Decreased [18F]spiperone binding in putamen in idiopathic focal dystonia

Abstract

In this study we have investigated the pathophysiology of two idiopathic focal dystonias: hand cramp with excessive cocontractions of agonist and antagonist hand or forearm muscles during specific tasks, such as writing, and facial dystonia manifested by involuntary eyelid spasms (blepharospasm) and lower facial and jaw spasms (oromandibular dystonia). We used positron emission tomography (PET) to measure the in vivo binding of the dopaminergic radioligand [18F]spiperone in putamen in 21 patients with these two focal dystonias and compared the findings with those from 13 normals. We measured regional cerebral blood flow and blood volume in each subject as well as the radiolabeled metabolites of [18F]spiperone in arterial blood. A stereotactic method of localization, independent of the appearance of the images, was used to identify the putamen in all of the PET images. We analyzed the PET and arterial blood data with a validated nonsteady-state tracer kinetic model representing the in vivo behavior of the radioligand. An index of binding called the combined forward rate constant was decreased by 29% in dystonics, as compared with normals (p < 0.05). There were no significant differences between dystonics and normals in regional blood flow, blood volume, nonspecific binding, permeability-surface area product of [18F]spiperone or the dissociation rate constant. These findings are consistent with a decrease of dopamine D2-like binding in putamen and are the first demonstration of a receptor abnormality in idiopathic dystonia. These results have important implications for the pathophysiology of dystonia as well as for function of the basal ganglia.

Fig. 1.

Arterial blood radioactivity after [¹⁸F]spiperone injection. This graph represents the measurements made from arterial blood samples in a single subject in this study. Total radioactivity was measured on 31 samples in a well counter cross-calibrated with the PET scanner, and the counts were decay-corrected to the time of radioligand injection. Thehorizontal axis is shown with a log scale to demonstrate that the majority of the area under the curveoccurs in the first few minutes. To delineate this time–activity curve accurately requires frequent sampling at the beginning of the study. The inset graph demonstrates the fraction of radioactivity in blood that represents radiolabeled metabolites, which decreases to ∼60% of the total activity and then remains nearly constant. The radiolabeled metabolites of [¹⁸F]SP were measured as described in Materials and Methods.

Fig. 2.

Tissue activity curve for putamen. After [¹⁸F]SP injection, 39 sequential PET scans were collected over 3 hr. The circles represent regional PET measurements of radioactivity averaged from the left and right putamen over the 3 hr. The measurements were cross-calibrated with the well counter used to measure blood radioactivity and then decay-corrected to time of radioligand injection. The solid curverepresents the best fit of the tracer kinetic model equations to the observed tissue activity data. This model represents the behavior of [¹⁸F]SP after injection within the field of view of the PET. The parameter estimation technique determines the optimal values of the unknown variables that yield the best fit of the model to the observed data. Each of the parameter estimations in this study converged to a single optimal solution.