CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most prevalent hereditary small vessel disease. CADASIL patients typically develop... Show moreCADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most prevalent hereditary small vessel disease. CADASIL patients typically develop recurrent strokes from mid-adult age onwards, leading to cognitive impairment and ultimately vascular dementia. As there is currently no therapy that can delay or prevent CADASIL, the CADASIL research group of the Leiden University Medical Center is developing a therapeutic approach for CADASIL, called “NOTCH3 cysteine correction”.The aim of this PhD-project was to advance CADASIL therapy development.The work in this thesis provides the first in human evidence that the therapeutic approach of NOTCH3 cysteine correction leads to reduced protein aggregation, by describing a family with naturally occurring NOTCH3 cysteine correction. Furthermore, this thesis includes the results of the longest follow-up study to date of individuals with CADASIL, as well as and the identification of Neurofilament Light-chain (NfL) as blood biomarker in CADASIL. In a pre-clinical CADASIL disease model, potential pre-clinical biomarkers were explored and this resulted in the development of a GOM deposit classification system. Show less
Neurological disorders may impair various aspects of walking ability that are needed for safe and independent walking. A comprehensive assessment addressing the key components of walking ability... Show moreNeurological disorders may impair various aspects of walking ability that are needed for safe and independent walking. A comprehensive assessment addressing the key components of walking ability may help to tailor management strategies to the individual needs of each patient. The aspect of walking adaptability is usually not assessed in clinical tests, but seems important for safe walking and is related to fall risk. The Interactive Walkway is a promising, unobtrusive, low-cost and comprehensive assessment tool of walking ability in daily practice. It is a walkway instrumented with an integrated multi-Kinect v2 set-up for markerless registration of 3D full-body kinematics. Besides performing quantitative gait assessments, the Interactive Walkway may also be used to assess walking adaptability. The Interactive Walkway is equipped with a projector to augment the entire walkway with (gait-dependent) visual context, such as obstacles, sudden-stop-and-start cues and stepping targets, demanding step adjustments under time pressure demands in a safe manner. The aim of this thesis was to examine if 1) this approach can provide a valid assessment of walking ability and, if so, 2) if it has clinical potential in the assessment of walking ability and fall risk in patients with stroke and Parkinson’s Disease. Show less