Diagnostic Imaging
June 2003

NUCLEAR MEDICINE

SPECT and PET compete in diagnosing Parkinson's

Techniques using new tracers can spot biologic brain conditions associated with the disorder

It is ironic that in this era of powerful diagnostic devices and techniques, most diagnoses of Parkinson's disease are confirmed only after the patient's death. Advances in nuclear medicine, however, offer hope to both patients and physicians seeking clues to early diagnosis of the disorder.

Structural imaging modalities such as CT and MRI provide scant diagnostic information regarding PD; MRI is done primarily for the purpose of excluding secondary causes. Now, however, there is hope that nuclear medicine techniques can diagnose certain biologic conditions within the brain that are indicative of Parkinson's.

"We may confirm the presence of a dopaminergic loss in the striatum of patients by using a SPECT technique with a ligand of the dopamine transporter such as ß-CIT or iodine-123-FP-CIT," said Dr. Philip Remy, a nuclear medicine physician at the Atomic Energy Commission's PET Center in Orsay, France.

The tracers, known as Dopascan and Datscan in North America and Europe, respectively, demonstrate the loss of nigrostriatal dopaminergic neurons, even at early stages of the disease, Remy said.

SPECT research with dopamine transporter ligands is growing, but the technique falls short of accurately quantifying dopaminergic loss. PET using fluorine-18 dopa is proving more reliable and accurate than SPECT, Remy said. In a study of 18 patients with Parkinson's, his group compared striatal uptakes of F-18 dopa with Altropane, another relatively new SPECT-based dopamine transporter ligand. They found that PET provided more information on dopamine loss than SPECT (Arch Neurol 2002;59[4]:580-586). F-18 dopa PET, however, is currently used in research only and is more expensive and less available than its scintigraphy counterparts. A lack of reimbursement adds to the downside. Unlike F-18 dopa PET, most SPECT imaging procedures are reimbursed.

Researchers are cautious about the actual role that SPECT and/or PET can play in the diagnosis of Parkinson's. Although most agree that functional imaging serves only to confirm a clinical diagnosis, some believe it can do more.

"SPECT imaging not only is useful but also helps diagnose Parkinson's while it is asymptomatic," said Dr. Ismael Mena, chief of neuroimaging at Las Condes Clinic in Santiago, Chile. "Radiotracers such as Datscan, iodine-123-labeled iodolisuride, and technetium-labeled Trodat-1 have shown promising test results."

In a study presented at the Congress of the World Federation of Nuclear Medicine and Biology in Santiago last October, Mena found that Tc-99m Trodat-1 could reliably distinguish between PD and Parkinson's-like syndromes and could also provide early diagnosis of PD in patients showing no clinical signs of the disease. Sensitivity and specificity with Trodat were 90% and 91%, respectively.

Trodat imaging could eventually surpass Datscan because it is less expensive and more widely available. Trodat-based scintigraphy may have a profound impact on imaging neurodegenerative disorders, especially in developing countries, where nuclear medicine has made huge advances but access to cyclotrons is limited.

DIFFERENTIAL DIAGNOSIS

Despite advances, many researchers believe that no currently available imaging technique can diagnose PD. Others say that early diagnosis using either PET or SPECT is possible, but techniques are not fault-free. Most agree, however, that nuclear imaging is helpful to distinguish between idiopathic PD and parkinsonism.

SPECT or PET can determine whether a patient with parkinsonism has multiple system atrophy (MSA) or a similar syndrome, and it can rule out PD, said Dr. Andrew S. Feigin, a neurologist at New York University's North Shore-Long Island Jewish Research Institute. Nuclear imaging cannot distinguish Parkinson's from clinical look-alikes, so it is effective only for the differential diagnosis.

Feigin and an international team of researchers assessed SPECT imaging for differential diagnosis of parkinsonism, comparing their results in 65 participants with those from a PET-based study protocol. They found both SPECT and PET similarly capable of discriminating between patients with Parkinson's, those with MSA, and healthy controls. Using a network analysis of the SPECT data, they identified a pattern characterized by increase in cerebellar, lentiform, and thalamic perfusion correlated with decreased perfusion in the frontal operculum and in the medial temporal cortex that helped distinguish PD patients from control subjects and MSA patients (Mov Disord 2002;17[6]:1265-1270).

