title: Assessment of disease progression and monitoring response to treatment using 18F-NaF PET/CT in patients with alkaptonuria
Creators: name: Alawadhi, Eman
Publisher: name: University of Liverpool Repository
Year: 2021

description: Alkaptonuria (AKU) is an ultra-rare, autosomal recessive metabolic disease caused by a deficiency of HGD enzyme leading to increased circulating homogentisic acid (HGA). HGA is deposited as ochronotic pigment in connective tissues, leading to multisystemic involvements including severe arthropathy and cardiovascular calcification. 18F-NaF PET/CT is a sensitive imaging modality which can offer unique and accurate information concerning the radiotracer activity at the ROI using PET semiquantitative assessment methods such as standardised uptake value (SUV). The main aims of this thesis were to investigate the utility of 18F-NaF PET/CT as an imaging biomarker for detecting the early stage of bone involvement, early disc degeneration, and the early stage of microvascular calcification for AKU patients. Part of this thesis aimed to assess the progression of the disease and the response of therapy over four years for SONIA 2 patients by evaluating the changes in 18F-NaF PET/CT scans. AKU patients who were enrolled in the SONIA 2 trial and underwent 18F-NaF PET/CT were included in the analysis in this thesis. HUmean and SUVmax were measured from lumbar vertebrae, femoral head, and lumbar disc. SUVmax, TBRmax, and HUmean were measured for the main cardiac arteries. The studies presented in this thesis show four key findings: First, high 18F-NaF uptake and low HUmean values were detected in the lower spine and hip lesions from 18F-NaF PET/CT scan, indicating active bone turnover and low bone density in AKU patients. Bone HUmean and SUVmax values in the spine consistently decrease with age, indicating decreased bone density, decreased osteoblastic activity, and reduced spine perfusion which may be assiocated with ochronosis and ageing. Second, disc degeneration was strongly associated with increased SUVmax in PET images and high Pfirrmann scores in MR images in AKU patients. Lumbar disc SUVmax increased gradually with age followed by a decline in the later years, which is related to the disease progression. In the advanced disc degeneration, less binding sites would be available to bind with 18F-NaF and was therefore associated with low SUV. Third, there were no significant differences between the nitisinone-treated and non-treated patients in the adjusted mean change in 18F-NaF PET/CT quantitative values for the spine. Minimal changes in the SUVmax and HUmean over the visits have been noted in both groups, suggesting that nitisinone may not directly affect spinal tissues or the impact of nitisinone needs more time to be noticeable. In fact nitisinone might slow the progression of ochronosis by stopping further pigmentation, but it is unlikely to reverse ochronosis or treat severe damage, specifically in the lumbar spine regions. Fourth, cardiac involvements appeared as increased 18F-NaF uptake and local dense areas in 18F-NaF PET/CT images, indicating cardiovascular calcification in AKU patients. Calcified vessels were detected in PET images due to the strong biological similarities between bone formation and vascular calcification as the main structural component in both events is hydroxyapatite; the 18F-NaF uptake mechanism in the calcified vessels is similar to that in bone tissues. Overall, this thesis reveals that 18F-NaF PET/CT scan is a promising imaging technique to identify early musculoskeletal and cardiovascular involvements in AKU patients. This thesis proposed novel and reliable 18F-NaF PET/CT semiquantitative assessment methods to assess disease progression and treatment response.