Cohort Study in Parkinsonism

Abstract

Objective

To evaluate gastric emptying (GE) and colonic transit in a cohort of patients with Parkinson disease and other parkinsonism disorders and to determine whether abnormal gut transit precedes motor onset of parkinsonism.

Methods

Medical record review of 84 patients with parkinsonism who underwent clinically indicated transit studies at Mayo Clinic (2001–2019) and 11 patients with transit studies who subsequently developed parkinsonism. Data are summarized as median (interquartile range).

Results

The 84 patients (52% female) with parkinsonism were aged 72 (66–76) years with a disease duration of 5 (2–8) years: Parkinson disease = 70, multiple system atrophy = 7, dementia with Lewy bodies = 4, progressive supranuclear palsy = 2, and parkinsonian syndrome = 1. Ten had delayed GE, 10 slow colonic transit, 16 accelerated GE (14 Parkinson disease, 1 multiple system atrophy, and 1 parkinsonian syndrome), and 49 normal transit. One patient with parkinsonian syndrome had both slow colonic and accelerated gastric transit. Longer disease duration and higher levodopa equivalent daily dose were observed for Parkinson disease compared with other parkinsonisms and with slow compared with normal colonic transit. Of 11 patients (5 female) with transit studies who later developed motor parkinsonism after 4 (3–5) years, 1 had accelerated GE, 1 had delayed GE, and 1 had both delayed GE and colonic transit.

Conclusions

Accelerated GE was newly identified in patients with parkinsonism, in addition to delayed GE or colonic transit. Furthermore, gut dysmotility was objectively identified to precede the motor onset of parkinsonism.

Gastrointestinal symptoms in Parkinson disease (PD) and atypical parkinsonian disorders (multiple system atrophy [MSA], progressive supranuclear palsy [PSP], and dementia with Lewy bodies [DLB]) include constipation, weight loss, nausea, and early satiety.¹ Delayed gastric emptying (GE), slow colonic transit (CT), and rectal evacuation disorders, which underpin these symptoms, can be objectively detected by gastrointestinal motility studies.² Constipation is the most common gastrointestinal symptom in PD, reported in up to 70% of patients,² and it may precede the motor onset of PD by 10–20 years.^3,4 However, there are no objective measurements documenting abnormal gut motility preceding the motor onset of PD.

Delayed GE has been reported to affect 70%–100% of patients with PD,⁵ although its symptomatic manifestation is less frequent.⁶ Delayed GE may be reported as nausea, vomiting, postprandial fullness,^5,7 reduced medication efficacy, or the on-off phenomenon.² Delayed GE and CT are generally believed to result from damage to the extrinsic or enteric nerves in PD.

The vagus nerve provides extrinsic neural control of nitrergic and other intrinsic inhibitory neurons involved in mediating gastric accommodation; failure of accommodation is associated with acceleration of GE. We explored the hypothesis that a subset of patients with parkinsonism disorders may experience accelerated GE.

Our aims were 2-fold: first, to investigate upper and lower gastrointestinal motility measurements in patients with PD and other parkinsonian disorders, and second, to determine whether abnormal gut transit precedes the motor onset of parkinsonism in patients evaluated at a single center.

Methods

Study Site

This study was conducted at Mayo Clinic, Rochester, MN.

Standard Protocol Approvals, Registrations, and Patient Consents

The study was approved by the Mayo Clinic Institutional Review Board (IRB #19-006953). Patients included in the study had granted consent for use of their electronic medical records for research purposes. Data were collected using the Mayo Clinic Advanced Cohort Explorer, which uses natural language processing for data retrieval.

Study Population and Design

We identified a cohort of 116 consecutive patients with a diagnosis of parkinsonism who had undergone clinically indicated scintigraphic gastrointestinal or CT studies at Mayo Clinic between January 2001 and November 2019. Patients were aged 18–85 years. A neurologist (A.H.) reviewed the medical records to identify the clinical diagnosis of neurodegenerative parkinsonism.

Eligibility Criteria

Inclusion criteria were clinical diagnosis of PD (as per UK Parkinson's Disease Society Brain Bank criteria)⁸ or other atypical neurodegenerative parkinsonian disorders including PSP (Movement Disorder Society–PSP criteria⁹), MSA (Gilman criteria¹⁰), DLB (McKeith criteria¹¹); or parkinsonian syndrome (Ps) when suspected to have neurodegenerative parkinsonism, but had not met the diagnostic criteria for either PD or an atypical parkinsonism disorder at the last follow-up visit. All patients had at least 1 comprehensive evaluation in the Mayo Clinic Department of Neurology.

