Biomarkers of Parkinson’s Disease

Abstract

Background

Parkinson’s disease (PD) is a degenerative brain disease characterised by motor and non-motor symptoms. Motor disabilities, including dystonia and dyskinesia, cause speech and movement difficulties and limit many aspects of life. Factors affecting PD refer to the various internal and external conditions that contribute to the onset, severity and progression of the disease. These factors can be broadly categorised into genetic, environmental and lifestyle-related factors.

Summary

The primary objective of this prospective cohort study is to investigate the association between environmental exposures and genetic predisposition and the risk of developing PD. Secondary objectives include examining the relationships between these factors and clinical outcomes in PD, such as disease severity and progression. We have utilised the data from other research studies, which primarily involve recruiting a cohort of individuals at high risk for PD based on their family history and/or environmental exposure history. These research studies also include participants who will undergo clinical evaluations, including neurological examinations and cognitive assessments, and provide biospecimens for genetic analysis. Environmental exposure histories will be obtained through questionnaires and medical records fetched by the authors of these research studies. In all these studies, participants were followed up regularly over several years to monitor the development of PD and to assess disease progression.

Key message

This study provided valuable insights into the role of environmental exposures and genetic predisposition in the development and progression of PD. The results of this study may inform strategies for preventing or delaying the onset of PD in high-risk individuals, as well as guide the development of targeted interventions for those already diagnosed with the disease.

Introduction

According to the World Health Organization, Parkinson’s disease (PD) is a degenerative brain disease characterised by motor and non-motor symptoms. Motor disabilities, including dystonia and dyskinesia, cause speech and movement difficulties and limit many aspects of life. ¹ Also, many people with PD develop dementia as the disease progresses. The development of all these symptoms leads to a high prevalence of deterioration and serious patient care.

PD is the most common movement disorder in addition to progressive supranuclear palsy, ataxia, dystonia, multiple system atrophy and chorea. ² Tremor, stiffness and slow movement are notable symptoms of PD. All movement disorders have the same problem with access to medication, diagnosis and treatment gaps, especially in low- and middle-income countries.

Compared to any other neurological condition, PD causes the most deaths and disabilities worldwide. In the past 25 years, the prevalence of PD has doubled. It is estimated that more than 8.5 million people worldwide will have PD in 2019. ³ According to current estimates, PD caused 5.8 million disability-adjusted life years to be lost in 2019, an increase of 81% since 2000. It was also responsible for 329,000 deaths in 2019, an increase of more than 100% since 2000.

While the young can also be affected, old age is a risk factor for developing PD. About 5% to 10% of people with PD have symptoms before the age of 50 years. However, it is often diagnosed after the age of 60 years. ² PD is usually, but not always, inherited with an early onset, and some differences have been associated with distinct genetic changes. It has been observed that men are more likely to develop PD than women.

Even though the exact aetiology of PD is unknown, numerous studies have demonstrated that it results from a dynamic interplay between hereditary factors and environmental variables such as pesticides, solvents, and air pollution exposure throughout life.

Individuals with PD frequently target stigma and prejudice, including unfair job discrimination and a lack of chances for engagement and community participation. ⁴

Like the general community, people with PD need adequate health services for their basic requirements, including medications, promotional and preventative programmes, and quick diagnosis, treatment and care. ⁵ Healthcare professionals’ lack of awareness and comprehension of PD and the misconceptions that it is a contagious illness or an essential part of ageing are significant barriers.

The World Health Assembly approved the Global Intersectoral Action Plan on Epilepsy and Other Neurological Disorders 2022–2031 in May 2022. The Action Plan will address issues and gaps in care and services for people to provide a comprehensive and coordinated response across sectors. ⁶ People with epilepsy and other neurological diseases, such as PD, are widespread worldwide. ⁷ This includes improving governance, setting higher policy priorities, providing rapid, accurate and responsive diagnosis, treatment and care, implementing strengthening and prevention measures, promoting research and innovation and strengthening the information system.

