abstracts of the movement disorder society's eleventh international congress of parkinson's disease...

ORAL PLATFORMPRESENTATION 4601

Tuesday, June 5, 20072:30 PM4:30 PMLocation: Marmara Room

RESTLESS LEGS SYNDROME ANDOTHER MOVEMENT DISORDERS

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Evidence for linkage of Restless legs syndrome to chromosome 9p:Are there two distinct loci?K. Lohmann-Hedrich, A. Ziegler, A. Neumann, A. Kleensang,T. Lohnau, H. Muhle, A. Djarmati, I.R. Konig, P.L. Kramer,U. Stephani, C. Klein (Luebeck, Germany)

Objective: To investigate the genetic cause of Restless legs syn-drome (RLS) in a large German family.

Background: RLS is a common sensory-motor disorder character-ized by paresthesias and an intense urge to move the legs with aconsiderable familial aggregation. To date, no gene mutation has beenfound but ve gene loci have been mapped in primary RLS to chro-mosomes 12q, 14q, 9p, 2q, and 20p (RLS1-5).

Methods: We identied a four-generational German RLS familywith 37 family members including 15 affected cases. We performedlinkage analysis using microsatellite markers at the ve known loci.Prompted by the identication of a potentially shared haplotype nearthe RLS3 locus, we expanded the investigated linkage region on chro-mosome 9p using additional DNA markers.

Results: Mode of inheritance in our RLS family was compatible withan autosomal dominant pattern and disease onset was mainly in child-hood or adolescence. We excluded linkage to the RLS1, RLS2, RLS4,and RLS5 loci. However, we identied a likely new RLS gene locus(RLS3*) on chromosome 9p with a maximum LOD score of 3.60generated by model-based multipoint linkage analysis. A haplotypecentromeric to RLS3, anked by D9S974 and D9S1118, was shared byall twelve investigated patients. In addition, eleven of them carried acommon haplotype extending telomeric to D9S2189 that is locatedwithin RLS3. Among the unaffected family members, only a 7-year oldchild carried the disease-associated haplotype. The RLS critical regionshared by all affected family members covers 20cM or 9.94Mb onchromosome 9p21 and is separated by5cM or 2.31Mb from the RLS3locus. The extended RLS critical region that is common to all but oneaffected comprises 26cM or 13.19Mb with an overlap with RLS3 of2cM or 0.93Mb.

Conclusions: We demonstrate linkage to a locus on chromosome 9pthat is probably distinct from RLS3. Our family with a rather homo-geneous phenotype and very early disease onset represents a uniqueopportunity to further elucidate the genetic causes of the frequent RLS.

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RLS patients can also develop compulsions on dopaminergic ago-nistsE. Pourcher, H. Cohen (Quebec, Canada)

Objective: The aim of this study was to assess the frequency ofself-reported compulsive behaviors, depressive and stress symptomsand sleep disorders in a population of Restless legs syndrome (RLS)patients treated with DA agonists.

Background: Recent reports by Tippmann-Peikert et al (2007) andRitz et al (2006) extend the risk of developing DA agonists relatedimpulse control disorders such as gambling, heightened sexual drive, orunreasonably overinvested repetitive activities to RLS patients.

Methods: A questionnaire covering RLS severity (IRLS-Walters etal 2003), mood variables, The Beck Depression Inventory II (Beck et

al 2003), a visual Analog Scale of current level of stress and sleepparameters (The MOS Sleepscale, Hays & Stewart 1992) was sent at 3points in time over twelve months in 2005 (February, June, October) to150 RLS patients cared for at the Quebec Memory & Motor SkillsDisorders Clinic. A last section exploring changes in hobbies, devel-opment of new habits and compulsions was added at the third mailing.

Results: Data derived from a population of 97 patients havinganswered all three mailings identied 17 positive responses to com-pulsions. After re-evaluation only 12 (8 women and 4 men) were foundto have truly compulsive behaviours. In two women, simple motorstereotyped sequences in response to sensory urge evoked the phenom-enology of Gilles de La Tourette Syndrome. In two other, one male,one female, a reactivation of trichottillomania previously exhibited inchildhood was observed. For the other eight patients, abnormal behav-ioural display was similar to complex compulsory behaviours withshort-term rewarding properties such as buying clothes, buying food,eating or gambling. In addition BDI and stress scores signicantlycontrasted the compulsion () vs compulsion (-) patients. Their MOSsub-scale sleep problem Index I and II showed signicantly higherscores and nally, the augmentation phenomenon was of higher prev-alence in the C group at the time of the 3rd questionnaire.

Conclusions: In summary, 12 out of 97 RLS patients on stable DAagonist therapy presented with progressive dishinibition of behaviourpossibly shaped by pre treatment gender and individual specicities.None had a previous diagnosis of anxious generalized disorder orobsessive compulsive disorder. They showed more dysphoric and rec-ognized themselves as more stressed than the compulsion (-) group ofRLS patients.

3Transcranial sonography in Restless legs syndromeJ. Godau, A.-K. Wevers, A. Gaenslen, A. Di Santo, E. Caliskan-Erle,T. Gasser, D. Berg (Tuebingen, Germany)

Objective: To investigate morphological abnormalities of patientswith restless legs syndrome (RLS) using transcranial sonography(TCS).

Background: Sonographic hypoechogenicity of the substantia nigra(SN) has been demonstrated as a typical nding in RLS, which isthought to be correlated with decreased SN iron content. Other sono-graphic features have not yet been examined. Especially commoncomorbidities such as depression, which is known to be correlated withhypoechogenicity of the raphe in primary depressive disorders, andperiodic limb movements, which have been shown to be correlated withred nucleus activation on fMRI, may be associated with sonographicabnormalities.

Methods: 103 RLS patients underwent TCS according to a standard-ized protocol by an experienced and independent rater, who wasblinded for the clinical presentation. Diagnosis of RLS and depressionwas made according to current diagnostic criteria after thorough clin-ical and neurological examination by a second experienced raterblinded for the TCS results.

Results: 71.8% of the patients were diagnosed with idiopathic RLS,17.4% with secondary RLS and in 10.6% RLS origin was uncertain.49.5% of the patients had depression or were on antidepressant therapy.64% of the patients reported PLM. 86.4% of all patients (93.1% inidiopathic RLS) showed SN hypoechogenicity, 61.1% hypoechogenic-ity of the raphe, 28.7% hyperechogenicity of the basal ganglia and64.2% hyperechogenicity of the red nucleus (NR). Raphe hypoecho-genicity correlated with depression (p0.03), NR hyperechogenicitycorrelated with reported PLM (p0.002). Hyperechogenicity of thebasal ganglia did not correlate with any assessed clinical feature. 27.7%showed 2 of the 4 features, 46.6% 3 of 4 and 6.8% all four features.

Conclusions: SN hypoechogenicity is a characteristic feature of RLS.Also, NR hyperechogenicity and raphe hypoechogenicity are typicaland independent ndings in RLS. Since they are associated with typicalclinical features, they may represent pathophysiologic changes of RLSrelated disorders. Further studies are needed to evaluate a potentialdiagnostic, differential diagnostic and therapeutic value of TCS forRLS.

Movement DisordersVol. 22, Suppl. 16, 2007, pp. S1S295 2007 Movement Disorder Society

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Movement Disorders, Vol. 22, Suppl. 16, 2007

4Original clinical and biological ndings in 3 new mutations of thesenataxin geneM. Anheim, M.C. Fleury, J. Franques, J.-P. Delaunoy, M. Moreira,M. Koenig, C. Tranchant (Strasbourg, France)

Objective: To report clinical and genetical pictures of 7 patients,issued from 4 unrelated families, affected with ataxia with oculomotorapraxia (AOA2).

Background: AOA2 is one of the most recently described non-Friedreich autosomal recessive cerebellar ataxia (ARCA), and is ge-netically dened by mutations of SETX localized in 9q34. AOA2 ischaracterized by cerebellar ataxia, sensory-motor axonal neuropathy,cerebellar atrophy on imaging and elevation of serum foeto-protein(AFP) level.

Methods: The four families affected with AOA2 were genotypedwith microsatellite markers present in the AOA2 region on chromo-some 9q34. We sequenced all exons of SETX of the patients linked tothe AOA2 locus and we tested for the presence or absence of themissense mutation by DHPLC analysis of 100 control DNA samples ofthe same geographic origin.

Results: Mutations (including 3 new mutations) of the senataxingene were found for the seven patients : nonsense mutations E343Xand K2209X, frameshift mutation 5264delC and missense mutationR2444H. Cerebellar ataxia, sensory-motor axonal neuropathy, cerebel-lar atrophy on imaging and elevation of serum foeto-protein (AFP)level were present in all patients. However oculomotor apraxia waspresent in only one case. First signs occured between 13 and 18 years.One patient presented with lower limb distal amyotrophy and fascicu-lations with elevated creatine kinase ranged from 500 to 20.000 UI/Lconfounding with lower motor neuron involvement. In the consanguin-eous family with the E343X mutation, an elevated AFP level was foundin 3 asymptomatic heterozygous patients.

Conclusions: These new cases underline the phenotypic homogene-ity of AOA2 despite the heterogeneity of SETX mutations, with 4mutations described. Our results suggests also that AFP level could bethe sign of heterozygosity in asymptomatic carriers and could be usefulfor genetic counselling.

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Silver syndrome variant of hereditary spastic paraplegia: Identi-cation of a novel locusA. Orlacchio, C. Patrono, F. Gaudiello, V. Moschella, A. Borreca,A. Orlacchio, R. Floris, G. Bernardi, T. Kawarai (Rome, Italy)

Objective: To assess genotype-phenotype associations, we carriedout a clinical and genetic study of two large Italian families with SilverSyndrome, SS (RM-36 and RM-51).

Background: SS is a complicated form of hereditary spastic para-plegia (HSP) associated with amyotrophy and weakness of the intrinsichand muscle. A recent genetic study has shown that SS can be causedby mutations in the BSCL2 gene (seipin) on chromosome 11q12-q14(SPG17). In this context, investigating the genotype-phenotype corre-lations is essential to understand the mechanism(s) of the disease.

Methods: Neurological evaluations, neurophysiological and neuro-psychological assessments, neuroimaging studies, linkage study, andsequencing.

