Mastic gum leads the way to better cognitive health …

Ulcer Bug Eradication
Empowers Galantamine

With regard to H. pylori research, perhaps there is another Nobel Prize in the making

By Will Block

O

A protected stomach protects the brain.

ur thoughts and conclusions are often driven by what seems probable, commensurate with our experience and knowledge. Does it seem probable that a bug can cause memory loss? That seems preposterous you might say … but you would be wrong!

Helicobacter pylori (Hp) is a bacterium with a Nobel Prize, in a manner of speaking. Identified in 1982 by Australian scientists Barry Marshall and Robin Warren to be present in patients with chronic gastritis and gastric ulcers—conditions that were not previously believed to have a microbial cause—Dr. Marshall put his hypothesis to the test.

In 1984, Marshall drank a Petri dish containing cultured Hp, anticipating that he would develop an ulcer in time, perhaps years later. Instead, within days he developed all the signs of an ulcer in the making, but by treating himself with antibiotics he reversed his conditions. This was a revolutionary step in gastroenterology, reversing decades of medical doctrine, which held that ulcers were caused by stress, spicy foods, and too much acid. For this discovery, Drs. Marshall and Warren justly received a Nobel Prize in 2005.

Ulcers Increase the Progression of Alzheimer’s Disease

With regard to Hp research, perhaps there is another Nobel Prize in the making. Over the past decade, research indicates that ulcers caused by Hp may increase the progression of dementia in Alzheimer’s disease (AD). In the most recent study, Chinese researchers from Taiwan examined 30,142 patients with both AD and peptic ulcers.1 They found that after eradication of the patient population’s Hp, the risk of AD progression was decreased. Before Hp eradication, among AD patients with peptic ulcers in the study, their AD got worse. However, after eradication, the efficacy of the acetylcholinesterase inhibitors (including galantamine) improved, compared to those with no eradication!

This was not the first time the relationship between Hp and AD has been studied. Nearly 10 years ago in 2004, a scientific paper found a possible link between Hp and AD.2 Two years later, researchers hypothesized that cholesterol glucosides arising from Hp infection may act as neurotoxins, promoting the degeneration of the dopaminergic neurons affected in Parkinson’s disease.3 Then in 2006, an article in the journal Neurology reported that in 50 patients with AD (as compared to controls without AD) the prevalence of Hp infection was significantly greater (88% in those with AD and 46.7% in controls).

H. Pylori and Mild Cognitive Impairment

Of great interest, in 2007 researchers found a connection between Hp and mild cognitive impairment (MCI). MCI is considered an early symptom and prodromal phase of AD.5 The prevalence of Hp infection was 88.9% (56/63) in MCI patients and 48.6% (17/35) in anemic controls, as confirmed by biopsy.

H. Pylori eradication Influences AD Manifestations

Altogether, over the years, there have been few clinical investigations of the Hp/AD relationship. So the appearance of a paper in the well-regarded Journal of Neurology in 2009 stepped up the pace of discovery. This research suggested that in patients diagnosed with AD, eradication of Hp can actually improve cognitive function to a significant degree.6


In 1984, Marshall drank
a Petri dish containing cultured Hp,
and developed an ulcer almost
immediately to prove his point.


In the first part of the study, 50 patients with AD and 30 age-matched anemic controls underwent an upper gastrointestinal endoscopy, and gastric mucosal biopsies to detect the presence of Hp infection. In the second part, Hp-positive AD patients received a triple eradication regimen (omeprazole, clarithromycin and amoxicillin), and all patients were followed up for 2 years, while treatment with cholinesterase inhibitors (such as galantamine) continued. Hp was detected in 88% of AD patients and in 46.7% of controls. Hp eradication was successful in 84.8% of treated patients. After 2 years cognitive and functional status parameters improved in the subgroup of patients where Hp eradication was successful demonstrating that Hp eradication influences AD manifestations.

The Causal Connections Between H. Pylori and AD

In 2012, researchers offered a possible mechanism when they found higher inflammatory agents in the cerebrospinal fluid of AD subjects who were also Hp positive.7 They found positive correlation between Hp immunoglobulin levels and homocysteine levels, thus concluding that the impact of Hp infection on the AD course may be attributed to cerebrovascular lesions and neuroinflammation.

In 2013, another study asked, “Does Helicobacter pylori infection increase incidence of dementia?”8 The authors investigated a group of 603 elderly individuals, 65 and older, living in southwest France who were free of dementia when the study began. Following the subjects for 20 years (from 1989 to 2008) the study’s aim was to determine whether Hp infection was associated with the risk of developing dementia. An analysis that measured dementia prevalence as well as Hp status was made at baseline with follow-up assessments for the duration of the study to determine the risk of developing dementia according to Hp status.

