Evaluation of Parkinson Disease and Alzheimer Disease with the Use of NeuromelaninMR Imaging and I-Metaiodobenzylguanidine Scintigraphy

BACKGROUND AND PURPOSE: Progressive changes in the substantia nigra pars compacta and locus ceruleus of patients with Parkinson disease and Alzheimer disease visualized by neuromelanin MRI and cardiac postganglionic sympathetic nerve function on I-metaiodobenzylguanidine scintigraphy have not been fully evaluated. We compared the diagnostic value of these modalities among patients with early Parkinson disease, late Parkinson disease, and Alzheimer disease. MATERIALS AND METHODS: We compared contrast ratios of signal intensity in medial and lateral regions of the substantia nigra pars compacta and locus ceruleus with those of the tegmentum of the midbrain and the pons, respectively, by use of neuromelanin MRI in patients with early Parkinson disease (n 13), late Parkinson disease (n 31), Alzheimer disease (n 6), and age-matched healthy control subjects (n 20).We calculated heart-to-mediastinum ratios on I-metaiodobenzylguanidine scintigrams after setting regions of interest on the left cardiac ventricle and upper mediastinum. RESULTS: The signal intensity of the lateral substantia nigra pars compacta on neuromelaninMRIwas significantly reduced in early and late Parkinson disease, and that of the medial substantia nigra pars compacta was gradually and stage-dependently reduced in Parkinson disease. The signal intensity of the locus ceruleus was obviously reduced in late Parkinson disease. Signal reduction was not significant in the substantia nigra pars compacta and locus ceruleus of patients with Alzheimer disease. The heart-to-mediastinum ratio on Imetaiodobenzylguanidine scintigrams was stage-dependently reduced in Parkinson disease and normal in Alzheimer disease. The signal intensity ratios in substantia nigra pars compacta and locus ceruleus on neuromelanin MRI positively correlated with the heart-tomediastinum ratio on I-metaiodobenzylguanidine scintigrams. CONCLUSIONS: Both neuromelanin MRI and I-metaiodobenzylguanidine scintigraphy can help to evaluate disease progression in Parkinson disease and are useful for differentiating Parkinson disease from Alzheimer disease. ABREVIATIONS: LC locus ceruleus; MIGB I-metaiodobenzylguanidine; NmMRI neuromelaninMR imaging; PD Parkinson disease; SNc substantia nigra pars compacta Early Parkinson disease (PD) can easily be mistaken for any number of disorders, including other forms of parkinsonism, such as multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies. Other degenerative diseases, such as Alzheimer disease and primary lateral sclerosis, can also be mistaken for PD. Improving diagnostic accuracy is critical for the early differentiation of PD and other neurodegenerative types of parkinsonism because their prognoses are very different and the choice of treatment strategy is extremely important. Neuromelanin is a dark pigment that locates within certain catecholamine neurons of the human brain, such as the dopaminergic neurons of the substantia nigra pars compacta (SNc) and the noradrenergic neurons of the locus ceruleus (LC). It is thought to be formed as a by-product of the catecholamine metabolism cascade through enzymatic and/or oxidative polymerization. PD is characterized by the progressive loss of dopaminergic neurons that contain neuromelanin in the SNc and of noradrenergic neurons in the LC. Several pathologic studies have shown the selective loss of ventral intermediate and lateral cell groups of the SNc in PD. Noradrenergic neurons are also lost in the LC of patients with Alzheimer disease. It is reported that neuromelanin MRI (NmMRI) could visualize decreased signal intensity in regions that reflect the loss of Received December 2, 2012; accepted after revision January 25, 2013. From the Division of Radiology (F.M., T.O., S.-i.K., Y.S., M.T., S.F., T.K.), Department of Pathophysiological Therapeutic Science; and Division of Neurology (M.K.), Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan. Please address correspondence to Toshihide Ogawa, MD, Division of Radiology, Department of Pathophysiological Therapeutic Science, Faculty of Medicine, Tottori University, 36–1, Nishi-cho, Yonago 683–504, Japan; e-mail: ogawa@ med.tottori-u.ac.jp http://dx.doi.org/10.3174/ajnr.A3567 AJNR Am J Neuroradiol 34:2113–18 Nov 2013 www.ajnr.org 2113 neurons containing neuromelanin and the signal intensity in the SNc and LC was greatly reduced on NmMRI from patients with PD. Several investigators subsequently reported that NmMRI could show a reduction in the contrast ratio and volume of the SNc. The physiologic analog of noradrenaline, I-metaiodobenzylguanidine (MIBG), traces uptake and transport both in noradrenaline presynaptic sympathetic nerve terminals and in subsequent vesicular storage. Postganglionic presynaptic cardiac sympathetic nerve endings can be noninvasively assessed by MIBG scintigraphy because a reduction of MIBG uptake indicates postganglionic sympathetic dysfunction. Cardiac MIBG uptake is reduced in patients with Lewy body diseases such as PD, as well as dementia with Lewy bodies, and MIBG scintigraphy can also help to differentiate PD from other types of parkinsonism. However, progressive changes in PD and Alzheimer disease have not been fully evaluated by NmMRI and MIBG scintigraphy. We determined the usefulness of these modalities for differentially diagnosing