Extrastriatal dopamine D(2) receptor binding in Huntington's disease

Abstract

Huntington's disease (HD) is a neurodegenerative disorder, primarily affecting medium spiny neurones in the striatum. The density of striatal dopamine D(2) receptors is reduced in HD but there is little known about this biomarker in brain regions outside the striatum. The primary objective of this study was to compare extrastriatal dopamine D(2) receptor binding, in age-matched control subjects and patients with HD. All subjects were examined using a high-resolution positron emission tomography system and the high-affinity dopamine D(2) receptor radioligand [(11) C]FLB 457. A ROI based analysis was used with an atrophy correction method. Dopamine D(2) receptor binding potential was reduced in the striatum of patients with HD. Unlike the striatum, dopamine D(2) receptor binding in thalamic and cortical subregions was not significantly different from that in control subjects. A partial least square regression analysis which included binding potential values from all investigated cortical and subcortical regions revealed a significant model separating patients from controls, conclusively dependent on differences in striatal binding of the radioligand. Some clinical assessments correlated with striatal dopamine D(2) receptor binding, including severity of chorea and cognitive test performance. Hence, the present study demonstrates that dopamine D(2) receptors extrinsic to the striatum are well preserved in early to mid stage patients with HD. This observation may have implication for the development of therapy for HD.

Figure 1

PET images overlaid on MR images showing [11C]FLB 457 BP in the brain of a patient with HD (left) and a control subject (right).

Figure 2

Time‐activity curves following [11C]FLB 457 injection, in a patient with HD (a) and an age‐matched control (b). The green, blue, and red curves in the upper panels correspond to the putamen, temporal cortex and cerebellum, respectively. Lower panels show the SRTM fit and the estimated parameters R, k2 and BP for putamen and temporal cortex.

Figure 3

Object score plot (t1 vs. t2) from a PLS model discriminating patients with HD from control subjects. Each marker corresponds to one subject; squares: HD, circles: controls. The score on each PLS component (x‐axis: component 1, Y‐axis: component 2) represents a composite of all striatal and extrastriatal BP data which is used in the model. Patients with HD and control subjects are separated with minor overlap, reflecting differences in BP values.

Figure 4

Regression coefficients obtained from the PLS model discriminating regional BP values between HD patients and healthy subjects. The coefficients shown were scaled and centered with 95% confidence limits estimated by the jack‐knife method (Simca‐P+ 12.0, Umetrics, Inc.). Large negative coefficients indicate decreased BP of the ROIs in HD vs. healthy controls. The differentiation of HD vs. healthy controls in this model is mainly driven by decreased BP in the caudate nucleus and putamen of patients with HD. Abbreviations: Caud, caudate nucleus; Put, putamen; INS, insular cortex; DLPC, dorsolateral prefrontal cortex; HIP, hippocampus; AMG, amygdala; OC, occipital cortex; OFC, orbitofrontal cortex; PFC, prefreontal cortex; TC, temporal cortex; THA, thalamus.