Primary dystonia Is abnormal functional brain architecture linked to genotype.код для вставкиСкачать
dimerization or oligomerization of the gene product is requisite for normal function. Whether or not these PARK6 heterozygotes with subclinical dysfunction will develop clinical parkinsonism over time is unknown. Repeated observation with clinical examination and repeat scanning over time in a much larger cohort will be necessary to confirm these findings. 15. Piccini P, Burn DJ, Ceravolo R, et al. The role of inheritance in sporadic Parkinson’s disease: evidence from a longitudinal study of dopaminergic function in twins. Ann Neurol 1999;45:577–582. 16. Piccini P, Morrish PK, Turjanski N, et al. Dopaminergic function in familial Parkinson’s disease: a clinical and 18F-dopa positron emission tomography study. Ann Neurol 1997;41: 222–229. 17. Strachen T, Read A. Human molecular genetics. 2nd ed. Oxford, UK: BIOS Scientific Publication, 2000. This study is funded by the Parkinson’s Disease Society (4000) and the Brain Research Trust (282, N.L.K.). We thank H. McDevitt, S. Ahier and A. Blyth for their expert help with scanning. References 1. Valente EM, Bentivoglio AR, Dixon PH, et al. Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35–p36. Am J Hum Genet 2001;68:895–900. 2. Valente EM, Brancati F, Ferraris A, et al. PARK6-linked parkinsonism occurs in several European families. Ann Neurol 2002;51:14 –18. 3. Bentivoglio AR, Cortelli P, Valente EM, et al. Phenotypic characterisation of autosomal recessive PARK6-linked parkinsonism in three unrelated Italian families. Mov Disord 2001;16: 999 –1006. 4. Fahn S, Elton R, Members of the UPDRS Development Committee. Fahn S, Marsden CD, Calne DB, et al. Recent developments in Parkinson’s disease. Vol 2. Florham Park, NJ: Macmillan Health Care Information, 1987:153–163, 293–304. 5. Hoehn M, Yahr M. Parkinsonism: onset, progression and mortality. Neurology 1967;17:427– 442. 6. Brooks DJ, Ibanez V, Sawle GV, et al. Differing patterns of striatal [18F]-dopa uptake in Parkinson’s disease, multiple system atrophy and progressive supranuclear palsy. Ann Neurol 1990;28:547–555. 7. Rakshi JS, Uema T, Ito K, et al. Frontal, midbrain and striatal dopaminergic function in early and advanced Parkinson’s disease A 3D [(18)F]dopa-PET study. Brain 1999;122: 1637–1650. 8. Talairach J, Tournoux P. Co-planar stereotaxic atlas of the human brain. Stuttgart: Thieme, 1988. 9. Gibb W, Lees A. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 1988;51:745–752. 10. Bernheimer H, Birkmayer W, Hornykiewicz O, et al. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 1973;20:415– 455. 11. 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. 12. Khan NL, Brooks DJ, Pavese N, et al. Progression of nigrostriatal dysfunction in a parkin kindred: an [18F]-dopa PET and clinical study. Brain 2002;125:2248 –2256. 13. Bezard E, Gross CE. Compensatory mechanisms in experimental and human parkinsonism: towards a dynamic approach. Prog Neurobiol 1998;55:93–116 14. Whone AL, Moore RY, Piccini PP, Brooks DJ. Compensatory changes in the globus pallidus in early Parkinson’s disease: an 18 F-dopa PET Study. Neurology 2001;56:A72. Primary Dystonia: Is Abnormal Functional Brain Architecture Linked to Genotype? Maja Tros̆t, MD,1,2 Maren Carbon, MD,1 Christine Edwards, MA,1,3 Yilong Ma, PhD,1 Deborah Raymond, MS,4 Marc J. Mentis, MD,1,3 James R. Moeller, PhD,5 Susan B. Bressman, MD,4 and David Eidelberg, MD1,3 The DYT1 dystonia mutation is associated with an abnormal metabolic brain network characterized by hypermetabolism of the basal ganglia, supplementary motor area, and the cerebellum. In this study, we quantified the activity of this network in carriers of other dystonia mutations to determine whether this functional abnormality is linked to genotype. The findings suggest that the DYT1 metabolic topography is not genotype specific and may be present in carriers of other dystonia mutations. Ann Neurol 2002;52:853– 856 Dystonia is a movement disorder characterized by sustained muscle contractions with twisting and repetitive movements or abnormal postures.1 A common cause of From the 1Center for Neurosciences, North Shore–Long Island Jewish Research Institute, Manhasset, NY; 2Department of Neurology, Division of Neurology, University Medical Centre Ljubljana, Ljubljana, Slovenia; 3Department of Neurology, North Shore University Hospital, Manhasset; and New York University School of Medicine, New York; 4Department