Greater inclusion of females in studies shows promise for pushing the boundaries of knowledge and precision treatments.

Dr. Samantha Schaffner’s interest in genetics and neurodegeneration took on a new meaning as people close to her were diagnosed with Alzheimer’s disease or Parkinson’s disease (PD). Under the supervision of Vancouver Coastal Health Research Institute researcher Dr. Silke Appel-Cresswell, Schaffner’s research explored the under-investigated realm of sex difference in PD, highlighting opportunities to push research into new directions toward novel discoveries and transformative treatments. 

Dr. Samantha Schaffner is a research associate in the Appel-Cresswell Lab, Pacific Parkinson’s Research Centre, Djavad Mowafaghian Centre for Brain Health and Edwin S. H. Leong Centre for Healthy Aging.

Affecting over 100,000 Canadians, PD is an incurable, chronic neurological condition with a genetic component.

“We know that estrogen has a neuroprotective effect against PD in women, but we do not have enough information on how other sex differences, including genotype and gender-based lifestyle factors, may be contributing to alterations in brain health and risk of developing PD,” states Appel-Cresswell. 

“Greater knowledge of the role of sex-dependent genetics, gene regulation, sex hormones and lifestyle factors in PD can lead to breakthroughs in our understanding of the disease and how we care for patients.”

Biological males have historically been over-represented in research, while females have been underrepresented and, in the past, even excluded from participating in clinical trials. Heightened awareness of this shortfall has initiated new protocols and procedures in research to achieve greater representation from different sexes in non-sex-specific clinical trials, for example, to test a new PD medication designed to treat all patients.

Dr. Silke Appel-Cresswell is a movement disorder neurologist and associate professor of medicine/neurology at the University of British Columbia (UBC). She is also the director of the Pacific Parkinson’s Research Centre and the UBC Movement Disorders Clinic.

Published in Biology of Sex Differences and conducted in collaboration with University of Saarland researcher Dr. Julia Schulze-Hentrich, Appel-Cresswell and Schaffner’s research reviewed leading studies on sex difference in PD, focusing on neurological development and gene regulation over the life course. Their review identified several areas for further exploration in PD research and treatment discovery. 

“Recent research suggests that the mechanisms leading to PD might be different in men and women, with approximately 1.4 times more men diagnosed with PD world-wide,” states Schaffner. 

“Greater understanding of disease drivers is essential to develop personalized risk profiles and intervention strategies for individual patients, including sex-specific treatments.” 

The biological underpinnings of PD often interact with environmental and lifestyle risk factors, including gender-specific social constructs, says Schaffner. For example, females in developing countries are more likely to be exposed to pesticides — which have been linked to PD onset — and be diagnosed with PD than females in developed countries. 

Towards tailored treatments for Parkinson’s

In PD research, scientists are becoming more aware of the potential role sex difference can play in disease onset and progression. 

“Sex differences found in embryos and heightened during adolescence and midlife may offer clues to a person’s risk of developing PD,” notes Appel-Cresswell. “Some of these factors may be traced back to complex interactions between hormones, lifestyle factors, genes and the aging process that have yet to be discovered and pursued through research studies.”

While controlling for sex is often required in smaller cohort studies with too little representation from either sex, larger cohort clinical trials with greater representation from individuals of both sexes open up new possibilities to look at sex-specific differences, states Schaffner. Researcher access to biorepositories of PD patient tissue samples from both sexes — such as the Bjorn Moller Research Repository — can also support greater female-representative research.

“The rise of large cohort studies within the past five to 10 years has taken research to the unique position in which we have enough representation from both sexes to detect sex-specific statistical differences in a more reliable way.”

To further elevate PD research, Appel-Cresswell and Schaffner underscore that future research should aim to recruit equal numbers of female and male participants and/or pursue more female-specific studies. 

“Consideration of sex-related factors, as well as gender, in study design, data analysis and the interpretation of results have the power to expand our knowledge of PD and inform prevention and therapeutic strategies tailored to each sex,” states Appel-Cresswell.
 

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