JYournal ofNeurology, Neurosurgery, and Psychiatry 1996;61:591-595

Brain MRI, lumbar CSF monoamineconcentrations, and clinical descriptors of patientswith spinocerebellar ataxia mutationsJ J Higgins, J D Harvey-White, L E Nee, M J Colli, T A Grossi, I J Kopin

AbstractObjectives-To serially assess changes inlumbar CSF biogenic amines, radi-ographic characteristics, and neurologi-cal signs in 34 patients with dominantlyinherited ataxia.Methods-Mutational analysis was usedto identify genetic subgroups. Annualassessment of lumbar CSF monoaminemetabolites using a gas chromato-graphic/mass spectrometric method andmorphometric measurements of the cere-belium, pons, and the cervical spinal cordon MRI were analysed for each patientand compared with normal controls.Results-Patients with CAG trinucleotiderepeat expansions on chromosome 6p(mutSCAl) and chromosome 14q(mutSCA3) had only about one half thenormal concentrations of lumbar CSFhomovanillic acid (HVA) whereas, 5-hydroxyindoleacetic acid (5-HIAA) con-centrations were similar to those in agematched normal subjects. The HVA and5-HIAA concentrations in clinically simi-lar patients without mutSCAl ormutSCA3 were normal. One year afterthe first study, HVA concentrations werereduced by a mean of 22% regardless ofthe patient's SCA mutation.Abnormalities on MRI were consistentwith a spinopontine atrophy in patientswith mutSCA3, spinopontocerebellaratrophy in patients with mutSCAl, and"pure" cerebellar atrophy in patientswithout these mutations.Conclusions-Quantitative MRI mea-surements were not useful in monitoringprogression of disease but lumbar CSFHVA concentrations and total scores on arevised version of the ataxia clinical rat-ing scale seemed to progress in parallel.

( Neurol Neurosurg Psychiatry 1996;61:591-595)

Keywords: spinocerebellar degeneration; cerebellarataxia; biogenic monoamines; nuclear magnetic reso-nance

Six genotypes have been assigned to a group ofneurodegenerative disorders called the autoso-mal dominant ataxias. 1-9 Two of these dis-orders are characterised by an expanded CAGtrinucleotide repeat at the SCAl locus onchromosome 6pl (mutSCAl) and at theSCA3 locus on chromosome 14q

(mutSCA3). 59 10 Few studies have evaluatedlumbar CSF monoamine metabolites or quan-titative MRI abnormalities in groups ofpatients with dominantly inherited ataxia."-16Thus the results of clinical studies performedbefore the discovery of mutSCAl andmutSCA3 are difficult to interpret. Patientswith dominantly inherited ataxia and "pure"cerebellar cortical atrophy on MRI have lowlumbar CSF concentrations of 5-hydroxyin-doleacetic acid (5-HIAA) and homovanillicacid (HVA).16 By contrast, necropsy specimensfrom patients with mutSCAl show low con-centrations of striatal HVA with normal toincreased striatal concentrations of5-HIAA.'7 18 Before products containing L-tryptophan were associated with theeosinophilia-myalgia syndrome,'9 the serotoninprecursor, L-5-hydroxytrytophan (5-L-HTP)was found to be an ineffective treatment forpatients with dominantly inherited ataxia(Schut-Haymaker type and Machado-Josephdisease). As expected from the lumbar CSFmonoamine profile, L-5-HTP did improve sta-tic ataxia symptoms in patients with an MRIdiagnosis of "pure" cerebellar cortical atrophyand a clinical diagnosis of Harding ADCA typeIII.16 20 However, despite a depletion of striataldopamine and lumbar CSF HVA, levodopatreatment did not ameliorate ataxic symptomsin patients with dominantly inheritedataxia."" The distinct lack of parkinsoniansigns in many patients with mutSCAl andmutSCA3 implies that dopamine deficiency isnot great but suggests that a dopaminergicdeficit does play a part in the pathogenesis ofthese genetic disorders. Even though the grosspostmortem neuropathology correlates wellwith the radiological features of patients withataxia,"4 15 evaluating patients in treatmentgroups categorised by MRI findings is unsatis-factory as it ignores genetic heterogeneity. Toclarify the topography of MRI lesions and todefine the monamine abnormalities in patientswith SCA mutations, we longitudinally quanti-fied atrophic changes on MRI, measured lum-bar CSF monoamine metabolites, andobjectively assessed neurological examinationson a revised version of the ataxia clinical ratingscale (ACRS-rev).24-26

