The diversity of Parkinson's disease manifests itself first and foremost in the physical and mental aspects of the symptoms. Somatic symptoms include bradykinesia, tremor, involuntary movements, stiffness, difficulty walking, and imbalance. Mentally manifested, difficulty sleeping, speech impairment, dysesthesia, and dementia.
In terms of psychiatric symptoms, Parkinson's disease is the second most common progressive dementia disease after Alzheimer's disease, with an estimated 10 million people worldwide, about 3 million in China, and nearly 1 million in the United States. Moreover, Parkinson's disease is not exclusive to the elderly and can occur at all ages, from adolescence to old age. The incidence of Parkinson's disease has doubled in the last 25 years, which may be related to population growth, aging, genetic predisposition, lifestyle changes, and environmental pollution.
One of the great similarities between Parkinson's disease and Alzheimer's disease is that the cause of the disease is still unknown. Past and new studies have shown that the diversity of Parkinson's disease is also manifested in the causes of its onset, both biomolecular and genetic, as well as psychosocial.
An elderly man with Parkinson's disease held his arm with his hand and tried to drink the soup. Visual China|Figure
From a genetic point of view, the 2024 Breakthrough Prize in Life Sciences is awarded to research results on the genetic causes of Parkinson's disease. Ellen Sidransky (USA), Thomas Gasser (USA) and Andrew Singleton (UK) shared the award for discovering the most common genetic cause of Parkinson's disease.
Sidlansky found that mutations in the GBA1 gene, which encodes an enzyme that breaks down fatty substances in cells, are genetic risk factors for Parkinson's disease; Gasse and Singleton independently found that mutations in the LRRK2 gene (also known as tremin, an important gene for Parkinson's disease that currently causes chromosomal dominant inheritance) led to increased activity of a protein encoded by this gene that damages neurons.
However, the genetic causes of Parkinson's disease are only one aspect, and a new study has revealed some of the pathologies and causes of Parkinson's disease from a neuromolecular perspective, thus linking Parkinson's disease to Alzheimer's disease (senile dementia).
A team of researchers from Arizona State University in the United States published a study in the February 2024 issue of the journal Brain suggesting that tau may play a role in the early stages of Parkinson's disease, and that tau protein aggregates initiate the process of neuronal damage and death characteristic of Parkinson's disease.
Past studies have suggested that α-synuclein is a typical diagnostic marker for Parkinson's disease, as it is thought to play a major role in the pathogenesis of Parkinson's disease. However, studies by researchers in the United States have now shown that α-synuclein is not the main cause of Parkinson's disease.
Researchers studied the posthumous brain tissue of older adults with no movement impairment and varying degrees of movement impairment (one of the main symptoms of Parkinson's disease), focusing on analyzing and comparing the brain tissue of people without movement disorders, those with mild movement disorders with and without Lewy body lesions in the substantia nigra area of the brain, and the brain tissues of patients with clinically diagnosed Parkinson's disease.
Lewy bodies, or α-synuclein, are the abnormal aggregation of the latter in the brain, which has also become a hallmark of many neurodegenerative diseases, including Parkinson's disease and Lewy body dementia. In cases of Parkinson's disease, Lewy bodies are predominantly found in the substantia nigra of the brain, an area that is essential for motor control and causes characteristic motor symptoms such as stiffness, tremor, and bradykinesia.
The U.S. researchers focused on analyzing a group of subjects with mild movement impairments who were not obvious enough to be diagnosed with Parkinson's disease, but still had more severe movement disorders. The researchers divided these people based on the presence or absence of α-synuclein and found that the tau protein in their brains had a common buildup in one area.
The brain tissue of those who died with mild motor impairment showed similar tau accumulation to the brain tissue of those who died of advanced Parkinson's disease, and was predominantly concentrated in the substantia nigra striatum region of the brain, suggesting that the action of tau occurred in the early stages of Parkinson's disease. This discovery means that tau protein can be used as a marker for early diagnosis and detection of Parkinson's disease, and it can also be used to co-treat Parkinson's disease and Alzheimer's disease by resisting and reducing tau protein.
At present, there are two well-recognized triggers for the etiology of Alzheimer's disease, one is the presence of neurotoxic β amyloid (A?) deposits in the brain and the formation of neurofibrillary tangles, and the hyperphosphorylation of tau protein (tau is a microtubule-associated protein involved in microtubule stabilization) also forms neuronal fibrillary tangles, so Alzheimer's disease is associated with the excessive deposition of β amyloid and tau proteins.
