002;Alonso et al., 2014;Pisa et al., 2015;Perry et al., 2016;Dominy et al., 2019;Ciaccio et al., 2021;Senejani et al., 2021). ...
... In addition to viruses, bacteria that can reach the brain generally will induce neuroinflammation, and subsequent neurodegeneration which are the major cascades of AD pathology (Balin et al., 1998;Lim et al., 2014;Tran et al., 2022). A series of investigations found different kinds of spirochetes in human AD brain tissues, possibly revealing a strong connection of these microbes with AD pathogenesis as well (Miklossy, 1993(Miklossy, , 2011(Miklossy, , 2015. Borrelia burgdorferi, the causative agent of Lyme disease, was detected in AD brains, as a co-localized form with amyloid markers (MacDonald and Miranda, 1987;Senejani et al., 2021). ...
While recent advances in diagnostics and therapeutics offer promising new approaches for Alzheimer's disease (AD) diagnosis and treatment, there is still an unmet need for an effective remedy, suggesting new avenues of research are required. Besides many plausible etiologies for AD pathogenesis, mounting evidence supports a possible role for microbial infections. Various microbes have been identified in the postmortem brain tissues of human AD patients. Among bacterial pathogens in AD, Chlamydia pneumoniae (Cp) has been well characterized in human AD brains and is a leading candidate for an infectious involvement. However, no definitive studies have been performed proving or disproving Cp's role as a causative or accelerating agent in AD pathology and cognitive decline. In this review, we discuss recent updates for the role of Cp in human AD brains as well as experimental models of AD. Furthermore, based on the current literature, we have compiled a list of potential mechanistic pathways which may connect Cp with AD pathology.
... Researchers have observed the presence of T. pallidum and an increased number of spirochetal plaques in the cerebral cortex of certain patients diagnosed with general paresis (GP), suggesting the invasion of the central nervous system by T. pallidum in individuals affected by syphilis. When the cerebral cortex shows extensive deterioration or manifests dementia symptoms, this condition is commonly referred to as "general paralysis of the insane" (GPI), "dementia paralytica," or simply "general paralysis" (Miklossy, 2015;Chakravarthi and Joshi, 2021;Ha et al., 2024). ...
Background
This study utilizes Hydrogen proton magnetic resonance spectroscopy (¹H-MRS) to investigate metabolite concentrations in the bilateral hippocampus of general paresis (GP) patients.
Methods
A total of 80 GP patients and 57 normal controls (NCs) were enrolled. Metabolite ratios in the bilateral hippocampus were measured using ¹H-MRS. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Based on MMSE scores, participants were categorized into normal control, mild cognitive impairment, and moderate-severe dementia groups. Metabolite ratios (N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/creatine (Cr), N-acetylaspartate (NAA)/choline (Cho), myoinositol (MI)/creatine (Cr), choline (Cho)/N-acetylaspartate (NAA)) were compared between groups, and correlations between metabolite ratios and cognitive performance were examined.
Results
MMSE scores progressively decreased in the normal, mild cognitive impairment, and moderate-severe dementia groups (p < 0.001). The moderate-severe dementia group showed significantly lower NAA/Cr ratios in the left hippocampus region (L-NAA/Cr ratios) (p < 0.001) and higher Cho/NAA ratios in the left hippocampus region (L-Cho/NAA ratios) (p < 0.05) compared to the other groups. However, differences in L-NAA/Cr and L-Cho/NAA ratios between the mild cognitive impairment group and the NC group were not significant in the hippocampus region (p > 0.05). NAA/Cho and NAA/Cr ratios in the right hippocampus region (R-NAA/Cho and R-NAA/Cr ratios) in the moderate-severe dementia group were lower than those in the control group (p < 0.05). No correlation was found between metabolite ratios and MMSE scores in bilateral hippocampus regions.
Conclusion
There are distinctive metabolic characteristics in the hippocampus of GP patients. GP patients exhibited lower NAA/Cr and NAA/Cho ratios in the bilateral hippocampus, indicating neuron loss in these areas, which may become more pronounced as the disease progresses.
