Orderly functioning of the gastrointestinal tract is fundamental to the maintenance of good nutrition, and gut dysfunction can lead to symptoms and marked impairment of quality of life. These issues are, accordingly, fundamental to achieving healthy ageing.
Gastrointestinal symptoms occur frequently in the elderly. A recent Italian survey involving over 3000 outpatients aged at least 60 years indicated that over 40% had experienced gut-related symptoms in the past week, and both the prevalence and severity of symptoms were associated with the number of comorbidities and prescribed drugs, and the need for assistance with activities of daily living . These observations highlight the importance of an holistic evaluation of older patients presenting with gastrointestinal complaints.
The following sections will focus on the recent insights concerning the pathophysiology of the ageing gut and the key gastrointestinal disorders that affect the elderly.
PATHOPHYSIOLOGY OF THE AGEING GUT
Motor activity of the gut is controlled by neural plexuses between the circular and longitudinal muscle layers (myenteric plexus) and in the submucosa, with the underlying rhythm of depolarization set by specialized pacemaker cells, the interstitial cells of Cajal (ICC).
Ageing is associated with loss of neurons in both the myenteric and submucosal plexus, beginning in adulthood and progressing thereafter . Neuronal loss in rat models of ageing involves predominantly cholinergic neurons, with parallel loss of enteric glia, and losses are greater in the distal than proximal gut . Such defects might be expected to predispose to delayed gastrointestinal transit, particularly in the colon. Vagal and sympathetic extrinsic nerves supplying the gut are also impacted, and display dystrophic axonal swelling and dilated varicosities . There have been some inconsistencies between the studies; a recent evaluation of longitudinal ileal smooth muscle in ageing rats indicated that the cholinergic nerve supply remained intact, although there was diminished sensitivity to acetyl choline, because of increased acetylcholinesterase activity .
Suggested mechanisms for neuronal loss with ageing include oxidative stress and mitochondrial dysfunction . Caloric restriction and supplementation with specific nutrients, for example, omega-3 fatty acids , can attenuate these effects in rodent models , whilst there is some evidence that 5HT4 agonists may promote the survival of enteric nerves . Intestinal epithelial cells and glia appear to influence the survival of enteric neurons, and the latter may have a particular role in protection against oxidative stress.
The progeric klotho mouse model, which has reduced levels of the antiageing protein klotho, associated with a premature ageing phenotype and early death , displays reduced expression of myosin in smooth muscle throughout the gut, but the number of ICCs and proportions of nitrergic and cholinergic neurons appear unaffected. Small intestinal transit is abnormally slow, but whole-gut transit is faster than normal, because of more rapid colonic transit and a shorter gut as a result of neuromuscular hypoplasia. These findings clearly differ from natural ageing, probably because they reflect impaired development rather than increased cell death .
The validity of rodent models has now been tested by examining human colon specimens over an age range of 33–99 years . There was a decline in enteric neuron cell bodies in the myenteric plexus, specifically affecting cholinergic rather than nitrergic neurons, which is consistent with the rodent studies . Such an increase in the proportion of inhibitory neurons might predispose to constipation, although human studies are inconsistent as to whether colonic transit time increases or is unchanged with age . Unlike rat models, there was no apparent decline in neurons in the submucosal plexus in humans . Examination of human tissue has shown a decline in ICC numbers in both stomach and colon in a linear fashion (∼13% every 10 years) between the third and tenth decade [8▪▪].
SWALLOWING DISORDERS IN THE ELDERLY
Dysphagia can be caused by disordered oropharyngeal function or oesophageal disorders. The latter encompasses both mechanical obstruction and disordered motor function, including achalasia.
Age-related changes in oropharyngeal function have been reviewed recently  and include reduced driving force of the tongue, decreased amplitude of pharyngeal wall contraction, and reduced pharyngeal swallowing, all of which favour retention of food in the valleculae and piriform sinuses. The afferent arm of laryngo-upper oesophageal sphincter reflex is impaired, and the gag reflex is reportedly absent in 40% of the healthy elderly . Cortical activation during swallowing is also altered with age, becoming more bilateral and symmetrical than in the young when evaluated by functional MRI ; this may represent a compensatory mechanism.