Although nuclear medicine could potentially be helpful in the diagnosis of PD, it is an area requiring better clinical assessment, said Dr. A. Jon Stoessl, director of the Pacific Parkinson's Research Centre at the University of British Columbia. Functional imaging for differential diagnosis might be feasible, but it is not robust enough for clinical application, and imagers may rely excessively on it.

If these imaging techniques could reliably distinguish between PD and any of the look-alike conditions such as supranuclear palsy or MSA, they could be extremely useful, according to Stoessl.

Researchers believe the onset of Parkinson's could be related to environmental and/or genetic factors, but the cause remains unknown. One fact is clear: PD patients experience a moderate to severe degeneration of nigrostriatal dopamine neurons, leading to dopamine depletion. Here lies an important issue associated with PET or SPECT imaging for diagnosis of Parkinson's, Stoessl said. UBC researchers have shown that the dopamine transporter is subject to significant degrees of regulation. They have found, for instance, that loss of binding cannot be explained by loss of nerve terminals alone, and other factors appear to affect the expression of the dopamine transporter.

No matter which compounds are used-PET or SPECT-based dopamine transporter ligands-when changes are visible, they could be related not only to neuronal loss, but also to compensatory effects in the brain's chemistry or the effects of medication.

"You need to be very careful interpreting this," Stoessl said.

L-DOPA VS DOPAMINE AGONISTS

Apprehensions notwithstanding, researchers have devoted considerable time to determining whether neuroimaging has a role in monitoring disease progression or for follow-up treatment. That issue has led to the latest controversy among PD researchers.

Levodopa (l-dopa) has been considered the most effective therapy for PD for over four decades. The long-term use of the drug, however, produces serious side effects, including dyskinesias, response fluctuations, behavioral and psychiatric problems, and even loss of the dopaminergic neurons it was supposed to protect, according to multiple studies. Researchers at University of Texas Southwestern Medical Center found that l-dopa could place patients at increased risk for heart disease (Arch Neurol 2003; 60[1]:59-64).

A number of researchers have proposed replacing l-dopa with dopamine agonists, such as FDA-approved bromocriptine, pergolide, pramipexole, or ropinirole. They argue that dopamine agonists' effects could be followed up and quantified using both PET and SPECT.

Two randomized controlled trials, one using SPECT to compare pramipexole and l-dopa (JAMA 2002;287:1653-1661) and the other using PET to compare ropinirole with l-dopa (Neurology 2002:58:A82A83), concluded that agonist monotherapy may be neuroprotective and that l-dopa is toxic. Results from these studies have raised concern among researchers, however.

Dr. C. E. Clarke, a neurologist at the University of Birmingham in the U.K., contends that both dopamine agonist trials were flawed. Researchers know that agonists' and l-dopa's effects over the dopamine transporter's regulatory mechanism manifest differently. This may have influenced the imaging outcomes in the SPECT study. While all agonists compared with l-dopa had certain advantages, they also showed some detrimental side effects, he said.

Noticeable disagreements between imaging and clinical results were seen in both studies. The Parkinson Study Group, a multicenter consortium of clinical investigators, released their results from a large double-blind study, the Elldopa Trial, which found that l-dopa did not contribute to worsening of the disease and in fact slowed the rate of progression. The study's neuroimaging results, however, were contradictory. The group's findings were presented in April at the annual American Academy of Neurology meeting.

"The pharmacologic effect of levodopa on this type of imaging study needs to be investigated," said lead author Dr. Stanley Fahn, chief of the movement disorders division of Columbia University's Neurological Institute of New York.

Neuroradiologists and nuclear medicine specialists believe that patients with Parkinson's would benefit greatly if the effect of neuroprotective therapy could be objectively evaluated. And researchers who see nuclear imaging as a potential biomarker for disease progression wholeheartedly agree.

"If we had a proven neuroprotective treatment, and if we could also reliably identify people at increased risk due to genetics or some kind of environmental exposure before they developed symptoms, then imaging would be fantastic," Stoessl said.

Diagnosis of Parkinson's remains fairly exclusive. Other conditions should first be ruled out before the definitive ruling-autopsy-applies. One lasting impression remains, though: The stage seems set for a change.