SONOGRAPHY IN PRECLINICAL PARKINSONISM 29. Hierholzer J, Cordes M, Venz S, et al. Loss of dopamine-D2 receptor binding sites in Parkinsonian plus syndromes. J Nucl Med 1998;39:954 –960. 30. Schelosky L, Hierholzer J, Wissel J, Cordes M, Poewe W. Correlation of clinical response in apomorphine test with D2-receptor status as demonstrated by 123I IBZM-SPECT. Mov Disord 1993; 8:453– 458. 31. Schulz JB, Klockgether T, Petersen D, et al. Multiple system atrophy: natural history, MRI morphology, and dopamine receptor imaging with 123IBZM-SPECT. J Neurol Neurosurg Psychiatry 1994;57:1047–1056. 32. Fearnley JM, Lees AJ. Striatonigral degeneration. A clinicopathological study. Brain 1990;113(Pt 6):1823–1842. 33. Daniel SE. The neuropathology and neurochemistry of multiple system atrophy. In: Mathias CJ, Bannister R, editors. Autonomic failure. A textbook of clinical disorders of autonomic nervous system. Oxford: Oxford University Press; 1999. p 321–328. 34. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases [see comments]. J Neurol Neurosurg Psychiatry 1992;55:181–184. 35. Gilman S, Low P, Quinn N, et al. Consensus statement on the diagnosis of multiple system atrophy. American Autonomic Society and American Academy of Neurology. Clin Auton Res 1998; 8:359 –362. 36. Mascalchi M, Tessa C, Moretti M, et al. Whole brain apparent diffusion coefficient histogram: a new tool for evaluation of leukoaraiosis. J Magn Reson Imaging 2002;15:144 –148. 37. Chun T, Filippi CG, Zimmerman RD, Ulug AM. Diffusion changes in the aging human brain. AJNR Am J Neuroradiol 2000;21:1078 –1083. 38. Verhoeff NP, Sokole EB, Stabin M, et al. Dosimetry of iodine-123 iodobenzamide in healthy volunteers. Eur J Nucl Med 1993;20: 747–752. 39. Verhoeff NP, Brucke T, Podreka I, Bobeldijk M, Angelberger P, van Royen EA. Dynamic SPECT in two healthy volunteers to determine the optimal time for in vivo D2 dopamine receptor imaging with 123I-IBZM using the rotating gamma camera. Nucl Med Commun 1991;12:687– 697. 40. Schwarz J, Oertel WH, Tatsch K. Iodine-123-iodobenzamide binding in parkinsonism: reduction by dopamine agonists but not L-Dopa. J Nucl Med 1996;37:1112–1115. 41. SPSS version 11.0 for Windows. Chicago: SPSS Inc. 2001. 42. Sawle GV, Playford ED, Brooks DJ, Quinn N, Frackowiak RS. Asymmetrical pre-synaptic and post-synaptic changes in the striatal dopamine projection in dopa naive parkinsonism. Diagnostic implications of the D2 receptor status. Brain 1993;116(Pt 4):853– 867. 43. Brucke T, Wenger S, Asenbaum S, et al. Dopamine D2 receptor imaging and measurement with SPECT. Adv Neurol 1993;60: 494 –500. 44. van Royen E, Verhoeff NF, Speelman JD, Wolters EC, Kuiper MA, Janssen AG. Multiple system atrophy and progressive supranuclear palsy. Diminished striatal D2 dopamine receptor activity demonstrated by 123I-IBZM single photon emission computed tomography. Arch Neurol 1993;50:513–516. 45. Antonini A, Schwarz J, Oertel WH, Beer HF, Madeja UD, Leenders KL. [11C]raclopride and positron emission tomography in previously untreated patients with Parkinson’s disease: influence of L-dopa and lisuride therapy on striatal dopamine D2-receptors. Neurology 1994;44:1325–1329. 46. Antonini A, Schwarz J, Oertel WH, Pogarell O, Leenders KL. Long-term changes of striatal dopamine D2 receptors in patients with Parkinson’s disease: a study with positron emission tomography and [11C]raclopride. Mov Disord 1997;12:33–38. 47. Brucke T, Podreka I, Angelberger P, et al. Dopamine D2 receptor imaging with SPECT: studies in different neuropsychiatric disorders. J Cereb Blood Flow Metab 1991;11:220 –228.
