How does cerebral small vessel disease cause neurodegeneration, and can this be reversed?

Context: Cerebral small vessel disease (cSVD) is the commonest vascular cause of cognitive impairment and dementia (VCI/VaD, 20% of dementias), and commonly causes mixed dementia with Alzheimer’s disease, totalling some 45-50% of dementias. cSVD also causes 25% of strokes (‘lacunar’), frailty, loss of independence and accelerated brain ageing. It is often detected incidentally on brain scans. With no effective treatment, cSVD constitutes a substantial global unmet need. The challenge is to determine how cSVD causes brain damage, both directly due to damaged blood vessels and/or other indirect mechanisms, what factors drive cSVD progression, and how this can be stopped or reversed. Although cSVD associates strongly with hypertension, diabetes, smoking, intensive vascular risk factor management has had limited effects on stopping cSVD progression. Human brain magnetic resonance imaging (MRI) studies suggested an abnormality in cSVD in the small blood vessel lining (endothelium) and vessel wall that leads to leaky blood-brain barrier, poor control of blood flow, impaired fluid and waste clearance, and both ‘direct’ vascular and secondary ‘indirect’ brain tissue damage. Importantly, cSVD brain lesions can reverse spontaneously, leading to improved clinical outcomes, but which lesions, and whether secondary brain damage can be stopped, is unknown. In the LACunar Intervention Trial-2 (LACI-2), in 363 patients with lacunar (cSVD) stroke, two endothelial-stabilising drugs, isosorbide mononitrate (ISMN) and cilostazol, acting at different points on complementary vascular pathways, improved cognitive, cerebrovascular, and physical outcomes, with possible synergy. Our aims and objectives are to: track how cSVD contributes to cognitive decline and neurodegeneration visualised on brain MRI; use blood biomarkers to identify cells and pathways linked with clinical and tissue outcomes; determine if ISMN and cilostazol improve outcomes by reducing cSVD vascular lesion and/or neurodegeneration features; define biomarkers for cSVD, its brain tissue and cognitive outcomes; and inform clinical practice. Funded Phase-3 (NIHR LACI-3, n=1300) and Phase-2 (AlzSoc CVD-Cog, n=400; LACI-Cog, n=60) clinical trials, testing ISMN and cilostazol, in three complementary but distinct cSVD populations, incorporating pre-trial MHRA Scientific Advice, provide exceptional, cost-efficient opportunities to add, at marginal cost, strategic baseline and follow-up brain MRI and blood for biomarkers. This will enable us to investigate cSVD mechanisms and vascular- and neurodegeneration-stabilising interventional mechanisms using experimental medicine approaches. Reduction in cSVD lesion progression and secondary neurodegeneration with endothelium-stabilising drugs will strongly support that cSVD is due to endothelial dysfunction and secondary effects of dysfunctional endothelium respectively. Applications and benefits include: ISMN and cilostazol are off-patent and inexpensive; positive results could rapidly change cSVD/VCI/VaD clinical practice for a very neglected patient group, currently without effective treatment. Patients and public repeatedly state that stopping cognitive decline due to vascular disease is an absolute priority, hence a main motivation for the LACI cSVD trials. Increased pharma confidence in tackling cSVD/VCI/VaD, to identify novel drug-development targets. Provide biomarker diagnostics and prognostics for cSVD/VCI/VaD. Biomarker-MRI data will inform future vascular-neurodegeneration trials. Raise awareness of vascular mechanisms in neurodegeneration amongst UK and international neurodegeneration initiatives. Team: Wardlaw (PL); Bath, Quinn, Heslegrave (PcL); Cheng, Thomalla (PcL(I)); Thrippleton, Hernandez (PES); Woodhouse (specialist); Brown (grant manager); all highly experienced in cSVD, clinical trials, MRI, lead the project and contributing trials combining UK and German strengths in vascular-neurodegenerative disease and motivated sites with MRI and blood sampling capabilities; LACI-3, CVD-Cog, LACI-Cog participant panels will support the project; Industry partners (Alamar Biosciences, Capitainer) support biomarker studies.