Assessment of synaptic density and mHTT aggregates in post-mortem human brain tissue of patients with Huntington's Disease.

Huntington's disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by mutant huntingtin (mHTT). Patients with HD exhibit progressive motor and cognitive decline, and development of psychiatric symptoms. Pathological features of HD include wide-spread progressive accumulation of mHTT, selective neurodegeneration, and forebrain atrophy. The synaptic vesicle glycoprotein 2A (SV2A) is a vesicle membrane protein expressed ubiquitously in synapses of the brain, involved in neurotransmitter release. SV2A can be used as a proxy to measure synaptic density in vivo using the radioligand [11C]UCB-J and positron emission tomography (PET). Based on our in vivo [11C]UCB-J PET imaging and in vitro [3H]UCB-J autoradiography findings in HD mice, demonstrating SV2A decline, we hypothesize the levels of SV2A to be decreased in patients with HD as a direct effect of mutant huntingtin accumulation as well as by the consequent neurodegeneration occurring with disease progression. Thus, the objective of this project is to provide evidence for the clinical significance of SV2A as a candidate biomarker in patients with HD in comparison to age- and gender-matched healthy non-demented subjects using in vitro autoradiography and immunohistochemistry in post-mortem samples from patients with HD and healthy subjects. The knowledge derived from this project will not only contribute to supporting the preclinical outcomes, filling the gap between preclinical and clinical findings, but it will represent a significant contribution in supporting SV2A as a candidate imaging biomarker for disease progression to be investigated in longitudinal SV2A PET imaging studies in patients with HD.

Keywords:HUNTINGTON DISEASE, CLINICAL RESEARCH, IMAGING TECHNIQUES

Disciplines:Nuclear imaging, Neurological and neuromuscular diseases