Aims: We aim to determine the differential imaging patterns of brain calcifications without a genetic cause and those that are caused by genetic mutations (primary familial brain calcifications [PFBC]) and their respective frequencies in the UK biobank dataset.
With the guidance of imaging, we aim to estimate the frequency of known mutations and detect novel genes associated with PFBC in the UK biobank dataset. This could increase our understanding of the causes of this disease and lead to disease specific treatment development for PFBC.
Scientific rationale: Brain calcifications are present in 5-20% of individuals who receive imaging of the brain for any reason. The frequency of brain calcifications increases with age. The calcifications usually involve only a small part of the brain. Most people with these calcifications do not have any symptoms. In some cases, the calcifications are more extensive and can involve a variety of brain areas. Individuals with extensive calcifications can develop a broad spectrum of neurological and neuropsychiatric symptoms. In some of these patients, genetic mutations that lead to the disease can be detected.
Calcifications can be visualized using MRI (quantitative susceptibility mapping – QSM). Using QSM, we observed that not all patients with “calcifications” show a calcium-signal. Patients with PFBC are more likely to show true calcium deposits compared to non-genetic cases. Based on this, we ask the question if genetic and non-genetic calcifications might have different disease mechanisms.
The UK biobank provides a unique possibility to study the frequency of brain calcifications in a large dataset with both genetic and imaging data. This could allow us to detect novel mutations associated with brain calcifications.
Methods: We will use MRI to evaluate the frequency and imaging patterns of brain calcifications in the UK biobank dataset. We will use genetic information to find an association of mutations with the imaging patterns. We will use MRI as a screening tool to evaluate novel genetic mutations that could lead to PFBC.
Project duration: We estimate a project duration of three years to establish the imaging and WES processing and analysis pipelines and to analyze the large amount of data.
The expected value of the research (public interest): The project could lead to the identification of novel genes that cause PFBC. This in turn can guide drug development for PFBC.
