Movement Disorders: FDOPA PET Guiding Therapy Selection, Moving in to Monitor Drug Therapy

	Source: Hôpital Neurologique Pierre Wertheimer, Bron, France

FDOPA PET is showing promise in diagnosing, guiding initial selection of therapy in movement disorders and monitoring functioning of dopamine cell implantation. Two pioneers in the field Stéphane Thobois, MD, PhD, of the Hôpital Neurologique Pierre Wertheimer, in Bron, France, and Daniel H. Silverman, MD, PhD, head of the neuronuclear imaging section at University of California in Los Angeles shared their views with Molecular Imaging Insight on how FDOPA PET is making a difference in imaging movement disorders.

Neuroimaging methods like FDOPA (3, 4-dihydroxy-6-[18F]-fluoro-L-phenylalanine) PET are helping in differential diagnosis of movement disorders, measuring efficacy of new therapies, elucidating the benefits and complications of surgical interventions and assessing the utility of neuroprotective strategies.

In 1983, FDOPA was first used to localize the dopaminergic pathways of the human brain and its uptake measured by PET (Garnett et al, 1983). Since then, it has widened its applications from “imaging motor disorders to brain imaging studies of low-grade brain tumors,” Silverman says.

FDOPA PET assesses the integrity of the presynaptic nigrostriatal pathway. In Parkinsonian syndromes, there is a degeneration of this pathway and a reduction of FDOPA uptake. In contrary, in the absence of such degeneration, the FDOPA uptake is normal, says Thobois.

Changes in FDOPA uptake are sensitive to movement disorders which include idiopathic Parkinson’s disease, as well as a group of disorders with overlapping symptoms, the Parkinsonian syndromes or “Parkinson-plus” disorders—corticobasal degeneration, multi-system atrophy, and progressive supranuclear palsy that originate in the nigrostriatal pathway, Silverman notes.

Emerging applications

Though it is possible to see changes pre-symptomatically, currently there is no clinical indication for doing so because Parkinson’s is not treated in the pre-symptomatic stage, and there are no preventive therapies currently available or easy ways to identify who should be screened, says Silverman. The sensitivity of FDOPA PET is very high, he adds. “By the time that patients are symptomatic, they will have already lost approximately 20 percent of their FDOPA uptake in at least one of the putamen [and even more from the posterior putamen specifically], which is readily measurable on FDOPA PET scans.”

Constant striatal FDOPA uptake rate has been a reliable measurement in Parkinson’s patients and the scan-to-scan intra subject standard deviation ranged from only 2 percent to 16 percent of the mean value (Vingerhoets et al, 1996). FDOPA PET is useful for confirming or excluding the degeneration of the dopaminergic pathway, Thobois notes, “even in pre-symptomatic stages of Parkinson’s disease, abnormalities of FDOPA uptake may be encountered.” However, he cautions, “in clinical practice, the access to FDOPA PET is very limited compared to the SPECT DaTSCAN, which provides the same information.”

Currently, FDOPA PET is more useful for guiding the initial selection of therapy, than for drug therapy monitoring. “However, with tissue implants, FDOPA can be used to monitor functioning of viable dopaminergic tissue noninvasively,” says Silverman. A recent clinical study showed that FDOPA PET imaging changes reliably correlated with clinical outcome for more than four years after dopamine cell transplantation. There was increased brain uptake of FDOPA followed by improved motor skills and brain function in Parkinson’s disease (Ma et al, 2010).

