Abstract
Parkinson’s disease (PD) is a complex neurodegenerative motor disorder caused by the loss of dopaminergic neurons in the substantia nigra pars compacta. The substantia nigra is neither the first nor the only brain region affected by PD. Recent and old studies have shown that PD does not only affect the CNS; in fact, autonomic innervation in the GIT, skin, and olfactory system was found to be affected by α-synuclein pathology outside the CNS, affecting patients’ quality of life. In the gastrointestinal system, dysphagia, constipation, and bacterial overgrowth in the small intestine are common in patients with PD. In addition, several skin conditions were reported in PD, including seborrheic dermatitis, rosacea, melanoma, and others. Finally, olfactory system dysfunction, such as reduced touch sensation and smell, was associated with motor abnormalities. Further high-quality studies are needed to develop reliable tests that could help in the early diagnosis of PD.
Parkinson’s disease (PD) is the second most common disorder of the central nervous system; it results in the progressive death of dopaminergic neurons in the brain.1 This neurodegenerative disease is projected to affect approximately 6 million people worldwide.2 People with PD experience neurodegeneration in the brain as well as the peripheral autonomic nervous system, which maintains involuntary processes such as heart rate, blood pressure, respiration, digestion, and sexual arousal.3 Patients with PD experience a variety of gastrointestinal (GI) tract abnormalities, but the cause of these symptoms remains unclear.4 The GI disorders such as dysphagia (difficulty or discomfort swallowing), gastroparesis (paralysis of the stomach), and bowel dysfunction (constipation) are among the most prevalent non-motor symptoms of PD.5 Moreover, the association between PD and the olfactory system (OS) and skin disorders has been used as a biomarker in the diagnosis of PD.6 Therefore, early PD pathology can be diagnosed not only by motor symptoms, but also by skin and OS abnormalities.7 Researchers have indicated that aging is responsible for hyposmia, or the reduced sense of smell, in patients with PD.8 This article aims to discuss PD beyond the brain, with a focus on the role of alpha-synuclein pathology in the GI tract, the OS, and skin disorders.
Gastrointestinal system
The GI abnormalities and symptoms are frequently present in patients with PD, but the extent of GI dysfunction in the development of PD remains unclear.9 The GI function is controlled by the enteric and autonomic nervous system. Enteric nervous system consists of distinct types of neurons and glial cells that can be found in the esophageal, gastric, and intestinal tissues. Input from the autonomic nervous system to the enteric nervous system is essential for gastric and intestinal function. In PD, it has been found that patients with PD have more localization of Lewy bodies enteric nervous system than healthy control. Also, PD patients were determined to have fewer dopaminergic neurons in the colonic enteric nervous system as well as low level of dopamine in the muscularis externa. All these changes are responsible for the non-motor symptoms in PD.
In recent years, researchers have highlighted GI dysfunction in patients with PD, including dysphagia, gastroparesis, also known as delayed gastric emptying, and bowel disorder (Table 1) (Figure 1).10 More recently, GI abnormalities have been identified as contributing to the development of depression in patients with PD. The GI dysfunction in these patients leads to progressive disorders and a significant reduction in quality of life.11
- Most common Parkinson’s disease-associated GI disorders.
- Association between Parkinson’s disease and gastrointestinal dysfunctions.
