Clinical Neurology and Neurosurgery 175 (2018) 16–24

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Clinical Neurology and Neurosurgery

journal homepage: www.elsevier.com/locate/clineuro

H. pylori and Parkinson’s disease: Meta-analyses including clinical severity T

a,⁎,1 a,1 b,c,1 a
Efthimios Dardiotis , Zisis Tsouris , Alexios-Fotios A. Mentis , Vasileios Siokas ,
Amalia Michalopouloua, Maria Sokratousa, Metaxia Dastamania, Dimitrios P. Bogdanosd,e,
Georgia Deretzif, Jannis Kountourasg
a
Department of Neurology, University Hospital of Larissa, University of Thessaly, Larissa, Greece
b
Public Health Laboratories, Hellenic Pasteur Institute, Athens, Greece
c
Department of Microbiology, University Hospital of Larissa, University of Thessaly, Larissa, Greece
d
Department of Rheumatology and Clinical Immunology, University Hospital of Larissa, University of Thessaly, Larissa, Greece
e
Cellular Immunotherapy & Molecular Immunodiagnostics, Biomedical Section, Centre for Research and Technology-Hellas (CERTH), Institute for Research and
Technology-Thessaly (IRETETH), Larissa, Greece
f
Department of Neurology, Papageorgiou General Hospital, Thessaloniki, Greece
g
Department of Medicine, Second Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

A R T I C LE I N FO A B S T R A C T

Keywords: The exact etiology of Parkinson’s disease (PD) remains unclear. Some evidence supports Helicobacter pylori in-
Helicobacter pylori fection as a trigger or driving event, but detection and eradication of H. pylori are not part of PD management.
Parkinson’s disease The aims of this case-control study and meta-analysis were to determine (i) the prevalence of H. pylori infection
Infection in PD patients, (ii) associations between H. pylori infection and clinical status, and (iii) differences in motor
Eradication
status in PD patients before and after H. pylori eradication. A literature search was performed using the PubMed
Meta-analysis
database. The prevalence of H. pylori infection in PD, its association with the unified Parkinson’s disease rating
UPDRS
scale (UPDRS), and the association of H. pylori eradication therapy with the UPDRS-III score were determined by
calculating the odds ratios (OR) and the standardized mean differences (SMD) with 95% confidence intervals
(CI). Fixed- and random-effects models were applied. Ten studies were included in the first meta-analysis (5043
PD patients, 23,449 HCs); H. pylori infection prevalence was higher in PD patients than in HCs [OR (95% CI):
1.47 (1.27, 1.70), Pz < 0.00001]. In seven studies reporting UPDRS scores (150 H. pylori infected, 228 non-
infected PD patients), there was a significant association between H. pylori infection and mean UPDRS scores
[SMD (95% CI): 0.33 (0.12, 0.54), Pz = 0.003]. Regarding H. pylori eradication, in five studies (90 PD patients),
there was a significant reduction in UPDRS-III scores after treatment [SMD (95% CI): 6.83 (2.29, 11.38),
Pz = 0.003]. In conclusion, the present meta-analysis revealed a higher prevalence of H. pylori infection in PD
patients suggesting that H. pylori may contribute to PD pathophysiology. In addition, the significantly lower
UPDRS scores in non-infected PD patients and in patients after H. pylori eradication therapy demonstrate that the
infection may deteriorate the clinical severity of the disease.

1. Introduction Helicobacter pylori (H. pylori) infection is one of the commonest

Parkinson’s disease (PD) is the commonest movement disorder and
second most common neurodegenerative disorder to Alzheimer’s dis-
ease [1,2]. Neuropathological hallmarks are progressive dopaminergic
neuron degeneration and loss in the midbrain substantia nigra com-
pacta, Lewy body formation, and abnormal α-synuclein accumulation
[3,4]. Genetic, neuronal aging, and environmental factors (such as
constipation and low levels of physical activity) appear to be associated
with an increased risk of PD [2,5–7].
chronic infections. Its prevalence approaches 50% in middle-aged
adults even in developed countries, although there is some suggestion
that its prevalence has decreased over the last century [8]. H. pylori
mostly causes gastritis and peptic ulcer disease but is also linked to
extra-gastrointestinal disorders [9] including neurological diseases such
as cerebrovascular diseases [10], dementia [11,12], multiple sclerosis
[13,14], glaucoma (described as “ocular Alzheimer disease”) [15], and
PD [16]. Eradication of H. pylori might therefore inhibit the develop-
ment and delay the progression of many diseases.

