Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT06002477 |
| Other study ID # |
230736 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
Early Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
June 1, 2024 |
| Est. completion date |
June 30, 2028 |
Study information
| Verified date |
March 2024 |
| Source |
Vanderbilt University Medical Center |
| Contact |
Kimberly Albert, PhD |
| Phone |
6159364559 |
| Email |
kimberly.albert[@]vumc.org |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This study will use an anticholinergic pharmacological probe to examine attention network
function in SCD using EEG. The overall hypothesis is that in older adults with SCD, normal
cognitive performance is maintained by compensatory attention network activity, supported by
enhanced cholinergic function. The investigators anticipate that SCD will be associated with
greater compensatory attention network activity and that disrupting this compensatory process
through anticholinergic challenge will result in a greater negative effect on attentional
performance (Attention Network Test, ANT) and attention network functioning (EEG) in older
adults with greater subjective cognitive concern.
Description:
Overview: Cognitively normal older adults with and without subjective cognitive decline (SCD)
(n = 80) will complete two study visits that will be double blinded and randomized for
anticholinergic challenge (mecamylamine or placebo). Drug challenge visits will include
cognitive testing and an electroencephalography (EEG) session.
AIM 1: Test for anticholinergic effects on attentional network function by cognitive concern
severity. Under anticholinergic challenge, compared to placebo, greater subjective cognitive
concerns will be associated with…:
Hyp. 1a: greater reduction in orienting attention network activity (ERP amplitude for early
attention orienting).
Hyp. 1b: greater negative change in orienting attention performance.
Screening Procedures:
We will assure participants do not have MCI using the MoCA and GDS. Participants scoring
below 26 on the MoCA or above 3 on the GDS will be excluded.
Medical history and comorbidity will be quantified using the Cumulative Illness Rating Scale
(CIRS) 90. Self-reported medical histories, and problem lists from electronic medical records
will be reviewed for excluded medication and illness. Vital signs (weight, and height) will
be assessed. Participants will complete an electrocardiogram and blood samples will be
collected for a comprehensive metabolic panel and thyroid stimulating hormone levels.
All participants will be evaluated to exclude individuals with significant psychiatric
symptoms using a partial Structured Clinical Interview for DSM-IV-TR (SCID). Participants
will also complete the Beck Depression Rating Scale (BDI) and the Beck Anxiety Inventory
(BAI). Participants scoring above a BDI of 7 or a BAI of 15 will be excluded.
Study Drug Administration: During challenge drug study visits, participants will receive
double-blinded administration of study drug (20 mg oral mecamylamine) 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. At the doses to be used in this study, the expected physiologic effects of
mecamylamine include cycloplegia, mydriasis, drowsiness, partial amnesia, decreased bowel
motility, tachycardia and decreased salivation. We have used mecamylamine extensively in
clinical studies in identical doses to those proposed here.
EEG: Each participant will be tested individually in a quiet private room. EEG signals will
be recorded using a 128-channel Geodesic sensor net (EGI, Inc., Eugene, OR). The net is made
of Ag/AgCl-coated carbon electrodes embedded in soft electrolytic sponges and arranged into a
net using elastomer strings. Each electrode is connected via carbon wiring to a
high-impedance (1MOhm) low-noise amplifier that provides analogue-to-digital (A/D) conversion
of the EEG signals.
Prior to application, the net is soaked in warm saline (KCl) solution. The electrode
impedances will be kept at or below 40 kOhms. The use of high-impedance amplifiers minimizes
any decrease in signal-to-noise ratio and allows collection of high-quality data without
having to abrade the scalp, thus minimizing any discomfort and reducing infection risks.
Tests of this system reported no significant signal loss over a range of EEG frequencies.
Another advantage of this system is fast electrode application and impedance adjustments (<
10 minutes). The EEG signals will be sampled every 4ms with filters set at 0.1 Hz - 100 Hz.
During data collection, all electrodes will be referred to vertex (Cz). EEG will be
continuously monitored and during periods of motor activity or inattention, stimulus
presentation will be suspended until behavior quiets. The entire recording session will last
approximately 30 minutes.