of Neurology, Philips Ambulatory Care Center, Beth Israel Medical Center, New York; and 5Department of Biological Psychiatry, New York State Psychiatric Institute, Columbia College of Physicians and Surgeons, New York, NY. Received Jul 1, 2002, and in revised form Sep 4. Accepted for publication Sep 4, 2002. Address correspondence to Dr Eidelberg, Center for Neurosciences, North Shore–Long Island Jewish Research Institute, 350 Community Drive, Manhasset, NY 11030. E-mail: email@example.com Tros̆t et al: Network Abnormality in Dystonia Mutations 853 early onset primary torsion dystonia (PTD) is the GAG deletion in the DYT1 gene at 9q34.1.2 Using 18Ffluorodeoxyglucose (FDG) and positron emission tomography (PET) and network analysis, we previously demonstrated that DYT1 carrier status is associated with an abnormal pattern of regional glucose utilization, characterized by hypermetabolism of the basal ganglia, cerebellum, and supplementary motor area.3 This distinct metabolic topography was identified in the FDG/PET scans of clinically unaffected (nonmanifesting) carriers of the DYT1 mutation. Nonetheless, this regional covariance pattern also has been detected in DYT1 affecteds3 and in ungenotyped groups of PTD patients.4,5 It is, however, currently not known whether this torsion dystonia–related pattern (TDRP) is a specific metabolic feature of the DYT1 genotype or whether it is present in other inherited forms of dystonia. To answer this question, we prospectively quantified TDRP network activity in FDG/PET scans obtained from a new cohort of DYT1 mutation carriers as well as from members of two North American Mennonite families with autosomal dominant PTD linked to the DYT6 locus.6 In this automated blinded analysis, we also included scans from patients with dopa-responsive dystonia (DRD), a phenotypically distinct autosomal dominant syndrome that responds to low doses of 1,7 L-dopa. We hypothesized that the network identified in DYT1 would be present in DYT6 carriers but not in the phenotypically distinct DRD patients. Subjects and Methods Subjects We studied four groups of subjects: (1) DYT1: six clinically unaffected Ashkenazic Jewish DYT1 carriers (age, 56.6 ⫾ 14.9 years, mean ⫾ standard deviation) who were unrelated to the previously reported cohort of seven gene carriers.3 (2) DYT6: Six members of a North American Mennonite Amish family (age, 48.0 ⫾ 18.6 years) linked to DYT6. Three of the subjects were clinically unaffected obligate carriers; the other three exhibited a “mixed” phenotype of cranial, cervical, and limb dystonia beginning in childhood or early adulthood. One of the affecteds was unmedicated; one was treated with intermittent botulinum toxin injection, and one with chronic low-dose anticholinergic therapy (trihexyphenidyl 3mg/day). (3) DRD: Seven patients with DRD (age, 38.3 ⫾ 7.9 years) affecting primarily the lower limbs. All patients responded to low doses of L-dopa (mean daily dose, 282mg); none received anticholinergic medication. (4) Controls: Thirteen healthy volunteer subjects (age, 38.6 ⫾ 13.7 years) served as controls. This group was composed of six genenegative family members (three siblings and three spouses of DYT1 carriers) and seven neurologically normal volunteers recruited from the staff of North Shore University Hospital and Columbia University. 854 © 2002 Wiley-Liss, Inc. Positron Emission Tomography All subjects fasted overnight before PET imaging. Medications were withheld in the affected subjects for at least 12 hours before scanning. FDG/PET studies were performed in three-dimensional mode using the GE Advance tomograph (General Electric, Milwaukee, WI) at North Shore University Hospital, Manhasset, NY. The details of the scanning procedure have been presented elsewhere.3 The institutional review board of North Shore University Hospital gave ethical permission for these studies. Written consent was obtained from each subject after detailed explanation of the procedures. The PET data were analyzed in two steps. First, we reanalyzed the original cohort of nonmanifesting DYT1 carriers and control subjects3 using a new voxel-based network mapping approach.8 This completely data-driven analysis showed a significant covariance pattern that discriminated nonmanifesting DYT1 carriers from controls ( p ⬍ 0.002, F test according to Wilks ). The topography of this pattern closely resembled that of the original TDRP that we previously identified using manually placed regions.3 