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48. Hajnal JV, Doran M, Hall AS, et al. MR imaging of anisotropically restricted diffusion of water in the nervous system: technical, anatomic, and pathologic considerations. J Comput Assist Tomogr 1991;15:1–18. 49. Kume A, Takahashi A, Hashizume Y. Neuronal cell loss of the striatonigral system in multiple system atrophy. J Neurol Sci 1993;117:33– 40. 50. Ichise M, Ballinger JR. SPECT imaging of dopamine receptors. J Nucl Med 1996;37:1591–1595. 51. Pirker W, Asenbaum S, Wenger S, et al. Iodine-123-epideprideSPECT: studies in Parkinson’s disease, multiple system atrophy and Huntington’s disease. J Nucl Med 1997;38:1711–1717. 52. Prunier C, Tranquart F, Cottier JP, et al. Quantitative analysis of striatal dopamine D2 receptors with 123 I-iodolisuride SPECT in degenerative extrapyramidal diseases. Nucl Med Commun 2001; 22:1207–1214. 53. Pierpaoli C, Jezzard P, Basser PJ, Barnett A, Di Chiro G. Diffusion tensor MR imaging of the human brain. Radiology 1996;201:637– 648.
Brain Parenchyma Sonography Detects Preclinical Parkinsonism Uwe Walter, MD,1* Christine Klein, MD,2 Ruediger Hilker, MD,3 Reiner Benecke, MD,1 Peter P. Pramstaller, MD,4 and Dirk Dressler, MD1 1 Department of Neurology, University of Rostock, Rostock, Germany; 2Department of Neurology, University of Luebeck, Luebeck, Germany; 3Department of Neurology, University of Cologne, Koeln, Germany; 4Department of Neurology, Regional General Hospital, Bolzano, Italy
Abstract: Substantia nigra (SN) hyperechogenicity on brain parenchyma sonography (BPS) is highly characteristic for idiopathic PD. We studied 7 symptomatic and 7 asymptomatic parkin mutation carriers (PMC) from a large kindred with adult-onset parkinsonism. BPS revealed larger SN echogenic sizes in PMC with parkin mutations on both alleles (homozygous, compound-heterozygous), compared to PMC with only one mutated allele (Mann–Whitney U test, P ⴝ 0.007). In symptomatic PMC, larger SN echogenic size was correlated with younger age at onset of the disease (Spearman rank correlation, Rho ⴝ ⴚ0.937, P ⴝ 0.002) but not with age, disease duration, or disease severity. BPS demonstrated SN hyperechogenicity, in concordance with abnormal nigrostriatal 18F-dopa positron emission tomography (PET), in all symptomatic and 3 asymptomatic PMC. In 2 asymptomatic PMC, PET and BPS were normal. How-
*Correspondence to: Dr. Uwe Walter, Department of Neurology, University of Rostock, Gehlsheimer Str. 20, D-18147 Rostock, Germany. E-mail:
[email protected] Received 28 November 2003; Revised 23 January 2004; Accepted 16 February 2004 Published online 16 June 2004 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.20232
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ever, in another 2 asymptomatic PET-normal PMC, SN hyperechogenicity could be detected. Data suggest SN hyperechogenicity as an early marker to detect preclinical parkinsonism. © 2004 Movement Disorder Society Key words: brain parenchyma sonography; Parkinson’s disease; parkin; PARK2; substantia nigra; substantia nigra hyperechogenicity
In Parkinson’s disease (PD) approximately 60% of the nigrostriatal neurons of the substantia nigra (SN) are degenerated before patients fulfill the clinical criteria of PD.1,2 Therefore, to improve the efficacy of any neuroprotective therapy, the detection of preclinical stages becomes crucial. Brain parenchyma sonography (BPS) is a novel, noninvasive imaging method that reveals SN hyperechogenicity in idiopathic PD.3 This finding is highly characteristic for idiopathic PD, independent of phenotype or disease duration, and is thought to reflect increased amounts of iron, bound to proteins other than ferritin in the SN.3– 8 The finding of SN hyperechogenicity in 9% of young healthy subjects corresponds to decreased striatal 18F-dopa uptake on PET scanning and was proposed as a marker for susceptibility to nigrostriatal injury.9 Recently, homozygous, heterozygous, and compound-heterozygous mutations in the parkin gene were reported to cause hereditary adult-onset parkinsonism, in some families clinically indistinguishable from idiopathic PD.10 Moreover, heterozygous parkin mutations have also been associated with many cases of sporadic PD.11–14 Here, we investigated the potential of BPS to detect preclinical changes by studying asymptomatic and symptomatic parkin mutation carriers (PMC).