Attention Network Test (15 minutes): A task designed to test three attentional networks: (1)
alerting, (2) orienting, and (3) executive control. The ANT combines attentional and spatial
cues with a flanker task (a central stimulus is flanked by distractors that can indicate the
same or opposite response to the central stimulus). On each trial a spatial cue is presented,
followed by an array of five arrows presented at either the top or the bottom of the computer
screen. The participant must indicate the direction of the central arrow in the array of
five.
The cue that precedes the arrows can be non-existent, a center cue, a double cue (one
presented at each of the two possible target locations), or a spatial cue that
deterministically indicates the upcoming target location. The alerting network contrasts
performance (RT) with and without cues, the orienting network contrasts performance on the
task with a spatial or neutral cue, and executive control (conflict) is measured by assessing
interference from congruent and incongruent flankers.
Incidental Memory Task (8 minutes): A passive incidental visual memory paradigm will be used
to evaluate changes in basic memory processes. Subjects will be asked to view a slide show of
novel color photographs depicting complex natural scenes. A small subset of the stimuli will
be presented repeatedly (x5) throughout the session; the rest will be shown once. To
encourage attention to the stimulus sequence, 20 attention probes (yellow smiley face) will
be presented throughout the test session and require a button press response.
Cognitive Assessments: Following the EEG session participants will complete cognitive
assessments of memory, and psychomotor speed. Administration takes approximately 35 minutes.
Our group has significant experience using these tests in older adult populations. Tests will
be administered in the order indicated below. Participants will be trained to stable
performance in the cognitive tasks to reduce learning effects on the repeated testing.
Different versions of all tests will be used during training and at each administration to
minimize the likelihood of carryover effects.
The tasks chosen are designed to assess a range of cognitive domains including multiple
attention, and visual-spatial and verbal memory processes, as well as psychomotor speed.
These tasks will be completed under placebo and anticholinergic challenge. The cognitive
battery will assess 1)Attention Capacity: Multiple Object Tracking, Digit Symbol Coding; 2)
Attention Vigilance: Critical Flicker Fusion; 3)Psychomotor Speed: Choice Reaction Time;
4)Visual Episodic Memory: Picture Sequence Memory Task (NIH Toolbox); 5)Verbal episodic
Memory: Buschke Selective reminding Task; 6)Visual-Spatial Working Memory: Visual-Spatial
N-Back. The time to complete the cognitive battery will be less than two hours which is well
within the 4-6-hour duration of effect of 10 mg mecamylamine.
Statistical Analysis Plan:Power was calculated for the Aim1 primary outcome measure of
correlation between CCI score and anticholinergic challenge effect on ANT orienting P1
amplitude. With a sample size of n = 80 and alpha = 0.05, for a weak moderate correlation (r
= 0.40) we will have over 95% power. This sample size is also appropriate for the
resting-state fMRI analyses.
AIM 1 examines anticholinergic challenge effects on:
Hyp 1a: Peak P1 amplitude in parietal regions for Orienting trials of the Attention Network
Test (ANT)
The primary ANT ERP measure will be P1 amplitude for the orienting trials in parietal
electrodes. The P1 ERP peak amplitude will be measured between 150 - 250 ms after spatial
orienting cue onset. Peak P1 amplitude measured between 150 - 250 ms after the non-spatial
cue will be used as the baseline P1 measure. Exploratory analyses will also examine peak P1
amplitude averaged across frontal electrodes and peak Executive P3 amplitude measured between
250 - 500 ms after executive incongruent target onset (compared to P3 amplitude for congruent
targets).
Cognitive concern severity will be measured as the number of items endorsed on the 20 item
Cognitive Change Index (CCI).
Hyp 1a will be analyzed using a linear mixed effects model analysis, with Orienting P1
amplitude as the dependent variable and drug challenge (mecamylamine or placebo), CCI score,
and their interaction, as fixed factors.
