Relationship between Dysphagia and Serum Substance P Level in Chronic Central Nervous Disease

doi:10.4236/ijcm.2013.42016

Paper Menu >>

Journal Menu >>

International Journal of Clinical Medicine, 2013, 4, 86-90

http://dx.doi.org/10.4236/ijcm.2013.42016 Published Online February 2013 (http://www.scirp.org/journal/ijcm)

Relationship between Dysphagia and Serum Substance P

Level in Chronic Central Nervous Disease

Yoshiyuki Kishida, Naoto Maeda, Yoshikazu Murawaki

Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Japan.

Email: [email protected]

Received December 17th, 2012; revised January 18th, 2013; accepted January 25th, 2013

ABSTRACT

Purpose: We compared serum substance P (SP) levels in underlying diseases and dysphagia, or its absence, in patients

with cerebrovascular disease, neurodegenerative disease or Alzheimer’s disease, to investigate the relationship between

dysphagia and serum SP in chronic central nervous disease. Methods: Subjects comprised 94 patients admitted to a

hospital or nursing home during the 5 years between April 2007 and April 2012 with central nervous symptoms. Serum

SP levels were measured by enzyme immunoassay, and video endoscopy using a nasal endoscope in all subjects to ob-

jectively evaluate swallowing function. Results: Serum SP level was very similar in central nervous disease without

dysphagia and controls without central nervous disease. Conversely, serum SP level was significantly lower in central

nervous disease with dysphagia. When comparing underlying diseases, serum SP was significantly lower in Parkinson’s

disease than in other disease groups (cerebrovascular disease, Alzheimer’s disease). Looking at changes in serum SP

levels over time after disease onset, SP level was significantly low in subjects without dysphagia at the time of onset

who went on to develop dysphagia during the disease course, whereas serum SP level tended to be higher in subjects

with dysphagia at the time of onset and improvement during the disease course. With Parkinson’s disease and cere-

brovascular disease, serum SP was low, particularly in subjects thought to have severe damage to the basal ganglia.

Conclusion: Serum SP is generally thought to decrease in patients with cerebrovascular disease accompanied by dys-

phagia, but these results suggest that serum SP levels can be expected to improve to some extent, even if dysphagia is

present at disease onset, assuming, for example, that some basal ganglia function remains. Positive therapeutic interven-

tions such as swallowing rehabilitation should be promoted in such patients, with the goal of improving swallowing

function.

Keywords: Substance P; Dysphagia; Central Nervous Disease

1. Introduction

Together with motor function and higher brain function,

swallowing is one of the basic human functions, but

could be considered the most important in terms of a

direct connection to survival. The rapid increase in the

elderly population in recent years has been accompanied

by a large number of cases involving cerebrovascular

diseases, neuromuscular diseases such as Parkinson’s

disease, and age-related brain changes. In many cases,

swallowing function is impaired as a result. Such im-

pairments increase the risk of aspiration pneumonia and

choking [1,2] during oral intake of nutrients. In Japan,

nasogastric intubation or gastrostomy is therefore stan-

dard practice to manage dysphagia arising from patho-

logical changes in the higher brain. Because some pa-

tients develop serious complications such as aspiration

pneumonia through reflux of enteral nutrients, further

study of the suitability of gastrostomy as a means of ad-

ministering nutrition in dysphagic patients is needed.

Ideally such patients would regain the ability to take nu-

trients orally by recovering from dysphagia, but no ob-

vious, measurable markers have been identified to indi-

cate those patients most likely to recover.

Substance P (SP) is a neurotransmitter belonging to the

tachykinin peptide family. Widely distributed throughout

the peripheral and central nervous systems of vertebrates,

SP is known to have a wide range of biological activities:

as well as contributing to pain transmission via primary

afferent neurons in the peripheral nerves, and to emo-

tional responses such as depression, anxiety and fear by

bonding with neurokinin 1 (NK1) receptors in the central

nervous system, it also acts directly on immune cells to

modify inflammatory and immune responses.