When the study began, 391 [about 2⁄3 of the subjects were women, a total of 348 with a mean age 73.9 ± 6.5)] were identified to have Hp. Dementia prevalence was higher in the infected group (5.4% vs 1.4%). After 20 years of follow-up, 148 cases of dementia were diagnosed. The group was controlled for age, sex, educational level, apolipoprotein E4 status, cardiovascular risk factors, and then tested with the MMSE (the Mini–Mental State Examination, a standard benchmark for AD progression) score. Hp infection was determined to be a risk factor for developing dementia.

Epidemiological Support for Bug-Caused Neurodegeneration

Figure 1: Prevalence of H. pylori infection by age in developing and developed countries. From Logan RP, Walker MM. ABC of the upper gastrointestinal tract: Epidemiology and diagnosis of Helicobacter pylori infection. BMJ. 2001 Oct 20;323(7318):920-2.
LEM1403pylori_graph274.gif
(click on thumbnail for full sized image)

Hp seropositivity is a potential risk for poor cognition among US adults. In a longitudinal population-based study, scientists found additional epidemiological support for the hypothesis that there is an association between dementia and Hp infection, which may enhance neurodegeneration.9 When combined with the dramatic increase of Hp infections with age, it stands to reason that this is a major problem the world over (see Fig. 1). The sum of the world’s memory and economy is greatly diminished from this treatable condition.

In the last few years there has been increasing interest in the effect of Hp infection on different extragastric diseases.10 A few case–control studies have reported a significant association between chronic Hp infection and AD11-13 and the results of the current Taiwan Chinese prospective study confirm and strengthen this link, with a significantly greater risk of developing dementia in subjects who are Hp positive.


This was a revolutionary step in
gastroenterology, reversing decades of
medical doctrine, which held that
ulcers were caused by stress, spicy
foods, and too much acid.


Infected Subjects More Cognitively Impaired

When the study began, infected subjects were more cognitively impaired and had a higher prevalence of dementia. The Hp-positive subjects were also older, were more likely to be male, and had less schooling than Hp-negative subjects. They also had a poorer health profile; hypertension was more frequent, and they were more frequently overweight. Investigation of the occurrence of dementia after 20 years of follow-up strengthens these results, finding a 45% greater risk of developing dementia in Hp–positive subjects.

Potentiating Cardiovascular Risk Factors Possibility

These findings support the link between Hp infection and dementia. Chronic Hp infection may also lead to the accumulation of cardiovascular risk factors during aging, which in turn leads to greater risk of developing dementia or worsening cognitive decline. Furthering that idea, epidemiological studies have suggested that Hp infection may be an independent risk factor for ischemic cerebrovascular diseases by increasing atherosclerosis, especially for stroke caused by small-artery occlusion.


Eradication of Hp infection was
determined to be a risk factor for
developing dementia.


Homocysteine to Endothelial Damage to Cardiovascular Lesions AND Neurodegeneration

Echoing the 2012 paper cited above,7 the mechanism by which Hp infection may play a role in neuron damage leading to dementia is that it causes a higher plasma homocysteine level, leading to endothelial damage, cerebrovascular lesions, and ultimately neurodegeneration.14 Hp could promote chronic atrophic gastritis, which in turn could result in low vitamin B12 and folate levels, and thus secondary hyperhomocysteinemia could result. Not to mention that systemic and chronic inflammation leading to atherosclerosis could increase neuroinflammation.

Another proposal suggests another pathogenic mechanism. The release of inflammatory mediators may disrupt the blood-brain barrier and promote the entry of immune cells and Hp proteins into the central nervous system, resulting in the development of AD pathologies by inducing Aβ peptide fibril formation.15,16

Eradication of H. Pylori Reduces Comorbidities

Hp reduction was associated with significant lower incidence of comorbidities (diabetes mellitus, hypertension, cerebrovascular disease, coronary artery disease, congestive heart failure and hyperlipidemia). These add to the decreased risk of AD progression as compared with no Hp eradication, which did not reduce comorbidities. Eradication of Hp was associated with a decreased progression of dementia as compared to no eradication of Hp in AD patients with peptic ulcers.

