Introduction

Dysphagia is a very common but difficult Parkinson’s disease (PD) symptom to treat [1]. Its reported prevalence varies across studies since it depends on the age, PD subtype, disease severity, and cognition status [1,2,3]. Dysphagia is significantly associated with aspiration pneumonia, which is the highest mortality cause in patients with PD [4], and thus significantly affects their quality of life [1]. Pathophysiology underlying PD-associated dysphagia remains unclear. Reduced cortical activation and severe cognitive dysfunction are negatively associated with swallowing ability [5]. Additionally, neuronal death in the substantia nigra pars compacta and dysfunction of the swallowing central pattern generator located in the medulla might cause dysphagia in PD [5, 6]. Therefore, cortical function, as well as the interaction between the basal ganglia and brainstem, could affect swallowing function modulation. Moreover, PD-associated dysphagia could be reported in early-stage PD and is not always associated with PD severity [7]. The definite dysphagia cause and its effective treatments currently remain unclear; moreover, conventional dopaminergic treatment and deep brain stimulation are ineffective in improving dysphagia in patients with PD [8, 9]. Therefore, non-dopaminergic systems could play a crucial role in dysphagia [10]. There have been few reports regarding PD-associated dysphagia even in the early disease stages; moreover, functional swallowing disability mostly involves the oral swallowing phase [11, 12]. Most studies on PD-associated dysphagia have assessed the dysphagia risk or analyzed factors associated with dysphagia [13]. However, it is more important to prevent aspiration and maintain swallowing ability in patients with PD. Generally, swallowing rehabilitation, as well as behavioral and electrophysiological treatments, has been attempted in patients with dysphagia [14]. However, insufficient foods have been developed for alleviating swallowing disorders. This study aimed to develop elderly friendly swallowing supplements that are easier to swallow than commercialized yogurt. Furthermore, we aimed to evaluate the safety and tolerability of our swallowing supplements in patients with PD compared with age-matched healthy controls.

Methods

Participants

We enrolled 30 patients with PD who regularly visited the movement disorder clinic without changing of medication within 8 weeks, as well as 50 age-matched healthy controls. All the patients with PD lacked a history of uncomfortable dysphagia and aspiration. Most patients with PD are unaware of their swallowing impairment [15]; therefore, the term “symptomless dysphagia” was employed for patients unaware of their swallowing impairment revealed by an objective swallowing test. Furthermore, we used the term “presbyphagia” for elderly healthy controls to differentiate them from patients with PD [16]. We excluded participants with neurological diseases, head and neck cancer, and diagnosed dementia. We assessed cognitive status in both groups using the Mini-Mental State Examination (MMSE). Furthermore, a movement disorder specialist (E.O) assessed the disease status using the Hoehn and Yahr (H&Y) stage, the Unified Parkinson’s Disease Rating Scale-III, disease duration, and levodopa equivalent dose in the PD group. Furthermore, we excluded patients with dysphagia, which is affected by the status of PD medication. This study was approved by the ethics committee of Chungnam National University Hospital. All the participants provided informed consent before data collection.

Swallowing analysis

Videofluoroscopic swallowing studies

We used the videofluoroscopic swallowing studies (VFSS) as an objective measurement tool since it is the gold standard for evaluating PD-related dysphagia [1, 17]. VFSS was performed in a medication on state. Moreover, we simultaneously video-recorded at 30 frames per second (INFINITT PACS video) to analyze dysphagia patterns (FLEXAVISION; Shimadzu Corp., Kyoto, Japan). The participants were seated upright in the fluoroscopy chair. Subsequently, each participant was required to swallow 5 bolus types as follows: rice porridge, yogurt (Dongwon Co., Seoul, Korea), water (Jeju Province Developmental Co., Jeju, Korea) 2.5 cc, water 5 cc, and steamed rice in that order. The boluses were administered using a tablespoon mixed at a 1:1 ratio with a contrast medium. All VFSS images were viewed in the lateral plane, which included the lips anteriorly to the vertebrae posteriorly, as well as the soft palate superiorly to the sixth cervical vertebra inferiorly. The VFSS was immediately discontinued in case of aspiration due to chocking from any boluses were noticed or the participants complained of dyspnea. A wall suction was equipped in a fluoroscopy room and a physician closely monitored vital signs during the entire examination time.