Recent findings have also shown that SP may be a

biological indicator of dysphagia [3,4], based on the fact

that SP is present in vagal non-cholinergic nerve fibers

Relationship between Dysphagia and Serum Substance P Level in Chronic Central Nervous Disease 87

innervating the respiratory tract [5] and is involved in

mechanisms for preventing aspiration, such as the cough

reflex and swallowing movements. In fact, reports have

described decreased serum ST levels in patients with

cerebrovascular disease involving dysphagia [6,7]. The

present investigation examined the relationship between

serum SP levels and presence or absence of dysphagia,

and discusses the significance of serum SP levels in

chronic dysphagia.

2. Subjects and Methods

2.1. Subjects

Subjects comprised 94 patients in admitted to a hospital

or nursing home during the 5 years between April 2007

and April 2012 with central nervous symptoms due to

conditions including cerebrovascular disease, Parkinson

disease and Alzheimer’s disease, along with a control

group of 4 subjects without central nervous symptoms.

When, in addition to the underlying disease, all symp-

toms and findings were stable, we examined whether the

subject had dysphagia, and measured serum SP levels at

the same time. For 17 subjects (18.0%), we also per-

formed the same examinations and measurements 3 years

after first measurement.

Each subject or their family received a written expla-

nation of the research and provided written consent be-

fore enrolment in the study.

2.2. Evaluation of Swallowing Function

We performed video endoscopy (VE) using a nasal en-

doscope (Olympus Medical Systems ENT-GP, Tokyo,

Japan) in all subjects to objectively evaluate swallowing

function. After nasal insertion of the endoscope, the in-

ternal structures were examined for organic abnormali-

ties of the pharynx and larynx, operation of the airway

defense mechanisms, movement ability of organs of swal-

lowing and presence or absence of aspiration, and these

were evaluated in accordance with the evaluation form

proposed by the Japanese Society of Dysphagia Reha-

bilitation (http://info.fujita-hu.ac.jp/%7Erehabmed/jsdr/)

(Figure 1).

2.3. Measurement of Serum SP Levels

SP serum levels were measured by enzyme immunoassay

(Substance P Enzyme Immunoassay Kit; Assay Designs,

MI, USA) using blood samples taken in the morning be-

fore breakfast during regular health monitoring at least 6

months after symptoms had reached a stage where there

was considered to be no possibility of improvement.

2.4. Statistical Methods

Prism 5 for Mac OS X version 5 software (Tokyo, Japan)

was used for statistical analyses. Student’s t-test was

used for intergroup comparisons based on sex differences,

and Pearson’s correlation coefficient was used to evalu-

ate associations between age and serum SP level, and

between serum albumin and serum SP levels. The dif-

ference of SP and albumin among diseases was tested by

one-way analysis of variance. A significance level of P <

0.05 was set for each test.

3. Results

3.1. Subject Background Factors (Table 1)

Table 1 shows the background and clinical data of the

subjects. The 94 subjects (17 men, 77 women) showed a

(a) (b)

Figure 1. Findings of the endosc opic e valuation of swallowing function. (a) Inflow of the saliva into the glottis. (b) Backflow of

he liquid content from the tracha. t

Relationship between Dysphagia and Serum Substance P Level in Chronic Central Nervous Disease

Table 1. Background and clinical data of patients.