Results: Linkage analyses demonstrated that the two families areexcluded for linkage to the BSCL2 locus. Sequence of the seipin generevealed no disease-causing nucleotide substitution. Having excludedthe multiple known HSP loci in the pedigree RM-36, we performed agenome-wide search for linkage of SS, which showed a novel SS locuson chromosome 4p. The clinical features of this family are comparableto those in SS. Linkage analyses at the currently-known ADHSP locishowed evidence of linkage to SPG4 in the pedigree RM-51. SPG4sequence analysis revealed a novel frameshift mutation in exon 6(c.961insG) resulting in premature termination at the codon 326(p.N326X). PCR-RFLP analysis showed that the mutation segregateswith the disease and the mutation was not found in 200 controlchromosomes. Clinical investigations in the family carrying the frame-

shift mutation in SPG4 demonstrated decreased vibration sense inlower limbs, pes cavus, cognitive dysfunctions, and temporal lobeepilepsy (TLE), in addition to SS typical clinical manifestations. Anal-ysis of age at onset and degree of disease severity among generationsrevealed a general impression of genetic anticipation. Electrophysio-logical studies revealed the involvement of lower motor neurons aswell as upper motor neurons.

Conclusions: The data presented in this study identify a second locusfor the SS variant of HSP. Our study also demonstrates that SPG4-HSPmay include clinical features observed in SS and widen the spectrum ofgenetic abnormalities of the disorder.

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Spectrum of gait impairments in presymptomatic and symptomaticHuntingtons disease: Cross sectional dataA.K. Rao, L.M. Muratori, E.D. Louis, C.B. Moskowitz, K.S. Marder(New York, New York, USA)

Objective: To quantify gait impairments in presymptomatic andsymptomatic Huntingtons disease (HD) subjects using a cross-sec-tional design, and examine the sensitivity of gait measures.

Background: Gait impairments are important because they may leadto an increased risk for falls. Little is known about gait impairments inthe presymptomatic stage. We thus quantied gait impairments in HDusing a cross-sectional analysis of presymptomatic carriers and symp-tomatic individuals across stages of the disease.

Methods: Our sample (n65) included presymptomatic gene carriers(PSGC) (n 15), symptomatic HD subjects (n 30) and healthycontrols (n 20). Gait data were collected with the GaitRITE (CIRSystems, Inc.: Havertown, PA). For PSGC and symptomatic HD sub-jects, we collected CAG repeat length (if available), UHDRS totalmotor score and TFC scale score, and number of years since symptomonset (for symptomatic HD subjects). Subjects were requested to walkat a preferred speed on the GAITRite mat and completed three trials fordata analysis.

Results: PSGC demonstrated decreased gait velocity (p0.01),stride length (p0.022), and increased time in double support (p0.04)compared with controls; and demonstrated higher variability in stridelength (p0.01)and step time variability (p0.05) compared withcontrols. These impairments worsened with increasing disease severityfor symptomatic HD subjects. Gait impairments were correlated withpredicted years to onset in PSGC (gait velocity-.65; cadence-.70,step time-.71) and demonstrated high sensitivity (velocity 0.72;stride length 0.66; percent double support 0.66) and specicity(velocity 0.93; stride length 0.82; percent double support 1) indistinguishing between controls and those with a trinucleotide expan-sion. In contrast, UHDRS scores did not reveal impairments in gait andbalance.

Conclusions: Gait bradykinesia and dynamic balance impairmentsare present in the presymptomatic stage of HD and continue to worsenfollowing onset of clinically evident motor symptoms. Quantitative gaitmeasures were sensitive in differentiating between individuals with andwithout an expanded trinucleotide repeat sequence even when theseimpairments are not detected by clinical neurological examination.

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Frequency of dementia in FMR1 premutation carriersM. Sevin, Z. Kutalik, P. Damier, M. Vercelletto, P. Renou,P. Boisseau, S. Bergmann, J.-M. Rival, S. Jacquemont (Nantes,France)

Objective: To study the frequency of dementia in older male carriersof the FMR1 premutation.

Background: The Fragile Xassociated tremor ataxia syndrome (FX-TAS) is a neurodegenerative disorder caused by the premutation (aCGG repeat expansion) of the FMR1 gene. Only a subgroup of pre-mutation carriers develop symptoms of FXTAS and primarily presentwith cerebellar ataxia and intention tremor. Cognitive impairment hasalso been reported in patients affected with FXTAS. This is the rst

S2 11TH INTERNATIONAL CONGRESS OF PARKINSONS DISEASE AND MOVEMENT DISORDERS


study addressing the frequency of cognitive decline and dementia inpremutation carriers.

Methods: 67 males aged 50 years or older were recruited from fragileX families, regardless of their medical history or genetic status. TheMattis Dementia Rating Scale (MDRS) was used to quantify globalcognitive capacities. Other tests assessed executive functioning, verbaland non-verbal working memory, visuospatial skills, and reasoningcapacities. The study was double blinded in that genetic status andCGG repeat length were obtained after evaluation.

Results: Molecular testing revealed 30 premutation carriers and 37intrafamilial controls. Age and education level distributions were sim-ilar in both groups. Based on a cut-off score of 129 for the MDRS andan education level corrected at 12 years, the frequency of dementia atage 70 among individuals with large premutation (90 CGG), smallpremutation (60 CGG) and controls was 40%, 15%, and 4% respec-tively. At age 60 these frequencies were 5%, 0%, and 0% respectively.All of these differences were highly signicantly (p0.001). Multir-egression analysis accounting for age and education, found a signicantcorrelation between the CGG repeat length and the MDRS, tests ofexecutive functions (Wisconsin Card Sorting Test, verbal uency),visuospatial performances, and reasoning capacities (p0.001). Work-ing memory tasks were not affected by the premutation size.

Conclusions: The frequency of signicant cognitive decline anddementia among carriers of large premutation is particularly high. It isless frequent for smaller premutation alleles, however there is still ameasurable effect. This is of importance since smaller alleles are muchmore frequent in the general population.

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Intrafusal effects of botulinum toxin injection in patients withupper motor neuron syndromeC. Trompetto, G. Francavilla, C. Ogliastro, L. Avanzino, M. Bove,A. Berardelli, G. Abbruzzese (Genova, Italy)

Objective: To evaluate the role of intrafusal chemodenervation in thetreatment of post-stroke upper limb spasticity with botulinum toxintype A (BoNT-A).

Background: Evidences from animal and human studies suggest thatBoNT-A, besides its effect on extrafusal motor bres, can act also ongamma motor endings thus modifying spindle afferent discharges fromthe injected muscles. This effect can be studied in humans by investi-gating BoNT-A induced changes of the tonic vibration reex (TVR).

Methods: In 7 patients (4 men, aged 6417 years) with upper motorneuron syndrome due to stroke and never treated with BoNT-A, wemeasured the maximal M-wave (Mmax), the H/M ratio, the maximalvoluntary contraction (MVC) and the TVR in the injected wrist andnger exor muscles before (T0), 1 month (T1) and 4 months (T2) afterinjection. The ratio between pre- and post-injection values was calcu-lated. Muscle tone was clinically evaluated using the Modied Ash-worth Score (MAS). In two subjects, the physiological assessment wasperformed also 8 months after the treatment.

Results: The TVR was signicantly more inhibited than Mmax andMVC at T1 (p 0.05). At T2, Mmax and MVC reached the pre-injection values, while the TVR remained depressed. The H/M ratio,slightly decreased at T1, regained the pre-injection value at T2. AfterBoNT-A injection muscle tone was reduced both at T1 and T2. In thetwo subjects studied 8 months after treatment, the TVR resulted stilldepressed, while the MAS value matched that at T0 and the H/M ratiowas found to be increased compared to pre-injection values.

Conclusions: The special sensitivity of TVR to suppression byBoNT-A depends on the chemodenervation of intrafusal muscle bers,leading to a reduced spindle inow to the central nervous system duringvibration. This effect possibly explains the residual clinical benet atT2. The lack of clinical evidence of increased spasticity at T3, in spiteof the raised H/M ratio, suggests that the chemodenervation of intra-fusal bers could counteract the progressive increase of spinal excit-ability, thus preventing further development of spasticity.


Tuesday, June 5, 20072:30 PM4:30 PMLocation: Halic Room

ATYPICAL PARKINSONISM ANDDYSTONIA

9Effect of disease duration on the pattern of cerebral glucose me-tabolism in patients with multiple system atrophyJ.H. Lee, C.H. Lyoo, S.H. Oh, M.S. Lee (Seoul, Republic of Korea)

Objective: To investigate the effect of disease duration on the 18[F]-deoxyglucose positron emission tomography (FDG PET) ndings inpatients with early multiple system atrophy (MSA).

Background: Using a region of interest method, a previous FDG PETstudy of the patients with early MSA showed reduced glucose uptakeat the putamen, cerebellum and brainstem. However, no voxel basedFDG PET study has been reported about the effect of disease durationon the pattern of metabolic changes in the patients with early MSA.

Methods: We included 38 patients who had a shorter than 3 yearshistory of motor or cerebellar symptoms compatible with probableMSA. We also included 16 age-matched controls. According to thedisease duration, we classied the patients into three groups (1YRgroup: patients with disease duration between 1 and 12 months; 2YRgroup: patients with disease duration between 13 and 24 months; 3YRgroup: patients with disease between 25 and 36 months). The quanti-tative FDG PET scan studies with arterial blood samplings wereperformed, according to the method reported previously. Using thegroup comparison statistics in the SPM2 (statistical parametric map-ping) software, we compared each group of MSA with normal controls.We considered the cerebral regions signicant when the cluster-levelcorrected p value was less than 0.05.

Results: In the 1YR group, the glucose metabolism was reduced in thecerebellum, brainstem, medial frontal (BA10) and lateral frontal (BA8)cortices. The 2YR group showed reduced metabolism at the temporo-parieto-occipital association cortices, thalamus, caudate and posterior partof the putamen, in addition to the areas involved in 1YR group. In 3YRgroup, the pattern of hypometabolism was similar to that of 2YR group,but the striatal hypometabolism spread to involve its anterior part.

Conclusions: The hypometabolism of cerebellum, brainstem andfrontal motor association cortices occurs within one year after the onsetof motor or cerebllar symptoms. Hypometabolism of the putamen andtemporo-parieto-occipital cortices occurs in patients with disease du-ration longer than one year. Hypometabolism of the anterior part of thestriatum occurs in patients with duration longer than two years.10Neuroprotection and Natural History in Parkinson Plus Syn-dromes (NNIPPS): Results of a randomized placebo-controlledtrial of riluzole in PSP and MSAP.N. Leigh, A. Ludolph, Y. Agid, G. Bensimon, The NNIPPSConsortium (London, United Kingdom)

Objective: To test the efcacy of riluzole in progressive supranuclearpalsy (PSP) and multiple system atrophy (MSA) and to investigate thenatural history of PSP and MSA presenting as parkinsons plussyndromes.