Factors affecting PD refer to the various internal and external conditions that contribute to the onset, severity and progression of the disease. These factors can be broadly categorised into genetic, environmental and lifestyle-related factors. ⁸

Genetic factors: Certain genetic mutations have been linked to an increased risk of developing PD. For example, mutations in the SNCA gene can cause an overproduction of alpha-synuclein protein, which is a hallmark of PD. Other genetic mutations that have been linked to PD include LRRK2, PARK7 and PINK1. ⁹

Environmental factors: Exposure to certain toxins and chemicals has been linked to an increased risk of developing PD. ¹⁰ For example, exposure to pesticides, herbicides and other chemicals used in agriculture has been linked to an increased risk of PD. Other environmental factors that have been linked to PD include head injuries, viral infections and lack of access to clean drinking water. ¹¹

Lifestyle-related factors: Certain lifestyle factors can also affect the risk of developing PD. For example, smoking has been shown to increase the risk of PD, while exercise has been shown to reduce the risk. ¹² Other lifestyle-related factors that have been linked to PD include diet, alcohol consumption and exposure to sunlight.

Understanding the various factors that affect PD can help individuals and healthcare professionals develop strategies for preventing and managing the disease.

Research Objectives

• The primary objective of this cohort study is to investigate the association between environmental exposures and genetic predisposition and the risk of developing PD.

• The secondary objectives include examining the relationships between these factors and clinical outcomes in PD, such as disease severity and progression.

Hypothesis

Environmental factors, such as exposure to pesticides and other toxins, in combination with genetic predisposition, increase the risk of developing PD and its progression.

Methodology

We have utilised the data from other research studies, which primarily involve recruiting a cohort of individuals at high risk for PD based on their family history and/or environmental exposure history. These research studies also include participants who will undergo clinical evaluations, including neurological examinations and cognitive assessments, and provide biospecimens for genetic analysis. Environmental exposure histories will be obtained through questionnaires and medical records fetched by the authors of these research studies. In all these studies, participants were followed up regularly over several years to monitor the development of PD and to assess disease progression.

Expected Outcomes

This study will provide valuable insights into the role of environmental exposures and genetic predisposition in the development and progression of PD. The results of this study may inform strategies for preventing or delaying the onset of PD in high-risk individuals, as well as guide the development of targeted interventions for those already diagnosed with the disease.

Research Evidence

The below-mentioned data highlights the factors that can cause PD among adults in their 60s. Researchers highlighted the biological and environmental causes and focussed on oxidant stress as a significant factor that can cause PD even at an early age. Various authors in their study also provided a brief on prevention and treatment plans for PD.

This section is divided into three categories: biological factors, environmental factors and oxidative stress.

Biological Factors

Corti et al. (2011) studied what genetics tells us about the causes and mechanisms of PD. The research concluded that understanding the role played by protein byproducts may lead to the identification of neurodegenerative pathways common to hereditary and sporadic PD. Clinically, similar early-onset autosomal recessive PD variants produced by mutations in the Parkin and PINK1 genes, as well as DJ-1, strongly suggest that mitochondrial dysfunction plays an important role. This is supported by a good body of data from several animal systems. ¹² In contrast, the accumulation of alpha-synuclein in Lewy bodies is a feature of various diseases, including sporadic and autosomal dominant variants of PD and specific late-onset forms of PD and PD dementia. However, the pathogenic significance of Lewy bodies is unknown, as they may or may not be present in PD forms with the same LRRK2 mutation.

Schapira and Jenner (2011) researched on aetiology and pathogenesis of PD. The research is based on the activities of toxins, post-mortem studies, and gene deficiencies accountable for familial PD. It concludes that cell malfunction and death by apoptosis or autophagy are thought to be caused by mitochondrial failure, oxidative stress, altered protein synthesis and inflammatory changes. The most significant risk element for PD is age. The biochemical alterations that occur due to ageing increase these abnormalities in the PD brain—focussing on the processes that characterise PD, especially mitochondrial failure and Lewy body development, maybe the key to furthering our knowledge of aetiology and leveraging these pathways to identify targets for neuroprotection. The study suggests placing the mix and sequence of processes leading to cell death, and whether this is the same in all brain areas where pathology develops and in all PD. ¹³

Ammal Kaidery and Thomas (2018) discussed how familial PD genes and environmental variables interact with pathways that regulate the mitochondrial activity, possibly linking familial and sporadic PD at the level of mitochondrial integrity. It also provides an overview of the current status of treatments targeting mitochondrial dysfunction in PD. Uncovering the putative mechanisms of mitochondrial homeostasis in PD may be necessary for therapeutic intervention in this severe neurodegenerative movement disorder.

