Cholinergic Mechanisms of Attention in Aging

Overview: Cognitively normal older adults with and without subjective cognitive decline (SCD) (n = 20; SCD = 10, Non-SCD = 10) will complete two study visits that will be double blinded and randomized for anticholinergic challenge (mecamylamine/scopolamine or placebo). Drug challenge visits will include cognitive testing and an electroencephalography (EEG) session.

Aim 1: Feasibility of EEG during mecamylamine/scopolamine challenge

The primary outcome measures for Aim 1 will be the rate of completion of study visits with drug challenge and of completion of EEG tasks during the study visits with drug challenge.

Attention Network Test: The attention network test (ANT) is designed to test selective attention , and combines attentional cues with a flanker task. Behavioral measures of the ANT will be 1) Alerting: reaction time (RT) non-cue trials - cue trials; 2) Orienting: RT neutral cue trials - spatial cue trials; 3) Executive: RT incongruent trials - congruent trials.

EEG, Task-related Event Related Potentials: Each participant will complete the ANT during EEG with primary event relation potential (ERP) measures: 1) Alerting: early sensory ERP (P1) amplitude; 2) Orienting: early sensory ERP (P1) amplitude; 3) Executive: target and conflict evaluation ERP (P3) amplitude. Other ERP signals related to attention and sensory processing will be examined in exploratory analyses.

Incidental Memory: Incidental Memory Task during EEG, a passive visual memory paradigm that will allow an exploratory examination of the relationship between SCD and brain activity for memory recognition.

Psychomotor Speed: The Choice Reaction Time task will be used as a test of psychomotor speed. This task decomposes overall reaction time into recognition and motor components, allowing for the assessment of response and motor time that cannot be attained during the ANT.

Episodic Memory: The Selective Reminding Task (SRT) is a multi-trial verbal list-learning task that offers measures of storage into and retrieval from both short term and long term memory and intrusion errors. Outcome measures will be total recall (8 trials), total recall failures (8 trials), and delayed recall (20 minutes).

Study Drug Administration: During challenge drug study visits, participants will receive double-blinded administration of study drug (either 20 mg oral mecamylamine or 2.5 μg/kg intravenous scopolamine) or placebo. The order of administration will be randomized across study days. Randomization and dispensing will be managed by VUMC Investigational Drug Services.

Mecamylamine is a centrally and peripherally active non-competitive antagonist of nicotine (and presumably acetylcholine) at C6 (ganglionic) type nicotinic receptors. Peak cognitive and physiologic effects occur by 2-3 hours and dissipate by 4-6 hours after oral administration. Scopolamine is a centrally active antimuscarinic anticholinergic compound and is a competitive antagonist of the effects of acetylcholine on postganglionic cholinergic nerves. At the doses to be used in this study, the expected physiologic effects of scopolamine include cycloplegia, mydriasis, drowsiness, partial amnesia, decreased bowel motility, tachycardia and decreased salivation. After intravenous administration, the early effects of scopolamine include tachycardia, dryness of mouth, and inhibition of lacrimation and sweating. Memory and attention changes are maximal between 90 and l50 minutes after an IV dose. The drug is distributed throughout the body with a serum half-life of approximately 2-3 hours. We have used both mecamylamine and scopolamine extensively in clinical studies in identical doses to those proposed here.

Statistical Analysis Plan:This project is a pilot study to determine the feasibility and participant tolerability for conducting EEG during the mecamylamine/scopolamine challenge. The proposed sample size (n =20) is designed to provide sufficient experience with the protocol to determine our ability to complete this protocol in a larger study and determine completion rates for the two participant groups (SCD and Non-SCD) as preliminary data for an NIH K01 application resubmission for Dr. Albert. Dr. Hakmook Kang is the biostatistics consultant for this project.

Descriptive statistics will be used to identify the rate of completion of study visits with drug challenge (proportion of participants that complete both study days), and of completion of EEG tasks (proportion of participants who complete both tasks on each study visits with drug challenge). These measures will be calculated for all participants (n = 20), and for participant groups separately (SCD, n = 10; Non-SCD, n = 10).

The investigators have hypothesized that > 80 % of participants will complete both study visits with drug challenge based on their experience using anticholinergic challenge with 88% of participants completing 2 study visits including anticholinergic challengeor placebo administration. The investigators have hypothesized that > 70 % of participants will complete both EEG tasks (ANT and incidental memory) during study visits with drug challenge, based on previous completion rates of 72% for non-EEG tasks during study visits including anticholinergic challenge or placebo administration, and 100% for EEG tasks with no drug challenge.

Inclusion criteria

• age ≥ 55
• Montreal Cognitive Assessment (MoCA) > 25 AND Global Deterioration Scale (GDS) rating < 3
• Non-smokers

Exclusion criteria

• medical contraindications to the drug challenge
• primary neurological disorder (such as stroke, epilepsy, etc.)