Key Points
-
PET enables noninvasive detection and quantification of inflammation, microcalcification and hypoxia, which are all associated with plaque rupture in carotid atherosclerosis
-
The temporospatial evolution of acute ischaemia and secondary neuroinflammation can be visualized using PET
-
PET studies have elucidated complex interactions between cerebral small vessel disease, neuroinflammation and amyloid deposition, and demonstrated different uptake patterns in vascular cognitive impairment
-
PET-based metabolic imaging not only offers improved understanding of disease mechanisms but also provides sensitive end points for use in clinical trials and has the potential to improve clinical risk-stratification
Abstract
Cerebrovascular disease encompasses a range of pathologies that affect different components of the cerebral vasculature and brain parenchyma. Large artery atherosclerosis, acute cerebral ischaemia, and intracerebral small vessel disease all demonstrate altered metabolic processes that are key to their pathogenesis. Although structural imaging techniques such as MRI are the mainstay of clinical care and research in cerebrovascular disease, they have limited ability to detect these pathophysiological processes in vivo. By contrast, PET can detect and quantify metabolic processes that are relevant to each facet of cerebrovascular disease. Information obtained from PET studies has helped to shape the understanding of key concepts in cerebrovascular medicine, including vulnerable atherosclerotic plaque, salvageable ischaemic penumbra, neuroinflammation and selective neuronal loss after ischaemic insult. PET has also helped to elucidate the relationships between chronic hypoxia, neuroinflammation, and amyloid-β deposition in cerebral small vessel disease. This Review describes how PET-based imaging of metabolic processes at the neurovascular interface has contributed to our understanding of cerebrovascular disease.
Similar content being viewed by others
Change history
03 April 2018
In this article as originally published, Prof. J. C. Baron was credited as the source of Figure 3. However, we omitted to state that permission to reproduce Figure 3 was obtained from Oxford University Press, the publisher of Prof. J. C. Baron’s article. This omission has been corrected online as of 3 April 2018.
References
Mochizuki, T. et al. FDG uptake and glucose transporter subtype expressions in experimental tumor and inflammation models. J. Nucl. Med. 42, 1551–1555 (2001).
Irkle, A. et al. Identifying active vascular microcalcification by 18F-sodium fluoride positron emission tomography. Nat. Commun. 6, 7495 (2015).
Owen, D. R. et al. Two binding sites for 3H-PBR28 in human brain: implications for TSPO PET imaging of neuroinflammation. J. Cereb. Blood Flow Metab. 30, 1608–1618 (2010).
Ross, R. Atherosclerosis — an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).
Davies, J. R. et al. Identification of culprit lesions after transient ischemic attack by combined 18F fluorodeoxyglucose positron-emission tomography and high-resolution magnetic resonance imaging. Stroke 36, 2642–2647 (2005).
Mizoguchi, M. et al. Pioglitazone attenuates atherosclerotic plaque inflammation in patients with impaired glucose tolerance or diabetes a prospective, randomized, comparator-controlled study using serial FDG PET/CT imaging study of carotid artery and ascending aorta. JACC Cardiovasc. Imaging 4, 1110–1118 (2011).
Fayad, Z. A. et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet 378, 1547–1559 (2011).
Baron, J. C. Mapping the ischaemic penumbra with PET: a new approach. Brain 124, 2–4 (2001).
Mann, J. M. & Davies, M. J. Vulnerable plaque. Relation of characteristics to degree of stenosis in human coronary arteries. Circulation 94, 928–931 (1996).
Maldonado, N. et al. A mechanistic analysis of the role of microcalcifications in atherosclerotic plaque stability: potential implications for plaque rupture. Am. J. Physiol. Heart Circ. Physiol. 303, H619–H628 (2012).
Vengrenyuk, Y. et al. A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps. Proc. Natl Acad. Sci. USA 103, 14678–14683 (2006).
Sluimer, J. C. et al. Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis. J. Am. Coll. Cardiol. 51, 1258–1265 (2008).
Murdoch, C., Muthana, M. & Lewis, C. E. Hypoxia regulates macrophage functions in inflammation. J. Immunol. 175, 6257–6263 (2005).
