Why does Parkinson's cause constipation?

When people think of Parkinson's disease they often think of tremors however often people who actually have Parkinson's are more concerned by the symptoms that are not to do with movement and tremors (non-motor symptoms). The commonest of these symptoms are constipation, tiredness, difficulty sleeping, anxiety and needing to pass urine multiple times at night. These symptoms are not always as immediately obvious to people without Parkinson's but they can be extremely troubling. In this blog I want to talk a bit more about constipation and why people with Parkinson's get constipation.

Constipation is when it is more difficult to go for a poo or when the amount of time between opening your bowels increases. Usually your poo will become a lot harder when this happens and sometimes can result in a bloated feeling and pain in your tummy. So the question is how does Parkinson's, a brain disease, affect your bowels in this way?

The answer lies in looking at the large intestine. This is a large pipe near the end of the path from your mouth to your bum (the GI tract). By the time your dinner reaches the large colon it has mainly been digested and had all of the useful vitamins, protein and carbohydrates removed from it. This means that when your dinner reaches the large colon it is made up of waste products (poo) and lots of water; in fact it is so watery at this point that it is completely liquid. The role of the large colon is to turn this liquid into a solid poo and to get the water out of it so that you can stay hydrated. So what changes in Parkinson's disease?

In Parkinson's disease if you measure the amount of time it takes a piece of food to move from the beginning of the large intestine to exiting out of your bum it would take double the amount of time that it would take a healthy person. In other words: poo moves through the large intestine at half the speed if you have Parkinson's. Because the large intestine is so good at draining water from your poo, the poo becomes much drier and harder as the large intestine has double the amount of time to remove as much water as possible. This explains why people with Parkinson's have drier harder poos and subsequently have more constipation.

The large intestine pushes food along it by tensing the muscles around it in a rhythmic way that propels the poo downstream. Like the rest of the body, in Parkinson's, these movements become much slower. The reason for this is not as clear but is probably due to the layer of nerve cells around the gut wall called the enteric nervous system. Studies where they have looked at samples of the gut wall have found build ups of Lewy Bodies (the characteristic thing found in the brain in Parkinson's) also in the gut wall. It is possible that this build up is what also causes the slowness in the gut.

It is important to remember that there are many other things that cause constipation other than Parkinson's. There are many medications that can be tried to help improve constipation but some of the simple things that can help are increasing the amount of water you drink or increasing the amount of fibre that you eat, but discuss with your doctor if this is a problem for you.

Curr Treat Options Neurol. 2018 Oct 25;20(12):54. doi: 10.1007/s11940-018-0539-9.

Gastrointestinal Dysfunction in Parkinson's Disease.

Pfeiffer RF

Author information

Abstract

PURPOSE OF REVIEW:

During the past 25 years, there has been an explosion of information regarding the occurrence of gastrointestinal dysfunction in Parkinson's disease. In this review, the clinical features of gastrointestinal dysfunction in Parkinson's disease will be described and information regarding the potential role of the enteric nervous system and the gut microbiome in the genesis of Parkinson's disease will be addressed.

RECENT FINDINGS:

Recognition is growing regarding the role that gastroparesis and small intestinal dysfunction may play in Parkinson's disease, especially with regard to erratic responses to anti-Parkinson medication. The presence of enteric nervous system involvement in Parkinson's disease is now well established, but whether the enteric nervous system is the starting point for Parkinson's disease pathology remains a source of debate. The potential role of the gut microbiome also is beginning to emerge. Gastrointestinal dysfunction is a prominent nonmotor feature of Parkinson's disease and dysfunction can be found along the entire length of the gastrointestinal tract. The enteric nervous system is clearly involved in Parkinson's disease. Whether it is the initial source of pathology is still a source of controversy. There also is growing recognition of the role that the gut microbiome may play in Parkinson's disease, but much more research is needed to fully assess this aspect of the disorder.

PLAIN ENGLISH: Metabolic syndrome and risk of Parkinson disease: A nationwide cohort study

This is a really nice study which looks at the link between the 'metabolic syndrome' and Parkinson's. As the authors describe, the metabolic syndrome is a combination of things that increase the risk of heart disease (among other things) and earlier death... things like higher blood pressure and cholesterol, diabetes, and central obesity. 

The study shows a clear link between each of these things and risk of a future diagnosis of Parkinson's... this is interesting because it might mean that controlling blood pressure and diabetes etc in mid-life might lower risk of Parkinson's in the future.

The big advantages are the size of the study (more than 17 million people), which in turn is a large proportion of the entire population over the age of 40 in South Korea. Another big advantage is that there were relatively few exclusions from the study where data were missing for participants. Both of these facts guard against incorrect results.