Background: PSP and MSA often present as parkinson plus syn-dromes. The natural history is poorly understood, and diagnosis isproblematic. Excitotoxicity may contribute to neuronal damage. Weinvestigated the effect of riluzole, a glutamate release inhibitor, onsurvival and function and acquired prospective data on diagnosticcriteria, natural history, MRI changes, and pathology.

Methods: NNIPPS is an European multicentre, stratied, randomized(PSP or MSA) parallel-group trial of riluzole (50mg-200mg daily)

ORAL PLATFORM PRESENTATION 4602, TUESDAY, JUNE 5, 2007 S3


versus placebo in patients with PSP and MSA. The primary outcomemeasure was survival at 36 months. Secondary outcome measuresincluded functional status, cognition, quality of life, service costs, andMRI abnormalities. Power calculations were based on published esti-mates of survival. The primary analysis was intent-to-treat (ITT).Treatment effect was analyzed by the Kaplan-Meier method using astratied Log-Rank test, and the Cox proportional hazards model.

Results: 766 subjects (363 PSP, 403 PSP) were recuited in UK,France, and Germany, randomized over 3 years and followed double-blind for up to 36 months. Pathological diagnosis in 112 cases showed90% sensitivity and specicity for PSP and MSA using NNIPPSdiagnostic criteria. Median survival from onset was 7.8 years for PSPand 8.7 for MSA. There was no signicant difference in survivalbetween PSP and MSA from randomization. PSP subjects were moreimpaired on measures of clinical and cognitive function. Analysis ofthe ITT population showed no evidence of a signicant treatment effectof riluzole in the population as a whole, or in the PSP or MSA strata.

Conclusions: Riluzole has no neuroprotective effect in PSP or MSA,but survival can be used as a primary outcome measure for trials inearly-stage PSP and MSA (parkinsons plus syndromes). NNIPPSprovides a unique resource for understanding motor, cognitive, neuro-imaging, and genetic factors in MSA and PSP.

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Degeneration of cardiac sympathetic nerve can occur in multiplesystem atrophyS. Orimo, T. Kanazawa, A. Nakamura, T. Uchihara, F. Mori,A. Kakita, K. Wakabayashi, H. Takahashi (Tokyo, Japan)

Objective: The pathophysiological mechanism accounting for theslight decrease in meta-iodobenzylguanidine (MIBG) uptake in somepatients with multiple system atrophy (MSA) remains to be elucidated.For conrmation, we examined cardiac tissue and sympathetic gangliafrom patients with MSA.

Background: Decreased cardiac uptake of MIBG on MIBG myocar-dial scintigraphy, a sensitive biological marker for Parkinsons disease(PD), is related to cardiac sympathetic denervation in patients with PD.A slight decrease in cardiac uptake of MIBG has also been reported insome patients with MSA.

Methods: We immunohistochemically examined each specimen of15 patients with MSA together with 10 control subjects using antibod-ies against tyrosine hydroxylase (TH) and neurolament (NF).

Results: The number of TH-immunoreactive nerve bers in theepicardium was preserved in 8 of 15 patients with MSA, as well as in10 control subjects. The number of TH-immunoreactive, but not ofNF-immunoreactive nerve bers in the epicardium, was mildly ormoderately decreased in six patients with MSA, of whom four showeda decrease of TH immunoreactivity in the neuronal somata in thesympathetic ganglia. Moreover, TH- and NF-immunoreactive nervebers almost entirely disappeared in the heart in one patient with MSA,in whom Lewy body pathology was present in the sympathetic ganglia.

Conclusions: These ndings suggest that mild degeneration of thecardiac sympathetic nerve can occur in MSA, which is closely relatedto the pathological change of neurons in the sympathetic ganglia,accounting for the slight decrease in cardiac uptake of MIBG. More-over, concurrent Lewy body pathology in the sympathetic gangliamight accelerate cardiac sympathetic denervation even in MSA.

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Correlates of side-to-side symmetry of motor manifestations inParkinsonian disordersR.P. Munhoz, H.A. Teive, L.C. Werneck (Curitiba, PR, Brazil)

Objective: To study the clinical prole of Parkinsons disease (PD)patients with symmetric motor symptoms in comparison with thosepresenting more typical asymmetric parkinsonism.

Background: Although symptoms of PD are initially unilateral, bothbody sides will eventually become affected with some degree of asymme-try remaining evident throughout the disease course. In cases of symmetricsymptoms, the possibility of atypical forms of parkinsonism should be

suspected. A minority of cases, however, will not fulll criteria for diag-noses other than PD despite exhibiting symmetric symptoms.

Methods: A total of 909 patients with parkinsonism were assessedafter a 12 hour drug withdrawal following a standardized protocolincluding clinical data, UPDRS-III, Hoehn & Yahr staging, assessmentof cognition, and psychosis. Asymmetry was dened subjectively ac-cording to history of side of symptom onset and most affected side onexamination concordant with objective side to side comparison ofUPDRS items scores for motor signs.

Results: Symmetric symptoms were detected in 240 (26.4%) sub-jects: 69 (28.7%) had PD, 56 (23.3%) drug induced parkinsonism(DIP), 40 (16.6%) vascular parkinsonism (VP), 25 (10.4%) Lewy bodydementia (LBD), 22 (9.1%) multiple system atrophy (MSA), 20 (8.3%)progressive supranuclear palsy (PSP), 8 (3.3%) normal pressure hydro-cephalus. Among the 669 subjects with asymmetrical symptoms, 24(3.5%) had non-PD diagnoses: 7 MSA, 4 each with VP, LBD andcorticobasal degeneration, 3 with DIP and 2 with PSP. Patients withsymmetrical PD (SPD) were signicantly older than those with asym-metrical symptoms (APD), age of onset was signicantly later for SPDpatients. Psychosis but not dementia was more frequent in the SPDgroup. Rigid akinetic parkinsonism with worse postural instability wassignicantly more common among SPD patients.

Conclusions: SPD is an unusual presentation of PD and usuallyinidicates alternative diagnoses. We hypothesize that some of theaspects that differentiate SPD and APD may reect a more widespread,extra nigral neurodegeneration.

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The dystonia-associated protein torsinA modulates synaptic vesiclerecyclingA. Granata, G. Schiavo, T.T. Warner (London, United Kingdom)

Objective: Investigate the role of torsinA in dystonia by identifyingnew protein binding partner.

Background: Most of cases of early-onset torsion dystonia arecaused by a dominantly inherited in-frame GAG deletion in the DYT1(TOR1A) gene, which results in the loss of a glutamic acid in theC-terminal region of the encoded protein, torsinA. There is no evidencefor neurodegeneration, implying that there is a functional neuronaldefect. TorsinA is a member of the AAA ATPase superfamily ofchaperone-like proteins, which is present in the cytoplasm and in thelumen of endoplasmic reticulum (ER). Mutant torsinA (E-torsinA) isredistributed from ER to the nuclear envelope (NE) and it is accumu-lated in large perinuclear membranous inclusions. These inclusionshave been detected in DYT1 brain, supporting their role in the patho-genesis of dystonia.

Methods: We performed a yeast two-hybrid screening using full-length wt-torsinA and E-torsinA as baits to identify interacting part-ners. We then analyzed vesicle recycling in human neuroblastomaSH-SY5Y cell lines, stably transfected with the wt and E-torsinA.Two methods were used to measure synaptic vesicle (SV) trafc: 1.labelling with the antibody raised against the intravesicular epitope ofsynaptotagminI (Syt-I); 2. analysis of loading and unloading of thelipophilic dye FM1-43.

Results: The two-hybrid screen identied Snapin, a SNAP25 (syn-aptosomal associated protein of 25 kDa) binding protein and its inter-action with both wild-type and mutant torsinA was conrmed by invitro and in vivo assays. Snapin is required to enhance the interactionbetween the SNAREs and the synaptic calcium sensor, Synaptotag-minI. This is a crucial step in the mechanism of fusion of the SVtriggered by calcium inux. Both experiments to monitor SV recyclingshowed that wt-torsinA negatively affected the endocytic mechanism,whereas the mutant E-torsinA had the opposite effect of increasingvesicle loading.

Conclusions: These ndings suggest that torsinA has a role incontrolling SV turnover, which may be mediated by its interaction withsnapin. This may affect neuronal trafc of neurotransmitters, such usdopamine, leading to abnormal signalling in the pathway involved inthe control of movement.



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Pallidal deep brain stimulation improves quality of life in segmen-tal and generalized dystonia: Results from a prospective, random-ized sham-controlled trialJ. Mueller, I.-M. Skogseid, R. Benecke, W. Poewe, G. Deuschl,A. Kupsch, T. Trottenberg, J. Volkmann (Innsbruck, Austria)

Objective: To evaluate the impact of deep brain stimulation (DBS)on health-related quality of life (HRQoL) and symptoms of depressionin a randomized, sham-stimulation-controlled trial of DBS in primarysegmental and generalized dystonia.

Background: Trials of pallidal DBS have shown promising results inpatients with medically refractory dystonia, but little is known aboutthe effects of this treatment on HRQoL and symptoms of psychologicaldistress.

Methods: 40 pts. with medically refractory primary generalized(n24) or segmental dystonia (n16) were implanted with electrodesinto GPI and randomized to either active or sham-stimulation for 3months, followed by either 3 or 6 months of open-label treatment, fora total of 6 months of neurostimulation in each group. HRQoL wasassessed by SF-36, depression with BDI. Severity of dystonia wasmeasured with BFMDRS Movement score, and disability with BFM-DRS Disability score.

Results: At baseline, all SF-36 domain scores were signicantlyreduced in the patient group compared to data from a normal popula-tion sample. Randomized study period: Active stimulation as comparedto sham-stimulation resulted in signicant reductions of BFMDRSMovement and Disability scores, and of pain scores after 3 months.Signicant improvement of HRQoL was observed in the active stim-ulation group only. Open-label study extension: After 6 months ofcontinuous DBS, the average BFMDRS Movement score reduction wassignicant both in generalized (-42%) and segmental dystonia (-53%).Comparisons of baseline and 6-month data for the entire group showedsignicant improvements in all SF-36 domains and the BDI score.

Conclusions: This rst sham-controlled DBS trial in dystonia provesa positive effect on HRQoL in patients with medically refractorysegmental and generalized dystonia. Three months of active stimulationresulted in signicant improvement of the severity of dystonia, andphysical aspects of HRQoL, compared to sham stimulation. Notably,none of the SF-36 dimensions improved with sham-stimulation. Theclinical benet was sustained after 6 months of continuous DBS, andthe symptomatic benet translated into a signicant improvement of allSF-36 domains, as well as of depression scores.

