Mukherjee A, Biswas A, Das SK. Gut dysfunction in Parkinson's disease. World J Gastroenterol 2016; 22(25): 5742-5752
Corresponding Author of This Article
Shyamal Kumar Das, MD, DM, Professor, Head, Department of Neurology, Bangur Institute of Neurosciences and Institute of Post Graduate Medical Education and Research, 52/1A Sambhu Nath Pandit Street, Kolkata, West Bengal 700025, India. email@example.com
Checklist of Responsibilities for the Scientific Editor of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Adreesh Mukherjee, Atanu Biswas, Shyamal Kumar Das
Adreesh Mukherjee, Atanu Biswas, Shyamal Kumar Das, Department of Neurology, Bangur Institute of Neurosciences and Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal 700025, India
ORCID number: $[AuthorORCIDs]
Author contributions: All authors equally contributed to this paper with conception and design of the study, literature review and analysis, drafting and critical revision and editing, and final approval of the final version.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Shyamal Kumar Das, MD, DM, Professor, Head, Department of Neurology, Bangur Institute of Neurosciences and Institute of Post Graduate Medical Education and Research, 52/1A Sambhu Nath Pandit Street, Kolkata, West Bengal 700025, India. firstname.lastname@example.org
Telephone: +91-33-22230003 Fax: +91-33-22236677
Received: March 27, 2016 Peer-review started: March 28, 2016 First decision: May 12, 2016 Revised: May 30, 2016 Accepted: June 15, 2016 Article in press: June 15, 2016 Published online: July 7, 2016
Early involvement of gut is observed in Parkinson’s disease (PD) and symptoms such as constipation may precede motor symptoms. α-Synuclein pathology is extensively evident in the gut and appears to follow a rostrocaudal gradient. The gut may act as the starting point of PD pathology with spread toward the central nervous system. This spread of the synuclein pathology raises the possibility of prion-like propagation in PD pathogenesis. Recently, the role of gut microbiota in PD pathogenesis has received attention and some phenotypic correlation has also been shown. The extensive involvement of the gut in PD even in its early stages has led to the evaluation of enteric α-synuclein as a possible biomarker of early PD. The clinical manifestations of gastrointestinal dysfunction in PD include malnutrition, oral and dental disorders, sialorrhea, dysphagia, gastroparesis, constipation, and defecatory dysfunction. These conditions are quite distressing for the patients and require relevant investigations and adequate management. Treatment usually involves both pharmacological and non-pharmacological measures. One important aspect of gut dysfunction is its contribution to the clinical fluctuations in PD. Dysphagia and gastroparesis lead to inadequate absorption of oral anti-PD medications. These lead to response fluctuations, particularly delayed-on and no-on, and there is significant relationship between levodopa pharmacokinetics and gastric emptying in patients with PD. Therefore, in such cases, alternative routes of administration or drug delivery systems may be required.
Core tip: Gut is involved in early Parkinson’s disease (PD) with extensive synuclein pathology, following a rostrocaudal gradient along the gastrointestinal system. It may act as the starting point of PD pathology with prion-like spread toward the central nervous system. The clinical manifestations include malnutrition, oral and dental disorders, sialorrhea, dysphagia, gastroparesis, constipation, and defecatory dysfunction. These are distressing for the patients and need to be managed properly by pharmacological or non-pharmacological measures. Gut dysfunction also leads to response fluctuations in PD and this may require alternative routes of administration or drug delivery systems for anti-PD medications.
Citation: Mukherjee A, Biswas A, Das SK. Gut dysfunction in Parkinson's disease. World J Gastroenterol 2016; 22(25): 5742-5752
Parkinson’s disease (PD) is a common neurodegenerative disorder affecting people across the globe. It is clinically defined by its motor features such as bradykinesia, rigidity, rest tremor, and postural impairment. However, “non-motor” features of PD play a vital role in the disease process, and recently this has gained increasing significance, clinically as well as from the etiopathogenesis point of view. Non-motor manifestations such as loss of sense of smell and taste, rapid eye movement sleep behavior disorder, and clinical evidence of autonomic dysfunction can predate motor features by years and sometimes can dominate the clinical picture.
Gastrointestinal (GI) or gut dysfunction in PD can be because of both motor and non-motor (dysautonomic) impairment. A better description of gut dysfunction in PD is available, and it is now established that GI disturbances are common and affect virtually all levels of the GI system. Although initially considered to be late manifestations of PD, GI disturbances are present early in the course of the disease in relatively high frequency. The gut dysfunction includes drooling, dental problems, diminished taste, swallowing disorders, impaired gastric emptying, weight loss, and constipation. Other than clinical gut manifestations, the GI system is a significant contributor to the pathogenesis of PD and gut may even act as route for the spread of pathology to the central nervous system (CNS). Moreover, early involvement of gut is considered a possible presymptomatic stage of PD.
In this review, we aim to discuss gut dysfunction in PD including the role of gut synuclein as biomarker for early PD. We also summarize various GI manifestations along with their management.
GUT PATHOLOGY IN PD
PD is classified as synucleinopathy. It is pathologically characterized by the presence of Lewy neurites and Lewy bodies in the brain, which are abnormal inclusions consisting of nearly insoluble aggregates within cellular processes and somata of involved neurons. These are chiefly made of α-synuclein along with ubiquitin and phosphorylated neurofilaments. Until now, postmortem detection of α-synuclein aggregation in brain by immunohistochemistry along with neuronal loss in substantia nigra is considered gold standard for definite diagnosis of PD. For pathological diagnosis of PD in early stages, alternative approaches are studied including identification of Lewy bodies and α-synuclein in extra-CNS locations , and the gut appears to be a promising area because of its accessibility.
Distribution of gut pathology
Distribution of α-synuclein pathology in gut in relation to its nature, appearance, staining properties, and distribution along the GI system has been documented (Table 1). A rostrocaudal gradient of α-synuclein associated histopathology within GI system is likely. Earlier studies showed characteristic inclusions that were histologically and ultrastructurally identical to Lewy bodies in Auerbach’s and Meissner’s plexuses, which were abundant in the lower esophagus. Another study confirmed the highest involvement in lower esophagus and submandibular gland followed by stomach and small intestine, whereas colon and rectum had the lowest involvement. This rostrocaudal gradient along enteric nervous system (ENS) coincides with the distribution of vagal innervation from dorsal motor nucleus of vagus (DMV). However, this gradient is not unequivocally evident in all studies. Interestingly, a recent study on patients with no history of neurological disease showed vermiform appendix enriched in α-synuclein in its mucosal plexus. The authors concluded that appendix may be used as candidate anatomical locus for the initiation of enteric α-synuclein aggregation.
Helicobacter pylori and small intestinal bacterial overgrowth
Clinical phenotypic correlation
Spreading from the gut?
