Hypertension, Mild Cognitive Impairment
Conditions
Keywords
Cerebrovascular function
Brief summary
The aim of this study is to conduct a 1-year double blind randomized control trial comparing candesartan to lisinopril in 140 individuals with hypertension and executive mild cognitive impairment in their effects on executive function, neuroimaging markers, and vascular indicators.
Detailed description
* Hypertension is associated with cognitive impairment even in the absence of clinical dementia. To date, no specific treatment is available for this pattern of mild cognitive impairment related to hypertension. * Objectives or purpose: The aims of this study are to investigate the effects of candesartan on executive function decline and on changes in cerebral perfusion, cerebrovascular reserve and microvascular brain injury. The study also intends to identify potential underlying mechanisms related to vascular structure and function, including atherosclerosis, vascular inflammation, vascular stiffness, and endothelial progenitor cells, by which candesartan may affect the cognitive and cerebrovascular outcomes. * Study methodology:This is a double blind randomized clinical trial that will be conducted in 140 individuals (70 in the candesartan group, 70 in the lisinopril group). Our target population is subjects: 55 years or older with hypertension and Executive Mild Cognitive Impairment. * Endpoints to be measured:Our measures include cognitive function, cerebral perfusion and reserve, markers of vascular brain damage, atherosclerosis, stiffness, vascular inflammation and endothelial function. * Description of intervention, follow-up, and duration of study: Eligible participants will undergo randomization into 2 groups and will be seen frequently until their blood pressure is controlled (\<140/90 mmHg). Participants will be seen at 3, 6 and 12 months afterwards.
Interventions
DRUGCandesartan
blinded
DRUGLisinopril
Blinded
Sponsors
National Institute on Aging (NIA)
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
55 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. age: 55 years or older; 2. Hypertension: SBP≥140 mm Hg or DBP≥ 90 mm or receiving antihypertensive medications. 3. Executive MCI will be defined using these criteria: 1. The Montreal Cognitive Assessment (MoCA) score less than or equal to 26 2. Executive dysfunction: A performance at the 10th percentile or below on at least one of four screening tests for executive function: Trail Making Test, Part B (TMT-B), modified Stroop interference, Digit Span and Digit Sequencing, and Letter fluency. 3. Minimal Functional limitation as reflected by the Functional Assessment Questionnaire (FAQ)≤7
Exclusion criteria
1. Intolerance to study drugs; 2. SBP \>200 or DBP \>110 mm Hg; 3. Renal disease or hyperkalemia 4. Active medical or psychiatric problems 5. Uncontrolled congestive heart failure; 6. History of stroke in the past 3 years; 7. Inability to perform the study procedures 8. Women of childbearing potential 9. diagnosis of dementia 10. In those who lack decision capacity, a study surrogate who can sign on their behalf will be required. Since we are enrolling only those with MCI, we anticipate that most participants will have decision capacity 11. Current use of Lithium, as most antihypertensive classes may lead to increased lithium toxic levels.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Executive Function | 12 months | Executive function will be assessed using Trail Making Test (part B-A). Part A was collected to correct for motor speed and visual-perceptual demands on TMT by subtracting completion time for TMT Part A from completion time for Part B (TMT B - A). TMT Part B-A provides a relatively purer measure of executive functioning. It has a timed scale from 0 sec (min) to 300 secs (max). Along this scale, a lower score is better. |
| NINDS-initiated EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research or EXAMINER Tool Box. | 12 months | EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research or EXAMINER tool box. This test batteryThe battery includes 11 tasks that generate 15 primary variables. Within this set, the EXAMINER includes: working memory, inhibition, set shifting, and fluency. The parts of EXAMINER that were used for this study include: Flanker task (inhibition) which involves responding to a central stimulus while ignoring flanking stimuli that are either compatible or incompatible with the central stimulus; Set-shifting, a measure of mental flexibility; Spatial 1-Back test assesses spatial working memory; Dot Counting test assesses verbal working memory; Verbal Fluency tested using a List Generation test which require the participant to generate words beginning with a specific letter, and category fluency in which the participant generates words from a specified category (e.g., animals, fruits). Higher are reflective of better executive function (-1 to +1) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Attention Measured Using Digit Span Backward | 12 months | The Digit Span test is a subtest of both the Wechsler Adult Intelligence Scale (WAIS) and the Wechsler Memory Scales (WMS). For the digit span backwards, subjects are read a sequence of numbers and asked to repeat the same sequence back to the examiner in reverse order (backward span). Backward span is an executive task particularly dependent on working memory. The Digit Span backward is scored for backwards performance. Scale: 0 (minimum) to 16 (maximum). A higher score represents a better outcome. |