However the disadvantages of the study centre on the fact that it does not adequately take account of reverse causation, that is, undiagnosed Parkinson's causing changes in blood pressure, and the risk of high cholesterol, diabetes and obesity. You have to remember that Parkinson's is 'clinical diagnosis' which means that it is made by an expert on the basis of the clinical examination findings. The doctors assessing these patients in routine healthcare settings were not looking for signs of Parkinson's specifically and therefore subtle signs could have easily been missed.

Parkinson's changes in the brain are likely to be happening 5, 10, 15 or more years before that diagnosis is eventually made. This means that event though the authors of this study excluded new case of Parkinson's within 4 years of finding of high blood pressure, high cholesterol, diabetes and obesity, that is probably not a sufficient amount of time. Increasingly sedentary lifestyle in the early and undiagnosed phase of Parkinson's could have resulted in an increased likelihood of some of these factors. 

It is also likely that people with increasing features of the 'metabolic syndrome' are at higher risk of death before they get diagnosed with Parkinson's, which in itself could have resulted in biased results. However, the authors took account of this in one of their analyses and even mentioned that they did this following a comment from someone who reviewed their paper. As a footnote, I have never seen this mentioned in a paper before (that a reviewer asked for something and the authors included it) even though it frequently happens. I think it is great! The peer review process for scientific papers often improves them (sometimes it doesn't !) and we should feel able to acknowledge improvements at every stage before publication...

- Alastair Noyce

Ga Eun Nam, Seon Mee Kim , Kyungdo Han, Nan Hee Kim, Hye Soo Chung, Jin Wook Kim, Byoungduck Han, Sung Jung Cho, Ji Hee Yu, Yong Gyu Park, Kyung Mook Choi  

PLOS Medicine

Published: August 21, 2018

https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002640

Background

The association of metabolic syndrome (MetS) with the development of Parkinson disease (PD) is currently unclear. We sought to determine whether MetS and its components are associated with the risk of incident PD using large-scale cohort data for the whole South Korean population.

Methods and findings

Health checkup data of 17,163,560 individuals aged ≥40 years provided by the National Health Insurance Service (NHIS) of South Korea between January 1, 2009, and December 31, 2012, were included, and participants were followed up until December 31, 2015. The mean follow-up duration was 5.3 years. The hazard ratio (HR) and 95% confidence interval (CI) of PD were estimated using a Cox proportional hazards model adjusted for potential confounders. We identified 44,205 incident PD cases during follow-up. Individuals with MetS (n = 5,848,508) showed an increased risk of PD development compared with individuals without MetS (n = 11,315,052), even after adjusting for potential confounders including age, sex, smoking, alcohol consumption, physical activity, income, body mass index, estimated glomerular filtration rate, and history of stroke (model 3; HR, 95% CI: 1.24, 1.21–1.27). Each MetS component was positively associated with PD risk (HR, 95% CI: 1.13, 1.10–1.16 for abdominal obesity; 1.13, 1.10–1.15 for hypertriglyceridemia; 1.23, 1.20–1.25 for low high-density lipoprotein cholesterol; 1.05, 1.03–1.08 for high blood pressure; 1.21, 1.18–1.23 for hyperglycemia). PD incidence positively correlated with the number of MetS components (log-rank p < 0.001), and we observed a gradual increase in the HR for incident PD with increasing number of components (p < 0.001). A significant interaction between age and MetS on the risk of incident PD was observed (p for interaction < 0.001), and people aged ≥65 years old with MetS showed the highest HR of incident PD of all subgroups compared to those <65 years old without MetS (reference subgroup). Limitations of this study include the possibilities of misdiagnosis of PD and reverse causality.

Conclusions

Our population-based large-scale cohort study suggests that MetS and its components may be risk factors of PD development.

Kaplan–Meier curves of incidence probability of Parkinson disease (PD) for up to 7 years according to the number of metabolic syndrome (MetS) components.

Having an increased number of MetS components was associated with increased risk of PD development during the follow-up period compared to having no components (log-rank p < 0.001).

An overview of sleep and circadian dysfunction in Parkinson's disease

A relationship between Parkinson's disease and sleep has been recognised for many years. Patients with PD suffer from REM sleep behaviour disorder, excessive daytime somnolence, insomnia, reversal of sleep-wake cycle, and some if not all of these can predate the diagnosis of PD.