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Patients with writers cramp show a reduced activation of the leftsubthalamic region during handwriting with the affected handM. Peller, K. Zeuner, M. Weiss, A. Knutzen, M. Hallett, G. Deuschl,H.R. Siebner (Kiel, Schleswig-Holstein, Germany)

Objective: To use functional MRI (fMRI) at 3 T to investigatechanges in regional neuronal activity during handwriting and scribblingin patients with writers cramp (WC). We hypothesized that patientswith writers cramp would show an abnormal activation of the con-tralateral substantia nigra during handwriting, but not during scribbling.

Background: Writers cramp is a task-specic hand dystonia affect-ing handwriting. Though current concepts assume a dopaminergicdysfunction in the basal ganglia, motor activation studies during hand-writing have mainly revealed changes in cortical activity.

Methods: 22 patients with WC and 18 healthy controls were studiedwith BOLD-sensitive fMRI at 3 T. We used an epoch-related fMRIdesign with alternating periods of rest and task. There were twoexperimental tasks which were performed in blocks. Participants re-peatedly wrote the german German word alle or produced consecu-tive up- and down strokes with their right dominant hand. Each blockconsisted of ve trials which were repeated every 5s. Participants werefamiliarized with the task prior to fMRI and the written trace ofhandwriting and scribbling was recorded outside the MR scanner. Tominimize dystonia during writing, a foam grip was attached to the shaftof the pen. fMRI data were analyzed with SPM2 (Wellcome Dept. of

Imaging Neuroscience, UCL, UK). We performed a small volumecorrection using spherical regions-of-interest tha covered the right andleft substantia nigra (30 mm diameter). Signicance threshold was setat P0.05 (FDR; cluster level).

Results: Dystonic symptoms were very mild during scribbling andhandwriting. The comparison of regional BOLD signal changes duringhandwriting and scribbling revealed a between-group difference intask-related activity in the left substantia nigra. Patients with WCshowed a relative decrease in activation of the substantia nigra duringhandwriting as opposed to scribbling (T 4.06; x,y,z -9,-18,-9).

Conclusions: This is the rst fMRI study that shows a task-specicunderactivation of the substantia nigra contralateral to the affectedhand. The relative underactivition of the substantia nigra during hand-writing indicates a context-specic functional abnormality of the basalganglia in writers cramp.16Clinical and electrophysiological phenotype of myoclonus dystoniadue to epsilon sarcoglycan gene mutationsE. Apartis, E. Roze, F. Clot, I. Guyon-Marechal, S. Thobois,C. Tranchant, P. Damier, Y. Beaugendre, A. Durr, M. Vidailhet(Paris, France)

Objective: To describe the clinical and electrophysiological pictureof myoclonus, in myoclonus dystonia (M-D) or essential myoclonus(E-M) syndromes, caused by mutations in the epsilon-sarcoglycan gene(SGSE).

Background: SGSE gene mutations are present in up to 30 % of M-Dor E-M syndromes. Myoclonus in M-D or E-M is the predominantfeature, with alcohol sensitive brisk jerks involving mainly the face,neck and upper limbs. Myoclonus is documented as sub cortical, but agenetic signature lacks in electrophysiological studies.

Methods: We conducted a multi centric prospective clinical andelectrophysiological study of myoclonus in 35 patients - from 21families - carrying a SGSE mutation with M-D or E-M syndromes.Electrophysiological analysis included polymyography (n35), C-re-ex recording (n27) at rest and during mild contraction and EEGjerk-locked-back-averaging (JLBA) (n15).

Results: Myoclonus involved the face (31%), voice (34%), fourlimbs (50%) with upper limbs predominance, two upper limbs (23%) orlower limbs (4%) and almost always the axis. It was symmetrical in60% of the cases or asymmetrical/unilateral. Generally, myoclonusoccurred at rest and was increased by action. Nevertheless, it wasabsent at rest in 7 cases. It was never responsive to somesthetic stimuliand rarely (5 %) induced by loud sounds. Brief shock-like myoclonusoccurred without any temporo-spatial organization. The duration ofmyoclonic bursts recorded at rest and during action was 95.7/-37.4ms (m/-SD; range 32-256 ms; n287 bursts) and there was nodifference in both conditions. Rhythmic myoclonus occurred in 8 cases(frequency: 3-10 Hz). Negative myoclonus was an exception. C-reexwas negative and JLBA failed to detect any premyoclonic corticalpotential. Moreover, we describe in detail the associated dystonia, ifpresent.

Conclusions: We provide a straightforward and comprehensive elec-tro clinical description of myoclonus in a large series of patientscarrying diverse mutations in the SGSE gene. We conrm that briefshock-like myoclonus observed in this condition is of sub-corticalorigin.

ORAL PLATFORM PRESENTATION 4602, TUESDAY, JUNE 5, 2007 S5



Wednesday, June 6, 20072:30 PM4:30 PMLocation: Marmara Room

PARKINSONS DISEASE17

The physiological effects of pedunculopontine stimulation in pa-tients with Parkinsons diseaseS. Tisch, J.C. Rothwell, V. Di Lazzaro, M. Dileone, F. Capone,P. Proce, A. Insola, P. Mazzone (London, United Kingdom)

Objective: To study the effects of pedunculopontine (PPN) stimula-tion on motor cortex and spinal excitability in patients with Parkinsonsdisease (PD).

Background: The PPN is a brainstem nucleus involved in motorcontrol and locomotion and has emerged as a promising new target forDBS in PD, although little is known about the physiological effects ofPPN stimulation in humans.

Methods: Four patients with PD implanted in PPN were studied withthe DBS electrode externalized. EMG was recorded from rst dorsalinterosseous muscle, TMS was applied to the motor cortex at anintensity to elicit a 1 mV motor evoked potential (MEP) unconditionedand with prior single stimuli to PPN at interstimulus intervals (ISI) of2,4,6,8 and 10ms. PPN stimuli were bipolar, 2-4 V, 60-90 sec dura-tion. H-reexes were recorded from soleus and exor carpi radialiswith single stimuli, 1s trains and continuous PPN stimulation at 25Hz.In one patient we recorded scalp EEG during 0.2 Hz PPN stimulation.

Results: Single PPN stimuli inhibited the MEP from the ipsilateralmotor cortex by a mean of 37% 9 maximal for ISI 4-6 ms. Noinhibition was observed in the contralateral hemisphere. Single andtrains of PPN stimuli did not alter H-reex amplitude. Continuousstimulation resulted in progressive increase in H-reex amplitude overminutes (mean 67% 21) which persisted for several minutes afterPPN stimulation was stopped, independent of changes in M-waveamplitude. PPN stimulation produced a distinct central cortical evokedpotential with an early negative waveform (onset latency 4.6 ms, peak8 ms, amplitude 0.61 V) and a later larger positive waveform (onsetlatency 33 ms, peak 47ms, amplitude 2.2 V).

Conclusions: We have demonstrated ipsilateral short latency motorcortex inhibition after PPN stimulation and an evoked potential earlycomponent at a similar latency. These effects may be due to antidromicstimulation of cortico-PPN bres or activation of adjacent mediallemniscus or cerebellar bres. The progressive facilitation of H-reexesduring and after 25 Hz PPN stimulation suggests short-term plasticitywithin descending reticulospinal control of spinal excitability, and mayexplain why patients experience progressive benet, over minutes, afterPPN DBS is commenced.

18Clinimetric testing of the new UPDRS (MDS-UPDRS) vs. originalversionC.G. Goetz, B.C. Tilley, S. Shaftman, G.T. Stebbins, S. Fahn,P. Martinez-Martin, W. Poewe, C. Sampaio, M.B. Stern, R. Dodel,B. Dubois, R. Holloway, J. Jankovic, J. Kulisevsky, A.E. Lang,A.J. Lees, S. Leurgans, P.A. LeWitt, D. Nyenhuis, C.W. Olanow,O.O. Rascol, A. Schrag, J. Teresi, J.J. van Hilten (Chicago, Illinois,USA)

Objective: Compare the original Unied Parkinsons Disease RatingScale (UPDRS) and the new version of the scale (MDS-UPDRS) forinternal consistency, measurement characteristics, and score equiva-lency.

Background: The standard rating scale for Parkinsons disease (PD)patient monitoring is the UPDRS. In 2001, after a Movement Disorder

Society-sponsored critique of the scale, the society ofcially endorsedthe development of a new version of the UPDRS to address weaknessesand to expand the assessment of PD to include more non-motor aspects.The new scale (MDS-UPDRS) was adapted in response to cognitivepretesting, more data have been gathered, and this report is an initialcomparison of the original and new versions in a large PD patientsample.

Methods: Movement disorder physicians and experienced study co-ordinators examined PD patients with both scales. Scores were sub-mitted to a central data base, and all queries were resolved before thedatabase was locked. An emphasis was placed on assessing patientsfrom diverse racial/ethnic backgrounds and across all Hoehn and Yahrstages. Patients receiving levodopa or other drug treatments, untreatedpatients, and those who had undergone neurosurgical procedures werepermitted. All patients and raters spoke uent English. Sample sizecalculations to assess equivalency between the total scores on the twoscales, as well as item-by-item evaluations required a sample of 700patients. Data are reported as means and standard deviations (SDs);associations are measured with spearman correlation coefcients. TheMDS-UPDRS and UPDRS total scores were compared using a pairedt-test (new version minus old version).

Results: Data entry closed on January 31, 2007 with 809 patientsenrolled, approximately two-thirds men. The majority was Caucasian(675), but minority representation (total 134, 16.6%) included 8 NativeAmericans, 41 Asians, 47 African-Americans, and 42 participants ofother ethnicities. Hoehn and Yahr stage at the time of UPDRS andMDS-UPDRS scoring was: Stage I72, Stage II459, Stage III173,Stage IV74, Stage V27. The number of patients receiving levodopaalone or in combination with another symptomatic treatment for PDwas 741, while 66 were untreated. Internal consistency was high forboth instruments (Cronbachs alpha UPDRS 0.945; MDS-UPDRS 0.940). The distributions of scores were similar: Mean, SD, UPDRS 56.7, 27.0, covering 55 items; MDS-UPDRS 63.6, 27.1, covering 65items. The mean difference between the MDS-UPDRS and the UPDRSwas 8.41 (SD8.77, p0.0001, paired t-test). The correlation betweenthe total scores (r 0.95), combined Parts I and II (Mentation andActivities of Daily Living from UPDRS and Non-motor and MotorExperiences of Daily Living from MDS-UPDRS) (r 0.90), Part III(Motor examination for both UPDRS and MDS-UPDRS) (r 0.95),and Part IV (items 32-39 on dyskinesias and motor uctuations onUPDRS and Motor Complications on MDS-UPDRS) (r 0.88) werehigh.