Exclusion criteria were incomplete records (n = 2), secondary (e.g., drug-induced) parkinsonism (n = 3), absence of parkinsonism diagnosis (n = 10), and transit study before onset of neurologic symptoms (n = 17). The final cohort was 84 patients with either PD or other atypical neurodegenerative parkinsonism who had undergone transit measurement. Among the 17 patients who had undergone a transit study before the clinical diagnosis of parkinsonian disorder, there were 7 PD, 3 Ps, and 1 possible PSP; this subgroup is detailed separately as a group with prodromal dysmotility. Potential for bias was addressed by inclusion of all patients fulfilling eligibility criteria.

Review of Medical Records

Medical records were reviewed by 2 authors (K.K. and A.H.) to extract demographics (sex and age at transit study), clinical features of parkinsonism (age at first motor symptom, disease duration [motor symptom] at the time of the transit study, final neurologic diagnosis, and antiparkinsonism medications), gastrointestinal symptoms at the time of the transit study, and gastrointestinal transit data. The levodopa equivalent daily dose (LEDD) was calculated for all 84 patients with parkinsonism at the time of the transit study.¹² Similar information was collected for the 11 patients who developed parkinsonism after the transit study.

Among the 84 patients with parkinsonism, 70 had PD, and the Hoehn & Yahr (H&Y) score¹³ was calculated (1 unavailable) based on the neurologic examination recorded in the same year as the transit studies. Brain autopsy results were available for 2 patients: 1 patient clinically diagnosed with dementia with Lewy bodies had autopsy-proven mixed Alzheimer disease and vascular parkinsonism and had normal transit studies; the second patient had clinical and autopsy-proven PD and had delayed GE.

Measurements of Gastrointestinal and CT

Gastrointestinal and CT measurements were performed by standardized and validated tests.^14–16 The standard instruction before the clinical transit study was for patients to stop all medications with potential effects on gastrointestinal or CT 48 hours before the start of the transit study. GE was measured after an overnight fast, with participants ingesting a ^99mTc-labeled egg meal (320 kcal, 30% fat)¹⁴ and gamma camera anterior and posterior abdominal images at 0, 1, 2, and 4 hours. Colonic filling of the ^99mTc at 6 hours serves as a surrogate of small bowel transit. Scintigraphic CT was performed using a pH-sensitive methacrylate-coated capsule that dissolves in the ileocolonic region, delivering ¹¹¹In-charcoal to the colon. Imaging was performed at 24 and 48 hours.¹⁵

CT results were summarized¹⁵ as the geometric center (GC) or weighted average of isotope in the 4 regions of the colon (ascending [AC], transverse [TC], descending [DC], rectosigmoid [RS], and stool at 24 and 48 hours:

Outcomes Measured and Definitions of Abnormal Transit

The outcomes measured were GE at 1, 2, and 4 hours and colonic GC at 24 and 48 hours. Based on normal values in 319 healthy adults for GE¹⁷ and in 220 adults for CT (using fifth percentile),¹⁶ slow GE was defined as <25% emptied at 2 hours or <75% emptied at 4 hours. Slow CT constipation was defined by colonic GC24h ≤1.3 (corresponding to midway between the hepatic flexure and the mid-transverse colon), GC48h ≤1.9 (corresponding to the splenic flexure), or delta GC48h–GC24h ≤0.3.¹⁸ Accelerated GE was defined by GE of solids >50% at 1 hour or by the combination of >25% GE at 1 hour and >79% GE at 2 hours.¹⁶

Statistical Analysis

Descriptive analysis was used to summarize continuous data or categorical H&Y scores. All data are presented as median and interquartile range (IQR) unless otherwise stated. Group comparisons were conducted using analysis of variance (ANOVA) or Kruskal-Wallis ANOVA on ranks for 3 or more group comparisons and Wilcoxon rank-sum test or Tukey test for 2-group comparisons. Proportions of patients receiving antiparkinsonism medications in the patients with PD compared with atypical parkinsonian disorders and in patients with abnormal compared with normal transit were compared using the χ² test.

Data Availability

All the data pertaining to the study are included in this article.

