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Primary dystonia Is abnormal functional brain architecture linked to genotype.

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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
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293–304.
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Psychiatry 1988;51:745–752.
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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.
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Prog Neurobiol 1998;55:93–116
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changes in the globus pallidus in early Parkinson’s disease: an
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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: david1@nshs.edu
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.
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topography of essential blepharospasm: a focal dystonia with
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11. Vitek JL, Giroux M. Physiology of hypokinetic and hyperkinetic movement disorders: model for dyskinesia. Ann Neurol
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13. Carbon M, Ghilardi MF, Dhawan V, et al. 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.
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