Oropharyngeal dysphagia and aspiration are common in older people and associated with high morbidity and mortality. For example, amongst frail elderly with dysphagia, those with unsafe swallowing, as determined by delayed laryngeal vestibule closure on videofluoroscopy, had a much higher mortality at 1 year (∼50%) than those whose swallowing was deemed safe (13%). Stroke, Parkinson's disease, dementia, and illnesses associated with a reduced level of consciousness are risk factors for oropharyngeal dysphagia. Aspiration may be silent and associated only with desaturation or fever. A recent position statement suggested that modified barium swallow and fibreoptic evaluation of swallowing are helpful investigations in the setting of a multidisciplinary team assessment . Videofluoroscopy may demonstrate abnormally slow laryngeal closure, upper oesophageal sphincter opening and vertical hyoid motion, and weaker tongue propulsion than healthy young controls . A modified diet, oral care, and attention to positioning are important aspects of management, although the evidence base for each is limited. It should be noted that nasogastric or gastrostomy tube feeding do not necessarily prevent aspiration .
Reported age-related changes in oesophageal function include reduction in both primary and secondary peristalsis and an increase in nonpropulsive contractions, decreased oesophageal wall compliance , and both a reduction and an elevation  in lower oesophageal sphincter (LOS) pressure.
Achalasia is characterized by a loss of ganglia in the oesophagus. The incidence peaks in the third and seventh decades of life, so this is an important disorder in older patients who tend to have a longer duration, but lesser severity of symptoms when compared to the young .
A Korean series reported higher basal and residual LOS pressures in an older group (>60 years) when compared to younger patients (≤40 years) with ‘classic’ achalasia, but there were no differences for ‘vigorous’ achalasia . In contrast, a Brazilian series reported lower LOS pressure in the elderly than the young, and the elderly were less symptomatic .
Whether laparoscopic myotomy or pneumatic dilatation represents the optimal initial treatment remains controversial, but myotomy appears to be relatively safe and effective in older patients; a consecutive series of 51 patients aged at least 65 years recorded no perioperative mortality, few complications, and a median hospital stay of 3 days . On follow-up of 2–4 years, about 20% required additional therapy postoperatively (pneumatic dilatation or botulinum toxin injection), but all had symptomatic improvement.
GASTRO-OESOPHAGEAL REFLUX DISEASE
The high prevalence of symptomatic gastro-oesophageal reflux disease (GORD, ∼25%) reported amongst long-term nursing home residents in a cross-sectional US study  is not surprising given that in the general population, some 40% have occasional and 20% weekly reflux symptoms [17,18]. It should be recognized that apparent differences in prevalence between studies can arise from whether GORD is defined by symptoms or endoscopic findings [19,20].
Multiple factors contribute to GORD, several of which can be influenced by age, including hiatus hernia, LOS pressure, acid production and clearance, salivary and bicarbonate secretion, and gastric emptying . A recent Japanese study suggested that lumbar kyphosis is a risk factor , perhaps because of its effects in intra-abdominal pressure. Whether the frequency of transient LOS relaxations, the major mechanism of reflux in the general population , is affected by ageing has not been studied.
The severity of reflux oesophagitis increases with age, but that of symptoms decreases [17,19]. A recent study of patients with GORD confirmed that those of at least 60 years have reduced perception of oesophageal acid infusion and respond with a lower swallow frequency . Whilst typical GORD symptoms are purported to be less common in older compared to younger patients, and atypical symptoms more common, this has been challenged by a recent Japanese study indicating that elderly patients less frequently had atypical symptoms than the young .
Endoscopy is indicated to investigate GORD in the elderly when ‘alarm features’ such as weight loss, anaemia, dysphagia, or gastrointestinal bleeding are present and may be helpful when symptoms are atypical ; it is generally safe in the elderly. Whether endoscopy is indicated to screen for Barrett's oesophagus is unclear; economic modelling suggests that Caucasian men older than 50 years with at least 5 years of heartburn symptoms may be a cost-effective group to screen. In patients with known Barrett's oesophagus, the risk of developing adenocarcinoma is greatest between 65 and 74 years. It has been suggested that surveillance should cease when life-expectancy is less than 1 year, or when an individual is unable to tolerate surgical or endoscopic therapy if high-grade dysplasia were found .
Proton pump inhibitors (PPIs) are widely prescribed for the treatment of GORD, and rates of healing of oesophagitis in the elderly are much greater for PPIs than is the case for histamine receptor antagonists. However, long-term maintenance therapy is likely to be needed. Diarrhoea, abdominal pain, constipation, and headache are the most common side-effects of PPI therapy, albeit relatively infrequent. PPIs are possibly associated with an increased prevalence of fundic gland polyps, and with a decline in B12 levels, but the clinical significance of these is probably minimal. Of more concern are the increases (approximately double) in the incidence of Clostridium difficile colitis and community-acquired pneumonia. A possible interaction to inhibit the formation of the active metabolite of clopidogrel has received wide attention; this effect is possibly less for pantoprazole than other PPIs, but the clinical significance has been controversial. Finally, there has been controversy as to whether PPI use increases osteoporosis or fracture risk; the odds ratio for hip fracture has generally been reported as less than 2, and most studies had retrospective case–control designs, with inherent risk of bias, nor was the risk increased in all .
