Abstracts of online articleImpact of chronic Helicobacter pylori infection on Alzheimer's disease: preliminary results
Introduction
Alzheimer's disease (AD) is the main cause of dependency and disability in the elderly, and its incidence is currently increasing at a rate of 220,000 new cases per year in France (Helmer et al., 2006). No curative treatment for dementia is available, and most of the currently identified risk factors such as age, sex, and genetic factors like apolipoprotein E allele ε4 are not subject to intervention (Farrer et al., 1997). It has therefore become urgent to identify risk factors on which interventions would be possible. As an attempt to determine the etiology of late-onset AD and to search for new treatment, several groups have investigated the association between various infectious agents and AD. The first agent concerned was herpes simplex virus type 1 (HSV-1). HSV-1 may persist in a quiescent but persistent form known as latent infection, notably in the peripheral nervous system rather than in the central nervous system, and the mechanism for how HSV-1 may reactivate in the hippocampus remains unknown (Itzhaki et al., 1997). However the involvement of HSV is still debated. Wozniak and Itzhaki provided evidence that supports a causal role for HSV-1 in AD. The cascade of events leading to AD might involve reactivation of latent HSV-1 in the brain. Infection would cause both direct and indirect damage, inflammatory-mediated damage, and in apolipoprotein E allele ε4 carriers the damage would be greater, possibly through greater viral replication and spread, eventually leading to AD (Wozniak and Itzhaki, 2010).
Another major infectious pathogen incriminated was Chlamydia pneumoniae as up to 90% of AD brain biopsy specimens may be positive for C. pneumoniae as detected by polymerase chain reaction (PCR), especially in brain regions that exhibit AD pathology (Balin et al., 1998). However, in an interventional study in 100 patients, Loeb et al. (2004) could not prove a definite C. pneumoniae involvement in AD pathophysiology.
Recent observations also showed that several types of spirochetes, including Borrelia burgdorferi and oral Treponema may be involved in the pathogenesis of AD, but results remain controversial (Miklossy, 2008).
More recently, an association between AD and Helicobacter pylori infection was reported. H. pylori infection is a chronic infection usually acquired in childhood and which remains for life when no specific treatment is given. An increase in H. pylori prevalence with age is explained by changes in socioeconomic conditions. In fact, studies reported that when cohorts of 70-year-old subjects born in 1901 or 1902 and 1922 were compared, the latter cohort showed a significantly lower H. pylori positive serology. In Western Europe there is still more than a third of the population older than 60 years who are infected. H. pylori is a heterogenous bacterial species. Genomic studies have shown that some strains may harbor a pathogenicity island namely cag (cag PAI), which encodes a type IV secretion system and 1 of its effectors, CagA, which triggers a strong inflammatory response (Backert and Selbach, 2008).
Recent data suggested that H. pylori infection plays a role in extradigestive diseases (Figura et al., 2010) and in AD but controversial results persist. Indeed, in addition to 2 case-control studies pointing out an association between H. pylori infection and AD (Kountouras et al., 2006, Malaguarnera et al., 2004), an interventional study has shown that H. pylori eradication positively influences AD manifestations, especially cognitive decline (Kountouras et al., 2009). On the contrary, Shiota et al. (2011) showed negative results, but the authors based their diagnosis on antibody tests on urine samples which has been shown to be unreliable (Leodolter et al., 2003).
Preliminary results of a cohort study conducted in our laboratory concluded that H. pylori infection was a significant risk factor for developing AD (submitted for publication). We hypothesized that H. pylori infection could act as a trigger in the clinical revelation of AD or in the accumulation of AD lesions via cerebral hypoperfusion due to atherosclerosis, or via an exacerbation of neuroinflammation.
In order to test this hypothesis, we have compared, in this study, the cognitive impairment, cerebrospinal fluid (CSF)-β amyloid1–42 (Aβ1–42), -total tau (Tau), and -phosphorylated tau (pTau181) proteins, cerebrovascular lesions assessed by brain magnetic resonance imaging (MRI), and markers of neuroinflammation in a group of AD patients according to their H. pylori status.
Section snippets
Study population
Since 2003, serum and CSF samples from 213 demented patients were collected in Lyon, France by NeuroBioTec, CRB HCL (Hospices Civils de Lyon, France). Written informed consent allowing research, including genetic research, was obtained from each patient participating in the study. The study was approved by the local Ethics Committee (CPP).
Population characteristics
The NeuroBioTec dementia collection (plasma or CSF collection) was composed of 77 AD, 64 fronto-temporal dementia, 14 corticobasal degeneration, 22 dementia with Lewy bodies, 8 vascular dementia, 4 Creutzfeldt-Jakob disease, and 24 other dementias. Only 53 patients were diagnosed AD with available CSF markers. As shown in Table 1, included patients had identified risk factors of AD, i.e., mean age higher than 65 years, female gender, and overrepresentation of ε4 alleles of apolipoprotein E. A
Discussion
This study explored, for the first time, the association between H. pylori infection and AD severity. The strength and originality of this study are based on the strict selection of AD patients, according to NINCDS-ADRDA criteria, completed by CSF biomarkers. Indeed, Tau, pTau181, and Aβ1–42 CSF levels, combined with clinical criteria, are known to have high specificity and sensitivity for the diagnosis of AD (Clark et al., 2003).
