Background
Worldwide, 55 million people live with dementia. Dementia is caused by multiple diseases, most commonly Alzheimer's disease, and cannot yet be cured. If we could improve the way to detect important biological processes that lead to dementia, with so‐called biomarkers, we can better understand and monitor the underlying diseases, target the disease processes, and diagnose patients. This requires the development of reliable technologies that can detect and track such biomarkers in individual patients and assess the effect of new therapies. This is the ambition of our consortium, which applies innovative technologies to assess Cerebral HemodynamIcs, Metabolism and clearancE (CHIME), key biological processes affected in dementia, to develop a framework for non‐invasive testing of pharmaceuticals that will ultimately provide relief in early stages of neurological diseases.
Cerebral Hemodynamics uitklapper, klik om te openen
Compared to FDG‐PET, MRI is cheaper, more patient friendly, and has the potential for assessing the following additional markers of hemodynamics beyond perfusion that reflect key aspects of neurovascular function: microvascular reactivity, microvascular pulsatility and non‐contrast BBB integrity. Microvascular reactivity to a neuronal or CO2 stimulus indicates the vascular health and its capacity to accommodate physiological challenges. Microvascular pulsatility is interesting not only because it can cause cerebrovascular damage, but also because it has been postulated to be an important driving force of brain clearance. Breakdown of BBB integrity is hypothesized to happen early in the disease chain of neurodegeneration leading to inflammation of neuropil.
Objective: To develop, optimize and validate MRI methods for quantitative mapping of multiple hemodynamic markers.
Metabolism uitklapper, klik om te openen
Metabolism is a fundamental brain process that becomes dysfunctional in dementia. Brain metabolism encompasses a range of processes: glucose metabolism and ATP production, oxygen supply, and the regulation of inflammation, among others. All play critical roles in ensuring that the brain has the energy and resources it needs to carry out its functions. PET‐based methods have shown promising results in measuring brain metabolism but suffer from a range of limitations, such as being invasive. Existing MR‐approaches (such as 1H MR‐spectroscopy (MRS)) most often provide steady‐state metabolite information from large volume‐of‐interest (VOI). We posit that the key to comprehend the pathophysiology of AD lies not in static metabolic information, but rather in the dynamic information related to the broad range of mitochondrial dysfunction and cellular energy deficits. Developing clinically translatable non‐invasive methods that can capture the spatially resolved dynamics of metabolic pathways in patients is essential.
Objective: To develop, optimize and validate advanced MR‐based methods that provide quantitative maps of dynamic metabolic processes in the brain.
Clearance uitklapper, klik om te openen
Impaired brain clearance is an important component in multiple dementia types, but so far mainly studied in rodents. There is an urgent need for human brain waste clearance markers. The traditional viewpoint is that the brain does not have a lymphatic‐like system, which is responsible for the clearance of waste products in other organs. It was hypothesized that phagocytosis and efflux over the BBB was the only means of brain clearance. However, around 2010 it was postulated that cerebrospinal fluid (CSF) and interstitial fluid (ISF) are central in brain clearance by extracting waste material from the neuropil and subsequent efflux via perivascular spaces (‘Glymphatics’) or intramurally. A better formulation would be repostulated because hypotheses along these lines have been present in the scientific world since the 18th century but were largely neglected. Impaired clearance is thought to be an important component of neurodegenerative diseases, especially because of the hallmark depositions of waste products, like amyloid beta in the vessel wall (cerebral amyloid angiopathy) as well as in the neuropil (Alzheimer’s Disease). So far, our main knowledge on CSF‐mediated brain clearance originates mainly from rodents, which makes it challenging in humans to proof target engagement of new treatment approaches that aim to improve for brain clearance. Therefore, there is an urgent need for human CSF‐mediated brain waste clearance markers, which should preferably provide information on the efficiency non‐invasively (so that it can be repeatedly measured during a clinical trial), accurately, precise, and within reasonable scan‐time.
Objective: To develop and validate human whole brain mapping of brain waste clearance markers.