Review 7 Tesla MRI in cerebral small vessel disease Philip Benjamin1*†, Olivia Viessmann2†, Andrew MacKinnon3, Peter Jezzard2, and Hugh S. Markus4 Cerebral small vessel disease (SVD) is a major cause of stroke and cognitive decline. Magnetic resonance imaging (MRI) currently plays a central role in diagnosis, and advanced MRI techniques are widely used in research but are limited by spatial resolution. Human 7 Tesla (7T) MRI has recently become available offering the ability to image at higher spatial resolution. This may provide additional insights into both the vascular pathology itself as well as parenchymal markers which could only previously be examined post mortem. In this review we cover the advantages and limitations of 7T MRI, review studies in SVD performed to date, and discuss potential future insights into SVD which 7T MRI may provide. Key words: 7T MRI, small vessel disease
Introduction Cerebral small vessel disease (SVD) describes a group of pathological processes that affect the perforating cerebral arterioles and capillaries resulting in brain injury to the subcortical gray and white matter (1). It is associated with a number of brain parenchymal pathologies including small deep infarcts, areas of diffuse gliosis, ischemic demyelination and axonal loss corresponding to regions of radiological leukoaraiosis, microbleeds, and diffuse brain atrophy (2). Clinically SVD presents with lacunar strokes, and is also the major cause of vascular cognitive impairment. In addition, it appears to interact with Alzheimer’s disease, exacerbating the degree of cognitive impairment (3). Thus, SVD is an Correspondence: Philip Benjamin*, Neurosciences Research Centre, St Georges University of London, Cranmer Terrace, London SW17 0RE, UK. E-mail: [email protected] 1 Neurosciences Research Centre, St George’s University of London, London, UK 2 Functional MRI of the Brain (FMRIB) Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 3 Atkinson Morley Regional Neuroscience Centre, St George’s NHS Healthcare Trust, London, UK 4 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
enormous health burden. Despite this, there is a limited understanding of the disease and the mechanisms underlying it, which has hindered treatment approaches. As the disease is slowly progressive and lacunar stroke is associated with a low early mortality compared with other stroke subtypes, there is limited neuropathological data available, particularly earlier in the disease process. Magnetic resonance imaging (MRI) at field strengths up to 3 Tesla is widely used for the clinical diagnosis in SVD and has provided many insights into disease pathogenesis. Recently, higher field strength imaging at 7 Tesla (7T) has become available on human MR systems offering the ability to image at higher signal to noise ratios (SNR) and therefore higher spatial resolution. This has the potential to improve our understanding of SVD by visualizing the vascular pathology itself as well as parenchymal markers which could only previously be examined post mortem.
Disease pathogenesis Early pathological descriptions of SVD were made by C. Miller Fisher in the 1950s and 1960s who observed that occlusion of the small perforating arteries occurred by two main pathologies: a diffuse arteriopathy with hyaline deposition (which he termed lipohyalinosis) or atherosclerosis (4). He reported that while lipohyalinosis (characterized by loss of normal arterial architecture and mural foam cells) affected smaller arteries (200–800 μm diameter), atherosclerosis affected the larger perforating arteries near their origins and resulted in larger isolated lacunar infarcts (5). How the vascular lesions cause brain injury and in particular the diffuse ischemic changes seen as leukoaraiosis is not fully understood. The conventional hypothesis is that chronic ischemic changes occur in internal watershed regions, and both reduced blood flow (6) and impaired cerebral autoregulation (7) have been reported. However more recently a role for endothelial dysfunction and increased blood brain barrier permeability, resulting in exudation of potentially toxic plasma constituents into the brain parenchyma, has been proposed (8).
Received: 19 November 2014; Accepted: 4 February 2015 †Authors contributed equally to the manuscript. Conflicts of interest: None declared. Funding: This work is supported by a Neurosciences Research Foundation (NRF) grant (PB) (Registered Charity No. 288438). Hugh Markus is supported by an NIHR Senior Investigator award. His research is supported by the Cambridge University Hospitals NINR Comprehensive Biomedical Research Centre. The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7/2007–2013/under REA grant agreement n° [316716] (OV). We also thank the Dunhill Medical Trust for salary support (PJ). DOI: 10.1111/ijs.12490 © 2015 World Stroke Organization
The current status of MRI in SVD MRI plays a crucial role in the diagnosis of SVD and is a key research technique in the field. Common features seen on conventional MRI include lacunes, white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), perivascular spaces (PvS) and brain atrophy. WMHs are best seen on T2-weighted sequences, and contrast between WMHs and normal tissue is further increased on Fluid Attenuated Inversion Recovery (FLAIR) sequences in which signal from cerebrospinal fluid (CSF) is suppressed. Lacunar infarcts are seen acutely on diffusion-weighted images (9), while old lacunar infarcts with Vol ••, •• 2015, ••–••
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Review tissue destruction (lacunes) can be seen as CSF filled spaces on T1-weighted and T2-FLAIR sequences. CMBs are best observed on Gradient Echo (GRE) images or by using Susceptibility Weighted Imaging (SWI) (2). Correlations between clinical parameters such as cognition and conventional MRI measures such as T2 WMH volume or CMBs have been inconsistent and weak, particularly in patients with more advanced disease (10,11). Lacunes and brain volume have shown better associations with cognitive impairment (12). More advanced techniques, particularly diffusion tensor imaging (DTI), have also been extensively applied. DTI is very sensitive to tissue damage and shows abnormalities in apparently normal appearing white matter, and the extent of this abnormality has been shown to correlate with cognition in a number of SVD cohorts (2,11). DTI has been proposed as a surrogate disease marker, although more data from longitudinal prospective cohorts and from intervention studies are required to show that this is indeed the case (2,11). Network analysis applied to structural DTI datasets has shown evidence of disrupted networks in SVD, and suggested that lacunar infarcts and white matter lesions may cause cognitive decline via disruption of these distributed networks (13). Despite the major contribution of MRI to SVD research, current imaging using field strengths up to 3T has significant limitations. Although the large basal intracranial vessels can be seen, the perforating arteries in which SVD pathology occurs cannot be well visualized. The degree of resolution is also insufficient to see some pathologies, and this has been highlighted by the recent pathological description of cortical microinfarcts in the disease (14). Human 7T MRI offers potential advantages, primarily by allowing higher resolution imaging. Using 7T one can obtain high resolution anatomical images of the human brain providing more detailed structural information and brain parenchymal changes that are invisible at lower field strengths. In this review we cover the application of 7T to SVD, including studies to date and future potential directions.