One Million Randomly Selected Subjects

The database used in the Taiwan Chinese study1 included one million randomly selected subjects from the 1996–2007 Taiwan National Health Insurance Research Database, a research database with linked data from the demographic and enrollment records, hospital claims, ambulatory care visits, and pharmacy dispensing claims from hospitals, outpatient clinics, and community pharmacies.

AD patients were collected from the outpatient pharmacy database between January 1, 1997, and December 31, 2004, with a primary diagnosis of dementia and who were regularly taking anticholinesterase medications (such as galantamine) for more than 3 months. From within this group, the researchers then selected AD patients with the diagnosis of peptic ulcer divided into two subgroups: 1) those who received Hp eradication therapy and 2) those who did not receive Hp eradication therapy. When neuropsychological assessment worsened as measured by the standard Alzheimer’s MMSE test, a shift from anticholinesterase medications (donepezil, rivastgmine, or galantamine) to memantine (a later stage Alzheimer’s drug), was observed. This shift represented a worsening of dementia.

Hp eradication was accomplished with triple or quadruple therapy (proton pump inhibitor or H2 receptor blocker, plus clarithromycin or metronidazole, plus amoxicillin or tetracycline, with or without Bismuth). One year was chosen as the cutoff value based on the distribution of Hp eradication date after hospitalization.


Hp can actually improve cognitive
function to a significant degree.


A total of 30,142 AD patients were included in the analysis. A total of 1,538 AD patients with peptic ulcer were then selected and classified into two groups: those with Hp eradication (675 subjects) and those without Hp eradication (863 subjects). Between these two groups enrolled in the study, several baseline characteristics—including diabetes mellitus, hypertension, cerebrovascular disease, congestive heart failure, coronary artery disease, and hyperlipidemia—were higher in frequency in patients without Hp eradication. In a previous study, the researchers had found that the eradication rate of Hp was 89.4% to 90.5%.17 From this, it was estimated that 90% of the patients in the current study (675 subjects) had successful eradication of Hp.

As compared with no Hp eradication, Hp eradication was associated with a decreased risk of changing anticholinesterase medication.

Killing the H. Pylori Bugs Slows AD and Improves Overall Health of the Mind and Body

When Hp was eradicated in AD patients with peptic ulcers, AD progression slowed, as compared to no Hp eradication. There was also a higher frequency of comorbidities in patients without eradication therapy of Hp. Among the comorbidities reduced were diabetes mellitus, hypertension, and cerebrovascular disease. In patients with diabetes mellitus, Hp infection or seropositivity not only increases the risk of atherosclerosis and cardiovascular disease but also contributed to promoting insulin resistance and increased microalbuminemia.


The shift from early- to late-stage
Alzheimer’s drugs represented a
worsening of dementia.


Chronic Hp infection has been shown to increase gastric juice pH level, leading to reduced folate absorption and increased blood homocysteine level, both of which would result in damaged vascular endothelial cells and increased risk of atherosclerosis.

The current study may provide some support for the hypothesis of Hp infection causing atherosclerosis and risk of cerebrovascular disease. Indeed, vascular risk factors, including adult-onset diabetes mellitus, hypertension, atherosclerosis, and atrial fibrillation, are known to increase the risk of AD.


The strength of the current study is
the enrollment of a nationally
representative cohort of
a large sample size.


Cerebral vascular dysfunction may cause the accumulation of amyloid-beta protein and neuroinflammation in animal models, and reduction of amyloid-beta protein deposition may ameliorate the neuroinflammation. Neuroinflammation disrupting the blood brain barrier, together with fibrinogen, may be one of the contributing factors for familial cerebral amyloid angiopathy and Alzheimer’s disease.

Strength of the Study

It is plausible to propose that antibacterial treatment of chronic inflammation caused by Hp (or other pathogens like spirochete) may reduce neuroinflammation and thus help prevent dementia. The strength of the current study is the enrollment of a nationally representative cohort of a large sample size.

Mastic Can Eradicate Hp

If you are currently taking galantamine, for preventive or treatment purposes, based on the results of the Taiwan study, it may be a good idea to take care of any Hp infection with mastic, which has been shown to eradicate Hp, but without any of the side effects of the antibiotic treatment. Also, mastic may be taken at a maintenance level so reinfection is less likely. (See “Mastic: Curtains for Ulcer-Causing Bacteria” in the January, 2010 issue).

The major take home point is the finding that the eradication of Hp deceases AD and enhances the beneficial effects of acetylcholinesterase inhibitors such as galantamine.

