Hypertension, Intracranial Pulsatility and Brain Amyloid-beta Accumulation in Older Adults (HIPAC Trial)

Phase 2

Completed

Conditions: Hypertension

Interventions: Drug: Standard Care
Drug: Intensive Treatment

Registration Number: NCT03354143

Lead Sponsor: University of Texas Southwestern Medical Center

Brief Summary: The aim of this study is to determine if lowering blood pressure using FDA approved medication (antihypertensive drugs) alters brain pulsatility and reduces brain amyloid beta protein accumulation in older adults. Amyloid beta protein is high in the brain of older adults with Alzheimer's disease. Hypertension may increase brain amyloid beta protein accumulation and affect memory and thinking ability in older adults. However, whether lowering blood pressure reduces brain amyloid beta protein and improves brain function is inconclusive.

The investigators hypothesize that treating high blood pressure alters brain pulsatility, which in turn reduces brain amyloid beta protein accumulation and improves brain structure and function.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 85

Inclusion Criteria

Age 55-79, all races/ethnicities, and both women and men are eligible;
Mini-mental state exam (MMSE) > 26 to exclude cognitive impairment or dementia;
Healthy normotensive subjects (24-hour ambulatory BP<125/75 mmHg without use of antihypertensive medication);
Patients with hypertension defined as 24-hour SBP ≥130 mmHg , patients on BP medications are eligible;
Patients with hypertension are willing to be randomized into either treatment group and ability to return to clinic or laboratory for follow-up visits over 12 months;
Fluency in English, adequate visual and auditory acuity to allow neuropsychological testing;
Screening laboratory tests and ECG without significant abnormalities that might interfere with the study

Exclusion Criteria

History of stroke, transient ischemic attack, traumatic brain injury or severe cerebrovascular disease by clinical diagnosis or past MRI/CT;
Diagnosis of AD or other type of dementia and neurodegenerative diseases;
Evidence of severe depression or other DSM-V Axis I psychopathology
Unstable heart disease based on clinical judgment (heart attack/cardiac arrest, cardiac bypass procedures within previous 6 months and congestive heart failure), evidence of atrial fibrillation on ECG, or other severe medical conditions;
Chronic kidney diseases with GFR < 40 ml/min;
Orthostatic hypotension, defined as standing SBP<100 mmHg;
History of significant autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis and polymyalgia rheumatica;
History of drug or alcohol abuse within the last 2 years;
Diagnosis of uncontrolled diabetes mellitus (fasting blood sugar ≥126 mg/dL or A1C >7.5%)
Obstructive sleep apnea;
Regularly smoking cigarette within the past year;
Severe obesity with BMI ≥ 45;
Participants enrolled in another investigational drug or device study within the past 2 months;
Carotid stent or sever stenosis (> 50%);
Pacemaker or other medical device of metal that precludes performing MRI;
History of B12 deficiency or hypothyroidism (stable treatment for at least 3 months is allowable);
Any conditions judged by the study investigators to be either medically inappropriate, or risky for participant or likely to have poor study adherence;
Claustrophobia;
Pregnancy

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Standard Care	Standard Care	Subjects in the standard care arm will receive calcium channel blocker (CCB, amlodipine), angiotensin II receptor blocker (ARB, losartan), and other antihypertensive drugs to reduce 24-hour SBP ≤ 130 mmHg. Drug doses will be titrated to reach the BP target.
Intensive Treatment	Intensive Treatment	Subjects in the intensive treatment arm will receive calcium channel blocker (CCB, amlodipine), angiotensin II receptor blocker (ARB, losartan), and other antihypertensive drugs to reduce 24-hour SBP ≤ 120 mmHg.

