A Tissue Test for Parkinson Disease?

Bret S. Stetka, MD; Charles H. Adler, MD, PhD


February 10, 2014

Editorial Collaboration

Medscape &

Editor's Note:
Medscape recently spoke with Charles H. Adler, MD, PhD, Professor, Department of Neurology, Mayo Clinic College of Medicine, Scottsdale, Arizona, about his past and future research into the potential of submandibular gland biopsy as a useful diagnostic tool in Parkinson disease (PD).

Medscape: Please tell us about your study looking at the potential use of submandibular gland biopsy in PD diagnosis.

Dr. Adler: We have something called the Arizona Study of Aging and Neurodegenerative Disorders that has been ongoing for the past 17 years. As part of the study, all participants agreed to an autopsy at the end of life. Initially, only brain biopsies were performed, but since 2005 the patients have undergone whole-body autopsies.

I run the clinical part of the study, whereas my neuropathologist colleague Dr. Tom Beach handles the autopsy and pathology part. Dr. Beach has done a survey of multiple different organs looking for phosphorylated synuclein staining in areas other than the brain. [Editor's note: Aggregates of the alpha-synuclein protein are a pathologic hallmark of PD.] He found dense synuclein staining in the submandibular gland; all 28 patients with PD who were autopsied had evidence of phosphorylated synuclein staining in their submandibular gland.

Dr. Beach did a proof-of-concept study where by doing a needle biopsy in frozen tissue, he was able to identify 17 of the 19 cases with synuclein staining. It meant that 2 of them did not show synuclein in the needle biopsy, so somehow the tissue that had the synuclein staining was missed.

We then translated that finding to the clinic and did a study looking at 15 patients with advanced PD, meaning patients who had had disease for more than 5 years. The reason we chose that population is that in the autopsy series that Dr. Beach did, the disease duration was pretty advanced because those patients had already come to autopsy -- so the majority of patients had had PD for more than 5 years.

In a biopsy study that's now in press, we did a biopsy in 15 patients, 12 of whom had submandibular tissue we could look at, and 9 of those patients were synuclein-positive. We took that as proof of concept that you actually can find phosphorylated alpha-synuclein staining in living human submandibular glands.

We have moved forward now with the current study, which is to look at 25 patients with earlier or shorter disease duration -- meaning disease duration less than 5 years -- and 10 controls as a comparison group to make sure that the staining is only picking up synuclein in persons who do have PD.

Medscape: Could you talk about the methods of this new study.

Dr. Adler: I first examine all participants -- both those with PD and the controls. For the patients with PD, we then do a dopamine transporter scan called the DaTscan, looking to see whether they have abnormalities in dopamine uptake that would be suggestive of PD. We do a smell test of all the individuals in this study, because individuals with PD usually have loss of the sense of smell. Those are 2 other markers that we're looking at.

Then we have 1 of 2 ear, nose, and throat doctors in the practice do the biopsies. The biopsies are done by putting some numbing medication in the skin overlying the submandibular gland, which sits right under the jawline, and then we do 4 or 5 needle passes per patient. Dr. Beach then stains the samples for synuclein.

Medscape: Have you begun collecting data yet?

Dr. Adler: We've enrolled 18 or so patients out of the 35 who need to be enrolled, so we're a little over halfway through enrollment. We haven't looked at any data yet.

Medscape: Do you have a sense of where in the disease course synuclein might be detected compared with other markers of PD, such as olfactory dysfunction?

Dr. Adler: I think that's part of what we're trying to determine. The question is how early can we actually detect synuclein in the gland, and that's something we don't know yet. My expectation is that of the 25 individuals with PD, we should get a good idea of what percentage of those cases are positive to be able to say that this does or does not happen early in the disease course.

Is it a premotor marker? Is it possible that if you were to biopsy samples from people who have loss of the sense of smell, they would have synuclein in the submandibular gland even before they had tremor or slowness of movement? Those are all questions that would still need to be answered.


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