Literature search strategy References were identified by searching PubMed using the following search items: ‘((7T MRI) OR 7 Tesla) AND cerebral small vessel disease’, ‘((7T MRI) OR 7 Tesla) AND cerebral microbleeds’, ‘((7T MRI) OR 7 Tesla) AND cerebral microinfarcts’, ‘((7T MRI) OR 7 Tesla) AND lacunar’, ‘((7T MRI) OR 7 Tesla) AND white matter lesions’, ‘((7T MRI) OR 7 Tesla) AND perivascular spaces’, ‘((7T MRI) OR 7 Tesla)) AND (lenticulostriate OR perforating arteries)’, ‘((7T MRI) OR 7 Tesla)) AND vessel wall imaging’. This search was supplemented with manual searching of reference lists contained in all included articles and in relevant review articles. The final selection was based on relevance, as judged by the authors.
Opportunities and challenges at 7 Tesla Moving from clinically established lower field strengths of 1·5 and 3T to an ultra-high field strength of 7T offers opportunities for better image quality and more detailed imaging, but poses a
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P. Benjamin et al. number of technical challenges (15–18). Imaging protocols therefore need to be optimized by careful consideration of several factors including image contrast, SNR, scan acquisition time, spatial resolution and image artefacts. The best known argument for using higher field strengths is the approximately linear increase in SNR with the main magnetic field (B0) (19). This improvement in SNR may be traded to provide better spatial resolution (since SNR is also proportional to the voxel volume). SNR depends on multiple other factors (relaxation constants, spin density and RF coil characteristics) that vary among field strengths, subjects and scanner systems, and a precise comparison between 7T and lower field strengths is therefore difficult to perform rigorously. Nevertheless, as a rule of thumb an isotropic voxel of 1 mm at 1·5T or 3T can be reduced at 7T to (1·5/7)1/3 ≈ 0·6 mm and (3/7)1/3 ≈ 0·75 mm, respectively, without SNR penalty. This assumes that the acquisition time is kept constant by reducing the overall imaging volume. A significant technical challenge at 7T is inhomogeneity in the B1 (radio-frequency) field, which is responsible for sample excitation. This results in spatially varying flip angles which degrade image quality (20) and affect image contrast. Also, equivalent RF pulse excitations at 7T lead to increased power deposition in the subject compared to lower field strengths, often restricting imaging protocols due to specific absorption rate (SAR) restrictions. As SAR is approximately proportional to the square of B1 (21), contrasts requiring large flip angles demand longer repetition times (TR), a reduction in brain coverage or even a change in sequence design. This is particularly relevant for T2-FLAIR, which is used in most clinical MRI protocols and which is used for the assessment of WMHs in SVD. The issue of B1 inhomogeneity is currently addressed using pulse sequence designs that minimize B1 dependency (e.g. with adiabatic pulses) and the issue of SAR is addressed by using low flip angle readout schemes with lengthened RF pulses whenever possible. New hardware approaches such as multiple transmission coils (parallel transmission) may also offer solutions in the future (22). The increasing B0 also leads to changes in the relaxation constants T1, T2 and T2*. The longitudinal relaxation constant (T1) increases significantly from 3T to 7T. The T1 of gray matter increases from approximately 1300 ms to 2100 ms and that of white matter from approximately 840 ms to 1200 ms (23). The longer T1 specifically benefits MR Angiography (MRA), using Time of Flight (ToF). ToF applies repetitive excitation pulses in the imaging slab to saturate static tissue spins which suppresses the signal from background tissue. Spins from inflowing blood, conversely, give a strong signal as a result of being unsaturated as they travel through the imaging slab. This contrast between static tissue and inflowing blood is increased at 7T as the gray/white matter signal recovers more slowly within the same TR compared to lower field strengths. The combination of better background suppression and increased spatial resolution allows for more detailed visualization of the smaller vessels such as the lenticulostriate arteries in vivo. A disadvantage of the longer T1 at 7T, however, is the need for a prolonged TR in T2 weighted imaging, such as in T2-FLAIR and T2 turbo-spin echo (TSE), which increases the acquisition time. © 2015 World Stroke Organization
P. Benjamin et al. At 7T the transverse relaxation constant (T2) is slightly reduced and the same holds for T2*. The shortened T2* and the increased magnetic susceptibility effect (which is linearly proportional to B0) (24) allow for easier detection of paramagnetic substances like hemosiderin, calcium, deoxyhaemoglobin and iron. These substances appear as signal voids in the image. As susceptibilityinduced intravoxel dephasing (i.e. signal loss) is increased with higher field strengths, 7T imaging may provide useful insights into other aspects of SVD such as CMBs, iron deposition and venous anatomy. T2*-weighted imaging (GRE) does not require large flip angles and subsequently has fewer SAR restrictions allowing full brain coverage in relatively short scan times. A final issue relevant to high field is the MR compatibility of the subject. A device or implant being categorized MR safe at 1·5T or 3T does not guarantee MR safety at 7T. Metallic implants that have been tested safe at lower field strengths may experience resonance effects and local tissue heating at 7T. Various studies that have tested temperature and position changes of metallic implants and other objects already demonstrated safe at lower fields (25–29), have shown 7T to be safe; however generalizations should not be made and each manufacturer/user should test their respective products for contraindications. This is underlined by the observation that a programmable shunt assistant completely lost its functional capability at 7T even though it was preserved at 3T (30).