Analysis of swallowing physiology

Two skilled physiatrists analyzed the video files under the supervision of an aspiration rehabilitation specialist (S.A). The physiatrists counted the number of frames and determined the time (seconds) taken during each swallowing phase. The oral transit time (OTT) was defined as the time taken for the main bolus in the oral cavity to start moving to the posterior until the bolus head reached the lower edge of the mandibular ramus. The pharyngeal transit time (PTT) was defined as the time from the head of the main bolus reaching the lower edge of the mandibular ramus to the bolus tail passing through the cricopharyngeal region approximately 1 cm below the true vocal folds. The pharyngeal delay time (PDT) is a PTT component defined as the time from the bolus head arriving at the lower edge of the mandibular ramus to triggering of the pharyngeal swallow. Temporal data were acquired through analysis of the bolus position in the oropharynx as previously defined [18]. The videofluoroscopic dysphagia scale (VDS), which developed by Hahn et al., was measured. This scale is expressed as a score out of 100 and comprehensively reflects the findings of the videofluoroscopy test [19]. A skilled rehabilitation physician performed VDS scoring for each participant.

Functional measurement of swallowing

The modified penetration aspiration scale (mPAS) and the American Speech-Language-Hearing Association National Outcome Measurement System (ASHA-NOMS) describe the swallowing abilities with higher ASHA-NOMS scores indicating improved swallowing function [20]. The mPAS is a revised PAS version that evaluates airway invasion severity based on the level of swallowing materials (levels 1 to 5). Penetration and aspiration refer to the materials not passing and passing below the vocal cord level, respectively. Higher mPAS scores indicate decreased swallowing function [21]. One skilled rehabilitation physician performed scoring for each participant.

Swallowing supplement

The viscosity of the swallowing supplement was a spoon thick, which is most frequently used for the dysphagia test given the convenience of controlling the bolus speed, pharyngeal residue clearance, and penetration or aspiration [22]. The swallowing supplement was developed by the Korea Food Research Institute (KFRI) as a probiotic thickened liquid containing 5% lipid nanoparticle carrier with 200 ppm of vitamin D3 and vitamin E. It has similar texture and smell as commercialized plain yogurt with a color of bright white yellow and overall sweet taste.

Questionnaire and survey for the swallowing supplement

We assessed oral health-related quality of life using the Geriatric Oral Health Assessment Index (GOHAI) and swallowing quality of life (swal-QoL) questionnaires. The GOHAI is a 12-item questionnaire that consists of three positive and nine negative items for assessing oral health in elderly individuals. Here, participants selected one of five responses to the 12 questions to indicate whether oral discomfort occurred during the previous 3 months [23]. The 6-point scale was adapted to a 3-point scale. The coding of the three positive items was reversed since a high GOHAI score indicates low impairment. As a result, the score of the GOHAI scale ranged from 12 to 36 with a higher total score indicating a higher oral health index [23]. The swal-QoL was developed to assess the quality of life of patients with swallowing disorders [24, 25]. It comprises of 44 questions evaluating 11 QOL domains (burden, eating duration, eating desire, symptom frequency, food selection, communication, fear, mental health, social functioning, sleep, and fatigue). The possible responses are “strongly agree” (1 point), “agree” (2 points), “neutral (3 points), “disagree” (4 points), and “strongly disagree” (5 points). The score for each domain was calculated by adding the points of the responses to its questions with the score being positively associated with the quality of life. After the videofluoroscopic study, the participants underwent a survey and ate the swallowing supplement. The survey assessed “convenience to swallow”; “residual sense after swallowing”; and 6 preference items, including appearance, flavor, taste, texture, overall preference, and purchase intent.

Statistical analysis

Independent t tests were used for between-group comparisons of each demographic variable, swallowing measurement, and questionnaire. Pearson’s correlation coefficient analysis was performed within the patient group to examine the relationships between nutritional status and swallowing function. Statistical analyses were performed using SPSS ver. 21.0 software (IBM Company, Armonk, NY, USA) with the significance level set at P value < 0.05.

Results

Demographics and clinical characteristics

Table 1 presents the demographics, clinical characteristics, and oral conditions of participants in both groups. There was no between-group difference in muscle and fat mass, as well as body mass index. However, there were significantly lower albumin and hemoglobin levels in the PD group than in the control group. Compared with the control group, the PD group had significantly lower cognitive status as measured using the MMSE score. Furthermore, compared with the control group, the PD showed decreased overall dental condition, sensory and motor tongue function, and salivation.