... Infections are recognized risk factors for dementia, including Alzheimer's disease (AD), vascular dementia, and other types of dementia (Sipila et al., 2021). A variety of pathogens such as herpes simplex virus (HSV) (Lopatko Lindman et al., 2021), human cytomegalovirus (CMV) (Lopatko Lindman et al., 2021), Epstein-Barr virus (EBV) (Zhang N. et al., 2021), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Fernandez-Castaneda et al., 2022); Helicobacter pylori (H.P) , Treponema pallidum (TP) (Miklossy, 2015), Borrelia burgdorferi (Herrera-Landero et al., 2019), Chlamydia (Lopatko Lindman et al., 2021;Chacko et al., 2022), and Toxoplasma gondii (Torres et al., 2018), may contribute to the cognitive decline. Most of these pathogens can cross the blood-brain barrier (BBB) and involve the meninges or parenchyma, inducing infectious encephalopathies. ...
Cognitive impairments, such as learning and memory deficits, may occur in susceptible populations including the elderly and patients who are chronically ill or have experienced stressful events, including surgery, infection, and trauma. Accumulating lines of evidence suggested that peripheral inflammation featured by the recruitment of peripheral immune cells and the release of pro-inflammatory cytokines may be activated during aging and these conditions, participating in peripheral immune system-brain communication. Lots of progress has been achieved in deciphering the core bridging mechanism connecting peripheral inflammation and cognitive impairments, which may be helpful in developing early diagnosis, prognosis evaluation, and prevention methods based on peripheral blood circulation system sampling and intervention. In this review, we summarized the evolving evidence on the prevalence of peripheral inflammation-associated neurocognitive impairments and discussed the research advances in the underlying mechanisms. We also highlighted the prevention and treatment strategies against peripheral inflammation-associated cognitive dysfunction.
... B. burgdorferi can form biofilms in the brain using quorum sensing mechanisms and bacterial amyloids, specifically curli fibers. The curli peptides trigger TLR-2 for the upregulation of NFκB and TNF-α, which may trigger neuronal death [125] . T. pallidum, an even stronger neuroinflammatory microbe, is well known to colonize and persist in the brain. ...
Disturbances in the local and peripheral immune systems are closely linked to a wide range of diseases. In the context of neurodegenerative disorders such as Alzheimer’s disease (AD), inflammation plays a crucial role, often appearing as a common manifestation despite the variability in the occurrence of other pathophysiological hallmarks. Thus, combating neuroinflammation holds promise in treating complex pathophysiological diseases like AD. Growing evidence suggests the gut microbiome’s crucial role in shaping the pathogenesis of AD by influencing inflammatory mediators. Gut dysbiosis can potentially activate neuroinflammatory pathways through bidirectional signaling of the gut-brain axis; however, the precise mechanisms of this complex interweaved network remain largely unclear. In these milieus, this review attempts to summarize the contributing role of gut microbiome-mediated neuroinflammatory signals in AD pathophysiology, while also pondering potential mechanisms through which commensal and pathogenic gut microbes affect neuroinflammation. While certain taxa such as Roseburia and Escherichia have been strongly correlated with AD, other clades such as Bacteroides and Faecalibacterium exhibit variations at the species and strain levels. In order to disentangle the inflammatory aspects of neurodegeneration attributed to the gut microbiome, it is imperative that future mechanistic studies investigate the species/strain-level dependency of commensals, opportunistic, and pathogenic gut microbes that consistently show correlations with AD patients across multiple associative studies.
Background
The immunopathological mechanisms underlying neurosyphilis remain incompletely elucidated, and the diagnosis of neurosyphilis presents challenges.
Methods
We used an antibody microarray to detect 640 proteins in cerebrospinal fluid (CSF) samples collected from 6 non-neurosyphilis and 10 neurosyphilis patients. The levels of CSF CXCL1, CXCL8, G-CSF, LCN2, MMP8, and MMP9 in 46 non-neurosyphilis, 51 untreated neurosyphilis, and 31 post-treatment neurosyphilis patients were quantified using enzyme-linked immunosorbent assay. The associations between the levels of these proteins and clinical parameters in neurosyphilis were evaluated using Spearman's analysis, and the diagnostic performance of these proteins in neurosyphilis was assessed using receiver operating characteristic curve.
Results
A total of 102 differentially expressed proteins between neurosyphilis and non-neurosyphilis were identified. The levels of significantly elevated neutrophil-associated proteins (CXCL1, CXCL8, G-CSF, LCN2, MMP8, and MMP9) in neurosyphilis were positive correlations with WBC counts, RPR titer, and protein concentration in CSF. The combination of CSF CXCL8, MMP9, and LCN2 yielded an AUC of 0.92 for diagnosing neurosyphilis, surpassing that of CSF RPR.