Results

Demographics and Clinical Characteristics of Patients With Parkinsonism

Of 84 total patients (44 female; 52%), 70 had PD, and 14 had atypical parkinsonian disorders, including 7 possible or probable MSA, 4 possible DLB, 2 possible PSP, and 1 had a Ps. The patients with PD (39 female; 56%) had a median age of 72 years (IQR 67–76 years) at the time of the transit study, with a median disease duration of 5 years (IQR 3–9 years). The group LEDD was 600 (IQR 30–900) and H&Y scores median 2.0. The most common GI symptoms were constipation (60%), weight loss (51%), abdominal pain (43%), bloating (32%), early satiety (26%), vomiting (18%), dysphagia (14%), and heartburn/reflux (13%).

The other 14 patients with parkinsonism (5 females, 36%) had a median age of 67 years (IQR 63–74 years) at the time of the transit study, with a median disease duration of 2 years (IQR 1–5 years). The group LEDD was 113 (IQR 0–416). The most common GI symptoms were constipation (72%) and nausea and abdominal pain (both 43%).

Gastrointestinal Transit and Symptoms at the Time of the Transit Study

Of the 84 patients with parkinsonism, 80 had GE measured, 42 had CT measured, and 39 had both GE and CT measured. Table 1 summarizes the transit results for the different parkinsonian disorders: 10 delayed GE, 16 accelerated GE, 10 slow CT, 1 with both rapid GE and slow CT, and 49 normal transit. Table 2 shows a summary of the gastrointestinal and CT data. The most common gastrointestinal symptoms in the subgroup with normal transit were bloating (37%), weight loss (51%), abdominal pain (47%), constipation (61%), and nausea (45%). In those with delayed GE, the most common symptoms were weight loss (70%), abdominal pain (60%), and constipation (80%). In patients with slow CT, the most common gastrointestinal symptoms were weight loss (44%) and constipation (89%). The most common gastrointestinal symptoms in the accelerated GE group were nausea and constipation (38% each).

Table 1.

Demographic and Clinical Characteristics, Parkinsonism Subtypes, and Transit Study Outcomes in the Cohort of 84 Patients

Table 2.

Gastric, Small Bowel, and Colonic Transit in 84 Patients With Parkinson Disease/Parkinsonism Disorders (N Refers to Number With Available Data)

Disease Duration From the First Motor Symptom at the Time of the Transit Study

Disease duration was significantly longer in the PD group compared with other parkinsonism syndromes (median 5 vs 2 years, p = 0.007). There was no significant difference in disease duration in those with abnormal compared with normal transit (p = 0.123). Among the 3 groups of patients with abnormal transit studies, there was an overall difference in disease duration (p_ANOVA = 0.034), with longer duration in patients with slow CT compared with delayed GE (mean difference 6.1 years, p = 0.032) (table 1).

Antiparkinsonism Medications at the Time of the Transit Study

LEDD was significantly higher in PD compared with other parkinsonian disorders (p = 0.010), which is an expected finding. It was also significantly higher in slow CT compared with normal transit (p = 0.015; difference in mean LEDD = 520.7 mg, and difference in median LEDD = 575 mg).

A higher proportion of patients with PD compared with atypical parkinsonian disorders or those with abnormal compared with normal transit were receiving a COMT inhibitor (entacapone or tolcapone) (χ² test, both p < 0.01). There was no significant difference in prescription of dopamine agonists, monoamine oxidase type B inhibitors, or amantadine between the subgroups. None of the patients were prescribed anticholinergic medications for parkinsonism.

Almost all patients with slow CT (8/10) or delayed GE (9/10) were taking levodopa compared with about three-quarters of patients with accelerated GE (11/15) or normal transit (36/47). Dopamine agonists (ropinirole and pramipexole) were taken by a larger proportion of patients with accelerated GE (5/15; 33%) or slow CT (3/10; 30%) compared with delayed GE (2/10; 20%) or normal transit (7/47; 15%). Monoamine oxidase B inhibitors (selegiline and rasagiline) and amantadine were taken by a very small number of patients with either normal or slow CT.

Subsets With Abnormal Transit

Table 1 summarizes age, duration of parkinsonism, and H&Y score (calculated only for patients with PD) at the time of the transit test in the 3 subsets with abnormal transit and the normal transit subset. Delayed GE and CT were each identified in 12% of the cohort.

The 10 patients (7 females) with delayed GE (all PD diagnosis) had a median parkinsonism duration of 2 years. Delayed GE was documented at 4 hours in 10/10 and at 2 hours in 3/10.

