Brain tissue from living patients: A new perspective on Parkinson’s Disease
When diagnosing diseases of the body, doctors often take biopsies or tissue samples to figure out what is wrong. However, when the disease involves the brain, our most complex organ protected by a thick skull, it is not exactly easy to remove a piece of the brain. Doctors often must rely on symptoms or other biomarkers (measurable indicators of a disease) that can give indirect hints towards a diagnosis. Much of our knowledge of brain diseases is held back by the fact that we can’t just take out parts of the living brain to figure out what is wrong. Or can we?
In a cutting-edge study from Western University, lead investigator Dr. Matthew Hebb and his team are furthering our understanding of one of the most common neurodegenerative disorders by removing and studying brain tissue from living patients. Parkinson’s disease is a movement disorder caused by loss of brain matter in specific parts of the brain. It is characterized by tremors, difficulty walking and rigidity, each of which progressively get worse over time. There is currently no cure, and the cause of Parkinson’s disease is not fully understood. By studying tissue from living patients, researchers can gain new insight into how Parkinson’s changes the brain, which has the potential to advance diagnosis, treatment and understanding of the disease.
The tissue samples were obtained when the patients were undergoing a treatment called deep brain stimulation. In Parkinson’s disease, the patient’s movement symptoms are thought to be caused by the loss of a certain brain chemical called dopamine. Deep brain stimulation is a current Parkinson’s disease treatment that implants a device deep in the brain, which sends electrical signals and causes more dopamine production and improved movement. During this procedure, part of the brain is exposed, and the doctors used this opportunity to obtain a very small sample of brain tissue. Don’t worry, taking this tissue will not have any side effects on the individual since it is such a small sample.
The researchers specifically looked at tissue from the front part of the brain, called the frontal lobe. Although this area is not primarily implicated in Parkinson’s disease pathology, it is still known to show changes in Parkinson’s patients, and importantly, it is an accessible, low-risk site for biopsies. The researchers also obtained similar tissue samples from a group that did not have Parkinson’s (referred to as the “control” group) but were undergoing an unrelated surgery to remove a brain tumor in a different location.
The study, led by PhD candidate Simon Benoit, specifically looked at gene expression between the Parkinson’s patients and control patients in these brain tissue samples. Differences in the expression of genes can give hints as to what causes the degeneration of brain cells or what is affected during the disease progression. This kind of information could also be used to gain a look into the patient’s future disease progression. “Those are the genes that ultimately my work is trying to narrow down on” said Benoit, “the ones that are actually important for determining what kind of outcome Parkinson's disease may have for one person”.
While this study is the first to look at changes in the brain tissues of living patients, previous researchers have studied other tissue types for biomarkers of the disease. Most of the previous research has used post-mortem brain samples, which is brain tissue that has been obtained after the individual has passed away. However, Hebb and Benoit explain that there are some problems with using this tissue to characterize Parkinson’s. For example, there are many changes that occur in the brain after death. Notably, there can be widespread changes in gene expression that are not related to Parkinson’s disease. Further, post-mortem tissue is usually obtained from individuals that have had Parkinson’s for many years and have much greater loss of brain cells. Therefore, tissue from living brains may more accurately reflect the disease-relevant state of gene expression which can provide information that is more useful for characterizing the underlying cause of the disease. There have been a few studies from other researches that investigated changes in gene expression in other tissues of the body, such as skin, blood and cerebrospinal fluid (the fluid that surrounds the brain); however these tissues are indirect measures of what is actually happening to gene expression in the brain. Benoit and his colleagues did a comprehensive review of these previous studies and compared this with the tissue they obtained from living patients.
The paper, published in Neurobiology of Disease in April, identified 123 genes that were unique to the living Parkinson’s brain, meaning they had not previously been associated with Parkinson’s in other studies. They also found another 144 genes that were either expressed in higher or lower amounts compared to other studies of Parkinson’s patients. The known roles of these genes can give clues to the disease process. For example, a gene called glial cell-derived neurotrophic factor (GDNF) was found to be lower in Parkinson's patients compared to the control group. GDNF is involved in the survival and regeneration of dopamine cells, which are important for motor function. Another gene involved in the blood clotting process was higher in Parkinson’s patients, which may suggest an association between stroke or coronary artery disease and Parkinson’s – a link that has had conflicting evidence in previous literature. This gene expression data, collected from living patients, may have more relevance to the causes of cell degeneration and can help guide researchers towards specific mechanisms of disease progression and cause.
Overall, the study is the first to show how living brain tissue of Parkinson’s patients differs from healthy brain tissue. This is an important advancement for the field and demonstrates the possibilities that come with studying the living brain. Benoit hopes to expand his findings to identify key genes as biomarkers for earlier diagnosis. “If we can notice that the gene expression of these genes is changing earlier on, maybe we can predict that a person might get Parkinson's.” Given the complex nature of human genetics, he is now sifting through genes to identify these key markers with the help of advanced computational tools.
Original Article: Benoit SM, Xu H, Schmid S, et al. Expanding the search for genetic biomarkers of Parkinson's disease into the living brain. Neurobiol Dis. 2020;140:104872. doi:10.1016/j.nbd.2020.104872 https://www.sciencedirect.com/science/article/pii/S0969996120301479?via%3Dihub