Fundoplication remains a treatment option for GORD in the elderly, as in younger patients. Functional status and comorbidities are the most important considerations in determining risk and efficacy of antireflux surgery, rather than age itself .
STOMACH FUNCTION AND AGEING
Motor function of the stomach is relatively well preserved with healthy ageing, with very modest slowing of gastric emptying . Acid secretion was thought to decline with age, but this was probably confounded by atrophic gastritis because of Helicobacter . There is evidence for impaired mucosal defence mechanisms, with decreased mucus and bicarbonate secretion, reduced prostaglandin production, and impaired mucosal blood flow. A rat model has also indicated impairments of apoptosis, angiogenesis, and sensory nerve activation .
Upper gastrointestinal sensory function was recently investigated in older individuals (>60 years) compared to younger controls (<40 years), by means of a nutrient drink test ; the former reported substantially lower scores for abdominal pain and nausea.
SMALL INTESTINAL DISORDERS, INCLUDING POSTPRANDIAL HYPOTENSION
Like the stomach, there are only minor changes in small intestinal motor function with healthy ageing, including a decreased frequency of the migrating motor complex and an increase in propagated clustered contractions; most, but not all, studies have shown no effect on small bowel transit .
Postprandial hypotension is an important problem in the elderly, potentially leading to falls and cardiovascular events . Recent evidence indicates that gastrointestinal function is pivotal in this disorder, as the fall in blood pressure is related to the rate of small intestinal nutrient exposure, and is associated with an increase in superior mesenteric artery blood flow. In the healthy elderly, blood pressure only falls when glucose is infused into the small intestine at more than 1 kcal/min . Nutrient or non-nutrient distension of the stomach can attenuate postprandial hypotension , even at relatively small volumes (∼100 ml) .
Glucose tolerance is known to decrease with ageing, related at least in part to declining insulin secretion and increasing insulin resistance . It is now recognized that the release of ‘incretin’ hormones [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] in response to small intestinal nutrient exposure is an important determinant of postprandial blood glucose control, and GLP-1 agonists are now used widely in the treatment of type 2 diabetes. Both GLP-1 and GIP stimulate insulin secretion under conditions of elevated blood glucose; GLP-1 also slows gastric emptying and suppresses glucagon. Incretin hormone secretion does not appear to be deficient in healthy ageing .
COLON AND ANORECTUM
A number of early studies reported prolongation of colon transit time with ageing, but more recent publications have observed no change in the absence of comorbidities . Ageing is also associated with decreased rectal compliance and altered rectal sensation .
As many as 50% of community-dwelling elderly report constipation and over 70% of those residing in nursing homes . ‘Constipation’ may refer to straining or incomplete evacuation, hard stool, or diminished stool frequency, and it is important for clinicians to identify the key symptoms. Underlying mechanisms include slow colonic transit or dyssynergic defaecation, and contributing factors include poor mobility, comorbidities (e.g. stroke, dementia, depression, diabetes, or Parkinson's disease), medications (opiates and anticholinergics), and impaired anorectal sensation. Often more than one contributing cause can be identified . Faecal impaction must be excluded by digital rectal examination.
The literature does not indicate any clear benefit from increasing the fluid intake, but increasing the intake of fibre and introducing scheduled toilet training (after waking or 30 min after a meal) are recommended, whilst straining for more than 5 min should be avoided . An intervention to provide toileting assistance, exercise, and food and fluid supplements at intervals throughout the day was recently reported to improve bowel frequency in nursing home residents .
Subsequent treatment options include senna or bisacodyl, sorbitol or lactulose, or polyethylene glycol-based osmotic laxatives. Biofeedback is indicated for dyssynergic defaecation, although its benefit in patients with severe comorbidities or any degree of dementia has not been established .
Newer laxatives include lubiprostone (a chloride channel activator), linaclotide (a guanylate cyclase C receptor agonist), prucalopride (a 5HT4 agonist), and methylnaltrexone (a peripheral mu-receptor opioid antagonist of value in opioid-induced constipation), but there is little specific evidence for the use of these in the elderly . One randomized controlled trial has indicated that prucalopride was well tolerated in older patients .