Incidence of Parkinson’s Across the World

Parkinson’s disease is among the most prevalent neurological disorders worldwide. More than 6.3 million people are living with Parkinson’s, while about 1 million Americans have the disease, according to the European Parkinson’s Disease Association. Many more cases remain undiagnosed. Incidence of Parkinson’s increases with age, but an estimated 4 percent of people with Parkinson’s disease are diagnosed before the age of 50. Slightly more men than women have Parkinson’s, but ratios depend on the country in which they live. Only in Japan does the number of women with the disease outnumber the men. A just-released study of United States Medicare beneficiaries aged 65 and older found that the disease is twice as likely to strike whites and Hispanics as blacks and Asians (Wright Willis et al, Neuroepidemiology, 2010). Across the globe, the highest prevalence of Parkinson’s disease is found among the Amish population, a small religious community living in the Northeastern United States (incidence rate: 970 per 100,000 population)—where the disease is two to three times more prevalent than anywhere else in the world. The world’s next highest prevalence (407 per 100,000) is near Brescia, Italy, the home of many ferromanganese plants. Manganese is a known cause of the disease. The Parsi community of Mumbai, India, also has a high prevalence of Parkinson’s Disease (328.3 per 100,000), although prevalence in the rest of the country is low. This higher concentration could be attributed to a religious practice of Zoroastrianism involving the burning of Aspand seeds that include MAO Inhibitors that, after long-term exposure, has been proven to cause Parkinson’s. The prevalence for each country per 100,000 of population from highest to lowest is: USA 329-107, Japan 193-76, San Marino 185, Faeroe Islands 206-183, Germany 183, Spain 170-122, Italy 168-104, Finland 166-120, Bulgaria 164-137, Estonia 152, Australia 146-104, Wales 142, England 139-121, Portugal 135, Cuba 135, Canada 125, China 119-57, Scotland 129, Norway 102, Japan 192 - 76, Sweden 76, New Zealand 76, Nigeria 67, Poland 66, Jordan 59, Bolivia 50, Libya 31, Colombia 31, Tanzania 20, Korea 19, Ethiopia 7.

FDOPA also has been used to assess the neuroprotective effect of drugs. Thobois’ group has been using FDOPA and 11C-raclopride, a D2/D3 dopamine receptor ligands, for many years. “We have shown that the annual rate of dopaminergic degeneration is quicker at disease onset. Furthermore, we have shown that, in young onset Parkinson’s disease, the profile of presynaptic dopaminergic degeneration is similar in patients with and without Parkinson gene mutation. Using 11C-raclopride, we have demonstrated that subthalamic nucleus stimulation did not induce significant dopamine release,” says Thobois. “Furthermore, we demonstrated that chronic dopaminergic treatments induce a downregulation of dopamaine receptors, which is reversible after withdrawal of these drugs and that apathy in Parkinson’s disease was related to greater mesolimbic dopaminergic degeneration.”

The REAL-PET (Requip as early therapy versus L-dopa and PET) multinational study funded by GlaxoSmithKline compared the rates of loss of dopamine-terminal function in de novo patients with clinical and FDOPA PET evidence of early Parkinson’s disease. The trial showed a significantly lower reduction in putamen FDOPA uptake over 2 years in randomized patients and ropinirole was associated with slower progression of Parkinson’s disease when compared with levodopa (Whone et al, 2003).

However, questions have been raised on the decision to exclude 11 percent of patients in the REAL-PET trial from analysis on the grounds that the result of their initial PET scan was within the normal range. It also was noted that clinically, there was no significant difference in the rate of progression between the two groups, casting doubt on the validity of the functional imaging result (Morrish, 2003). Another PET study using FDOPA also suggests that the neurodegenerative process in Parkinson’s disease follows a negative exponential course and slows down with increasing symptom duration (Hilker et al, 2005). Further studies using FDOPA will not only answer many questions and provide meaningful insights into mechanisms underlying various movement disorders, but will also help physicians make early differential diagnosis as well as personalize treatment.

References

• Garnett ES, Firnau G, Nahmias C. Dopamine visualized in the basal ganglia of living man. Nature. 1983 Sep 8-14; 305(5930):137-8.
• Vingerhoets FJ, Schulzer M, Ruth TJ, Holden JE, Snow BJ. Reproducibility and discriminating ability of fluorine-18-6-fluoro-L-Dopa PET in Parkinson’s disease. J Nucl Med. 1996 Mar;37(3):421-6.
• Ma Y, Tang C, Chaly T, Greene P, Breeze R, Fahn S, Freed C, Dhawan V, Eidelberg D. Dopamine cell implantation in Parkinson’s disease: long-term clinical and (18)F-FDOPA PET outcomes. J Nucl Med. 2010 Jan; 51(1):7-15.
• Whone AL, Watts RL, Stoessl AJ, Davis M, Reske S, Nahmias C, Lang AE, Rascol O, Ribeiro MJ, Remy P, Poewe WH, Hauser RA, Brooks DJ; REAL-PET Study Group. Slower progression of Parkinson’s disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol. 2003 Jul;54(1):93-101.
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