Panicker et al. (2021) researched the discovery of PARK genes implicated in PD’s uncommon, inheritable variants, improving our understanding of the disease’s biology. These genes encode proteins such as alpha-synuclein, LRRK2, VPS35, parkin, PINK1 and DJ-1, which can cause monogenetic PD when mutated. Investigating these proteins’ biological roles has helped uncover signalling pathways that cause pathology in PD and neuroprotective mechanisms that are active during homeostatic and pathological situations. Many PD-associated proteins now appear to have numerous activities in PD-associated signalling pathways in neurons. Furthermore, some PARK proteins participate in non-cell-autonomous neuron death pathways, such as neuroinflammation. The study suggests that a thorough knowledge of the cell-autonomous and non-cell-autonomous mechanisms involved in PD is required to develop treatments that may slow or stop its progression.

Hirsch et al. (2013) researched the pathogenesis of PD and suggested that variations in mitochondrial bioenergetics, disturbance of calcium homeostasis and reduced mitochondrial turnover are some of the proposed cell-autonomous processes. The potential non-cell-autonomous techniques include misfolded proteins that behave like prion diseases and neuroinflammation. This shows that a multifactorial cascade of pathogenic events contributes to cell death in PD and contends that numerous medication interventions may be required for a successful neuroprotective treatment.

Environmental Causes

Elbaz and Tranchant (2007) reviewed the epidemiological studies on environmental aetiologies in PD. It focuses on two ecological exposures consistently linked to PD—cigarette smoking and pesticide exposure—and will briefly summarise the findings for other directions. Understanding the processes behind these epidemiological relationships is critical for understanding the genesis of this neurodegenerative disease and, ideally, developing neuroprotective medicines.

Kieburtz and Wunderle (2013) examine environmental variables that may increase the risk of PD and the data supporting those factors. There is enough evidence to imply that ageing is a cause of PD. Gender, cigarette usage and caffeine are all linked to the development of PD. Other environmental variables (pesticide exposure, occupation, blood urate levels, nonsteroidal anti-inflammatory drug (NSAID) usage, brain damage and exercise) show inconsistent or limited evidence of a link to PD. It suggests that future studies must not overlook the influence of these environmental variables on the development of PD, particularly possible gene–environment interactions.

Chen et al. (2022) present all the authors’ perspectives on how the Braak and dual-hit theories may aid in the search for environmental triggers and modifiers of PD, summarises extant experimental and epidemiological evidence and discusses research gaps and solutions. It emphasises that new evidence supports the gut microbiota’s crucial involvement in PD pathogenesis and suggests that they may control or moderate the impact of environmental risk factors for PD.

Ball et al. (2019) used a mixed-method approach that includes both patient history and chemical analysis to understand environmental factors affecting PD, which increased research robustness, especially in population-based investigations. Environmental toxins, including heavy metals, pesticides and illegal substances, have been related to PD-associated neurodegeneration. These sources of exposure are directly related to rural living, lending credence to the notion that rural living may be a significant risk for PD. It suggests that each instance of PD is unique to the individual. Given the illness’s variability, one might speculate that individual vulnerability to environmental variables plays a significant part in PD pathogenesis. However, the complexity of PD only adds to the difficulties of determining its causation.

Rosas et al. (2022) aimed to determine how genetic and non-genetic factors influence the age of onset and survival in a cohort of 753 patients with PD, and how these variables are combined to determine absolute risk. Gender, cigarettes, alcohol, PD (genetic, gPD or idiopathic, iPD) and three genetic variants were considered: rs5848-GRN, rs1042522-TP53 and APOE. The researchers analysed two cohorts Parkinson’s Progression Markers Initiative (PPMI) and International Parkinson Disease Genomics Consortium (IPDGC) to reproduce the good results. Regarding the age at onset, smokers had a significantly lower mean age than non-smokers (P = .001). APOE-4 carriers showed a lower age of onset in the Spanish cohort than non-carriers (P = .03), but these results were not replicated in other cohorts.

Oxidative Stress

Elbaz and Tranchant (2007) reviewed the epidemiological studies on environmental aetiologist in PD. It focusses on two ecological exposures consistently linked to PD—cigarette smoking and pesticide exposure—and will briefly summarise the findings for other directions. Understanding the processes behind these epidemiological relationships is critical for understanding the genesis of this neurodegenerative disease and, ideally, developing neuroprotective medicines.

