Stiletto: A computational model of the cerebral perforating arteries in health and disease

Welcome to Stiletto!

Our project aims to develop a computational model of the cerebral perforating arteries, the structure, hemodynamics and vascular flow reactivity, autoregulation and their relation with the neurovascular unit (NVU) in health and disease. The project will provide a framework to simulate scenarios to try to better understand complex phenomena such as aging, the exposome and genetics involved in brain homeostasis and dysfunction.

The cerebral perforating arteries are a group of small vessels that supply important areas of the brain, including the basal ganglia. These arteries play a critical role in the brain, and their dysfunction is evidenced in the context of the small vessel disease (SVD) and neurodegenerative disorders. Given their sub-voxel caliber, the deep cerebral perforating arteries are difficult to evaluate and reconstruct using conventional radiological methods.

Small vessel disease encompasses a group of microangiopathies that share common radiological and clinical patterns, with a negative impact on the brain parenchyma. SVD is one of the leading causes of cognitive impairment in our societies. Cerebral microangiopathies are responsible of 25% of strokes and 45% of dementia [1] . SVD poses a serious and growing burden to the individual and the public health system.

The perforating arteries are very small vessels (diameter < 1mm) that, unlike larger arteries, are difficult to study with conventional radiological methods. The SVD term is used to group arteriopathies that share a common clinical and radiological pattern in the brain parenchyma, secondary to the original vascular lesion. White matter hyperintensities (WMI), leukoaraiosis (white matter rarefaction), microbleeds, lacunes and cerebral atrophy [2] are some radiological signs associated to this group of disorders. The relationship between these radiological findings, the clinical signs and cognitive impairment remains unclear.

The etiology of SVD is diverse: Inflammatory/immune (vasculitis), atherosclerotic (Binswanger) and genetic (CADASIL) are some examples of underlying causes. Endothelial dysfunction and neurovascular unit (NVU) impairment are common in these arteriopathies.

The exposome represents the sum of environmental factors that have an effect on the health of the individual throughout their life. Differences in SVD onset, severity and disease progression suggest the role of environmental and epigenetic factors. For instance, low-grade chronic inflammation is involved in autoimmune and neurodegenerative processes [3]. Low-grade chronic inflammation has a higher prevalence among low socioeconomic status, poor nutritional habits and high emotional stress groups [4]. We hope Stiletto can be a valuable tool to further study the role of environmental stressors on the brain microcirculation.

The Stiletto project will make use of computational models to simulate scenarios and interactive visualization. Our project will work on the basis of current anatomical knowledge and with human brain specimens, to better understand the micro anatomical features of the vasculature in health and disease contexts. We will initially focus on the deep branches of the middle cerebral artery (MCA), the lateral lenticulostriate arteries.These small perforating arteries,with a mean diameter of 469 µm [5], originate from the M1 segment of the MCA, and provide nutrients to the basal ganglia.Due to the similarities among the deep perforating arteries, results from our project could be extrapolated to other perforators.

In addition, Stiletto will also be able to process clinical, genetic and demographic data from the participating institutions databases. The project will use solely Free/Libre software, libraries and datasets, such as GNU Health [6], three.js [7] , UniProtKB [8] and Orthanc [9]

We hope the Stiletto project will be useful in the following areas:

• Education: A computer model to the brain microcirculation and the neurovascular unit.
• Research on the cerebral small vessel disease (SVD): To get a better understanding of the underlying processes of the small vessel disease and its effect on the brain parenchyma.
• Precision medicine: To assess the environmental, genetic and epigenetic factors unique to the individual's brain microcirculation.
• In silico drug discovery: To provide an alternative, ethical, and human-focused computational model to drug discovery that does not use animal models and animal cruelty.

Stiletto is part of the Global Exposome Project (GEP) [10]. The source code will be released under the GNU GPL v3 [11] and its documentation will be available under Creative Commons (CC-BY-SA) [12]. As a member from the Global Exposome Project, any individual and institution that uses Stiletto will commit to open science and to a compassionate, human relevant biomedical research, without the use of nonhuman animal models [13]