Daniel M. Keller, PhD

June 21, 2015

SAN DIEGO — The sequence of denervation of gut organs may reflect the stage of Parkinson's disease (PD), a study suggests.

When Danish researchers used 11C-donepezil as a biomarker in positron emission tomography (PET) to look at parasympathetic innervation, they found decreased binding in the small intestine, indicating denervation, but not in the pancreas of newly diagnosed patients with PD in the premotor phase of the disease. Denervation of the pancreas occurred in the motor phase of PD.

"We know that Parkinson's patients, many of them have constipation many years prior to diagnosis. That is a symptom of the parasympathetic nervous system," senior author Per Borghammer, MD, PhD, DMSc, associate professor in the Department of Nuclear Medicine and the PET Center at Aarhus University Hospital in Denmark, told Medscape Medical News.

He added that the dorsal motor nucleus of the vagus nerve in the brainstem is "perhaps the key structure, the first structure, to be hit in [PD] in the brain, and that is also a very important parasympathetic structure." Vagal deficits also may explain the gastroparesis and decreased heart rate variability experienced by many patients with PD.

The research was presented here at the 19th International Congress of Parkinson's Disease and Movement Disorders (MDS).

Dr Borghammer said he started a line of research 3 years ago to image the parasympathetic nervous system. 11C-donepezil binds to acetylcholinesterase, and is therefore a marker of cholinergic neurons and their loss.

The current study enrolled 16 patients with PD with Hoehn and Yahr stages I, II, and III (n = 7, 8, 1, respectively). The median time since PD diagnosis was 1.25 years. Dopamine transporter single PET/computed tomography scans on 12 patients were consistent with PD. Ten age- and sex-matched control subjects also participated.

Visual difference in the small intestine between a patient with Parkinson's disease and a control subject. The former has a "pale" small intestine.

The researchers performed 11C-donepezil PET/computed tomography scans of the thorax and abdominal organs on all subjects, and standard uptake values were determined from the final PET frame at 45 to 50 minutes after biomarker injection.

Denervation of Intestine, Not Pancreas

In this study of patients with de novo PD, intestine showed a marked decrease in PET signal compared with controls, whereas pancreas did not.

Table. 11C-donepezil PET Results (Standard Uptake Values)

Group Patients Controls P-value
Patients with de novo PD      
 Intestine 6.4 8.4 <.001
 Pancreas 21.7 20.5 .52
Patients with early to moderate PD      
 Intestine 7.1 11 .003
 Pancreas 16.5 21.1 .001

A previous study by the same group (Gjerloff T et al. Brain. 2015;138:653-663) of 12 early- to moderate-stage patients with a median disease duration of 4.5 years indicated denervation of both organs.

"There's nearly no overlap," Dr Borghammer said. "Nearly all the patients have this decrease. And we saw more or less the same in the pancreas. That's another organ that's heavily innervated by the parasympathetic nervous system."

Although the researchers believe they are imaging parasympathetic elements, one caution is that the technique is not specific because acetylcholinesterase is produced by cells other than parasympathetic ones.

The researchers said they did not see any differences in the liver, spleen, or kidneys when patients were compared with control patients.

Dr Borghammer concluded that 11C-donepezil PET may be useful as a diagnostic marker in the premotor, prodromal phase of PD, at which stage patients are difficult to diagnose.

"That's really the goal: to be able to find prodromal PD patients in the future," he said.

The stepwise progression of denervation from intestine to pancreas "could actually be used also to monitor disease progression, and also to monitor if the patient gets some kind of disease-modifying agent. Then one of the ways we could follow these patients is to see if the innervation of the pancreas is preserved," he added.

Maurizio Facheris, MD, senior associate director for research programs at the Michael J. Fox Foundation for Parkinson's Research, commented to Medscape Medical News that the findings are interesting because they correlate "clinical symptomatology, like constipation, heart rate variability, [and] low blood pressure, that are all symptoms in Parkinson's that for some people are related to the medication that they take, but also are independent from the medication."

That's really the goal: to be able to find prodromal PD patients in the future. Dr Per Borghammer

The reduced uptake of the biomarker is "like a proxy of denervation of the parasympathetic system," he said. "That might explain some of the symptoms of Parkinson's disease...the nonmotor component, nonmotor plethora of symptoms."

The study was supported by the Lundbeck Foundation. Dr Borghammer has no other commercial relationships. Dr Facheris is an employee of the Michael J. Fox Foundation for Parkinson's Research.

19th International Congress of Parkinson's Disease and Movement Disorders (MDS). Abstract LBA7. Presented June 17, 2015.


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