Materials and methodsPATIENT SELECTION AND CLINICAL TESTINGInformed consent was obtained from eachpatient before all genetic, radiological, andclinical tests. This study was approved by the

Clinical NeurogeneticsUnit, MedicalNeurology BranchJ J HigginsL E NeeM J ColliT A GrossiAminergicMechanisms Section,Clinical NeuroscienceBranch, NationalInstitute ofNeurological Disordersand Stroke, NationalInstitutes of Health,Bethesda, Maryland,USAJ D Harvey-WhiteI J KopinCorrespondence to:Dr J J Higgins, ClinicalNeurogenetics Unit, MedicalNeurology Branch, NationalInstitute of NeurologicalDisorders and Stroke,National Institutes of Health,Building 10, Room 5N234,Bethesda, Maryland 20892,USA.Received 16 January 1996and in final revised form14 June 1996Accepted 19 July 1996

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Figure 1 RepresentativeTl weighted MRI images(TR = 400 ms, TE =16 ms) displayed on theimage analyser monitorshowing the boundariesused to calculate (A) themediosagittal areas of thecerebellum, pons andposterior fossa and (B) theaxial area of the cervicalspinal cord.

Institutional Review Board of the NationalInstitute of Neurological Disorders andStroke. Investigators were blinded from thegenetic profiles of asymptomatic subjects.Patients from families with ataxia for three or

more consecutive generations were recruitedby the Neurogenetics Unit. JJH performed allneurological examinations and was blinded tothe ACRS scores when the patients were re-

evaluated at yearly intervals. The ACRS was

revised to account for the progressive loss oftone and reflexes in our population of patientsby assigning positive scores for decreases inthese items (ACRS-rev).

ASSAY OF CSF HVA AND 5-HIAA

After five days on a standard low monoaminediet and after eight hours of bed rest, a lumbarpuncture was performed in the lateral decubi-tus position. Routine CSF studies were per-

formed on the initial 4 ml CSF; for assay ofHVA and 5-HIAA an additional 10 ml wascollected in four 2-5 ml aliquots. All aliquotsof CSF were frozen immediately on dry iceand stored at - 70°C. To minimise the effectsof CSF monoamine concentration gradients,the fourth aliquot of CSF was used for analysis.Extraction, derivatisation, and measurementof HVA and 5-HIAA were performed as pre-viously described27 on a Hewlett PackardMSD 5970 mass spectrometer/gas chroma-tograph 5890 with preserved acid extracts ofCSF supematant liquid. The investigators(JDH-W, IJK) analysing the CSF sampleswere blinded to the patient's clinical andgenetic information.

GENETIC TESTINGA pair of fluorescein labelled oligonucleotidesflanking the genetic region of interest wereused in the polymerase chain reaction toamplify the CAG triplet repeats on chromo-somes 6p and 14q as previously described.9

MRI MORPHOLOGICAL MEASUREMENTSBrain MRI was performed twice at a oneyear interval, using a 0 5 Tesla unit scanner(Picker International Inc, model HPQ). Three5-0 mm mediosagittal images were obtainedparallel to the longitudinal fissure. The axialarea of the cervical spinal cord (CSC; perpen-dicular to the first cervical vertebra) and themediosagittal areas of the pons (P; an ellipticalpontine area bounded by the anterior surfaceof the pons, the interpeduncular fossa, and theputative medial lemniscus), cerebellum (Cb)and the posterior fossa (PF; a quadrangulararea bounded by the tentorium cerebelli, theinner table of the skull, and the clivus) werequantified using ANALYZETM version 6-2software (Biomedical Imaging Resources,Mayo Foundation, Rochester, MN) on aDIGITALTm DEC station 5000/125 (fig 1).Two investigators (MJC, TAG) were blindedto the ACRS scores and the genetic testingresults at the time of the MRI analysis.Triplicate measurements of each neu-roanatomical area were used to calculate themean area in pixels. The size of the Cb and Pwere expressed as a ratio to the PF to adjustfor variations in head size. Identical areas from10 normal volunteers were used for compar-isons with study participants.

