[18F]flubatine: a Novel Biomarker of Cholinergic a4ß2 Nicotinic Receptors and Cognition in Parkinson's Disease
Mild cognitive impairment and dementia are frequent non-motor complications of moderate to advanced Parkinson's disease (PD). Cholinergic denervation is related to cognitive impairment in PD. The most widely used medications to mitigate cognitive impairment are acetylcholinesterase inhibitors (AChE-I). Currently, rivastigmine is the only FDA-approved AChE-I for the treatment of PD patients with mild to moderate dementia. Clinical experience indicates, however, that the benefits of AChE-I drugs in dementia are modest at best. There is an unfulfilled clinical need to study cholinergic compounds that effectively stimulate cholinergic neurotransmission. A particularly important class of cholinergic receptors within the CNS is ionotropic a4ß2 nicotinic receptors (a4ß2 nAChRs). a4ß2 nAChRs are regulators of attentional control with the forebrain cholinergic system. There is also converging evidence that a4ß2 nAChRs play a role in cognitive decline in PD. The overarching goal of this study is to examine the association between a4ß2 nAChRs and cognition in PD. We propose to introduce the highly selective a4ß2 nAChR PET ligand [18F]flubatine (also known as [18F]NCFHEB) as a novel biomarker of a4ß2 nAChRs and cognition in PD subjects. We propose to quantify a4ß2 nAChRs in PD patients and normal controls (NCs). We hypothesize that decreased binding of [18F]flubatine to a4ß2 nAChRs in PD patients will be associated with decreased cognitive functioning. To assess a causal relationship between a4ß2 nAChRs expression and cognition in PD subjects we will administer a subacute dose of varenicline, a selective a4ß2 nAChR partial agonist drug. We will measure cognitive responses to our subacute varenicline challenge with the highly specialized sustained attention task with the distractor condition (dSAT). Positive findings in this study would establish a4ß2 nAChRs as an important contributor to cognitive dysfunction in PD and would identify a4ß2 nAChR partial agonist medications as an important route to mitigate cognitive decline in PD. [18F]flubatine could serve as an important biomarker to identify those patients who may benefit most from a4ß2 nAChR partial agonist drug treatment.
Michael J. Fox Foundation for Parkinson's Research
(RFA 2013 Program letter dated Dec. 3, 2013)
Funding Period: 12/31/2013 to 12/31/2016
Health and well-being in later life: Chronic Disease