7T MRI in SVD: the story so far To justify the use of 7T MRI in SVD, it must provide better imaging resolution than imaging at lower field strengths and/or new information (e.g. on disease mechanisms or potential surrogate markers) within reasonable acquisition times. In SVD it has the potential to improve visualization of the parenchymal damage as well as imaging of the arterial disease itself; both of these applications are reviewed below. Lesions of the brain parenchyma Lacunes and perivascular spaces Lacunes and PvS are best visualized on T1 weighted imaging. One study in ischemic stroke which included lacunar strokes showed that T1-weighted images at 7T depicted the internal structure of stroke lesions with higher detail compared to 3T (31). Image contrast between lesions and healthy tissue was also shown to be superior at 7T allowing better depiction of perilesional abnormalities (31). Enlarged PvS have been implicated as another MRI marker of SVD and are associated with age, lacunar stroke and white matter lesions (32). 7T MRI increases the detection of PvS and allows them to be visualized in greater detail than at 3T (31). Of note, the acquisition time for T1 weighted imaging at 7T can be comparable to that of 3T without sacrificing the spatial resolution advantage (31,33). White matter hyperintensities 7T is comparable to 3T in the depiction of WMHs and their distribution using T2-FLAIR (31,34). In order to achieve the nec© 2015 World Stroke Organization
Review essary T2 contrast at 7T, additional magnetization preparation modules are needed to suppress T1 weighting (35). The TSE readout sequence of T2-FLAIR traditionally uses 180° refocusing flip angles that would lead to a prohibitive SAR at 7T. Implementing variable low flip angle schemes allows whole brain coverage (36) and isotropic resolution of 0·8 mm can be achieved within 10 to 15 mins (33,36). Cerebral microbleeds and iron deposition Due to their paramagnetic nature CMBs are best observed on GRE imaging as small signal voids. 7T has been shown to be more sensitive for detecting microbleeds when compared to 1·5T (34,37). There is evidence to suggest that it is also superior to 3T but larger studies are needed to confirm this (38). Although these enhanced susceptibility effects provide the opportunity of creating better tissue contrast there are potential disadvantages. As echo time and susceptibility both influence the amount of signal loss in GRE, the so called ‘blooming’ effect seen with CMBs is increased at 7T which may overestimate the size of the underlying hemosiderin deposit (37,39). Iron accumulation in the brain, possibly due to blood brain barrier dysfunction, may be increased in SVD (40). A study using 7T MRI showed that patients with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; a hereditary form of SVD) had increased diffuse iron accumulation in the caudate and putamen (40). Such quantification of iron deposition may be more sensitive at 7T due to the increased susceptibility effect. Whether it is superior to 3T is yet to be investigated. Cerebral microinfarcts An emerging concept in stroke and SVD is the role of cerebral microinfarcts (CMIs). CMIs in the sub-millimeter range can be visualized neuropathologically in SVD and have been reported as an independent risk factor contributing to brain atrophy and cognitive decline (14). CMIs are not reliably detectable using conventional MRI (33), but cortical CMIs were visible at 7T (Fig. 1) and could be histopathologically validated (33,41). Patients with spontaneous intracranial haemorrhage were found to have more cortical CMIs than controls (42), although patients with type 2 diabetes did not have increased CMIs (43). The significance of CMIs in Alzheimer’s disease (AD) has also been investigated in two small studies with conflicting results (44,45). 7T MRI can currently detect only relatively large CMIs and probably underestimates true CMI burden. CMIs are best visualized using a combination of T1 imaging and T2-FLAIR to see the tiny cavity with surrounding FLAIR hyperintensity. Studies are now required to determine whether CMIs detected at 7T MRI correlate with cognitive function in SVD. It will also be important to determine in prospective studies their contribution to the cortical atrophy seen in SVD, which itself independently correlates with cognitive decline. Whether this cortical atrophy is due to intrinsic cortical pathology such as CMI, or is secondary to white matter tract disruption due to subcortical pathology, is unknown. Vol ••, •• 2015, ••–••
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Fig. 1 Possible cerebral microinfarct (CMI) visualized using 7·0 T MRI. The cortical CMI is seen as a hyperintense cortical lesion on a FLAIR sequence. (a; 0·8 × 0·8 × 0·8 mm3) and a T2 weighted (b; 0·7 × 0·7 × 0·7 mm3), and as a hypointense lesion on a T1 weighted (c; 1·0 × 1·0 × 1·0 mm3) image on a transversal view of the brain. Scale bar indicates 4 mm. Reproduced with permission from van Veluw et al. J Cereb Blood Flow Metab 2013; 33:322–329.
