Scientists at the Center have brought us a step closer to being able to detect the deadly spread of alpha synuclein, the misfolded protein associated with damage in the brains of patients with Parkinson disease and multiple system atrophy.
Eight years ago, they embarked on a mission to unite the academic medical centers across the world in a collaborative effort to study patients with low blood pressure standing – a condition known as orthostatic hypotension. The project, which is part of the Autonomic Disorders Consortium and sponsored by the National Institutes of Health, was the first of its kind, dedicated to mapping the clinical course of patients that present with orthostatic hypotension as the sole clinical feature. Read more (here) about the study on clinicaltrials.gov.
After following patients with orthostatic hypotension for many years, Dr. Horacio Kaufmann, lead investigator, realized that a number of patients would develop difficulty with movement and eventually receive the diagnosis of Parkinson disease. On rare occasions, he would need to break the news carefully that the patient had a rare form of very aggressive Parkinsonism known as multiple system atrophy (MSA).
“I saw orthostatic hypotension as a window into spotting MSA in the pre-motor phase”, explained Dr. Kaufmann. He enlisted the brightest minds from the best academic medical centers across the US to help identify clinical clues to recognize MSA before the damage in the brain spreads to affect the ability to move.
The collaborative teams found 100 patients with low blood pressure standing caused by failure of the autonomic nervous system, studied them in detail, and followed them each year. Over the next 8-years, we started to see a subset of patients developing MSA. Each time a person was diagnosed with MSA, we went back to look in at their clinical characteristics when we first enrolled them in the study
Predictors of developing MSA
Dr. Kaufmann had a breakthrough moment. He say that although the blood pressure problems were similar, the group that went on to develop MSA had distinctive differences. First, they had all a history of REM sleep behavior disorder. Normally when you dream you are paralyzed. In recent years, evidence has emerged that when people begin speaking or acting out dreams regularly it is an early sign that there is a problem with the brain.
Another fascinating issue was smell. Losing the ability to smell has long been known as a risk factor for developing Parkinson disease. But as Dr. Kaufmann noted, the situation was the opposite for the pre-motor MSA patients, who retained their ability to discriminate smells.
A final piece of the puzzle was heart rate. We found that patients that went on to develop MSA had faster heart rates that those that were later diagnosed with Parkinson disease. This particular sign is something we have long suspected. It points to the fact that Parkinson disease destroys the autonomic nerves outside the brain around the heart, whereas in MSA those nerves are mostly spared and the brunt of the synuclein deposition and nerve death occurs within the brain.
In a patient with orthostatic hypotension, REM sleep behavior disorder, intact smell and signs that the autonomic nerves outside the brain are mostly spared are key features that suggest an increased risk of developing MSA.
Stopping the alpha-synuclein spread
Of all the patients followed in the study, there were around 15% that remained with just autonomic symptoms and showed no signs of developing a more widespread brain disease. Those patients, as Dr. Kaufmann explained, provide really useful insights into what happens in the disease. They have very severe destruction of the autonomic nervous system outside the brain, but it appears that the process is halted there. Figuring out why the alpha synuclein remains in the body and doesn’t spread to the brain is the next step. We could potentially harness this advantage to help stop these diseases there, so that they do not go on to affect the ability to move.
The study was published in the Annals of Neurology, Official journal of the American Neurological Association.
Kaufmann H, Norcliffe-Kaufmann L, Palma JA, Biaggioni I, Low PA, Singer W, Goldstein DS, Peltier AC, Shibao CA, Gibbons CH, Freeman R, Robertson D; Autonomic Disorders Consortium. The Natural History of Pure Autonomic Failure: a U.S. Prospective Cohort. Ann Neurol. 2017 Jan 17. doi: 10.1002/ana.24877.