STATISTICSStatView'M version 4-01 software (AbacusConcepts, Inc, Berkeley, CA, USA) was usedto compute all statistics. Differences betweengroups were examined by the Wilcoxonsigned rank test.28 A simple regression modelusing measures obtained at the beginning ofthe study as predictor variables and the mea-surements of these variables one year later asthe outcome variables was applied to the data.Residual values were plotted against thepredicted values to verify the accuracy ofthe regression equations. The Bonferonnimethod was applied to adjust the a levelaccording to the number of comparisons thatwere tested.29

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Brain MRI, lumbar CSF monoamine concentrations, and clinical descriptors ofpatients with spinocerebellar ataxia mutations

ResultsSERIAL CLINICAL FINDINGSThere were two families with mutSCAl, fivewith mutSCA3, and three without mutSCAlor mutSCA3 included in the study. Four of sixmembers from one family and two of threemembers from another family withoutmutSCAl or mutSCA3 had the clinical fea-tures of Harding ADCA type III. However,the four remaining members from these fami-lies without mutSCAl or mutSCA3 had theneurological signs (supranuclear gaze palsy,dementia, and extrapyramidal signs) associ-ated with Harding ADCA type I. All the fami-lies, regardless of genotype, exhibited thephenotypic variability seen in Harding ADCAtype I. Neurological findings on the ACRSwere similar in the 34 patients (mutSCAl,n = 7; mutSCA3, n = 17; without mutSCAlor mutSCA3, n = 10) examined. All patientshad gait ataxia varying from mild to severe.Cranial nerve findings included dysarthria,nystagmus, internuclear ophthalmoplegia,supranuclear gaze palsies, slowed saccadicmovements, tongue fasciculations, and cough-ing dyspnoea. Retinoschisis and Parkinson'ssyndrome were present in one family withoutmutSCAl or mutSCA3 but these featureswere not found in any of the patients involvedin the MRI or CSF analyses. Deep tendonreflexes and muscle tone ranged betweenextremes. Sensation in the limbs varied fromnormal to complete loss of position and painsensation. Limb atrophy, myoclonus, and sco-liosis also varied. There were no significantdifferences in sex, disease duration, age atonset of disease, or total ACRS-rev scoresbetween patients with mutSCAl, mutSCA3,or those patients without these mutations. Atthe onset of the study, patients withoutmutSCAl or mutSCA3 were older (63-6(3.3), mean (SEM)) than patients with

mutSCAl (35-8 (2-3)) and mutSCA3 (47d1(3-0)). In patients that were examined at ayearly interval (n = 14), the initial total scoreon the ACRS-rev was 27 (5) and one year laterit was significantly (P = 0-001) worse at 45(7). In patients with mutSCA3 (n = 11), theinitial total score was 34 (8) and was also sig-nificantly (P = 0 02) worse one year later at55 (10). As predicted by a simple regressionmodel, the initial total ACRS-rev scoreschanged 14 to 16 points in one year in allpatients regardless of genotype (fig 2A).

MONOAMINE METABOLITESThe opening pressure, protein, glucose, andthe microscopical appearance of the CSF wasnormal in all subjects. Lumbar CSF HVAconcentrations were about 54% to 55% lowerin patients with mutSCAl (n = 7) andmutSCA3 (n = 15), but 5-HIAA concentra-tions were not significantly different fromthose of normal subjects (n = 20). The ratioof HVA to 5-HIAA was significantly(P < 0 01) lower in patients with mutSCA3than in controls suggesting a monoaminergicneurotransmitter imbalance (table). A secondlumbar puncture was performed on ninepatients one year after the initial one. In thesepatients, lumbar CSF HVA concentrationsdecreased significantly (P < 0-01) by 22 (range0-42)%. Regression analysis predicted a rela-tion between the initial lumbar CSF HVAconcentrations and concentrations one yearlater (fig 2B).

FNDINGS ON MRITwo independent blinded investigators quan-tified the areas of the Cb P, PF, and CSC on1176 MRI images. In patients withoutmutSCAl or mutSCA3 (n = 7), quantitativeMRI findings were consistent with a cerebellaratrophy (Cb/PF = 65-3 (4 6); % normal

Figure 2 Longitudinalmeasurements of clinicaland biochemical variablesin patients with autosomaldominant ataxia. (A)Relation of initial totalACRS-rev scores to scoresafter a one year period ofobservation. (B) Relationof initial lumbar CSFHVA concentrations toconcentrations after a oneyear period of observation.