Dysphagia
Upper GI tract complaints, such as dysphagia, are present in 9%–77% of patients with PD, with a clear tendency to increase in frequency and severity as the population ages. Dysphagia is more closely associated with a substantial fatality rate due to malnutrition and pulmonary disorders. This symptom occurs mostly in patients who are in the late stages of PD. The exact mechanism of oropharyngeal dysphagia in PD is still not well defined.12 A meta-analysis was conducted to estimate the severity and prevalence of dysphasia in patients with PD in different counties. The authors included 20,530 patients with PD from 58 studies. The estimated pooled prevalence of dysphagia in patients with PD was 36.9% (95% CI 30.7%–43.6%). Instrumental assessment indicated a higher prevalence rate of 57.3% (95% CI 44.3%–69.1%). Oceania exhibited the highest prevalence and severity of dysphagia followed by Africa, Asia, Europe, and America.13
Small intestinal bacterial overgrowth
Patients with PD also experience small intestinal bacterial overgrowth (SIBO), which results in the production of tyrosine decarboxylate.14 The prevalence of SIBO in patients with PD has been estimated at 25–55%. A variety of gut microbes have been identified in various studies in patients with PD, and these bacterial species are implicated in GI disorders.15 Here, we describe a mechanism by which the efficacy of levodopa, which is used as a dopamine replacement agent for the treatment of PD, is reduced by changes in the composition of the gut microbiome. The first stage is associated with intestinal dysfunction resulting in secondary bacterial overgrowth. In this mechanism, tyrosine decarboxylase produced by certain types of bacteria in the gut is also involved in the decarboxylation of levodopa, which reduces its efficacy in patients with PD. Tyrosine decarboxylase blocks the circulation of dopamine in the brain.16
Constipation
Constipation is one of the main non-motor symptoms of the lower GI tract in patients with PD: It occurs when bowel motility is reduced, and stool passage becomes difficult.17 Constipation may even precede motor symptoms due to early alpha-synuclein pathology of the enteric nervous system and vagus nuclei.18 A study was conducted to examine the relationship between constipation and the progression of PD. The pooled odds ratio for constipation was 2.27 (95% CI 2.09–2.46) in patients with PD compared with healthy controls. Therefore, this meta-analysis suggests that constipation may trigger and increase the progression of PD compared with a healthy individual.19 Another study was conducted to examine the prevalence of GI symptoms among 103 patients with PD and 81 healthy individuals. The participants were given a questionnaire that included questions about GI symptoms such as constipation, indigestion, dysphagia, diarrhea, nausea, vomiting, bloating, and abdominal pain. The authors concluded that the risk of constipation was higher in people with PD (78.6%) compared with healthy individuals (28.4%). Many people with PD also complain of other GI symptoms.20-24
In conclusion, patients with PD commonly experience various GI tract symptoms. However, the available meta-analyses and systematic research, based on questionnaires, are insufficient to assess disease severity and prevalence. Early screening for GI abnormalities in PD could prevent or mitigate the complications by early intervention. In addition, more research is needed to better understand the connection between PD and GI abnormalities, thus discovering better therapeutic strategies.
Olfactory system
While PD is commonly linked with motor symptoms, numerous studies have shown that along with various other non-motor symptoms, olfactory dysfunction emerges as a particularly crucial feature for PD diagnosis, being present in approximately 96% of PD patients.25 The OS is the sensory system that is crucial for the sense of smell in humans.26 The initial symptoms of olfactory dysfunction are often sensory and include a reduced sense of touch and smell.27,28 Hyposmia (loss of the sense of smell) is one of the most important symptoms for early detection of PD.29 The exact mechanism responsible for OS impairment in patients with PD is still unknown. However, there are various factors that are involved in the pathology of OS disorders. As described by Braak staging, a method used to categorize the degree of pathology in PD, LB pathology originating in the olfactory bulb and the dorsal nucleus of the vagus nerve corresponds to the early pathology of OS dysfunction.30 Autopsy revealed an early deposition of alpha-synuclein in the entorhinal cortex, the central nucleus of the amygdala, the piriform cortex, and the anterior olfactory cortex, which might be responsible for this symptom.31,32 Another factor implicated in OS impairment is changes in neurotransmitter (i.e., dopamine, acetylcholine, and serotonin) levels.33
Prevalence of olfactory system dysfunction and act as a biomarker in PD
A meta-study was conducted to estimate the prevalence of OS impairment in patients with PD in Europe and Australia. Among the 400 patients with PD, 51.7% had hyposmia, 45.0% had anosmia (partial or complete loss of smell), and 3.3% had a normal sense of smell.34 Haehner et al35 evaluated 474 patients with OS dysfunction, and 9.8% of patients were diagnosed with PD after a few years, suggesting that OS dysfunction may be an early sign of PD.