Conclusions: In the beginning phases of the clinimetric analysis, theMDS-UPDRS demonstrates good validity for total and sub-sectionscores. As expected, a positive difference was detected between the twototal scores as they were not designed to be in exact agreement. TheMDS-UPDRS was designed to be an expanded version of the UPDRSand this is consistent with the positive mean difference when old issubtracted from new. A full Item Response Theory analysis will beimportant to assess the similarities between the two scales, to under-stand the psychometric properties of the newly added items, and toeliminate duplicative items. The additional analyses will also includedeveloping an algorithm to interpret UPDRS scores when a comparisonto the MDS-UPDRS is required.

19The 2 adrenergic antagonist pamezole prolongs the anti-parkin-sonian actions of L-DOPA in the MPTP-lesioned macaqueT.H. Johnston, J.-M. Savola, S.H. Fox, J.M. Brotchie (Toronto,Ontario, Canada)

Objective: To assess the quality of the extended on-time observedwhen L-DOPA is combined with pamezole in the MPTP-lesionedmacaque.

Background: We have previously shown that the 2 adrenergicantagonist pamezole is effective at reducing peak-dose L-DOPA-induced dyskinesia and increases the duration of anti-parkinsonianaction of L-DOPA in both MPTP-lesioned primates and PD patients.

Methods: Six cynomolgus monkeys (Macaca fascicularis) were ren-dered parkinsonian by repeated administration of MPTP and motor



complications were induced by twice daily L-DOPA treatment(16.9mg/kg) for 6 months. For each animal, two doses of L-DOPA, lowand high were dened such that the lower dose (20-30mg/kg) providedan anti-parkinsonian benet that lasted only 2h but was not compro-mised by disabling dyskinesia while the high dose (40-60mg/kg) pro-vided a longer, 3-4h, antiparkinsonian benet but was compromised bysignicant levels of disabling dyskinesia. These doses of L-DOPA wereco-administered, orally, with either vehicle or pamezole (10mg/kg).

Results: Fipamezole signicantly increased the duration of action,i.e. total on-time, of both the low and the high dose of L-DOPA, by76% and 43% respectively. Fipamezole also decreased the severity ofpeak dose chorea, but not dystonia, seen following administration ofthe high dose L-DOPA. These actions were associated with an increasein the amount of good on time, i.e. on-time during which dyskinesiawas not disabling, or was absent, by 74% and 98%, after combinationof pamezole with the low and high doses of L-DOPA respectively.

Conclusions: These data conrm that pamezole can reduce peak-dose dyskinesia and increase the time for which L-DOPA providesanti-parkinsonian action. Moreover, the increase in on-time is notassociated with disabling dyskinesia thus pamezole provides a meansto increase good on-time after each administration of L-DOPA.These data further support to the concept of developing pamezole toreduce motor complications in PD.

20

Topography of -synuclein pathology in Parkinsons diseaseM.E. Kalaitzakis, M.B. Graeber, S.M. Gentleman, R.K.B. Pearce(London, United Kingdom)

Objective: Assessment of the topographical distribution of-synuclein (aSN) pathology in the Parkinsons disease (PD) brain.

Background: It has been proposed that the development of aSNpathology in PD follows an ascending stereotypical pattern starting inthe lower brainstem to then involve what are considered less vulnerablecell groups in more rostral brainstem areas. Involvement of higher braincentres and the cerebral cortex would be secondary. However, thereliability of this staging of aSN pathology originally proposed byBraak has been questioned.

Methods: 75 brains (57 PD and 18 with other neurodegenerativedisorder; mean age at death 77.5 years) were examined. Alpha-synuclein immunohistochemistry was carried out for the dorsal motornucleus of the vagus (DMV), locus coeruleus (LC), substantia nigra(SN), Nucleus Basalis of Meynert (NBM), amygdaloid complex (AC),CA2 sector of the hippocampus, entorhinal cortex (EC) and superiorfrontal gyrus (SFG) followed by semi-quantitative assessment. In 14PD cases the spinal cord (SC) was also examined.

Results: Among PD subjects, the SN was affected in 100% of theanalyzed cases as expected. The NBM was affected in 98.2% of thecases, making it the second most vulnerable nucleus. The neurons ofthe DMV were aSN immunopositive in 92.9% and LC in 91.2% ofcases. The involvement of AC was seen in 85.9% followed by the EC84.2%. The CA2 sector of the hippocampus was affected in 78.9% ofthe cases whereas the least affected region was the SFG (77.1%). TheDMV was unaffected in 4 PD cases in whom aSN pathology wasobserved in rostral brainstem structures (including the SN) and thecerebral cortex. In addition, 15 of the analyzed PD cases did not seemto t the predicted caudo-rostral spread of aSN pathology. The SC wasaffected in all (n14) PD cases analyzed with accompanied affectionof the DMV.

Conclusions: Our results demonstrate a predominant involvement ofthe SN and NBM but do not support the existence of a medullaryinduction site of aSN pathology in the PD brain.

21

Prospective comparison of weight gain and energy intake aftersubthalamic (STN), pallidal (GPi) and thalamic (VIM) deep brainstimulation (DBS) in Parkinsons diseaseS. Blanchard, G. Drillet, P. Sauleau, S. Drapier, A.-S. Gillioz,T. Rouaud, J. Peron, M. Verin (Rennes, France)

Objective: To study both quality and specicity of changes in foodintake after STN DBS.

Background: Little is known about the mechanism of weight gainobserved after STN DBS.

Methods: We assessed prospectively the weight, body mass index(BMI) and daily energy intake (DEI) recorded by a dietary interview in48 parkinsonian patients three months before and six months after STN(n24), GPi (n12) or VIM (n12) DBS. In addition, motor andneuropsychological evaluations were performed in the same sessionsaccording to the Core Assessment Program for Intracerebral Transplan-tations protocol.

Results: Weight and BMI increased signicantly in STN group incomparison with both GPi and VIM groups. DEI increased in STNgroup, mainly because of increase of glucides intake. This increase wasnot correlated with the motor improvement. DEI dramatically de-creased in GPi group, correlated with motor improvement, and re-mained unchanged in VIM group.

Conclusions: STN DBS induced food intake and energy balancedysregulation, mainly because of increase of glucides intake, neitherobserved after GPi nor VIM DBS. These results are consistent with theinvolvement of human STN in motivation for food, already demon-strated in animal models.

22

Staging of lewy-related pathology in a community-based sample ofdementia: Evidence for disease-dependent anatomic distributionJ.B. Leverenz, E.B. Larson, D. Vavrek, E.R. Peskind, J.D. Bowen,W.C. McCormick, L. Teri, W.A. Kukull, T.J. Montine, D.W. Tsuang(Seattle, Washington, USA)

Objective: To examine the anatomic distribution of LRP in a com-munity-based autopsy sample of dementia.

Background: Published criteria for the staging of Lewy-related pa-thology (LRP) in normal elderly, Parkinsons disease (PD), and de-mentia with Lewy bodies suggest a caudal (medulla) to rostral (neo-cortex) progression of this pathologic change. However, there isevidence that in some patients, particularly those with dementia, theanatomic distribution of LRP is not always consistent with this stagingscheme.

Methods: Cases from this autopsy sample were enrolled in a longi-tudinal study of dementia in a community-based setting. All cases wereexamined for LRP using alpha-synuclein immunohistochemistry in themedulla, substantia nigra, amygdala, cingulate gyrus/parahippocampalgyrus, and frontal cortex. Severity of LRP in each region was rated, andcases were assigned a LRP classication based on a modication ofpublished criteria.

Results: 260 autopsy cases from the sample were available foranalysis. LRP was observed in 126 of these cases (49%). In the LRPpositive cases 16% had brainstem predominant LRP, 19% were amyg-dala predominant, 18% were limbic, and 44% were neocortical. Coex-istent Alzheimers disease (AD) was associated with an atypical ana-tomic distribution of LRP. Thus, 96% of amygdala predominant LRPpositive cases (limited or no brainstem LRP) had AD, while only 40%of the brainstem predominant LRP cases also had AD.

Conclusions: LRP is common in dementia, as evidenced by thepresence of this pathology in nearly half of the cases. Of note, nearlyhalf of these had neocortical LRP. The distribution of LRP in a subsetof this sample, those with amygdala predominant LRP, was inconsis-tent with published staging criteria for LRP in PD and dementia withLewy bodies. In addition, nearly all of these cases had coexistent AD.The results suggest that the progression of LRP in AD may not followthe pattern observed in more pure LRP-associated diseases such asPD.

ORAL PLATFORM PRESENTATION 5601, WEDNESDAY, JUNE 6, 2007 S7


23Neuropsychological and psychiatric sequelae of deep-brain stimu-lation for Parkinsons disease a randomized controlled multi-center studyC. Daniels, K. Witt, J. Reiff, P. Krack, M. Krause, K. Boetzel,A. Schnitzler, L. Wojtecki, R. Hilker, E. Kalbe, G.H. Schneider,A. Kupsch, G. Deuschl, for the German Parkinson Study Group,Neurostimulation Section (Kiel, Germany)

Objective: To evaluate the neuropsychological and psychiatric ef-fects of bilateral deep brain stimulation of the subthalamic nucleus-(STN-DBS) compared to optimized medical treatment in advancedParkinsons disease (PD) in a randomized controlled study.

Background: STN-DBS markedly reduces parkinsonian symptomsin patients with advanced Parkinsons disease and leads to a signicantimprovement of quality of life. Two controlled studies on the neuro-psychological effects of STN-DBS reported a mild deterioration ofattention and executive functioning, but in both studies no randomiza-tion between surgery and best medical treatment was performed.

Methods: 134 pairwise randomized patients from the Randomizedtrial of deep brain stimulation for Parkinsons disease1 underwentneuropsychological and psychiatric examinations to evaluate thechanges from baseline to six month after STN-DBS or optimizedmedical treatment.

Results: The STN-DBS group showed a signicant decline in verbaluency and the Stroop test. All other neuropsychological tests and thepsychiatric scales did not reveal signicant differences between theSTN-DBS group and the medication group. However, adverse eventsassociated to neuropsychological or psychiatric symptoms were morefrequent in the STN-DBS group.