Usman, A., Sadat, U., Graves, M. J. & Gillard, J. H. Magnetic resonance imaging of atherothrombotic plaques. J. Clin. Neurosci. 22, 1722–1726 (2015).
Bucerius, J. et al. Optimizing 18F-FDG PET/CT imaging of vessel wall inflammation: the impact of 18F-FDG circulation time, injected dose, uptake parameters, and fasting blood glucose levels. Eur. J. Nucl. Med. Mol. Imaging 41, 369–383 (2014).
Tawakol, A. et al. In vivo18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. J. Am. Coll. Cardiol. 48, 1818–1824 (2006).
Huet, P., Burg, S., Le Guludec, D., Hyafil, F. & Buvat, I. Variability and uncertainty of FDG PET imaging protocols for assessing inflammation in atherosclerosis: suggestions for improvement. J. Nucl. Med. 56, 552–559 (2015).
Yun, M. et al. 18F FDG uptake in the large arteries: a new observation. Clin. Nucl. Med. 26, 314–319 (2001).
Rudd, J. H. F. et al. Imaging atherosclerotic plaque inflammation with 18F-fluorodeoxyglucose positron emission tomography. Circulation 105, 2708–2711 (2002).
Marnane, M. et al. Carotid plaque inflammation on 18F-fluorodeoxyglucose positron emission tomography predicts early stroke recurrence. Ann. Neurol. 71, 709–718 (2012).
Kim, H. J. et al. Carotid inflammation on 18F-fluorodeoxyglucose positron emission tomography associates with recurrent ischemic lesions. J. Neurol. Sci. 347, 242–245 (2014).
Moustafa, R. R. et al. Carotid plaque inflammation is associated with cerebral microembolism in patients with recent transient ischemic attack or stroke: a pilot study. Circ. Cardiovasc. Imaging 3, 536–541 (2010).
Howard, D. P. et al. Symptomatic carotid atherosclerotic disease: correlations between plaque composition and ipsilateral stroke risk. Stroke 46, 182–189 (2015).
Figueroa, A. L. et al. Distribution of inflammation within carotid atherosclerotic plaques with high-risk morphological features: a comparison between positron emission tomography activity, plaque morphology, and histopathology. Circ. Cardiovasc. Imaging 5, 69–77 (2012).
Silvera, S. S. et al. Multimodality imaging of atherosclerotic plaque activity and composition using FDG-PET/CT and MRI in carotid and femoral arteries. Atherosclerosis 207, 139–143 (2009).
Hyafil, F. et al. Rupture of nonstenotic carotid plaque as a cause of ischemic stroke evidenced by multimodality imaging. Circulation 129, 130–131 (2014).
Rudd, J. H. et al. Relationships among regional arterial inflammation, calcification, risk factors, and biomarkers: a prospective fluorodeoxyglucose positron-emission tomography/computed tomography imaging study. Circ. Cardiovasc. Imaging 2, 107–115 (2009).
Subramanian, S. et al. High-dose atorvastatin reduces periodontal inflammation: a novel pleiotropic effect of statins. J. Am. Coll. Cardiol. 62, 2382–2391 (2013).
Chróinín, D. N. et al. Serum lipids associated with inflammation-related PET-FDG uptake in symptomatic carotid plaque. Neurology 82, 1693–1699 (2014).
Bernelot Moens, S. J. et al. Carotid arterial wall inflammation in peripheral artery disease is augmented by type 2 diabetes: a cross-sectional study. BMC Cardiovasc. Disord. 16, 237 (2016).
Yoo, H. J. et al. Vascular inflammation in metabolically abnormal but normal-weight and metabolically healthy obese individuals analyzed with 18F-fluorodeoxyglucose positron emission tomography. Am. J. Cardiol. 115, 523–528 (2015).
Kim, S. et al. Concurrent carotid inflammation in acute coronary syndrome as assessed by 18F-FDG PET/CT: a possible mechanistic link for ischemic stroke. J. Stroke Cerebrovasc. Dis. 24, 2547–2554 (2015).