⁎
Corresponding author.
E-mail address: edar@med.uth.gr (E. Dardiotis).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.clineuro.2018.09.039
Received 5 January 2018; Received in revised form 24 September 2018; Accepted 26 September 2018
Available online 01 October 2018
0303-8467/ © 2018 Elsevier B.V. All rights reserved.
E. Dardiotis et al.
Patients with PD have an excessive number of peptic ulcers [17].
Altschuler [18] hypothesized on causal link between H. pylori and PD,
while neuronal damage in PD has been recently proposed as a response
to chronic H. pylori infection [16]. Several studies have suggested an
increased prevalence of H. pylori infection in PD patients [19–22].
Furthermore, a large population study suggested that there is an in-
creased prescription of anti-Helicobacter drugs for chronic H. pylori in-
fection prior to the diagnosis of PD [23]. Likewise, other studies have
suggested that motor performance in PD patients is affected by the
presence of H. pylori infection [20,24].
As the duodenum is the main site for levodopa absorption, duodenal
H. pylori infection [25] might affect levodopa bioavailability by indu-
cing inflammation, disrupting the duodenal mucosa, and releasing re-
active oxygen species that reduce levodopa absorption or inactivate the
drug [21]. However, there is no consensus in the different published
studies regarding the extent to, and the way in which, H. pylori eradi-
cation influences motor symptoms and affects levodopa absorption
[20,26–28].
Despite this potential link between H. pylori infection and PD,
screening for H. pylori is not specifically advocated in the management
of PD. A recent meta-analysis [29] examined the effects of H. pylori
infection on PD; however, it did not include all available studies and did
not examine the relationship between H. pylori infection and the clinical
status in PD patients, or the effect of H. pylori eradication on disease
severity. Hence, the aim of this meta-analysis was to assess the pre-
valence of H. pylori infection in PD patients and to elucidate the re-
lationship between the infection and PD clinical status. We were also
interested in examining the possible influence of H. pylori eradication
on PD motor severity as expressed by the UPDRS.
2. Methods
2.1. Literature search strategy
Eligible studies were selected by searching the PubMed database
using combinations of the following terms: “Helicobacter pylori” and
“Parkinson’s disease”. The complete search algorithm is available in S1
File. The final literature search was performed on 13 November 2017.
The references in all the retrieved publications were also reviewed to
identify any studies missed in our initial search.
2.2. Data extraction
Eligible articles were first sorted by screening titles and abstracts
and assessing the full text of eligible studies. Data extracted directly
from the articles were: study design, H. pylori infection detection
method, clinical assessment scale, H. pylori eradication therapy pro-
tocol, number of participants, number of infected patients and controls,
sex ratio, and mean age. Data values were presented as in the original
articles. If those data were not provided, they were calculated using
related study data. The number of participants and the means and
standard deviations (SD) of unified PD rating scale (UPDRS) scores
were extracted from the RCTs. Two investigators (E.D. and Z.T.) in-
dependently conducted data extraction and evaluated the methodolo-
gical quality with disagreements resolved by a third investigator (V.S.).
2.3. Inclusion criteria
2.3.1. H. pylori infection in PD patients vs. healthy controls
Studies included in the first part of the meta-analysis met the fol-
lowing criteria: a) case-control as well as observational studies in-
cluding PD patients (i.e., cases) and healthy controls (i.e., controls); b)
both PD patients and healthy controls tested for H. pylori infection; c)
studies reporting either cardinal number or percentage of subjects re-
garding H. pylori infection for both groups; d) English language; e)
studies conducted in humans. Studies with incomplete or not
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Clinical Neurology and Neurosurgery 175 (2018) 16–24
mentioned original data were excluded from the meta-analysis.
2.3.2. Mean UPDRS scores between H. pylori infected and non-infected PD
patients
Studies included in the second part of the meta-analysis met the
following criteria: a) case-control as well as observational studies in-
cluding H. pylori infected PD patients (i.e., cases) and H. pylori non-
infected PD patients (i.e., controls); b) all PD patients tested for H.
pylori infection; c) mean UPDRS-III or total UPDRS score (and SD)
provided separately for both groups of patients; d) English language; e)
studies conducted in humans. Studies with incomplete or not reported
data were excluded from the meta-analysis.
2.3.3. Mean UPDRS scores before and after H. pylori eradication therapy
Studies included in the third part of the meta-analysis met the fol-
lowing criteria: a) randomized controlled trials (RCTs) including motor
assessment before and after H. pylori eradication therapy; b) eradica-
tion therapy and duration mentioned in all studies; c) mean UPDRS-III
score (and SD) provided before and after eradication; d) English lan-
guage; e) studies conducted in humans; f) supportive criteria were also
sought from studies preferring to use objective rather than subjective
