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From the bowel to the brain?
NEW YORK—Identifying connections between health conditions and how they affect or trigger each other—such as diabetes and heart disease, or Down syndrome and Alzheimer's disease—is important for understanding and treatment of those conditions. In fact, pinpointing the link between health conditions or disease states can reveal ways to prevent disease or new methods for monitoring disease progression. In the latest discovery along those lines, scientists at the Icahn School of Medicine at Mount Sinai have published a study looking at the link between inflammatory bowel disease (IBD) and Parkinson's disease. The research was published in JAMA Neurology in a paper titled “Anti–Tumor Necrosis Factor Therapy and Incidence of Parkinson Disease Among Patients With Inflammatory Bowel Disease.”
Previous studies have implicated that the two diseases could be connected, given that they share genetic and pathophysiologic similarities, and the JAMA Neurology study's authors themselves have in the past identified several genetic variants that relate to an increased risk of Parkinson's and Crohn's disease (a subtype of IBD), or a decreased risk of both diseases.
The research team was headed up by lead investigator Inga Peter, Professor in the Department of Genetics and Genomic Sciences at Mount Sinai. The observational cohort study looked at administrative claims data from more than 170 million individuals and found that individuals with IBD have a 28-percent higher risk of developing Parkinson's disease than those who don't have IBD. The latter disease is commonly treated with anti-tumor necrosis factor (TNF) α therapy, to help control inflammation, and their data showed a 78-percent reduction in the incidence of Parkinson's disease in individuals with IBD who were treated with anti-TNFα therapy compared to those who did not receive such treatment.
“Systemic inflammation is a major component of IBD, and it’s also thought to contribute to the neuronal inflammation found in Parkinson’s disease,” Peter commented in a press release. “We wanted to determine if anti-TNFα therapy could mitigate a patient’s risk in developing Parkinson’s disease.”
Anti-TNFα therapies have been believed to have only limited effects in the central nervous system, as the size of the compounds means they cannot penetrate the blood-brain barrier. Given the impact on Parkinson's disease incidence seen in this study, an Icahn School of Medicine press release noted, “it may not be necessary for the drug to pass through the blood brain barrier to treat or prevent inflammation within the central nervous system, or that the blood-brain barrier in patients with IBD may be compromised, allowing the large molecules of the compound to pass through.”
“These findings support a role of systemic inflammation in the pathogenesis of both diseases,” the authors stated in their paper. "Further studies are required to determine whether anti-TNF treatment administered to high-risk individuals may mitigate PD risk."
A JAMA Neurology editorial on the study, titled “Discovering New Benefits From Old Drugs With Big Data—Promise for Parkinson Disease,” noted that the observational nature of this study is likely a boon—if not a necessity—in this disease space. “To conduct a prevention trial for PD from scratch would be incredibly difficult and expensive,” the editorial reported. “It has never been done, although several prevention trials are on the way for Alzheimer disease. Only 11 to 33 annual incident PD cases (“converters”) are expected per 10 000 individuals aged 50 years or older.3 The Parkinson Associated Risk Study,4 for example, screened 9398 eligible participants with a smell test, identifying 669 persons with hyposmia [reduced ability to detect odors, an early symptom of Parkinson's disease] and 23 individuals at high risk (having both hyposmia and a dopamine transporter neuroimaging deficit), 14 of whom converted to PD within 4 years.”
The editorial noted that another research group, Mittal et al, also tried this repurposing approach to studying Parkinson's disease, "finding in a high-throughput screen that administration of ß2-adrenergic receptor agonists (used to treat asthma) were associated with a lower endogenous expression of the PD α-synuclein gene SNCA. Looking at the entire population of Norway, the authors then found that salbutamol, a common asthma drug, was associated with reduced risk of PD. Computational analysis of these big data sets takes months, rather than several years for a real-life prevention trial, and incurs modest costs. Overall, such virtual repurposing trials are incredibly powerful for generating novel hypotheses based on patients instead of animal models, and for an initial in-silico preclinical evaluation in humans.” (The paper in question, “β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson’s disease,” was published in Science in September 2017.)
That approbation was tempered with realism, however, as the editorial also pointed out that “there are many caveats to this approach;” in the case of this recent JAMA Neurology study, “the number of PD cases was relatively small: 371 in total, with only two incident cases in the IBD group that received anti-TNF therapy.” Still, the authors note that virtual repurposing studies such as this “[enable] researchers to turn the drug development paradigm on its head: instead of conducting human trials at the end of the traditional research and development pipeline, virtual repurposing provides a sneak preview in humans up front, before committing to extensive preclinical studies and costly Phase 1 through 3 clinical trials.”