Aging, Alzheimer Disease, Age-related Cognitive Decline
Conditions
Brief summary
In the current study, we will examine how daily paced breathing affects plasma amyloid beta levels and the rate of learning in older adults. Healthy adults aged 50-70 who meet all eligibility criteria will be invited to this study. Participants will be randomly assigned to one of the two conditions: 1) Daily memory and attention training followed by a paced breathing protocol designed to increase relaxation or 2) Daily memory and attention training followed by a paced breathing protocol to increase alertness. Participants will be asked to complete pre and post intervention cognitive testing online, engage in 10 weeks of daily brain training (starting Week 2) and 9 weeks of paced breathing (starting Week 3) at home. They will also be asked to come in for lab visits on Weeks 2, 7 and 12 to provide blood and urine samples to assess amyloid beta levels and to complete magnetic resonance imaging scans to assess perivascular space volume.
Interventions
BEHAVIORALBrain training
Participants will play a few brain training games using an online interface each day. These games train attention, memory and other cognitive functions.
BEHAVIORALPaced breathing
After completing brain training, they will then immediately do one 15-minute session of paced breathing, followed by a second 15-min session of paced breathing later in the day. During the paced breathing sessions, participants will clip a pulse monitor to their ear lobe and try to inhale and exhale in synchrony with a ball that moves up and down on the screen. They will receive heart rate biofeedback regarding whether they are achieving their relaxation/alertness goal.
Sponsors
University of California, Irvine
University of Southern California
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* speak English fluently * between the age of 50-70 * healthy adult who weighs at least 110 pounds * non-pregnant and non-menstruating (for at least the past year) * normal or corrected-to-normal vision and hearing * have a home computer with a physical keyboard and have access to reliable internet * have an email account that you check regularly * have a phone that receives text messages * willing to provide a blood sample and a urine sample at three lab visits * willing to devote up to 60 minutes daily to the study for 12 weeks (in addition to lab visits)
Exclusion criteria
* have a disorder that would impede performing the breathing intervention (e.g., abnormal cardiac rhythm, heart disease including coronary artery disease, angina, and arrhythmia, cognitive impairment, dyspnea) * regularly practicing any relaxation, biofeedback, or breathing technique (e.g., meditation) for more than an hour a week * regularly played Lumosity games in the past 6 months * participated in heart rate biofeedback studies in the USC Emotion & Cognition Lab * have any conditions listed below that are not safe for MRI * Claustrophobia * Have worked as a machinist, metal worker, or in any profession or hobby grinding metal? * Have had an injury to the eye involving a metallic object (e.g., metallic slivers, shavings, or foreign body) * Cardiac pacemaker * Implanted cardiac defibrillator * Aneurysm clip or brain clip * Carotid artery vascular clamp * Neurostimulator * Insulin or infusion pump * Spinal fusion stimulator * Cochlear, otologic, ear tubes or ear implant * Prosthesis (eye/orbital, penile, etc.) * Implant held in place by a magnet * Heart valve prosthesis * Artificial limb or joint * Other implants in body or head * Electrodes (on body, head or brain) * Intravascular stents, filters * Shunt (spinal or intraventricular) * Vascular access port or catheters * IUD * Transdermal delivery system or other types of foil patches (e.g., Nitro, Nicotine, Birth control, etc.) that cannot be removed for MRI * Shrapnel, buckshot, or bullets * Tattooed eyeliner or eyebrows * Body piercing(s) that cannot be removed for MRI * Metal fragments (eye, head, ear, skin) * Internal pacing wires * Aortic clips * Metal or wire mesh implants * Wire sutures or surgical staples * Harrington rods (spine) * Bone/joint pin, screw, nail, wire, plate * Wig or toupee that cannot be removed for MRI * Hair implants that involve staples or metal * Hearing aid(s) that cannot be removed for MRI * Dentures or retainers that cannot be removed for MRI
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma Amyloid Beta (Aβ) Levels | Measured from blood draws at lab visits on Weeks 2, 7, and 12 | We computed an aggregate Z-score based on plasma Aβ40 and Aβ42 levels (pg/mL). A Z-score of 0 represents the sample mean. Higher values indicate a greater level of plasma Aβ, which in cognitively normal individuals has been found to be associated with a higher risk of converting to Alzheimer's disease (Song et al., 2011). This score was compared across three time points: Week 2 (pre-intervention), Week 7 (mid-intervention), and Week 12 (post-intervention). We conducted a time (Week 2, 7, 12) × condition ANOVA to test for a time × condition interaction in plasma Aβ levels, assessing group differences in change over time. |
