Cholinergic Nicotinic Receptors and Cognition in PD

[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. Brain positron emission tomography (PET) study findings confirm post-mortem evidence that cholinergic loss is related to cognitive impairment in Parkinson's disease. However, current cholinergic augmentation therapy is not always effective and it should only target those Parkinson's disease patients who have evidence of cholinergic system impairment. The objective of this study is to study the association of a particular subtype of cholinergic receptors, so-called nicotinic acetylcholine receptors, with cognition in Parkinson's disease using a novel PET marker of cholinergic system integrity.

Parkinson's disease patients will undergo nicotinic acetylcholine receptor PET imaging with the radioligand [18F]flubatine and MRI on one day and extensive neuropsychological testing on another day. The degree of nicotinic receptor expression obtained with PET imaging will be correlated with the neuropsychology test results.

Positive [18F]flubatine PET findings in this study would establish nicotinic receptors as an important contributor to cognitive dysfunction in Parkinson's disease and could kindle pharmaceutical interest in pursuing these agents for Parkinson's disease applications.

We expect that lower nicotinic receptor expression is associated with impaired cognitive functioning in Parkinson's disease. In a personalized medicine approach the PET radioligand [18F]flubatine could serve as an important marker to identify those patients who are expected to benefit most from nicotinic receptor drug treatment.

Inclusion criteria:

• PD subjects (M/F, non-smoking, ≥ 50 years old, Hoehn & Yahr stages 1-4)
• Normal control subjects (N=15, M/F, non-smoking, ≥ 50 years old)

Exclusion Criteria:

• Active smoking, use of other tobacco products, or use of nicotinic drugs such as nicotine patches or varenicline.
• Subjects with contra-indications to MR imaging, including pacemakers or claustrophobia.
• Evidence of large vessel stroke or mass lesion on MRI.
• Use of (anti-)cholinergic or neuroleptic drugs.
• Dementia or severe cognitive impairment confirmed by clinical and detailed neuropsychological assessment precluding safe study participation, performing study procedures, or unable to follow directions by study personnel.
• Evidence of atypical parkinsonism on neurological exam.
• Subjects limited by participation in research procedures involving ionizing radiation.
• Pregnancy (test within 48 hours of each PET session) or breastfeeding