outcome criteria (e.g., [30]). Studies with incomplete or not reported
data were excluded from the meta-analysis.
2.4. Statistical analysis
2.4.1. H. pylori infection in PD patients and healthy controls
The association between H. pylori infection and PD was determined
by calculating the 95% confidence interval (95% CI) and the pooled
odds ratio (OR). The Z test was used to determine the statistical sig-
nificance of the OR, and significance was set at p < 0.05.
2.4.2. Mean UPDRS scores between H. pylori infected and non-infected PD
patients
To examine the association between H. pylori infection and mean
UPDRS scores in PD patients, a second meta-analysis was performed.
The association was determined by calculating the standardized mean
difference (SMD) [31], and the 95% CI was estimated by using the Z
test. Statistical significance was set at p < 0.05.
2.4.3. Mean UPDRS scores before and after H. pylori eradication therapy
To examine the association between H. pylori eradication therapy
and mean UPDRS scores in PD patients, a third meta-analysis was
performed. The association was determined by calculating the stan-
dardized mean difference (SMD) [32], and the 95% CI was estimated by
using the Z test. Statistical significance was set at p < 0.05.
2.4.4. Tests of heterogeneity
Cochran’s Q and I2 indices were calculated to estimate the statistical
heterogeneity of the studies. In cases of substantial heterogeneity
(PQ < 0.10 or/ and I2 > 75%), a random effects model was applied.
Otherwise, the fixed effects model was used. Funnel plots were used to
assess for possible publication bias [33]. All statistical analyses were
performed in Review Manager (RevMan) Version 5.3 software (The
Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen,
Denmark (http://tech.cochrane.org/revman)). PRISMA guidelines for
reporting reviews and meta-analyses were applied (S2 File) [34].
3. Results
3.1. Selection and characteristics of the included studies
The initial PubMed database search and examination of the refer-
ences of the retrieved publications yielded 85 studies published be-
tween 1 November 1996 and 13 November 2017 (after removal of
duplicates). After reviewing titles and abstracts, articles not eligible for
E. Dardiotis et al.
Fig. 1. Flow chart presenting the selection process of eligible studies.
the meta-analysis were excluded, resulting in 28 potentially eligible
studies. A case-control study was written in Polish and was therefore
excluded from the meta-analysis [35]. Furthermore, the following stu-
dies were excluded: a) five studies for not using the UPDRS scale for
motor assessment [30,36–39]; b) two studies, as they did not provide H.
pylori seropositivity results [40,41]; and c) three studies due to possible
sample overlap [20,26,42]. In one protocol, the mean (and SD) UPDRS
scores of H. pylori positive and negative groups were calculated from
the pooled mean and SD of the two positive and two negative groups,
respectively (S3 File). Finally, seventeen studies were included in the
quantitative meta-analysis involving in total 5043 PD patients and
23,449 healthy controls in the first part, one-hundred fifty H. pylori-
infected and 228 non-infected PD patients in the second part, and 90 PD
patients before and after H. pylori eradication in the third part. The
selection algorithm is shown in Fig. 1.
3.1.1. H. pylori infection in PD patients and healthy controls
Ten studies used in the first part of the meta-analysis were published
between 1999 and 2017 and their main characteristics are presented in
Table 1. All were case-control studies. Higher prevalence of H. pylori
infection was reported in 7 studies [15,19,22,23,30,43,44] while 3
studies [13,45,46] did not report a significant difference.With respect
to H. pylori detection, serology by enzyme-linked immunosorbent assay
(ELISA) was used in five studies [13,19,44,45,47], while in the other
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Clinical Neurology and Neurosurgery 175 (2018) 16–24
two studies 13C-urea breath testing (UBT) was performed [22,46]. From
the remaining protocols, one was a population-based study and H.
pylori infection status was determined by medical prescription records
[23], one used gastroscopy and histological examination [15], and one
determined positivity by detecting H. pylori-specific DNA by RT-PCR
[43]. The cases in all studies were diagnosed with PD, and all the
subjects used as controls were healthy. The case and control groups
were age and sex matched in five studies and only age matched in one
study [47].
3.1.2. Mean UPDRS score between H. pylori infected and non-infected PD
patients
Seven studies used in the second part of the meta-analysis were
published between 2008 and 2017 [21,22,24,27,28,46,48]. Their main
characteristics are shown in Table 2. Only 3 out of 7 studies [24,46,48]
reported that H. pylori infection may worsen the mean UPDRS score,
while the rest of them [21,22,27,28] could not demonstrate a sig-
nificant association between H. pylori and mean UPDRS score. In all
studies, case-control analysis was conducted between H. pylori infected
and non-infected PD patients. Regarding H. pylori detection, UBT was
used in five studies [21,22,24,46,48], while the antigen stool test was
used in one study [27] and ELISA in another [28]. Section III of the
UPDRS and total UPDRS score were used for motor assessment of the
patients. Specifically, in six studies [21,22,27,28,46,48], section III of
E. Dardiotis et al. Clinical Neurology and Neurosurgery 175 (2018) 16–24