Table 1 Demographics and clinical characteristics of PD patients and elderly healthy controls. Values are mean ± SD; PD, Parkinson’s disease; SMM, skeletal muscle mass; BMI, body mass index; MMSE, Mini-Mental State Examination; H&Y, Hoehn and Yahr; UPDRS, unified Parkinson’s disease rating scale; LED, levodopa equivalent dose, *P < 0.05,**P < 0.01,***P < 0.001
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Between-group comparison of swallowing function

Compared with the control group, the PD group had significantly lower total VDS scores and sub-scores regarding the oral stage, including bolus formation, mastication, premature bolus loss, and oral transit time. Furthermore, compared with the control group, the PD group had significantly impaired vallecular residue, pyriform sinus residue, and aspiration and penetration of the pharyngeal stage (Fig. 1). Between-group comparisons of the OTT, PDT, and PTT for the general diet were performed with adjustment for sex and age. Compared with the control group, the PD group had a significantly impaired PDT (P < 0.05). However, there was no significant between-group difference in the mPAS score for 5 food types (Fig. 1). The mean ASHA-NOMS was 5.83 ± 1.12 and 6.72 ± 0.54 in the PD and control groups, respectively, with the between-group difference being significant (data was not shown).

Fig. 1
figure 1

The percentage of subject who showed abnormal findings in the items of videofluoroscopic dysphagia scale (VDS) (upper), swallowing physiology including oral transit time (OTT), pharyngeal delay time (PDT), and pharyngeal transit time (PTT), and modified penetration aspiration scale (mPAS) with commercial yogurt between healthy controls and PD patients

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Swallowing supplements in patients with PD

Table 2 shows the comparison of swallowing function using the VFSS between commercialized plain yogurt and swallowing supplement in patients with PD. There was no significant between-diet difference in the mPAS score. However, the PDT and PTT were significantly shorter with the swallowing supplement than with the commercialized plain yogurt (P = 0.000, 0.009, respectively). The OTT showed a tendency to shorten with swallowing supplement; however, there was no significant between-diet difference. The total VDS score was lower with swallowing supplements than with commercialized yogurt. In the VDS sub-score, the pharyngeal wall coating, PTT, and aspiration showed a significant improvement with swallowing supplement (P = 0.000, 0.001, 0.032; respectively).

Table 2 Evaluation of swallowing functions between commercial yogurt and swallowing supplement in PD patients
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Survey for the swallowing supplement

All the patients with PD underwent a survey for the newly developed swallowing supplement after finishing the swallowing evaluation. In a preference survey, most patients with PD selected a high score for “easy to swallow” and above-average to good scores for the “pharyngeal residual sense.” Moreover, the preferential survey of the six items, including appearance, flavor, taste, texture, overall preference, and purchase intent (range: 0~4.5) scored an average of ≥ 3. The texture score was the highest (average > 4) followed by the overall preference (average > 3.5) (Fig. 2).

Fig. 2
figure 2

a–c Survey for the new developing swallowing supplements. The majority of PD patients estimated the swallowing supplements as easy to swallow and above average pf pharyngeal residual sense. The evaluation of the six items for swallowing supplements were generally tolerable

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Questionnaire for oral health and swallowing QOL

The total GOHAI scores, which are comprised of 12 sub-items, were significantly lower in the PD group than in the healthy control group (P < 0.000) (Table 3). In the swal-QoL questionnaire, the total score and scores of 8 sub-items, except the “food selection” sub-item, were significantly lower in the PD group than in the control group (Table 4).

Table 3 Geriatric Oral Health Assessment Index score between Parkinson’s disease (PD) patients and elderly healthy controls
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Table 4 Swallowing quality of life between PD patients and elderly healthy controls
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Discussion

We found that patients with PD and healthy controls preferred or could tolerate newly developed swallowing supplements compared with commercialized yogurt. Furthermore, about 30% of the included patients with PD presented “symptomless dysphagia,” which was revealed by penetration/aspiration and moderate vallecular residue degree seen in the VFSS. Therefore, “symptomless dysphagia” is prevalent among early-stage patients with PD where there is a potential risk of progressing to symptomatic dysphagia. Kalf et al. [2] reported that a high percentage of early-stage patients with PD without subjective dysphagia presented objective swallowing dysfunctions, including abnormal VFSS findings. Swallowing dysfunction could be involved in the preclinical or early PD stage [26] as a bottom-up progression of α-synuclein pathology according to the Braak hypothesis [27]. However, we could not perform a detailed analysis of this specific patient group and compare it with those without dysphagia in the VFSS. Patients with PD described feeling “something seems to be hanging inside the neck” or “sticky swallowing.” Most of these patients were examined in the department of otorhinolaryngology or pulmonology; however, there were no true pharyngeal or respiratory problems. These patients received more clinical attention and further evaluation using proper swallowing measurement tools was needed.

