Does PET Tracer Reveal Severity of Parkinson's?

In order to gauge the effectiveness of disease-modifying therapies for Parkinson’s, researchers are looking for a biomarker that measures how far a person’s disease has advanced. In the April 21 JAMA Neurology, scientists led by Kun-Ju Lin and Chin-Song Lu, Chang Gung University, Taoyuan, Taiwan, claim that PET with the tracer AV-133 is a prime contender. Also known as 18F-dihydrotetrabenazine (DTBZ), this tracer binds to the vesicular monoamine transporter type 2 (VMAT2), a protein that pumps dopamine into synaptic vesicles. In this way, AV-133 visualizes intact dopaminergic neurons in the brain. AV-133 signals appear to decline as Parkinson’s disease progresses, Lin and colleagues report. “Our findings suggest that DTBZ PET imaging has the potential to measure dopaminergic degeneration in vivo and can monitor the severity of disease in PD,” co-first author Yi-Hsin Weng, Chang Gung Memorial Hospital, wrote to Alzforum in an email. 

AV-133 was originally developed by Hank Kung at the University of Pennsylvania, Philadelphia, and is owned by Avid Radiopharmaceuticals, Philadelphia, which developed the Aβ ligand Amyvid.

A 3-D rendering of the AV-133 signal in the nigrostriatal pathway of a person with mild Parkinson’s. Red indicates more dopaminergic innervation, blue less. [Image courtesy of the American Medical Association, © 2014. All rights reserved.]

Scientists have developed other imaging ligands to measure the extent of neuronal loss in PD, but their uptake in the brain may be perturbed by commonly prescribed Parkinson's medication (see Ahlskog, 2003). For this reason, some scientists question whether these agents accurately estimate dopaminergic degeneration. VMAT2 is only transiently affected by drugs for PD (see de la Fuente Fernández et al., 2009); 12 hours without medication restores its true pattern. A previous study reported that less binding of a carbon-11 form of DTBZ in the brain correlated with severity of PD (see Bohnen et al., 2006). In this study, the authors addressed whether the same was true for the F18-labelled form.

Weng and co-first author Ing-Tsung Hsiao, Chang Gung Memorial Hospital, recruited 17 healthy controls and 53 people with PD for the study. Of the latter, 22 had mild disease, 20 moderate, and 11 advanced, according to scores on the modified Hoehn and Yahr Scale and the Unified Parkinson’s Disease Rating Scale taken when the patients were off their medications temporarily. Each participant underwent one PET scan with AV-133. The researchers then determined whether the strength of the signal correlated with the clinical stage of their disease.

In the posterior putamen, people with mild disease took up 70 percent less AV-133 than healthy controls did, while people with moderate and advanced disease took up about 90 percent less. Similar trends were seen in the anterior putamen, substantia nigra, and caudate, the authors report. While the difference in signal between controls and patients was stark, the difference among patients was smaller.

Nevertheless, the authors concluded that AV-133 may predict how far dopaminergic neurons have degenerated, especially in early Parkinson’s, and help evaluate whether future therapies slow that process. Weng implied that the ligand would outperform other Parkinson’s imaging agents, for example the DAT SPECT scan. Besides arguing that AV-133 is less burdensome than DAT, with a shorter wait between injection and scan and shorter scan time, she also cited her recent side-by-side comparison that suggests AV-133 corresponds better than DAT imaging agents to clinical observation (see Hsiao et al., 2014). AV-133 may aid in differential diagnosis early in PD or in preclinical identification, wrote Weng. In a previous study, the group had found that for people in the early stages of PD, the striatum and substantia nigra took up significantly less 18F-DTBZ than controls (see Lin et al., 2014). 

Kenneth Marek, Institute for Neurodegenerative Disorders, New Haven, Connecticut, agreed that the study adds evidence that AV-133 could help assess PD, especially in its early stages. However, the tracer is unlikely to be useful in staging a given person’s disease because data suggests that in many cases symptoms do not track closely with the extent of nigrostriatal degeneration, he added.

Kirk Frey, University of Michigan, Ann Arbor, noted that the field needs a good biomarker to help evaluate potential neuroprotective drugs, but thinks this one misses the mark. “I am skeptical that this imaging approach will contribute to the staging of PD patients because the data are variable and cannot distinguish among patients with moderate to severe disease,” he told Alzforum. Lin responded that he thinks it is too early to draw that conclusion, as the difference was noticeable in the anterior putamen at these later stages. His group plans to study this in more detail in a longitudinal study with more subjects. 