| Change in Plasma Ab42/40 Ratio | Measured from blood draws at lab visits on Weeks 2, 7, and 12 | The plasma Aβ42/40 ratio was calculated by dividing the plasma Aβ42 concentration (pg/mL) by the plasma Aβ40 concentration (pg/mL) at each time point. We conducted a time (Week 2, 7, 12) × condition ANOVA to test for an interaction effect, using plasma Aβ42/40 ratio scores as the dependent variable to assess group differences over time. A higher Aβ42/40 ratio indicates a better outcome, reflecting greater brain clearance of Aβ. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Brain Training Performance on 12 Lumosity Games | Measured at pre-intervention during week 2 and at the end of the intervention during week 12 | Participants completed 12 brain-training games on the Lumosity platform (https://www.lumosity.com/) targeting six cognitive domains: Attention, Flexibility, Language, Math, Memory, and Reasoning. Performance scores were expressed in arbitrary units, with minimum scores generally in the hundreds. The exact lower limits vary across games, and the upper limits differ substantially between games. Across all games, higher scores indicate better cognitive performance. For analyses, standardized performance scores (z-scores) were derived from the raw Lumosity game scores. Scores were standardized within each game across all participants; therefore, some values may appear negative, reflecting scores below the sample mean. A z-score of 0 represents the sample mean, with higher z-scores indicating better cognitive function. Standardized scores across games were combined using Partial Least Squares Correlation (PLSC) analyses. |
| Change in Hippocampal Volume | Measured from magnetic resonance imaging completed at lab visits on Weeks 2, 7, and 12 | We tested whether there were group differences in changes in hippocampal volume. We performed a two-way mixed ANCOVA on hippocampal volume, with condition as the between-subjects factor and time point (Week 2, 7, 12) as the within-subjects factor, controlling for intracranial volume as a covariate. |
| Change in Brain Perivascular Space Volume | Measured from magnetic resonance imaging completed at lab visits on Weeks 2, 7, and 12 | We tested whether there were group differences in changes in perivascular space (PVS) volume. PVS volume was defined as the percentage of PVS volume relative to white matter volume in the centrum semiovale, our main region of interest. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma pTau-181/Tau Ratio | Measured from blood draws at lab visits on Weeks 2, 7, and 12 | We will conduct a time (Week 2, 7, 12) X condition ANOVA to test for a time X condition interaction with plasma pTau-181/tau ratio as the dependent variable (to assess group differences in change). |
| Change in Urine Ab42 | Measured from urine samples at lab visits on Weeks 2, 7, and 12 | We will conduct a time (Week 2, 7, 12) X condition ANOVA to test for a time X condition interaction with urine Ab42 as the dependent variable (to assess group differences in change). |
Countries
United States
Participant flow
Pre-assignment details
Out of the 91 participants enrolled, 10 dropped after enrolling but before Week 1 home assessments, and an additional 19 dropped before condition assignment.
Participants by arm
| Arm | Count |
|---|---|
| Brain Training and Paced Breathing to Stimulate Alertness Brain training: Participants will play a few brain training games using an online interface each day. These games train attention, memory and other cognitive functions.
Paced breathing: After completing brain training, they will then immediately do one 15-minute session of paced breathing, followed by a second 15-min session of paced breathing later in the day. During the paced breathing sessions, participants will clip a pulse monitor to their ear lobe and try to inhale and exhale in synchrony with a ball that moves up and down on the screen. They will receive heart rate biofeedback regarding whether they are achieving their relaxation/alertness goal. | 31 |
| Brain Training and Paced Breathing to Relax Brain training: Participants will play a few brain training games using an online interface each day. These games train attention, memory and other cognitive functions.
Paced breathing: After completing brain training, they will then immediately do one 15-minute session of paced breathing, followed by a second 15-min session of paced breathing later in the day. During the paced breathing sessions, participants will clip a pulse monitor to their ear lobe and try to inhale and exhale in synchrony with a ball that moves up and down on the screen. They will receive heart rate biofeedback regarding whether they are achieving their relaxation/alertness goal. | 31 |
| Total | 62 |
Baseline characteristics
| Characteristic | Brain Training and Paced Breathing to Stimulate Alertness | Total | Brain Training and Paced Breathing to Relax |
|---|---|---|---|
| Age, Continuous | 59.77 years STANDARD_DEVIATION 6.17 | 60.15 years STANDARD_DEVIATION 5.77 | 60.52 years STANDARD_DEVIATION 5.42 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 11 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 49 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 12 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 7 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) White | 16 Participants | 34 Participants | 18 Participants |
| Region of Enrollment United States | 31 participants | 62 participants | 31 participants |
| Sex: Female, Male Female | 17 Participants | 34 Participants | 17 Participants |
| Sex: Female, Male Male | 14 Participants | 28 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 31 |
| other Total, other adverse events | 3 / 31 | 3 / 31 |
| serious Total, serious adverse events | 0 / 31 | 0 / 31 |
Outcome results
Primary
Change in Plasma Ab42/40 Ratio
The plasma Aβ42/40 ratio was calculated by dividing the plasma Aβ42 concentration (pg/mL) by the plasma Aβ40 concentration (pg/mL) at each time point. We conducted a time (Week 2, 7, 12) × condition ANOVA to test for an interaction effect, using plasma Aβ42/40 ratio scores as the dependent variable to assess group differences over time. A higher Aβ42/40 ratio indicates a better outcome, reflecting greater brain clearance of Aβ.