The voxel-based TDRP (Fig 1) accounted for 12% of the subject ⫻ voxel variance and was characterized by covarying metabolic increases in the posterior putamen, extending into the pallidum, the caudal supplementary motor area, and the cerebellar hemisphere (Crus I).9 Fig 1. Regional metabolic covariance pattern identified with 18 F-fluorodeoxyglucose and positron emission tomography and network analysis in nonmanifesting DYT1 gene carriers and control subjects (see text). This torsion dystonia–related pattern was characterized by bilateral covarying metabolic increases in the putamen, extending into the globus pallidus (GP), the supplementary motor area (SMA), and the cerebellar hemisphere. Subject scores for this pattern discriminated the DYT1 carriers from controls (p ⬍ 0.002). The display represents voxels that contribute significantly to the network at p ⫽ 0.001. Voxels with positive region weights (metabolic increases) are color-coded red. We next used an automated algorithm3,10 to quantify the expression of the TDRP in individual subjects on a prospective single scan basis. FDG/PET scans from all four groups (n ⫽ 32) were combined and analyzed simultaneously using a voxel approach; network quantification was blind to genotype and clinical status.3 The resulting TDRP subject scores were Z-scored and offset to a mean of zero for the control group. TDRP scores were compared across groups using analysis of variance with a post hoc correction for multiple group comparisons. Group differences were considered significant for p ⬍ 0.05. All network computations were conducted on PCs running Windows 2000 with software available at http://www.northshorepet.com. Statistical comparisons were conducted using JMP software for PC. Results TDRP subject scores differed significantly across groups [F (3,31) ⫽ 7.7, p ⬍ 0.001; Fig 2]. Post hoc analysis indicated that subject scores for the prospective cohort of six nonmanifesting DYT1 carriers were elevated with respect to control values ( p ⬍ 0.001). TDRP scores also were elevated in the DYT6 cohort ( p ⬍ 0.007) with similar network expression in affected and nonmanifesting gene carriers. TDRP activity in this group did not differ from DYT1 values ( p ⫽ 0.7). By contrast, TDRP scores in DRD were lower than for DYT1 and DYT6 carriers ( p ⬍ 0.01) but did not differ from normal control values ( p ⫽ 0.4). Fig 2. Scatter diagram of torsion dystonia–related pattern subject scores computed prospectively in six new nonaffected DYT1 gene carriers, six DYT6 gene carriers, seven doparesponsive dystonia (DRD) patients, and 13 control subjects. Subject scores were abnormally elevated in DYT1 (p ⬍ 0.001) and DYT6 carriers (p ⬍ 0.007), but not in DRD patients (p ⫽ 0.4). The error bars indicate subgroup standard errors of the mean. (circles) normal controls; (squares) subjects with genotypes associated with primary torsion dystonia; (triangles) DRD patients; (open symbols) clinically nonmanifesting subjects; (filled symbols) affected dystonia patients. Discussion Our findings indicate that the distinctive metabolic network that was originally identified in DYT1 gene carriers can be expressed in other mutations associated with primary dystonia. The results raise several issues relevant to the study of PTD and related disorders. Using a new voxel-based network mapping approach, we found that TDRP expression is elevated in a new prospective cohort of nonmanifesting carriers of the DYT1 mutation. Thus, the TDRP metabolic topography is a reproducible feature of the DYT1 genotype, even in the absence of clinical manifestations.3 Consistent with our initial hypothesis, this network is not present in DRD patients. Given the well-described striatal dopamine deficiency that underlies DRD,7 it is likely that a different metabolic network abnormality characterizes this specific form of dystonia. It is also not surprising that abnormal TDRP expression is a feature of other PTD mutations. As a group, the DYT6 carriers also exhibited an elevation in TDRP scores, reflecting increased activity of a functional circuit comprising the striatum/GP, supplementary motor area, and the lateral cerebellum. Our findings suggest that overactivity of these regions is an important trait feature of dystonia.3,11 In other words, increased TDRP expression may represent a permissive condition for the development of clinical manifestations in both DYT1 and DYT6 dystonia, suggesting similar physiological mechanisms in the two