Parkinson’s Disease (PD) is a devastating neurodegenerative disease. It progresses slowly, destroying quality of life for those who suffer from it. PD affects muscle control, balance and movement. It is the second most common age-related neurodegenerative disorder, behind either Alzheimer’s or dementia, depending on whose data you rely. Three percent of all adults over 65 years of age are affected by PD and five percent of those over 85.
Parkinson’s has previously been thought of as a brain disorder. This is largely due to 20th century research showing a loss of pigmented dopaminergic neurons in the substantia negra. This structure, located in the midbrain, plays a critical role in reward and movement. Recent research, however, has clearly shown that PD has variations and probably consists of several subtypes.
This recent work has raised an interesting question: does Parkinson’s Disease originate in the brain or in the gut?
A new hypothesis, published in the Journal of Parkinson’s Disease, offers evidence that PD can be split into at two subtypes. Danish researchers believe that PD can be “gut-first,” originating in the peripheral nervous system of the gut and then spreading into the brain or “brain-first,” either originating in the brain or entering the brain via the olfactory system and spreading to the brain stem and peripheral nervous system.
The research team included Per Borghammer, MD, PhD, DMSc, Nuclear Medicine & PET, Aarhus University Hospital, Denmark, and Nathalie Van Den Berge, MSc, PhD, Department of Clinical Medicine, Aarhus University, Denmark. They explored the origins of PD onset.
Their research began with a review of evidence that Lewy body disorders (LBD,) including PD and dementia with Lewy bodies (DLB,) can be broken into two distinct subtypes. The first is a gut-originated phenotype defined by marked damage to the peripheral autonomic nervous system which precedes measurable damage to the brain, including dopaminergic cells. The second is a brain-first phenotype distinguished by marked damage to the brain preceding measurable damage to the peripheral autonomic nervous system.
“Evidence from autopsy studies of brains from PD patients has suggested that PD may start in the peripheral nervous system of the gut and nose. The pathology then spreads via the nerves into the brain. However, not all autopsy studies agree with this interpretation,” explained Dr. Borghammer. “In some cases, the brains do not contain pathology at the important ‘entry points’ into the brain, such as the dorsal vagus nucleus at the bottom of the brain stem. The gut-first versus brain-first hypothesis posited in this review provides a scenario that can reconcile these discrepant findings from the neuropathological literature into one single coherent theory about the origins of PD.”
“The discussion about the origins of PD is often framed as an ‘either-or’, i.e., either all PD cases start in the gut or all cases start in the brain,” added Dr. Van Den Berge. “However, much of the evidence seems compatible with both these interpretations. Thus, we need to entertain the possibility that both scenarios are actually true.”
The research provides a detailed review of existing evidence from imaging studies of humans and tissue studies from both human and animal models. The brain-first hypothesis of PD has always been more compatible with the imaging and histology studies than the gut-first hypothesis. If the hypothesis of the Danish team is correct, it would seem that Parkinson’s is more complex than originally understood. Interventions targeting PD as brain-first would be ineffective for those whose PD is gut-originated. Since the fraction of patients with gut-first PD versus those with brain-first PD can’t currently be identified, new diagnostic tools aimed at identifying the PD origin would be require to better target treatments.
“If the brain-first vs body-first hypothesis is correct, we need to intensify the research into understanding risk factors and triggering factors for these two subtypes,” noted Dr. Van Den Berge.
“It is probable that these different types of PD need different treatment strategies,” commented Dr. Borghammer. “It may be possible to prevent the ‘gut-first’ type of PD through interventions targeting the gut, such as probiotics, fecal transplants, and anti-inflammatory treatments. However, these strategies might not work with respect to treating and preventing the brain-first type. Thus, a personalized treatment strategy will be required, and we need to be able to identify these subtypes of PD in the individual patient.”
Parkinson’s Disease destroys the lives of those who have it, as well as the families of those diagnosed with it. The more we know about it, the better we can target treatments and maybe, just maybe, improve the lives of those who have it. We may even be able to eliminate it completely.
Keep the faith and keep after it!
Journal Reference – Per Borghammer, Nathalie Van Den Berge. Brain-First versus Gut-First Parkinson’s Disease: A Hypothesis. Journal of Parkinson’s Disease, 2019