Hypertension, Brain Clearance, and Markers of Neurodegeneration

Study Overview
=================
Brief Summary
-----------------
The purpose of this research study is to measure cerebrospinal fluid (CSF) clearance in subjects with and without high blood pressure. CSF cushions the brain from impact and carries waste products from the brain to the bloodstream. This process is known as clearance. Impaired removal of proteins from the aging brain causes their buildup and may contribute to an increased risk for Alzheimer's disease. It is also suspected that clearance may be related to the health of vessels carrying the blood throughout the brain. It is known that high blood pressure damages blood vessels and thus may impair clearance. In this project we will examine if having high blood pressure is related to impaired brain clearance and whether treating high blood pressure improves clearance and reduces buildup of Alzheimer's disease-related proteins. Participants will be asked to undergo a medical examination, testing of memory, brain imaging (both magnetic resonance and positron emission tomography, and spinal tap at the beginning of the study and 1 -2 years later.

Detailed Description
-----------------
Over 5 years the investigator will conduct a 24-month longitudinal study of 80 cognitively healthy subjects 60-80 years old, classified at baseline into the following groups: 1) Normotensive NT (n=20), 2) Controlled hypertension C-HTN (n=20), 3) Uncontrolled hypertension or Untreated hypertension UU-HTN (n=30). For subjects in the NT and C-HTN groups this will be an observational longitudinal study with clinical, imaging and CSF (cerebrospinal fluid) assessment at baseline and 24 month follow-up, with 3 visits to monitor BP (blood pressure) in-between (both at the office and using home BP monitoring). Subjects in the UU-HTN group after having completed their baseline evaluation will be referred for a further evaluation of HTN (hypertension) and an intervention. Intervention: the initiation of treatment or treatment modification to achieve the SBP (systolic blood pressure) goal of <140 mmHg. Subjects will be referred to their physician or, in case they do not have one, to the study cardiologist for treatment according to current guidelines. Imaging at 0 and 24 month consist of MRI (magnetic resonance imaging) with ASL (arterial spin labeling) and brain clearance imaging using 18F-MK6240 PET (positron emission tomography). CSF assessment includes Aβ42 (amyloid beta 42), t-tau (total tau) and p-tau181 (tau phosphorylated at threonine 181).

Official Title
-----------------
Hypertension, Brain Clearance, and Markers of Neurodegeneration

Conditions
-----------------
Hypertension, Mild Cognitive Impairment

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male and female subjects between 60-80 years old All subjects will speak English as their first language or demonstrate proficiency in English. All subjects will have normal cognition at baseline: a Clinical dementia rating CDR=0, Global deterioration Scale GDS <2 For the HTN subjects: systolic HTN defined according to Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood pressure (JNC) 7 report. Specifically: Blood pressure in the ranges greater or equal to 140 mmHG, which is a mean of three seated BP readings on each of two or more office visits Exclusion Criteria: Non-essential hypertension Diabetes Isolated diastolic hypertension Neurodegenerative disorders (i.e Parkinson disease) Dementia or Mild cognitive impairment at baseline Long life major depression. Baseline scores greater or equal to 20 on Beck Depression Inventory at baseline Long-life DSM-IV axis 1 disorders Mental retardation Substance abuse

Ages Eligible for Study
-----------------
Minimum Age: 60 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Untreated Hypertension<br>in office SBP ≥140 at two separate occasions and currently treated with antihypertensive medications (uncontrolled), or in office SBP ≥ 140 at two different occasions and no current treatment (untreated). | |
| Normotensive<br>in office SBP<140 mmHg, no treatment with antihypertensive medications | |
| Controlled Hypertension<br>in office SBP <140 and current treatment with antihypertensive medications | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cerebral blood flow | cerebral blood flow with arterial spin labeling MRI | Baseline and 24 month follow up | 
| Change in Brain Clearance | the rate of radiotracer removal from the brain ventricle after injection of MK-6240 images, measured with positron emission tomography | Baseline and 24 month follow up | 
| Change in total tau | total tau protein measured in cerebrospinal fluid | Baseline and 24 month follow up | 
| Change in amyloid 42 | amyloid 42 protein measured in cerebrospinal fluid | Baseline and 24 month follow up | 
| Change in cognitive performance | A composite score of tests assessing: Immediate and delayed memory (score ranges in parentheses): Craft Story immediate (0-44) and delayed recall (0-44), Guild battery immediate (0-21) and delayed recall (0-21) of paragraph and word pairs immediate (0-10) and delayed (0-10). Working memory: Number Span test forward (0-14) and backward (0-14) Naming: Verbal Naming Test (0-26). Attention: Trail Making Test part A (0-25) Executive functions: Trail Making Test Part B (score range 0-13) and Wisconsin Sorting Card Test (0-128). Verbal Fluency: Category Fluency: animals (0-30) and vegetables (0-30), category letters F (0-30) and L (0-30). Each test is transformed into normative z-score. For each domain the scores are expressed as a composite z-score of all the tests assessing a given domain. The score range from -3.0 - to +3.0 higher indicating better performance. | Baseline and 24 month follow up |