Araki N., Yamanaka Y., Poudel A., Fujinuma Y., Katagiri A., Kuwabara S., Asahina M. Electrogastrography for diagnosis of early-stage Parkinson’s disease. Parkinsonism and Related Disorders. 86 (2021) 61–66.

Авторы: Araki N. / Yamanaka Y. / Poudel A. / Fujinuma Y. / Katagiri A. / Kuwabara S. / Asahina M.

Electrogastrography for diagnosis of early-stage Parkinson’s disease

^a Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuoku, Chiba City, Chiba, 260-8677, Japan
^b Department of Neurology Kimitsu Chuo Hospital, 1010 Sakurai, Kisarazu City, Chiba, 292-0822, Japan
^c Urayasu Rehabilitation Education Center, Chiba University Hospital, 7-2-32 Takasu, Urayasu City, Chiba, 279-0023, Japan
^d TUMS Urayasu Hospital, 7-2-32 Takasu, Urayasu City, Chiba, 279-0023, Japan
^e Department of Neurology, Kanazawa Medical University, 1-1, Daigaku, Uchinada cho, Kahoku gun, Ishikawa, 920-0293, Japan


ABSTRACT

Introduction: Patients with Parkinson’s disease (PD) often present with gastric symptoms. Electrogastrography (EGG) can noninvasively assess gastric electric activity and may be useful for early PD diagnosis. The present study aimed to compare the efficacy of EGG in early PD diagnosis with those of ¹²³I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy and odor stick identification test – Japanese version (OSIT-J).

Methods: Thirty-seven untreated PD patients (mean age ± SD, 66 ± 8 years; disease duration < 3 years) and 20 healthy control subjects (68 ± 6.9 years) were recruited. EGG and OSIT-J were performed in both groups, and MIBG scintigraphy in the PD group. EGG parameters were assessed in the preprandial and early and late postprandial segments using power spectrum analysis.

Results: Irregular EGG waves were observed in PD patients. The preprandial instability coefficient of dominant frequency (ICDF), an index of EGG irregularity, in PD patients (9.5% [6.3%]) was higher than that in controls (3.9% [3.9%], p = 0.00005). The OSIT-J score was also lower in PD patients (4.6 [3.3]) than in controls (7.7 [3.3], p = 0.006). In receiver operating characteristics analyses, the areas under the curves of preprandial ICDF and OSIT-J were 0.83 and 0.72, respectively. The sensitivities of preprandial ICDF and MIBG (delayed-phase) scintigraphy were 73% and 70%, respectively.

Conclusions: Early and untreated PD patients showed irregular EGG waves and high ICDF. EGG showed better accuracy than the olfactory test for early PD diagnosis and similar sensitivity to MIBG scintigraphy.

ARTICLE INFO

Keywords: electrogastrography, Parkinson’s disease, autonomic function, MIBG scintigraphy, olfactory

ht tps://doi.org/10.1016/j.parkreldis.2021.03.016

* Corresponding author.

E-mail addresses: wild-tree115@mtj.biglobe.ne.jp (N. Araki), y-yama@jk9.so-net.ne.jp (Y. Yamanaka), anupamauprety@yahoo.com (A. Poudel), fujinuma@tb3. so-net.ne.jp (Y. Fujinuma), akira-ww@jcom.home.ne.jp (A. Katagiri), kuwabara-s@faculty.chiba-u.jp (S. Kuwabara), asahina@kanazawa-med.ac.jp (M. Asahina).


1. Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disease classically characterized by the accumulation of Lewy bodies in the substantia nigra and other subcortical nuclei [1]. Early or prodromal diagnosis of PD is important in case disease-modifying therapy for PD is developed [2]. Alpha-synuclein can be found in peripheral sympathetic nerves or olfactory structures, even in early or premotor PD stages [1]. ¹²³I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy, which assesses the sympathetic terminal innervation of the heart, and olfactory function testing have reported efficacies in early PD diagnosis [1].