Table 1
Characteristics of the studies included in the meta-analysis: H. pylori infection in PD patients and healthy controls.
Author Year Study design H. pylori detection PD patients Controls

H. pylori Mean age Sex (F/M) H. pylori Mean age Sex (F/M)
(+/−) (+/−)

Charlett et al. 1999 Case-control ELISA 23/10 75 19/14 14/25 69 23/16

Dobbs et al. 2000 Case-control ELISA 50/55 74 50/55 83/127 70 103/107
Charlett et al. 2009 Cross-sectional ELISA 57/120 NM NM 77/196 NM NM
Nielsen et al. 2012 Population-based case- Prescription of H. pylori eradication 138/4,346 70.8 1,808/ 505/21,911 70.8 9,038/
control treatment 2,676 13,378
Nafisah et al. 2013 Cross-sectional Urea breath test 14/15 64.1 13/16 5/18 61.3 8/15
Fasano et al. 2013 Case-control Urea breath test 11/22 67.8 15/18 8/22 65.4 17/13
Blaecher et al. 2013 Case-control RT-PCR 17/60 62 26/34 42/256 52 136/120
Bu et al. 2015 Case-control ELISA 60/71 67 63/68 44/97 68 66/75
Tsolaki et al. 2015 Case-control Gastroscopy and histological 6/9 NM NM 14/31 NM NM
examination
Efthymiou et al. 2017 Case-Control ELISA 14/39 68.7 20/19 33/68 47.4 40/28

ELISA, enzyme-linked immunosorbent assay; PD, Parkinson’s disease; UPDRS, unified Parkinson's disease rating scale; RCT, randomized controlled trial; NM, not
mentioned; SD, standard deviation.