The 10 patients (6 females; 9 PD and 1 Ps) with slow CT had a median duration of parkinsonism of 13 years. One patient had slow CT based on slow progression of isotope through the colon, 5 had slow CT at 24 and 48 hours, and 4 had abnormal GC24.

The16 patients (6 females; 14 PD, 1 Ps, and 1 possible MSA) with accelerated GE had a median parkinsonism duration of 6 years. This represents a prevalence of 19% of the entire cohort. Examples of accelerated GE of solids or slow CT are shown in the figure. The patient with Ps also had coexistent slow CT. Two of the patients with accelerated GE had been previously prescribed metoclopramide; we cannot be certain that the medication was stopped at least 48 hours before the GE test.

Figure. Examples of Abnormal Transit Study Results in Patients.

(A) Female patients with Parkinson disease (PD) with delayed gastric emptying and accelerated gastric emptying. (B) Male patient with Parkinsonism with slow colonic transit. (C) Combination of delayed gastric emptying and slow colonic transit identified 3 years before diagnosis of PD in a male patient.

Patients With Motility Studies Before the Diagnosis of PD

The additional 11 patients (7 PD, 3 Ps, and 1 possible PSP) had a median age of 64 (59–67) years at the time of the transit study and developed motor onset of parkinsonism a median of 4 (3–5) years later. Three of the 11 had abnormal transit studies. One patient had both slow CT on both GC24h and GC48h and delayed GE at 4 hours; that patient developed tremor 3 years later and was diagnosed with Ps. One patient had delayed GE at 4 hours and developed micrographia and gait disorder 3 years later and was diagnosed with Ps. One patient had accelerated GE at 1 hour and developed gait disorder with falls 6 years later and was diagnosed with possible PSP (figure).

Discussion

This study identified 84 patients with parkinsonism (70 PD and 14 atypical parkinsonian disorders) who underwent detailed gastric and CT studies. A subset (19%) had accelerated GE, which has not been previously described. Other patients had delayed GE (12%) or slow CT (12%). Moreover, among 11 patients who underwent a transit study before the motor onset of a parkinsonian disorder, 3 had objective evidence of abnormal transit.

Almost all of the patients with parkinsonism with abnormal transit studies had PD (n = 33), whereas only 2 had either possible MSA or an indeterminate Ps. In comparison, 12/14 patients with atypical parkinsonian disorders had normal transit despite prominent gastrointestinal symptoms. There are only small prior series assessing gut transit studies in atypical parkinsonism disorders; slow CT was identified in MSA^19,20 and delayed GE and slow CT in DLB.²¹

Acceleration of GE in PD has not previously been reported in the literature. Several possible mechanisms include extrinsic or intrinsic neuropathy, abnormal vagal nucleus, or effects of medications.

Vagal dysfunction may lead to impaired gastric accommodation and subsequent accelerated GE due to compromised function of the vagal nucleus in the brainstem, vagal afferents, or abnormality of intrinsic inhibitory, nonadrenergic and noncholinergic motor neurons (e.g., nitric oxide and purinergic neurons), possibly from accumulation of α-synuclein in the enteric nervous system. Of interest, nitric oxide also plays a role in the neurodegenerative processes in PD,¹⁷ and α-synuclein oligomers interact with adenosine triphosphate synthase and induce mitochondrial dysfunction in PD.²² Alterations in neurotransmitters, particularly dopamine deficiency in intrinsic nerves in PD, could lead to accelerated GE, as dopamine is associated with inhibition of intrinsic cholinergic neurons.²³

Effects of medications on GE do not appear to be an important confounder. There were no significant differences in the medication groups or LEDD between patients who had accelerated GE compared with those with delayed GE.

The finding of accelerated GE is relevant, as it may possibly contribute to nonmotor symptoms including abnormal postprandial hypotension²⁴ and worsening of parkinsonian symptoms.²⁵ Further prospective studies are needed to confirm our findings and to assess whether there is a correlation with alterations in blood pressure and other motor or nonmotor PD symptoms. In addition, studying whether accelerated GE is related to on- vs off-medication states would be of interest.

The prevalence of objectively slow CT in patients with PD (12%) is lower than the 60% reporting symptomatic constipation without a standard questionnaire. Nevertheless, the 12% prevalence was higher than the ∼6% slow CT in constipated adults studied at our institution.²⁶ Patients with slow CT were prescribed approximately double the LEDD and had longer disease duration. Our analysis cannot determine whether LEDD or disease duration is the more important factor for slow CT.