(M:F) Age SP (pg/ml)Albumin (g/dl) Dysphagia (%)

All

cases

(17:77) 84.6 ± 8.6 114.4 ± 50.43.8 ± 0.5 38 (40.4)

CVD 31

(6:25) 83.0 ± 7.5 130.1 ± 56.63.7 ± 0.6 12 (38.7)

AD 50

(8:42) 86.9 ± 7.4 108.0 ± 44.43.8 ± 0.5 17 (34.0)

PD 9 (1:8) 79.4 ± 14.868.0 ± 14.33.5 ± 0.5 9 (100)

Control 4 (2:2) 81.1 ± 5.5 164.8 ± 40.54.3 ± 0.4 0 (0)

SP: serum substance P concentration (mean ± SD); CVD: cerebral vascular

disease; AD: Alzheimer’s disease; PD: Parkinson’s disease.

mean age of 84.6 ± 8.6 years, serum SP 114.4 ± 50.4

pg/mL, and albumin 3.8 ± 0.5 g/dL. Dysphagia was con-

firmed in 38 subjects (40.4%). Dividing these subjects

into four groups by disease (cerebrovascular disease,

Alzheimer’s disease, Parkinson’s disease, or control

group), there were 31 subjects (6 men, 25 women) in the

cerebrovascular disease group, 50 subjects (8 men, 42

women) in the Alzheimer’s disease group, 9 subjects (1

man, 8 women) in the Parkinson’s disease group and 4

control group subjects (2 men, 2 women). Serum SP lev-

els in these groups were 130.1 ± 56.6 pg/mL for cere-

brovascular disease, 108.0 ± 44.4 pg/mL for Alzheimer’s

disease, 68.0 ± 14.3 pg/mL for Parkinson’s disease and

164.8 ± 40.5 pg/mL for healtly elders, respectively, with

significantly lower levels for the Parkinson’s disease

group (P < 0.05) than for the cerebrovascular disease or

Alzheimer’s disease groups. No significant differences in

serum SP levels were identified between the cerebrovas-

cular disease, Alzheimer’s disease and control groups.

3.2. Sex differences in SP Levels

No obvious sex differences in serum SP levels were evi-

dent, with mean levels of 108.4 ± 47.7 pg/mL for men

and 115.7 ± 51.2 pg/mL for women.

3.3. SP levels and Age

No obvious correlations were seen between age and se-

rum SP level (r = −0.08, P = 0.44).

3.4. Association between Dysphagia and Serum

When comparing serum SP levels in subjects with and

without dysphagia, levels were significantly lower in the

38 subjects with dysphagia (78.9 ± 34.5 pg/mL) than in

the 56 subjects with central nervous disorders but no

dysphagia (138.4 ± 44.9 pg/mL; P < 0.001).

3.5. Presence/Absence of Dysphagia and Changes

in Serum SP Level over Time

To examine changes in serum SP level over the course of

dysphagia, we investigated serum SP levels 3 years after

initial measurement in 10 subjects without dysphagia at

the onset of underlying disease and in 7 subjects with

dysphagia at disease onset.

Five of the 10 subjects without dysphagia at disease

onset developed dysphagia during the course of the dis-

ease. In this group (cerebrovascular disease, n = 1; Alz-

heimer’s disease, n = 4), serum SP levels fell signifi-

cantly from 119 ± 15.7 pg/mL to 66.7 ± 15.1 pg/mL (P <

0.001; Figure 2). In contrast, among the 7 subjects with

dysphagia at disease onset, three (all cerebrovascular

disease patients) showed improvement in dysphagia dur-

ing the disease course, and serum SP levels in these 3

subjects followed an upward trend, rising from 102.8 ±

24.6 pg/mL to 173 ± 56.9 pg/mL (P = 0.053; Figure 3).

The remaining 4 subjects showed no improvement in dys-

phagia, and all had severe damage to the basal ganglia.