Data from over 9000 community-dwelling participants aged at least 65 in the Canadian Study of Health and Ageing indicate a self-reported prevalence of faecal incontinence of 4% , which is similar to previous reports from population-based studies. Faecal incontinence was associated with age, female sex, and higher degrees of cognitive impairment, and also with institutionalization and mortality, but the latter two were largely explained by confounding comorbidities including cognitive impairment . A Korean study, indicating an overall prevalence of faecal incontinence of 6.4%, attests to the significance of the problem across different ethnicities . In a longitudinal US study, risk factors for faecal incontinence in community-dwelling individuals aged at least 65 years included white race, depression, chronic diarrhoea, and urinary incontinence; only the latter was a factor in men .
Obstetric injury has been emphasized as a risk factor for faecal incontinence, but even women who have only delivered by Caesarean are susceptible, and ageing per se appears to be associated with deterioration in anal resting and squeeze pressures . Indeed, the female : male ratio for faecal incontinence may be less disparate than generally thought .
A newer treatment option for faecal incontinence is sacral nerve stimulation , although this has not been evaluated specifically in the elderly. However, its benefits in urinary dysfunction appear to be maintained in older patients.
GASTROINTESTINAL DYSFUNCTION IN PARKINSON'S DISEASE
Dysphagia, impaired gastric emptying, and constipation occur frequently in Parkinson's disease. Recent evidence indicates that these gastrointestinal features are evident early in the course of the disease, even before formal neurological diagnosis, probably reflecting the involvement of the dorsal motor nucleus of the vagus and the enteric nervous system .
Dysphagia is associated with an impaired quality of life, and the severity increases with disease progression . The pathophysiology includes reduced mechanosensation at the base of the tongue .
A total of 70–100% of Parkinson's patients attending neurology clinics have abnormally delayed gastric emptying, which does not correlate with disease duration . A Japanese study indicated that both ‘early stage’ untreated patients and those with ‘advanced’ disease on L-Dopa therapy had similarly delayed emptying compared to healthy controls [45▪]. Nausea and vomiting are reported in approximately 25% and bloating in up to approximately 45% of patients with Parkinson's disease. Although L-Dopa therapy itself can induce these symptoms, there have been few attempts to correlate them with disordered gastric emptying. Gastroparesis can impair the absorption of L-Dopa and lead to unpredictable on and off phases, and duodenal delivery of L-Dopa is a therapeutic option to provide more predictable delivery .
In the Honolulu-Asia Study of 8000 Japanese-American men, constipation was identified as a risk factor for the future development of Parkinson's disease . In a study examining colonic biopsies, 21 of 29 patients with Parkinson's disease had Lewy neurites in the submucosal plexus, which correlated with declining neuron numbers, L-Dopa unresponsiveness, and constipation . Lewy neurites were absent in healthy controls. Mechanisms contributing to constipation in Parkinson's disease include slow colonic transit (which may be worsened by anticholinergic drugs, but probably not L-Dopa) and obstructed defaecation because of a focal form of dystonia . Osmotic laxatives are the mainstay of treatment.
Although gut function is generally well preserved with healthy ageing, loss of cholinergic neurons and ICCs are evident in humans throughout adult life, particularly in the distal gut. Older individuals may, therefore, have less functional reserve and are prone to disordered gut function with comorbid illnesses. Constipation and faecal incontinence are particular problems associated with ageing, whereas disordered gut function often represents an early manifestation of Parkinson's disease.
The authors’ research work in this area has been funded by the National Health and Medical Research Council of Australia.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 111).
1. Pilotto A, Maggi S, Noale M, et al. Association of upper gastrointestinal symptoms with functional and clinical charateristics in elderly. World J Gastroenterol 2011; 17:3020–3026.
2. Bitar K, Greenwood-Van Meerveld B, Saad R, Wiley JW. Aging and gastrointestinal neuromuscular function: insights from within and outside the gut. Neurogastroenterol Motil 2011; 23:490–501.
3. Wiskur B, Greenwood-Van Meerveld B. The aging colon: the role of enteric neurodegeneration in constipation. Curr Gastroenterol Rep 2010; 12:507–512.
4. Hoyle CH, Saffrey MJ. Effects of aging on cholinergic neuromuscular transmission in isolated small intestine of ad libitum fed and calorically-restricted rats. Neurogastroenterol Motil 2012; 24:586–592.