the UPDRS was evaluated, and in one study, the total UPDRS score was
used to assess clinical status. All the studies provided mean UPDRS
scores with SD. Furthermore, six of the seven studies presented mean
age and sex ratios for both H. pylori infected and non-infected patients
[21,24,27,28,46,48], while one did not [22].
3.1.3. Mean UPDRS score before and after H. pylori eradication therapy
Five studies used in the third part of the meta-analysis were pub-
lished between 2001 and 2017 [21,24,28,49,50]. Their main char-
acteristics are shown in Table 3. Four of the studies [18,24,26,28,49]
reported a significant association between H. pylori eradication and
decrease of the mean UPDRS-III score, while one study [21] did not.
Except, in the study of Pierantozzi et al. [50], in which patients were
given 250 mg levodopa per day, the average daily consumption of le-
vodopa in the Helicobacter positive patients was about 500 mg per day,
in all the other included studies. In all studies, UPDRS section III was
used for motor assessment before and after H. pylori eradication in PD
patients. Regarding the H. pylori eradication therapy, a seven-day
treatment protocol with omeprazole, amoxicillin, and clarithromycin
was used in one study [50], while in two studies [28,49] a 14-day
protocol was applied. In the other two studies [21,24], seven-day
therapy with esomeprazole, amoxicillin, and clarithromycin was used.
All the studies provided mean UPDRS scores with SD.
3.2. Subgroup analysis
3.2.1. H. pylori infection in PD patients and healthy controls
The fixed-effects model was applied to the first group of studies due
to low heterogeneity (I2 = 31%, PQ = 0.16). H. pylori infection was
significantly more prevalent among PD patients than among controls
[OR (95% CI): 1.47 (1.27, 1.70); Pz < 0.00001]. The results of the
meta-analysis for the prevalence of H. pylori infection in PD patients
are presented in Fig. 2A. The funnel plot presented in Fig. 2B without
revealing any significant asymmetry.
3.2.2. Mean UPDRS scores between H. pylori infected and non-infected PD
patients
The fixed-effects model was applied to the second group of studies
due to low heterogeneity (I2 = 19%, PQ = 0.28). There was significant
association between H. pylori infection and higher mean UPDRS scores
[standardized mean difference, SMD (95% CI): 0.33 (0.12, 0.54),
Pz = 0.003]. The results of the meta-analysis for the mean UPDRS score
between H. pylori infected and non-infected PD patients are presented
in Fig. 3A. The funnel plot presented in Fig. 3B without revealing any
significant asymmetry.
3.2.3. Mean UPDRS scores before and after H. pylori eradication therapy
The random-effects model was applied to the third group of studies
due to high heterogeneity (I2 = 67%, PQ = 0.02). There was significant

Table 2
Characteristics of the studies included in the meta-analysis: Mean UPDRS scores in H. pylori infected (+) and non-infected (-) PD patients.
Author Year Study H. pylori Assessment scale H. pylori (+) patients H. pylori (−) patients
design detection
n UPDRS Mean age Sex n UPDRS Mean age Sex (F/
(mean ± SD) (F/M) (mean ± SD) M)

Lee et al. 2008 RCT & Case- Urea Breath UPDRS section III 35 22.9 ± 7.4 60 15/20 30 23.1 ± 7 60.2 14/16
control Test medication “on”
Nafisah et al. 2013 Case-control Urea Breath UPDRS III motor 14 19.43 ± 8.864 NM NM 15 19.2 ± 11.66 NM NM
Test examination
Fasano et al. 2013 RCT & Case- Urea Breath UPDRS III total score 11 40.61 ± 7.98 69.3 6/5 22 36.86 ± 13.53 67.2 9/13
control Test medication “off”
Narozanska 2014 Case-control Antigen Stool UPDRS part III in “off” 18 38.8 ± 19.7 59.8 10/8 19 37.6 ± 12.8 60.4 8/11
et al. Test
Hashim et al. 2014 RCT & Case- Urea Breath UPDRS total score 21 85.05 ± 25.48 65.1 11/10 55 63.98 ± 29.17 67.5 31/24
control Test
Tan et al. 2015 Case-control Urea Breath UPDRS section III in 33 33.97 ± 13.04 68.4 13/20 69 27.32 ± 10.05 63.8 28/41
Test “on”
Mridula et al. 2017 RCT & Case- ELISA UPDRS part III in “off” 18 54.1 ± 5.2 59 5/13 18 52.3 ± 11 61 12/6
control

UPDRS, unified Parkinson's disease rating scale; RCT, randomized controlled trial; NM, not mentioned; SD, standard deviation.

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E. Dardiotis et al. Clinical Neurology and Neurosurgery 175 (2018) 16–24

Table 3
Characteristics of the studies included in the meta-analysis: Mean UPDRS scores before and after H. pylori eradication in PD patients.
Author Year Study H. pylori eradication therapy L-DOPA Assessment n Mean Age Sex Before eradication After eradication
design Average scale (F/M)
Daily dose
mg/day
UPDRS UPDRS
(mean ± SD) (mean ± SD)