Gastric myoelectrical activity can be noninvasively recorded using a cutaneous electrogastrogram recorder, which can detect sine waves, called “slow waves” (SW), at around 3 cycles per minute (cpm) [3]. SW originate at the pacemaker of gastric peristaltic motion on the major curvature of the stomach, and its rhythm is generated by the interstitial cells of Cajal and mediated by parasympathetic vagal activities. Electrogastrography (EGG) is used clinically to evaluate gastric electroactivity as an index of gastric motility in several disorders, including functional dyspepsia, diabetic gastropathy, achalasia [3], and neurological diseases [4,5]. SW frequency is highly reliable and reproducible. EGG parameters obtained from power spectral analysis include dominant frequency (DF) reflecting SW frequency, instability coefficient of DF (ICDF) as an index of SW cycle variability, and percentage rate of the normal range (2.0–4.0 cpm) power to the total power (NFR%). ICDF may particularly be a useful biomarker in distinguishing early-stage PD from healthy subjects or from multiple system atrophy [5], which is often difficult to differentiate from PD.

Abnormal gastric electric activities, such as irregular SW, were previously observed in PD patients [5,6]. Furthermore, the gastric emptying time is known to be delayed even in early PD stages without upper gastrointestinal symptoms [7], and the accumulation of alpha-synuclein has been observed in the gastric plexus, as well as in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and in the olfactory nucleus, before the onset of PD motor symptoms [8]. Therefore, abnormal gastric electric activities could be detected in early- or prodromal-stage PD. However, previous EGG studies have only ever evaluated advanced or treated PD patients [5,6,9]. Gastric dysmotility deteriorates with disease progression in PD patients [10], and anti-Parkinsonian drugs could affect gastric motility [6,9]. Whether abnormal gastric electric activities could also be seen in early-stage, untreated PD is still unknown. To reveal the usefulness of EGG in early-stage PD diagnosis, we evaluated EGGs obtained in early-stage and untreated PD patients and healthy control subjects and compared its diagnostic utility with those of MIBG myocardial scintigraphy and olfactory testing.

2. Materials and methods

2.1. Subjects

Early-stage (duration of motor symptoms < 3 years) PD patients who were all drug-naïve were enrolled. The patients were followed up for three years to confirm the diagnosis and fulfill the diagnostic criteria of PD [11]. In addition, healthy subjects above the age of 40 years were recruited as age-matched controls.

Participants who had organic gastrointestinal disease, diabetes, a history of gastric surgery, nasal disease, atrial fibrillation, or cardiac infarction were excluded. Likewise, participants under medication that could affect gastrointestinal function were excluded. Drugs that could modulate MIBG accumulation were discontinued in the enrolled PD patients. All participants were evaluated at the Chiba University School of Medicine, and all provided their informed consent. The experiments conformed to the principles of the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of the Chiba University School of Medicine.

2.2. Electrogastrography

EGG was performed in a quiet room at a constant temperature range of 24^◦C-27^◦C. Participants arrived at the laboratory at 10.00 a.m. after overnight fasting and underwent electrogastrogram recording. The recording was performed for 75 min in the supine posture — 35 min in a preprandial state and 40 min in a postprandial state (including the meal intake time) —using a four-channel EGG recorder (Nipro EG; Nipro, Japan) at a sampling rate of 1 Hz. Reference and four ECG surface electrodes (Vitrode J; Nihon Kohden, Japan) were placed on the abdominal skin surface, as shown in Fig. 1A [4].

Fig. 1. Raw data and dominant frequency in electrogastrography of patients with Parkinson’s disease and healthy subjects. Four recording electrodes and one reference electrode were placed on abdominal skin. (A) Regular, preprandial gastric slow waves becoming irregular during the early postprandial period, but returned to regular during late postprandial in a healthy subject. (B) Irregular gastric waves in preprandial and early and late ostprandial periods in a patient with Parkinson’s disease. (C) Gray squares and black circles indicate means of dominant frequency in healthy controls and patients with Parkinson’s disease, respectively. Vertical bars indicate standard errors.


After the preprandial measurement, each participant drank 250 mL liquid test meal (400 kcal; 53.6 g of carbohydrates, 15.0 g of protein, and 13.4 g of fat) within 10 min through a straw while in the supine posture. Three 20-min EGG segments were selected from 75 min of recording: preprandial (10–30 min) and early (35–55 min, including meal intake time) and late (55–75 min) postprandial states.