| White Matter Lesion Volume | 12 months | White Matter Lesion volume: high-resolution anatomical images are acquired for the measurement of microvascular disease. WMH volumes will be obtained from Fluid attenuated inversion recovery (FLAIR) imaging sequence and reported as total volume (in mm3). Higher values means greater WMH |
| Memory | 12 months | To assess episodic memory, the Hopkins Verbal Learning Test-Revised (HVLT-R) will be used. The retention (%) score is calculated by dividing the delayed recall trial by the higher of 3 learning trials. Each trial scores 0 (min) to 12 (max). The HVLT-R retention score is a percentage, and a higher percentage represents a better outcome. |
| Attention Measured Using Digit Span Forward | 12 months | This will be measured using Digit Span Forward. The Digit Span test is a subtest of both the Wechsler Adult Intelligence Scale (WAIS) and the Wechsler Memory Scales (WMS). For the digit span forward, subjects are read a sequence of numbers and asked to repeat the same sequence back to the examiner in the correct order (forward span). Forward span captures attention efficiency and capacity. The Digit Span forward is scored for forwards performance. Scale: 0 (minimum) to 16 (maximum). A higher score represents a better outcome. |
| Cerebral Perfusion | 12 months | ASL-MRI: Arterial Spin Labeling (ASL) MRI is non-invasive measure of perfusion that does not require contrast, and allows multiple brain regions mapping of perfusion and reserve. ASL-MRI provides measures of cerebral blood flow (CBF). Higher values indicates higher CBF. |
| Language | 12 months | This will be measured using the Boston Naming Test. BNT is a neuropsychological test used to assess visual confrontation naming and language performance in participants with cognitive decline. Its short 15-item version consists of drawings of objects ranging from common objects to less familiar objects. Scale: 0 (min score) to 15 (max score). For this test, a higher score/response represents a better outcome. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Candesartan To achieve blood pressure control, we will use a stepwise protocol as follows: candesartan (blinded) 8mg→ 16mg→ 32mg. Both groups will also receive (unblinded) , if needed to achieve blood pressure control, HCTZ 12.5mg→ 25mg, Amlodipine 2.5mg→ 5mg →10mg and metoprolol succinate extended release 12.5mg→ 25mg→ 50mg. Antihypertensive medications will be increased every 2 weeks until control is achieved.
Candesartan: blinded | 87 |
| Lisinopril To achieve blood pressure control we will use a stepwise protocol as follows: lisinopril (blinded) 10mg→ 20mg→ 40mg. Both groups will also receive (unblinded), if needed to achieve blood pressure control, HCTZ 12.5mg→ 25mg, Amlodipine 2.5mg→ 5mg→ 10mg and metoprolol succinate extended release 12.5mg→ 25mg→ 50mg. Antihypertensive medications will be increased every 2 weeks until control is achieved.
Lisinopril: Blinded | 89 |
| Total | 176 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 19 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Withdrawal by Subject | 4 | 3 |
Baseline characteristics
| Characteristic | Candesartan | Lisinopril | Total |
|---|---|---|---|
| Age, Continuous | 66.1 years STANDARD_DEVIATION 8.3 | 65.8 years STANDARD_DEVIATION 7.2 | 65.9 years STANDARD_DEVIATION 8.1 |
| MoCA score | 21.4 points STANDARD_DEVIATION 3.4 | 21.7 points STANDARD_DEVIATION 3.5 | 21.5 points STANDARD_DEVIATION 3.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 56 Participants | 57 Participants | 113 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 29 Participants | 31 Participants | 60 Participants |
| Region of Enrollment United States | 87 participants | 89 participants | 176 participants |
| Sex: Female, Male Female | 47 Participants | 54 Participants | 101 Participants |
| Sex: Female, Male Male | 40 Participants | 35 Participants | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 87 | 0 / 89 |
| other Total, other adverse events | 87 / 87 | 89 / 89 |
| serious Total, serious adverse events | 0 / 87 | 0 / 89 |
Outcome results
Primary
Executive Function
Executive function will be assessed using Trail Making Test (part B-A). Part A was collected to correct for motor speed and visual-perceptual demands on TMT by subtracting completion time for TMT Part A from completion time for Part B (TMT B - A). TMT Part B-A provides a relatively purer measure of executive functioning. It has a timed scale from 0 sec (min) to 300 secs (max). Along this scale, a lower score is better.
Time frame: 12 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Candesartan | Executive Function | 87.23 seconds | Standard Error 5.46 |
| Lisinopril | Executive Function | 111.37 seconds | Standard Error 5.89 |
Comparison: All analyses were conducted using the intention-to-treat principle. Results are provided as adjusted least-square means with SE and effect size (ES) estimates (calculated from mixed model with repeated measures (MMRM) as the adjusted difference in cognitive change between the 2 groups over the study period).95% CI: [-23.6, -3.7]
Primary
NINDS-initiated EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research or EXAMINER Tool Box.
EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research or EXAMINER tool box. This test batteryThe battery includes 11 tasks that generate 15 primary variables. Within this set, the EXAMINER includes: working memory, inhibition, set shifting, and fluency. The parts of EXAMINER that were used for this study include: Flanker task (inhibition) which involves responding to a central stimulus while ignoring flanking stimuli that are either compatible or incompatible with the central stimulus; Set-shifting, a measure of mental flexibility; Spatial 1-Back test assesses spatial working memory; Dot Counting test assesses verbal working memory; Verbal Fluency tested using a List Generation test which require the participant to generate words beginning with a specific letter, and category fluency in which the participant generates words from a specified category (e.g., animals, fruits). Higher are reflective of better executive function (-1 to +1)
Time frame: 12 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Candesartan | NINDS-initiated EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research or EXAMINER Tool Box. | 0.07 units on a scale | Standard Error 0.07 |
| Lisinopril | NINDS-initiated EXecutive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research or EXAMINER Tool Box. | 0.25 units on a scale | Standard Error 0.07 |
Secondary
Attention Measured Using Digit Span Backward
The Digit Span test is a subtest of both the Wechsler Adult Intelligence Scale (WAIS) and the Wechsler Memory Scales (WMS). For the digit span backwards, subjects are read a sequence of numbers and asked to repeat the same sequence back to the examiner in reverse order (backward span). Backward span is an executive task particularly dependent on working memory. The Digit Span backward is scored for backwards performance. Scale: 0 (minimum) to 16 (maximum). A higher score represents a better outcome.
Time frame: 12 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Candesartan | Attention Measured Using Digit Span Backward | 5.14 Number of correct responses | Standard Error 0.25 |
| Lisinopril | Attention Measured Using Digit Span Backward | 5.16 Number of correct responses | Standard Error 0.26 |
Secondary
Attention Measured Using Digit Span Forward
This will be measured using Digit Span Forward. The Digit Span test is a subtest of both the Wechsler Adult Intelligence Scale (WAIS) and the Wechsler Memory Scales (WMS). For the digit span forward, subjects are read a sequence of numbers and asked to repeat the same sequence back to the examiner in the correct order (forward span). Forward span captures attention efficiency and capacity. The Digit Span forward is scored for forwards performance. Scale: 0 (minimum) to 16 (maximum). A higher score represents a better outcome.
Time frame: 12 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Candesartan | Attention Measured Using Digit Span Forward | 9.67 Number of correct responses | Standard Error 0.61 |
| Lisinopril | Attention Measured Using Digit Span Forward | 8.93 Number of correct responses | Standard Error 0.66 |
Secondary
Cerebral Perfusion
ASL-MRI: Arterial Spin Labeling (ASL) MRI is non-invasive measure of perfusion that does not require contrast, and allows multiple brain regions mapping of perfusion and reserve. ASL-MRI provides measures of cerebral blood flow (CBF). Higher values indicates higher CBF.
Time frame: 12 months
Population: Of 176 randomized participants, 27 did not complete an MRI scan at baseline (15 had metal implants with either pacemaker, stent, or inferior vena cava filter and 12 were claustrophobic). Of 141 participants who returned for their 12-month visit, an additional 8 participants refused to have a follow-up MRI. The final sample with both baseline and 12-month MRI was 104 participants (73.8%), including 51 participants in the candesartan group and 53 participants in the lisinopril group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Candesartan | Cerebral Perfusion | 45.48 ml/100g/min | Standard Error 1.47 |
| Lisinopril | Cerebral Perfusion | 47.65 ml/100g/min | Standard Error 1.08 |
Secondary
Language
This will be measured using the Boston Naming Test. BNT is a neuropsychological test used to assess visual confrontation naming and language performance in participants with cognitive decline. Its short 15-item version consists of drawings of objects ranging from common objects to less familiar objects. Scale: 0 (min score) to 15 (max score). For this test, a higher score/response represents a better outcome.
Time frame: 12 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Candesartan | Language | 13.42 number of correct responses | Standard Error 0.18 |
| Lisinopril | Language | 13.84 number of correct responses | Standard Error 0.18 |
Secondary
Memory
To assess episodic memory, the Hopkins Verbal Learning Test-Revised (HVLT-R) will be used. The retention (%) score is calculated by dividing the delayed recall trial by the higher of 3 learning trials. Each trial scores 0 (min) to 12 (max). The HVLT-R retention score is a percentage, and a higher percentage represents a better outcome.
Time frame: 12 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Candesartan | Memory | 82.71 percentage of retention | Standard Error 3.26 |
| Lisinopril | Memory | 79.47 percentage of retention | Standard Error 3.39 |
Secondary
White Matter Lesion Volume
White Matter Lesion volume: high-resolution anatomical images are acquired for the measurement of microvascular disease. WMH volumes will be obtained from Fluid attenuated inversion recovery (FLAIR) imaging sequence and reported as total volume (in mm3). Higher values means greater WMH
Time frame: 12 months
Population: Of 176 randomized participants, 27 did not complete an MRI scan at baseline (15 had metal implants with either pacemaker, stent, or inferior vena cava filter and 12 were claustrophobic). Of 141 participants who returned for their 12-month visit, an additional 8 participants refused to have a follow-up MRI. The final sample with both baseline and 12-month MRI was 104 participants (73.8%), including 51 participants in the candesartan group and 53 participants in the lisinopril group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Candesartan | White Matter Lesion Volume | 2.68 mm^3 | Standard Error 1.23 |
| Lisinopril | White Matter Lesion Volume | 5.73 mm^3 | Standard Error 1.22 |