Conclusions: This is the rst randomized controlled study evaluatingneuropsychological and psychiatric sequelae of STN-DBS. STN-DBSseems to be relatively safe concerning neuropsychological and psychi-atric side effects in carefully selected patients. The decline of executivefunctioning is in line with the ndings of previous studies. However,the implications of the decline in executive functioning after STN-DBSfor daily life still need to be investigated in detail. The evaluation ofmood and overall psychiatric functioning did not reveal signicantchanges on group level, though patients with STN-DBS more fre-quently developed neuropsychological or psychiatric symptoms.

1 Deuschl et al. A randomized trial of deep-brain stimulation forParkinsons disease. N Engl J Med. 2006 Aug 31;355(9):896-908.24

Neuropathological characteristics of Parkinsons disease associatedwith LRRK2 I2020T (Sagamihara family)S. Ujiie, Y. Ogino, M. Ogino, T. Uchihara, S. Yagishita,K. Hasegawa, H. Kowa, F. Sakai (Sagamihara, Kanagawa, Japan)

Objective: To evaluate neuropathological characteristics of Parkin-sons disease associated with LRRK2 I2020T (Sagamihara family).

Background: In spite of the high prevalence of LRRK2 mutation infamilial Parkinsons disease, neuropathological studies have been per-formed only on limited number of cases and the results so far haveshown a pleomorphic picture. This pathological heterogeneity isthought to be characteristics of the disease with LRRK2 mutations.Here we report pathological ndings of this family in detail.

Methods: Six autopsied cases (ve women, one man) with Parkin-sons disease associated with LRRK2 I2020T (Sagamihara family)were studied. Age at onset was 52.34.9, disease duration was19.34.9 (years) and age at death was 71.79.9. The initial symptomwas clumsiness of unilateral leg movement in ve cases and difcultyin walking in one case. Response to L-Dopa was good for long time.Autonomic symptom was absent or mild and there was no cognitivedysfunction. Brain sections of six autopsy cases were studied. Brainsections were stained with hematoxylin-eosin, anti phosphorylatedalfa-synyclein and anti-PHF tau(AT8) antibodies.

Results: Our results showed marked neuronal loss and gliosis in Sub-stantia Nigra (SN). In comparison with SN, the changes of Locus Ceruleus(LC) were very mild. Lewy Bodies (LBs) were found in only one case in

SN, LC, Dorsal Vagal Nucleus (DVN) and Amygdara. In contrast, no LBswere found in other cases. Anti-tau antibodies (AT8) immunostainingperformed in four cases revealed tau positive structure in LC in all casesand in mid-brain Central gray matter in two cases. Tau positive structuresin Hippocampus were not found in three out of four cases.

Conclusions: The core pathologic ndings of this family weremarked neuronal loss and gliosis in SN with preservation of LC. LBswere not found in most cases but denitely positive in one case. Despitesimilarity in clinical features and distribution of neuronal loss, exis-tence of pathological aggregates is heterogeneous. And we suppose thattau positive deposits mainly found in LC and mid-brain central graymatter are unique to this family.


Wednesday, June 6, 20072:30 PM4:30 PMLocation: Halic Room

CLINICAL ELECTROPHYSIOLOGYAND IMAGING

25

Probing a heterosynaptic manifestation of homeostatic plasticity inthe intact human motor cortexM. Poetter, S. Fischer, G. Deuschl, A. Quartarone, H. Siebner (Kiel,Germany)

Objective: The aim of our study was to investigate homeostaticmechanisms of primary motor hand area (M1-Hand) excitabilitychanges induced by paired associative stimulation (PAS).

Background: Homeostatic control mechanisms represent an impor-tant tool to stabilize cortical excitability changes within a physiologicalscope. We tried to establish a valid human model to investigate in vivohomeostatic mechanisms of heterosynaptic plasticity of the corticospi-nal output projections in the M1-Hand.

Methods: In 10 healthy subjects, we performed two experimentalsessions separated by at least 1 week. In one session we appliedfacilitatory premotor rTMS (5Hz, 5300stimuli, I90%active MT,biphasic pulse) prior to facilitatory PAS. The PAS protocol consisted of200 paired stimuli (0.25Hz) of electrical conditoning stimuli applied tothe right median nerve at the wrist (I300%sensory threshold) preced-ing single monophasic TMS-pulses at left M1-Hand (IMEP1mV) ininterstimulus interval (ISI) adjusted to the N20 latency of the corticalSSEP of the median nerve (ISI: N20 latency2ms). In the secondsession we used inhibitory premotor TMS (1Hz, 2750stimuli) beforeapplication of inhibitory PAS (ISI: N20 latency-5ms). To probe corti-cospinal excitability, we recorded 4 blocks of MEP before and afterrTMS and PAS from the rst dorsal interosseus (FDI, target muscle),the right abductor pollicis brevis (APB) and abductor digiti minimi(ADM) muscle (80-2500Hz, sampling rate 5000Hz).

Results: With preceding 5Hz rTMS, the facilitatory PAS protocolinhibited the MEP amplitudes at rest (FDI: pre PAS 1.650.09 mV;post PAS 1.080.17mV). Conversely, when 1Hz rTMS was appliedprior to inhibitory PAS, MEP were facilitated by the inhibitory Pasprotocol (FDI: pre PAS 0.830.09 mV; post PAS 1.420.15mV).3factorial ANOVA with the factors session (1Hz premotorTMS-iPASvs. 5Hz premotor rTMS-fPAS), muscle (FDI, APB, ADM) and time(t1-4) revealed a signicant interaction of intervention x time (p0.26,F3.9, Greenhouse-Geisser).

Conclusions: The impact of PAS on M1-HAND critically dependson the preexisting state of excitability of the conditioned M1-HAND.Our ndings suggest the existence of heterosynaptic homeostatic meta-plasticity in the M1-Hand that keeps corticospinal excitability within aphysiological range.



26Impaired temporal preparation in Parkinsons disease: Slow brainpotential and oscillatory manifestationsP. Praamstra, P. Pope (Birmingham, United Kingdom)

Objective: To investigate temporal preparation in Parkinsons dis-ease (PD) under conditions where temporal preparation is incidental tothe primary task.

Background: One of the functions attributed to the basal ganglia isthe processing of temporal information. Performance on time percep-tion and production tasks in PD provide support for such a role.However, evidence from explicit timing tasks is not necessarily rele-vant to timing in motor performance. Here we use EEG measures ofimplicit timing to investigate preparation under conditions where prep-aration is optional.

Methods: PD patients (n10) and age-matched control subjects (CS;n12) conducted a choice reaction task with two temporally regularstimulus presentation regimes, both including occasional deviant inter-stimulus intervals. EEG was recorded continuously from 128 scalpelectrodes and analyzed to extract slow brain potentials and event-related spectral perturbations during the interstimulus intervals.

Results: Control subjects, but not patients, demonstrated temporalpreparation in the form of an adjustment in time course of slow brainpotentials to the duration of the interstimulus interval. Deviant intervalswere accompanied by a slow brain potential amplitude drop at the timeof expected stimulus occurrence, demonstrating intact representation oftime in patients. Oscillatory activity in beta and alpha bands showedreduced post-movement event-related synchronisation (ERS) and at-tenuated preparatory desynchronisation (ERD) in patients. Althoughthe modulation of beta activity was abnormal, beta activity was notincreased compared to controls.

Conclusions: PD patients demonstrate impaired temporal preparationbut intact encoding of temporal intervals. This dissociation, ie. thefailure to translate the registration of temporal regularity into prepara-tory activity, may be explained by impaired dopamine dependentstriatal learning mechanisms.

27

Simultaneous EMG-fMRI; relating movement and brain activity intremorA.-F. van Rootselaar, N.M. Maurits, R. Renken, J.H.T.M. Koelman,J.M. Hoogduin, K.L. Leenders, M.A.J. Tijssen (Amsterdam,Netherlands)

Objective: 1) To investigate the additional value of electromyography(EMG) during functional magnetic resonance imaging (fMRI) in Move-ment Disorders patients, and 2) To gain insight in the origin of tremor.

Background: Simultaneous EMG-fMRI is a new method proven tobe feasible in healthy controls. It potentially permits to investigate thefunctional abnormalities of involuntary movements. Familial corticalmyoclonic tremor with epilepsy (FCMTE) and essential tremor (ET)are both clinically characterized by tremulous movements of the limbsand both show cerebellar pathology. However, in FCMTE functionalabnormalities of the cerebral cortex are likely.

Methods: Eight FCMTE patients, eight ET patients and nine healthycontrols performed wrist exion-extension movement and posture (ex-tended wrist and ngers). Surface EMG was recorded from wrist extensormuscles. The design matrix incorporated both conventional block designand residual EMG power regressors, after Gram-Schmidt orthogonaliza-tion of the EMG-regressors with respect to the block-design regressors forposture and movement. For the rst-level analyses SPM2 and for thesecond-level random effects analysis SnPM was used.

Results: Major ndings: 1) In controls block movement contrastcorrelated with the known motor areas whereas the residual EMGmovement contrast correlated with the ipsilateral cerebellum; 2) In ETpatients the block contrasts showed less involvement of motor areasand more (contra)lateral cerebellar activity; 3) In FCMTE patients allcontrasts showed less cerebellar activity. Residual-EMG posture con-trast (tremor-activity) corrrelated with bilateral sensory areas wereasblock posture contrast did not (Figure).

Conclusions: Results of residual EMG-contrasts differed from theblock contrasts. In healthy controls, the variability in exion-extensionmovement (EMG) correlated with the cerebellum, whereas duringsustained posture no specic area was identied with EMG. TheFCMTE patients, with high EMG variability during posture, showedbilateral activity of the somatosensory area, compatible with corticalhyperexcitability. Continuous EMG recording during fMRI-scanninggives, additionally to information concerning task execution, insight inbrain activation related to (superuous) movement.

28Change in water diffusion MRI following repetitive transcranialmagnetic stimulationM. Abe, T. Mima, N. Sawamoto, S. Urayama, T. Aso, H. Fukuyama(Kyoto, Japan)

Objective: To examine whether diffusion-weighted imaging (DWI)technique can detect cortical changes elicited by repetitive transcranialmagnetic stimulation (rTMS).

FIG. 1 (27).

ORAL PLATFORM PRESENTATION 5602, WEDNESDAY, JUNE 6, 2007 S9


Background: rTMS can modulate the cortical excitability, which canlast beyond the end of stimulation. Recent neuroimaging studies havesuggested lasting synaptic activity at the stimulated site and distantareas after the end of rTMS. DWI is a useful tool for measuringmicroscopic states of the brain tissue by probing water diffusion. Wehypothesized that DWI technique can detect the cellular changes elic-ited by rTMS. Previous reports examining alternations of water diffu-sion in the stimulated site were controversial. In the present study, weexplored brain regions showing rTMS-induced cortical alternations ofwater diffusion in the stimulated site and remote areas.

