G15 Switch of cerebral A1 adenosine receptor radioligand binding during phenoconversion of Huntington disease: a PET study. (29th August 2012)

• Record Type: Journal Article
• Authors: Matusch, A; Saft, C; Elmenhorst, D; Kraus, PH; Gold, R; Hartung, H-P; Bauer, A
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 83(2012)Supplement 1
• Page Start: A31
• Page End: A31
• Publication Date: 2012-08-29
• Subjects: Premanifest Huntington's disease -- [18F]CPFPX PET -- adenosine A1 receptor; Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2012-303524.95
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : 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 (A1 AR) 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 A1 AR radioligand [ 18 F]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 A1 AR density: preHD-A > preHD-B = controls > manifest HD. Cerebral A1 AR in preHD-A subjects were 5%–10% higher than in controls, while A1 AR 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%). A1 AR BP ND strongly correlated with the time to predicted symptom onset. The comparison of regional profiles of A1 AR BP ND 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 [ 18 F]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.