Dysphagia prevalence in the elderly (presbyphagia) remains unclear; however, it has been estimated to be approximately 15% [28]. PD-related dysphagia is more frequent than dysphagia in elderly person and the oral stage mostly disturbed [1, 11]. The oral phase of swallowing was associated with trouble with swallowing initiation in patients with PD. Compared with the control group, the PD group showed greater disruption bolus formation, mastication and premature bolus loss in the oral phase. These findings could be attributed to impaired oral conditions; decreased tongue sensory and motor function in patients with PD. The oral phase of swallowing is under the voluntary controls of the mouth, tongue, and neck muscles [11]. Therefore, disharmony between the mouth and surrounding muscles caused by bradykinesia and rigidity in patients with PD could have oral effects. This hypokinetic dysphagia has been reported to respond to dopaminergic treatment unlike the other swallowing stage in PD [29].

In addition, dysfunction of the pharyngeal phase, including delayed PDT, as well as increased residual material and aspiration, was observed in the PD group than in the control group. Delayed PDT is indicative of slower triggering of the pharyngeal motor response and laryngeal elevation. We speculated that somatosensory deficits in the pharyngeal wall and a reduced rate of spontaneous swallowing increased the residue in the pyriform sinus [11, 30]. Regarding the dysfunction of the oral and pharyngeal phases, the swallowing reflex is controlled by the swallowing pattern generator (SPG), which is associated with the nucleus tractus solitarius (NTS) [31]. The NTS, which is interconnected with neural circuits, are involved in oral, pharyngeal, and esophageal swallowing stages. The pharyngeal striated muscle is innervated by the nucleus ambiguous; moreover, the dorsal vagal motor nucleus innervates the lower pharynx and esophageal muscles [31, 32]. Therefore, degeneration of the dorsal vagal nucleus could disrupt both the pharyngeal and esophageal phases.

We compared the swallowing function between commercialized yogurt and swallowing supplement in patients with PD to determine whether the swallowing supplement allowed safe swallowing. Subsequently, we assessed factors regarding nutrition, flavor, texture, and convenience with respect to the patient’s needs. We had to consider the various cases of PD-associated dysphagia since it can be caused by PD medication, disease severity, and PD progression. Taken together, it is best to modulate swallowing supplements as individualized therapy; however, this is difficult due to the various characteristics of swallowing supplements, including mass production and commercialization. Various diets for dysphagia have already been commercialized in liquid, gelatin, and powder forms for use in place of food, nutrient, and meal replacement (www.diaphagia-diet.com). However, the development of these dysphagia diets did not involve an objective evaluation of the swallowing function as performed in our study. Furthermore, these diets were developed for general dysphagia regardless of the disease type. The National Dysphagia Diet Task Force redefined the international standardized terminology and definitions for texture-modified foods and liquids for individuals with dysphagia [33]. In addition, it recommended standardized therapies for dysphagia management, including three different levels of food textures and four types of liquids suitable for patients with mild to severe degree dysphagia. The levels for solid foods include ground/pure (level 1), mechanical soft/chopped (level 2), and regular/advanced (level 3) while the four thickness liquid levels are thin, nectar thick, honey-thick, and spoon thick [33]. Our swallowing supplement was similar spoon thick, which was formulated with the Korean dining culture considered where spoons and chopsticks are used. Moreover, we considered the color and texture where the color was bright white yellow and the texture was non-clumpy and soft like pudding; however, it was not sticky. VDS analysis with commercialized yogurt showed that the PD group had more delayed PDT, as well as increased residue and coating around the pharynx, compared with the control group. However, our swallowing supplement significantly shortened the PDT and PTT, as well as improved aspiration and pharyngeal wall coating compared with commercialized yogurt. This indicates that the texture of the swallowing supplement should allow light swallowing based on low surface friction coefficient, as well as moderate viscosity without stickiness. The odor of the swallowing supplement is not a significant factor since hyposmia and anosmia are common early non-motor PD symptoms [34]. The nutrition composition of swallowing supplement is as important as its safety aspects. Since the indication of the swallowing supplement could alter between an own and additive meal depending on its nutritional composition, we developed it as a thickened liquid to allow both uses.