Tawakol, A. et al. Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study. Lancet 389, 834–845 (2017).
Abdelbaky, A. et al. Focal arterial inflammation precedes subsequent calcification in the same location: a longitudinal FDG-PET/CT study. Circ. Cardiovasc. Imaging 6, 747–754 (2013).
Joshi, F. R. et al. Does vascular calcification accelerate inflammation?: a substudy of the dal-PLAQUE trial. J. Am. Coll. Cardiol. 67, 69–78 (2016).
Tarkin, J. M., Joshi, F. R. & Rudd, J. H. PET imaging of inflammation in atherosclerosis. Nat. Rev. Cardiol. 11, 443–457 (2014).
Tahara, N. et al. Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. J. Am. Coll. Cardiol. 48, 1825–1831 (2006).
Tawakol, A. et al. Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study. J. Am. Coll. Cardiol. 62, 909–917 (2013).
Derlin, T. et al. Quantification of 18F-FDG uptake in atherosclerotic plaque: impact of renal function. Ann. Nucl. Med. 25, 586–591 (2011).
Bucerius, J. et al. Position paper of the cardiovascular committee of the European Association of Nuclear Medicine (EANM) on PET imaging of atherosclerosis. Eur. J. Nucl. Med. Mol. Imaging 43, 780–792 (2016).
Fujimura, Y. et al. Increased peripheral benzodiazepine receptors in arterial plaque of patients with atherosclerosis: an autoradiographic study with 3H-PK 11195. Atherosclerosis 201, 108–111 (2008).
Bird, J. L. et al. Evaluation of translocator protein quantification as a tool for characterising macrophage burden in human carotid atherosclerosis. Atherosclerosis 210, 388–391 (2010).
Gaemperli, O. et al. Imaging intraplaque inflammation in carotid atherosclerosis with 11C-PK11195 positron emission tomography/computed tomography. Eur. Heart J. 33, 1902–1910 (2012).
Laitinen, I. et al. Uptake of inflammatory cell marker 11C-PK11195 into mouse atherosclerotic plaques. Eur. J. Nucl. Med. Mol. Imaging 36, 73–80 (2009).
Tarkin, J. M. et al. Detection of atherosclerotic inflammation by 68Ga-DOTATATE PET compared to 18F-FDG PET imaging. J. Am. Coll. Cardiol. 69, 1774–1791 (2017).
Chen, W. & Dilsizian, V. Targeted PET/CT imaging of vulnerable atherosclerotic plaques: microcalcification with sodium fluoride and inflammation with fluorodeoxyglucose. Curr. Cardiol. Rep. 15, 364 (2013).
Bluestein, D. et al. Influence of microcalcifications on vulnerable plaque mechanics using FSI modeling. J. Biomech. 41, 1111–1118 (2008).
Kelly-Arnold, A. et al. Revised microcalcification hypothesis for fibrous cap rupture in human coronary arteries. Proc. Natl Acad. Sci. USA 110, 10741–10746 (2013).
Derlin, T. et al. Feasibility of 18F-sodium fluoride PET/CT for imaging of atherosclerotic plaque. J. Nucl. Med. 51, 862–865 (2010).
Hawkins, R. A. et al. Evaluation of the skeletal kinetics of fluorine-18-fluoride ion with PET. J. Nucl. Med. 33, 633–642 (1992).
Janssen, T. et al. Association of linear 18F-sodium fluoride accumulation in femoral arteries as a measure of diffuse calcification with cardiovascular risk factors: a PET/CT study. J. Nucl. Cardiol. 20, 569–577 (2013).
Joshi, N. V. et al. 18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial. Lancet 383, 705–713 (2014).
Dweck, M. R. et al. Coronary arterial 18F-sodium fluoride uptake: a novel marker of plaque biology. J. Am. Coll. Cardiol. 59, 1539–1548 (2012).
Cocker, M. S. et al. 18F-NaF PET/CT identifies active calcification in carotid plaque. JACC Cardiovasc. Imaging 10, 486–488 (2017).