Conclusions
CXCL1, CXCL8, G-CSF, LCN2, MMP8, and MMP9 could be associated with central nervous system damage of neurosyphilis. The combination of CSF CXCL8, MMP9, and LCN2 is a promising biomarker for diagnosing neurosyphilis.
Background and aim
Invasion of the central nervous system by Treponema pallidum can occur at any stage of syphilis. In the event that T. pallidum is not cleared promptly, certain individuals may experience progression to neurosyphilis, which manifests as cognitive and behavioral abnormalities, limb paralysis, and potentially fatal outcomes. Early identification or prevention of neurosyphilis is therefore crucial. The aim of this paper is to conduct a critical and narrative review of the latest information focusing exclusively to the pathogenesis and clinical management of neurosyphilis.
Methodology
To compile this review, we have conducted electronic literature searches from the PubMed database relating to neurosyphilis. Priority was given to studies published from the past 10 years (from 2013 to 2023) and other studies if they were of significant importance (from 1985 to 2012), including whole genome sequencing results, cell structure of T. pallidum, history of genotyping, and other related topics. These studies are classic or reflect a developmental process.
Results
Neurosyphilis has garnered global attention, yet susceptibility to and the pathogenesis of this condition remain under investigation. Cerebrospinal fluid examination plays an important role in the diagnosis of neurosyphilis, but lacks the gold standard. Intravenous aqueous crystalline penicillin G continues to be the recommended therapeutic approach for neurosyphilis. Considering its sustained prominence, it is imperative to develop novel public health tactics in order to manage the resurgence of neurosyphilis.
Conclusion
This review gives an updated narrative description of neurosyphilis with special emphasis on its pathogenesis, susceptibility, diagnosis, treatment, and prevention.
This review advances an understanding of several dementias, based on four premises. One is that capillary hemorrhage is prominent in the pathogenesis of the dementias considered (dementia pugilistica, chronic traumatic encephalopathy, traumatic brain damage, Alzheimer’s disease). The second premise is that hemorrhage introduces four neurotoxic factors into brain tissue: hypoxia of the tissue that has lost its blood supply, hemoglobin and its breakdown products, excitotoxic levels of glutamate, and opportunistic pathogens that can infect brain cells and induce a cytotoxic immune response. The third premise is that where organisms evolve molecules that are toxic to itself, like the neurotoxicity ascribed to hemoglobin, amyloid- (A), and glutamate, there must be some role for the molecule that gives the organism a selection advantage. The fourth is the known survival-advantage roles of hemoglobin (oxygen transport), of A (neurotrophic, synaptotrophic, detoxification of heme, protective against pathogens) and of glutamate (a major neurotransmitter). From these premises, we propose 1) that the brain has evolved a multi-factor response to intracerebral hemorrhage, which includes the expression of several protective molecules, including haptoglobin, hemopexin and A; and 2) that it is logical, given these premises, to posit that the four neurotoxic factors set out above, which are introduced into the brain by hemorrhage, drive the progression of the capillary-hemorrhage dementias. In this view, A expressed at the loci of neuronal death in these dementias functions not as a toxin but as a first responder, mitigating the toxicity of hemoglobin and the infection of the brain by opportunistic pathogens.
This is a retrospective analysis of clinical data from individuals diagnosed with neurosyphilis, aiming to enhance healthcare professionals’ understanding of the disease and expedite early diagnosis and intervention.
A retrospective analysis was conducted on the clinical records of 50 patients who received a diagnosis of symptomatic neurosyphilis and were admitted to the Neurology Department during the period spanning January 2012 to December 2022.
Clinical manifestations encompassed diverse phenotypes, with syphilitic meningitis accounting for 16% of cases, characterized by symptoms such as headache, blepharoptosis, paralysis, blurred vision, and tinnitus. Meningovascular syphilis presented in 36% of cases, exhibiting episodic loss of consciousness, limb numbness, and limb convulsion. Paralytic dementia manifested in 36% of cases, featuring symptoms such as memory loss, sluggish response, and slow movement. Tabes dorsalis was observed in 12% of cases, presenting with weakness, numbness, and staggering. Routine cerebrospinal fluid (CSF) analysis indicated abnormal white blood cell counts in 60% of patients, while biochemical testing revealed abnormal protein content in 52% of patients. Notably, statistically significant differences were observed between patients with interstitial and parenchymatous neurosyphilis (Z = 2.023, P = 0.044) in terms of CSF protein content. Electroencephalogram (EEG) results were abnormal in six patients, and imaging studies unveiled diverse findings in 46 patients.