Methods: Ten healthy volunteers received rTMS at 0.9 Hz (10min;subthreshold) applied over the left primary hand motor area (M1HAND)within a 3-T MR scanner. We scanned 5 sets of DWI data (before(twice), and 0min, 10min and 20 min after rTMS), and measured motorevoked potentials (MEPs) of the hand intrinsic muscle for estimatingthe motor cortical excitability. Images were analyzed with the statisticalparametric mapping software (SPM2). Signal changes between datasets before and just after the intervention were statistically determinedby a voxel-by-voxel one-way ANOVA. The intervention-induced al-terations of MEP size were also assessed by using paired two-tailed ttests.

Results: MEP size tended to have a lasting reduction within 10 minafter end of rTMS, consistent with previous reports. Following therTMS, water diffusion was signicantly increased in bilateral sensori-motor cortex (SMC), premotor cortex (PMC) and prefrontal cortex(PFC). Among these areas, the alterations in right PMC and bilateralPFC lasted for longer than 10 min after cessation of the intervention:the former recovered within 20 min. the latter kept for 50 min.

Conclusions: We found the increased water diffusion elicited byrTMS in SMC, PMC, PFC bilaterally. It was possible that the cellularwater diffusion changes might reect trans-synaptic neural plasticityelicited by rTMS.

29

White matter changes in the diagnosis of presymptomatic neuro-degenerative diseases: The example of Huntingtons diseaseS. Kloppel, B. Draganski, S.J. Tabrizi, R.S.J. Frackowiak (London,Germany)

Objective: 1.) Can diffusion tensor MRI-data (DTI) from patients inthe presymptomatic stage of a neurodegenerative disease like Hunting-tons disease (HD) be used as a diagnostic tool. 2.) Can mapping ofwhite matter bre tracts identify region-specic neuropathology.

Background: HD is a neurodegenerative disorder with primary pa-thology in the striatum and characteristic abnormalities of movement,cognition and behaviour. It is caused by a known genetic mutation andcan therefore be diagnosed in patients many years before the onset ofsymptoms. The disease constitutes an important model for investigat-ing other neurodegenerative disorders for which no genetic test isavailable.

Methods: We present diffusion tensor MRI-data (DTI) from 22pre-symptomatic gene carriers (PSC) and 20 matched controls. Thesignal obtained depends on the diffusion of water along white matterbre tracts and is used to compute the local fractional anisotropy (FA),a marker of white matter integrity. The principal direction of diffusionin each white matter voxel can be used to generate streamlines thatidentify anatomical connections.

Results: Using a multivariate support-vector machine we classied80% of subjects correctly as either PSC or controls based on theirsubject-specic FA-map alone. Comparing fronto-striatal connectionsbetween PSC and controls we found a region specic degeneration ofbre tracts from superior frontal gyrus, compatible with neuropatho-logical studies suggesting a loss of pyramidal neurons in that area.

Conclusions: Taken together our study indicates that classicationby DTI is a sensitive diagnostic tool for this pre-symptomatic neuro-degenerative disorder. The region-specic pattern of bre degenerationmay provide differential information for clinically similar disorders andsuggests further studies of selective neuronal vulnerability in the patho-physiology of HD.

30Hyposmia, midbrain hyperechogenity and Parkinsons disease:Findings in a population-based studyK. Seppi, H. Stockner, S. Kiechl, J. Schwaiger, M. Sawires,J. Willeit, W. Poewe (Innsbruck, Austria)

Objective: Assessment of the association of nigral hyperechognicityand hyposmia with Parkinsons disease PD in a population-basedcohort.

Background: In recent years a number of potential biomarkers forParkinsons disease (PD) have been identied including transcranialsonography (TCS) of the substantia nigra (SN) and the assessment ofolfaction by smell tests.

Methods: Subjects: Population-based cohort of 562 subjects aged55-94 years. Methods: TCS from both sides, a thorough neurologicalassessment and assessment of olfactory dysfunction (odor identicationof the 12 items of the Snifn Sticks Screening test). For the purposeof the present study, hyperechogenicity was dened as an area ofechogenic signal of 0.16cm2 or greater at least on one side (i.e. 75thpercentile of controls), hyposmia was dened as a correct identicationof less than or equal to 8 of the 12 items of the smell test (i.e. 25thpercentile of controls).

Results: 15% of the individuals had an insufcient bone window,therefore analysis was performed in 480 participants. About one quarterof total population were found to have SN hyperechogenicity at least onone side and hyposmia. 16 subjects out of the sample were diagnosedwith PD. Of these, 94% had hyperechogenic areas and 63% hadhyposmia compared to 22% and 24% of healthy participants. Patientswith PD had signicantly increased mean echogenic areas (0.19cm2vs0.10cm2) and signicantly decreased olfactory function scores (6vs10) compared to controls. Among normosmic subjects with normo-echogenic SN, none of the subjects had PD, PD was present in 3% ofthe hyposmic subjects with normal SN echogenity; among the normos-mic subjects with SN hyperechogenicity the proportion of subjects withPD was 7%; the proportion of PD rose to over 30% in the subcohort ofhyposmic subjects with SN hyperechogenicity.

Conclusions: This is the rst population-based study assessing as-sociations of two potential biomarkers for PD with the prevalence ofPD. The prevalence of PD was highest in the subcohort of hyposmicsubjects with hyperechogenic SN and second highest in the subcohortof subjects with SN hyperechogenity and normosmia. This data sug-gests that hyperechogenicity is a risk marker for PD and that PD riskfurther increases in individuals with both SN hyperechogenity andhyposmia.

31Firing patterns of STN in early stage PD patients implanted withDBSC.H. Harrison, N.D. Manus, C.E. Gill, C.C. Kao, M.S. Remple,T.L. Davis, J.S. Neimat, P.E. Konrad, P.D. Charles (Nashville,Tennessee, USA)

Objective: To compare the size and ring patterns of the subthalamicnucleus (STN) in early Parkinsons disease (EPD) patients to thosewith more advanced disease (APD).

Background: Recent literature has begun to explore the use of deepbrain stimulation (DBS) as a treatment of PD before patients developdisabling motor uctuations. Intraoperative microelectrode recordings(MER) facilitate optimal lead placement and provide valuable dataabout cell ring patterns. Excessive glutaminergic outow from STNmay contribute to neuronal loss in the substantia nigra pars compacta(SNc). Animal data suggest stimulation of STN slows the rate of SNcdopaminergic cell loss.

Methods: We collected MER in the rst three subjects randomized toDBS as part of a prospective investigation of DBS in EPD (Hoehn andYahr II). Two to four recording electrodes were advanced in 500micrometer increments along a trajectory determined by preoperativeneuroimaging. Electrical potentials were recorded at each point andanalyzed for multi-unit ring rate and background noise. Firing fre-quencies of individual neurons in the STN were determined by ofine



analysis. The length of STN in each recording tract was determined bythe relative hyperactivity characteristic of the nucleus. These ndingswere compared with MER using a similar trajectory from three age andgender matched patients with H&Y IV PD previously implanted asstandard of care.

Results: There was no signicant difference in the length of STN(4.760.24mm for EPD vs. 4.710.94mm for APD [n12]). The ratioof background noise in STN to substantia nigra pars reticulata (SNr)was signicantly lower in EPD (2.120.63 versus 3.190.41 for APD,p0.01). For ring frequency, a total of 119 STN units were isolatedacross patients. Average ring was signicantly lower in EPD (23.09Hz, n61) relative to APD (26.99 Hz, n58, p0.02).

Conclusions: STN mapping of three EPD patients shows that hyper-active neuronal activity similar to that observed in APD can be used toguide DBS lead placement. Relative increases in background noise andring frequency of STN in APD indicate increased activity with diseaseprogression. Given the potential toxicity of STN output on SNc, thesedata may support the argument for earlier initiation of DBS therapy.32Connections between premotor and motor cortex in healthy sub-jects and in patients with Parkinsons diseaseA. Suppa, M. Bologna, C. Lorenzano, F. Gilio, M. Napoletani,A. Berardelli (Rome, Italy)

Objective: To investigate whether subthreshold rTMS over premotorcortex (PM) lead to changes in the MEP facilitation elicited by rTMSof M1.

Background: Suprathreshold 5 Hz repetitive transcranial magneticstimulation (rTMS) over primary motor cortex (M1) evokes motorpotentials (MEPs) in hand muscles that progressively increase in am-plitude (MEP facilitation).

Methods: 15 right handed normal subjects were studied in threeseparate experimental sessions using a conditioningtest rTMS para-digm. In all experimental sessions test-rTMS consisted of trains of 10stimuli delivered at 5 Hz over the left M1. Conditioning-rTMS con-sisted of trains of 1500 subthreshold stimuli (90% active motor thresh-old, AMT) delivered randomly in two separate sessions at 1 Hz or 5 Hzover PM. The changes in MEP facilitation were measured and analyzedbefore and after 1 Hz conditioning (real and sham) or 5 Hz PM-rTMSstimulation. We also conducted a preliminary study on the connectionbetween the premotor area and the hand area of the primary motorcortex in 5 parkinsonian (PD) patients, while off and on therapy.

Results: In normal subjects 1 Hz rTMS over PM signicantly de-creased the degree of MEP facilitation. The inhibitory effect lasted forabout 30 minutes after conditioning stimulation ended. There was noeffect on MEP facilitation after 5 Hz PM-rTMS. Test-rTMS deliveredin trains at 5-Hz frequency over the primary motor cortex, had nofacilitatory effect on the size of MEPs in PD patients off therapy, andonly a non signicant facilitatory effect in patients on therapy. Condi-tioning-rTMS with 5Hz suprathreshold trains over the premotor cortexhad no facilitatory effects on MEP in the off state, whereas there wasan increase of the MEP facilitation during the train in the on state.

Conclusions: In normal subjects 1 Hz PM-rTMS reduces the mech-anism of short-term cortical plasticity underlying MEP facilitationinduced by 5 Hz M1-rTMS, probably by acting through PM-to-M1cortico-cortical connections. In Parkinsons disease suprathreshold 5Hz rTMS of the left premotor cortex in PD patients facilitates shortterm cortical plasticity, only when PD patients are in the on state.

