Adenosine A2A receptor dysfunction correlates with age at onset anticipation in blood platelets of subjects with Huntington's disease

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Abstract
Huntington's disease (HD) may manifest at an earlier age in affected offspring than in transmitting parents. Earlier onset in successive generations (anticipation) only partially depends on intergenerational parent–child elongation of the CAG expanded mutation. An aberrant amplification of adenosine A2A receptor signaling documented in peripheral blood cells of subjects with HD implies that this cellular dysfunction may be related to clinical and genetic features. Prompted by evidence of higher receptor densities in siblings of HD subjects with stronger onset anticipation, in this study we investigated a possible relationship between A2A receptor densities and age at onset. We measured adenosine A2A receptor densities in blood cell platelets from 32 patients with HD and healthy control siblings, and sought a possible linear correlation between maximum platelet A2A receptor binding (Bmax) values for the whole cohort of HD subjects and anticipation in years. The increased Bmax values for the 32 subjects with HD (220 in patients vs. 137 in healthy control subjects, P = 0.0001) correlated significantly with anticipation in years (r2, 0.48, P = 0.0001 by linear correlation analysis). An increased platelet A2A receptor Bmax may belong in a cascade of toxic events leading to earlier onset of HD: as such it could be a useful marker of onset anticipation.