Fig. 3 Arterial imaging using 7T MRI in a patient with SVD. 7T ToF MRA (resolution = 0·31 mm isotropic) of highly tortuous lenticulostriate arteries (red arrow) seen in a patient with confluent white matter hyperintensities and several lacunar infarcts. Image is displayed in radiological convention.
greater anatomical detail, and displayed more first and second order branches of the main cerebral arteries (31). Differences in the lenticulostriate arteries of patients with SVD (46), hypertension (47) and previous stroke (48) have been reported with a reduced number of stems and branches compared to healthy controls. In patients with CADASIL the perforating arteries were found not to differ from control subjects even in the presence of severe white matter lesions or lacunar infarcts (49). In one study, it was even possible to identify the individual lenticulostriate artery associated with a specific lacunar infarct (50). Such high resolution imaging at 7T is currently only suitable for visualization of selected brain regions. Fig. 2 Arterial imaging using 7T MRI. (a) 3D reconstruction of a 3T ToF MRA maximum intensity projection (resolution = 0·4 mm isotropic) of large lenticulostriate arteries originating from the middle cerebral arteries on the right and left in a normal volunteer. (b) 3D reconstruction of a 7T MRA image obtained from the same subject (resolution = 0·31 mm isotropic). Images are displayed in radiological convention.
Vascular imaging MR angiography 7T MRI allows non-invasive imaging of the cerebral perforating arteries, i.e. the pathological arteries themselves (Figs 2,3). A study comparing ToF MRA at 3T and 7T showed that 7T imaging was able to depict the branches of the middle cerebral artery in
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Vessel wall imaging Angiographic techniques depict the lumen of the vessel and can therefore only detect luminal narrowing when it is relatively severe. Being able to visualize the vessel wall itself allows the detection of atheroma and other vessel wall pathology before luminal narrowing becomes apparent. 3T MRI is being increasingly used to visualize characteristics of the atherosclerotic plaque in the extracranial carotid arteries (51) but the smaller size of the middle cerebral artery makes visualization of atheroma in this vessel much more challenging. Studies at 3T have shown that the vessel wall was visible only in the presence of large atherosclerotic lesions or vessel wall inflammation (52–54). At 7T, however, it is © 2015 World Stroke Organization
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Fig. 4 Vascular wall imaging in SVD. (a) Transverse 3-dimensional magnetization preparation inversion recovery (MPIR) turbo spin-echo (TSE) image in an 83-year-old man with a history of TIAs showing irregularly thickened anterior cerebral artery vessel wall on the right, corresponding to local luminal narrowing on transverse time-of-flight MRA angiogram (b). Sagittal vessel wall image reconstructions showing middle cerebral artery and anterior cerebral artery bifurcation with narrow proximal anterior cerebral artery (c), narrowing further more distally as compared to middle cerebral artery (d). Reproduced from van der Kolk A G et al. Stroke. 2011;42:2478–2484 with permission.
possible to visualize even healthy intracranial vessel walls using a 3D inversion recovery turbo spin-echo (MPIR-TSE) sequence. The inversion pulse was used to null the CSF and black blood was obtained due to flow between excitation and refocusing in the TSE train (55,56). As such, 7T MRI can be used to visualize basal intracranial vessel wall disease (Fig. 4) and therefore may be useful in determining the role of intracranial atheroma in the pathogenesis of lacunar infarction.
