https://doi.org/10.36866/pn.123.32

Dr Alastair Noyce, Queen Mary University of London, UK

Dr Dayne Beccano-Kelly, Cardiff University, UK

Dr Sara Bandres-Ciga, National Institutes of Health, Bethesda, US

Dr Artur Schumacher Schuh, Universidade Federal do Rio Grande do Sul, Brazil

Dr Yared Zenebe, Addis Ababa University, Ethiopia

Bernadette Siddiqi, Michael J Fox Foundation, US

Neurodegenerative diseases, such as Parkinson’s disease (PD) and Alzheimer’s disease, increasingly rival infection, cancer and cardiovascular disease as leading global causes of death and disability (GBD 2016 Parkinson’s Disease Collaborators, 2018). Large increases in the burden of neurodegenerative diseases have been observed over the last two decades, with some of the greatest increases observed in low and low-middle income countries.

The pathological hallmarks of PD include severe and progressive depletion of dopaminergic neurones concentrated in the substantia nigra and widespread neuronal loss in other brain regions. In surviving neurones, there exist aggregations of abnormally folded proteins, with alpha-synuclein as the predominant constituent.

Once believed to be predominantly a motor disorder characterised by slowness, stiffness and tremor, PD is now recognised as a highly heterogeneous progressive disease, that manifests in the central,
autonomic and peripheral nervous systems. Non-motor manifestations of PD include changes in mood, autonomic function (constipation, erectile dysfunction, hypotension, bladder complaints), sleep disorders and loss of smell. There is no cure, despite effective symptomatic treatment for motor symptoms having been available for around 60 years.

Fundamental to the search for better treatment and cures is understanding the underlying pathophysiology of disease. As for other complex diseases, most investigation has been undertaken in persons of mainly European ancestry, residing in high-income countries, who are affluent and well educated. As such, our understanding of the genetic basis, environmental risk factors, clinical manifestations and response to treatment is heavily biased (Ben-Joseph et al., 2020). However, there is growing momentum to tackle the biases that foster and perpetuate inequality. In this article we will outline some of the work that has been done, the initiatives that are underway or beginning, and commitments that must be made to further erode inequality in our understanding of PD.

Research efforts thus far

To date there are limited examples of minoritised ethnic groups being included effectively into research programmes seeking to understand the basis of PD. Non-European cases of PD (both familial
and sporadic) were instrumental in our early understanding of important genes and pathways that are affected (Kitada et al.,1998; Hulihan et al., 2008). Yet nowadays, understanding of common genetic variation that underpins sporadic PD has largely been shaped by the inclusion of participants of white, European ancestry into genetic studies (Nalls et al., 2019). This is changing, as outlined below.

Studies exploring environmental risk factors for PD have also systematically failed to recruit persons of colour adequately, and so our understanding of the epidemiology of PD is also heavily skewed by this bias. Whilst studies describing clinical aspects of PD have been undertaken outside of Europe and North America, there exist few examples of clinical studies of PD undertaken in diverse populations in high-income countries. Of note, it is not just participant recruitment that has the potential for serious bias; standard assessments used within clinical studies are not well validated for use in minoritised groups and may lack “cultural fairness” (i.e. they may perform differently in different groups, again leading to bias).

Switching focus to low and low-middle income countries; more than a quarter of the world’s population resides in Africa and Latin America. With sustained economic growth and improved life expectancy, many more people in these regions are surviving to older age and the burden of age-related conditions such as PD is expected to grow. Despite the growing public health threat, scientific progress in these regions is very limited. The reasons are multifactorial; limited numbers of skilled healthcare workers, inadequate infrastructure, misconceptions in communities and social stigma, lack of funding or availability of resources more generally, and government/NGO commitment to other disease areas all play a role. For many African countries, the focus of health research is very much on infectious diseases, women’s health and reducing child mortality, rather than neurodegeneration. Even receiving an accurate diagnosis of PD and effective treatment may be improbable in some African countries, and PD research in Africa until recently has involved export of samples and data, rather than local capacity building (Dekker et al., 2020). In Latin America, there may be better general recognition of PD, but research is also limited and data are scarce. One possible exception is Brazil, a country that experienced steady increase in research productivity during the last two decades, attached to its economic growth. However, financial constraints and politics now threaten further progress.

Current initiatives to address knowledge gaps

The Global Parkinson’s Genetics Program (GP2), supported by the Aligning Science Across Parkinson’s (ASAP) initiative (Riley and Schekman, 2021), is an international, collaborative effort to understand the genetic basis of PD from a truly global perspective (gp2.org). It does this by generating and integrating clinical and genetic data from around the world, and similarly providing data access and training opportunities back to clinicians and researchers, wherever they are (GP2, 2021). One specific example of GP2’s commitment to increased representation of communities is the Black and African American Connections to Parkinson’s Disease (BLAAC PD) study. BLAAC PD has been set up with the hope that beyond genetics, this study will also serve as a foundational cohort to assess the diverse aspects of PD in this population. GP2 has also already partnered with investigators from Africa, East and South Asia, North, Central and South America, Europe, the Middle East, and Oceania.

The Latin American Research Consortium on the Genetics of PD (LARGE-PD) is a part of GP2, but independent in its own right. It was founded in 2005 with the goal of deciphering the genetic architecture (the sum contribution of genetic variation that underlies a given trait) of PD in the Latino population. LARGE-PD involves centres in 13 Latin America countries (large-pd.org) and, amongst several important projects exploring the genetic basis of PD in the region, it recently generated the first large PD case- control genome-wide association study of Latinos (Sarihan et al., 2021).

