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18 October 2022

2022 CANTAB Research Grant: Assessing Chemotherapy-Related Cognitive Impairment (CRCI)

We caught up with 2022 CANTAB Research Grant winner Peter Mukli, who tells us about how the grant will enable him and his team to investigate the impact of chemotherapy on cognition in breast cancer survivors. 

I am originally from Hungary and obtained my MD and PhD degrees from Semmelweis University in Budapest. I then continued my journey as a postdoctoral fellow at the University of Oklahoma Health Sciences Center in the Department of Neurosurgery. Currently, I work as a physiologist in the Translational Geroscience Laboratory led by Dr Andriy Yabluchanskiy. In our current projects, I study the vascular mechanisms of cognitive impairment in healthy aging, and in various pathological conditions that impact the vascular system such as peripheral artery disease, long COVID syndrome, and chemotherapy. My long-term goal is to conduct research focused on healthy brain aging.

What is the project about and why is this important?

As many as 44% of adult breast cancer survivors who have been treated with chemotherapy report short and long-term cognitive impairment, lasting months to years after completion of their treatment1. Their symptoms primarily involve the domains of memory, attention, executive function, and processing speed, and can have profound effects on quality of life including occupational and social functioning. 

Unfortunately, the mechanisms underlying the development of chemotherapy-related cognitive impairment (CRCI) are poorly understood. Given the extent of the impact of CRCI, there is a need to enhance our understanding of its underlying biological mechanisms. Recently we started an on-campus collaboration with a gynaecological fellow, Dr Anna Kuan-Celarier (Peggy and Charles Stephenson Cancer Center, Oklahoma City) who is very interested in the mechanisms of cognitive decline following chemotherapy.

Our hypothesis is that chemotherapy damages brain capillaries, which contribute to progressive impairment of cerebrovascular health, a predictor of cognitive dysfunction in cancer survivors. The main research question originates from preclinical studies conducted in our collaborator’s laboratory investigating the cerebrovascular mechanism of chemotherapy-related cognitive impairment.

We will recruit at least 30 female breast cancer survivors more than 12 months after they have completed their final chemotherapy session. Our research team has close ties to breast cancer patients  through our well-established collaboration with Stephenson Cancer Center at Oklahoma University Health Sciences Center.  

What are you hoping to discover?

Through the proposed research supported by the 2022 CANTABTM Research Grant, we would like to gain a better understanding of the impact of chemotherapy on cerebrovascular health and cognitive function. The data generated from this project will help us design longitudinal studies focusing on the vascular mechanisms of chemotherapy-related cognitive decline. The primary purpose of our study is to demonstrate that chemotherapy induces dysregulation of cerebral blood flow and impairs neurovascular coupling, an essential homeostatic mechanism for brain tissue health. We think that these mechanisms critically contribute to the development of cognitive changes in cancer survivors. We hope to develop clinically relevant biomarkers for future preventive and interventional strategies. 

If our hypothesis is justified, we would propose to perform a clinical trial to evaluate the effect of lifestyle interventions (including intermittent fasting and dietery supplements aimed at restoring NAD-levels in brain capillaries) that have a cerebrovascular benefit to understand whether this can impact CRCI. 

Which CANTABTM tests will you use and why?

We have an extensive protocol consisting of questionnaires, physiological measurements and cognitive assessments. Therefore, we chose a set of tests from the CANTABTM Connect battery that can be accomplished in around 20 minutes. Since the duration of the whole protocol usually takes around 2.5 hours to complete, which may be exhausting for vulnerable patients, it was important to include the most relevant and sensitive tests from the battery that can be administered in a relatively short time period. Based on previous research on the impact of chemotherapy on cognitive functions, we will use the Motor Screening Task (MOT), Spatial Working Memory (SWM), Delayed Matching to Sample (DMS) and Rapid Visual Information Processing (RVP). Since we hypothesize that chemotherapy accelerates vascular and hence cognitive aging, I chose a battery that consists of tests sensitive to detecting age-related changes in fluid abilities that concern working memory, processing speed, episodic memory, and executive functioning. 

The main part of our protocol is a series of physiological measurements that will investigate the association between neurovascular coupling responses and chemotherapy-related cognitive impairment. We will measure endothelial function and neurovascular responses using functional near-infrared spectroscopy, transcranial Doppler flowmetry and dynamic analysis of retinal vessels in female breast cancer survivors. 

How important was funding from Cambridge Cognition for your work?

This support allows for an important extension of our study since this project received funding as a pilot study without a dedicated budget for cognitive assessment. To better characterize cognitive function of female breast cancer survivors, I will use the CANTABTM Connect Research tool for objective measures of cognitive function. I strongly believe that with the use of cognitive measures provided by Cambridge Cognition, we will be able to develop a competitive federally funded NIH application. 

Cambridge Cognition’s support is helping us to address a significant, yet understudied problem in everyday clinical practice. Cambridge Cognition provides access to support from the scientific team who have expertise in advanced analysis and interpretation of cognitive outcome measures, which is very important for this study. Finally, this grant provides further opportunities to disseminate the results of this important translational research project to scientific communities. 

References

1. Whittaker AL, George RP, O'Malley L. Prevalence of cognitive impairment following chemotherapy treatment for breast cancer: a systematic review and meta-analysis. Scientific Reports. 2022;12(1):2135-. doi: 10.1038/s41598-022-05682-1. PubMed PMID: 35136066.

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Peter Mukli, University of Oklahoma Health Science Center