Kieburtz and Wunderle (2013) examine environmental variables that may increase the risk of PD and the data supporting those factors. There is enough evidence to imply that ageing is a cause of PD. Gender, cigarette usage and caffeine are all linked to the development of PD. Other environmental variables (pesticide exposure, occupation, blood urate levels, NSAID usage, brain damage and exercise) show inconsistent or limited evidence of a link to PD. It suggests that future studies must not overlook the influence of these environmental variables on the development of PD, particularly possible gene–environment interactions.

Chen et al. (2022) present all the authors’ perspectives on how the Braak and dual-hit theories may aid in the search for environmental triggers and modifiers of PD, summarises extant experimental and epidemiological evidence and discusses research gaps and solutions. It emphasises that new evidence supports the gut microbiota’s crucial involvement in PD pathogenesis and suggests that they may control or moderate the impact of environmental risk factors for PD.

Ball et al. (2019) used a mixed-method approach that includes both patient history and chemical analysis to understand environmental factors affecting PD, which increased research robustness, especially in population-based investigations. Environmental toxins, including heavy metals, pesticides and illegal substances, have been related to PD-associated neurodegeneration. These sources of exposure are directly related to rural living, lending credence to the notion that rural living may be a significant risk for PD. It suggests that each instance of PD is unique to the individual. Given the illness’s variability, one might speculate that individual vulnerability to environmental variables plays a significant part in PD pathogenesis. However, the complexity of PD only adds to the difficulties of determining its causation.

Rosas et al. (2022) aimed to determine how genetic and non-genetic factors influence the age of onset and survival in a cohort of 753 patients with PD, and how these variables are combined to determine absolute risk. Gender, cigarettes, alcohol, PD (gPD or iPD) and three genetic variants were considered: rs5848-GRN, rs1042522-TP53 and APOE. The researchers analysed two cohorts (PPMI and IPDGC) to reproduce the good results. Regarding the age at onset, smokers had a significantly lower mean age than non-smokers (P = .001). APOE-4 carriers showed a lower age of onset in the Spanish cohort than non-carriers (P = .03), but these results were not replicated in other cohorts. ¹⁴

Tanner (1992) reviews each group of agents known to cause parkinsonism, discussing familiar sources of exposure, the clinical course and proposed mechanisms of toxicity. Parkinsonism is defined and contrasted with PD, and general concepts essential to considering toxic effects on the central nervous system are noted. Manganese, carbon disulfide, organic solvents, carbon monoxide and related substances are some of the covered agents. ¹⁵

Surendran and Rajasankar (2010) researched that decreased expression of catecholamines and oxidative stress are the two main contributing factors to PD, a neurodegenerative condition. Tremor, stiffness, bradykinesia and postural impairment are symptoms of the illness. In PD, oxidative stress is a significant factor in neurodegeneration and motor impairments. These modifications alter the protein’s levels, which results in a malfunctioning ubiquitin-proteasome pathway. A similar process underlies the neurodegeneration present in Canavan disease, and PD. Recent research indicates that herbal medications may help with the molecular alterations and motor dysfunctions associated with PD.

Taylor et al. (2013) studied neuroinflammation in PD, with an emphasis on genetic and toxin-based models of the condition. These investigations have shown that pro-inflammatory responses and high oxidative stress occur early in the illness, and that these mechanisms either cause or worsen nigrostriatal degeneration. Furthermore, the experimental models covered here have shown compelling evidence that these pathways are a crucial connection between the familial and sporadic forms of PD. Anti-inflammatory therapies’ possible role in reducing the mortality of dopaminergic neuronal cells in these models is reviewed. Data suggest that more research into their usage in multi-targeted clinical trials is necessary. ¹⁶

Puspita et al. (2017) examined the function of oxidative stress in triggering several pathogenic processes that culminate in cell death in PD. Understanding the links between these events, with oxidative stress as the common denominator underpinning these processes, is required to design more effective treatment solutions. ¹⁷

Wei et al. (2018) aimed to quantitatively summarise the oxidative stress indicator data in PD patients’ blood and cerebrospinal fluid (CSF). Studies were considered if they provided information on oxidative stress markers in peripheral blood and CSF in PD patients and healthy control (HC) participants. This was done by a systematic search of PubMed and Web of Science. Three researchers independently retrieved data from the 80 included trials, which comprised 6,037 HC individuals and 7,212 PD patients. The meta-analysis confirmed the clinical evidence that PD is associated with increased oxidative stress by showing higher blood concentrations of 8-hydroxy-2′-deoxyguanosine (8-OhdG), malondialdehyde (MDA), nitrite and ferritin and lower blood concentrations of catalase, uric acid, glutathione and total cholesterol in PD patients.