As the pathological involvement of gut is unfolding, a hypothesis that gut/ENS may act as initiation point of PD pathology or route to centripetal involvement of CNS has gained importance. Braak et al suggested that pathology may be caused by a pathogen that can penetrate the mucosal barrier of the GI tract and, via postganglionic enteric neurons, reaches the CNS along preganglionic fibers derived from the vagus by retrograde axonal and transneuronal transport, thus reaching selectively vulnerable subcortical nuclei.
In addition, a dual-hit hypothesis is proposed, which suggests that a neurotropic pathogen, probably viral, enters the brain via two routes-nasal and gastric-following swallowing of nasal secretions in saliva. These secretions might contain a neurotropic pathogen that penetrates the epithelial lining and reaches preganglionic parasympathetic motor neurons of the vagus nerve by transsynaptic transmission through axons of Meissner’s plexus. This would allow retrograde transport into the medulla, followed by caudo-rostral propagation to substantia nigra. The early involvement of ENS has also been demonstrated in an animal study, which concluded that ENS abnormalities preceded CNS changes.
This hypothesis of spread of synuclein pathology across various sections of nervous system has suggested another aspect of PD pathogenesis, that is, the possibility of prion-like propagation. This is based on two recent reports showing Lewy bodies in grafted neurons in subjects with PD suggesting probable spread of α-synuclein aggregates from host to graft neurons[15,16]. Studies on animal models of PD have shown that intracerebral injection of exogenous α-synuclein induces a progressive α-synuclein immunoreactive staining pattern suggestive of α-synuclein pathology propagation via a prion-like process.
Role of gut microbiota
Furthermore, the emerging role of gut microbiota adds to the contribution of GI system in PD. Microbiota may interact with gut-brain axis through different mechanisms, most importantly via modulation of intestinal barrier. In PD, gut microbiota changes associated with intestinal inflammation may contribute to α-synuclein misfolding. Moreover, priming of the innate immune system by gut microbiota may enhance the inflammatory response to α-synuclein. The role of peripherally-induced inflammation inflicting damage on dopaminergic neurons has also been studied in animals. The role of Helicobacter pylori (H. pylori) in PD has been investigated. A Cochrane review concluded that there is limited evidence to suggest that H. pylori eradication improves absorption of levodopa and consequently motor symptoms. However, a recent study showed that H. pylori infection is linked with worse motor severity of PD. The study investigating the contribution of small intestinal bacterial overgrowth (SIBO) to pathophysiology of motor fluctuations in PD showed that SIBO eradication resulted in improved motor fluctuations without affecting pharmacokinetics of levodopa. Recently, a study explored the relation of gut microbiota with clinical phenotype of PD and compared fecal microbiomes of patients with PD with control subjects and showed a reduction of Prevotellaceae in PD. Moreover, the relative abundance of Enterobacteriaceae was positively related with the severity of postural instability and gait difficulty. These findings offer some insight into the possible effect of gut microbiota on PD.
Enteric α-synuclein as a biomarker of early PD
Because of extensive involvement of the GI tract and its easy accessibility, there is growing interest to utilize enteric α-synuclein as a possible biomarker of early PD. However, some reports were critical about gut biopsy utilization. A study showed that there was no neuronal loss in myenteric plexus in PD and that Lewy body pathology parallels parasympathetic autonomic input from DMV. Pathologic species or strain of α-synuclein, considered to be responsible for PD pathology, have been detected using immunoreactive staining of α-synuclein, and future studies should concentrate on α-synuclein immunoreactivity for identifying these specific species. However, although studies have utilized antibodies reactive for phosphorylated α-synuclein as a marker of pathologic α-synuclein in the GI tract, α-synuclein phosphorylation may be a normal event in adult human brain. Based on recent evidence that soluble, oligomeric aggregates of α-synuclein may ultimately be pathogenic, it was suggested that antibodies reactive to oligomeric forms of α-synuclein could improve specificity and sensitivity for pathological staining in the GI tract. The other concern about gut sampling is the appropriate site for biopsy. Although colonic biopsy shows positive results, a recent evaluation of the procedure has questioned its applicability in the current form. Another recent study on colonic mucosal biopsy showed elevated levels of aggregated hyperphosphorylated α-synuclein in both PD and control subjects and suggested that the colonic deposition of α-synuclein cannot be a useful diagnostic test for PD. One option may be to use vagally innervated segments of the GI tract for biopsy. Conversely, biopsy of submandibular salivary glands appears to be useful. These glands have high intensity of PD pathology, and their feasibility and applicability have been demonstrated[28,29]. Thus, further studies for evaluating the role of enteric α-synuclein as a biomarker for PD should be conducted, including search for optimal biopsy site as well as methods of tissue sampling/preparation and possible pathological α-synuclein targets.
CLINICAL MANIFESTATIONS OF GI DYSFUNCTION
PD is associated with weight alteration, which maybe either loss or gain of weight. Unintended weight loss is common and correlates with worsened quality of life (QOL). Malnourishment in PD is linked to reduced food intake because of loss of appetite and GI dysfunction such as dysphagia, constipation, and early satiety. It is associated with increased severity and duration of disease, psychiatric symptoms such as depression or anxiety, and fatigue[30,33,34]. The decreased body mass index during initial 6 mo of follow-up in PD was an indicator for future risk of dementia. Increasing levodopa dosages were associated with the risk of malnutrition. Micronutrient deficiencies, particularly vitamin D deficiency/insufficiency are common in PD and these may be related to malnutrition, immobility, and sunlight deprivation. Patients with PD may have low bone mineral density and osteoporosis. Levodopa therapy causes vitamin B12 and folic acid deficiency with hyperhomocysteinemia and may contribute to osteoporosis. Increasing evidence suggests that impaired insulin signaling and mitochondrial dysfunction lead to neurodegeneration, and these processes might also contribute to weight loss in PD.
Recent studies have shown that PD may be associated with weight gain[39,40]. Moreover, compulsive eating and weight gain have been related to dopamine agonist use. Also deep brain stimulation (DBS) of subthalamic nucleus (STN) has been associated with post-operative weight gain.
Malnutrition in PD needs early intervention and patients should be advised regarding lifestyle changes, exercise, and dietary supplementation. Adverse effects of dopaminergic therapy must also be considered. Bisphosphonates, supplementation of vitamin D and calcium is useful in osteoporosis in PD.
Oral and dental disorders
Patients with PD have poor oral hygiene. They have fewer remaining teeth, more caries, gingival recession, and increased tooth mobility. The poor oral health may be because of lower frequencies of tooth brushing, motor impairment, apathy, depression, and cognitive impairment[43,44]. There are reports of PD being associated with bruxism, temporomandibular disorders, and subjective taste impairment. Burning mouth syndrome is more common in PD and this could be because of decreased dopamine levels and dopamine dysregulation. A patient was found to develop burning mouth syndrome with carbidopa/levodopa, which improved when this was replaced with pramipexole.