Recently, other than in terms of nutrients, the market of functional food has grown among elderly individuals and according to consumer needs. Functional food was shown to have physiological benefits and to decrease the risk of chronic and neurodegenerative diseases, including PD [35]. Moreover, using nutraceuticals derived from natural sources has been reported to support the beneficial roles in PD prevention as antioxidants, anti-apoptosis, and mitochondrial homeostasis [36]. However, the nutrients of our swallowing supplement lacked protective and disease-modifying effects; rather, it was composed of the daily recommended essential nutrition for elderly individuals. Subsequent addition of the features of functional food and nutraceuticals to our swallowing supplement could improve its prevention of neurodegenerative disease and attenuation of PD-related health problems. Our swallowing supplement has good portability given the possibility of disposable individual packaging.

Initially, it is important to decide when patients with PD use swallowing supplements. Self-awareness of dysarthria progression or the use of a self-report questionnaire for patients with PD provided the initial dysphagia clues. The swallowing disturbance questionnaire (SDQ) and non-motor symptoms questionnaire (NMSQ) are generally used for PD-related dysphagia [37, 38]. However, it is difficult to administer the SDQ to participants unaware of swallowing disturbances even though it is an accurate and sensitive tool for identifying swallowing disturbance [37]. In addition, SDQ scores are affected by medication on and off states, as well as mood symptoms, including anxiety in patients with PD. The NMSQ is a useful clinical tool for screening non-motor problems; however, dysphagia is a PD motor symptom. Consequently, we used the GOHAI, which is regarded as the most comprehensive assessment tool for measuring oral health-related quality of life [23]. Furthermore, the GOHAI evaluates the highly prevalent dental diseases that affect swallowing in elderly people [23]. In addition, the swal-QoL specifically evaluates the impact caused by changes in quality of life for swallowing [25]. With respect to quality of life, it is useful to differentiate swallowing in healthy adults with dysphagia from that involving various diseases [39]. We observed that patients with PD obtained lower scores in all domains of the swal-QoL than healthy controls. Consequently, the burden for swallowing was high in patients with PD, which resulted in a reduced swal-QoL. To address the possible inconsistency between subjective awareness and objective dysphagia measurement, we performed confirmation VFSS analysis [40]. The VFSS is a widely used tool for objectively evaluating swallowing function and allowing visualization of the structure and dynamics of the swallowing process. We quantitatively measured functional dysphagia through video-fluoroscopy, which could comprehensively reflect swallowing functions.

PD-related dysphagia can be predicted by various clinical indicators, including the H&Y stage, body mass index < 20 kg/m2, drooling, dysarthria, cognitive impairment, and gait disturbance [1, 8, 9, 41]. The advanced PD stage involves more dysphagia symptoms with high levodopa treatment not improving dysphagia symptoms. This refutes the suggestion that the non-dopaminergic pathway is involved in PD-related dysphagia [10]. The non-dopaminergic pathways, including the central cholinergic system, are involved in dysphagia, cognition, and gait difficulty. Brainstem cholinergic systems have been implicated in the pharyngeal and esophageal stages of swallowing and in generating rhythmic or propulsive esophageal motility [42]. Taken together, the swallowing supplements decreased the aspiration frequency and reduced aspiration pneumonia. The optimal degrees of viscous and elastic components of texture-modified food have been suggested to affect the resulting findings [43].

Our findings should be carefully considered. First, our sample size was insufficient for comparing the advantages of our swallowing supplement. Second, there were no significant between-group differences in the swallow physiology of general diets except PDT. This could be attributed to differences in the PD stage. Third, there was a significant between-group difference in cognitive status, which could have a confounding effect on swallowing dysfunction since the cholinergic pathway affects dysphagia in patients with PD [44].

In conclusion, we found that several patients with PD presented “symptomless dysphagia” upon VFSS evaluation. In addition, our swallowing supplement was easier to swallow than a general diet and tolerable to patients with PD. This elderly friendly swallowing supplement could contribute toward reducing the chance of aspiration and dysphagia complications in patients with PD.