Chen et al. (2021) conducted several systematic reviews (SRs) and meta-analyses on non-genetic risk factors for the onset of PD, with varying degrees of success. This summary of SRs sought to analyse the causes of the inconsistent findings and to summarise information on non-genetic determinants for the emergence of PD from the published SRs. It implies that changeable lifestyle elements such as exercise, tea and coffee consumption may lower the risk of PD, which may provide PD preventive techniques and research ideas for the future.

Discussion

The research on factors affecting PD reveals a complex interplay of biological, environmental and oxidative stress-related factors. This multifaceted aetiology underscores the challenges in both understanding and treating the disease, highlighting the need for a comprehensive approach to PD research and management.

Biological factors, particularly genetic mutations, play a significant role in PD pathogenesis. Mutations in genes such as SNCA, LRRK2, VPS35, parkin, PINK1 and DJ-1 have been linked to monogenetic forms of PD (Panicker et al., 2021). ¹⁸ These genetic factors contribute to various cellular dysfunctions, including mitochondrial impairment, oxidative stress and protein aggregation, which are hallmarks of PD (Corti et al., 2011; Schapira & Jenner, 2011). The discovery of these genetic links has not only improved our understanding of PD mechanisms but also opened up new avenues for targeted therapies and early detection strategies. ¹³

Environmental factors have also been consistently associated with PD risk, demonstrating the importance of external influences on disease development. Exposure to pesticides, herbicides and other agricultural chemicals has been linked to increased PD risk (Ball et al., 2019; Elbaz & Tranchant, 2007). This association underscores the potential impact of occupational and residential exposures on neurological health. Interestingly, certain lifestyle factors such as cigarette smoking and caffeine consumption have been associated with a decreased risk of PD (Kieburtz & Wunderle, 2013). ¹⁹ This paradoxical protective effect of smoking highlights the complex nature of PD aetiology and suggests potential avenues for neuroprotective strategies. However, it also raises important questions about the mechanisms underlying these protective effects and how they might be harnessed without the harmful consequences associated with smoking. ²⁰

Oxidative stress emerges as a critical factor in PD pathogenesis, serving as a common denominator in various pathogenic processes. The meta-analysis by Wei et al. (2018) provided strong clinical evidence for increased oxidative stress in PD patients, demonstrating altered levels of various oxidative stress markers in blood and CSF. This finding not only supports the central role of oxidative stress in PD but also suggests potential targets for therapeutic interventions. Antioxidant therapies, for instance, might prove beneficial in slowing disease progression or even preventing onset in high-risk individuals. However, the challenge lies in developing interventions that can effectively target the specific oxidative processes involved in PD without disrupting the normal redox balance in healthy cells. ²¹

The interaction between genetic predisposition and environmental exposures appears to be crucial in PD development, pointing to a gene–environment interaction model of disease aetiology. For instance, Chen et al. (2022) proposed that the gut microbiota might mediate or moderate the effects of environmental risk factors on PD pathogenesis. This intriguing hypothesis not only highlights the need for a more holistic approach to studying PD aetiology but also opens up new possibilities for interventions targeting the gut-brain axis. It suggests that dietary modifications or probiotic treatments could potentially influence PD risk or progression, although more research is needed to confirm these potential effects.

Recent research has also emphasised the potential of modifiable lifestyle factors in PD prevention. Chen et al. (2021) suggested that exercise, tea and coffee consumption may lower PD risk, providing valuable insights for preventive strategies. These findings are particularly important, as they offer hope for individuals at high risk of PD, suggesting that lifestyle modifications could potentially delay or even prevent disease onset. However, it is crucial to note that the protective effects of these factors may vary among individuals, and more research is needed to understand the optimal ‘dosage’ and timing of these interventions. ²²

The role of ageing in PD development is another critical area of investigation. As the primary risk factor for PD, understanding how age-related changes in the brain contribute to disease onset and progression could provide valuable insights into potential interventions. Future research should explore how age-related processes such as cellular senescence, mitochondrial dysfunction and chronic inflammation interact with genetic and environmental risk factors to promote PD pathogenesis. ²³

