Article Text

G15 Switch of cerebral A1 adenosine receptor radioligand binding during phenoconversion of Huntington disease: a PET study
  1. A Matusch1,
  2. C Saft2,
  3. D Elmenhorst1,
  4. PH Kraus2,
  5. R Gold2,
  6. H-P Hartung3,
  7. A Bauer1,3
  1. 1Institute of Neuroscience and Medicine (INM-2), Forschungszentrum Jülich, Jülich, Germany
  2. 2Department of Neurology, Huntington Centre NRW, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
  3. 3Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany


Background Cellular metabolic and mitochondrial dysbalance has been assumed a hallmark and promoter of HD. Extracellular adenosine accumulates in conditions such as excitotoxicity as degradation product of ATP liberated as co-transmitter from firing neurons and in states of metabolic failure via leakage from the intracellular compartment. A1 adenosin receptors (A1AR) limit cellular activity when a tissue is operating beyond energy homeostasis. Human and animal findings congruently point to increased adenosine levels in HD trinucleotide repeat expansion gene carriers. Microdialysis studies evidenced 50% higher concentrations in R6/2 mice. Genome wide association studies discovered hypoxia induced factor as one principal up-regulated protein which in turn causes a rise of extracellular adenosine.

Aims, methods and techniques The A1AR radioligand [18F]CPFPX and PET allow to non-invasively monitor the adenosinergic system indirectly in humans. In the present cross-sectional study were included: premanifest individuals far from (preHD-A; n=7) or near to (preHD-B; n=6) the predicted symptom onset; manifest HD patients (n=8), and controls (n=36).

Results Group comparisons of partial-volume corrected PET data revealed a biphasic change of A1AR density: preHD-A > preHD-B = controls > manifest HD. Cerebral A1AR in preHD-A subjects were 5%–10% higher than in controls, while A1AR values from manifest HD patients were significantly lower compared to preHD-B subjects and controls (striatum, 14%–19%; fronto-parieto-temporal cortex, thalamus and amygdala, 8%–11%). A1AR BPND strongly correlated with the time to predicted symptom onset. The comparison of regional profiles of A1AR BPND as a function of time to onset pointed to an early affection of amygdale and Heschl gyri, affection at indermediate state of the frontal cortex and comparatively late affection of the striatum. The thalamus showed the highest up-regulation in preHD-A coinciding with reports on supra-normal [18F]FDG uptake there. In the occipital cortex, the impact of HD was smallest.

Conclusions We describe an imaging biomarker for HD that switches from supra- to subnormal values during phenoconversion pointing to underlying pathophysiological processes of the adenosine system and a potential therapeutic target.

  • Premanifest Huntington's disease
  • [18F]CPFPX PET
  • adenosine A1 receptor

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