4. Discussion

This study found no differences in serum SP levels be-

tween subjects with chronic central nervous disease but

not dysphagia and a control group with no central nerv-

ous disease. However, when comparing diseases, sub-

jects with the degenerative Parkinson’s disease showed

serum SP levels significantly lower than those with cere-

brovascular disease. This may be partly due to the fact

that Parkinson’s disease, which involves damage to the

basal ganglia, is accompanied by decreases in dopamine,

which is released from the substantia nigra, and the neu-

rotransmitter SP [4]. In fact, this applies not only to

Parkinson’s disease, but also to patients with significant

damage to the basal ganglia due to cerebrovascular dis-

ease [3]. Such patients are thought to be susceptible to

Figure 2. Temporal change of the serum SP value of cases

without dysphagia. *The case developed dysphagia during

the course of the disease. Ssp: serum sunbstance P concen-

tration (mean ± SD); CVD: cerebral vasoular disease; AD:

Alzheimer’s disease; PD: Parkinson’s disease.

Relationship between Dysphagia and Serum Substance P Level in Chronic Central Nervous Disease 89

Figure 3. Temporal change of the serum SP value of cases

with dysphagia. **The case showed improvement in dys-

phagia during the disease course. sSP: serum sunbstance P

concentration (mean ± SD); CVD: cerebral vasoular disease;

AD: Alzheimer’s disease; PD: Parkinson’s disease.

aspiration because the swallowing reflex and cough re-

flex are unable to function normally due to the low levels

of SP in the blood. This represents a major cause of age-

related pneumonia [1]. Dysphagia has been treated with

ACE (Angiotensin converting enzyme) inhibitors, which

increase SP levels in peripheral nerves by blocking SP-

degrading enzymes, and by pharyngeal administration of

a substance such as capsaicin (the active component of

chili peppers), which increases SP levels in the oral cav-

ity and respiratory tract via afferent C fibers, thereby

promoting the swallowing reflex [8,9]. However, these

treatments are only thought to be effective in patients

assumed to have low SP production due to “partial”

damage to the basal ganglia.

When looking at changes over the clinical course of

dysphagia, serum SP levels were significantly low in

subjects without dysphagia at time of onset who went on

to develop dysphagia during the course of the disease,

whereas serum SP showed an upward trend in subjects

with dysphagia that was present at time of onset but

showed improvement during the course of the disease.

This indicates a negative correlation between dysphagia

and serum SP level. Furthermore, all subjects in whom

dysphagia resolved showed cerebrovascular disease,

whereas all Parkinson’s disease patients failed to show

any improvement in dysphagia and also exhibited virtu-

ally unchanged serum SP levels. This may be due to dif-

ferences in the extent of functional loss in the basal gan-

glia in Alzheimer’s disease, Parkinson’s disease and

cerebrovascular disease. In addition, patients with Park-

inson’s disease would be expected to show a persistent,

progressive decline in SP, since Parkinson’s is a progres-

sive degenerative disease.

These findings suggest that among patients with chro-

nic central nervous disorders involving dysphagia, those

with complete loss of basal ganglia function will have

persistently low serum SP levels. On the other hand, pa-

tients with an intact basal ganglia are likely to sustain the

capacity for SP production, who have the possibility that

serum SP levels wound rise with recovery from dys-

phagia. This means that when treating patients with an

intact basal ganglia, medical interventions such as gas-

trostomy and swallowing rehabilitation should be ac-

tively considered in the expectation that symptoms will

resolve through physicochemical stimulation of the intes-

tinal tract. However, it has been pointed out that a gas-

trostomy installed in the early stage of cerebrovascular

disease can lead to a loss of swallowing function, and

also results in an increased risk of aspiration pneumonia

as a result of gastroesophageal reflux following func-

tional declines in gastric secretion [10,11]. This problem

could be overcome by providing parenteral nutrition for

dysphagia when it occurs at the onset of cerebrovascular

disease, then introducing a gastrostomy after the disease

has stabilized.

A number of limitations must be considered when in-

terpreting the present results: the number of subjects was

small; the causal relationships with the underlying dis-

eases were unclear; the study design was not prospective;

and the effects of age may have introduced a type II error

(false-negative error). Age and sex differences in serum

SP levels have not been indicated in previous studies,

and we similarly dispensed with discussion of the effects

of sex and age on serum SP levels. However, almost no

research has been reported on swallowing function in the

chronic phase. Therefore, in the investigation of the link

between serum SP levels and improvement of dysphagia,

this study is of considerable importance as preliminary

research in this area.