PD and Alzheimer disease by analyzing changes in signal intensity in the SNc and LC and MIBG uptake in the left cardiac ventricle and evaluated correlations between NmMRI and MIBG scintigraphy findings. MATERIALS AND METHODS Patients We investigated patients who had been tentatively diagnosed with suspected PD and who were finally confirmed as having PD or Alzheimer disease between December 2008 and April 2012. Both MRI and MIBG scintigraphy acquired within 1 month were retrospectively evaluated. Probable PD and Alzheimer disease were diagnosed according to the criteria of the United Kingdom Brain Bank and National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association, respectively. Patients with PD were assigned to groups with either early or late PD on the basis of Hoehn and Yahr staging. Early PD comprised stages I and II, and late PD comprised stages III, IV, and V. Patients with symptomatic cerebrovascular diseases and other central nervous system disorders were strictly excluded from the NmMRI evaluation, and those with cardiac diseases, diabetes mellitus, and/or medications that can interfere with MIBG uptake were excluded from the MIBG scintigraphy assessment. We finally enrolled 13 (male, n 5; female, n 8), 31 (male, n 14; female, n 17), and 6 (male and female, n 3 each) patients with early PD, late PD, and Alzheimer disease, respectively (Table 1) [ages (mean SD with range) 68.3 5.88 (59–85), 71.8 8.95 (59–83), and 75.7 9.52 (58–84) years, respectively]. The mean ( SD with range) duration of early PD, late PD, and Alzheimer disease was 4.30 5.37 (0–9), 9.48 6.86 (2–27), and 2.5 3.00 (1–3) years, respectively. We used the Hasegawa Dementia Scale-Revised to determine cognitive impairment or dementia, which is similar to the Mini-Mental State Examination and has a total score of 30. Hasegawa Dementia Scale-Revised scores in patients with Alzheimer disease ranged from 6–17 (mean SD, 12.8 4.76). Twenty age-matched patients (male, n 5; female, n 15) [ages (mean SD with range) 74.8 5.41 (64 – 87) years] without a history of motor or cognitive impairment and significant abnormalities on brain MRI during the same period served as a control group of NmMRI. However, we did not obtain MIBG scintigraphic data from the control group during this period. Our institutional review board approved the study, and written informed consent was waived. Image Acquisition All MR images were acquired by means of a clinical 3T MR scanner (Signa Excite HD, GE Healthcare, Milwaukee, Wisconsin). Axial images were acquired parallel to the anterior/posterior commissure line. T1-weighted fast spin-echo sequences were applied to NmMRI with the following parameters: TR/TE, 600/13 ms; echo-train length, 2; section thickness, 2.5 mm with 1mm intersection gaps; matrix size, 512 512; FOV, 220 mm; acquisition time, 12 minutes. The scan covered the area from the upper border of the midbrain to the inferior border of the pons. We excluded other coexisting central nervous system disorders by use of axial T1and T2-weighted images, fluid-attenuated inversion recovery images, and diffusion-weighted images of the entire brain according to the following standard protocol for adult brain imaging at our hospital: T1-weighted spin-echo sequence, TR/TE, 600/15 ms; section thickness, 5 mm; FOV 220 mm; matrix 512 512; T2-weighted fast spin-echo sequence, TR/TE, 4000/90 ms; section thickness, 5 mm; FOV 220 mm; matrix 512 512; fluid attenuated inversion recovery sequence, TR/TE/IR, 4000/90/20; section thickness, 5 mm; FOV 220 mm; matrix 512 512; and diffusion-weighted imaging sequence, TR/TE, 4000/90 ms; section thickness, 5 mm; FOV 220 mm; matrix 512 512; maximum b factor, 1000 mm/s. The patients received an intravenous injection of 111 MBq of I-MIBG, and static planar images of the chest were acquired 30 minutes later for 4 minutes in a 256 256 matrix by use of a dualhead gamma camera with a large field of view and a low-energy, highresolution collimator (e.cam; Siemens, Erlangen, Germany). Image Analysis Signal intensity was measured for quantitative NmMRI by setting regions of interest. We equally divided the SNc into medial and lateral regions at the level of the inferior colliculus and defined Table 1: Clinical characteristics of patient and control groups Early Parkinson Disease Late Parkinson Disease Alzheimer Disease Control Patients, n 13 31 6 20 Hoehn and Yahr stage I:3, II:10 III:16, IV:12, V:3 / / Male/female 5/8 14/17 3/3 5/15 Age, y, mean SD 68.3 5.88 71.8 8.95 75.7 9.52 74.8 5.41 Duration, y, mean SD 4.30 5.37 9.48 6.86 2.5 3 / Hasegawa Dementia Scale-Revised, mean SD / / 12.8 4.76 / Note:—Age does not differ between patient and control groups (P .082; 1-way analysis of variance). 2114 Miyoshi Nov 2013 www.ajnr.org ROIs in these areas that included high signal intensity on NmMRI. We also defined ROIs symmetrically in the ventral tegmentum located in the anterolateral areas of aqueduct as controls. Concerning the LC, we defined the ROIs in the anterolateral areas around the fourth ventricle at the level of upper pons and also defined ROIs symmetrically in the tegmentum located just behind the medial lemniscus as controls. The sizes of the region of interest were 8, 2, and 10 mm on the SNc, LC, and tegmentum of the midbrain and pons, respectively. We calculated the contrast ratios of the 3 bilateral portions by dividing their signal intensity by that of control areas such as the tegmentum of