Pierantozzi 2001 RCT Omeprazole, amoxicillin and 250.0 UPDRS-III 7 70.4 NM 34.1 ± 10.5 23.1 ± 8.8
et al. clarithromycin 7-day therapy
Lee et al. 2008 RCT & Case- Esomeprazole, amoxicillin and 544.5 UPDRS-III 34 NM NM 22.9 ± 7.4 22.3 ± 8
control clarithromycin 7-day therapy
Hashim et al. 2014 RCT & Case- Esomeprazole, amoxicillin and 500.0 UPDRS-III 21 65.1 11/10 50.62 ± 13.62 37 ± 15.56
control clarithromycin 7-day therapy
Mridula et al. 2017 RCT & Case- Omeprazole, amoxicillin and 470.4 UPDRS-III 18 59 5/13 22.3 ± 6.6 15.3 ± 3.8
control clarithromycin 14-day therapy
Liu et al. 2017 Cohort Omeprazole, amoxicillin and 599.5 UPDRS-III 10 63.2 5/5 25.9 ± 8.37 18.3 ± 8.38
study clarithromycin 14-day therapy

UPDRS, unified Parkinson's disease rating scale; RCT, randomized controlled trial; NM, not mentioned; SD, standard deviation.

association between H. pylori eradication and lower mean UPDRS-III 4. Discussion

scores [standardized mean difference, SMD (95% CI): 6.83 (2.29,
11.38), Pz = 0.003]. The results of the meta-analysis for the mean
UPDRS-III score before and after H. pylori eradication in PD patients are
presented in Fig. 4A. The funnel plot presented in Fig. 4B without re-
vealing any significant asymmetry.
Here we present the results of a meta-analysis examining the asso-
ciation between H. pylori infection status and PD. The first part of the
meta-analysis revealed a significantly higher prevalence of H. pylori
infection in PD patients than in healthy controls. Regarding the motor
status of PD patients, there was a significant association between H.
pylori infection and mean UPDRS scores. Furthermore, we found a
significantly lower mean UPDRS-III score after H. pylori eradication

Fig. 2. (A) Forest plot: meta-analysis of the prevalence of H. pylori infection in the PD patient group compared with the healthy control group. (B) Funnel plot to
detect publication bias in the studies reporting H. pylori infection in PD patients and healthy controls.

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E. Dardiotis et al. Clinical Neurology and Neurosurgery 175 (2018) 16–24

Fig. 3. (A) Forest plot: standardized mean difference of mean UPDRS scores between H. pylori infected (Hp+) and non-infected (Hp-) PD patients. (B) Funnel plot to
detect publication bias in the studies reporting mean UPDRS scores in H. pylori infected and non-infected PD patients.

Fig. 4. (A) Forest plot: standardized mean difference of mean UPDRS-III scores before and after H. pylori eradication therapy in PD patients. (B) Funnel plot to detect
publication bias in the studies reporting mean UPDRS-III scores before and after H. pylori eradication therapy in PD patients.

