Aging
Conditions
Keywords
Alzheimer's disease, Senescence
Brief summary
The purpose of this pilot study is to demonstrate the safety and feasibility of administering intermittent doses of Dasatinib and Quercetin (D+Q) in older adults at risk of Alzheimer's disease (AD). The study will evaluate whether giving D+Q may improve cerebral blood flow regulation, mobility, and cognition in older adults, and thus may prevent progression to Alzheimer's disease.
Detailed description
The investigators will conduct a 12-week single arm, open label, pre-post pilot study in 12 adults aged 65 or older with slow gait speed (\<1.0 m/sec) and Mild Cognitive Impairment (MCI, defined as a Telephone Montreal Cognitive Assessment Score (MoCA) \<19). Participants will be asked to take 100mg of Dasatinib and 1,250mg of Quercetin for 2 consecutive days, every two weeks over a period of 12 weeks (12 doses in total, given over 6 cycles). At baseline, enrolled participants will undergo gait speed and neurocognitive testing, and provide blood and urine to evaluate biomarkers of senescence. At visits 3,4, 6, and 7, participants will have safety labs drawn, and the study team will assess medication adherence and adverse events. At visits 2, 5, and 8, participants will undergo cognitive assessments, gait speed testing, cerebral blood flow and neurovascular coupling testing. At the final study visit, participants will again provide blood and urine to assess biomarkers of senescence.
Interventions
DRUGDasatinib
Dasatinib 100 mg for 2 consecutive days, every two weeks for 12 weeks
DRUGQuercetin
Quercetin 1,250 mg for 2 consecutive days, every two weeks for 12 weeks
Sponsors
Lewis Lipsitz
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men and women \>/= 65 years * Ambulatory, * Community dwelling, * Slow gait speed (\<1 m/second), * Mild Cognitive Impairment (Telephone MoCA score \<21, which is indicative of cognitive impairment)
Exclusion criteria
, or as per clinical judgment: * Telephone MoCA score \<10 points * Unwilling to take study medications or follow study protocol * Inability to independently perform Katz Activities of Daily Living (ADLs), * Allergies to Dasatinib or Quercetin, * Hospitalization within 6 months, * Unstable coronary artery disease (myocardial infarction within 6 months or angina), * Stroke or transient ischemic attack in the past 6 months, * Chronic heart failure, * Current or chronic history of liver disease, * Neurodegenerative disease including Parkinson's disease, * Anemia, * Chronic renal disease, * Drug or alcohol abuse in the last 5 years, * QTc prolongation, * Thrombocytopenia, * Neutropenia, * Prolonged prothrombin time or INR, * Indications of current fluid retention, * History or current diagnosis of pulmonary hypertension, * Inability to insonate the middle cerebral artery through a temporal bone window on at least one side using transcranial Doppler ultrasound, or * Chronic use of any of the following medications: anti-arrhythmic medications, antipsychotics, anxiolytics, anti-platelet or anti-coagulant medications other than aspirin, quinolone antibiotics, or drugs metabolized by the same liver enzymes as Quercetin or Dasatinib.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neurovascular Coupling | Screening, 8, and 14 weeks | Change in cerebral blood flow during an N-back cognitive task using transcranial doppler ultrasound. |
| Executive Function | Baseline, 8, and 14 weeks | Assess change in executive cognitive function using TRAILS test, corrected for response time. Higher scores indicate worse executive functioning. |
| Gait Speed | Baseline, 8, and 14 weeks | Assess change in gait speed. Performed without a distracting cognitive task. |
| Montreal Cognitive Assessment (MoCA) Score | Baseline, 8, and 14 weeks | The Montreal Cognitive Assessment evaluates global cognition. Scores range from 0-30 points, with higher scores indicating better cognition |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| P16 ink4a Expression in CD3 Positive Cells | Screening and 14 weeks | Measure of P16 ink4a expression in senescent CD3 lymphocytes in the blood. |
| Physical Performance | Baseline, 8, and 14 weeks | Assessment of overall physical function using the short physical performance battery (SPPB) scored from 0-12, based on a composite of balance, strength, and walking speed. Higher scores indicate better mobility. |
| SASP Factors in Blood and Urine | Screening and 14 weeks | Measure of the senescence-associated biomarkers IL-1alpha picogram/mL and IL-6 picogram/mL. |
| Mobility | Baseline, 8, and 14 weeks | Test of mobility using timed up and go test, including standing from a chair, walking, and turning. |
| Grip Strength | Baseline, 8, and 14 weeks | Measure of grip strength using a hand dynamometer. |
| Gait Speed During Cognitive Task | Baseline, 8, and 14 weeks | Measure of gait speed during a cognitive task. |
Countries
United States
Participant flow
Recruitment details
This study was conducted from 2022-2024 in the greater Boston, MA area. Individuals were recruited through a recruitment firm that utilizes online targeted advertisements based on an individual's browsing history, as well as senior housing presentations, study flyers at clinical practices, and invitations to previous research volunteers who agreed to be in our participant registries.