Drooling is an important component of PD, which leads to worse QOL and significant social and emotional consequences[47,48]. Its frequency varies from 10% to 84% probably because of lack of standard definition and criteria for diagnosing drooling. Drooling in PD has been linked to dysphagia with less efficient swallowing[50-52] rather than increased salivary production (Table 2). Studies have reported decrease in salivary production in PD. Drooling was correlated with unintentional mouth opening because of hypomimia, abnormal head posture, and dysarthria. Other features associated with drooling are longer disease duration, disease severity, dementia, hallucinations,orthostatic hypotension, and a history of using antidepressants.
Drooling increases the risk of silent aspiration and laryngeal penetration of saliva in patients with PD, therefore, this must be addressed in all affected patients. Its treatment consists of pharmacological and non-pharmacological measures. Glycopyrrolate is effective in reducing sialorrhea in patients with PD. Studies have demonstrated benefit from anticholinergics used as topical preparations with less systemic adverse effects. These include sublingual ipratropium bromide spray and intra-oral tropicamide films. Another effective and safe option is the use of ultrasound-guided intra-salivary gland injection of botulinum neurotoxin (both botulinum toxin A and B)[62,63]. The non-pharmacological approaches include chewing gum and behavioral modification. Radiotherapy is effective in the treatment of sialorrhea and it can be used in cases refractory to medical therapy[64,65].
Dysphagia is an important component of PD, which adversely affects QOL. As shown by a meta-analysis, patients are less likely to voluntarily complain about dysphagia, which revealed a pooled frequency estimate of 35% for subjective dysphagia and of 82% for objectively measured dysphagia. Dysphagia in PD may be due to dysfunction of oral, pharyngeal, and esophageal phases of swallowing. Several abnormalities have been described and oropharyngeal bradykinesia and incoordination plays an important role in PD. However, contributors to pathophysiology of dysphagia are much widespread. Recent studies have shown the involvement of cortical areas in dysphagia[70,71]. The role of central cholinergic dysfunction in dysphagia has also been suggested. Pathology has also been demonstrated in pharyngeal motor and sensory nerves[73,74]. Dysphagia has been associated with male gender, older age, longer disease duration, dementia, depression, and severity of motor symptoms[75-77]. Although dysphagia is considered to arise in later parts of the disease, it is present in early stages of PD, particularly when a multimodal approach is used for its assessment[78,79]. This can be evaluated by bedside screening such as swallow trial, videofluoroscopy of swallowing act, fiberoptic endoscopic evaluation of swallowing, manometry, modified barium swallow studies, and cough reflex testing (Table 3)[80-83].
Besides causing difficulty in ingesting food and medicine, dysphagia in PD with prolonged swallowing time is associated with the risk of aspiration pneumonia[84,85]. Therefore, dysphagia needs to be diagnosed and treated early. Treatment options include compensatory maneuvers such as thickening liquids to nectar or honey consistency, chin-tuck maneuver, frequency/multiple swallowing technique, and rehabilitation maneuvers such as exercises of tongue strengthening and control along with vocal exercises. Logopedic dysphagia treatment by an experienced speech therapist consists of oral motor exercises, airway-protecting maneuvers, and postural compensation. Other options such as expiratory muscle strength training and video-assisted swallowing therapy may be effective. Percutaneous endoscopic gastrostomy placement may be rarely needed in severe dysphagia. Role of levodopa in improving dysphagia has been found conflicting[89,90]. A recent study showed that rotigotine transdermal patch improved swallowing in PD patients with dysphagia. Effect of DBS on dysphagia in PD remains debatable. However, unilateral STN-DBS appears to have adverse effect on the swallowing function in contrast to unilateral globus pallidus internus DBS.
Gastroparesis is quite common in PD, observed in about 70%-100% of subjects and may be present in both early and advanced stages of the disease[94-96]. The severity of motor impairment is correlated with gastroparesis in PD. The symptoms of delayed gastric emptying include nausea, vomiting, early satiety, and postprandial fullness, and can lead to weight loss, malnutrition and dehydration. Delayed gastric emptying is defined as > 60% retention at 2 h postprandially and/or > 10% retention at 4 h, using 4-h imaging protocol after ingestion of a radioactive technetium Tc 99m-labeled solid food. Alternatively, breath tests using nonradioactive 13C-sodium octanoate bound into solid meal may be employed for evaluating gastric emptying. Other methods used to assess gastric motility in PD are real time visualization by magnetic resonance imaging and electrogastrography.
A major impact of gastroparesis on PD is the occurrence of response fluctuations, particularly delayed-on (delay in onset of “on-phase”) to no-on (without “on-phase”) with levodopa, and significant relationship were indicated between levodopa pharmacokinetics and gastric emptying[102,103]. In contrast, it has been suggested that levodopa itself can lead to the development of delayed gastric emptying. Therefore, management of gastroparesis is essential. Other than dietary changes and exercise, one may use pharmacotherapy using domperidone. Although domperidone is useful in treating gastroparesis without interference with antiparkinsonism treatment, concerns have been raised about its arrhythmogenic potential with risk of long QT syndrome. Recent studies have shown improvement of gastroparesis with Nizatidine, and the role of ghrelin agonist needs further evaluation. Moreover, low levels of vitamin D has been suggested to contribute to gastric dysmotility in PD, but this finding needs further corroboration. Benefits from botulinum neurotoxin injection in the pyloric sphincter and STN-DBS have been reported. In refractory cases, gastric electrical stimulation may be attempted (Table 4).
Botulinum neurotoxin injection into the pyloric sphincter
Gastric electrical stimulation
STN: Subthalamic nucleus; DBS: Deep brain stimulation.
To circumvent levodopa pharmacokinetic derangements associated with gastroparesis, several options have been studied. These include orally dissolving or soluble formulations[112,113]. Levodopa-carbidopa intestinal gel, subcutaneous apomorphine, and rotigotine patch are beneficial in gastroparesis as well as severe dysphagia[114,115]. STN-DBS is a useful surgical option.
H. pylori infection and small intestinal bacterial overgrowth
The other aspect of gastric involvement in motor fluctuations is the putative role of H. pylori. Investigations for H. pylori infection include serology, urea breath test, and stool antigen test. There are mixed views on effect of H. pylori infection; however, recent studies show that H. pylori infection is associated with worse motor severity of PD. Therefore, H. pylori eradication preferably using a combination regimen is indicated. Similarly, the role of SIBO has been evaluated. SIBO is diagnosed by culture of intestinal aspirates, or more practically, by hydrogen lactulose, and glucose breath tests. Treatment for SIBO in PD is indicated as recent studies show improvement in motor fluctuations following eradication of SIBO.
Constipation and defecatory dysfunction
Constipation is probably the commonest GI manifestation in PD and is present in more than 50% of the cases. It is approximately two to four times commoner in patients with PD than in controls. Constipation and defecatory dysfunction is found in early stages of PD, and in fact, studies have shown that constipation can predate motor symptoms of PD by even 20 years. Thus, constipation is one of the earliest manifestations of PD. Interestingly, studies have shown increased occurrence of future PD in persons with constipation, which may be in a dose-dependent manner[122,123].