21
E. Dardiotis et al.
therapy.
Charlett et al. [19] reported that H. pylori seropositivity was two-
fold higher in patients with idiopathic parkinsonism than disease-free
controls [19]. It was reported that peptic ulcers were more common in
PD patients [17,18]. Furthermore, several studies have revealed a high
prevalence of H. pylori infection in PD patients [21,39,47,48] and these
results were consistent with the results of the first part of our meta-
analysis. In addition, a recent meta-analysis [29] showed a statistically
significant correlation between H. pylori infection and risk of PD [OR
(95% CI): 1.59 (1.37,1.85)]. The same significant association was
maintained in the subgroup analyses for study design, study location,
and studies adjusted and not adjusted for other covariates. This further
reinforces the notion that H. pylori infection plays an important role in
the course or even in the pathogenesis of PD.
Nielsen et al. [23] showed that prescription of H. pylori eradication
therapy and proton pump inhibitors five or more years prior to the
diagnosis of PD were associated with a 45% and 23% increase in PD
risk, respectively. They concluded that chronic H. pylori infection and/
or gastritis contribute to PD pathogenesis or that they come before are
PD-related motor symptoms [23].
Even though most studies suggest that the prevalence of H. pylori
infection is higher in PD than in disease-free status, considerable con-
troversy remains on whether the clinical status of H. pylori infected and
non-infected PD patients differs. Five relevant studies [21,24,28,49,50]
suggested that H. pylori-infected patients tended to have increased
motor fluctuations and worse mean UPDRS scores, which were found to
be controlled by L-Dopa. Also, H. pylori eradication has been shown to
ameliorate symptoms of PD [38]. H. pylori eradication has been sug-
gested in PD patients treated with levodopa, as it may improve drug
bioavailability and decrease motor fluctuations [21,24,37,46]. Thus, it
was previously reported [20,24,51] that there is an enhanced gut ab-
sorption of levodopa in PD patients who had H. pylori eradication, as
compared to PD patients with H. pylori infection who received placebo.
The results of our meta-analysis were consistent with most of the in-
cluded studies [21,24,27,28,46,48–50], showing an association be-
tween H. pylori infection and the clinical status (i.e., mean UPDRS
score) of PD patients and a significant clinical improvement (i.e., lower
mean UPDRS-III score) after H. pylori eradication therapy.
Mechanistically, there is evidence that inteleukin-1β (IL-1β), IL-6,
tumor necrosis factor-α (TNF-α), other proinflammatory cytokines, and
C-reactive protein play important roles in neurodegenerative disorders
including PD [52]. H. pylori induces the release of large amounts of IL-
1β, −6, −8, −10, −13 and TNF-α, eicosanoids, and acute phase
proteins and activates monocytes, which may result in disruption of the
blood brain barrier (BBB), microglial activation, and deleterious effects
on the nigrostriatal dopaminergic system [53]. In this respect, neu-
roinflammation seems to contribute to neurodegeneration with acti-
vation of microglia [54]. Alternatively, noxious chemicals produced by
H. pylori can be transmitted through the vagal axonal afferent pathway
and affect brainstem neurons, as indicated by animal and human stu-
dies [53], or H. pylori might access the brain via the oral-nasal-olfactory
pathway through a disrupted BBB [55]. Conversely, α-synuclein has
been recently reported to reach the gastric wall via preganglionic vagal
route, suggesting brain-to-stomach interactions with implications in PD
[56].
In addition, H. pylori infection is capable of inducing apoptosis via
multiple apoptotic pathways including the Fas-FasL pathway, the mi-
tochondrial pathway, or through inducible nitric oxide to cause neu-
rodegeneration [57]. Furthermore, auto-antibodies against dopami-
nergic neurons found in the cerebrospinal fluid or the blood of PD
patients [58] might represent molecular mimicry from H. pylori infec-
tion [59]. A potentially important mechanism in other neurological
diseases such as multiple sclerosis [60,61], molecular mimicry (in this
case between H. pylori and host antigens) might trigger auto-antibody
production, leading to chronic inflammation that contributes to the
pathology of both gastric and systemic diseases including PD [36].
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Clinical Neurology and Neurosurgery 175 (2018) 16–24
Additional H. pylori-mediated pathogenetic mechanisms in PD could be
caused by the production of toxins by H. pylori (intriguingly, toxic ac-
tions could even be raised by H. pylori-mediated glycosylation of human
cells’ cholesterol) a disrupted intestinal microbiome, or remarkably, by
H. pylori-mediated alterations in the pharmacokinetic properties of
levodopa (all elegantly reviewed in [51]).
This meta-analysis has certain limitations. First, we included studies
regardless of their H. pylori detection method. While both ELISA and
UBT reflect the infection status of patients, there are several differences
between these methods, especially that serology tends to overestimate
the prevalence of infection. ELISA could remain positive months after
potential H. pylori spontaneous elimination [8]. Second, H. pylori status
could represent a marker of hygiene status, making the associations
more correlational than causal. Third, we observed significant hetero-
geneity between the scales used to assess the clinical status of PD pa-
tients. Although UPDRS was used in most of the studies, different sec-
tions of the scale were applied in different disease states. Moreover,
when considering small-study effects, random-effects testing may
overestimate summary effects [62]. Finally, several H. pylori eradica-
tion protocols with different treatment duration were applied in most of
the studies.
5. Conclusion
H. pylori infection may contribute to the pathogenesis and prognosis
of PD, given its higher prevalence in PD patients. Despite the difficulty
of therapeutic regimens due to high antibiotic resistance rates, suc-
cessful H. pylori eradication therapy may positively influence the clin-
ical outcome of PD. However, further large-scale studies with unified
clinical data and adequate statistical power for reproducibility (as
emphasized in [62] for neurological studies) are required to accurately
estimate the impact of the infection and elucidate the detailed me-
chanisms by which H. pylori is involved in PD pathogenesis.
Acknowledgements
A.-F.A.M. is supported by an educational scholarship fromthe
Onassis Public Benefit Foundation, who played no role in the design of
the study, collection and/or interpretation of data, or writing of the
article.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.clineuro.2018.09.039.
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