Pre-assignment details
Of the 332 individuals that expressed interest in the study, 115 were screened via telephone. Sixty were ineligible due to not meeting the pre-specified inclusion/exclusion criteria. Of the 55 eligible telephone screeners, 24 were not enrolled due to loss of interest (n=12), loss to follow-up (n=10), or closed enrolment (n=2). Of the 31 participants that were screened in-person, 16 were excluded for various reasons, while 15 individuals were eligible and willing to participate.
Participants by arm
| Arm | Count |
|---|---|
| Dasatinib and Quercetin Participants took 100 mg of Dasatinib and 1,250 mg of Quercetin for 2 consecutive days, every two weeks for 12 weeks | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Dasatinib and Quercetin |
|---|---|
| 4-meter Gait Speed | 0.8 meters/second STANDARD_DEVIATION 0.1 |
| Age, Continuous | 77 years STANDARD_DEVIATION 7 |
| Body Mass Index | 27 kg/m^2 STANDARD_DEVIATION 4 |
| Depression | 4 Participants |
| Eye Disease | 8 Participants |
| High Blood Pressure | 5 Participants |
| High Cholesterol | 6 Participants |
| Highest Level of Education Associates Degree | 1 Participants |
| Highest Level of Education Bachelors Degree | 5 Participants |
| Highest Level of Education Graduate/Doctoral/Law Degree | 7 Participants |
| Highest Level of Education No Diploma | 1 Participants |
| Highest Level of Education Some College/Vocational School | 1 Participants |
| Osteo- or Degenerative Arthritis | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 8 Participants |
| Stomach Disease (e.g., Acid Reflux) | 7 Participants |
| Telephone Montreal Cognitive Assessment Score | 17 points STANDARD_DEVIATION 2 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 15 |
| other Total, other adverse events | 12 / 15 |
| serious Total, serious adverse events | 1 / 15 |
Outcome results
Primary
Executive Function
Assess change in executive cognitive function using TRAILS test, corrected for response time. Higher scores indicate worse executive functioning.
Time frame: Baseline, 8, and 14 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib and Quercetin | Executive Function | Baseline (Week 2) | 80.6 seconds | Standard Deviation 80.2 |
| Dasatinib and Quercetin | Executive Function | Week 8 | 75.0 seconds | Standard Deviation 61.4 |
| Dasatinib and Quercetin | Executive Function | Week 14 | 63.4 seconds | Standard Deviation 44.6 |
Primary
Gait Speed
Assess change in gait speed. Performed without a distracting cognitive task.
Time frame: Baseline, 8, and 14 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib and Quercetin | Gait Speed | Baseline (Week 2) | 0.87 meters/second | Standard Deviation 0.15 |
| Dasatinib and Quercetin | Gait Speed | Week 8 | 0.85 meters/second | Standard Deviation 0.16 |
| Dasatinib and Quercetin | Gait Speed | Week 14 | 0.87 meters/second | Standard Deviation 0.14 |
Primary
Montreal Cognitive Assessment (MoCA) Score
The Montreal Cognitive Assessment evaluates global cognition. Scores range from 0-30 points, with higher scores indicating better cognition
Time frame: Baseline, 8, and 14 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib and Quercetin | Montreal Cognitive Assessment (MoCA) Score | Baseline | 23 points | Standard Deviation 2 |
| Dasatinib and Quercetin | Montreal Cognitive Assessment (MoCA) Score | 8 Weeks | 25 points | Standard Deviation 3 |
| Dasatinib and Quercetin | Montreal Cognitive Assessment (MoCA) Score | 14 Weeks | 24 points | Standard Deviation 2 |
Primary
Neurovascular Coupling
Change in cerebral blood flow during an N-back cognitive task using transcranial doppler ultrasound.