As part of the International Parkinson’s disease Genomics Consortium (IPDGC), the IPDGC Africa project has been created to improve the scientific understanding of PD and other neurodegenerative conditions in Africa. IPDGC Africa is formed by a collaborative group of scientists and clinicians from academic institutions in 12 African countries (https://www.ipdgc-africa.com/). IPDGC Africa aims to study the clinical and genetic diversity of PD in Africa with the goal of achieving equality and genetic discovery in this population.

These are just some examples of the initiatives that will generate valuable data in the effort to uncover the molecular complexity underlying PD aetiology. Equally important will be the emergence of a new vibrant network of researchers from areas previously underrepresented in science, and generating new research capacity where it is much needed.

Diversity, equality, and inclusivity in research leadership

Although an important step in the right direction, it is not enough to simply be more inclusive when it comes to recruitment and participation in research. Gender diversity in senior roles and in management is recognised to be associated with greater performance and better decision-making. Few could argue against the benefits of having better representation of women at senior levels, yet unconscious bias and large gaps still exist, and in many cases the COVID-19 pandemic may have widened these. Representation from persons of colour in senior roles across all sectors is lacking and has not yet been tackled with the same energy as gender diversity efforts.

In the UK, evidence from the UK All-Party Parliamentary Group inquiry on equity in the STEM workforce showed that when it comes to ethnicity, at least at a high level, parity exists relative to the rest of the UK workforce. However, these data do not paint a complete picture. For instance, the Higher Education Statistics Agency reported that only 1% of all academic staff were Black, whilst individuals who identify as Black comprise 2.7% of the workforce. Notably none of these are employed at professor level within the areas of physiology and anatomy. This in turn suggests underrepresentation of certain groups in the most senior roles.

Priorities from a funder’s perspective

Research funders are increasingly utilising their unique position to advance diversity and inclusion in PD research, recognising that previous efforts do not reflect the real- world diversity of those living with disease. In 2020, The Michael J. Fox Foundation (MJFF), the world’s largest non-profit funder of PD research, revised one of its core funding initiatives (the Therapeutic Pipeline Program) to request community partnerships and inclusive recruitment plans (Michael J. Fox Foundation, 2021). Moreover, MJFF offered all applicants invited to the final stage of grant review a free consultation with community engagement experts to support their development of inclusive recruitment strategies. These efforts seek to change the landscape of PD research so that data more accurately represent the whole PD community and improve the generalisability of research findings.

Other examples funded by the MJFF include work to understand the barriers and motivations to research participation for underrepresented groups, through the Fostering Inclusivity in Research Engagement for Underrepresented Populations in Parkinson’s Disease (FIRE-UP PD) study. Most recently, the MJFF launched a dedicated funding initiative focused on PD research in underrepresented populations. The Promoting Diversity, Equity and Inclusion in Parkinson’s Disease Research call is aiming to support research on the incidence, aetiology, pathology, clinical presentation, and/or access to care in underrepresented populations. Over 90 research proposals have been received from around the world and funded initiatives will aim to build a more holistic understanding of PD, to the benefit of all.

Similar momentum is beginning in the UK to address ethnic disparities in PD research participation. Parkinson’s UK has assembled a steering group of members of the PD community from diverse backgrounds and is partnering with organisations embedded in underrepresented communities to tackle related issues and accelerate progress.

Conclusion

A problem such as PD, which affects the global population, requires global representatives to better understand it and to deliver global solutions. Here the term “global” is used not only to describe a “worldwide” context, but one that is comprehensive, inclusive, and equitable. It should be noted that these issues are not unique to PD and action is required in many disease areas. Momentum may be starting to build, not only in PD, but in other conditions too, such as multiple sclerosis (Wood, 2021). Increasing representation in research is not simply about paying “lip service” to an agenda, it is fundamental to achieving a better understanding of the pathways and mechanisms, and a brighter future with respect to treatment and, one day, cure.

References

Ben-Joseph A et al. (2020). Ethnic variation in the manifestation of Parkinson’s Disease: A narrative review. Journal of Parkinson’s Disease 10(1), 31-45. https://doi.org/10.3233/JPD-191763

Dekker MCJ et al. (2020). Parkinson’s Disease research on the African continent: Obstacles and opportunities. Frontiers in Neurology 11, 512. https://doi.org/10.3389/fneur.2020.00512

GBD 2016 Parkinson’s Disease Collaborators (2018). Global, regional, and national burden of Parkinson’s disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurology 17(11), 939-953. https://doi.org/10.1016/S1474-4422(18)30295-3

Global Parkinson’s Genetics Program, 2021. GP2: The Global Parkinson’s Genetics Program. Movement Disorders 36(4), 842-851. https://doi.org/10.1002/mds.28494

Hulihan MM et al. (2008). LRRK2 Gly2019Ser penetrance in Arab-Berber patients from Tunisia: a case-control genetic study. Lancet Neurology 7(7), 591-594. https://doi.org/10.1016/s1474-4422(08)70116-9

Kitada T et al. (1998). Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392(6676), 605-608. https://doi.org/10.1038/33416

Michael J Fox Foundation (2021). Therapeutic Pipeline Program. https://www.michaeljfox.org/grant/therapeutic-pipeline-program-2

Nalls MA et al. (2019). Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurology 18(12), 1091-1102. https://doi.org/10.1016/S1474-4422(19)30320-5

Riley EA and Schekman R (2021). Open science takes on Parkinson’s disease. Elife 10, e66546. https://doi.org/10.7554/eLife.66546

Sarihan EI et al. (2021). Genome-wide analysis of copy number variation in Latin American Parkinson’s Disease patients. Movement Disorders 36(2), 434-441. https://doi.org/10.1002/mds.28353

Wood H (2021). Racial differences in the response to multiple sclerosis therapy. Nature Reviews Neurology 17, 327. https://doi.org/10.1038/s41582-021-00507-7