Retina is a Marker for Cerebrovascular Heath

Study Overview
=================
Brief Summary
-----------------
Cerebral small vessel disease (SVD), present in 80-94% of adults over age 65 years, increases the risk of stroke by 2-fold, and dementia by 2.3-fold. There is currently no treatment to slow SVD progression. This study aims to test whether impaired cerebral and retinal vasoreactivity may serve as biomarker for SVD progression, and to evaluate the safety and efficacy of cilostazol (antiplatelet agent with vasodilatory and anti-inflammatory properties) for the treatment of SVD.

Detailed Description
-----------------
This is a prospective, observational nested pilot randomized controlled study to discover retinal biomarkers that would predict cerebral small vessel disease progression, and evaluate the safety/efficacy of cilostazols in slowing SVD progression. Twenty CADASIL, 40 sWMD, 20 lobar CMB, and 20 age-matched healthy controls from the Mayo Clinic Florida Familial Cerebrovascular Disease Registry and neurology clinic will be recruited. All participants will undergo OCTA retinal scan, MRI-BOLD brain scan, cognitive battery evaluation, and blood sample at baseline and a 12-month follow-up visit. Key outcome measures are: RVR, CVR, cognition, WMH volume, and CMB volume. The 40 patients diagnosed in the course of routine clinical care with sWMD will be randomized in 1:1 ratio to receive cilostazol 100mg bid (or 50 mg bid if taking medications known to affect metabolism of cilostazol) or no cilostazol, and followed for WMD progression, and secondarily for changes in cognition, RVR and CVR. Flow diagram below outlines the study design. Note that in addition to what is shown in the trial flow diagram, patients will have telephone visits between baseline and 12 month clinic visits biweekly for 3 months and then monthly thereafter. These visits will consist of a survey for adverse events and at the 1-, 3-, 6- and 9-month telephone visits patients will also get a modified Rankin scale assessment, a Six-item screener (cognitive assessment) and a PHQ-2 (depression screen).

Official Title
-----------------
Retinal Vasoreactivity is a Marker for Cerebral Small Vessel Disease Progression

Conditions
-----------------
Cerebral Small Vessel Diseases, Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy, Cerebral Microbleeding, Sporadic White Matter Disease

Intervention / Treatment
-----------------
* Drug: Cilostazol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥18 yo. Diagnosis of CADASIL, sporadic WMD or lobar CMB and age-matched healthy controls (eg. patient's spouse or unrelated friends without SVD) Exclusion Criteria: Age<18yo Pregnant Breast feeding Unable to follow commands Unable to tolerate MRI

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

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

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

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

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cilostazol<br>Cilostazol 100mg BID | Drug: Cilostazol<br>* Cilostazol 100mg BID<br>|
| No Intervention: No intervention<br> | |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| white matter disease volume | change in total white matter disease volume | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cognition | global Z-score and by cognitive domain | 1 year | 
| stroke | ischemic stroke or hemorrhagic stroke | 1 year | 
| cerebrovasoreactivity | change in blood oxygen level dependence (BOLD) per unit of end tidal PCO2 mmHg | 1 year | 
| retinal vasoreactivity | change in retinal vessel density pre/post CO2 challenge | 1 year |