5. Robson LG, Dyall S, Sidloff D, Michael-Titus AT. Omega-3 polyunsaturated fatty acids increase the neurite outgrowth of rat sensory neurones throughout development and in aged animals. Neurobiol Aging 2010; 31:678–687.
6. Asuzu DT, Hayashi Y, Izbeki F, et al. Generalized neuromuscular hypoplasia, reduced smooth muscle myosin and altered gut motility in the klotho model of premature aging. Neurogastroenterol Motil 2011; 23:e309–e323.
7. Bernard CE, Gibbons SJ, Gomez-Pinilla PJ, et al. Effect of age on the enteric nervous system of the human colon. Neurogastroenterol Motil 2009; 21:746–e46.
8▪▪. Gomez-Pinilla PJ, Gibbons SJ, Sarr MG, et al. Changes in interstitial cells of cajal with age in the human stomach and colon. Neurogastroenterol Motil 2011; 23:36–44.
This is the first systematic study of ICC loss with ageing and has implications for impaired control of gut function as age increases.
9. Malandraki GA, Sutton BP, Perlman AL, Karampinos DC. Age-related differences in laterality of cortical activations in swallowing. Dysphagia 2010; 25:238–249.
10. Australian and New Zealand Society for Geriatric Medicine. Position statement – dysphagia and aspiration in older people. Australas J Ageing 2011; 30:98–103.
11. Rofes L, Arreola V, Romea M, et al. Pathophysiology of oropharyngeal dysphagia in the frail elderly. Neurogastroenterol Motil 2010; 22:851–858.e230.
12. Besanko LK, Burgstad CM, Mountifield R, et al. Lower esophageal sphincter relaxation is impaired in older patients with dysphagia. World J Gastroenterol 2011; 17:1326–1331.
13. Schechter RB, Lemme EM, Novais P, Biccas B. Achalasia in the elderly patient: a comparative study. Arq Gastroenterol 2011; 48:19–23.
14. Jung KW, Jung HY, Yoon IJ, et al. Basal and residual lower esophageal pressures increase in old age in classic achalasia, but not vigorous achalasia. J Gastroenterol Hepatol 2010; 25:1452–1455.
15. Craft RO, Aguilar BE, Flahive C, et al. Outcomes of minimally invasive myotomy for the treatment of achalasia in the elderly. JSLS 2010; 14:342–347.
16. Moore KL, Boscardin WJ, Steinman MA, Schwartz JB. Age and sex variation in prevalence of chronic medical conditions in older residents of U.S. nursing homes. J Am Geriatr Soc 2012; 60:756–764.
17. Poh CH, Navarro-Rodriguez T, Fass R. Review: treatment of gastroesophageal reflux disease in the elderly. Am J Med 2010; 123:496–501.
18. Scholl S, Dellon ES, Shaheen NJ. Treatment of GERD and proton pump inhibitor use in the elderly: practical approaches and frequently asked questions. Am J Gastroenterol 2011; 106:386–392.
19. Becher A, Dent J. Systematic review: ageing and gastro-oesophageal reflux disease symptoms, oesophageal function and reflux oesophagitis. Aliment Pharmacol Ther 2011; 33:442–454.
20. Zuchelli T, Myers SE. Gastrointestinal issues in the older female patient. Gastroenterol Clin North Am 2011; 40:449–466.x.
21. Imagama S, Hasegawa Y, Wakao N, et al.
Influence of lumbar kyphosis and back muscle strength on the symptoms of gastroesophageal reflux disease in middle-aged and elderly people. Eur Spine J (in press).
22. Hershcovici T, Mashimo H, Fass R. The lower esophageal sphincter. Neurogastroenterol Motil 2011; 23:819–830.
23. Chen CL, Yi CH, Liu TT, Orr WC. Altered sensorimotor responses to esophageal acidification in older adults with GERD. Scand J Gastroenterol 2010; 45:1150–1155.
24. Furuta K, Kushiyama Y, Kawashima K, et al. Comparisons of symptoms reported by elderly and nonelderly patients with GERD. J Gastroenterol 2012; 47:144–149.
25. Kang JM, Kim N, Kim JH, et al. Effect of aging on gastric mucosal defense mechanisms: ROS, apoptosis, angiogenesis, and sensory neurons. Am J Physiol Gastrointest Liver Physiol 2010; 299:G1147–G1153.