One mechanism is prolonged colon transit time. Another dysfunction is defecatory pelvic floor dyssynergia or functional pelvic outlet obstruction by paradoxical contraction of striated anal sphincter muscles during straining for defecation, which is considered dystonia in some studies[120,125]. Constipation is a known adverse effect of drugs used in PD, such as anticholinergics and dopaminergic agents; however, intrinsic disease pathophysiology may be responsible for it. The use of beta-blockers in PD is associated with lower risk of constipation, whereas dopaminergic treatments tend to increase it. Conversely, levodopa improves paradoxical sphincter contraction and anorectal constipation in patients with PD supporting the presence of more than one mechanism for constipation in PD. Likewise, symptoms include infrequent bowel movements, unsuccessful attempts at defecation, and a sense of incomplete rectal emptying at defecation.
In general, evaluation of chronic constipation usually comprises clinical assessment by digital anorectal examination followed by relevant investigations (Table 5). Colonic transit is evaluated by radiopaque markers, scintigraphy, or wireless motility capsule, and defecatory disorder is assessed by anorectal manometry, rectal balloon expulsion, or defecography. In patients with PD, mostly colon transit time and manometry are utilized. Additionally, electromyography of external anal sphincter has been used to demonstrate neurogenic changes. The treatment starts with high fiber diet, proper fluid intake, psyllium, and physiotherapy. However, many patients require additional treatment. The effective options for slow transit constipation in PD are Macrogol and lubiprostone; Nizatidine was also effective (Table 5)[131-133]. Other drugs such as prucalopride needs to be considered in PD. Treatment for dyssynergic defecation include biofeedback therapy and levodopa or apomorphine injections[134,135]. Botulinum neurotoxin type A injection into puborectalis muscle under ultrasonographic guidance is useful for dyssynergic outlet-obstruction constipation[134,136].
2Lubiprostone-chloride channel activator (increases fluid secretion in the intestine).
Apart from constipation and defecatory dysfunction, existence of fecal incontinence in PD has been described and its frequency may be significant.
In PD, gut is affected early and extensively. It appears to participate in pathogenesis of the disease. Further studies are required to understand whether it indeed acts as an initiation point in PD pathology and if so, its mechanism of involvement including the role of gut microbiota. To establish the potential role of enteric α-synuclein as a biomarker of early PD, studies are needed with adequate reproducibility regarding optimal sampling site and technique and appropriate pathogenic targets. The GI manifestations in PD are distressing for patients with significant morbidity and complications. Therefore, these should be identified promptly and treated. This requires the clinician to pay due attention to these symptoms during the evaluation of PD patient. The management of these conditions may be tricky as it includes not only symptomatic treatment but also optimization of anti-Parkinsonian drugs, particularly anticholinergics and dopaminergic agents. Studies on novel therapeutic agents and non-pharmacotherapeutic interventions would be helpful. Moreover, newer dopaminergic drug delivery systems should be studied to circumvent dysfunctional gut. The role of DBS in these conditions needs further evaluation.
Manuscript Source: Invited manuscript
Specialty Type: Gastroenterology and Hepatology
Country of Origin: India
Peer-Review Report Classification
Grade A (Excellent): A
Grade B (Very good): B
Grade C (Good): 0
Grade D (Fair): 0
Grade E (Poor): 0
P- Reviewer: Franceschi F, Garcia-Mena J S- Editor: Ma YJ L- Editor: A E- Editor: Wang CH
Kalia LV, Lang AE. Parkinson’s disease.Lancet. 2015;386:896-912.
Goldstein DS, Sewell L, Sharabi Y. Autonomic dysfunction in PD: a window to early detection?J Neurol Sci. 2011;310:118-122.
Sung HY, Park JW, Kim JS. The frequency and severity of gastrointestinal symptoms in patients with early Parkinson’s disease.J Mov Disord. 2014;7:7-12.
Del Tredici K, Rüb U, De Vos RA, Bohl JR, Braak H. Where does parkinson disease pathology begin in the brain?J Neuropathol Exp Neurol. 2002;61:413-426.
Ruffmann C, Parkkinen L. Gut Feelings About α-Synuclein in Gastrointestinal Biopsies: Biomarker in the Making?Mov Disord. 2016;31:193-202.
Wakabayashi K, Takahashi H, Takeda S, Ohama E, Ikuta F. Parkinson’s disease: the presence of Lewy bodies in Auerbach’s and Meissner’s plexuses.Acta Neuropathol. 1988;76:217-221.
Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White Iii CL, Akiyama H, Caviness JN, Shill HA, Sabbagh MN. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders.Acta Neuropathol. 2010;119:689-702.
Cersosimo MG, Benarroch EE. Pathological correlates of gastrointestinal dysfunction in Parkinson’s disease.Neurobiol Dis. 2012;46:559-564.
Hilton D, Stephens M, Kirk L, Edwards P, Potter R, Zajicek J, Broughton E, Hagan H, Carroll C. Accumulation of α-synuclein in the bowel of patients in the pre-clinical phase of Parkinson’s disease.Acta Neuropathol. 2014;127:235-241.
Gray MT, Munoz DG, Gray DA, Schlossmacher MG, Woulfe JM. Alpha-synuclein in the appendiceal mucosa of neurologically intact subjects.Mov Disord. 2014;29:991-998.
Braak H, Rüb U, Gai WP, Del Tredici K. Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen.J Neural Transm (Vienna). 2003;110:517-536.
Hawkes CH, Del Tredici K, Braak H. Parkinson’s disease: a dual-hit hypothesis.Neuropathol Appl Neurobiol. 2007;33:599-614.
Kuo YM, Li Z, Jiao Y, Gaborit N, Pani AK, Orrison BM, Bruneau BG, Giasson BI, Smeyne RJ, Gershon MD. Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated alpha-synuclein gene mutations precede central nervous system changes.Hum Mol Genet. 2010;19:1633-1650.
Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease.Nat Med. 2008;14:504-506.
Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Björklund A. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation.Nat Med. 2008;14:501-503.
Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems.Ann Gastroenterol. 2015;28:203-209.
Mulak A, Bonaz B. Brain-gut-microbiota axis in Parkinson’s disease.World J Gastroenterol. 2015;21:10609-10620.
Rees K, Stowe R, Patel S, Ives N, Breen K, Clarke CE, Ben-Shlomo Y. Helicobacter pylori eradication for Parkinson’s disease.Cochrane Database Syst Rev. 2011;CD008453.
Tan AH, Mahadeva S, Marras C, Thalha AM, Kiew CK, Yeat CM, Ng SW, Ang SP, Chow SK, Loke MF. Helicobacter pylori infection is associated with worse severity of Parkinson’s disease.Parkinsonism Relat Disord. 2015;21:221-225.