The EGG data were downloaded to a personal computer and analyzed using EGS2 Ver.1.31 (Gram, Japan) and Lab Chart (AD Instruments, Australia). Power spectral analysis was performed for each EGG segment using a fast Fourier transform (FFT) with an analysis range of 1.6–9.0 cpm. The frequency at which the overall power spectrum displayed the peak power in the 2.0–4.0 cpm range was defined as the DF [3]. The frequency ranges were classified into low (LFR, 1.6–2.0 cpm), normal (NFR, 2.0–4.0 cpm), and high (HFR, 4.0–9.0 cpm). The percentage rate of LFR (LFR%), NFR (NFR%), and HFR (HFR%) components to total power was calculated. In addition, a running spectral analysis was performed to obtain the ICDF, for which FFT was applied to consecutive 512-s signal stretches with 87.5% overlap. The ICDF was defined as the ratio of the standard deviation to the mean DF values is [3].

2.3. Olfactory test

Olfactory function was assessed using the Japanese version of the odor stick identification test (OSIT-J, Daiichi Yakuhin Sangyo Co. Ltd., Japan) [12]. The total number of correct answers to the 12 odors constituted the OSIT-J score.

2.4. MIBG myocardial scintigraphy

MIBG myocardial scintigraphy was performed in the PD group. Planar scintigraphic images in the anterior view were captured by a single-head gamma camera (GCA-7200A/UI; Toshiba, Japan) 15 min (early) and 3 h (delayed) after the intravenous injection of MIBG (111 MBq). To measure MIBG uptake, the heart (left ventricle) and mediastinal regions of interest were drawn manually. The heart-tomediastinum (H/M) ratio were calculated from the early and delayed images. The normal lower limit for H/M ratio at our institution is 2.09 in the delay phase (data not shown). For all participants, MIBG scintigraphy was performed within 1 month (before or after) the EGG measurement.

2.5. Statistical analysis

Statistical analyses were performed using SPSS statistics version 20 (IBM, USA). Statistical differences between two groups were analyzed using Pearson’s chi-square test or the Mann–Whitney U test. Correlations between EGG variables, OSIT-J scores, and MIBG scintigraphy variables were analyzed using Spearman’s rank correlation coefficient. Receiver operating characteristic (ROC) curves were generated by plotting sensitivity against 1-specificity with the respective areas under the curves (AUC) representing the predictive power of each variable. The optimal cut-off point was chosen on the curve as the point closest to the upper left-hand corner.

3. Results

3.1. Recruitment

Of the 53 patients who participated this study, 16 were excluded (9 patients could not accomplish the tests, 5 patients conflicted exclusion criteria, and 2 patients appeared to have multiple system atrophy and vascular Parkinsonism at three years follow-up). A final total of 37 earlystage untreated PD patients (19 men and 18 women; mean age ± standard deviation [SD], 66 ± 8.1 years; mean disease duration 17 ± 7.2 months) and 20 healthy control subjects (8 men and 12 women; mean age, 68 ± 6.9 years) participated in our study. The incidences of gastric and autonomic symptoms (orthostatic symptoms, urinary problems, constipation, appetite loss, and nausea) in the PD and control groups are shown in Table 1.

3.2. EGG

Raw electrogastrogram data are shown in Fig. 1B. The controls clearly showed a temporal DF fall 5–10 min after meal intake (postprandial dip), whereas the dip was indistinct and prolonged in the PD group (Fig. 1C). Reflecting the postprandial dip, DF during the early postprandial phase was slightly lower than that during the preprandial phase (Fig. 2A). No significant differences in DF were found between the two groups at any time period (Fig. 2A).
Fig. 2. Meal injection effects on electrogastrogram variabilities in patients with Parkinson’s disease and healthy subjects. (A) DF, dominant frequency; (B) ICDF, instability coefficient of DF; (C) LFR%, percentage rate of the low frequency range; (D) NFR%, percentage rate of the normal frequency range; and (E) HFR%, percentage rate of the high frequency range. Closed and open circles indicate mean values in patients with Parkinson’s disease and healthy subjects, respectively. Vertical bars indicate standard errors.


In the control group, ICDF increased after meal intake (early postprandial period) and returned to the baseline in the late postprandial period. On the other hand, ICDF remained high in the PD group throughout the fasted and postprandial phases, and the change after meal intake was inconclusive (Fig. 2B). The preprandial ICDF in the PD group was significantly higher than that in the control group (p = 0.00005; Figs. 2B and 3A). No significant differences were found in both the early and late postprandial ICDFs between the two groups (Fig. 2B). The ICDF increase in the early postprandial phase was significantly greater in the control group compared with the PD group (p = 0.0001; Table 2).

