Environmental and genetic causes of cerebral small-vessel disease

Cerebral small vessel disease (SVD) represents a heterogeneous group of pathologies that share radiological and clinical findings. They are chronic and progressive processes, with a high impact on the physical, emotional, family and socioeconomic aspects of the people who suffer from them. Many cases of dementia are caused by small vessel disease. Among the main causes are lifestyle, age, genetic (CADASIL) or immune-mediated (vasculitis) conditions.

Environmental causes and lifestyle play a leading role in the origin and evolution of small vessel disease. Pathologies of high prevalence in our society such as obesity, diabetes, hypertension or hyperlipidemia stiffen (atherosclerosis) and damage the function of the endothelium of these tiny vessels. This generates a chain reaction of complex vascular, molecular and inflammatory mechanisms that disrupt the neurovascular unit (NVU), leading to the destruction of the white matter and neuronal death.

In radiological studies, magnetic resonance imaging shows hyperintensities (leukoaraiosis) in the cerebral white matter secondary to vascular damage. As the disease progresses, the lesions increase, the neuronal population decreases and structural and volumetric changes characteristic of the neurodegenerative process become evident.

Among the genetic causes of small vessel disease, we highlight CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts Leukoencephalopathy). As its acronym indicates, CADASIL is transmitted in an autosomal dominant pattern, so that descendants have a 50% chance of inheriting the gene with the pathological variant (“mutation”) from their parent. Currently the diagnosis of CADASIL is made by study of the NOTCH3 gene. More than 100 clinically significant natural variants of the NOTCH3 gene have been described.

Although CADASIL has a high penetrance, the clinical picture and severity varies from person to person. The expressivity, age of onset and progression of the disease is highly variable between natural variants, even in people who have the same mutation, so we must study concomitant genetic, epigenetic and environmental factors.

In recent decades, and once the clear impact on health has become evident, interest in research on small vessel disease has increased. At PrecisionMed we are working on the Stiletto project, part of the Global Exposome Project, focused on the role of perforating cerebral arteries in both health and disease, blood vessels smaller than one millimeter in diameter that supply and nourish deep brain regions such as the basal ganglia.

From a clinical point of view, the signs and symptoms associated with cerebral small vessel disease will depend on the time of evolution, the underlying disease(s) and mechanism(s), and the age of the individual, to name a few variables. They are usually insidious processes, which may debut with mood disturbances, gait problems, transient ischemic attacks (TIAs), sleep pattern changes, and progress to cognitive impairment and even dementia. The progression of small vessel disease is also variable in each individual.

Regarding the socio-familial sphere, people with advanced stages of small vessel disease are patients with a high level of dependency, who may need cognitive, emotional, physical and motor support for day-to-day tasks. When cerebral small vessel disease is genetic in origin, appropriate genetic counseling is essential.

In summary, small vessel disease, rather than a disease per se, represents a set of complex processes that share clinical and radiological features. Although there are genetic cases and vasculitis that produce small vessel disease, environmental factors and lifestyle are themselves causative and conditioning factors when the disease has another origin.

There is no single treatment, so we must adapt and personalize it to each individual, with a holistic and multidisciplinary approach, which enhances the cognitive, nutritional, physical and emotional state of the person.

At PrecisionMed we support and treat patients with chronic diseases. We provide the latest advances in biomedicine, precision medicine and integrative health. We know that each person suffering from small vessel disease is unique from the biological, familial and social point of view. We put our experience, knowledge and medical humanism to restore the quality of life to each person and family who visits us.