SUBJECTS AND METHODS Subjects A total of 7 symptomatic and 7 asymptomatic members of a kindred from Northern Italy with well-defined parkin mutations were studied.10 Table 1 shows their demographic, clinical, and genetic data. In this family, two parkin deletions (del exon 7 ⫽ MUT1, and 1072delT ⫽ MUT2) occurred in the homozygous, compound-heterozygous or heterozygous state. Symptomatic PMC had a mean age of 65.6 ⫾ 14.4 years, a mean age at symptom onset of 52.0 ⫾ 16.7 years, a disease duration of 13.6 ⫾ 11.3 years, and a disease severity of 39.1 ⫾ 20.5 on the motor part of the Unified Parkinson’s Disease Rating Scale. Asymptomatic PMC had a mean age of 34.6 ⫾ 5.1 years (t test; P ⬍ 0.001). In all symptomatic PMC, positron emission tomography (PET) revealed decreased presynaptic striatal 18F-dopa uptake (mean Ki values [min⫺1]: caudate, 0.0087 ⫾ 0.0035; putamen, 0.0068 ⫾ 0.0043) comparable to idiopathic PD patients.15 Three asymptomatic PMC had reduced 18Fdopa uptake (Ki: 0.0088 ⫾ 0.0009; 0.0078 ⫾ 0.0021) and were referred to as asymptomatic PET-abnormal. Four had normal 18F-dopa uptake (Ki: 0.0107 ⫾ 0.0017; 0.0110 ⫾ 0.0010) and were referred to as asymptomatic PET-normal. Brain Parenchyma Sonography BPS was performed through the preauricular acoustic bone window, using a phased-array ultrasound system with a 2.5-MHz transducer (Elegra, Siemens, Erlangen, Germany).9 BPS investigation and analysis of BPS data were conducted by an experienced sonographer blinded
TABLE 1. Demographic and genetic data of the patients studied Patient no.
Age (yr)
Sex
Mutational status
Phenotype
Age at disease onset (yr)
UPDRS III (score)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
39 54 66 71 74 75 80 35 38 42 29 36 27 35
F M M M M F F M F F F F M M
Hom 1 Hom 2 Comp. 1⫹2 Comp. 1⫹2 Comp. 1⫹2 Het 2 Het 2 Het 2 Het 2 Het 2 Het 2 Het 1 Het 1 Het 1
AR-P sx LL TD-P sx UL TD-P dx UL AR-P bil TD-P sx UL TD-P dx UL TD-P dx UL Asymptomatic Asymptomatic Asymptomatic Asymptomatic Asymptomatic Asymptomatic Asymptomatic
36 43 31 49 64 65 76
26 23 49 68 54 9 45
UPDRS III, Unified Parkinson’s Disease Rating Scale (motor part); Hom 1, homozygous parkin MUT1 on both alleles; Hom 2, homozygous parkin MUT2 on both alleles; Comp 1⫹2, compound heterozygous parkin MUT1 on the paternal allele and MUT2 on the maternal allele; Het 1, heterozygous parkin MUT1 (on only one allele); Het 2, heterozygous parkin MUT2 (on only one allele); AR-P, akinetic–rigid type parkinsonism; TD-P, tremor-dominant parkinsonism; dx, dexter; sx, sinister; bil, bilateral; UL, upper limb; LL, lower limb.