Meal intake decreased NFR% and increased LFR% and HFR%, particularly during the early postprandial period in the control group, but these changes were indefinite in the PD group (Fig. 2C–E). Compared with the control group, preprandial and late postprandial LFR % (Fig. 2C) were significantly higher (p = 0.005 and 0.03, respectively), and preprandial and late postprandial NFR% (Fig. 2D) significantly lower, in the PD group (p = 0.01 and 0.02, respectively). No significant differences were identified in HFR% and HFR% changes after meal intake between the two groups (Fig. 2E).

Fig. 3. Comparison of electrogastrography and olfactory function test (OSIT-J) for distinguishign between patients with Parkinson’s disease (PD) and healthy subjects. (A) Instability coefficients of dominant frequency (ICDF) during the preprandial phase in PD patients were significantly higher than those in healthy controls. (B) OSIT-J scores in PD patients were significantly lower than both the OSIT-J scores and ICDF in control subjects; however, the distributions of the OSIT-J scores in the two groups were almost overlapping. In ROC analysis, (C) area under the curve (AUC) for preprandial ICDF was 0.830, whereas (D) AUC for OSIT-J was 0.720. Closed and open circles indicate PD patients and healthy controls, and horizontal lines represent mean values in scatter plots (A and B).


3.3. Other tests

The OSIT-J score was significantly lower in the PD group (4.6 ± 3.3) than in the controls (7.6 ± 3.8; p = 0.006; Fig. 3B). In MIBG myocardial scintigraphy, the early and delayed H/M ratios were 2.1 ± 0.69 and 2.0 ± 0.92, respectively, in the PD group. The prevalence of patients having abnormal MIBG parameters were 70% for the delayed H/M ratio. No significant correlation could be established between postprandial EGG variables and either OSIT-J scores or H/M ratios in MIBG scintigraphy for the PD group.

3.4. ROC curves of ICDF and OSIT-J

ROC curves of preprandial ICDF and OSIT-J scores are shown in Fig. 3C and D, respectively. The AUC for distinguishing the PD patients from the controls were 0.83 for preprandial ICDF and 0.72 for OSIT-J, but no significant difference was found between the AUC values. The ROC curve of preprandial ICDF indicated 73% sensitivity and 80% specificity at a cut-off value of 3.2, whereas OSIT-J showed 60% sensitivity and 75% specificity at a cut-off value of 5.5.

4. Discussion

Alpha-synuclein deposition in the gastric plexus, which plays an important role in electrical conduction in gastric pacemaker rhythms [3], was observed even in patients with prodromal PD [1]. In the present study, our early-stage untreated PD patients showed irregular gastric SW. Some EGG variables, such as ICDF, LFR%, and NFR%, differed between the PD and control groups. In particular, ICDF, which is an index for gastric electrical rhythm variability, was significantly higher during the preprandial phase in PD patients compared with the healthy controls. These findings may reflect gastric dysmotility associated with alpha-synuclein pathology. Although high ICDF [5,6] and low NFR% [6] were reported in treated PD patients, we observed EGG abnormalities even in early-stage untreated PD patients.

In terms of the differentiation between PD patients and healthy controls, our ROC analysis showed higher AUC for preprandial ICDF (0.83) compared with OSIT-J scores (0.72). Although MIBG myocardial scintigraphy was not performed in our control subjects, previous MIBG studies have reported AUC of 0.755–0.96 in the delayed H/M ratio, which distinguished PD from other diseases [13–16], and 0.85 in PD patients with a motor symptom history of 3 years or less [15]. These AUC values are almost equal to the AUC for the preprandial ICDF in our study. Furthermore, in our study, the sensitivity of preprandial ICDF (73%) was higher than that of the delayed H/M ratio in MIBG myocardial scintigraphy (70%), which was similar to that in PD patients having a disease duration of 3 years or less (73.3%) [15]. EGG is low-cost, and the measurement time for preprandial evaluation only takes about 20 min. ICDF could therefore be as useful a diagnostic marker as MIBG myocardial scintigraphy for early PD.

