Detecting microvascular dysfunction during the development of co-morbidity-induced vascular cognitive impairment

According to the World Health Organization (WHO), over 55 million people worldwide were diagnosed with dementia. As a result of our increased life expectancy and aging society, the prevalence of dementia is rapidly increasing, becoming one of the leading causes of disability and dependency worldwide. With the rapidly increasing numbers, the disease burden of dementia will become a major socio-economic challenge for our society.

Vascular Cognitive Impairment (VCI) is a group of complex cerebrovascular disorders related to cognitive deficits associated with aging, vascular risk factors and cerebrovascular diseases. While in literature, VCI is often referred to as the second most common type of cognitive impairment after Alzheimer’s disease (AD), cerebrovascular alterations can play a role in several neurodegenerative diseases potentially leading to dementia. Recent studies suggest that AD may have a vascular origin, with amyloid-plaques, which are a hallmark of AD, being a consequence or a symptom of microvascular dysfunction rather than a cause of AD 1, 2. Therefore, cerebrovascular alterations could be considered as the most important contributor to cognitive impairment and dementia. Unfortunately, there are currently no specific treatment options available for VCI. Existing therapies focus on managing the underlying vascular risk factors, which might delay but not prevent disease development. Therefore, there is an urgent need for a biomarker in the early detection of VCI, before the onset of clinical symptoms

The most common cause of VCI in elderly is recognized as a disease of the cerebral microcirculation, referred to as cerebral Small Vessel Disease (cSVD). cSVD often silently progresses over a long period of time before the first clinical symptoms become visible, making early diagnosis even more challenging. A better understanding of the pathophysiological alterations to the cerebral vasculature in the presence of vascular risk factors might provide important prognostic information about the underlying mechanisms and the disease progression.

In this thesis, we used different imaging methods to investigate the disease progression in a pre-clinical rat model of multiple vascular co-morbidities that mimics the clinical pathology of sporadic cSVD, the ZSF1 obese rat. We combined non-invasive and invasive imaging methods at several stages of the development of VCI to identify early pathological alterations in the cerebral vasculature due to the presence of multiple vascular risk factors.

Non-invasive imaging methods currently used for assessing cSVD are typically limited to diagnosing the consequences of cerebrovascular alterations in the brain. Due to technical limitations in the spatial resolution, direct non-invasive assessment of the cerebral microcirculation is currently impossible. However, perfusion MRI can indirectly measure (pathological) alterations to the cerebral vasculature. In this thesis, we used two conventional perfusion MRI techniques (Arterial Spin Labeling and Dynamic Susceptibility Contrast enhanced MRI), and a more novel technique (Intravoxel Incoherent Motion MRI) to non-invasively identify when microvascular alterations occurred in our rat model of multiple vascular co-morbidities. To cross-validate our perfusion MRI measurements, we performed invasive immunohistochemical measurements that enabled us to directly measure the cerebral vasculature at a high spatial resolution. We performed quantitative measurements of the cerebrovascular morphology and blood brain barrier permeability at each stage of the development.

By combining these measures, we were able to demonstrate functional alterations in the cerebral vasculature at an early stage of the cerebrovascular pathology, while no morphological differences were found. Our results suggest that microvascular dysfunction, rather than structural changes in the microvasculature, play a CRUCIAL role in the early pathogenesis of comorbidity induced sporadic cSVD. We have demonstrated that cerebral perfusion MRI, in particular Arterial Spin Labeling, has the potential to be used as a non-invasive diagnostic tool for detecting these early changes in the cerebral vasculature and further investigating the underlying pathophysiological mechanisms of VCI.