However, it is important to note the limitations of current research. Many studies face challenges such as selection bias, measurement bias and the difficulty of establishing causality in observational studies. Long-term cohort studies, while valuable, are often constrained by time and cost factors, which may limit sample sizes or the breadth of data collection. Additionally, the heterogeneity of PD, with its varied clinical presentations and progression rates, complicates efforts to identify universally applicable risk factors or interventions. ²⁴

Moreover, the potential for publication bias in the field cannot be overlooked. Positive findings are more likely to be published, which could lead to an overestimation of the effects of certain risk factors or protective agents. ²⁵ Future research should aim to address these limitations through improved study designs, larger and more diverse cohorts and more comprehensive data collection methods.

Limitations

Some potential limitations are as follows:

Selection bias: The study may be limited by selection bias if the cohort of participants is not representative of the broader population. Participants who agree to enrol in the study may differ systematically from those who do not, which could impact the generalisability of the findings.

Measurement bias: The study may be limited by measurement bias if the methods used to assess environmental exposures, genetic predisposition or clinical outcomes are not accurate or reliable. This could result in misclassification of exposure or outcome status, which could bias the study results.

Follow-up bias: The study may be limited by follow-up bias if participants who drop out of the study differ systematically from those who remain, or if participants do not adhere to the study protocol. This could impact the accuracy and completeness of the data collected over time.

Confounding: The study may be limited by confounding if there are unmeasured or unknown factors that are associated with both the exposure and outcome of interest. This could make it difficult to disentangle the effects of environmental exposures and genetic predisposition on the risk and progression of PD.

Causality: While the study may provide evidence of associations between environmental exposures, genetic predisposition and PD risk and progression, it may not be able to establish causality due to the inherent limitations of observational studies. Further experimental research would be needed to establish causality.

Time and cost constraints: Long-term cohort studies such as this one can be expensive and time-consuming, which may limit the sample size, length of follow-up or breadth of data collection. These constraints may impact the generalisability of the findings or limit the ability to explore other potential factors affecting PD.

It is important to acknowledge these limitations and address them as much as possible to ensure the validity and reliability of the study results.

Conclusion

The aetiology of PD is multifactorial, involving a complex interplay of genetic predisposition, environmental exposures and oxidative stress. While significant progress has been made in identifying risk factors and understanding pathogenic mechanisms, many questions remain unanswered. ²⁶ The complexity of PD aetiology underscores the need for a personalised medicine approach, recognising that the relative importance of different risk factors may vary among individuals.

Future research should focus on elucidating the interactions between different risk factors and exploring potential protective factors. Long-term prospective studies that combine genetic analysis, environmental exposure assessment and clinical outcomes are needed to provide a more comprehensive understanding of PD aetiology. These studies should also incorporate emerging technologies, such as advanced neuroimaging techniques and high-throughput genetic sequencing, to provide more detailed insights into disease mechanisms and progression. ²⁷

The identification of modifiable risk factors offers hope for developing preventive strategies. However, translating these findings into effective interventions requires further research and careful consideration of individual variability in PD susceptibility and progression. Clinical trials of potential preventive interventions, such as antioxidant therapies or lifestyle modifications, should be designed with long-term follow-up to assess their impact on PD risk and progression.

Moreover, future research should also focus on understanding the mechanisms underlying the protective effects observed with certain lifestyle factors. This could potentially lead to the development of novel therapeutic approaches that mimic or enhance these protective effects, without the associated risks of factors such as smoking.

The role of early detection and intervention in PD management cannot be overstated. As our understanding of PD risk factors improves, there is potential for developing more accurate risk assessment tools. These could enable the identification of high-risk individuals who might benefit most from preventive interventions or closer monitoring for early signs of disease.

Ultimately, a multidisciplinary approach that integrates insights from genetics, environmental science, neurobiology and clinical research will be crucial in advancing our understanding of PD and developing more effective prevention and treatment strategies. This approach should also consider the potential impact of socioeconomic factors and healthcare disparities on PD risk and outcomes, ensuring that future interventions are accessible and effective for all populations. ²⁸

As we move forward, it will be essential to maintain a balance between pursuing promising lines of research and remaining open to new and unexpected findings. The complex nature of PD means that breakthrough insights could come from any area of study, and maintaining a broad, interdisciplinary approach will be key to making meaningful progress in our understanding and management of this challenging disease.