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were measured on a standardized diencephalic axial scanning plane. RESULTS
FIG. 1. Relation of substantia nigra (SN) echogenicity to clinical and positron emission tomography (PET) findings. Asymptomatic parkin mutation carriers (PMC) were divided into two groups according to normal or abnormal results of PET analysis of their nigrostriatal dopaminergic system. SN echogenic sizes were estimated bilaterally in each individual; the larger size was used for classification. Sizes of less than 0.2 cm2 were referred to as normal, sizes of 0.25 cm2 and above as marked hyperechogenicity, and sizes in between as moderate hyperechogenicity. The fraction of PMC with SN hyperechogenicity increases from group 1 (asymptomatic, PET-normal) to group 3 (symptomatic). White, normal SN echogenicity; gray, moderate SN hyperechogenicity; black, marked SN hyperechogenicity.
to the clinical, genetic, and PET data. Computerized measurements of SN echogenic sizes were performed on axial BPS scans of the mesencephalic brainstem, after manually encircling the outer circumference of the SN echogenic area.4 –9 SN echogenic sizes of less than 0.2 cm2 are classified as normal, sizes of 0.25 cm2 and above as markedly hyperechogenic, and sizes in-between as moderately hyperechogenic.4 – 6 For qualitative assessment, SN echogenicity of each individual was classified according to the more affected side. Echogenicity of the thalami, the lenticular nuclei, and the caudate nuclei was rated as hyperechogenic when it was more intense than the surrounding white matter. The widths of the third ventricle and of the frontal horns of the lateral ventricles
Qualitative Assessment of SN Echogenicity All subjects were adequately assessable by BPS. Figure 1 and Table 2 show the relation of SN echogenicity to clinical and PET data. All symptomatic PMC exhibited bilateral SN hyperechogenicity, which was marked in 6 (86%) and moderate in 1 (14%). All 3 asymptomatic PET-abnormal PMC exhibited SN hyperechogenicity, which was marked in 1 and moderate in 2. Of the 4 asymptomatic PET-normal PMC, 1 exhibited marked and 1 moderate SN hyperechogenicity, and 2 exhibited normal SN echogenicity. Table 2 shows the relation of SN echogenicity to clinical, genetic, and PET data. In all homozygous and compound-heterozygous PMC, marked SN hyperechogenicity was detected. Normal SN echogenicity was only found in 2 asymptomatic heterozygous PMC. Quantitative Assessment of SN Echogenicity Median bilateral SN echogenic size of all symptomatic PMC was 0.26 cm2 (25% percentile, 0.24 cm2; 75% percentile, 0.30 cm2), of all asymptomatic PMC was 0.20 cm2 (0.11; 0.23; Mann–Whitney U test; P ⫽ 0.003), of the asymptomatic PET-abnormal PMC was 0.21 cm2 (0.20; 0.22; P ⫽ 0.025), and of the asymptomatic PETnormal PMC 0.13 cm2 (0.09; 0.24; P ⫽ 0.011). Median bilateral SN echogenic size of the 5 PMC with parkin mutations on both alleles (homozygous, compound-heterozygous) was 0.27 cm2 (0.25; 0.32), and of the 9 PMC with only one mutated allele was 0.22 cm2 (0.13; 0.24; P ⫽ 0.007).
TABLE 2. Relation of substantia nigra echogenicity to different types of parkin mutation SN hyperechogenicity Parkin mutation Asymptomatic (PET normal) Heterozygous (MUT 1) Heterozygous (MUT 2) Asymptomatic (PET abnormal) Heterozygous (MUT 1) Heterozygous (MUT 2) Symptomatic (PET abnormal) Homozygous Compound heterozygous Heterozygous (MUT 2)
SN echogenicity
Moderate
Marked
1 1
0 1
1 0
0 0
0 2
1 0
0 0 0
0 0 1
2 3 1
All homozygous and compound-heterozygous PMC exhibited marked SN hyperechogenicity. SN, substantia nigra; PET, positron emission tomography; PMC, parkin mutation carriers.