The identification of abnormal gut motility before motor onset of parkinsonism is important and correlates with subjective reports of constipation preceding PD in large studies.^3,4 Our objective observational findings are consistent with the hypothesis of Braak et al.²⁷ proposing that PD pathology may start in the gut and propagate centrally. Accumulation of α-synuclein, including in enteric neurons, has been reported in bowel tissue samples taken from patients with PD before the onset of the definite neurologic symptoms,²⁸ although the specificity for disease is still debated. The identification of accelerated GE preceding motor onset in 1 patient with possible PSP could potentially be explained by mechanisms outlined earlier for accelerated GE in patients with PD. However, unlike PD, the pathologic process in PSP has been reported in a paucity of studies²⁹ to be limited to the CNS and does not involve the enteric nervous system. We did not identify abnormalities in transit studies in 2 other patients with possible PSP, although this could have been missed given the very small numbers and warrants further study of motility in patients with PSP.

Limitations of our study include the retrospective nature. There is uncertainty as to whether dopaminergic or other medications affecting motility were held or taken at the time of the transit study, as this may have clearly influenced transit findings. However, the abnormal transit findings before development of parkinsonism were all performed in the absence of pro- or anti-dopaminergic medications. It would be helpful to perform future transit studies in patients with parkinsonian disorder, with both a medication-on state and after a medication washout, to see how this influences the findings. Patients fulfilled clinical diagnosis for parkinsonism disorders, but there may be a mismatch with pathologic diagnosis, as seen in the case with antemortem possible DLB and autopsy diagnosis of mixed Alzheimer disease and vascular parkinsonism pathology. This represents a well-known limitation of clinical studies of parkinsonism in general and where pathologic confirmation is often not available.^8,30

It is also possible that some of the patients may have experienced gastrointestinal symptoms, but they may not have reported them or sought treatment for those symptoms elsewhere, which is certainly conceivable given the inclusion of secondary or tertiary referral patients in this study. Future studies will be enhanced by focusing on patients identified in the Rochester Epidemiology Project cohort for whom essentially all clinical encounters are available.

Epidemiologic studies as well as prospective measurements of gut transit and defecatory function in both clinical and, ideally, autopsy-diagnosed patients with parkinsonism are required to address the generalizability as well as many of the questions and verification of the information garnered from this retrospective study at a tertiary care center. It is unclear why the prevalence of accelerated GE was higher than delayed GE in this cohort; thus, prospective studies are required to assess the relative prevalence of both accelerated and delayed GE in PD with or without gastrointestinal symptoms. This will require the use of valid and detailed measurement of GE, which was a pitfall in prior studies.⁶

Strengths of our study include the fact that all transit studies were performed at a single center with a well-validated method that assesses the transit of a solid meal through the stomach and small intestine and radiolabeled solid residue through the colon. Our study also included a relatively large patient cohort in the main group, although the numbers were lower in the other subset with symptom onset after the transit study was performed.

In addition to delayed gastric and CT, our study identified a subgroup of patients with parkinsonism who had accelerated GE. Furthermore, we identified cases of objectively delayed GE and CT that predated parkinsonism by several years. Further prospective studies of gut transit, particularly to confirm the finding of accelerated GE, with careful documentation of concomitant antiparkinsonism medications and association with postprandial hypotension would be of significant interest.

TAKE-HOME POINTS

• → Constipation and other gastrointestinal symptoms (such as unexplained weight loss and nausea) are common in Parkinson disease and may precede the motor onset of parkinsonism.

• → Delayed gastric emptying and slow colonic transit are recognized objective gut dysmotility disorders in Parkinson disease.

• → In this study, accelerated gastric emptying was newly identified in patients with parkinsonism disorders.

• → A higher proportion of patients with abnormal compared with normal transit were receiving a COMT inhibitor (entacapone or tolcapone).

• → Gut dysmotility was also newly identified to precede the motor onset of parkinsonism, providing objective evidence for constipation as a prodromal symptom.

Appendix. Authors

Study Funding

No specific funding was received for this work. M. Camilleri receives funding for research on therapeutics in gastroparesis from NIH, grant no. R01-DK122280.

Disclosure

M. Camilleri serves as an advisor and equity holder in Enterin. The other authors have no conflicts of interest relevant to this work. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.