The days of the clinical exam leading the way in evaluating Parkinson’s disease are on the way out. A better understanding of how to use imaging has led to advances in diagnosing and monitoring the condition, and may hold the key to evaluating effective treatment.
One of the most compelling areas of Parkinson’s disease imaging research focuses on the preclinical phase or patients in the early stages of the condition, says David Eidelberg, MD, director of the Center for Neurosciences at the Feinstein Institute for Medical Research in Manhasset, N.Y. This is the time when treatment to slow progression is most important. “Just at the very point it’s of greatest interest to intervene is when the clinical exam is probably weakest.”
Every patient suspected of having Parkinson’s undergoes an MRI, though it mainly functions as a rule out test for non-Parkinson’s conditions, such as structural lesions. Until the early 2000s, diagnosis hinged almost exclusively on clinical evaluation of symptoms.
Enter dopamine active transporter (DAT) SPECT imaging, which has been increasing in clinical use since being approved in Europe in 2000 and by the FDA in 2011. DAT scans zero in on the major dopamine pathway from the substantia nigra and allow the visualization of the loss of dopaminergic cells, which have long been known to be part of Parkinson’s pathology. These scans are useful in differentiating benign tremors from Parkinson’s disease, says Eidelberg.
Where DAT imaging falls short is in monitoring treatment. It offers little help for understanding why a patient’s condition isn’t responding despite being administered drugs or deep brain stimulation to slow progression, and it isn’t specific to the subtle changes occurring during treatment. There’s a gap between sensitivity levels that work in a group evaluation, for which DAT imaging is adequate, and those that work on a subject level for individual diagnosis, notes Eidelberg. A primary challenge is to find an imaging tool that can be used in the evaluation of pharmacologic treatments and is sensitive enough to detect changes in treatment. It’s also imperative that patients with other conditions that mimic Parkinson’s—multiple system atrophy, progressive supranuclear palsy—aren’t enrolled in Parkinson’s trials as their rate of progression varies.
“It puts a real damper on these multicenter trials knowing that you could have … anywhere between 15 and 30 percent of people clinically thought to have Parkinson’s disease who actually have something else,” says Eidelberg. “That’s enough to really screw up your clinical trial.”
Test of progress
On the front lines in the search for better understanding the disease’s progression is the Parkinson’s Progression Markers Initiative (PPMI). This large observation study aims to pin down Parkinson’s disease biomarkers that can assist in determining changes in patients’ bodies as the disease progresses, according to John Seibyl, MD, executive director and senior scientist for the Institute of Neurodegenerative Disorders in New Haven, Conn. Seibyl serves on the steering committee for PPMI and is the principle investigator for the imaging core lab.
“There’s sometimes a disconnection between what you see clinically in a patient … and what’s happening in the brain,” says Seibyl. “There are compensatory mechanisms that come into play, so a patient may look a little better clinically than he or she is in terms of the actual patho-physiology of the disease, and that’s where imaging is really great.” One example of imaging’s insights, adds Seibyl, is that brain scans invariably demonstrate changes on both sides of the brain even with patients early in their disease course who only have symptoms on one side of the body.
PPMI has enrolled 400 patients and approximately 200 controls, and currently has collected mostly baseline data. Some early observations from PPMI researchers include a correlation between Parkinson’s disease and changes in cerebrospinal fluid, including the concentration of tau proteins normally associated with Alzheimer’s disease, explains Seibyl. Rates of progression based on imaging signals of dopamine transporters also are slightly faster than expected, but all PPMI data are very preliminary at this point.
One early PPMI observation that’s been a finding in itself is a remarkable trial compliance on the part of the patients, says Seibyl. Spinal taps are required every year and the reliability rate of patients has been very high, especially considering there was a feasibility question of whether a study of this scope could be pulled off, he adds.
Imaging on other fronts
Looking beyond DAT imaging, Eidelberg says that brain glucose imaging is making an impact, as well as diffusion imaging of dopamine cells in the substantia nigra. Seibyl points out there’s some interest in Europe for the use of ultrasound in Parkinson’s imaging, especially in Germany. While there’s not currently a commercially available PET marker, some agents are being investigated, including 18F-AV-133, a tracer that provides similar information and DAT imaging, but with the higher spatial resolution of PET.
Researchers at Massachusetts Institute of Technology in Cambridge have used structural MR to discover degeneration in Parkinson’s begins in the substantia nigra and then proceeds to the basal forebrain, confirming the neuropathological trajectory of the condition, according to results published in the February issue of JAMA Neurology.
The growth in Parkinson’s imaging research caught the attention of market analysis firm Frost & Sullivan. At a recent briefing summing imaging equipment market research, Roberto G. Aranibar, senior industry analyst for medical imaging, said neurology and the study of conditions like Parkinson’s is a clinical area that could shape future growth in the industry. “Given [the challenge of managing neurodegenerative diseases], there’s been a lot of emphasis on the introduction of new radiotracers for SPECT and PET imaging that are designed to help diagnose conditions like Parkinson’s in its earliest stages,” said Aranibar. “This trend is particularly interesting because traditionally SPECT and PET users have primarily included cardiologists and oncologists, so if the adoption of molecular imaging technologies by neurologists really starts to catch on, this could really open a big door for growth in this modality sector of the market.”
There’s a long road ahead, but through a focus on using imaging to analyze Parkinson’s, understanding of the disease is improving every year.
| The Trouble with Tremors |
While patients with tremors may seem to present problems for medical imaging, John Seibyl, MD, executive director and senior scientist for the Institute of Neurodegenerative Disorders in New Haven, Conn says patient movement has not been an issue during the Parkinson’s Progression Markers Initiative studies. Some sites may have restraints for keeping a head still, but all that’s needed is a roll of paper tape. A small amount of tape gently holds the head in place and helps remind the patient not to move. Tremors are intermittent, and head tremors often don’t present early in Parkinson’s. Slight movements during a SPECT scan also don’t present as many artifacts as the same amount of movement would during a more high resolution scan, such as MRI. Ironically, Seibyl reports that patient movement is more often an issue with healthy controls, especially younger subjects, rather than Parkinson’s disease patients, who are very motivated to remain still during the imaging procedure. |
Evan joined TriMed in 2011, writing primarily for Health Imaging. Prior to diving into medical journalism, Evan worked for the Nine Network of Public Media in St. Louis. He also has worked in public relations and education. Evan studied journalism at the University of Missouri, with an emphasis on broadcast media.