Emmanuel Gavalas

Association between Helicobacter pylori infection and mild cognitive impairment

The association of Helicobacter pylori infection and Alzheimers disease (AD) has recently been addressed, but no relative data exist regarding mild cognitive impairment (MCI), a prodromal phase of AD. The aim of this prospective study was to evaluate H. pylori infection, by histology in a Greek MCI cohort. Sixty‐three consecutive patients with amnestic MCI and 35 normal controls underwent upper gastrointestinal endoscopy, histologic and serological examinations. The prevalence of H. pylori infection was 88.9% (56/63) in MCI patients and 48.6% (17/35) in anaemic controls, as confirmed by biopsy (P < 0.001, odds ratio: 8.47, 95% CI: 3.03–23.67). Mean serum anti‐H. pylori IgG concentration and plasma total homocysteine (Hcy) titre were higher in MCI patients than controls (74.86 ± 57.22 vs. 17.37 ± 9.30 U/ml; and 16.03 ± 4.28 vs. 13.5 ± 1.20 μmol/l; P < 0.001 and P = 0.015, respectively). When compared with the anaemic participants, MCI patients exhibited more often multifocal (body and antral) gastritis (92.1% vs. 68.6%; P = 0.03); in H. pylori positive MCI patients cognitive state correlated with serum anti‐H. pylori IgG concentration. In conclusion, H. pylori prevalence was significantly higher in MCI patients than controls. This infection might contribute, at least in part, to the pathophysiology of MCI, possibly through induction of chronic atrophic gastritis and elevated Hcy consequences.

Increased Cerebrospinal Fluid Helicobacter Pylori Antibody in Alzheimer’s Disease

Background: Helicobacter pylori (H. pylori) infection may play a role in Alzheimers disease (AD). Aim: A prospective, nonrandomized, comparative study was car- ried out to examine the levels of anti-H. pylori-specific IgG antibodies in the cerebrospinal fluid (CSF) and serum of AD patients, compared with those of age-matched cognitively normal controls. Patients: CSF was aspirated from 27 AD patients and 27 age-matched cognitively normal patients with prostate hyperplasia or long-bone fractures necessitating surgery after epidural anesthesia. Serum samples were obtained from AD patients and the day before surgery from controls. Methods: CSF and serum anti-H. pylori IgG concentrations were measured by means of an enzyme-linked immunosorbent assay. Results: The mean concentration of anti-H. pylori-specific IgG was significantly greater in (a) the CSF of AD patients (10.53 ± 12.54 U/mL) than in controls (8.63 ± 8.01 U/mL, p = 0.047), and (b) the serum of AD patients (30.44 ± 33.94 U/mL) than in controls (16.24 ± 5.77 U/mL, p = 0.041). CSF anti-H. pylori IgG antibodies correlated with the degree of severity of the disease. Conclusion: H. pylori-specific IgG antibody levels are significantly increased in CSF and serum of AD; its titer in CSF might reflect the AD severity, thereby supporting a role for this common infection in the pathobiology of the disease.

Gastrointestinal Immune System and Brain Dialogue Implicated in Neuroinflammatory and Neurodegenerative Diseases

A common characteristic of the central nervous system (CNS) neurodegenerative disorders is neuroinflammation, marked by augmented numbers of activated and primed microglia, increased inflammatory cytokines and decreased anti-inflammatory molecules. CNS neuroinflammation is a critical component in the progression of several neurodegenerative diseases which sensitize the brain to produce an exaggerated response to immune stimuli in the periphery. Neuroinflammation might initiate from the periphery and peripheral conditions through disrupted blood-brain barrier powerfully influence various brain pathologies. Gastrointestinal tract (GIT) represents a vulnerable area through which pathogens influence the brain and induce CNS neuroinflammation. The pathogens may access the CNS through blood, the nasal olfactory pathways and the GIT. Potential GI pathogens, such as Helicobacter pylori, induce humoral and cellular immune responses that, owing to the sharing of homologous epitopes (molecular mimicry), cross-react with CNS components thereby contributing and possibly perpetuating neural tissue damage. GIT is strictly connected to the CNS and a bi-directional communication exists between them. The brain is involved in regulating the immune and gut system. Conversely, limited attention has been paid on the GIT role in the development and regulation of the CNS autoimmune diseases. The GIT is the primary immune organ with specialized immunoregulatory and anti-inflammatory functions, represented by the gastrointestinal immune system (GIS). This review focuses on the potential GIS and brain dialogue implicated in neurodegenerative diseases. Gaining a better understanding of the relationship between GIS and CNS could provide an insight on the pathogenesis and therapeutic strategies of these disorders.

Familial prevalence of autoimmune disorders in multiple sclerosis in Northern Greece.