Fasano A, Bove F, Gabrielli M, Petracca M, Zocco MA, Ragazzoni E, Barbaro F, Piano C, Fortuna S, Tortora A. The role of small intestinal bacterial overgrowth in Parkinson’s disease.Mov Disord. 2013;28:1241-1249.
Scheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E, Haapaniemi E, Kaakkola S, Eerola-Rautio J, Pohja M. Gut microbiota are related to Parkinson’s disease and clinical phenotype.Mov Disord. 2015;30:350-358.
Annerino DM, Arshad S, Taylor GM, Adler CH, Beach TG, Greene JG. Parkinson’s disease is not associated with gastrointestinal myenteric ganglion neuron loss.Acta Neuropathol. 2012;124:665-680.
Lebouvier T, Chaumette T, Damier P, Coron E, Touchefeu Y, Vrignaud S, Naveilhan P, Galmiche JP, Bruley des Varannes S, Derkinderen P. Pathological lesions in colonic biopsies during Parkinson’s disease.Gut. 2008;57:1741-1743.
Muntané G, Ferrer I, Martinez-Vicente M. α-synuclein phosphorylation and truncation are normal events in the adult human brain.Neuroscience. 2012;200:106-119.
Visanji NP, Marras C, Hazrati LN, Liu LW, Lang AE. Alimentary, my dear Watson? The challenges of enteric α-synuclein as a Parkinson’s disease biomarker.Mov Disord. 2014;29:444-450.
Visanji NP, Marras C, Kern DS, Al Dakheel A, Gao A, Liu LW, Lang AE, Hazrati LN. Colonic mucosal a-synuclein lacks specificity as a biomarker for Parkinson disease.Neurology. 2015;84:609-616.
Beach TG, Adler CH, Dugger BN, Serrano G, Hidalgo J, Henry-Watson J, Shill HA, Sue LI, Sabbagh MN, Akiyama H; Arizona Parkinson’s Disease Consortium. Submandibular gland biopsy for the diagnosis of Parkinson disease.J Neuropathol Exp Neurol. 2013;72:130-136.
Adler CH, Dugger BN, Hinni ML, Lott DG, Driver-Dunckley E, Hidalgo J, Henry-Watson J, Serrano G, Sue LI, Nagel T. Submandibular gland needle biopsy for the diagnosis of Parkinson disease.Neurology. 2014;82:858-864.
van der Marck MA, Dicke HC, Uc EY, Kentin ZH, Borm GF, Bloem BR, Overeem S, Munneke M. Body mass index in Parkinson’s disease: a meta-analysis.Parkinsonism Relat Disord. 2012;18:263-267.
Akbar U, He Y, Dai Y, Hack N, Malaty I, McFarland NR, Hess C, Schmidt P, Wu S, Okun MS. Weight loss and impact on quality of life in Parkinson’s disease.PLoS One. 2015;10:e0124541.
Sheard JM, Ash S, Mellick GD, Silburn PA, Kerr GK. Malnutrition in a sample of community-dwelling people with Parkinson’s disease.PLoS One. 2013;8:e53290.
Fereshtehnejad SM, Ghazi L, Shafieesabet M, Shahidi GA, Delbari A, Lökk J. Motor, psychiatric and fatigue features associated with nutritional status and its effects on quality of life in Parkinson’s disease patients.PLoS One. 2014;9:e91153.
Pilhatsch M, Kroemer NB, Schneider C, Ebersbach G, Jost WH, Fuchs G, Odin P, Reifschneider G, Bauer M, Reichmann H. Reduced body mass index in Parkinson’s disease: contribution of comorbid depression.J Nerv Ment Dis. 2013;201:76-79.
Kim HJ, Oh ES, Lee JH, Moon JS, Oh JE, Shin JW, Lee KJ, Baek IC, Jeong SH, Song HJ. Relationship between changes of body mass index (BMI) and cognitive decline in Parkinson’s disease (PD).Arch Gerontol Geriatr. 2012;55:70-72.
Laudisio A, Vetrano DL, Meloni E, Ricciardi D, Franceschi F, Bentivoglio AR, Bernabei R, Zuccalà G. Dopaminergic agents and nutritional status in Parkinson’s disease.Mov Disord. 2014;29:1543-1547.
Lv Z, Qi H, Wang L, Fan X, Han F, Wang H, Bi S. Vitamin D status and Parkinson’s disease: a systematic review and meta-analysis.Neurol Sci. 2014;35:1723-1730.
van den Bos F, Speelman AD, Samson M, Munneke M, Bloem BR, Verhaar HJ. Parkinson’s disease and osteoporosis.Age Ageing. 2013;42:156-162.
Morales-Briceño H, Cervantes-Arriaga A, Rodríguez-Violante M, Calleja-Castillo J, Corona T. Overweight is more prevalent in patients with Parkinson’s disease.Arq Neuropsiquiatr. 2012;70:843-846.
Vikdahl M, Carlsson M, Linder J, Forsgren L, Håglin L. Weight gain and increased central obesity in the early phase of Parkinson’s disease.Clin Nutr. 2014;33:1132-1139.
Nirenberg MJ, Waters C. Compulsive eating and weight gain related to dopamine agonist use.Mov Disord. 2006;21:524-529.
Strowd RE, Herco M, Passmore-Griffin L, Avery B, Haq I, Tatter SB, Tate J, Siddiqui MS. Association between subthalamic nucleus deep brain stimulation and weight gain: Results of a case-control study.Clin Neurol Neurosurg. 2016;140:38-42.
Hanaoka A, Kashihara K. Increased frequencies of caries, periodontal disease and tooth loss in patients with Parkinson’s disease.J Clin Neurosci. 2009;16:1279-1282.
Müller T, Palluch R, Jackowski J. Caries and periodontal disease in patients with Parkinson’s disease.Spec Care Dentist. 2011;31:178-181.
Zlotnik Y, Balash Y, Korczyn AD, Giladi N, Gurevich T. Disorders of the oral cavity in Parkinson’s disease and parkinsonian syndromes.Parkinsons Dis. 2015;2015:379482.
Coon EA, Laughlin RS. Burning mouth syndrome in Parkinson’s disease: dopamine as cure or cause?J Headache Pain. 2012;13:255-257.
Leibner J, Ramjit A, Sedig L, Dai Y, Wu SS, Jacobson C, Okun MS, Rodriguez RL, Malaty IA, Fernandez HH. The impact of and the factors associated with drooling in Parkinson’s disease.Parkinsonism Relat Disord. 2010;16:475-477.
Kalf JG, Smit AM, Bloem BR, Zwarts MJ, Munneke M. Impact of drooling in Parkinson’s disease.J Neurol. 2007;254:1227-1232.
Srivanitchapoom P, Pandey S, Hallett M. Drooling in Parkinson’s disease: a review.Parkinsonism Relat Disord. 2014;20:1109-1118.