genotypes. Although the number of DYT6 subjects was low, qualitative review of the TDRP data indicated the network was abnormally expressed in manifesting as well as nonmanifesting carriers of the mutation. Indeed, of the six individuals scanned, the highest subject score was associated with an individual without clinical manifestations. This observation is compatible with the notion of broader penetrance of autosomal dominant PTD mutations that would be assumed strictly on routine neurological examination.12 Indeed, recent psychophysical and brain activation studies have suggested that consistent motor sequence learning abnormalities are present in clinically nonmanifesting DYT1 carriers.13 It is unknown whether abnormal TDRP expression in DYT6 subjects is associated with comparable forms of impairment. Although the data support the notion of mean elevation of TDRP activity in certain dystonia subtypes, within-group variation can be substantial. We note that in prior studies slightly better group separation was achieved using a manual region of interest approach.3 It is possible that the voxel mapping technique is noisier by virtue of its inclusion of functionally irrelevant regions that overlap or lie between the sampled regions of interest. Despite these potential advantages, the region of interest approach can be subject to operator bias and is generally more time consuming. Tros̆t et al: Network Abnormality in Dystonia Mutations 855 With larger subject samples, it may be possible to refine the spatial topography of the voxel-based TDRP thus providing a more accurate metabolic marker for individual subject classification. The identification of a metabolic imaging marker for PTD may have several potential applications. Network quantification can prove valuable in genetic studies. Clinically unaffected family members of primary dystonia patients can be scanned with FDG/PET and tested for TDRP network expression. Subjects with positive imaging findings can then be categorized as potential gene carriers and further involved in linkage or other genetic studies aimed at identifying novel genes. We acknowledge that neither of the carrier groups reported in this study was completely separable from controls based on TDRP expression. We note that this metabolic pattern was identified in a relatively small group of DYT1 carriers. The prospective assignment of individual cases may be improved using related topographies extracted from large homogeneous populations of genotyped subjects. Elevated TDRP expression also may prove useful as a potential marker for selecting appropriate candidates for stereotaxic surgical intervention. Severely affected DYT1 dystonia patients often display remarkable improvement with deep brain stimulation.14 Because the TDRP topography is characterized by hypermetabolism at critical nodes of the motor cortico-striatopallido-thalamocortical loop and related pathways,11,15 it is possible that similar therapeutic responses can be achieved in other forms of dystonia in which this pattern is expressed. Whether modulation of network activity by surgery is correlated with clinical outcome is a topic of ongoing investigation. This work was supported by the NIH (RO1 NS 37564, D.E.) and the Dystonia Medical Research Foundation (D.E.). 856 Annals of Neurology Vol 52 No 6 December 2002 The authors thank Drs V. Dhawan and T. Chaly for valuable technical support and C. Margouleff for his assistance. References 1. Fahn S, Bressman SB, Marsden CD. Classification of dystonia. Adv Neurol 1998;78:1–10. 2. Breakefield XO, Kamm C, Hanson PI. TorsinA: movement at many levels. Neuron 2001;31:9 –12. 3. Eidelberg D, Moeller JR, Antonini A, et al. Functional brain networks in DYT1 dystonia. Ann Neurol 1998;44:303–312. 4. Eidelberg D, Moeller JR, Ishikawa T, et al. The metabolic topography of idiopathic torsion dystonia. Brain 1995;118: 1473–1484. 5. Hutchinson M, Nakamura T, Moeller JR, et al. The metabolic topography of essential blepharospasm: a focal dystonia with general implications. 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Brain networks subserving motor sequence learning in DYT1 gene carriers. Neurology 2002;58:A203. 14. Coubes P, Roubertie A, Vayssiere N, et al. Treatment of DYT1-generalised dystonia by stimulation of the internal globus pallidus. Lancet 2000;355:2220 –2221. 15. Wichmann T, DeLong MR. Functional and pathophysiological models of the basal ganglia. Curr Opin Neurobiol 1996;6: 751–758.