7 T MRI reveals diffuse iron deposition in putamen and caudate nucleus in CADASIL

Michael K Liem, Saskia A J Lesnik Oberstein, Maarten J Versluis, Marion L C Maat-Schieman, Joost Haan, Andrew G Webb, Michel D Ferrari, Mark A van Buchem, Jeroen van der Grond
2012 Journal of Neurology, Neurosurgery and Psychiatry  
and Purpose Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary small vessel disease, is characterized by ischemic as well as neurodegenerative changes. Both of these brain processes have been linked to increased diffuse iron deposition in the brain. The aim of this study is to quantify diffuse iron deposition in CADASIL, using high-field in-vivo MRI and ex-vivo MRI imaging, as well as histopathologic analysis. Methods Twenty-five
more » ... TCH3 mutation carriers and 15 healthy controls were examined using high resolution T2*-weighted imaging on a 7 Tesla whole body MRI scanner. Susceptibility weighted MRI scans were analyzed for areas of signal loss and increased phase shift. Phase shift measurements in deep grey nuclei, cortex and subcortical white matter were compared between mutation carriers and controls. For confirmation, ex-vivo brain specimens from another 3 CADASIL patients were analyzed for iron deposition using ex-vivo MRI combined with iron histochemistry. Results In-vivo MRI showed areas of decreased signal intensity and increased phase shift in mutation carriers. Compared to healthy controls, mutation carriers had significantly higher phase shift in the putamen (p=0.0005) and caudate nucleus (p=0.008). Ex-vivo MRI showed decreased signal intensity in the putamen and caudate nucleus in all specimens. Histochemistry confirmed the presence of iron deposition in these nuclei. Conclusions This study demonstrates increased diffuse iron accumulation in the putamen and caudate nucleus in CADASIL patients. 105 7T MRI reveals diffuse iron deposition in the putamen and caudate nucleus in CADASIL InTRODuCTIOn Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by mutations in the NOTCH3 gene. (1) The mutations cause abnormalities in small calibre arteries and arterioles of the cerebrum, consisting of deposition of granular osmiophilic material (GOM), degeneration of vascular smooth muscle cells and fibrous thickening of the vessel wall. (2) Diffuse iron deposition in brain is a process that has been demonstrated in neurodegenerative diseases, in brain ischemia from large vessel occlusion, and in healthy subjects of older age.(3-7) Over the last few years, evidence is increasing that iron deposition is an important biomarker of various disease processes in the brain.(8;9) MRI scans in CADASIL, a small vessel disease, show both ischemic and secondary neurodegenerative changes. (10-12) Increasingly sensitive detection of iron accumulation in the brain has been made possible by the advent of high field MRI, using magnitude and phase imaging of T2* gradient echo scans.(4;13) The aim of this study is to investigate the potential presence and pattern of iron accumulation in CADASIL using high field MRI in vivo and ex vivo, as well as histopathological confirmation of iron accumulation. METHODS Patients Participants consisted of 25 symptomatic (n=14) or asymptomatic (n=11) NOTCH3 mutation carriers (MCs) and 15 healthy age-and sex-matched volunteers. Informed consent was obtained from all participants. Approval for the study was given by the medical ethics committee of the Leiden University Medical Center. A full medical history was obtained. Disease duration was determined based on first occurrence of neurological symptoms excluding migraine aura. In-vivo Magnetic Resonance Imaging MRI was performed on a whole body human 7T MR system (Philips Healthcare, Best, the Netherlands). Whole brain imaging was performed with all sequences in an axial plane parallel to the inferior border of the genu and splenium of the corpus callosum. Additionally, high resolution imaging in a 2.2 cm thick axial slab of interest that included the thalamus, corpus striatum and parts of the frontal, parietal, temporal as well as occipital lobes was performed. Chapter 8 106 The following scan protocol was used: • Whole brain 3D T1-weighted images with a scan duration of 12 minutes; repetition time (TR)/ echo time (TE)/ flip angle = 19 ms / 9.2 ms / 8°, 280 slices, 210 x 169 mm field of view, 700 x 563 matrix size -resulting in a nominal resolution of 0.3 x 0.3 x 0.5 mm.
doi:10.1136/jnnp-2012-302545 pmid:22923513 fatcat:ch3mz3eelbcjbat6i2pp2k72xm