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Minocycline for sporadic and hereditary cerebral amyloid angiopathy (BATMAN): study protocol for a placebo-controlled
S Voigt1,2, E A Koemans3, I Rasing3
1Department of Neurology, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands. s.voigt@lumc.nl.
Insights
This clinical trial investigates minocycline's effect on cerebral amyloid angiopathy (CAA), a disease linked to dementia. The study aims to reduce neuroinflammation and gelatinase pathway markers in patients with CAA.
Area of Science:
- Neurology and Neuroinflammation Research
- Clinical Trials in Neurodegenerative Diseases
- Amyloid-beta Proteinopathies
Background:
- Cerebral amyloid angiopathy (CAA) is a significant cause of stroke and dementia in the elderly, driven by amyloid-beta protein accumulation.
- Amyloid-beta in vessel walls may trigger chronic neuroinflammation via astrocyte and microglia activation.
- Minocycline, a tetracycline antibiotic, influences inflammation, gelatinase activity, and angiogenesis, pathways implicated in CAA.
Purpose of the Study:
- To assess minocycline's target engagement in patients with cerebral amyloid angiopathy (CAA).
- To investigate if 3-month minocycline treatment reduces neuroinflammation and gelatinase pathway markers in cerebrospinal fluid (CSF).
- To evaluate the impact of minocycline on hemorrhagic markers using 7-T MRI.
Main Methods:
- A double-blind, placebo-controlled randomized clinical trial (BATMAN study) involving 60 participants with hereditary Dutch type CAA or sporadic CAA.
- Participants are randomized to receive either minocycline or a placebo.
- Cerebrospinal fluid (CSF) and blood samples, 7-T MRI scans, and demographic data are collected at baseline and 3 months.
Main Results:
- Primary outcomes include changes in CSF neuroinflammation markers (IL-6, MCP-1, IBA-1) and gelatinase pathway markers (MMP2/9, VEGF).
- Secondary outcomes involve assessing the progression of hemorrhagic markers on 7-T MRI.
- Serum biomarkers will also be investigated to further understand minocycline's effects.
Conclusions:
- This proof-of-principle study will determine minocycline's potential for target engagement in CAA.
- Results will inform future therapeutic strategies targeting neuroinflammation and vascular pathology in CAA.
- The study contributes to understanding CAA pathogenesis and potential treatment avenues.
Background:
Cerebral amyloid angiopathy (CAA) is a disease caused by the accumulation of the amyloid-beta protein and is a major cause of intracerebral hemorrhage (ICH) and vascular dementia in the elderly. The presence of the amyloid-beta protein in the vessel wall may induce a chronic state of cerebral inflammation by activating astrocytes, microglia, and pro-inflammatory substances. Minocycline, an antibiotic of the tetracycline family, is known to modulate inflammation, gelatinase activity, and angiogenesis. These processes are suggested to be key mechanisms in CAA pathology. Our aim is to show the target engagement of minocycline and investigate in a double-blind placebo-controlled randomized clinical trial whether treatment with minocycline for 3 months can decrease markers of neuroinflammation and of the gelatinase pathway in cerebrospinal fluid (CSF) in CAA patients.
Methods:
The BATMAN study population consists of 60 persons: 30 persons with hereditary Dutch type CAA (D-CAA) and 30 persons with sporadic CAA. They will be randomized for either placebo or minocycline (15 sporadic CAA/15 D-CAA minocycline, 15 sporadic CAA/15 D-CAA placebo). At t = 0 and t = 3 months, we will collect CSF and blood samples, perform a 7-T MRI, and collect demographic characteristics.
Discussion:
The results of this proof-of-principle study will be used to assess the potential of target engagement of minocycline for CAA. Therefore, our primary outcome measures are markers of neuroinflammation (IL-6, MCP-1, and IBA-1) and of the gelatinase pathway (MMP2/9 and VEGF) in CSF. Secondly, we will look at the progression of hemorrhagic markers on 7-T MRI before and after treatment and investigate serum biomarkers.
Trial Registration:
ClinicalTrials.gov NCT05680389. Registered on January 11, 2023.