POSTER SESSION ITuesday, June 5, 20079:00 AM4:00 PMRumeli Hall, Lower LevelPoster Numbers 33345 and PosterNumber 683Authors Present: 12:30 PM2:30 PM

ATAXIA33High eld proton MR spectroscopy of sporadic and hereditaryspinocerebellar ataxiasG. Oz, I. Iltis, D. Hutter, C.M. Gomez (Minneapolis, Minnesota, USA)

Objective: To compare neurochemical alterations in cerebella and ponsof patients with cerebellar multiple system atrophy (MSA/C) to twoprototypic hereditary ataxias, SCA2, a cerebellar-predominant multiplesystem atrophy and SCA6, a pure cerebellar ataxia, as well as healthycontrols.

Background: SCAs are characterized by loss of cerebellar Purkinjecells in combination with neuronal loss in other regions, such as thepons. Most MRS studies of SCAs reported differences in ratios ofNAA, creatine and choline between patients and controls. Utilizing a 4tesla (T) magnet allows measurement of concentrations of numerousneurochemicals, such as neurotransmitters (glutamate, GABA) andgliosis markers (myo-inositol, glutamine) in the human brain (Oz et al,Neurology, 2005, 64:434).

Methods: Neurochemical proles of the vermis, cerebellar whitematter and pons of healthy controls (N16) and patients with MSA/C,SCA2 and SCA6 (N5 in each group) were obtained by ultra-shortecho time (5 ms) 1H MR spectroscopy at 4 T using previously de-scribed methods (Oz et al, Neurology, 2005, 64:434). Concentrations of9-12 metabolites were measured reliably in the three volumes-of-interest and corrected for atrophy.

Results: Signicant neuronal loss in the vermis was indicated in bothMSA/C and SCA2 by reduced NAA and glutamate (p0.05). Vermiangliosis was indicated in all three diseases by increased myo-inositol(p0.001), but was most prominent in MSA/C, where glutamine wasalso increased (p0.05). Creatine was increased in the vermis in SCA2and MSA/C (p0.001), which may also result from gliosis. Metabolicdisturbances in vermis in MSA/C and SCA6 were implied by increasedlactate (p0.05). Involvement of cerebellar white matter was morepronounced in SCA2 and MSA/C than SCA6 based on alterations inNAA, glutamate, myo-inositol, glutamine and creatine, while increasedcholine, likely due to myelin loss, was only signicant in SCA2 andSCA6. Involvement of pons was restricted to SCA2 and MSA/C, andmore prominent in MSA/C based on more drastic changes in NAA andmyo-inositol (p0.0002).

Conclusions: Alterations in MSA/C were more similar to SCA2 thanSCA6, consistent with known pathology. Proton MRS at 4 T can beused to non-invasively evaluate disease- and brain region-speciccellular and biochemical events in sporadic and hereditary SCAs.

34Frequency of the MCP sign in FMR1 premutation carriers andFXTASM.A. Leehey, D. Rubinstein, A.G. Brega, D. Hall, F. Tassone,L. Zhang, R. Hagerman, P.J. Hagerman, J. Grigsby (Denver,Colorado, USA)

Objective: To dene the frequency of increased signal intensity in themiddle cerebellar peduncles on MR imaging, the MCP sign among: 1)carriers of fragile X mental retardation 1 (FMR1) premutation, 2) non-carriers of FMR1 premutation, 3) carriers with fragile X-associated tremor/ataxia syndrome (FXTAS) and 4) carriers without FXTAS.

POSTER SESSION I, TUESDAY, JUNE 5, 2007 S11


Background: FXTAS is a recently described late-onset disorder char-acterized by progressive action tremor, gait ataxia and cognitive decline;other signs include parkinsonism, autonomic and possibly neuropathicdysfunction. The disorder typically affects male carriers with CGG repeatexpansions in the premutation range (55-200) of FMR1. Larger expansions(200 repeats) cause fragile X syndrome, the most common heritableform of mental retardation. MR imaging may reveal the unusual anddistinctive MCP sign, but it is unclear how often affected and non-affectedcarriers have this sign. To date the MCP sign has been described in onlytwo persons shown to have a normal FMR1 repeat size.

Methods: All males over age 50 with FMR1 repeat size in the controlor premutation range that participated in a genotype-phenotype study ofFXTAS at two academic centers and that underwent standardized MRscanning were included. Carriers were considered affected if they hadaction tremor or cerebellar ataxia. Images were scored by a neurora-diologist (D.R.) blinded to FMR1 repeat size for the presence, symme-try and intensity of MCP signs.

Results: Among the 106 men that participated, 67 were premutationcarriers, of which 39 were affected. Average age (SD) of affectedcarriers was 68.18.5, unaffected carriers 63.811.1, and non-carriers59.19.7. The MCP sign was present in 23 of the 67 carriers (34%) andin none of the non-carriers. Twenty of 39 (51%) affected carriers and threeof 28 unaffected carriers (11%) had the MCP sign. MCP signs varied inintensity; all were bilateral and frequently extended into the cerebellum.

Conclusions: While the MCP sign is present in only about half ofpersons with FXTAS and a third of older male premutation carriers, itseems specic for the FMR1 premutation status.35NARP-MILS syndrome caused by 8993T>G mitochondrial DNAmutation showing ragged-red bersJ. Youn, J.Y. Kim, W.Y. Lee, E.J. Chung, W.T. Yoon, Y.-L. Suh,C.S. Ki (Seoul, Republic of Korea)

Objective: To report a 32-year-old NARP-MILS patient with8993TG mutation in mitochondrial DNA, who presented atypicaldyskinesia and ragged-red bers in muscle biopsy.

Background: The 8993TG mutation in mitochondrial DNA isrelated with variable clinical ndings of neuropathy, ataxia, retinitispigmentosa (NARP) and inherited Leighs syndrome (MILS). NARP-MILS syndrome has been reported to seldom have ragged-red bers ordyskinetic symptoms.

Methods: In this patient, we examined neurologically and ophthalmo-logically, and performed nerve conduction study (NCS), muscle biopsy,brain MRI and direct sequencing analysis of the mitochondrial DNA.

Results: In the neurological, she had truncal ataxia and dyskineticmovement affecting face (Video). Fundoscopic examination revealedretinitis pigmentosa in both eyes. NCS demonstrated sensory dominantsensorimotor polyneuropathy in all extremities. Her muscle biopsyshowed ragged-red bers and neuropathic myopathy under light levelhistopathology and mitochondriopathy associated cytoarchitecturalchanges under electron microscopy (Figure 1). Brain MRI showedsignicant cerebellar atrophy. Direct sequencing analysis of the mito-chondrial DNA revealed the m.8993TG mutation in the patient(Figure 2).

Conclusions: It is rare case showing abnormal dyskinetic movementand ragged-red bers on muscle biopsy in genetically conrmedNARP-MILS syndrome.

36

Gordon Holmes spinocerebellar ataxia with retinal dystrophyS.-J. Kim, E.-J. Chung, J.-H. Joo (Busan, Korea)

Objective: To report a case of Gordon Holmes spinocerebellar ataxiawith retinal dystrophy.

Background: Gordon Holmes spinocerebellar ataxia is characterizedby co-occurance of progressvie spinocerebellar ataxia and hypogonad-ism. It is rare disease which was rst described by Gordon Holmes in1907. This disease is highly heterogeneous syndrome with insidiousonset in second decade of life. Gordon Holmes spinocerebellar ataxiamay be associated with cognitive impairment, choreoathetosis, retinop-athy, deafness, hypercalcemia or pyramidal signs.

Methods: We present a case with ataxia, hypogonadism and retinop-athy.

Results: An 18-year-old male patient visited our clinic with progres-sive ataxia. On past history, he was diagnosed as retinal dystrophy at12-years-old. On physical examination, he had no axillary and pubichair. The genital examination showed small penis and testis. Neuro-logical examination revealed cerebellar ataxia and gaze evoked nys-tagmus. Routine and specic laboratory analyses focusing on metabolicor inammatory disease gave no evidence for abnormalities. Endocri-nological assessment revealed a low serum levels of testosterone 0.23pg/ml (2.8-8.0 pg/ml), follicle stimulating hormone 0.86 mIU (1.4-18.1mIU) and luteinizing hormone 0.51 mIU (1.5-9.3 mIU). In summary,these results were consistent with hypogonadotrophic hypogonadism.Brain MRI showed diffuse cerebellar atrophy and normal pituitarygland.

Conclusions: We report clinical and laboratory features of a patientwith ataxia and hypogonadism, typical phenotype of Gordon Holmesspinocerebellar ataxia and retinal dystrophy.

37

Ataxin-2 localizes at the Endoplasmic reticulum and co-sedimentswith polysomesS. van de Loo, J. Nowock, R. Hilker, G. Auburger (Frankfurt/Main,Germany)

Objective: To understand the physiological functions of ataxin-2, wehave analyzed its subcellular distribution by immunocytochemistry andsubcellular fractionation.

Background: Spinocerebellar ataxia type 2 (SCA2) is a neurodegen-erative disorder with pronounced atrophy of cerebellar Purkinje, ponto-olivary, nigral and motoneurons, caused by the unstable expansion of apolyglutamine domain in the disease protein ataxin-2.

Methods: Immunocytochemical analyses were performed on COS-7cells and on primary cultures of murine hippocampal neurons. Endo-plasmic reticulum and polysomal fractions were generated using sub-cellular fractionantion and ultracentrifugation experiments of mousebrain homogenates.FIG. 1 (35).



Results: Ataxin-2 immunostaining was exclusively observed in thecytoplasm, particularly at a prominent structure adjacent to the nucleus,and in punctae towards the cell periphery. The pathogenic form ofataxin-2 with an expanded polyQ domain showed the same distributionpattern. Double-labeling and confocal microscopy identied the jux-tanuclear structure as endoplasmic reticulum (ER). Further, ataxin-2was found to colocalize in part with endosomes. Ultracentrifugationexperiments found ataxin-2 to co-sediment with the polysomal fraction.

Conclusions: These results are in agreement with recent ndings thatataxin-2 is recruited to stress granules which represent transient struc-tures of stalled mRNA synthesis under environmental stress. For theataxin-2 homologue of drosophila, an association with polyribosomeshas also been shown. These data in conjunction with the proteinarchitecture of ataxin-2 suggest that ataxin-2 is involved in mRNAprocessing and/or regulation of translation.

38

A phase III double-blind, randomised, placebo-controlled study ofthe efcacy, safety and tolerability of idebenone in the treatment ofFriedreichs ataxia patientsP. Giunti, J. Gray, N.W. Wood (London, United Kingdom)

Objective: The study aims to conrm the positive effect on neuro-logical function, assessed using the International Cooperative AtaxiaRating Scale (ICARS) and the Friedreichs Ataxia Rating Scale(FARS). Effects on cardiac mass and

abstracts of the movement disorder society's eleventh international congress of parkinson's disease...

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