Primary Outcome Measures

Name	Time	Method
Changes in Gray Matter Intracranial Pulsatility	Baseline and 12-months	Changes (12 month timepoint minus baseline) in intracranial pulsatility will be measured with CINE phase-contrast MRI. We will use the velocity-encoded CINE PC MRI to measure intracranial pulsatility. Pulsatility measured in mm per cardiac cycle

Secondary Outcome Measures

Name	Time	Method
Brain Neural Network Functional Connectivity Via Magnetic Resonance Imaging (MRI)	Baseline and 12-months	The brain's functional connectivity, particularly within the Default Mode Network (DMN), can be assessed using functional magnetic resonance imaging (fMRI) through the correlations between the activity of the brain regions within a network. In this report, the DMN regions were identified with a seed-based approach from another clinical trial with 420 subjects of a similar population. By identifying regions of interest (ROIs) within the DMN, researchers can analyze how these regions connect and interact with each other, revealing information about brain activity and potentially aiding in the diagnosis and understanding of various neurological and psychiatric conditions. Here, the functional connectivity of the DMN brain regions is reported in the unit of Pearson correlation R, with a range of 0 to 1 in this application. A high R value indicates a high level of connectivity.
Changes in Overall Average 24 Hour Systolic Blood Pressure	Baseline and 12-months	changes in overall average 24 hr ambulatory systolic blood pressure will be assessed SpaceLabs monitor
NIH PROMIS Patient-reported Outcome Measures of Physical Health	Baseline and 12-months	PROMIS® (Patient-Reported Outcomes Measurement Information System) is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children. Four items are used to assess global physical health. Three of these are administered using five-category response scales, and one item (rating of pain on average) uses a response scale of 0-10 that is recoded to five categories (0 = 1; 1-3 = 2; 4-6 = 3; 7-9 = 4; 10 = 5). T-score Metric: PROMIS measures use a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. On the T-score metric: A score of 40 is one SD lower than the mean of the reference population. A score of 60 is one SD higher than the mean of the reference population. For PROMIS measures, higher scores equals more of the concept being measured (e.g., more Fatigue, more Physical Function).A score of 60 is one standard deviation above the average population
NIH PROMIS Patient-reported Outcome Measures of Mental Health	Baseline and 12-months	PROMIS® (Patient-Reported Outcomes Measurement Information System) is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children. Four items are used to assess global physical health. Three of these are administered using five-category response scales, and one item (rating of pain on average) uses a response scale of 0-10 that is recoded to five categories (0 = 1; 1-3 = 2; 4-6 = 3; 7-9 = 4; 10 = 5). T-score Metric: PROMIS measures use a T-score metric in which 50 is the mean of a relevant reference population and 10 is the standard deviation (SD) of that population. On the T-score metric: A score of 40 is one SD lower than the mean of the reference population. A score of 60 is one SD higher than the mean of the reference population. For PROMIS measures, higher scores equals more of the concept being measured (e.g., more Fatigue, more Physical Function). A score of 60 is one standard deviation above the average population
Changes in Overall Average 24hr Diastolic Blood Pressure	Baseline and 12-months	changes in overall average 24 hr ambulatory diastolic blood pressure will be assessed SpaceLabs monitor
Regional Cortical Thickness Via Magnetic Resonance Imaging (MRI)	Baseline and 12-months
Brain White Matter Hyperintensity (WMH) Via Magnetic Resonance Imaging (MRI)	Baseline and 12-months	White matter hyperintensities (WMH) on brain T2 fluid-attenuated inversion recovery (FLAIR) magnetic resonance images (MRI) are commonly observed in older adults over 65 years old, and more extensive in those with vascular or Alzheimer's disease type of dementia. Qualitative and quantitative WMH characterization has been used as a biomarker to assist cerebral small vessel disease diagnosis and to assess treatment effects. In this report, the size of the WMH has been assessed with the PGS software, the top performer of the deep-learning algorithms from the 2017 MICCAI WMH segmentation challenge. The unit of the WMH total size presented in this report is in mL.
Brain White Matter Microstructural Integrity Via Magnetic Resonance Imaging (MRI)	Baseline and 12-months	Fractional Anisotropy (FA) values are a measure of how directed diffusion is in a tissue, typically ranging from 0 to 1. A value of 0 indicates isotropic diffusion (diffusion is the same in all directions), while a value of 1 indicates highly anisotropic diffusion (diffusion is restricted to a single direction). FA is often used in diffusion tensor imaging (DTI) and is thought to reflect fiber density, axonal diameter, and myelination in white matter.