There is a fascinating literature emerging on the role the circadian rhythm plays in Parkinson's disease. Circadian rhythm not only regulates our body clock but also has a major bearing on our mood, appetite, bowel habit etc. I started thinking a few years ago about whether abnormalities in circadian rhythm could explain much about the pre-diagnostic phase of PD. I wondered whether the structures in the brain that control circadian rhythm were affected early in PD... I later learned from colleagues that they were not. Now I am starting to wonder whether abnormalities in circadian rhythm are not simply an early manifestation of Parkinson's, but instead an actual risk factor for Parkinson's...

Research shows that normal circadian function is important for maintaining normal processes that go on with cells... it is plausible that when circadian rhythm goes awry brain cells stop clearing proteins so effectively and these then start to accumulate... or that mitcohondria in brain cells don't work so effectively when there is disordered circadian rhythm. Some of my recent research looks directly at the nature of the relationship between circadian rhythm and Parkinson's [watch this space!] but for now I agree with the authors of this review... normalising circadian rhythm may be an important therapeutic target for Parkinson's disease...

- Alastair Noyce

J Sleep Res. 2018 Mar 1. doi: 10.1111/jsr.12673. [Epub ahead of print]
Mantovani S, Smith SS, Gordon R, O'Sullivan JD

http://onlinelibrary.wiley.com/doi/10.1111/jsr.12673/abstract;jsessionid=D053C900C0F2B819BB00734F213B98FB.f02t02

Sleep and circadian alterations are amongst the very first symptoms experienced in Parkinson's disease, and sleep alterations are present in the majority of patients with overt clinical manifestation of Parkinson's disease. However, the magnitude of sleep and circadian dysfunction in Parkinson's disease, and its influence on the pathophysiology of Parkinson's disease remains often unclear and a matter of debate. In particular, the confounding influences of dopaminergic therapy on sleep and circadian dysfunction are a major challenge, and need to be more carefully addressed in clinical studies. The scope of this narrative review is to summarise the current knowledge around both sleep and circadian alterations in Parkinson's disease. We provide an overview on the frequency of excessive daytime sleepiness, insomnia, restless legs, obstructive apnea and nocturia in Parkinson's disease, as well as addressing sleep structure, rapid eye movement sleep behaviour disorder and circadian features in Parkinson's disease. Sleep and circadian disorders have been linked to pathological conditions that are often co-morbid in Parkinson's disease, including cognitive decline, memory impairment and neurodegeneration. Therefore, targeting sleep and circadian alterations could be one of the earliest and most promising opportunities to slow disease progression. We hope that this review will contribute to advance the discussion and inform new research efforts to progress our knowledge in this field.

Sniffing around for answers

We are somewhat preoccupied with smell at PREDICT-PD; smell loss is one of the most sensitive risk factors for development of Parkinson's - although it is non specific and may be seen in a number of conditions. It is particularly interesting as it can be studied non-invasively and remotely. While self-reported smell loss is less reliable, objective tests such as the University of Pennsylvania Smell Idenfification Test (UPSIT) have a high degree of accuracy and can be completed at home by research participants. 

This recognition sits well with the finding from post-mortem studies that there are early pathological changes in the olfactory bulb, the area just above the nose which receives smell inputs. The progressive brain changes in Parkinsons, defined by pathologist Heiko Braak, are now known as Braak stages, and the earliest stage, Braak stage 1 involves olfactory bulb involvement.

While smell loss is well characterised, its link with other features and particularly cognitive changes in in Parkinson's is less well explored. Smell loss is also associated with Alzheimer's so it wouldn't be surprising if it was also linked to cognitive changes in Parkinson's. The study below, from researchers in South Korea, looked at the relationship between these two features. 

They took a group of people just diagnosed with Parkinson's and compared those with cognitive impairment to those without, showing poorer smell in all aspects of the smell tests in patients with cognitive impairment. In many ways, this goes against the 'Braak hypothesis' which posits that pathology in the higher cortical areas and the cognitive impairment which goes with it is a later phenomenon. It would be interesting to see if smell loss was particularly associated with specific domains of cognition and the areas more directly connected with the olfactory bulb.  

As we have previously mentioned, cognitive impairment may be related to many underlying pathologies and it may be that the pathology described in Braak staging is not primarily responsible for cognitive impairment in Parkinson's. Certainly more work is needed in this area to tease out these relationships. 

-Anna

https://www.ncbi.nlm.nih.gov/pubmed/29233469

Parkinsonism Relat Disord. 2018 Jan;46:69-73. doi: 10.1016/j.parkreldis.2017.11.334. Epub 2017 Nov 14.

Olfactory dysfunctions in drug-naïve Parkinson's disease with mild cognitive impairment.

Park JW, Kwon DY, Choi JH, Park MH, Yoon HK.