Our results showed that H. pylori-infected patients tended to
Disclosure statement
The authors disclose no conflicts of interest.
Written informed consent allowing research, including genetic research, was obtained from each patient participating in the study. The study was approved by the local Ethics Committee (CPP).
Acknowledgements
We thank the “Association de recherches gérontologiques” for its financial support, Neurobiotec for its precious collaboration, especially Nathalie Dufay, Danièle Claudy, and Agnès Sassolas.
References (44)
- et al.
Increasing CSF phospho-tau levels during cognitive decline and progression to dementia
Neurobiol. Aging
(2008) - et al.
“Mini-mental state”A practical method for grading the cognitive state of patients for the clinician
J. Psychiatr. Res
(1975) - et al.
Imaging cerebral atrophy: normal ageing to Alzheimer's disease
Lancet
(2004) - et al.
Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI
J. Lipid Res
(1990) - et al.
Herpes simplex virus type 1 in brain and risk of Alzheimer's disease
Lancet
(1997) - et al.
IgG ELISA antibodies and detection of Helicobacter pylori in elderly patients
Lancet
(1996) - et al.
Helicobacter pylori and Alzheimer's disease: a possible link
Eur. J. Intern. Med
(2004) - et al.
Association of Helicobacter pylori infection with systemic inflammation and endothelial dysfunction in healthy male subjects
J. Am. Coll. Cardiol
(2005) - et al.
Role of type IV secretion in Helicobacter pylori pathogenesis
Cell. Microbiol
(2008) - et al.
Identification and localization of Chlamydia pneumoniae in the Alzheimer's brain
Med. Microbiol. Immunol
(1998)
Associations between Helicobacter pylori infection, co-morbid infections, gastrointestinal symptoms, and circulating cytokines in African children
Helicobacter
Cerebrospinal fluid tau and beta-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses?
Arch. Neurol
CSF tau markers are correlated with hippocampal volume in Alzheimer's disease
Neurobiol. Aging
The FAB: a Frontal Assessment Battery at bedside
Neurology
Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium
JAMA
Évaluation comparative de 29 trousses commercialisés pour le diagnostic sérologique de l'infection par Helicobacter pylori: étude multicentrique du Groupe d'Etude Français des Helicobacters (GEFH)
Feuillets de Biologie
MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging
AJR Am. J. Roentgenol
Extragastric manifestations of Helicobacter pylori infection
Helicobacter
The recurrence of Helicobacter pylori infection: incidence and variables influencing itA critical review
Am. J. Gastroenterol
Screening for dementia by memory testing
Neurology
Epidemiology of Alzheimer disease and related disorders [in French]
Med Sci (Paris)
Systemic inflammation and disease progression in Alzheimer disease
Neurology
Cited by (36)
3.26 - Microbiome Management of Neurological Disorders
2022, Comprehensive Gut MicrobiotaRole of the gut microbiome in the pathophysiology of brain disorders
2022, Neurobiology of Brain Disorders: Biological Basis of Neurological and Psychiatric Disorders, Second EditionDoes Alzheimer's disease stem in the gastrointestinal system?
2021, Life SciencesCitation Excerpt :Thus, the pathogen can lead to neural cell destruction and apoptosis particularly through releasing inflammatory molecules, producing reactive oxygen species, and circulating lipid peroxides [140]. There is evidence that AD patients with H. pylori infection exhibit higher CSF levels of H. pylori-specific IgG antibody, TNF-α, and IL-8 compared with uninfected AD patients [129,132]. Vitamin B12 deficiency is a common condition among patients with H. pylori-associated chronic atrophic gastritis, which can cause serum levels of homocysteine to be higher than normal.
The interactions between gut and brain in psychiatric and neurological disorders
2021, The Complex Interplay Between Gut-Brain, Gut-Liver, and Liver-Brain AxesModulation of the microbiota-gut-brain axis by bioactive food, prebiotics, and probiotics decelerates the course of Alzheimer's disease
2021, Studies in Natural Products ChemistryCitation Excerpt :Interestingly, enhanced antibody titers are associated with higher Aβ levels in plasma of AD patients, who also showed higher life-span exposure to pathogens [25,26]. Moreover, H. pylori-infected AD patients present higher tau concentrations in CSF, lower scores in the Mini-Mental State Examination (MMSE), and tend to develop more severe dementia compared to noninfected AD patients [27]. From this, there is a notion that harmful substances derived from microbial constituents cause inflammation.