Targeting 18kDa Translocator Protein (TSPO) to Improve Brain Endothelial Cell Function in Cerebral Small Vessel Disease

Inclusion criteria

Aged 60-90 years inclusive Male or postmenopausal female

• Men are eligible to participate if they are willing to use the contraception methods listed in the PIS, during treatment and for 90 days after the last dose of treatment Able to provide written informed consent prior to any study-mandated procedures AA genotype at rs6971 (TSPO) locus Imaging-based diagnosis of cSVD (Fazekas score of at least 2 for periventricular and 2 for deep white matter) Mild cognitive impairment (MoCA 18-30) Willing to be genotyped at TSPO and ApoE loci

Inclusion criteria

(Healthy Volunteers):

Aged 60-90 years inclusive Male or female Able to provide written informed consent prior to any study-mandated procedures.

Willing to be genotyped at TSPO and ApoE loci

Exclusion criteria

History of clinical stroke History of frequent migraines Known Alzheimer's disease, lewy body disease or evidence of non-vascular neurological diseases Conditions affecting safe engagement in the intervention. Conditions preventing completion of study procedures, e.g. severe loss of vision or hearing Clinically-significant renal disease (eGFR <30 ml/min per 1.73m2) Clinically-significant elevation of serum transaminases or known clinically significant liver disease Contraindications to MRI scanning or exposure to gadolinium-based contrast agents Newly commenced (within 2 months of study start) statins, antihypertensives or antiplatelet treatments Severe respiratory disease with chronic hypoxia (sats <92%), known CO2 retention or need for home oxygen therapy.

Use of the following medications or therapies:

• Severe and moderate P450 CY3A4 inhibitors: Boceprevir, Clarithromycin, Cobicistat, Idelalisib, Itraconazole, Ketoconazole, Nelfinavir, Ritonavir, Saquinavir, Telaprevir, Telithromycin, Voriconazole, Aprepitant, Conivaptan, Crizotinib, Diltiazem, Dronedarone, Erythromycin, Fluconazole, Imatinib, Isavuconazole, Nefazodone, Netupitant, Nilotinib, Posaconazole, Tofisopam, Verapamil, Delavirdine.
• Severe and moderate P450 CY3A4 inducers: Carbamazepine, Enzalutamide, Fosphenytoin, Mitotane, Phenytoin, Rifampicin, Bosentan, Efavirenz, St John's wort, Barbiturates, Nevirapine, Primidone, Rifabutin, Rifapentine.
• Oral contraceptives
• Levothyroxine

Exclusion criteria

(Healthy Volunteers):

Contraindications to MRI scanning or exposure to gadolinium-based contrast agents Pregnant women of childbearing potential Clinically significant renal disease (eGFR <30 ml/min per 1.73m2) Severe respiratory disease with chronic hypoxia (sats <92%), known CO2 retention or need for home oxygen therapy.