Conclusion 7T MRI offers a number of novel insights into the arterial and parenchymal lesions associated with SVD. The ability to visualize the perforating arteries will allow the role of atherosclerosis and focal stenosis in disease pathogenesis to be explored. The ability to visualize CMIs will allow their role in SVD including their contribution to brain atrophy and cognitive decline to be determined. In addition, there is research potential using other MR techniques such as diffusion imaging where high levels of neuroanatomical detail can be achieved, and spectroscopy where 7T can provide an extra degree of sensitivity to detect metabolites associated with neuronal loss and blood brain barrier dysfunction. Although 7T MRI is unlikely to replace 3T in the general clinical diagnosis of SVD, it does provide us with new information and potential novel surrogate markers of the disease. It can also facilitate an understanding of key disease mechanisms which will have an impact on early recognition and treatment of SVD. Technical developments and increasing installation of 7T systems will undoubtedly extend the use of 7T in SVD research in the years to come. © 2015 World Stroke Organization
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Introduction Cerebral small vessel disease (SVD) describes a group of pathological processes that affect the perforating cerebral arterioles and capillaries resulting in brain injury to the subcortical gray and white matter (1). It is associated with a number of brain parenchymal pathologies including small deep infarcts, areas of diffuse gliosis, ischemic demyelination and axonal loss corresponding to regions of radiological leukoaraiosis, microbleeds, and diffuse brain atrophy (2). Clinically SVD presents with lacunar strokes, and is also the major cause of vascular cognitive impairment. In addition, it appears to interact with Alzheimer’s disease, exacerbating the degree of cognitive impairment (3). Thus, SVD is an Correspondence: Philip Benjamin*, Neurosciences Research Centre, St Georges University of London, Cranmer Terrace, London SW17 0RE, UK. E-mail: [email protected] 1 Neurosciences Research Centre, St George’s University of London, London, UK 2 Functional MRI of the Brain (FMRIB) Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK 3 Atkinson Morley Regional Neuroscience Centre, St George’s NHS Healthcare Trust, London, UK 4 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
enormous health burden. Despite this, there is a limited understanding of the disease and the mechanisms underlying it, which has hindered treatment approaches. As the disease is slowly progressive and lacunar stroke is associated with a low early mortality compared with other stroke subtypes, there is limited neuropathological data available, particularly earlier in the disease process. Magnetic resonance imaging (MRI) at field strengths up to 3 Tesla is widely used for the clinical diagnosis in SVD and has provided many insights into disease pathogenesis. Recently, higher field strength imaging at 7 Tesla (7T) has become available on human MR systems offering the ability to image at higher signal to noise ratios (SNR) and therefore higher spatial resolution. This has the potential to improve our understanding of SVD by visualizing the vascular pathology itself as well as parenchymal markers which could only previously be examined post mortem.
Disease pathogenesis Early pathological descriptions of SVD were made by C. Miller Fisher in the 1950s and 1960s who observed that occlusion of the small perforating arteries occurred by two main pathologies: a diffuse arteriopathy with hyaline deposition (which he termed lipohyalinosis) or atherosclerosis (4). He reported that while lipohyalinosis (characterized by loss of normal arterial architecture and mural foam cells) affected smaller arteries (200–800 μm diameter), atherosclerosis affected the larger perforating arteries near their origins and resulted in larger isolated lacunar infarcts (5). How the vascular lesions cause brain injury and in particular the diffuse ischemic changes seen as leukoaraiosis is not fully understood. The conventional hypothesis is that chronic ischemic changes occur in internal watershed regions, and both reduced blood flow (6) and impaired cerebral autoregulation (7) have been reported. However more recently a role for endothelial dysfunction and increased blood brain barrier permeability, resulting in exudation of potentially toxic plasma constituents into the brain parenchyma, has been proposed (8).
Received: 19 November 2014; Accepted: 4 February 2015 †Authors contributed equally to the manuscript. Conflicts of interest: None declared. Funding: This work is supported by a Neurosciences Research Foundation (NRF) grant (PB) (Registered Charity No. 288438). Hugh Markus is supported by an NIHR Senior Investigator award. His research is supported by the Cambridge University Hospitals NINR Comprehensive Biomedical Research Centre. The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7/2007–2013/under REA grant agreement n° [316716] (OV). We also thank the Dunhill Medical Trust for salary support (PJ). DOI: 10.1111/ijs.12490 © 2015 World Stroke Organization
The current status of MRI in SVD MRI plays a crucial role in the diagnosis of SVD and is a key research technique in the field. Common features seen on conventional MRI include lacunes, white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), perivascular spaces (PvS) and brain atrophy. WMHs are best seen on T2-weighted sequences, and contrast between WMHs and normal tissue is further increased on Fluid Attenuated Inversion Recovery (FLAIR) sequences in which signal from cerebrospinal fluid (CSF) is suppressed. Lacunar infarcts are seen acutely on diffusion-weighted images (9), while old lacunar infarcts with Vol ••, •• 2015, ••–••
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Review tissue destruction (lacunes) can be seen as CSF filled spaces on T1-weighted and T2-FLAIR sequences. CMBs are best observed on Gradient Echo (GRE) images or by using Susceptibility Weighted Imaging (SWI) (2). Correlations between clinical parameters such as cognition and conventional MRI measures such as T2 WMH volume or CMBs have been inconsistent and weak, particularly in patients with more advanced disease (10,11). Lacunes and brain volume have shown better associations with cognitive impairment (12). More advanced techniques, particularly diffusion tensor imaging (DTI), have also been extensively applied. DTI is very sensitive to tissue damage and shows abnormalities in apparently normal appearing white matter, and the extent of this abnormality has been shown to correlate with cognition in a number of SVD cohorts (2,11). DTI has been proposed as a surrogate disease marker, although more data from longitudinal prospective cohorts and from intervention studies are required to show that this is indeed the case (2,11). Network analysis applied to structural DTI datasets has shown evidence of disrupted networks in SVD, and suggested that lacunar infarcts and white matter lesions may cause cognitive decline via disruption of these distributed networks (13). Despite the major contribution of MRI to SVD research, current imaging using field strengths up to 3T has significant limitations. Although the large basal intracranial vessels can be seen, the perforating arteries in which SVD pathology occurs cannot be well visualized. The degree of resolution is also insufficient to see some pathologies, and this has been highlighted by the recent pathological description of cortical microinfarcts in the disease (14). Human 7T MRI offers potential advantages, primarily by allowing higher resolution imaging. Using 7T one can obtain high resolution anatomical images of the human brain providing more detailed structural information and brain parenchymal changes that are invisible at lower field strengths. In this review we cover the application of 7T to SVD, including studies to date and future potential directions.