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FIG. 2. Correlation between substantia nigra (SN) echogenic size in symptomatic parkin mutation carriers and age at onset of disease. After bilateral measurement in each individual, the larger individual SN echogenic size was used. SN echogenic size was negatively correlated with age at onset of disease (Spearman rank correlation, ⫽ ⫺0.937; P ⫽ 0.002).
In the 7 symptomatic PMC, the larger SN echogenic size of each individual showed a significant negative correlation with the age at symptom onset (Spearman rank correlation, Rho ⫽ ⫺0.937, P ⫽ 0.002) as shown in Figure 2. There was no correlation with age (P ⫽ 0.44), disease duration (P ⫽ 0.73), or severity (P ⫽ 0.97). In the 6 symptomatic PMC with asymmetrical parkinsonism, median SN echogenic size was larger contralateral to the clinically more affected side (0.30 cm2 [0.27; 0.32] vs. 0.25 cm2 [0.24; 0.26]), but the difference failed statistical significance due to small sample size (P ⫽ 0.053). Other Brain Structures A total of 5 (71%) symptomatic and 3 (43%) asymptomatic PMC exhibited caudate nucleus hyperechogenicity (Mann–Whitney U test, not significant). A total of 4 (57%) symptomatic and 2 (29%) asymptomatic PMC showed lentiform nucleus hyperechogenicity (not significant). The thalami were normoechogenic in all PMC. Widths of the third and lateral ventricles were 7.9 ⫾ 2.3 mm and 12.7 ⫾ 2.9 mm in symptomatic PMC, and 6.4 ⫾ 1.2 mm and 10.8 ⫾ 1.8 mm in asymptomatic PMC (t test, not significant). DISCUSSION BPS demonstrated SN hyperechogenicity in all symptomatic PMC, regardless of their particular parkin mutation and number of mutated alleles. This finding corresponds to a previously reported SN hyperechogenicity in 91%, 96%, and 100% of sporadic idiopathic PD patients.4 – 6 The median SN echogenic size of 0.26 cm2 in symptomatic PMC conforms to median SN echogenic
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size of 0.25 cm2 reported for sporadic idiopathic PD.4 – 6 Moreover, the trend to larger median SN echogenic size contralateral to the clinically more affected side in PMC is in agreement with previous findings in idiopathic PD patients.4 BPS findings of the caudate nuclei and the thalami and widths of the third ventricle and of the frontal horns of the lateral ventricles in symptomatic PMC are not different from previously reported data of idiopathic PD patients and of control subjects, whereas lentiform nucleus hyperechogenicity is more frequent in symptomatic PMC.5,6 With similarities in phenotype and PET findings, SN hyperechogenicity, highly characteristic for idiopathic PD, now detected in PMC, suggests similar pathophysiological mechanisms in PMC and sporadic idiopathic PD. SN hyperechogenicity was also present in all asymptomatic PMC with abnormal PET, regardless of their particular parkin mutation. Of the 4 asymptomatic PMC with normal PET, 2 exhibited SN hyperechogenicity but not even a tendency to decreased 18F-dopa uptake on PET (caudate, putamen Ki values [min⫺1] of the first subject: 0.0130, 0.0119; of the second subject: 0.0109, 0.0117). Because SN hyperechogenicity has been demonstrated as a highly characteristic finding for PD,3– 6 data suggest that BPS detects pathological changes before the dopaminergic deficit becomes evident on PET. In symptomatic PMC, larger SN echogenic sizes correlate with younger age at onset of PD (see Fig. 2). The independent nature of this finding from age or disease duration is supported by the absence of any correlation between SN echogenic sizes and age, PD duration, or PD severity. Moreover, PMC with parkin mutations on both alleles (homozygous, compound-heterozygous) had significantly larger SN echogenic sizes than PMC with only one mutated allele. Of the symptomatic PMC, those with onset of PD at younger than 50 years carry parkin mutations on both alleles, whereas 2 of the 3 PMC with late-onset PD are heterozygous. This finding is in agreement with the clinical observation that PMC differ in their age at disease onset