Like other diseases, the onset of Parkinson's disease has psychosocial factors. A study published on April 8, 2024 by a team of researchers from Fudan University showed that people with severe social isolation had a 19% higher risk of developing Parkinson's disease than those with mild social isolation. The study used participant data from the UK Biobank in 192,340 people aged 60 years or older who were initially free of dementia and Parkinson's disease, and 2,048 people developed Parkinson's disease during follow-up.
At the same time, the onset of Parkinson's is also related to genetics. In the high genetic risk group, people with severe social isolation had a 28% increased risk of future Parkinson's disease, but in the low genetic risk group, no association between social isolation and Parkinson's disease was found. This suggests that genetic and social isolation are synergistic causes of morbidity.
Social isolation refers to the lack of meaningful social connections, which can be judged by ratings. For example, whether you live alone (1 point for living alone), whether you have friends (1 point for less than 1 month), and whether you participate in leisure or social activities (1 point for not participating in activities). The scores are summed to give a score of social isolation (0-3), with higher scores indicating more severe social isolation.
Social isolation has been linked to the development of several diseases, such as an increased risk of depression, dementia, cardiovascular disease, and early death, and has now also been shown to be associated with Parkinson's disease. Moreover, Parkinson's patients with social isolation have a lower quality of life and a higher mortality rate.
Loneliness and isolation are linked to the onset of Parkinson's disease, which has been shown in larger studies. In November 2023, the Journal of the American Medical Association Neurology published the results of a study by a team of researchers from Florida State University College of Medicine. A 15-year follow-up of nearly 500,000 participants found that loneliness was associated with a 37% increased risk of Parkinson's disease. Loneliness was associated with a 25% increased risk of Parkinson's disease after combining factors such as demographic sociological factors, socioeconomic status, social isolation, Parkinson's polygenic risk score, smoking, exercise, body mass index (BMI), diabetes, hypertension, stroke, myocardial infarction, depression, and psychiatric experience.
The study also used participant data from the UK Biobank, and whether or not they felt lonely was reported by the participants themselves via a questionnaire. The study included 491603 participants, aged 38-73 years, with 54.4% of women and 45.6% of men. At 15.58 years of follow-up, 2822 participants were diagnosed with Parkinson's disease, of which 2273 did not feel lonely and 549 felt lonely.
The main conclusion of the US study was that participants who felt lonely had a 37% increased risk of developing Parkinson's disease compared to those who did not report loneliness, and this association was largely consistent across different risk assessment models, still showing an association between loneliness and Parkinson's disease risk after adjusting for factors such as age, gender, smoking, exercise, etc.
More notably, participants with loneliness still had a 32% increased risk of Parkinson's disease after additional corrections for physical health factors such as body mass index, diabetes, hypertension, myocardial infarction, and stroke, suggesting that loneliness is an important cause of Parkinson's disease.
Psychological and social factors work through biological and physiological factors. Studies from Fudan University and Florida State University also point to this relationship.
The Fudan University research team speculated that social isolation increases the risk of Parkinson's disease through biological mechanisms, which may be due to the imbalance of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, increased neuroinflammation and oxidative stress. At the same time, social isolation may limit people's access to social support and medical resources, making it difficult to control risk factors for Parkinson's disease in a timely manner, which can also increase the risk of developing the disease.
The Florida State University research team believes that, based on research findings, loneliness may increase the risk of Parkinson's disease through multiple pathways, such as metabolic, inflammatory, and neuroendocrine pathways. At the same time, researchers speculate that there may also be other factors in the pathogenesis of Parkinson's disease, such as neuromicroglia-mediated neuroinflammation in the brain.
The research team from Fudan University and Florida State University pointed out that the biological and physiological mechanisms by which loneliness may induce Parkinson's disease still need to be directly proved by more studies in the future. However, since studies in China and the United States have proven that loneliness and isolation are important triggers of Parkinson's disease, there is a need for corresponding intervention methods and mechanisms to prevent it.
Some simple intervention mechanisms may also be effective. For example, participating in social interactions, whether online or offline, avoiding the elderly living alone, and having some movement and visits between relatives and friends, will reduce people's loneliness, not only to prevent Parkinson's disease, but also to prevent other diseases, such as depression, cardiovascular and cerebrovascular diseases, cancer, etc.
ZHANG Tiankan
Editor-in-charge: Zhu Liyuan