Parkinson’s disease usually is thought of as a movement disorder. People with Parkinson’s typically first develop a tremor in one hand, followed by slowed movement, stiffness and loss of balance. But within 10 years of diagnosis, more than three-quarters of Parkinson’s patients also develop cognitive problems such as difficulty with memory and with performing sequential tasks and following instructions. The movement problems have been traced back to degeneration of a neurological pathway that controls movement. The source of the cognitive problems is more puzzling.
Joel S. Perlmutter, MD, professor of neurology at Washington University School of Medicine in St. Louis, has received a $3.2 million grant from the National Institute of Neurological Disorders and Stroke to investigate whether damage to motor pathways leads to brain inflammation and injury to the cerebral cortex. The cerebral cortex is the seat of higher-order thinking, so damage to the cerebral cortex might be linked to cognitive problems.
Perlmutter and colleagues also will assess whether an experimental drug that reverses damage to the motor pathway in animals also reduces dysfunction in the cortex.
The results of these studies are expected to lay the groundwork for clinical trials to assess whether the experimental drug synoxizyme reduces brain inflammation and cortical injury in people, thereby slowing, stopping or maybe even partially reversing motor or cognitive problems in people with Parkinson’s.
“We have lots of medicines to help reduce the motor symptoms but really almost nothing to help the cognitive problems,” said Perlmutter, who is also a professor of radiology, of neuroscience, of occupational therapy and of physical therapy. “That’s partly because we don’t know why it’s happening.”
Parkinson’s disease is caused by the degeneration of dopamine-releasing neurons in the nigrostriatal pathway deep within the brain. Replacing lost dopamine is the most common treatment for Parkinson’s. While drugs such as L-dopa reduce movement problems, they do nothing for cognitive symptoms.
In 2014, Perlmutter and Laura Dugan, MD, then at Washington University but now at Vanderbilt, published research showing that synoxizyme reversed damage to the nigrostriatal pathway and improved movement in an animal model of Parkinson’s disease. Surprisingly, further experiments showed that a few weeks after the nigrostriatal pathway was injured, the animals developed brain damage at sites distant from the original injury, in parts of the cortex that connect to the striatum.
Since synoxizyme scavenges reactive oxygen species and may directly reduce inflammation, the researchers surmised that the compound worked by reducing inflammation and injury due to reactive oxygen species in the brains of these animals. Further, by reducing damage to the nigrostriatal pathway, it may have the unexpected effect of limiting the spread of neurological damage to the cortex, thereby possibly reducing cognitive problems.
“When that paper came out, I had a drug company call me and say, ‘Can we put this in people?’ and I said, ‘No,’” Perlmutter said. “We don’t know whether this drug is hitting the right target in the brain. We don’t know how much drug is needed to reduce inflammation in the brain. We don’t know whether hitting that target translates into symptomatic benefit. I want to know what is happening before we move on to the next step.”
The problem was that there were inadequate available imaging agents to illuminate inflammation in the brain. Perlmutter and Dugan teamed up with Washington University’s Zhude “Will” Tu, professor of radiology, and Dong Zhou, assistant professor of radiology, as well as Robert Mach, professor of radiology at the University of Pennsylvania. All three were already in the process of developing imaging agents for brain inflammation and reactive oxygen species.
Now the team has three neuroinflammation imaging agents in hand. They plan to use the agents to explore the role of neuroinflammation in brain damage related to Parkinson’s disease and whether neuroinflammation contributes to the spread of damage from one part of the brain to another. They also will assess whether synoxizyme reduces inflammation in the brain, injury to the cortex, or both in an animal model of Parkinson’s disease.
The results of these studies could have implications beyond Parkinson’s. Multiple sclerosis (MS), Alzheimer’s disease, and many other neurodegenerative conditions have been linked to inflammation in the brain and proliferating neurological injury.