26. Gururatsakul M, Holloway RH, Adam B, et al. The ageing gut: diminished symptom response to a standardized nutrient stimulus. Neurogastroenterol Motil 2010; 22:e246–e277.
27. Luciano GL, Brennan MJ, Rothberg MB. Postprandial hypotension. Am J Med 2010; 123:281e281–e286.
28. Vanis L, Gentilcore D, Rayner CK, et al. Effects of small intestinal glucose load on blood pressure, splanchnic blood flow, glycemia, and GLP-1 release in healthy older subjects. Am J Physiol Regul Integr Comp Physiol 2011; 300:R1524–R1531.
29. Vanis L, Gentilcore D, Hausken T, et al. Effects of gastric distension on blood pressure and superior mesenteric artery blood flow responses to intraduodenal glucose in healthy older subjects. Am J Physiol Regul Integr Comp Physiol 2010; 299:R960–R967.
30. Vanis L, Gentilcore D, Lange K, et al. Effects of variations in intragastric volume on blood pressure and splanchnic blood flow during intraduodenal glucose infusion in healthy older subjects. Am J Physiol Regul Integr Comp Physiol 2012; 302:R391–R399.
31. Kuo P, Rayner CK, Horowitz M. Gastric emptying, diabetes and aging. Clin Geriatr Med 2007; 23:785–808.vi.
32. Trahair LG, Horowitz M, Rayner CK, et al. Comparative effects of variations in duodenal glucose load on glycemic, insulinemic, and incretin responses in healthy young and older subjects. J Clin Endocrinol Metab 2012; 97:844–851.
33. Rao SS, Go JT. Update on the management of constipation in the elderly: new treatment options. Clin Interv Aging 2010; 5:163–171.
34. Schnelle JF, Leung FW, Rao SS, et al. A controlled trial of an intervention to improve urinary and fecal incontinence and constipation. J Am Geriatr Soc 2010; 58:1504–1511.
35. Camilleri M, Beyens G, Kerstens R, et al. Safety assessment of prucalopride in elderly patients with constipation: a double-blind, placebo-controlled study. Neurogastroenterol Motil 2009; 21:1256–e117.
36. AlAmeel T, Andrew MK, MacKnight C. The association of fecal incontinence with institutionalization and mortality in older adults. Am J Gastroenterol 2010; 105:1830–1834.
37. Kang HW, Jung HK, Kwon KJ, et al. Prevalence and predictive factors of fecal incontinence. J Neurogastroenterol Motil 2012; 18:86–93.
38. Markland AD, Goode PS, Burgio KL, et al. Incidence and risk factors for fecal incontinence in black and white older adults: a population-based study. J Am Geriatr Soc 2010; 58:1341–1346.
39. Eogan M, O’Brien C, Daly L, et al. The dual influences of age and obstetric history on fecal continence in parous women. Int J Gynaecol Obstet 2011; 112:93–97.
40. Griebling TL. Sacral nerve stimulation in the elderly. Int Urogynecol J 2010; 21 (Suppl. 2):S485–S489.
41. Jost WH. Gastrointestinal dysfunction in Parkinson's disease. J Neurol Sci 2010; 289:69–73.
42. Leow LP, Huckabee ML, Anderson T, Beckert L. The impact of dysphagia on quality of life in ageing and Parkinson's disease as measured by the swallowing quality of life (SWAL-QOL) questionnaire. Dysphagia 2010; 25:216–220.
43. Leow LP, Beckert L, Anderson T, Huckabee ML. Changes in chemosensitivity and mechanosensitivity in aging and Parkinson's disease. Dysphagia 2012; 27:106–114.
44. Heetun ZS, Quigley EM. Gastroparesis and Parkinson's disease: a systematic review. Parkinsonism Relat Disord 2012; 18:433–440.
45▪. Tanaka Y, Kato T, Nishida H, et al. Is there a delayed gastric emptying of patients with early-stage, untreated Parkinson's disease? An analysis using the 13
C-acetate breath test. J Neurol 2011; 258:421–426.
This study indicates that delayed gastric emptying occurs early in Parkinson's disease, unrelated to L-Dopa therapy.
46. Ross GW, Abbott RD, Petrovitch H, et al. Premotor features of Parkinson's disease: the Honolulu-Asia Aging Study experience. Parkinsonism Relat Disord 2012; 18 (Suppl. 1):S199–S202.
47. Lebouvier T, Neunlist M, Bruley des Varannes S, et al. Colonic biopsies to assess the neuropathology of Parkinson's disease and its relationship with symptoms. PLoS One 2010; 5:e12728.