Literature search strategy References were identified by searching PubMed using the following search items: ‘((7T MRI) OR 7 Tesla) AND cerebral small vessel disease’, ‘((7T MRI) OR 7 Tesla) AND cerebral microbleeds’, ‘((7T MRI) OR 7 Tesla) AND cerebral microinfarcts’, ‘((7T MRI) OR 7 Tesla) AND lacunar’, ‘((7T MRI) OR 7 Tesla) AND white matter lesions’, ‘((7T MRI) OR 7 Tesla) AND perivascular spaces’, ‘((7T MRI) OR 7 Tesla)) AND (lenticulostriate OR perforating arteries)’, ‘((7T MRI) OR 7 Tesla)) AND vessel wall imaging’. This search was supplemented with manual searching of reference lists contained in all included articles and in relevant review articles. The final selection was based on relevance, as judged by the authors.
Opportunities and challenges at 7 Tesla Moving from clinically established lower field strengths of 1·5 and 3T to an ultra-high field strength of 7T offers opportunities for better image quality and more detailed imaging, but poses a
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P. Benjamin et al. number of technical challenges (15–18). Imaging protocols therefore need to be optimized by careful consideration of several factors including image contrast, SNR, scan acquisition time, spatial resolution and image artefacts. The best known argument for using higher field strengths is the approximately linear increase in SNR with the main magnetic field (B0) (19). This improvement in SNR may be traded to provide better spatial resolution (since SNR is also proportional to the voxel volume). SNR depends on multiple other factors (relaxation constants, spin density and RF coil characteristics) that vary among field strengths, subjects and scanner systems, and a precise comparison between 7T and lower field strengths is therefore difficult to perform rigorously. Nevertheless, as a rule of thumb an isotropic voxel of 1 mm at 1·5T or 3T can be reduced at 7T to (1·5/7)1/3 ≈ 0·6 mm and (3/7)1/3 ≈ 0·75 mm, respectively, without SNR penalty. This assumes that the acquisition time is kept constant by reducing the overall imaging volume. A significant technical challenge at 7T is inhomogeneity in the B1 (radio-frequency) field, which is responsible for sample excitation. This results in spatially varying flip angles which degrade image quality (20) and affect image contrast. Also, equivalent RF pulse excitations at 7T lead to increased power deposition in the subject compared to lower field strengths, often restricting imaging protocols due to specific absorption rate (SAR) restrictions. As SAR is approximately proportional to the square of B1 (21), contrasts requiring large flip angles demand longer repetition times (TR), a reduction in brain coverage or even a change in sequence design. This is particularly relevant for T2-FLAIR, which is used in most clinical MRI protocols and which is used for the assessment of WMHs in SVD. The issue of B1 inhomogeneity is currently addressed using pulse sequence designs that minimize B1 dependency (e.g. with adiabatic pulses) and the issue of SAR is addressed by using low flip angle readout schemes with lengthened RF pulses whenever possible. New hardware approaches such as multiple transmission coils (parallel transmission) may also offer solutions in the future (22). The increasing B0 also leads to changes in the relaxation constants T1, T2 and T2*. The longitudinal relaxation constant (T1) increases significantly from 3T to 7T. The T1 of gray matter increases from approximately 1300 ms to 2100 ms and that of white matter from approximately 840 ms to 1200 ms (23). The longer T1 specifically benefits MR Angiography (MRA), using Time of Flight (ToF). ToF applies repetitive excitation pulses in the imaging slab to saturate static tissue spins which suppresses the signal from background tissue. Spins from inflowing blood, conversely, give a strong signal as a result of being unsaturated as they travel through the imaging slab. This contrast between static tissue and inflowing blood is increased at 7T as the gray/white matter signal recovers more slowly within the same TR compared to lower field strengths. The combination of better background suppression and increased spatial resolution allows for more detailed visualization of the smaller vessels such as the lenticulostriate arteries in vivo. A disadvantage of the longer T1 at 7T, however, is the need for a prolonged TR in T2 weighted imaging, such as in T2-FLAIR and T2 turbo-spin echo (TSE), which increases the acquisition time. © 2015 World Stroke Organization
P. Benjamin et al. At 7T the transverse relaxation constant (T2) is slightly reduced and the same holds for T2*. The shortened T2* and the increased magnetic susceptibility effect (which is linearly proportional to B0) (24) allow for easier detection of paramagnetic substances like hemosiderin, calcium, deoxyhaemoglobin and iron. These substances appear as signal voids in the image. As susceptibilityinduced intravoxel dephasing (i.e. signal loss) is increased with higher field strengths, 7T imaging may provide useful insights into other aspects of SVD such as CMBs, iron deposition and venous anatomy. T2*-weighted imaging (GRE) does not require large flip angles and subsequently has fewer SAR restrictions allowing full brain coverage in relatively short scan times. A final issue relevant to high field is the MR compatibility of the subject. A device or implant being categorized MR safe at 1·5T or 3T does not guarantee MR safety at 7T. Metallic implants that have been tested safe at lower field strengths may experience resonance effects and local tissue heating at 7T. Various studies that have tested temperature and position changes of metallic implants and other objects already demonstrated safe at lower fields (25–29), have shown 7T to be safe; however generalizations should not be made and each manufacturer/user should test their respective products for contraindications. This is underlined by the observation that a programmable shunt assistant completely lost its functional capability at 7T even though it was preserved at 3T (30).