Vesey, A. T. et al. 18F-fluoride and 18F-fluorodeoxyglucose positron emission tomography after transient ischemic attack or minor ischemic stroke: case-control study. Circ. Cardiovasc. Imaging 10, e004976 (2017).
Quirce, R. et al. Contribution of 18F-sodium fluoride PET/CT to the study of the carotid atheroma calcification. Rev. Esp. Med. Nucl. Imagen Mol. 32, 22–25 (2013).
Derlin, T. et al. Correlation of inflammation assessed by 18F-FDG PET, active mineral deposition assessed by 18F-fluoride PET, and vascular calcification in atherosclerotic plaque: a dual-tracer PET/CT study. J. Nucl. Med. 52, 1020–1027 (2011).
Li, X. et al. Association between osteogenesis and inflammation during the progression of calcified plaque as evaluated by combined 18F-NaF and 18F-FDG PET/CT. J. Nucl. Med. 58, 968–974 (2017).
Takasawa, M., Moustafa, R. R. & Baron, J. C. Applications of nitroimidazole in vivo hypoxia imaging in ischemic stroke. Stroke 39, 1629–1637 (2008).
Leppanen, O. et al. ATP depletion in macrophages in the core of advanced rabbit atherosclerotic plaques in vivo. Atherosclerosis 188, 323–330 (2006).
Joshi, F. R. et al. Vascular imaging with 18F-fluorodeoxyglucose positron emission tomography is influenced by hypoxia. J. Am. Coll. Cardiol. 69, 1873–1874 (2017).
van der Valk, F. M. et al. Thresholds for arterial wall inflammation quantified by 18F-FDG PET imaging: implications for vascular interventional studies. JACC Cardiovasc. Imaging 9, 1198–1207 (2016).
Rudd, J. H. et al. 18F-fluorodeoxyglucose positron emission tomography imaging of atherosclerotic plaque inflammation is highly reproducible: implications for atherosclerosis therapy trials. J. Am. Coll. Cardiol. 50, 892–896 (2007).
Schwartz, G. G. et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med. 367, 2089–2099 (2012).
Astrup, J., Siesjo, B. K. & Symon, L. Thresholds in cerebral ischemia — the ischemic penumbra. Stroke 12, 723–725 (1981).
Heiss, W. D. The ischemic penumbra: how does tissue injury evolve? Ann. NY Acad. Sci. 1268, 26–34 (2012).
Wang, X. & Feuerstein, G. Z. The Janus face of inflammation in ischemic brain injury. Acta Neurochir. Suppl. 89, 49–54 (2004).
Amantea, D., Nappi, G., Bernardi, G., Bagetta, G. & Corasaniti, M. T. Post-ischemic brain damage: pathophysiology and role of inflammatory mediators. FEBS J. 276, 13–26 (2009).
Kriz, J. Inflammation in ischemic brain injury: timing is important. Crit. Rev. Neurobiol. 18, 145–157 (2006).
Xia, C. Y., Zhang, S., Gao, Y., Wang, Z. Z. & Chen, N. H. Selective modulation of microglia polarization to M2 phenotype for stroke treatment. Int. Immunopharmacol. 25, 377–382 (2015).
Marchal, G. et al. PET imaging of cerebral perfusion and oxygen consumption in acute ischaemic stroke: relation to outcome. Lancet 341, 925–927 (1993).
Marchal, G. et al. Value of acute-stage positron emission tomography in predicting neurological outcome after ischemic stroke: further assessment. Stroke 26, 524–525 (1995).
Marchal, G. et al. Prolonged persistence of substantial volumes of potentially viable brain tissue after stroke: a correlative PET-CT study with voxel-based data analysis. Stroke 27, 599–606 (1996).
Agarwal, S., Warburton, E. A. & Baron, J. C. From time is brain to physiology is brain: a case for reflection in acute stroke treatment decisions. Brain 138, 1768–1770 (2015).
Bivard, A. et al. Perfusion computed tomography to assist decision making for stroke thrombolysis. Brain 138, 1919–1931 (2015).