The study highlights the importance of neurological and/or ocular symptoms in diagnosing symptomatic neurosyphilis. Individuals with hypomnesia should be closely monitored for potential neurosyphilis. Integrating clinical manifestations, laboratory tests, EEG, and imaging can reduce misdiagnosis. This comprehensive approach shows promise in improving early identification and management of neurosyphilis.
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease characterized by cognitive and behavioral changes in older adults. Emerging evidence suggests poor oral health is associated with AD, but there is a lack of large-scale clinical studies demonstrating this link. Herein, we used the TriNetX database to generate clinical cohorts and assess the risk of AD and survival among >30 million de-identified subjects with normal oral health (n = 31,418,814) and poor oral health (n = 1,232,751). There was a greater than two-fold increase in AD risk in the poor oral health cohort compared to the normal oral health group (risk ratio (RR): 2.363, (95% confidence interval: 2.326, 2.401)). To reduce potential bias, we performed retrospective propensity score matching for age, gender, and multiple laboratory measures. After matching, the cohorts had no significant differences in survival probability. Furthermore, when comparing multiple oral conditions, diseases related to tooth loss were the most significant risk factor for AD (RR: 3.186, (95% CI: 3.007, 3.376)). Our results suggest that oral health may be important in AD risk, regardless of age, gender, or laboratory measures. However, more large-scale cohort studies are necessary to validate these findings and further evaluate links between oral health and AD.
Lyme disease, caused by vector-borne Borrelia bacteria, can present with diverse multi-system symptoms that resemble other conditions. The objective of this study was to evaluate disease presentations and Borrelia seroreactivity in individuals experiencing a spectrum of chronic and complex illnesses. We recruited 157 participants from Eastern Canada who reported one or more diagnoses of Lyme disease, neurological, rheumatic, autoimmune, inflammatory, gastrointestinal, or cardiovascular illnesses, or were asymptomatic and presumed healthy. Intake categories were used to classify participants based on their perceived proximity to Lyme disease, distinguishing between those with a disclosed history of Borrelia infection, those with lookalike conditions (e.g. fibromyalgia syndrome), and those with unrelated ailments (e.g. intestinal polyps). Participants completed three questionnaires, the SF-36 v1, SIQR, and HMQ, to capture symptoms and functional burden, and provided blood serum for analysis at an accredited diagnostic lab. Two-tiered IgG and IgM serological assessments (whole cell ELISA and Western blot) were performed in a blinded fashion on all samples. The pattern of symptoms and functional burden were similarly profound in the presumptive Lyme and Lyme-like disease categories. Borrelia seroprevalence across the study cohort was 10% for each of IgG and IgM, and occurred within and beyond the Lyme disease intake category. Western blot positivity in the absence of reactive ELISA was also substantial. Fibromyalgia was the most common individual diagnostic tag disclosed by two-tier IgG-positive participants who did not report a history of Lyme disease. Within the IgG seropositive cohort, the presence of antibodies against the 31 kDa Outer Surface Protein A (OspA) was associated with significantly better health outcomes. Previously, this marker has been linked to treatment-refractory Lyme arthritis. Overall, our findings support prior observations of phenotypic overlap between Lyme and other diseases. Seropositivity associated with non-specific symptoms and functional impairment warrants further mechanistic investigation and therapeutic optimization.
Propionibacterium acnes, an anaerobic corynebacterium, has been found in three out of four biopsies from frontal lobe cortex in patients with Alzheimer's disease; in the fourth case, the patient mistakenly received a cephalosporine injection before the biopsy. The basis of the anoxic milieu in the cortex is microangiopathy due to vascular risk factors (old age, high blood pressure, hyperinsulinemia, diabetes mellitus, hyperlipidemia, lack of estrogens. In line with this interpretation, persons with apolipoprotein E4 have an increased risk of Alzheimer's disease. The dementia of the Alzheimer type is probably not a primary neuronal degeneration. The implications for prevention are obvious: vasoprotective diet, physical activity, treatment of high blood pressure, estrogen replacement etc. For therapy, in addition to ACE inhibitors, natural estrogens and vasoactive drugs, cephalosporines are recommended.