Time frame: Measured from blood draws at lab visits on Weeks 2, 7, and 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Brain Training and Paced Breathing to Stimulate Alertness | Change in Plasma Ab42/40 Ratio | Week 2 | .040 ratio of Aβ42 to Aβ40 | Standard Error 0.001 |
| Brain Training and Paced Breathing to Stimulate Alertness | Change in Plasma Ab42/40 Ratio | Week 12 | .040 ratio of Aβ42 to Aβ40 | Standard Error 0.001 |
| Brain Training and Paced Breathing to Stimulate Alertness | Change in Plasma Ab42/40 Ratio | Week 7 | .041 ratio of Aβ42 to Aβ40 | Standard Error 0.001 |
| Brain Training and Paced Breathing to Relax | Change in Plasma Ab42/40 Ratio | Week 2 | .038 ratio of Aβ42 to Aβ40 | Standard Error 0.001 |
| Brain Training and Paced Breathing to Relax | Change in Plasma Ab42/40 Ratio | Week 7 | .039 ratio of Aβ42 to Aβ40 | Standard Error 0.001 |
| Brain Training and Paced Breathing to Relax | Change in Plasma Ab42/40 Ratio | Week 12 | .037 ratio of Aβ42 to Aβ40 | Standard Error 0.001 |
p-value: 0.147ANOVA
Primary
Change in Plasma Amyloid Beta (Aβ) Levels
We computed an aggregate Z-score based on plasma Aβ40 and Aβ42 levels (pg/mL). A Z-score of 0 represents the sample mean. Higher values indicate a greater level of plasma Aβ, which in cognitively normal individuals has been found to be associated with a higher risk of converting to Alzheimer's disease (Song et al., 2011). This score was compared across three time points: Week 2 (pre-intervention), Week 7 (mid-intervention), and Week 12 (post-intervention). We conducted a time (Week 2, 7, 12) × condition ANOVA to test for a time × condition interaction in plasma Aβ levels, assessing group differences in change over time.
Time frame: Measured from blood draws at lab visits on Weeks 2, 7, and 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Brain Training and Paced Breathing to Stimulate Alertness | Change in Plasma Amyloid Beta (Aβ) Levels | Week 2 | 0.343 Z-score | Standard Deviation 0.161 |
| Brain Training and Paced Breathing to Stimulate Alertness | Change in Plasma Amyloid Beta (Aβ) Levels | Week 12 | 0.410 Z-score | Standard Deviation 0.161 |
| Brain Training and Paced Breathing to Stimulate Alertness | Change in Plasma Amyloid Beta (Aβ) Levels | Week 7 | 0.381 Z-score | Standard Deviation 0.161 |
| Brain Training and Paced Breathing to Relax | Change in Plasma Amyloid Beta (Aβ) Levels | Week 12 | -0.387 Z-score | Standard Deviation 0.15 |
| Brain Training and Paced Breathing to Relax | Change in Plasma Amyloid Beta (Aβ) Levels | Week 2 | -0.371 Z-score | Standard Deviation 0.15 |
| Brain Training and Paced Breathing to Relax | Change in Plasma Amyloid Beta (Aβ) Levels | Week 7 | -0.332 Z-score | Standard Deviation 0.151 |
p-value: 0.817ANOVA
Secondary
Brain Training Performance on 12 Lumosity Games
Participants completed 12 brain-training games on the Lumosity platform (https://www.lumosity.com/) targeting six cognitive domains: Attention, Flexibility, Language, Math, Memory, and Reasoning. Performance scores were expressed in arbitrary units, with minimum scores generally in the hundreds. The exact lower limits vary across games, and the upper limits differ substantially between games. Across all games, higher scores indicate better cognitive performance. For analyses, standardized performance scores (z-scores) were derived from the raw Lumosity game scores. Scores were standardized within each game across all participants; therefore, some values may appear negative, reflecting scores below the sample mean. A z-score of 0 represents the sample mean, with higher z-scores indicating better cognitive function. Standardized scores across games were combined using Partial Least Squares Correlation (PLSC) analyses.