7T MRI in SVD: the story so far To justify the use of 7T MRI in SVD, it must provide better imaging resolution than imaging at lower field strengths and/or new information (e.g. on disease mechanisms or potential surrogate markers) within reasonable acquisition times. In SVD it has the potential to improve visualization of the parenchymal damage as well as imaging of the arterial disease itself; both of these applications are reviewed below. Lesions of the brain parenchyma Lacunes and perivascular spaces Lacunes and PvS are best visualized on T1 weighted imaging. One study in ischemic stroke which included lacunar strokes showed that T1-weighted images at 7T depicted the internal structure of stroke lesions with higher detail compared to 3T (31). Image contrast between lesions and healthy tissue was also shown to be superior at 7T allowing better depiction of perilesional abnormalities (31). Enlarged PvS have been implicated as another MRI marker of SVD and are associated with age, lacunar stroke and white matter lesions (32). 7T MRI increases the detection of PvS and allows them to be visualized in greater detail than at 3T (31). Of note, the acquisition time for T1 weighted imaging at 7T can be comparable to that of 3T without sacrificing the spatial resolution advantage (31,33). White matter hyperintensities 7T is comparable to 3T in the depiction of WMHs and their distribution using T2-FLAIR (31,34). In order to achieve the nec© 2015 World Stroke Organization
Review essary T2 contrast at 7T, additional magnetization preparation modules are needed to suppress T1 weighting (35). The TSE readout sequence of T2-FLAIR traditionally uses 180° refocusing flip angles that would lead to a prohibitive SAR at 7T. Implementing variable low flip angle schemes allows whole brain coverage (36) and isotropic resolution of 0·8 mm can be achieved within 10 to 15 mins (33,36). Cerebral microbleeds and iron deposition Due to their paramagnetic nature CMBs are best observed on GRE imaging as small signal voids. 7T has been shown to be more sensitive for detecting microbleeds when compared to 1·5T (34,37). There is evidence to suggest that it is also superior to 3T but larger studies are needed to confirm this (38). Although these enhanced susceptibility effects provide the opportunity of creating better tissue contrast there are potential disadvantages. As echo time and susceptibility both influence the amount of signal loss in GRE, the so called ‘blooming’ effect seen with CMBs is increased at 7T which may overestimate the size of the underlying hemosiderin deposit (37,39). Iron accumulation in the brain, possibly due to blood brain barrier dysfunction, may be increased in SVD (40). A study using 7T MRI showed that patients with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; a hereditary form of SVD) had increased diffuse iron accumulation in the caudate and putamen (40). Such quantification of iron deposition may be more sensitive at 7T due to the increased susceptibility effect. Whether it is superior to 3T is yet to be investigated. Cerebral microinfarcts An emerging concept in stroke and SVD is the role of cerebral microinfarcts (CMIs). CMIs in the sub-millimeter range can be visualized neuropathologically in SVD and have been reported as an independent risk factor contributing to brain atrophy and cognitive decline (14). CMIs are not reliably detectable using conventional MRI (33), but cortical CMIs were visible at 7T (Fig. 1) and could be histopathologically validated (33,41). Patients with spontaneous intracranial haemorrhage were found to have more cortical CMIs than controls (42), although patients with type 2 diabetes did not have increased CMIs (43). The significance of CMIs in Alzheimer’s disease (AD) has also been investigated in two small studies with conflicting results (44,45). 7T MRI can currently detect only relatively large CMIs and probably underestimates true CMI burden. CMIs are best visualized using a combination of T1 imaging and T2-FLAIR to see the tiny cavity with surrounding FLAIR hyperintensity. Studies are now required to determine whether CMIs detected at 7T MRI correlate with cognitive function in SVD. It will also be important to determine in prospective studies their contribution to the cortical atrophy seen in SVD, which itself independently correlates with cognitive decline. Whether this cortical atrophy is due to intrinsic cortical pathology such as CMI, or is secondary to white matter tract disruption due to subcortical pathology, is unknown. Vol ••, •• 2015, ••–••
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Fig. 1 Possible cerebral microinfarct (CMI) visualized using 7·0 T MRI. The cortical CMI is seen as a hyperintense cortical lesion on a FLAIR sequence. (a; 0·8 × 0·8 × 0·8 mm3) and a T2 weighted (b; 0·7 × 0·7 × 0·7 mm3), and as a hypointense lesion on a T1 weighted (c; 1·0 × 1·0 × 1·0 mm3) image on a transversal view of the brain. Scale bar indicates 4 mm. Reproduced with permission from van Veluw et al. J Cereb Blood Flow Metab 2013; 33:322–329.