A meta-analysis was conducted to explore the prevalence of hyposmia in patients with PD. The authors collected data from various databases such as the Cochrane Library and PubMed. They used the Newcastle–Ottawa Scale and a pooled analysis (i.e., statistical methods used when pooling and evaluating the results of multiple epidemiological studies) in their assessment. There were 3272 patients with symptoms of hyposmia and 176 patients with PD with 3–17 years of follow-up. The pooled odds ratio for hyposmia in patients with PD was 3.84 (95% CI 2.12–6.95). The result of this meta-analysis suggest that OS impairment is directly involved in the pathogenesis of PD.36
In another study, the authors aimed to explore the relationship between cognition, anxiety, and OS impairment with disease severity in PD. They divided 105 patients with PD into 2 groups: those with anosmia and those with normal smell. The authors used the University of Pennsylvania Smell Identification Test (UPSIT), a commercially available test that involves identifying odors to assess the functioning of an individual’s OS; the Unified PD Rating Scale (UPDRS), an evaluation tool used to evaluate the severity and progression of PD; and the Beck Depression Inventory (BDI-II), a 21-item self-report inventory designed to assess the presence and severity of depressive symptoms. Based on the BDI-II and UPSIT scores, the odds ratios of developing anosmia with cognitive dysfunction and depression were 2.74 (95% CI 1.01—7.46) and 2.58 (95% CI 1.06—6.29), respectively. Based on the UPDRS scores, the odds ratio for anosmia was 12.26 (95% CI 5.69–18.82). The results indicate that an increased severity of OS impairment in patients with PD leads to cognitive dysfunction and increases the pathogenesis of PD.37
Skin disorders in PD
As PD progresses, it is common to experience changes in skin. Skin changes such as melanoma (a form of skin cancer), excessive sweating, seborrheic dermatitis (a common form of eczema that usually affects the scalp), and rosacea (a long-term inflammatory skin condition that causes the skin to become red and itchy, usually on the nose and cheeks) are common symptoms of PD (Table 2).38 Recent studies have shown an increased prevalence of skin cancer among people with PD. Research in the field of dermatology can help us understand the physiological processes that cause this common disorder. Skin manifestations have long been examined as markers of PD, and collective studies show an enhanced prevalence of various dermatological disorders in PD.39 Seborrheic dermatitis is recognized as a premotor characteristic of PD that indicates autonomic nervous system dysregulation.40 It should be noted that early diagnosis of PD can be detected not only by changes in the structure of the brain, but also by changes outside nervous tissues. Consistently, high concentrations of alpha-synuclein have been identified in the skin of patients with PD.41
- Types of skin manifestations and their clinical implications.
The relationship and exact mechanism between melanoma and PD are still unknown. A large study was conducted to explore the association between melanoma and PD, including 2,106 patients from North American countries. The prevalence of melanoma in patients with PD was 2 times higher than in healthy controls.42
Sweating dysfunction is also a common symptom in patients with PD. Studies have indicated that about 38% of patients with PD complained of hyperhidrosis (increased sweating) and 15% of patients with PD had hypohydrosis (decreased sweating).43 In a Spanish case-control study, 56 patients with bullous pemphigoid and 112 healthy people were examined. The authors concluded that the prevalence of bullous pemphigoid was 17.9% in patients with PD and 3.6% in healthy people.44
As mentioned above, alpha-synuclein is abundant in the central nervous as well as the peripheral autonomic nervous system. Biomarkers that allow accurate detection of dysfunctional alpha-synuclein metabolism have been discovered in the peripheral nervous system and the skin.45 In one study, researchers evaluated the presence of alpha-synuclein in the skin of 17 healthy individuals and 17 patients with PD. Patients with PD had substantially more alpha-synuclein than healthy individuals.46
In one study, seborrheic dermatitis and hyperhidrosis were evaluated in 70 patients with PD and 22 healthy controls. Overall, 18.6% of patients had forehead seborrhea (excessive secretion of sebum from the sebaceous glands), and 51.4% showed normal sebum values after using non-invasive bioengineering methods. Hyperhidrosis was found in 36 patients and they had a lower pH on their foreheads than healthy controls. Seborrhea is uncommon in treated patients, but hyperhidrosis is commonly present in patients with PD.47-50
Conclusion
Parkinson’s disease is a complex neurological disorder that involves an interplay between central and autonomic nervous system. Motor symptoms are well known and well characterized in PD, however, non-motor symptoms often preceding diagnosis. Gastrointestinal abnormalities, notably dysphagia, constipation, bloating, and small intestinal bacterial overgrowth. Olfactory dysfunction emerges as a crucial feature for PD diagnosis, while skin disorders such as melanoma, excessive sweating, seborrheic dermatitis, and rosacea are common symptoms. A better understanding of non-motor symptoms in PD may lead to new diagnostic tools and therapeutic strategies.
Footnotes
Disclosure. Authors have no conflict of interests, and the work was not supported or funded by any drug company.
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