Studies on the efficacy of olfactory tests for differentiating PD patients from healthy subjects have shown variable results; high AUC values (0.886–0.97) in some studies [17,18], and low AUC values (0.567) in one other [19]. In our study, the mean ages of both the healthy controls (68 years) and PD patients (66 years) were over 65 years old. Olfactory function decreases with aging in a healthy population [20]. In a multicenter study for 400 PD patients, olfactory testing identified hyposmia in 96.7% of PD patients, but the sensitivity to distinguish from healthy subjects was not as high (74.5%) [21]. The sensitivity of the olfactory test may be too low for differentiating PD patients from healthy elderlies. In addition, we evaluated early-stage and untreated PD patients with less than 3 years of motor symptoms (mean disease duration, 17 ± 7.2 months). Previous studies on the prevalence of olfactory dysfunction in untreated PD patients was not high (67%–74.5%) [22,23]. The early disease stage may possibly reduce the sensitivity of the olfactory test for PD diagnosis.

In our healthy control subjects, the DF was temporarily decreased after meal intake, the postprandial dip [24]. However, in the PD group, the postprandial dip was ambiguous, and the recovery appeared to be delayed (Fig. 1C), which supports the findings of a previous study [25]. The delayed DF recovery after the postprandial dip might result in lower mean DF values in the early postprandial segment. In regard to other EEG parameters, NFR% decreased and ICDF increased after meal intake in our healthy controls, as likewise reported previously [3,26]. However, in our PD patients, the NFR% reduction after meal intake was unclear, and the ICDF remained high throughout the fasting and feeding phases. An increase in ICDF and a decrease in NFR% after meal intake in the healthy subjects mean an increased variability in the gastric pacemaker rhythm, which is considered to result mainly from increased vagal parasympathetic activity. In PD, the dorsal motor nucleus of the vagal nerve is involved in the early disease stage [8], as well as in gastric plexus abnormalities [27]. Thus, the poor EGG response to meal intake in our PD patients may indicate dysfunction in the parasympathetic nerves innervating the stomach. The recent report that found the interstitial cells of Cajal functioning normally in PD [28] may support this theory.

Although not examined in PD, it has been reported that abnormal gastric electrical activity indicates delayed gastric transit time in patients with gastroparesis [29]. In addition, although not examined in this study, NFR% has been found decreased in PD patients with gastrointestinal symptoms [30]. These findings suggest that abnormal gastric electrical activity may signify abnormal gastric motility in PD.

The gastric emptying time was reported to be delayed even in untreated early PD [10]. It may be as useful a biomarker as EGG. However, gastric emptying tests, such as the ¹³C-acetate breath test and scintigraphy using radiolabeled food, usually take more time than the EGG. In addition, the ¹³C-acetate breath test is an indirect method of detecting analytes via various other metabolic processes, whereas radioscintigraphy poses the risk of radiation exposure.

EGG readings have registered normal parameters in multiple system atrophy [5]; however, EGG readings in other Parkinsonian syndromes such as progressive supranuclear palsy and corticobasal degeneration have not yet been reported. The efficacy of EGG in differentiating PD from other neurological diseases should be investigated in the future.

The present study is the first to demonstrate EGG abnormalities in early-stage untreated PD patients. EGG has the potential to become a useful tool for PD diagnosis even during the early or prodromal stages. The advantages of EGG for early differential diagnosis needs further research.


Declaration of competing interest

None.

Acknowledgments

The authors would like to thank Enago (www. enago.jp) for the English language review.

Author’s contribution

Nobuyuki Araki: acquisition of data, analysis and interpretation of data, drafting the article, critically revising the article for important intellectual content, and final approval of the version to be submitted.

Yoshitaka Yamanaka: conception and design of the study, data acquisition, data analysis and interpretation, critically revising the article for important intellectual content, and final approval of the version to be submitted.

Anupama Poudel: data acquisition, data analysis and interpretation, critically revising the article for important intellectual content, and final approval of the version to be submitted.

Yoshikatsu Fujinuma: data acquisition, data analysis and interpretation, critically revising the article for important intellectual content, and final approval of the version to be submitted.

Akira Katagiri: data acquisition, data analysis and interpretation, critically revising the article for important intellectual content, and final approval of the version to be submitted.

Satoshi Kuwabara: critically revising the article for important intellectual content, and final approval of the version to be submitted.

Masato Asahina: conception and design of the study, data acquisition, data analysis and interpretation, critically revising the article for important intellectual content, and final approval of the version to be submitted.

Funding

This study was funded by Japan Society for the Promotion of Science KAKENHI Grant Number 22590953.


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