Fig. 3 Arterial imaging using 7T MRI in a patient with SVD. 7T ToF MRA (resolution = 0·31 mm isotropic) of highly tortuous lenticulostriate arteries (red arrow) seen in a patient with confluent white matter hyperintensities and several lacunar infarcts. Image is displayed in radiological convention.
greater anatomical detail, and displayed more first and second order branches of the main cerebral arteries (31). Differences in the lenticulostriate arteries of patients with SVD (46), hypertension (47) and previous stroke (48) have been reported with a reduced number of stems and branches compared to healthy controls. In patients with CADASIL the perforating arteries were found not to differ from control subjects even in the presence of severe white matter lesions or lacunar infarcts (49). In one study, it was even possible to identify the individual lenticulostriate artery associated with a specific lacunar infarct (50). Such high resolution imaging at 7T is currently only suitable for visualization of selected brain regions. Fig. 2 Arterial imaging using 7T MRI. (a) 3D reconstruction of a 3T ToF MRA maximum intensity projection (resolution = 0·4 mm isotropic) of large lenticulostriate arteries originating from the middle cerebral arteries on the right and left in a normal volunteer. (b) 3D reconstruction of a 7T MRA image obtained from the same subject (resolution = 0·31 mm isotropic). Images are displayed in radiological convention.
Vascular imaging MR angiography 7T MRI allows non-invasive imaging of the cerebral perforating arteries, i.e. the pathological arteries themselves (Figs 2,3). A study comparing ToF MRA at 3T and 7T showed that 7T imaging was able to depict the branches of the middle cerebral artery in
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Vessel wall imaging Angiographic techniques depict the lumen of the vessel and can therefore only detect luminal narrowing when it is relatively severe. Being able to visualize the vessel wall itself allows the detection of atheroma and other vessel wall pathology before luminal narrowing becomes apparent. 3T MRI is being increasingly used to visualize characteristics of the atherosclerotic plaque in the extracranial carotid arteries (51) but the smaller size of the middle cerebral artery makes visualization of atheroma in this vessel much more challenging. Studies at 3T have shown that the vessel wall was visible only in the presence of large atherosclerotic lesions or vessel wall inflammation (52–54). At 7T, however, it is © 2015 World Stroke Organization
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Fig. 4 Vascular wall imaging in SVD. (a) Transverse 3-dimensional magnetization preparation inversion recovery (MPIR) turbo spin-echo (TSE) image in an 83-year-old man with a history of TIAs showing irregularly thickened anterior cerebral artery vessel wall on the right, corresponding to local luminal narrowing on transverse time-of-flight MRA angiogram (b). Sagittal vessel wall image reconstructions showing middle cerebral artery and anterior cerebral artery bifurcation with narrow proximal anterior cerebral artery (c), narrowing further more distally as compared to middle cerebral artery (d). Reproduced from van der Kolk A G et al. Stroke. 2011;42:2478–2484 with permission.
possible to visualize even healthy intracranial vessel walls using a 3D inversion recovery turbo spin-echo (MPIR-TSE) sequence. The inversion pulse was used to null the CSF and black blood was obtained due to flow between excitation and refocusing in the TSE train (55,56). As such, 7T MRI can be used to visualize basal intracranial vessel wall disease (Fig. 4) and therefore may be useful in determining the role of intracranial atheroma in the pathogenesis of lacunar infarction.
Conclusion 7T MRI offers a number of novel insights into the arterial and parenchymal lesions associated with SVD. The ability to visualize the perforating arteries will allow the role of atherosclerosis and focal stenosis in disease pathogenesis to be explored. The ability to visualize CMIs will allow their role in SVD including their contribution to brain atrophy and cognitive decline to be determined. In addition, there is research potential using other MR techniques such as diffusion imaging where high levels of neuroanatomical detail can be achieved, and spectroscopy where 7T can provide an extra degree of sensitivity to detect metabolites associated with neuronal loss and blood brain barrier dysfunction. Although 7T MRI is unlikely to replace 3T in the general clinical diagnosis of SVD, it does provide us with new information and potential novel surrogate markers of the disease. It can also facilitate an understanding of key disease mechanisms which will have an impact on early recognition and treatment of SVD. Technical developments and increasing installation of 7T systems will undoubtedly extend the use of 7T in SVD research in the years to come. © 2015 World Stroke Organization
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