BACKGROUND:
Evaluation of olfactory function is valuable for the detection of pre-motor state of Parkinson's disease (PD). PD patients have an increased risk of associated dementia and one-third of PD patients have mild cognitive impairment (MCI) at the time of diagnosis. However, the characteristics of olfactory dysfunction in PD-MCI patients are unclear. This study examined the relationship between olfactory dysfunction and cognitive function in drug-naïve PD at the time of diagnosis with the patterns of olfactory function in PD-MCI patients using the Korean version of the Sniffin' stick test II (KVSS II).METHODS:
A total of 66 drug-naïve PD patients were enrolled. A neuropsychiatric assessment battery and KVSS II were performed. For the statistical analyses, univariate, multivariable linear regression and Student's t-test were used to determine the relationship between the variables and olfactory function.RESULTS:
Olfactory dysfunction was more prevalent in the PD-MCI group than in the PD-normal cognition (PD-CN) group. Each domains of odor threshold, discrimination, identification and total olfactory score were more impaired in the PD-MCI group than the PD-CN group. Whether cognitive impairment was single or multiple domain was not affected.CONCLUSION:
PD-MCI is more likely to be associated with severe olfactory impairment than PD-CN. There may be more extensive neurodegenerative processes affecting olfaction in PD-MCI patients. With further investigation and validation using neuropathological data, an objective olfactory function test could be used as a tool to evaluate disease progression. Further studies with prospective design investigating the prognostic value of olfactory dysfunction in PD-MCI patients are essential.

Autonomic dysfunction in Parkinson's disease: A prospective cohort study

The non motor symptoms of PD are so important. This study shows how autonomic dysfunction worsens significantly over short periods of follow up in patients that have a diagnosis of PD. We already know from other studies that autonomic dysfunction is a marker of Parkinson's disease severity and heralds a shorter survival of patients with PD. 

There has been quite a lot of focus on sleep, cognition and mood as non motor features of PD but we are not adequately addressing symptoms and consequences of autonomic dysfunction and studies such as this highlight the importance. Previously, marked autonomic involvement used to raise the suspicion of an alternative parkinsonian disease (such as multiple systems atrophy) and although autonomic dysfunction is a prominent feature of MSA, it is also very prevalent in PD. 

Of course autonomic dysfunction also often precedes a diagnosis of PD, whether in the form of orthostatic hypotension, or more commonly with constipation, erectile dysfunction or urinary symptoms. We at PREDICT-PD have a longstanding interest in how symptoms of autonomic dysfunction can be used to identify those that might one day go on to be diagnosed with PD...

Alastair Noyce

Mov Disord. 2017 Dec 26. doi: 10.1002/mds.27268. [Epub ahead of print]
Merola A1, Romagnolo A2, Rosso M1, Suri R1, Berndt Z1, Maule S3, Lopiano L2, Espay AJ1.

http://onlinelibrary.wiley.com/doi/10.1002/mds.27268/full

BACKGROUND: Dysautonomia is a frequent and disabling complication of PD, with an estimated prevalence of 30-40% and a significant impact on the quality of life.

OBJECTIVES: To evaluate the rate of progression of dysautonomia and, in particular, orthostatic hypotension, in a cohort of unselected PD patients, and assess the extent to which the progression of dysautonomia affects activities of daily living, health-related quality of life, and health care utilization in PD.

METHODS: We recruited 131 consecutive patients into a 12-month, prospective, observational cohort study. Clinical measures included the International Parkinson and Movement Disorder Society/UPDRS, the Scale for Outcomes in Parkinson Disease-Autonomic, the Orthostatic Hypotension Symptoms Assessment, and orthostatic blood pressure measurements. Health care utilization was quantified as the number of hospitalizations, emergency room visits, and outpatient clinic evaluations.

RESULTS: The overall severity of autonomic symptoms, as measured by the the Orthostatic Hypotension Symptoms Assessment total score, worsened by 20% over 12 months (P < 0.001), with an overall increase in orthostatic hypotension prevalence from 31.1% to 46.7% (P < 0.001). Worsening of autonomic symptoms was independently associated with deterioration in daily living activities (P = 0.021) and health-related quality of life (P = 0.025) adjusting for disease duration, cognitive impairment, and motor severity. Regardless of symptomatic status, orthostatic hypotension was associated with greater deterioration in daily living activities, health care utilization, and falls (P ≤ 0.009) compared to patients without orthostatic hypotension.

CONCLUSIONS: The severity of autonomic symptoms progressed by 20% over 1 year and was independently associated with impairments in daily living activities and health-related quality of life. Symptomatic and asymptomatic orthostatic hypotension were both associated with increased prevalence of falls and health care utilisation.

© 2017 International Parkinson and Movement Disorder Society.