Guadagno, J. V. et al. Does the acute diffusion-weighted imaging lesion represent penumbra as well as core? A combined quantitative PET/MRI voxel-based study. J. Cereb. Blood Flow Metab. 24, 1249–1254 (2004).
Guadagno, J. V. et al. The diffusion-weighted lesion in acute stroke: heterogeneous patterns of flow/metabolism uncoupling as assessed by quantitative positron emission tomography. Cerebrovasc. Dis. 19, 239–246 (2005).
Guadagno, J. V. et al. How affected is oxygen metabolism in DWI lesions? A combined acute stroke PET-MR study. Neurology 67, 824–829 (2006).
Marchal, G. et al. Voxel-based mapping of irreversible ischaemic damage with PET in acute stroke. Brain 122, 2387–2400 (1999).
Read, S. J. et al. Identifying hypoxic tissue after acute ischemic stroke using PET and 18F-fluoromisonidazole. Neurology 51, 1617–1621 (1998).
Alawneh, J. A. et al. Diffusion and perfusion correlates of the 18F-MISO PET lesion in acute stroke: pilot study. Eur. J. Nucl. Med. Mol. Imaging 41, 736–744 (2014).
Markus, R. et al. Topography and temporal evolution of hypoxic viable tissue identified by 18F-fluoromisonidazole positron emission tomography in humans after ischemic stroke. Stroke 34, 2646–2652 (2003).
Markus, R., Donnan, G., Kazui, S., Read, S. & Reutens, D. Penumbral topography in human stroke: methodology and validation of the 'Penumbragram'. Neuroimage 21, 1252–1259 (2004).
Spratt, N. J., Donnan, G. A. & Howells, D. W. Characterisation of the timing of binding of the hypoxia tracer FMISO after stroke. Brain Res. 1288, 135–142 (2009).
Lee, G. H. et al. 18F-fluoromisonidazole (FMISO) positron emission tomography (PET) predicts early infarct growth in patients with acute ischemic stroke. J. Neuroimaging 25, 652–655 (2015).
Markus, R. et al. Hypoxic tissue in ischaemic stroke: persistence and clinical consequences of spontaneous survival. Brain 127, 1427–1436 (2004).
Baron, J. C., Yamauchi, H., Fujioka, M. & Endres, M. Selective neuronal loss in ischemic stroke and cerebrovascular disease. J. Cereb. Blood Flow Metab. 34, 2–18 (2014).
Cramer, S. C. Repairing the human brain after stroke: I. Mechanisms of spontaneous recovery. Ann. Neurol. 63, 272–287 (2008).
Heiss, W. D. et al. Permanent cortical damage detected by flumazenil positron emission tomography in acute stroke. Stroke 29, 454–461 (1998).
Heiss, W. D. et al. Early 11C-flumazenil/H2O positron emission tomography predicts irreversible ischemic cortical damage in stroke patients receiving acute thrombolytic therapy. Stroke 31, 366–369 (2000).
Guadagno, J. V. et al. Selective neuronal loss in rescued penumbra relates to initial hypoperfusion. Brain 131, 2666–2678 (2008).
Carrera, E. et al. Is neural activation within the rescued penumbra impeded by selective neuronal loss? Brain 136, 1816–1829 (2013).
Kuroda, S. et al. Reduced blood flow and preserved vasoreactivity characterize oxygen hypometabolism due to incomplete infarction in occlusive carotid artery diseases. J. Nucl. Med. 45, 943–949 (2004).
Dohmen, C., Galldiks, N., Bosche, B., Kracht, L. & Graf, R. The severity of ischemia determines and predicts malignant brain edema in patients with large middle cerebral artery infarction. Cerebrovasc. Dis. 33, 1–7 (2012).
Stephenson, D. T. et al. Peripheral benzodiazepine receptors are colocalized with activated microglia following transient global forebrain ischemia in the rat. J. Neurosci. 15, 5263–5274 (1995).
Price, C. J. et al. Intrinsic activated microglia map to the peri-infarct zone in the subacute phase of ischemic stroke. Stroke 37, 1749–1753 (2006).
