Evaluating Magnetic Resonance Imaging and Serum Markers As Surrogate Endpoints for Clinical Trials in Cerebral Small Vessel Disease

Abstract

Cerebral small vessel disease (SVD) causes a quarter of all strokes and is the most common pathology underlying vascular cognitive impairment and dementia. White matter hyperintensities, lacunar infarcts, cerebral microbleeds and brain atrophy are characteristic features on conventional magnetic resonance imaging (MRI). More sensitive methods such as diffusion tensor imaging (DTI) show white matter ultrastructural damage and white matter tract disruption. As the vessel’s pathology is largely unknown and is difficult to image and as there is a low incidence of clinical events such as lacunar stroke and dementia conversion, imaging markers have been proposed as surrogate marker for phase-2 clinical trials. Results have shown that imaging markers such as DTI and some conventional MRI measures are sensitive to change over a few years and are further associated with later clinical outcome events such as dementia conversion. Recently there has also been growing interest in circulating biomarkers such as serum neurofilament light chain as they are easier to obtain from patients than imaging markers and as they can be centrally computed also in multicenter trials. The thesis aim is to evaluate imaging as well as circulating biomarkers as surrogate endpoints for clinical trials in SVD. Findings in Chapter 2 show that changes in conventional MRI markers may be more robust than in DTI markers for multicenter studies and therefore more suitable as a surrogate marker in this type of trial design. Evidence in Chapter 3 further indicates that DTI as a surrogate endpoint may depend on the disease severity and that conventional MRI such as brain atrophy and lacune incidences may increase the predictive accuracy for dementia conversion in severe SVD but not in mild SVD or mild cognitive impairment (MCI). Findings in Chapter 4 demonstrate that recently developed automatic or semi-automatic DTI markers may be promising surrogate markers for a phase-2 clinical trial and may require the lowest sample size in sporadic SVD. Chapter 5 tests the reproducibility of the recently developed markers both between scanner types and over time. Results showed that DTI markers’ reproducibility is only moderate between different scanner types. Findings of Chapter 6 show that the circulating biomarker serum neurofilament light chain may not be a suitable surrogate marker in SVD but may be used for selecting a SVD patient group with a higher risk for dementia conversion. All these findings indicate that automatic and semiautomatic DTI markers may be best suited as surrogate endpoint in a single-center clinical trial involving patients with severe sporadic SVD. The neurofilament light chain marker together with clinical markers as well as combined imaging marker scores may be employed to select severe SVD patients who have a higher risk for dementia conversion.