Nóbrega AC, Rodrigues B, Torres AC, Scarpel RD, Neves CA, Melo A. Is drooling secondary to a swallowing disorder in patients with Parkinson’s disease?Parkinsonism Relat Disord. 2008;14:243-245.
Nicaretta DH, Rosso AL, Mattos JP, Maliska C, Costa MM. Dysphagia and sialorrhea: the relationship to Parkinson’s disease.Arq Gastroenterol. 2013;50:42-49.
Kalf JG, Munneke M, van den Engel-Hoek L, de Swart BJ, Borm GF, Bloem BR, Zwarts MJ. Pathophysiology of diurnal drooling in Parkinson’s disease.Mov Disord. 2011;26:1670-1676.
Proulx M, de Courval FP, Wiseman MA, Panisset M. Salivary production in Parkinson’s disease.Mov Disord. 2005;20:204-207.
Ou R, Guo X, Wei Q, Cao B, Yang J, Song W, Shao N, Zhao B, Chen X, Shang H. Prevalence and clinical correlates of drooling in Parkinson disease: a study on 518 Chinese patients.Parkinsonism Relat Disord. 2015;21:211-215.
Kalf JG, Bloem BR, Munneke M. Diurnal and nocturnal drooling in Parkinson’s disease.J Neurol. 2012;259:119-123.
Ou R, Guo X, Wei Q, Cao B, Yang J, Song W, Chen K, Zhao B, Chen X, Shang H. Diurnal drooling in Chinese patients with Parkinson’s disease.J Neurol Sci. 2015;353:74-78.
Rana AQ, Khondker S, Kabir A, Owalia A, Khondker S, Emre M. Impact of cognitive dysfunction on drooling in Parkinson’s disease.Eur Neurol. 2013;70:42-45.
Rodrigues B, Nóbrega AC, Sampaio M, Argolo N, Melo A. Silent saliva aspiration in Parkinson’s disease.Mov Disord. 2011;26:138-141.
Arbouw ME, Movig KL, Koopmann M, Poels PJ, Guchelaar HJ, Egberts TC, Neef C, van Vugt JP. Glycopyrrolate for sialorrhea in Parkinson disease: a randomized, double-blind, crossover trial.Neurology. 2010;74:1203-1207.
Thomsen TR, Galpern WR, Asante A, Arenovich T, Fox SH. Ipratropium bromide spray as treatment for sialorrhea in Parkinson’s disease.Mov Disord. 2007;22:2268-2273.
Lloret SP, Nano G, Carrosella A, Gamzu E, Merello M. A double-blind, placebo-controlled, randomized, crossover pilot study of the safety and efficacy of multiple doses of intra-oral tropicamide films for the short-term relief of sialorrhea symptoms in Parkinson’s disease patients.J Neurol Sci. 2011;310:248-250.
Petracca M, Guidubaldi A, Ricciardi L, Ialongo T, Del Grande A, Mulas D, Di Stasio E, Bentivoglio AR. Botulinum Toxin A and B in sialorrhea: Long-term data and literature overview.Toxicon. 2015;107:129-140.
Egevad G, Petkova VY, Vilholm OJ. Sialorrhea in patients with Parkinson’s disease: safety and administration of botulinum neurotoxin.J Parkinsons Dis. 2014;4:321-326.
Postma AG, Heesters M, van Laar T. Radiotherapy to the salivary glands as treatment of sialorrhea in patients with parkinsonism.Mov Disord. 2007;22:2430-2435.
Hawkey NM, Zaorsky NG, Galloway TJ. The role of radiation therapy in the management of sialorrhea: A systematic review.Laryngoscope. 2016;126:80-85.
Carneiro D, das Graças Wanderley de Sales Coriolano M, Belo LR, de Marcos Rabelo AR, Asano AG, Lins OG. Quality of life related to swallowing in Parkinson’s disease.Dysphagia. 2014;29:578-582.
Kalf JG, de Swart BJ, Bloem BR, Munneke M. Prevalence of oropharyngeal dysphagia in Parkinson’s disease: a meta-analysis.Parkinsonism Relat Disord. 2012;18:311-315.
Suttrup I, Warnecke T. Dysphagia in Parkinson’s Disease.Dysphagia. 2016;31:24-32.
Kim YH, Oh BM, Jung IY, Lee JC, Lee GJ, Han TR. Spatiotemporal characteristics of swallowing in Parkinson’s disease.Laryngoscope. 2015;125:389-395.
Suntrup S, Teismann I, Bejer J, Suttrup I, Winkels M, Mehler D, Pantev C, Dziewas R, Warnecke T. Evidence for adaptive cortical changes in swallowing in Parkinson’s disease.Brain. 2013;136:726-738.
Kikuchi A, Baba T, Hasegawa T, Kobayashi M, Sugeno N, Konno M, Miura E, Hosokai Y, Ishioka T, Nishio Y. Hypometabolism in the supplementary and anterior cingulate cortices is related to dysphagia in Parkinson’s disease: a cross-sectional and 3-year longitudinal cohort study.BMJ Open. 2013;3.
Lee KD, Koo JH, Song SH, Jo KD, Lee MK, Jang W. Central cholinergic dysfunction could be associated with oropharyngeal dysphagia in early Parkinson’s disease.J Neural Transm (Vienna). 2015;122:1553-1561.
Mu L, Sobotka S, Chen J, Su H, Sanders I, Adler CH, Shill HA, Caviness JN, Samanta JE, Beach TG; Arizona Parkinson’s Disease Consortium. Alpha-synuclein pathology and axonal degeneration of the peripheral motor nerves innervating pharyngeal muscles in Parkinson disease.J Neuropathol Exp Neurol. 2013;72:119-129.
Mu L, Sobotka S, Chen J, Su H, Sanders I, Nyirenda T, Adler CH, Shill HA, Caviness JN, Samanta JE. Parkinson disease affects peripheral sensory nerves in the pharynx.J Neuropathol Exp Neurol. 2013;72:614-623.
Cereda E, Cilia R, Klersy C, Canesi M, Zecchinelli AL, Mariani CB, Tesei S, Sacilotto G, Meucci N, Zini M. Swallowing disturbances in Parkinson’s disease: a multivariate analysis of contributing factors.Parkinsonism Relat Disord. 2014;20:1382-1387.
Han M, Ohnishi H, Nonaka M, Yamauchi R, Hozuki T, Hayashi T, Saitoh M, Hisahara S, Imai T, Shimohama S. Relationship between dysphagia and depressive states in patients with Parkinson’s disease.Parkinsonism Relat Disord. 2011;17:437-439.
Kim JS, Youn J, Suh MK, Kim TE, Chin J, Park S, Cho JW. Cognitive and Motor Aspects of Parkinson’s Disease Associated with Dysphagia.Can J Neurol Sci. 2015;42:395-400.