Gerhard, A., Schwarz, J., Myers, R., Wise, R. & Banati, R. B. Evolution of microglial activation in patients after ischemic stroke: a 11C-(R)-PK11195 PET study. Neuroimage 24, 591–595 (2005).
Thiel, A. & Heiss, W. D. Imaging of microglia activation in stroke. Stroke 42, 507–512 (2011).
Schroeter, M. et al. Neuroinflammation extends brain tissue at risk to vital peri-infarct tissue: a double tracer 11C-PK11195 and 18F-FDG-PET study. J. Cereb. Blood Flow Metab. 29, 1216–1225 (2009).
Pappata, S. et al. Thalamic microglial activation in ischemic stroke detected in vivo by PET and 11C-PK1195. Neurology 55, 1052–1054 (2000).
Katchanov, J. et al. Selective neuronal vulnerability following mild focal brain ischemia in the mouse. Brain Pathol. 13, 452–464 (2003).
Weishaupt, N., Zhang, A., Deziel, R. A., Tasker, R. A. & Whitehead, S. N. Prefrontal ischemia in the rat leads to secondary damage and inflammation in remote gray and white matter regions. Front. Neurosci. 10, 81 (2016).
Radlinska, B. A. et al. Multimodal microglia imaging of fiber tracts in acute subcortical stroke. Ann. Neurol. 66, 825–832 (2009).
Thiel, A. et al. The temporal dynamics of poststroke neuroinflammation: a longitudinal diffusion tensor imaging-guided PET study with 11C-PK11195 in acute subcortical stroke. J. Nucl. Med. 51, 1404–1412 (2010).
Chen, M. K. & Guilarte, T. R. Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair. Pharmacol. Ther. 118, 1–17 (2008).
Imaizumi, M. et al. PET imaging with 11C-PBR28 can localize and quantify upregulated peripheral benzodiazepine receptors associated with cerebral ischemia in rat. Neurosci. Lett. 411, 200–205 (2007).
Fujita, M. et al. Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation. Neuroimage 40, 43–52 (2008).
Owen, D. R. et al. Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J. Nucl. Med. 52, 24–32 (2011).
Kreisl, W. C. et al. A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation. J. Cereb. Blood Flow Metab. 33, 53–58 (2013).
Gulyas, B. et al. Visualising neuroinflammation in post-stroke patients: a comparative PET study with the TSPO molecular imaging biomarkers 11C-PK11195 and 11C-vinpocetine. Curr. Radiopharm. 5, 19–28 (2012).
Gulyas, B. et al. Evolution of microglial activation in ischaemic core and peri-infarct regions after stroke: a PET study with the TSPO molecular imaging biomarker 11C-vinpocetine. J. Neurol. Sci. 320, 110–117 (2012).
Ribeiro, M. J. et al. Could 18F-DPA-714 PET imaging be interesting to use in the early post-stroke period? EJNMMI Res. 4, 28 (2014).
Boutin, H. et al. 18F-DPA-714: direct comparison with 11C-PK11195 in a model of cerebral ischemia in rats. PLoS ONE 8, e56441 (2013).
Chauveau, F. et al. Comparative evaluation of the translocator protein radioligands 11C-DPA-713, 18F-DPA-714, and 11C-PK11195 in a rat model of acute neuroinflammation. J. Nucl. Med. 50, 468–476 (2009).
Chauveau, F., Boutin, H., Van Camp, N., Dolle, F. & Tavitian, B. Nuclear imaging of neuroinflammation: a comprehensive review of 11C-PK11195 challengers. Eur. J. Nucl. Med. Mol. Imaging 35, 2304–2319 (2008).
Roman, G. C., Erkinjuntti, T., Wallin, A., Pantoni, L. & Chui, H. C. Subcortical ischaemic vascular dementia. Lancet Neurol. 1, 426–436 (2002).
Sabri, O. et al. Neuropsychological impairment correlates with hypoperfusion and hypometabolism but not with severity of white matter lesions on MRI in patients with cerebral microangiopathy. Stroke 30, 556–566 (1999).
Benson, D. F. et al. The fluorodeoxyglucose 18F scan in Alzheimer's disease and multi-infarct dementia. Arch. Neurol. 40, 711–714 (1983).
