In healthy people, blood flow to particular areas in the brain increases when the area becomes more active. This ensures that the brain gets enough blood at the right place and time. In people with cerebral small vessel disease (cSVD), this process is disrupted, and the increased blood flow in response to activity is decreased or absent. Damage to the endothelial cells, that form the inner lining of blood vessels, is a key pathological process in cSVD. The aim of this study is to find out whether endothelial cell function and blood flow in cSVD can be improved by altering the function of a protein called TSPO. We will do this by using a drug called XBD173, which binds to TSPO.
This is a double-blind, randomised, crossover study. cSVD patients will be recruited from memory clinics at Imperial College Healthcare NHS Trust. Participants will be invited to the clinical research facility (CRF) at Hammersmith Hospital and randomised to receive XBD173 or matched placebo, twice daily, for 4 weeks. After a 6-week washout, they will be switched to receive the other intervention. The study visits will involve MRI scans and blood tests to assess endothelial cell function.
Healthy volunteers will also be recruited for image optimisation and control data. They will attend for a single MRI scan and not receive XBD173.
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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
Crossover
XBD173
Drug4 weeks treatment
Neurovascular coupling
Change in primary visual cortex cerebral blood flow following an alertness task
Neurovascular coupling
Change in cerebral blood flow in a ROI generated by a group average mask of regions known to become activated in the frontal and temporal lobes
Blood-brain barrier leak
BBB leak (rate and volume) determined by gadolinium-enhanced DCE-MRI
Plasma biomarkers associated with cSVD
hsCRP, fibrinogen, IL6, Tnf, TNFR2, osteoprotegerin, VEGF, PGDF, MMP2/9
Plasma biomarkers associated with endothelial cell activation and dysfunction
VCAM-1, ICAM-1, E-selectin, von Willebrand factor, plasminogen activator inhibitor-1 activity, soluble ROBO4, VEGF-A, NOS3, tissue plasminogen activator, endothelin-1
Plasma biomarkers of continuing neurodegeneration
Neurofilament light chain
Cerebrovascular reactivity in response to CO2 inhalation
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