according to their mutational status.11–14 Similar to our finding in PMC, idiopathic PD patients with larger SN echogenic size were reported to have a significantly younger age at disease onset than those with small SN echogenic size, whereas there was no difference regarding PD duration or severity.4 Findings in idiopathic PD and in PMC suggest that SN hyperechogenicity does not result from the progressive dopaminergic cell loss. It rather suggests that SN hyperechogenicity reflects an early damage of dopaminergic cells, lowering their dopaminergic function and, thereby, antedating clinical manifestation of parkinsonism, which eventually
SONOGRAPHY IN PRECLINICAL PARKINSONISM results from slowly progressive neurodegeneration promoted by factors such as ageing. Our finding of larger SN echogenic size in PMC with two mutated alleles, compared to PMC with one mutated allele, further suggests that this assumed early damage of dopaminergic cells is influenced by genetic factors such as parkin mutation. To confirm and to specify the contribution of the parkin mutation in concurrence with other possible genetic factors generating SN hyperechogenicity (e.g., ferritin mutations),8 further BPS and genetic studies of this family, including members without parkin mutation, and of other families with PMC are warranted. Neuropathological findings suggest that approximately 10% of subjects older than 60 years reach “presymptomatic stages” of idiopathic PD.1 In concordance, 9 to 14% of normal subjects of all age groups, ranging from 2 to 83 years, were reported to exhibit marked SN hyperechogenicity.5,9,16 Although the rate of individuals with SN hyperechogenicity does not change with age, elderly patients without prediagnosed extrapyramidal disorder but with SN hyperechogenicity develop more frequent and more severe parkinsonian symptoms than those with a regular echogenicity of the SN.16 PET studies of clinically healthy subjects around 30 years of age with marked SN hyperechogenicity revealed decreased striatal 18F-dopa uptake in 60% of cases, indicating a functional impairment of the nigrostriatal system several decades of life before possible manifestation of parkinsonism.9 In light of our findings, the remaining 40% could represent earlier preclinical stages of idiopathic PD, identifiable by BPS but not yet by PET. These findings suggest BPS as a novel, noninvasive screening method to identify individuals at risk of developing parkinsonism.
8.
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marker for susceptibility to nigrostriatal injury. Arch Neurol 2002; 59:999 –1005. Felletschin B, Bauer P, Walter U, et al. Screening for mutations of the ferritin light and heavy genes in Parkinson’s disease patients with hyperechogenicity of the substantia nigra. Neurosci Lett 2003;352:53–56. Berg D, Becker G, Zeiler B, et al. Vulnerability of the nigrostriatal system as detected by transcranial ultrasound. Neurology 1999;53: 1026 –1031. Klein C, Pramstaller PP, Kis B, et al. Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype. Ann Neurol 2000;48:65–71. Lucking CB, Durr A, Bonifati V, et al. Association between early-onset Parkinson’s disease and mutations in the parkin gene. French Parkinson’s Disease Genetics Study Group. N Engl J Med 2000;342:1560 –1567. Kann M, Jacobs H, Mohrmann K, et al. Role of parkin mutations in 111 community-based patients with early-onset parkinsonism. Ann Neurol 2002;51:621– 625. Hedrich K, Marder K, Harris J, et al. Evaluation of 50 probands with early-onset Parkinson’s disease for Parkin mutations. Neurology 2002;58:1239 –1246. Foroud T, Uniacke SK, Liu L, et al. Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease. Neurology 2003;60:796 – 801. Hilker R, Klein C, Ghaemi M, et al. Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene. Ann Neurol 2001;49:367–376. Berg D, Siefker C, Ruprecht-Doerfler P, Becker G. Relationship of substantia nigra echogenicity and motor function in elderly subjects. Neurology 2001;56:13–17.
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