Time frame: Measured at pre-intervention during week 2 and at the end of the intervention during week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Brain Training and Paced Breathing to Stimulate Alertness | Brain Training Performance on 12 Lumosity Games | baseline performance (bin1) | -2.9144 Z-scores | Standard Deviation 1.3024 |
| Brain Training and Paced Breathing to Stimulate Alertness | Brain Training Performance on 12 Lumosity Games | final performance (bin 10) | 1.5021 Z-scores | Standard Deviation 2.258 |
| Brain Training and Paced Breathing to Relax | Brain Training Performance on 12 Lumosity Games | baseline performance (bin1) | -2.9242 Z-scores | Standard Deviation 1.1478 |
| Brain Training and Paced Breathing to Relax | Brain Training Performance on 12 Lumosity Games | final performance (bin 10) | 1.4551 Z-scores | Standard Deviation 1.9558 |
p-value: 0.99795% CI: [-0.072164, 0.072448]Mixed Models Analysis
Secondary
Change in Brain Perivascular Space Volume
We tested whether there were group differences in changes in perivascular space (PVS) volume. PVS volume was defined as the percentage of PVS volume relative to white matter volume in the centrum semiovale, our main region of interest.
Time frame: Measured from magnetic resonance imaging completed at lab visits on Weeks 2, 7, and 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Brain Training and Paced Breathing to Stimulate Alertness | Change in Brain Perivascular Space Volume | Week 2 | 0.0077 percentage of PVS volume | Standard Deviation 0.0034 |
| Brain Training and Paced Breathing to Stimulate Alertness | Change in Brain Perivascular Space Volume | Week 7 | 0.0083 percentage of PVS volume | Standard Deviation 0.0042 |
| Brain Training and Paced Breathing to Stimulate Alertness | Change in Brain Perivascular Space Volume | Week 12 | 0.0092 percentage of PVS volume | Standard Deviation 0.0054 |
| Brain Training and Paced Breathing to Relax | Change in Brain Perivascular Space Volume | Week 2 | 0.0079 percentage of PVS volume | Standard Deviation 0.0043 |
| Brain Training and Paced Breathing to Relax | Change in Brain Perivascular Space Volume | Week 7 | 0.0088 percentage of PVS volume | Standard Deviation 0.0052 |
| Brain Training and Paced Breathing to Relax | Change in Brain Perivascular Space Volume | Week 12 | 0.0080 percentage of PVS volume | Standard Deviation 0.0039 |
p-value: 0.096ANOVA
Secondary
Change in Hippocampal Volume
We tested whether there were group differences in changes in hippocampal volume. We performed a two-way mixed ANCOVA on hippocampal volume, with condition as the between-subjects factor and time point (Week 2, 7, 12) as the within-subjects factor, controlling for intracranial volume as a covariate.
Time frame: Measured from magnetic resonance imaging completed at lab visits on Weeks 2, 7, and 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Brain Training and Paced Breathing to Stimulate Alertness | Change in Hippocampal Volume | Week 2 | 7036 mm^2 | Standard Error 105 |
| Brain Training and Paced Breathing to Stimulate Alertness | Change in Hippocampal Volume | Week 7 | 7038 mm^2 | Standard Error 105.6 |
| Brain Training and Paced Breathing to Stimulate Alertness | Change in Hippocampal Volume | Week 12 | 7018 mm^2 | Standard Error 103.1 |
| Brain Training and Paced Breathing to Relax | Change in Hippocampal Volume | Week 2 | 7143 mm^2 | Standard Error 99.2 |
| Brain Training and Paced Breathing to Relax | Change in Hippocampal Volume | Week 7 | 7124 mm^2 | Standard Error 99.8 |
| Brain Training and Paced Breathing to Relax | Change in Hippocampal Volume | Week 12 | 7102 mm^2 | Standard Error 97.4 |
p-value: 0.64ANCOVA
Other Pre-specified
Change in Plasma pTau-181/Tau Ratio
We will conduct a time (Week 2, 7, 12) X condition ANOVA to test for a time X condition interaction with plasma pTau-181/tau ratio as the dependent variable (to assess group differences in change).
Time frame: Measured from blood draws at lab visits on Weeks 2, 7, and 12
Other Pre-specified
Change in Urine Ab42
We will conduct a time (Week 2, 7, 12) X condition ANOVA to test for a time X condition interaction with urine Ab42 as the dependent variable (to assess group differences in change).
Time frame: Measured from urine samples at lab visits on Weeks 2, 7, and 12