Time frame: Screening, 8, and 14 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib and Quercetin | Neurovascular Coupling | Week 8 | 0.26 cm/s | Standard Deviation 2.04 |
| Dasatinib and Quercetin | Neurovascular Coupling | Week 14 | 0.80 cm/s | Standard Deviation 2.13 |
| Dasatinib and Quercetin | Neurovascular Coupling | Screening | 0.68 cm/s | Standard Deviation 1.4 |
Secondary
Gait Speed During Cognitive Task
Measure of gait speed during a cognitive task.
Time frame: Baseline, 8, and 14 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib and Quercetin | Gait Speed During Cognitive Task | Week 8 | 0.75 meters/second | Standard Deviation 0.16 |
| Dasatinib and Quercetin | Gait Speed During Cognitive Task | Week 14 | 0.78 meters/second | Standard Deviation 0.14 |
| Dasatinib and Quercetin | Gait Speed During Cognitive Task | Baseline (Week 2) | 0.76 meters/second | Standard Deviation 0.13 |
Secondary
Grip Strength
Measure of grip strength using a hand dynamometer.
Time frame: Baseline, 8, and 14 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib and Quercetin | Grip Strength | Week 14 | 23.6 kilograms | Standard Deviation 5.3 |
| Dasatinib and Quercetin | Grip Strength | Baseline (Week 2) | 23.5 kilograms | Standard Deviation 7.2 |
| Dasatinib and Quercetin | Grip Strength | Week 8 | 22.7 kilograms | Standard Deviation 5.8 |
Secondary
Mobility
Test of mobility using timed up and go test, including standing from a chair, walking, and turning.
Time frame: Baseline, 8, and 14 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib and Quercetin | Mobility | Baseline (Week 2) | 14.2 seconds | Standard Deviation 2.6 |
| Dasatinib and Quercetin | Mobility | Week 8 | 13.9 seconds | Standard Deviation 3.1 |
| Dasatinib and Quercetin | Mobility | Week 14 | 13.6 seconds | Standard Deviation 2.4 |
Secondary
P16 ink4a Expression in CD3 Positive Cells
Measure of P16 ink4a expression in senescent CD3 lymphocytes in the blood.
Time frame: Screening and 14 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib and Quercetin | P16 ink4a Expression in CD3 Positive Cells | Screening | 10.6 relative expression to housekeeping gene | Standard Deviation 5.2 |
| Dasatinib and Quercetin | P16 ink4a Expression in CD3 Positive Cells | Week 14 | 9.4 relative expression to housekeeping gene | Standard Deviation 3.8 |
Secondary
Physical Performance
Assessment of overall physical function using the short physical performance battery (SPPB) scored from 0-12, based on a composite of balance, strength, and walking speed. Higher scores indicate better mobility.
Time frame: Baseline, 8, and 14 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib and Quercetin | Physical Performance | Baseline (Week 2) | 9 points | Standard Deviation 1 |
| Dasatinib and Quercetin | Physical Performance | Week 8 | 9 points | Standard Deviation 2 |
| Dasatinib and Quercetin | Physical Performance | Week 14 | 9 points | Standard Deviation 2 |
Secondary
SASP Factors in Blood and Urine
Measure of the senescence-associated biomarkers MMP-9 nanograms/mL and MMP-12 nanograms/mL.
Time frame: Screening and 14 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib and Quercetin | SASP Factors in Blood and Urine | Serum MMP-9 Screening | 458.5 nanograms/mL | Standard Deviation 189.4 |
| Dasatinib and Quercetin | SASP Factors in Blood and Urine | Serum MMP-9 Week 14 | 541.6 nanograms/mL | Standard Deviation 454.4 |
Secondary
SASP Factors in Blood and Urine
Measure of the senescence-associated biomarkers IL-1alpha picogram/mL and IL-6 picogram/mL.
Time frame: Screening and 14 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dasatinib and Quercetin | SASP Factors in Blood and Urine | Serum IL1-alpha Screening | 664.5 picograms/mL | Standard Deviation 368.1 |
| Dasatinib and Quercetin | SASP Factors in Blood and Urine | Serum IL1-alpha Week 14 | 742.2 picograms/mL | Standard Deviation 513.1 |
| Dasatinib and Quercetin | SASP Factors in Blood and Urine | Serum IL-6 Screening | 3.6 picograms/mL | Standard Deviation 1.7 |
| Dasatinib and Quercetin | SASP Factors in Blood and Urine | Serum IL-6 Week 14 | 2.8 picograms/mL | Standard Deviation 1.5 |