Objective: The objective of this study was to evaluate for up to 7 years the prevalence of autoimmune disorders among naïve (untreated) multiple sclerosis family members compared with a contemporary general control population in Northern Greece, in a prospective case-control study, and to examine the possible relationship between immunomodulatory treatment and the appearance of additional autoimmune disorders. Methods: The patients and controls enrolled comprised 1383 patients with definite MS and 4392 relatives in their families and a total of 452 controls families with 1652 members. Results: At baseline, 891 multiple sclerosis families with 3112 members (73 multiplex multiple sclerosis families with 292 members and 818 simplex families with 2820 members) and 355 control families with 1580 members were examined regarding whether they had any of 12 autoimmune diseases. The baseline affected multiplex plus simplex multiple sclerosis families, the family members and the coexistent additional autoimmune disorders were higher compared with controls. There was an increase in longitudinally affected multiple sclerosis families, multiple sclerosis family members and coexistent additional autoimmune disorders compared with respective findings at the baseline observation. Comparison analysis between two time point observations (after a mean 7.1 ± 2.2 years) for each autoimmune disorder in overall multiple sclerosis family members revealed increased rates for longitudinal autoimmune Hashimoto’s thyroiditis, Graves’ disease, insulin-dependent diabetes mellitus, psoriasis and vitiligo (p = 0.02, p = 0.006, p = 0.0004, p = 0.05, and p = 0.05, respectively). Some 145 newly developed, longitudinally definite autoimmune cases were recognized in multiplex plus simplex multiple sclerosis families; 116 (80%) of these disorders were observed in patients with multiple sclerosis treated with immunomodulatory medications, and 68 of these 116 (58.6%) cases exhibited baseline positive autoreactive antibodies. Binary logistic regression analysis revealed that immunotherapy predisposes to autoimmunity (odds ratio 2.8, p < 0.001) independently of the presence of baseline autoantibodies and patients’ gender. Conclusions: There is a longitudinally increased frequency of additional autoimmune disorders among multiple sclerosis family members, probably related to immunomodulatory therapy.

Potential implications of Helicobacter pylori-related neutrophil-activating protein

Helicobacter pylori (H. pylori) virulence factors promote the release of various chemoattractants/inflammatory mediators, including mainly the neutrophil-attractant chemokine interleukin-8 and neutrophil-activating protein (NAP), involved in H. pylori-induced gastric pathologies. Co-administration of Chios mastic gum (CMG), which inhibits H. pylori NAP, with an H. pylori eradication regimen might add clinical benefits against H. pylori-related gastric pathologies, but possibly not CMG as main therapy. Although H. pylori NAP and other H. pylori-related cytotoxins [i.e., vaculating cytotoxin (VacA)] appear to play a major role in generating and maintaining the H. pylori-associated gastric inflammatory response and H. pylori NAP is a promising vaccine candidate against H. pylori infection (H. pylori-I), concerns regarding its potential drawbacks, particularly neurogenic ones, due to possible cross-mimicry, should be considered. Possible cross-mimicry between H. pylori NAP and/or bacterial aquaporin (AQP) and neural tissues may be associated with the anti-AQP-4 antibody-related neural damage in multiple sclerosis (MS)/neuromyelitis optica patients. Moreover, the sequence homology found between H. pylori VacA and human Na+/K+-ATPase A subunit suggests that antibodies to VacA involve ion channels in abaxonal Schwann cell plasmalemma resulting in demyelination in some patients. A series of factors have been implicated in inducing blood-brain barrier (BBB) disruption, including inflammatory mediators (e.g., cytokines and chemokines induced by H. pylori-I) and oxidative stress. BBB disruption permits access of AQP4-specific antibodies and T lymphocytes to the central nervous system, thereby playing a major role in multiple sclerosis pathogenesis. Relative studies show a strong association between H. pylori-I and MS. H. pylori-I induces humoral and cellular immune responses that, owing to the sharing of homologous epitopes (molecular mimicry), cross-react with components of nerves, thereby contributing and perpetuating neural tissue damage. Finally, H. pylori NAP also plays a possible pathogenetic role in both gastric and colon oncogenesis.