Jones CA, Ciucci MR. Multimodal Swallowing Evaluation with High-Resolution Manometry Reveals Subtle Swallowing Changes in Early and Mid-Stage Parkinson Disease.J Parkinsons Dis. 2016;6:197-208.
Sung HY, Kim JS, Lee KS, Kim YI, Song IU, Chung SW, Yang DW, Cho YK, Park JM, Lee IS. The prevalence and patterns of pharyngoesophageal dysmotility in patients with early stage Parkinson’s disease.Mov Disord. 2010;25:2361-2368.
Speyer R. Oropharyngeal dysphagia: screening and assessment.Otolaryngol Clin North Am. 2013;46:989-1008.
Correa-Flores M, Arch-Tirado E, Villeda-Miranda A, Rocha-Cacho KE, Verduzco-Mendoza A, Hernández-López X. Analysis of oropharyngeal dysphagia through fibroendoscopy evaluation of swallowing in patients with Parkinson’s disease.Cir Cir. 2012;80:31-37.
Argolo N, Sampaio M, Pinho P, Melo A, Nóbrega AC. Videofluoroscopic Predictors of Penetration-Aspiration in Parkinson’s Disease Patients.Dysphagia. 2015;30:751-758.
Ellerston JK, Heller AC, Houtz DR, Kendall KA. Quantitative Measures of Swallowing Deficits in Patients With Parkinson’s Disease.Ann Otol Rhinol Laryngol. 2016;125:385-392.
Lin CW, Chang YC, Chen WS, Chang K, Chang HY, Wang TG. Prolonged swallowing time in dysphagic Parkinsonism patients with aspiration pneumonia.Arch Phys Med Rehabil. 2012;93:2080-2084.
Luchesi KF, Kitamura S, Mourão LF. Dysphagia progression and swallowing management in Parkinson’s disease: an observational study.Braz J Otorhinolaryngol. 2015;81:24-30.
Heijnen BJ, Speyer R, Baijens LW, Bogaardt HC. Neuromuscular electrical stimulation versus traditional therapy in patients with Parkinson’s disease and oropharyngeal dysphagia: effects on quality of life.Dysphagia. 2012;27:336-345.
van Hooren MR, Baijens LW, Voskuilen S, Oosterloo M, Kremer B. Treatment effects for dysphagia in Parkinson’s disease: a systematic review.Parkinsonism Relat Disord. 2014;20:800-807.
Melo A, Monteiro L. Swallowing improvement after levodopa treatment in idiopathic Parkinson’s disease: lack of evidence.Parkinsonism Relat Disord. 2013;19:279-281.
Sutton JP. Dysphagia in Parkinson’s disease is responsive to levodopa.Parkinsonism Relat Disord. 2013;19:282-284.
Hirano M, Isono C, Sakamoto H, Ueno S, Kusunoki S, Nakamura Y. Rotigotine Transdermal Patch Improves Swallowing in Dysphagic Patients with Parkinson’s Disease.Dysphagia. 2015;30:452-456.
Troche MS, Brandimore AE, Foote KD, Okun MS. Swallowing and deep brain stimulation in Parkinson’s disease: a systematic review.Parkinsonism Relat Disord. 2013;19:783-788.
Troche MS, Brandimore AE, Foote KD, Morishita T, Chen D, Hegland KW, Okun MS. Swallowing outcomes following unilateral STN vs. GPi surgery: a retrospective analysis.Dysphagia. 2014;29:425-431.
Tanaka Y, Kato T, Nishida H, Yamada M, Koumura A, Sakurai T, Hayashi Y, Kimura A, Hozumi I, Araki H. Is there a delayed gastric emptying of patients with early-stage, untreated Parkinson’s disease? An analysis using the 13C-acetate breath test.J Neurol. 2011;258:421-426.
Heetun ZS, Quigley EM. Gastroparesis and Parkinson’s disease: a systematic review.Parkinsonism Relat Disord. 2012;18:433-440.
Goetze O, Nikodem AB, Wiezcorek J, Banasch M, Przuntek H, Mueller T, Schmidt WE, Woitalla D. Predictors of gastric emptying in Parkinson’s disease.Neurogastroenterol Motil. 2006;18:369-375.
Pasricha PJ, Parkman HP. Gastroparesis: definitions and diagnosis.Gastroenterol Clin North Am. 2015;44:1-7.
Goetze O, Wieczorek J, Mueller T, Przuntek H, Schmidt WE, Woitalla D. Impaired gastric emptying of a solid test meal in patients with Parkinson’s disease using 13C-sodium octanoate breath test.Neurosci Lett. 2005;375:170-173.
Unger MM, Hattemer K, Möller JC, Schmittinger K, Mankel K, Eggert K, Strauch K, Tebbe JJ, Keil B, Oertel WH. Real-time visualization of altered gastric motility by magnetic resonance imaging in patients with Parkinson’s disease.Mov Disord. 2010;25:623-628.
Naftali T, Gadoth N, Huberman M, Novis B. Electrogastrography in patients with Parkinson’s disease.Can J Neurol Sci. 2005;32:82-86.
Müller T, Erdmann C, Bremen D, Schmidt WE, Muhlack S, Woitalla D, Goetze O. Impact of gastric emptying on levodopa pharmacokinetics in Parkinson disease patients.Clin Neuropharmacol. 2006;29:61-67.
Doi H, Sakakibara R, Sato M, Masaka T, Kishi M, Tateno A, Tateno F, Tsuyusaki Y, Takahashi O. Plasma levodopa peak delay and impaired gastric emptying in Parkinson’s disease.J Neurol Sci. 2012;319:86-88.
Soykan I, Sarosiek I, Shifflett J, Wooten GF, McCallum RW. Effect of chronic oral domperidone therapy on gastrointestinal symptoms and gastric emptying in patients with Parkinson’s disease.Mov Disord. 1997;12:952-957.
Rossi M, Giorgi G. Domperidone and long QT syndrome.Curr Drug Saf. 2010;5:257-262.
Doi H, Sakakibara R, Sato M, Hirai S, Masaka T, Kishi M, Tsuyusaki Y, Tateno A, Tateno F, Takahashi O. Nizatidine ameliorates gastroparesis in Parkinson’s disease: a pilot study.Mov Disord. 2014;29:562-566.
Karasawa H, Pietra C, Giuliano C, Garcia-Rubio S, Xu X, Yakabi S, Taché Y, Wang L. New ghrelin agonist, HM01 alleviates constipation and L-dopa-delayed gastric emptying in 6-hydroxydopamine rat model of Parkinson’s disease.Neurogastroenterol Motil. 2014;26:1771-1782.
Kwon KY, Jo KD, Lee MK, Oh M, Kim EN, Park J, Kim JS, Youn J, Oh E, Kim HT. Low Serum Vitamin D Levels May Contribute to Gastric Dysmotility in de novo Parkinson’s Disease.Neurodegener Dis. 2016;16:199-205.
