Striatal DAT SPECT: Caveat Emptor!

Abstract

Nigrostriatal dopaminergic pathways degenerate in people with Parkinson’s disease (PD). For decades, many of us have believed and taught that the striatal dopamine deficiency associated with degeneration in this pathway translated directly to the severity of the motor manifestations of PD, and that motor dysfunction was only manifest after 70% to 80% loss of striatal dopamine. The advent and widespread utilization of molecular imaging methods to quantify presynaptic nigrostriatal terminals potentially provided a means to test these hypotheses and, more important, to objectively quantify the severity of PD. As we stand on the threshold of the exciting possibility that disease-modifying therapies are within our reach, an objective biomarker gains ever greater importance. However, emerging data increasingly indicate that these notions provided an incomplete picture of the role of the nigrostriatal pathway in parkinsonism and that the situation is considerably more complex. Surprisingly, the severity of dopaminergic loss may only correlate with the severity of parkinsonism early in the course of the disorder and may begin with as little as 25% to 35% loss of either striatal dopamine or nigral dopaminergic neuronal cell bodies. In contrast, loss of nigral dopaminergic neurons may fully correlate with the severity of parkinsonism. These findings could support the notion that degeneration of the nigrostriatal pathways begins in the striatal terminal fields or striatal fibers with subsequent loss of nigral neurons. What role can single-photon emission computed tomography (SPECT) imaging of the plasmalemmal dopamine transporter (DAT) play in clarifying these relationships? In a previous report, Saari and colleagues demonstrated that striatal DAT SPECT did not correlate with counts of nigral dopaminergic cell bodies. However, nerve terminal DAT may not reflect what is happening in the cell bodies of origin for a variety of reasons: (1) nerve terminal loss may precede loss of nigral cell bodies; (2) nerve terminal fibers may sprout; and (3) DAT may be subject to regulation as a result of compensation or pharmacological treatment. The authors therefore went on to examine the relationship between striatal DAT binding as measured by SPECT and striatal tyrosine hydroxylase (TH) nerve fiber density, hypothesizing that this may yield a more robust correlation. The article by Honkanen and colleagues in this issue demonstrates that antemortem striatal DAT SPECT measures in 14 parkinsonian patients did not correlate with postmortem measures of striatal dopaminergic fibers. In both studies, the authors appropriately considered the interval between the antemortem SPECT scans and death. Their TH-stained fiber counts did not use an unbiased stereological counting approach, but they did try to identify brain sections that corresponded with the SPECT images and used histological counts done by two neuropathologists with high inter-rater reliability. Other limitations of the current study include relatively long intervals (1–8 days) between death and autopsy and lack of details on the fiber counting methods. However, the authors did consider time between death and autopsy as one of several covariates in the correlational analyses, which did not alter the results. More important, they found a correlation between striatal TH stained fiber counts and nigral TH neuronal counts, enhancing confidence in the adequacy of their methods. *Correspondence to: Dr. A. Jon Stoessl, Pacific Parkinson’s Research Centre, 2221 Wesbrook Mall, Vancouver, BC, Canada, V6T2B5; E-mail: [email protected]; or Dr. Joel S. Perlmutter, Washington University School of Medicine, 660 South Euclid, Campus Box 8225, St. Louis, MO 63110, USA; E-mail: [email protected]