Multiple sclerosis and seizures: possible role of Helicobacter pylori

We have read with interest the proposition by Anderson and Rodriguez [1] that an increase in interleukin (IL)-18, and its associated induction of indoleamine 2, 3-dioxygenase (IDO) and quinolinic acid, mediates seizure activity in multiple sclerosis (MS) at least partly via an increase in interferon-gamma (IFN-c), accompanied by blood–brain barrier (BBB) permeability. Recent studies showed an association between Helicobacter pylori infection (Hp-I) and epilepsy, especially with poor prognosis [2]. Moreover, using histology, the practical gold standard for current Hp-I diagnosis, we showed a strong association between Hp-I and MS in a Greek cohort [3]. In this respect, we proposed that Hp-I, by inducing pro-inflammatory cytokine production and BBB disruption [4], may lead to neuroinflammation and neuronal damage in epilepsy, thereby triggering seizures induction and epilepsy progression [5]. Specifically, a series of factors have been implicated in inducing BBB disruption, including inflammatory mediators (e.g. cytokines and chemokines induced by Hp-I) and oxidative stress [5,6]. Hp could indirectly affect the brain through the release of numerous pro-inflammatory cytokines, such as IL-1b, IL-18, IFN-c [7] mentioned by the authors, or tumor necrosis factor (TNF)-a acting at a distance. TNF-a may contribute to BBB disruption and pathogenesis of neuronal inflammatory damage in neurodegenerative diseases and epilepsy; IL-1b, IL-6, and TNF-a influence the pathogenesis of seizures and course of epilepsy, and the primary BBB lesion is involved in seizures induction/epileptogenesis [8]. Likewise, an influx of Hp-infected monocytes, owing to defective autophagy resulting in Hp replication in autophagic vesicles, through the disrupted BBB might lead to brain degeneration and epilepsy development partially by potential activation of natural killer cells and IFN-c production, detrimental for MS; Hp VacA cytotoxin promotes intracellular survival of the bacterium and modulates host immune responses. Of note, Hp is known to be associated with the increase in IDOdependent mechanisms. Viewing the aforementioned data and because half of the world s population is infected withHp, it would be interesting to know whether the authors have considered Hp-I as a potential confounder involved in the pathophysiology of MS-associated increased seizure activity and therefore its management.

Association between Helicobacter pylori infection and Alzheimer’s disease in Japan

We read with interest the paper by Shiota et al. [1], who reported that older age and male sex were significantly associated with Alzheimer’s disease. Moreover, the authors reported a lack of association between Helicobacter pylori infection (Hp-I) status and Alzheimer’s disease in their Japanese cohort, suggesting that their findings might be explained by the much higher prevalence of Hp-I in the general Japanese than in the European population. We herein wish to emphasize two essential concerns regarding the methodological limitations which may render the results of this study highly debatable. The first is that both age and sex, found to be associated with Alzheimer’s disease, were not matched in the two study groups (p \ 0.001 and p = 0.01, respectively), and thus comparisons between the two study groups (i.e., Alzheimer’s disease patients and controls) cannot be expected to establish any firm conclusions. The second concern is that the very high Hp-I prevalence in the general Japanese population around 70 years old, reported by the authors, and, deductively, in the control group of the study, renders the study underpowered, meaning it requires probably thousands of participants in order to prove whether an association between Alzheimer’s disease and Hp-I can be established or excluded; it requires a very large population to be screened to prove or not a statistical difference in Hp-I among patients with Alzheimer’s disease and the general Japanese population. In view of the aforementioned methodological limitations, we deduce that this study can neither confirm the lack of association between the Hp-I status and Alzheimer’s disease in the Japanese population, nor is it comparable with the European studies indicating such an association [2–4].

Neuroprotection in glaucoma: is there a future role of Helicobacter pylori eradication?

Dear Editor, We read with considerable interest the paper by Baltmr A et al. (Baltmr et al., 2010) summarizing the mechanisms in initiating the apoptotic glaucomatous damage and reviewing “current potential neuroprotective strategies targeting RGCs from the laboratory to the clinic”. However, the authors did not mention the role of environmental agents involved in the pathophysiology of glaucomatous neuropathy and the potential neuroprotective strategies against these agents. In this regard, although degenerative diseases, including glaucoma, have an increasingly high impact on aged population, their association with Helicobacter pylori (H. pylori) infection has only recently been addressed (Kountouras et al., 2001, 2003; Kountouras et al., 2004a; Kountouras, 2009). A relationship between glaucoma andH. pylori infection appears to exist based on the following comparable data: (a) both diseases affect mainly old people; (b) H. pylori infection has been implicated in a variety of extradigestive vascular conditions including functional vascular disorders caused by the release of diverse vasoactive and proinflammatory substances, hypertension, arteriosclerosisinduced increased platelet activation/aggregation, ischemic heart disease, and ischemic cerebrovascular disorders, also detected in glaucoma and other neurodegenerative diseases contributing to their clinical manifestations (Kountouras et al., 2001; Kountouras et al. 2003; Kountouras et al., 2004a; Kountouras, 2009); and (c) in the nervous system,H. pylori infection is thought to be associated with the development of autoimmune sequelae observed in peripheral neuropathies, Alzheimer’s disease (AD) and glaucomatous optic neuropathy (defined as “ocular” AD) (Kountouras et al., 2001, 2003, 2004a, 2007; Kountouras, 2009).

Association between Helicobacter pylori burden and Alzheimer's disease

Keywords: Alzheimers disease; bacterial infections; cognitive disorders and dementia; infections; mild cognitive impairment; neurological disorders

Helicobacter pylori may be a common denominator associated with systemic and multiple sclerosis.

Joint Bone Spine - In Press.Proof corrected by the author Available online since mardi 22 fevrier 2011