Gil RA, Hwynn N, Fabian T, Joseph S, Fernandez HH. Botulinum toxin type A for the treatment of gastroparesis in Parkinson’s disease patients.Parkinsonism Relat Disord. 2011;17:285-287.
Arai E, Arai M, Uchiyama T, Higuchi Y, Aoyagi K, Yamanaka Y, Yamamoto T, Nagano O, Shiina A, Maruoka D. Subthalamic deep brain stimulation can improve gastric emptying in Parkinson’s disease.Brain. 2012;135:1478-1485.
Ondo WG, Shinawi L, Moore S. Comparison of orally dissolving carbidopa/levodopa (Parcopa) to conventional oral carbidopa/levodopa: A single-dose, double-blind, double-dummy, placebo-controlled, crossover trial.Mov Disord. 2010;25:2724-2727.
Stocchi F, Zappia M, Dall’Armi V, Kulisevsky J, Lamberti P, Obeso JA; Melevodopa Plus Carbidopa Study Group. Melevodopa/carbidopa effervescent formulation in the treatment of motor fluctuations in advanced Parkinson’s disease.Mov Disord. 2010;25:1881-1887.
Olanow CW, Kieburtz K, Odin P, Espay AJ, Standaert DG, Fernandez HH, Vanagunas A, Othman AA, Widnell KL, Robieson WZ. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson’s disease: a randomised, controlled, double-blind, double-dummy study.Lancet Neurol. 2014;13:141-149.
Trenkwalder C, Chaudhuri KR, García Ruiz PJ, LeWitt P, Katzenschlager R, Sixel-Döring F, Henriksen T, Sesar Á, Poewe W, Baker M, Ceballos-Baumann A, Deuschl G, Drapier S, Ebersbach G, Evans A, Fernandez H, Isaacson S, van Laar T, Lees A, Lewis S, Martínez Castrillo JC, Martinez-Martin P, Odin P, O’Sullivan J, Tagaris G, Wenzel K; Expert Consensus Group for Use of Apomorphine in Parkinson’s Disease. Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson’s disease--Clinical practice recommendations.Parkinsonism Relat Disord. 2015;21:1023-1030.
Liu Y, Li W, Tan C, Liu X, Wang X, Gui Y, Qin L, Deng F, Hu C, Chen L. Meta-analysis comparing deep brain stimulation of the globus pallidus and subthalamic nucleus to treat advanced Parkinson disease.J Neurosurg. 2014;121:709-718.
Miftahussurur M, Yamaoka Y. Diagnostic Methods of Helicobacter pylori Infection for Epidemiological Studies: Critical Importance of Indirect Test Validation.Biomed Res Int. 2016;2016:4819423.
Gabrielli M, D’Angelo G, Di Rienzo T, Scarpellini E, Ojetti V. Diagnosis of small intestinal bacterial overgrowth in the clinical practice.Eur Rev Med Pharmacol Sci. 2013;17 Suppl 2:30-35.
Bassotti G, Maggio D, Battaglia E, Giulietti O, Spinozzi F, Reboldi G, Serra AM, Emanuelli G, Chiarioni G. Manometric investigation of anorectal function in early and late stage Parkinson’s disease.J Neurol Neurosurg Psychiatry. 2000;68:768-770.
Savica R, Carlin JM, Grossardt BR, Bower JH, Ahlskog JE, Maraganore DM, Bharucha AE, Rocca WA. Medical records documentation of constipation preceding Parkinson disease: A case-control study.Neurology. 2009;73:1752-1758.
Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, Grandinetti A, Blanchette PL, Popper JS, Ross GW. Frequency of bowel movements and the future risk of Parkinson’s disease.Neurology. 2001;57:456-462.
Lin CH, Lin JW, Liu YC, Chang CH, Wu RM. Risk of Parkinson’s disease following severe constipation: a nationwide population-based cohort study.Parkinsonism Relat Disord. 2014;20:1371-1375.
Jost WH, Schrank B. Defecatory disorders in de novo Parkinsonians--colonic transit and electromyogram of the external anal sphincter.Wien Klin Wochenschr. 1998;110:535-537.
Mathers SE, Kempster PA, Swash M, Lees AJ. Constipation and paradoxical puborectalis contraction in anismus and Parkinson’s disease: a dystonic phenomenon?J Neurol Neurosurg Psychiatry. 1988;51:1503-1507.
Pagano G, Tan EE, Haider JM, Bautista A, Tagliati M. Constipation is reduced by beta-blockers and increased by dopaminergic medications in Parkinson’s disease.Parkinsonism Relat Disord. 2015;21:120-125.
Tateno F, Sakakibara R, Yokoi Y, Kishi M, Ogawa E, Uchiyama T, Yamamoto T, Yamanishi T, Takahashi O. Levodopa ameliorated anorectal constipation in de novo Parkinson’s disease: The QL-GAT study.Parkinsonism Relat Disord. 2011;17:662-666.
Sakakibara R, Odaka T, Uchiyama T, Asahina M, Yamaguchi K, Yamaguchi T, Yamanishi T, Hattori T. Colonic transit time and rectoanal videomanometry in Parkinson’s disease.J Neurol Neurosurg Psychiatry. 2003;74:268-272.
Krogh K, Christensen P. Neurogenic colorectal and pelvic floor dysfunction.Best Pract Res Clin Gastroenterol. 2009;23:531-543.
Bharucha AE, Dorn SD, Lembo A, Pressman A. American Gastroenterological Association medical position statement on constipation.Gastroenterology. 2013;144:211-217.
Zangaglia R, Martignoni E, Glorioso M, Ossola M, Riboldazzi G, Calandrella D, Brunetti G, Pacchetti C. Macrogol for the treatment of constipation in Parkinson’s disease. A randomized placebo-controlled study.Mov Disord. 2007;22:1239-1244.
Ondo WG, Kenney C, Sullivan K, Davidson A, Hunter C, Jahan I, McCombs A, Miller A, Zesiewicz TA. Placebo-controlled trial of lubiprostone for constipation associated with Parkinson disease.Neurology. 2012;78:1650-1654.
Sakakibara R, Doi H, Sato M, Hirai S, Masaka T, Kishi M, Tsuyusaki Y, Tateno A, Tateno F, Aiba Y. Nizatidine ameliorates slow transit constipation in Parkinson’s disease.J Am Geriatr Soc. 2015;63:399-401.
Rossi M, Merello M, Perez-Lloret S. Management of constipation in Parkinson’s disease.Expert Opin Pharmacother. 2015;16:547-557.
Stern T, Davis AM. Evaluation and Treatment of Patients With Constipation.JAMA. 2016;315:192-193.
Cadeddu F, Bentivoglio AR, Brandara F, Marniga G, Brisinda G, Maria G. Outlet type constipation in Parkinson’s disease: results of botulinum toxin treatment.Aliment Pharmacol Ther. 2005;22:997-1003.