Kitagawa, K. et al. Relationship between cerebral blood flow and later cognitive decline in hypertensive patients with cerebral small vessel disease. Hypertens. Res. 32, 816–820 (2009).
Tatsch, K. et al. Cortical hypometabolism and crossed cerebellar diaschisis suggest subcortically induced disconnection in CADASIL: an 18F-FDG PET study. J. Nucl. Med. 44, 862–869 (2003).
Tuominen, S. et al. Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R133C Notch3 mutation. Stroke 32, 1767–1774 (2001).
Akiguchi, I., Tomimoto, H., Suenaga, T., Wakita, H. & Budka, H. Alterations in glia and axons in the brains of Binswanger's disease patients. Stroke 28, 1423–1429 (1997).
Kobayashi, K. et al. Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis. 4, e525 (2013).
Liu, Z. et al. Chronic treatment with minocycline preserves adult new neurons and reduces functional impairment after focal cerebral ischemia. Stroke 38, 146–152 (2007).
Yang, Y. et al. Attenuation of acute stroke injury in rat brain by minocycline promotes blood–brain barrier remodeling and alternative microglia/macrophage activation during recovery. J. Neuroinflamm. 12, 26 (2015).
Jalal, F. Y., Yang, Y., Thompson, J. F., Roitbak, T. & Rosenberg, G. A. Hypoxia-induced neuroinflammatory white-matter injury reduced by minocycline in SHR/SP. J. Cereb. Blood Flow Metab. 35, 1145–1153 (2015).
Yang, F., Zhou, L., Wang, D., Wang, Z. & Huang, Q. Y. Minocycline ameliorates hypoxia-induced blood–brain barrier damage by inhibition of HIF-1α through SIRT-3/PHD-2 degradation pathway. Neuroscience 304, 250–259 (2015).
Attems, J. & Jellinger, K. A. The overlap between vascular disease and Alzheimer's disease — lessons from pathology. BMC Med. 12, 206 (2014).
Kalaria, R. N. et al. Accumulation of the β amyloid precursor protein at sites of ischemic injury in rat brain. Neuroreport 4, 211–214 (1993).
Jendroska, K. et al. Ischemic stress induces deposition of amyloid β immunoreactivity in human brain. Acta Neuropathol. 90, 461–466 (1995).
Zhang, F., Eckman, C., Younkin, S., Hsiao, K. K. & Iadecola, C. Increased susceptibility to ischemic brain damage in transgenic mice overexpressing the amyloid precursor protein. J. Neurosci. 17, 7655–7661 (1997).
Mathis, C. A. et al. Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. J. Med. Chem. 46, 2740–2754 (2003).
Yang, J. et al. Risk factors for incident dementia after stroke and transient ischemic attack. Alzheimers Dement. 11, 16–23 (2015).
Ly, J. V. et al. Subacute ischemic stroke is associated with focal 11C PiB positron emission tomography retention but not with global neocortical Aβ deposition. Stroke 43, 1341–1346 (2012).
Kalheim, L. F. et al. Amyloid dysmetabolism relates to reduced glucose uptake in white matter hyperintensities. Front. Neurol. 7, 209 (2016).
Ye, B. S. et al. Effects of amyloid and vascular markers on cognitive decline in subcortical vascular dementia. Neurology 85, 1687–1693 (2015).
Grimmer, T. et al. White matter hyperintensities predict amyloid increase in Alzheimer's disease. Neurobiol. Aging 33, 2766–2773 (2012).
Jang, Y. K. et al. Early- versus late-onset subcortical vascular cognitive impairment. Neurology 86, 527–534 (2016).
Kim, H. J. et al. Clinical effect of white matter network disruption related to amyloid and small vessel disease. Neurology 85, 63–70 (2015).
Kim, Y. J. et al. Gray and white matter changes linking cerebral small vessel disease to gait disturbances. Neurology 86, 1199–1207 (2016).
Yoon, C. W. et al. Cognitive deficits of pure subcortical vascular dementia versus Alzheimer disease: PiB-PET-based study. Neurology 80, 569–573 (2013).