5. Conclusion

We demonstrated a strong link between dysphagia and

serum SP levels. In cerebrovascular disease involving

dysphagia, complete loss of basal ganglia function would

be unexpected, at least in patients with normal serum SP

levels at disease onset. This suggests that medical inter-

ventions such as gastrostomy and swallowing rehabilita-

tion should be actively considered on the expectation that

dysphagia symptoms will resolve through physicoche-

mical stimulation of the intestinal tract. This subject de-

mands further research, including a prospective study.

REFERENCES

[1] S. Teramoto, Y. Fukuchi, H. Sasaki, K. Sato, K. Seki-

zawa and T. Matsuse, “High Incidence of Aspiration

Pneumonia in Community- and Hospital-Acquired Pneu-

monia in Hospitalized Patients: A Multicenter, Prospec-

Relationship between Dysphagia and Serum Substance P Level in Chronic Central Nervous Disease

tive Study in Japan,” Journal of the American Geriatrics

Society, Vol. 56, No. 3, 2008, pp. 577-579.

doi:10.1111/j.1532-5415.2008.01597.x

[2] M. Yamawaki, “Prevalence of Aspiration Pneumonia,”

Sogo Riha, Vol. 37, 2009, pp. 105-109.

[3] T. Nakagawa, T. Ohrui, K. Sekizawa and H. Sasaki,

“Sputum Substance P in Aspiration Pneumonia,” Lancet,

Vol. 345, No. 8962, 1995, p. 1447.

doi:10.1016/S0140-6736(95)92638-0

[4] T. Nakagawa, K. Sekizawa, H. Arai, R. Kikuchi, K. Ma-

nabe and H. Sasaki, “High Incidence of Pneumonia in

Elderly Patients with Basal Ganglia Infarction,” Arch In-

ternational Medicine, Vol. 157, No. 3, 1997, pp. 321-324.

doi:10.1001/archinte.1997.00440240085013

[5] Y. S. Lee, K. M. Km, C. Shin, J. J. Shim, K. H. Kim, H.

K. Kang, H. S. Yoo and H. K. In, “Substance P-Immu-

noreactive Nerves in Endobronchial Biopsies in Cough-

Variant Asthma and Classic Asthma,” R espiration, Vol.

70, No. 1, 2003, pp. 49-53. doi:10.1159/000068413

[6] T. Nagamine, “Serum Substance P Levels in Patients with

Chronic Schizophrenia Treated with Typical or Atypical

Antipsychotics,” Neuropsychiatric Disease and Treat-

ment, Vol. 4, No. 1, 2008, pp. 289-294.

doi:10.2147/NDT.S2367

[7] S. Matsumoto, S. Shimodo and K. Kawahira, “Substance

P,” Geriatric Medic i ne, Vol. 45, 2007, pp. 1331-1335.

[8] Y. Jin, K. Sekizawa, T. Fukushima, M. Morikawa, H.

Nakazawa and H. Sasaki, “Capsaicin Desensitization Im-

hibits Swallowing Reflex in Guinea Pigs,” American

Journal of Respiratory and Critical Care Medicine, Vol.

149, No. 1, 1994, pp. 261-263.

[9] D. Ramsey, D. Smithard and L. Kalra, “Silent Aspiration:

What Do We Know?” Dysphgia, Vol. 20, No. 3, 2005, pp.

218-225. doi:10.1007/s00455-005-0018-9

[10] T. Kisa, Rinsyoueiyou, Vol. 106, 2005, pp. 327-333.

[11] S. Teramoto, “Aspiration Pneumonia May Not Be Pre-

vented by Gastrostmyalone,” Journal of Clinical Reha-

bilitation, Vol. 17, 2008, pp. 826-829.