IntroductionStrong evidence suggests a significant role for iron accumulation in the brain in addition to the well-documented neurodegenerative aspects of Huntington’s disease (HD). The putative... Show moreIntroductionStrong evidence suggests a significant role for iron accumulation in the brain in addition to the well-documented neurodegenerative aspects of Huntington’s disease (HD). The putative mechanisms by which iron is linked to the HD pathogenesis are multiple, including oxidative stress, ferroptosis and neuroinflammation. However, no previous study in a neurodegenerative disease has linked the observed increase of brain iron accumulation as measured by MRI with well-established cerebrospinal fluid (CSF) and blood biomarkers for iron accumulation, or with associated processes such as neuroinflammation. This study is designed to link quantitative data from iron levels and neuroinflammation metabolites obtained from 7T MRI of HD patients, with specific and well-known clinical biofluid markers for iron accumulation, neurodegeneration and neuroinflammation. Biofluid markers will provide quantitative measures of overall iron accumulation, neurodegeneration and neuroinflammation, while MRI measurements on the other hand will provide quantitative spatial information on brain pathology, neuroinflammation and brain iron accumulation, which will be linked to clinical outcome measures.MethodsThis is an observational cross-sectional study, IMAGINE-HD, in HD gene expansion carriers and healthy controls. We include premanifest HD gene expansion carriers and patients with manifest HD in an early or moderate stage. The study includes a 7T MRI scan of the brain, clinical evaluation, motor, functional, and neuropsychological assessments, and sampling of CSF and blood for the detection of iron, neurodegenerative and inflammatory markers. Quantitative Susceptibility Maps will be reconstructed using T2* weighted images to quantify brain iron levels and Magnetic Resonance Spectroscopy will be used to obtain information about neuroinflammation by measuring cell-specific intracellular metabolites’ level and diffusion. Age and sex matched healthy subjects are included as a control group.DiscussionResults from this study will provide an important basis for the evaluation of brain iron levels and neuroinflammation metabolites as an imaging biomarker for disease stage in HD and their relationship with the salient pathomechanisms of the disease on the one hand, and with clinical outcome on the other. Show less
Kuipers, S.; Overmars, L.M.; Es, B. van; Bresser, J. de; Bron, E.E.; Hoefer, I.E.; ... ; Haitjema, S. 2022
Biological processes underlying cerebral small vessel disease (cSVD) are largely unknown. We hypothesized that identification of clusters of inter-related bood-based biomarkers that are associated... Show moreBiological processes underlying cerebral small vessel disease (cSVD) are largely unknown. We hypothesized that identification of clusters of inter-related bood-based biomarkers that are associated with the burden of cSVD provides leads on underlying biological processes. In 494 participants (mean age 67.6 +/- 8.7 years; 36% female; 75% cardiovascular diseases; 25% reference participants) we assessed the relation between 92 blood-based biomarkers from the OLINK cardiovascular III panel and cSVD, using cluster-based analyses. We focused particularly on white matter hyperintensities (WMH). Nineteen biomarkers individually correlated with WMH ratio (r range: 0.16-0.27, Bonferroni corrected p-values <0.05), of which sixteen biomarkers formed one biomarker cluster. Pathway analysis showed that this biomarker cluster predominantly reflected coagulation processes. This cluster related also significantly to other cSVD manifestations (lacunar infarcts, microbleeds, and enlarged perivascular spaces), which supports generalizability beyond WMHs. To study possible causal effects of biological processes reflected by the cluster we performed a mediation analysis that showed a mediation effect of the cluster on the relation between age and WMH ratio (proportion mediated 17%), and hypertension and WMH-volume (proportion mediated 21%). In conclusion, we identified a cluster of blood-based biomarkers reflecting coagulation, that is related to manifestations of cSVD, corroborating involvement of coagulation abnormalities in the etiology of cSVD. Show less