Ly, J. V. et al. 11C-PIB binding is increased in patients with cerebral amyloid angiopathy-related hemorrhage. Neurology 74, 487–493 (2010).
Gurol, M. E. et al. Cerebral amyloid angiopathy burden associated with leukoaraiosis: a positron emission tomography/magnetic resonance imaging study. Ann. Neurol. 73, 529–536 (2013).
Rousset, O. G., Ma, Y. & Evans, A. C. Correction for partial volume effects in PET: principle and validation. J. Nucl. Med. 39, 904–911 (1998).
Izquierdo-Garcia, D. et al. Comparison of methods for magnetic resonance-guided 18F-fluorodeoxyglucose positron emission tomography in human carotid arteries: reproducibility, partial volume correction, and correlation between methods. Stroke 40, 86–93 (2009).
Keiner, S., Wurm, F., Kunze, A., Witte, O. W. & Redecker, C. Rehabilitative therapies differentially alter proliferation and survival of glial cell populations in the perilesional zone of cortical infarcts. Glia 56, 516–527 (2008).
Nelson, J. W. et al. Role of soluble epoxide hydrolase in age-related vascular cognitive decline. Prostaglandins Other Lipid Mediat. 113–115, 30–37 (2014).
Horti, A. G. et al. 18F-FNDP for PET imaging of soluble epoxide hydrolase. J. Nucl. Med. 57, 1817–1822 (2016).
Rotering, S. et al. Imaging of α7 nicotinic acetylcholine receptors in brain and cerebral vasculature of juvenile pigs with 18F-NS14490. EJNMMI Res. 4, 43 (2014).
Medoc, M. et al. In vivo evaluation of radiofluorinated caspase-3/7 inhibitors as radiotracers for apoptosis imaging and comparison with 18F-ML-10 in a stroke model in the rat. Mol. Imaging Biol. 18, 117–126 (2016).
Acknowledgements
N.R.E. is supported by a research training fellowship from The Dunhill Medical Trust (grant number RTF44/0114). J.M.T. is supported by a Wellcome Trust research training fellowship (104492/Z/14/Z). J.H.F.R. is part-supported by the Higher Education Funding Council for England (HEFCE), the British Heart Foundation, and the Wellcome Trust. H.S.M. is supported by the Medical Research Council (MRC) as a National Institute for Health Research (NIHR) Senior Investigator. E.A.W. is supported by the British Heart Foundation. H.S.M., J.H.F.R., and E.A.W. are supported by the NIHR Cambridge Biomedical Research Centre.
Author information
Authors and Affiliations
Contributions
N.R.E. wrote the manuscript. N.R.E., J.M.T. and J.H.F.R. researched data for the article. All authors (N.R.E., J.M.T., J.R.B., H.S.M., J.H.F.R. & E.A.W.) contributed substantially to discussions of the article content and undertook review and/or editing of the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Evans, N., Tarkin, J., Buscombe, J. et al. PET imaging of the neurovascular interface in cerebrovascular disease. Nat Rev Neurol 13, 676–688 (2017). https://doi.org/10.1038/nrneurol.2017.129
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrneurol.2017.129
- Springer Nature Limited
This article is cited by
-
Crossed cerebellar diaschisis-related supratentorial hemodynamic and metabolic status measured by PET/MR in assessing postoperative prognosis in chronic ischemic cerebrovascular disease patients with bypass surgery
Annals of Nuclear Medicine (2022)
-
In vivo Imaging of Cannabinoid Type 2 Receptors: Functional and Structural Alterations in Mouse Model of Cerebral Ischemia by PET and MRI
Molecular Imaging and Biology (2022)
-
Microglia and Stem-Cell Mediated Neuroprotection after Neonatal Hypoxia-Ischemia
Stem Cell Reviews and Reports (2022)
-
Neuroimaging Biomarkers for Alzheimer’s Disease
Molecular Neurodegeneration (2019)
-
Time window and “tissue window”: two approaches to assist decision-making in strokes
Journal of Neurology (2019)