Neurobiology of Vascular Dementia

Vascular dementia is, in its current conceptual form, a distinct type of dementia with a spectrum of specific clinical and pathophysiological features. However, in a very large majority of cases, these alterations occur in an already aged brain, characterized by a milieu of cellular and molecular events common for different neurodegenerative diseases. The cell signaling defects and molecular dyshomeostasis might lead to neuronal malfunction prior to the death of neurons and the alteration of neuronal networks. In the present paper, we explore some of the molecular mechanisms underlying brain malfunction triggered by cerebrovascular disease and risk factors. We suggest that, in the age of genetic investigation and molecular diagnosis, the concept of vascular dementia needs a new approach. 1. Vascular Dementia—Historical Considerations Just how far back in time should one go when searching data of vascular dementia (VaD)? In 1549, Jason Pratensis published De Cerebri Morbi, linking dementia to stroke [1], and in 1658, Johann Jakof Wepfer theorized that a broken brain blood vessel may cause apoplexy (stroke) [2]. The correlation between atherosclerotic disease and dementia was clearly identified only at the beginning of the 20th century by two well-known contributors to the field of neurodegeneration: Alois Alzheimer and Otto Binswanger [3]. The modern era of vascular dementia began in the 1960s, under the leadership of the Newcastle College of Medicine [4]. The concept of VaD was ever since under permanent scrutiny and revision, in light of new clinical, pathological, and imagery data (Figure 1). In the early 1970’s, multiple infarct dementia was recognized as a major type of dementia, apart from Alzheimer’s disease, characterized not by “neuronal atrophy” but by atherosclerotic burden. In 1975, Vladimir Hachinski defined the “ischemic score,” later used for the clinical diagnostic of vascular dementias [5]. However, the concept of VaD soon became controversial due to an increased discrepancy between the incidence of cognitive disorders and that of the “strategic stroke.” Furthermore, the early prevention of multi-infarct dementia (MID), the aging of the general population, and an arising need to define “normal aging” versus “pathological aging” [6] added to this controversy. The struggle to identify preventable and treatable factors widened the pathogenic spectrum of VaD [7]. Several epidemiological studies reported associations of hypertension, type 2 diabetes, obesity, and inflammation with VAD and, in some cases, AD. These all coincide with those of