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Project

Novel PET targets in stroke research

This thesis presents three novel PET targets in stroke research.

First we explore amyloid PET in the context of cerebral amyloid angiopathy. Cerebral amyloid angiopathy is a frequent cause of lobar intracerebral hemorrhage and is characterized by vascular amyloid β accumulation. Amyloid tracers, which were originally developed in the setting of Alzheimer disease, do not only bind to parenchymal amyloid plaques (as seen in Alzheimer disease), but also to vascular amyloid. Therefore, they can also visualize amyloid accumulation related to cerebral amyloid angiopathy. In chapter 1, we retrospectively focus on the value of amyloid PET in patients with lobar intracerebral hemorrhage, as we believe that the modified Boston criteria, which are currently seen as gold standard to diagnose cerebral amyloid angiopathy in vivo, have certain drawbacks in this population. We posit that – despite prior studies showing only moderate diagnostic accuracy of amyloid PET in diagnosing cerebral amyloid angiopathy – further research is needed just because most prior studies relied on the modified Boston criteria. We hypothesize amyloid PET to be a valuable tool to diagnose cerebral amyloid angiopathy in certain patients. In chapter 2, we describe a case series of patients presenting with cerebrovascular disease < 55 years old in whom (transmissible) cerebral amyloid angiopathy is the most likely diagnosis. Transmissible cerebral amyloid angiopathy is a – still controversial – entity marked by human-to-human transmission of amyloid β. Patients who undergo neurosurgery during childhood can present with cerebral amyloid angiopathy at relative young age, making it impossible to diagnose with the current modified Boston criteria. To assess its prevalence, large epidemiological studies are needed and we propose amyloid PET as non-invasive tool for in vivo diagnosis of transmissible cerebral amyloid angiopathy.

Second we use tau PET to evaluate if ischemic stroke triggers formation of neurofibrillary tangles, thereby (partially) explaining the increased risk of Alzheimer disease after stroke. 18F‑MK‑6240 is a second generation tau tracer that specifically binds to neurofibrillary tangles. In chapter 3, we discuss a prospective study in which patients with a first ischemic stroke undergo 18F‑MK‑6240 PET within the first weeks and at 6 months after stroke. We notice an increased PET signal within the lesion at baseline, but we stress that its interpretation is complicated by blood brain barrier breakdown. We also demonstrate an increased 18F‑MK‑6240 signal at 6 months after stroke and explain that it is plausible that this increased PET signal reflects specific binding to neurofibrillary tangles, implying that our data provides preliminary evidence of accumulation of neurofibrillary tangles after ischemic stroke.

Third we explore neural plasticity after stroke with synaptic density PET. Recovery after stroke is a complex phenomenon of which the underlying biological processes are poorly understood. Neural plasticity, including both reorganization of networks as well as reinforcement of existing connection, has been suggested to drive recovery after stroke. We investigate if 11C‑UCB‑J, a PET tracer that binds to synaptic vesicle protein 2A and is seen as proxy for synaptic density imaging, can visualize neural plasticity after stroke. In chapter 4, we first show that synaptic density is not influenced by age or sex, indicating that age- and sex matching is not too important in stroke studies. Next, we investigate changes in synaptic density after ischemic stroke by prospectively recruiting patients with a first ischemic stroke to undergo 11C‑UCB‑J PET within 2-4 weeks as well as 6 months after stroke. In chapter 5, we describe the baseline data and we illustrate synaptic density to be decreased within the lesion within the first weeks after stroke as well as in the ipsilesional hemisphere. In chapter 6, we report the 6 months follow up data that indicate that no increases of synaptic density can be found in any of the brain regions. However, we demonstrate that synaptic density further decreases in the ischemic lesion as well as in surrounding tissue.

In summary, this thesis introduces three novel PET targets in stroke research: one to aid in diagnosing cerebral amyloid angiopathy, a common etiology of hemorrhagic stroke, and two to further expand our knowledge on pathophysiological processes that occur after ischemic stroke.

Date:1 Oct 2018 →  6 Sep 2022
Keywords:PET-MR, Stroke
Disciplines:Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing
Project type:PhD project