Regarding diagnosis in earlier stages, physicians are generally comfortable determining whether a person has PD by assessing the response to dopamine replacement therapy, said Frey, who consults for Avid. He sees no clear need for an additional clinical diagnostic method. However, he does think AV-133 could help determine the underlying cause of dementia, as his previous work suggests it differentiates between dementia with Lewy bodies (DLB) and AD (see Burke et al., 2011). Independent researchers found the same result (Villemagne et al., 2012). The distinction is important, Frey said, because antipsychotic medications used to treat some AD patients can be acutely dangerous for people with DLB.  

Sources from Avid were unavailable to take questions on AV-133. Several studies of the ligand, including the PPMI, are currently ongoing, see clinical trials.gov.—Gwyneth Dickey Zakaib

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References

Paper Citations

  1. Ahlskog JE. Slowing Parkinson's disease progression: recent dopamine agonist trials. Neurology. 2003 Feb 11;60(3):381-9. PubMed.
  2. de la Fuente-Fernández R, Sossi V, McCormick S, Schulzer M, Ruth TJ, Stoessl AJ. Visualizing vesicular dopamine dynamics in Parkinson's disease. Synapse. 2009 Aug;63(8):713-6. PubMed.
  3. Bohnen NI, Albin RL, Koeppe RA, Wernette KA, Kilbourn MR, Minoshima S, Frey KA. Positron emission tomography of monoaminergic vesicular binding in aging and Parkinson disease. J Cereb Blood Flow Metab. 2006 Sep;26(9):1198-212. PubMed.
  4. Hsiao IT, Weng YH, Lin WY, Hsieh CJ, Wey SP, Yen TC, Kung MP, Lu CS, Lin KJ. Comparison of 99mTc-TRODAT-1 SPECT and 18 F-AV-133 PET imaging in healthy controls and Parkinson's disease patients. Nucl Med Biol. 2014 Apr;41(4):322-9. Epub 2014 Jan 10 PubMed.
  5. Lin SC, Lin KJ, Hsiao IT, Hsieh CJ, Lin WY, Lu CS, Wey SP, Yen TC, Kung MP, Weng YH. In vivo detection of monoaminergic degeneration in early Parkinson disease by (18)F-9-fluoropropyl-(+)-dihydrotetrabenzazine PET. J Nucl Med. 2014 Jan;55(1):73-9. Epub 2013 Nov 28 PubMed.
  6. Burke JF, Albin RL, Koeppe RA, Giordani B, Kilbourn MR, Gilman S, Frey KA. Assessment of mild dementia with amyloid and dopamine terminal positron emission tomography. Brain. 2011 Jun;134(Pt 6):1647-57. PubMed.
  7. Villemagne VL, Okamura N, Pejoska S, Drago J, Mulligan RS, Chételat G, O'Keefe G, Jones G, Kung HF, Pontecorvo M, Masters CL, Skovronsky DM, Rowe CC. Differential Diagnosis in Alzheimer's Disease and Dementia with Lewy Bodies via VMAT2 and Amyloid Imaging. Neurodegener Dis. 2012 Jan 17; PubMed.

External Citations

  1. clinical trials.gov

Further Reading

Papers

  1. Siderowf A, Pontecorvo MJ, Shill HA, Mintun MA, Arora A, Joshi AD, Lu M, Adler CH, Galasko D, Liebsack C, Skovronsky DM, Sabbagh MN. PET imaging of amyloid with Florbetapir F 18 and PET imaging of dopamine degeneration with 18F-AV-133 (florbenazine) in patients with Alzheimer's disease and Lewy body disorders. BMC Neurol. 2014 Apr 9;14:79. PubMed.
  2. Frey KA, Koeppe RA, Kilbourn MR, Vander Borght TM, Albin RL, Gilman S, Kuhl DE. Presynaptic monoaminergic vesicles in Parkinson's disease and normal aging. Ann Neurol. 1996 Dec;40(6):873-84. PubMed.

Primary Papers

  1. Hsiao IT, Weng YH, Hsieh CJ, Lin WY, Wey SP, Kung MP, Yen TC, Lu CS, Lin KJ. Correlation of Parkinson Disease Severity and 18F-DTBZ Positron Emission Tomography. JAMA Neurol. 2014 Jun 1;71(6):758-66. PubMed.

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