Parkinson's disease (PD), the second most common neurodegenerative disease after Alzheimer's disease, affects 1% of people over 60 years of age. In the past three decades, the number of PD cases has doubled globally from 2.5 million in 1990 to 6.1 million in 2016. As of 2022, there are ~10 million PD cases globally. In the United States, the estimated prevalence of PD by 2030 is estimated will be ~1.24 million. These numbers are expected to increase as life expectancy and the age of the general population increase. PD is considered to be a multisystem and multifactorial disease, where many factors, such as the environment, gut, lifestyle and genetics, play a significant role in the onset and progression of the disease.
Pathology
The neuropathological hallmarks of PD include the loss of dopaminergic neurons in the substantia nigra pars compacta region of the brain (shown in figure) and the presence of aggregated alpha-synuclein. Under physiological conditions, alpha-synuclein, a protein encoded by the SNCA gene, is found at the synapses of neurons, where it regulates synaptic signaling and plasticity by modulating the release of neurotransmitters. It is most abundantly found in the brain and to a smaller extent in other tissues, such as the gut and heart. Under pathological conditions in PD, alpha-synuclein undergoes a conformational change, resulting in a misfolded insoluble protein that aggregates into beta-sheets and forms protein inclusions called Lewy Bodies. Aggregated alpha-synuclein loses its ability to bind at the membrane, disrupting cellular processes and synaptic formation. It is hypothesized to propagate in a prion-like manner, spreading within and between other cells, eventually leading to neurodegeneration, which is seen in the illustration with the loss of dopaminergic neurons. These pathological changes are also found peripherally (outside of the central nervous system - CNS) in early stages of PD. However, the mechanisms involved in these changes are not well understood.
Symptomology
The clinical presentation of PD include both motor and non-motor symptoms. The cardinal motor symptoms of PD are rigidity, abnormal gait, resting tremor, stiffness, bradykinesia, and dystonia. Non-motor symptoms include autonomic dysfunction, olfaction dysfunction, cognitive impairment, urinogenital complications, hyposmia, depression, asymmetric vague shoulder pain, gastrointestinal (GI) dysfunction, and REM sleep behavior disorder (acting out dreams during REM). In early stages of PD, non-motor symptoms occur prior to the onset of motor symptoms, contributing to a delay in PD diagnosis and even misdiagnosis in up to 15% of cases. By the time motor symptoms appear and treatment is initiated, there is already over 50% dopaminergic neuronal cell loss in the substantia nigra. Therefore, non-motor symptoms are valuable biomarkers of early stages of PD and provide a potential avenue for early disease diagnosis and early intervention.
Gastrointestinal dysfunction GI symptoms can occur up to 20 years prior to the onset of clinical motor symptoms. The potential involvement of the gut in PD was first suggested over 200 years ago by James Parkinson, who describes PD as “a disordered state of the stomach and bowels (that) may induce a morbid action in a part of the medulla spinalis”. However, this crosstalk between the gut and the brain was not fully understood and was not extensively explored in PD until more recently in the last two decades. There is increasing evidence that have further reported on the role of gastrointestinal (GI) dysfunction in the initiation of neurodegeneration as well as the pathogenesis of PD. In the upper GI tract, dysphagia is a swallowing impairment that results in inadequate mastication (chewing), body mass index below than 20, weight loss and malnutrition. Drooling is also common as a result of the difficulties with swallowing and not with saliva secretion, which is actually decreased in PD. Oropharyngeal dysphagia results in choking or aspiration. Swallowing involves three phases - oral, pharyngeal, esophageal, of which the first two are affected in oropharyngeal dysphagia. This motor symptom affects 35% of patients and worsens with the disease progression, but does improve with medication. Gastroparesis results in the paralysis of the stomach that contributes to 50% of patients feeling bloated and full while 15% experience vomiting and nausea. Solid meal scintigraphy as well as a breath test are used to measure gastric emptying time (GET), which is prolonged in PD patients. Other methods include MRI based imaging and electromagnetic capsule system. Small intestinal bacterial overgrowth (SIBO): results in diarrhea, abdominal discomfort, bloating and can lead to absorption issues of PD medications. In the lower GI tract, constipation is characterized by straining during defecation or having less than 3 bowel movements per week, which occurs in 40-50% of PD patients.
Microbiome-GBA dysfunction in PD
Braak's hypothesis Aggregated alpha-synuclein pathology in the GI ENS of PD patients was only unveiled in the 1980s. Within the GI tract, pathology has a rostral-caudal gradient pattern with no pathology in the upper esophagus to the most affected regions in lower esophagus (contributing to the swallowing symptoms) and the stomach, followed by sparse pathology in the colon. Autopsy studies performed in PD patients showed pathology in the DMNV, olfactory bulb and vagus nerve. Based on these findings, Braak et al. proposed a retrograde spreading of alpha-synuclein (known as Braak's theory), where the dysfunction of the gut (resulting from altered microbiota or other contributing factors discussed below) triggers the aggregation of alpha-synuclein within the gut prior to spreading to the brain. This was further supported by the decrease in PD risk with truncal vagotomy, a procedure that involves the cutting of the fibers in the vagus nerve that connect to the stomach. Additionally, many animal studies have shown the bi-directional movement of alpha-synuclein between the CNS and ENS. Alpha-synuclein can be detected in the visceral motor nerve terminals and the preganglionic vagus nerve after the overexpression of alpha-synuclein in the midbrain of rats. Conversely, injections of preformed fibrils (pathological alpha-synuclein) into the colon of mice induced pathological changes in endogenous alpha-synuclein in the brainstem.
… excerpt ends here. Continue reading the full article.