References

  1. Chang YP, Chiu GF, Kuo FC, Lai CL, Yang YH, Hu HM, Chang PY, Chen CY, Wu DC, Yu FJ. Eradication of Helicobacter pylori Is Associated with the Progression of Dementia: A Population-Based Study. Gastroenterol Res Pract. 2013;2013:175729. doi: 10.1155/2013/175729. Epub 2013 Nov 25.
  2. Malaguarnera M, Bella R, Alagona G, Ferri R, Carnemolla A, Pennisi G. Helicobacter pylori and Alzheimer’s disease: a possible link. Eur J Intern Med. 2004 Oct;15(6):381-386.
  3. Schulz JD, Hawkes EL, Shaw CA. Cycad toxins, Helicobacter pylori and parkinsonism: cholesterol glucosides as the common denominator. Med Hypotheses. 2006;66(6):1222-6.
  4. Kountouras J, Tsolaki M, Gavalas E, Boziki M, Zavos C, Karatzoglou P, Chatzopoulos D, Venizelos I. Relationship between Helicobacter pylori infection and Alzheimer disease. Neurology. 2006 Mar 28;66(6):938-40.
  5. Kountouras J, Tsolaki M, Boziki M, Gavalas E, Zavos C, Stergiopoulos C, Kapetanakis N, Chatzopoulos D, Venizelos I. Association between Helicobacter pylori infection and mild cognitive impairment. Eur J Neurol. 2007 Sep;14(9):976-82.
  6. Kountouras J, Boziki M, Gavalas E, Zavos C, Grigoriadis N, Deretzi G, Tzilves D, Katsinelos P, Tsolaki M, Chatzopoulos D, Venizelos I. Eradication of Helicobacter pylori may be beneficial in the management of Alzheimer’s disease. J Neurol. 2009 May;256(5):758-67.
  7. Roubaud-Baudron C, Krolak-Salmon P, Quadrio I, Mégraud F, Salles N. Impact of chronic Helicobacter pylori infection on Alzheimer’s disease: preliminary results. Neurobiol Aging. 2012 May;33(5):1009.e11-9. doi: 10.1016/j.neurobiolaging.2011.10.021.
  8. Roubaud Baudron C, Letenneur L, Langlais A, Buissonnière A, Mégraud F, Dartigues JF, Salles N; Personnes Agées QUID Study. Does Helicobacter pylori infection increase incidence of dementia? The Personnes Agées QUID Study. J Am Geriatr Soc. 2013 Jan;61(1):74-8.
  9. Beydoun MA, Beydoun HA, Shroff MR, Kitner-Triolo MH, Zonderman AB. Helicobacter pylori seropositivity and cognitive performance among US adults: evidence from a large national survey. Psychosom Med. 2013 Jun;75(5):486-96.
  10. Suzuki H, Franceschi F, Nishizawa T et al. Extragastric manifestations of Helicobacter pylori infection. Helicobacter. 2011;16(Suppl 1):65–69.
  11. Figura N, Franceschi F, Santucci A et al. Extragastric manifestations of Helicobacter pylori infection. Helicobacter. 2010;15(1):60–68.
  12. Kountouras J, Boziki M, Gavalas E et al. Eradication of Helicobacter pylori may be beneficial in the management of Alzheimer’s disease. J Neurol. 2009 May;256(5):758-67.
  13. Pac-Soo C, Lloyd DG, Vizcaychipi MP, Ma D. Statins: the role in the treatment and prevention of Alzheimer’s neurodegeneration. J Alzheimers Dis. 2011;27(1):1-10.
  14. Deane R, Zlokovic BV. Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease. Curr Alzheimer Res. 2007 Apr;4(2):191-7.
  15. Roses AD. Apolipoprotein E and Alzheimer’s disease. A rapidly expanding field with medical and epidemiological consequences. Ann NY Acad Sci. 1996 Dec 16;802:50-7.
  16. Saunders AM, Schmader K, Breitner JC, Benson MD, Brown WT, Goldfarb L, Goldgaber D, Manwaring MG, Szymanski MH, McCown N, et al. Apolipoprotein E epsilon 4 allele distributions in late-onset Alzheimer’s disease and in other amyloid-forming diseases. Lancet. 1993 Sep 18;342(8873):710-1.
  17. Wu IC, Wu DC, Hsu PI, Lu CY, Yu FJ, Wang TE, Chang WH, Chen JJ, Kuo FC, Wu JY,Wang WM, Bair MJ. Rabeprazole- versus esomeprazole-based eradication regimens for H. pylori infection. Helicobacter. 2007 Dec;12(6):633-7.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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