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Lumbar CSF monoamine metabolites in normal subjects and in patients with SCA mutations

Genotype HVA 5-HIAA Ratio HVAI(n) (ng/ml) (ng/ml) 5-HIAA

mutSCAl (7) 18-10 (2 69) (10O91-31-46)* 11-67 (2 00) (5 93-22-52) 1-61 (0 35) (1-09-2 02)mutSCA3 (15) 17-71 (2-45) (4-6244 00)** 13-82 (1-14) (5-44-21-66) 1 38 (0-18) (0-28-2 94)**Other-t (8) 41-22 (7-81) (8 68-68 67) 18-26 (3 27) (534-32 29) 2 18 (0-21) (1 10-2 85)

Total (30) 24 06 (3 07) (4 62-68 67) 14-51 (1-18) (5 34-32 29) 1-65 (0-12) (0 28-2 94)*

Normal (20) 39-08 (3 02) (17 03-61-50) 17-26 (1-26) (6 67-26 40) 2-30 (0-12) (1 50-3-39)

Values are mean (SEM) (range).*P < 0-05; **P < 0 01; Significantly lower compared with normal using the Wilcoxon signed rank test.tAffected subjects without mutSCAl or mutSCA3. mutSCA = Spinocerebellar ataxia gene mutations; HVA = homovanillic acid;5-HIAA = 5-hydroxyindoleacetic acid.

(SEM); P < 0.01)) with sparing of the pons(P/PF = 100 0 (6-3)) and cervical spinal cord(CSC = 86-5 (5 6)). In patients withmutSCA3 (n = 19) all three neuroanatomicalareas seemed to be atrophic (Cb/PF = 83-1(1'6), P < 0 01; P/PF = 77 0 (3-6), P = 0-03;CSC = 80 (5 0)). Analysis of these same neu-roanatomical areas showed severe atrophy

Figure 3 QuantitativeMRIfindings in patientswith autosomal dominantataxia. (A) Thecerebellumlposterior fossaratio indicates the mostatrophy in patients withoutmutSCAl or mutSCA3followed by those withmutSCAl, mutSCA3,and patients at risk formutSCA3. (B)Ponslposteriorfossa ratioand (C) the area of thecervical spinal cordindicate that these regionsare relatively spared inpatients without mutSCAIor mutSCA3 and inpatients at risk formutSCA3. Data areaverages of triplicatedeterminations (SEM)from two investigators.

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(Cb/PF = 72-8 (7.1), P < 0-05; P/PF = 71-4(4.7), P < 0 05; CSC = 71-0 (7-1),P < 0-05)) in patients with mutSCAl (n = 7).A CAG trinucleotide repeat expansion onchromosome 14q was identified in two of thesix members at risk. Quantitative MRI testingdetected cerebellar atrophy (Cb/PF = 75-2)and cerebellopontine atrophy (Cb/PF = 75-6;P/PF = 78-0) in two of these asymptomaticsubjects but a correlation with their geneticinformation could not be made due to theblinded study design (fig 3A-C) There wereno significant changes in the sizes of the Cb, P,or CSC on MRI in any of the study partici-pants over a one year period of observation.

DiscussionThe postmortem lesions in the dominantlyinherited ataxias show variable involvement ofthe substantia nigra, inferior olives, pontinenuclei, Purkinje cells, dentate nuclei, spin-ocerebellar tracts, anterior horn cells, and

Normal peripheral nerves. Presumably, the neu-risk ropathological and biochemical lesions seen in

patients with mutSCAl and mutSCA3 are notdirectly caused by their widely expressed geneproducts. Based on our MRI analysis, it seemsthat atrophy mainly occurs in the cerebellumin patients without mutSCAl or mutSCA3.The cerebellum, pons, and spinal cord are allaffected in patients with mutSCAl, and aspinopontine atrophy predominates in patientswith mutSCA3. These MRI findings are inagreement with the neuropathological findingsin patients with mutSCAl and mutSCA3.03'The low concentrations of CSF HVA inpatients with mutSCAl and mutSCA3 corre-late with the MRI findings, suggesting a more

Normal severe biochemical lesion affecting brainstemrisk dopaminergic pathways. The slightly lower

CSF concentrations of 5-HIAA in patientswith mutSCAl and mutSCA3 may also reflecta diminished contribution from the spinal cordand the cerebellar serotonergic pathways. Bycontrast, in patients without mutSCAl ormutSCA3 there does not seem to be amonoaminergic imbalance despite a "pure"cerebellar atrophy on MRI. Other investiga-tors have documented reduced striatal enzymeconcentrations of aromatic L-amino aciddecarboxylase and tyrosine hydroxylase inpatients with severe dopamine loss and areduction in tyrosine hydroxylase but not aro-matic L-amino acid decarboxylase in patients

Normal with moderate dopamine loss.'7 These findingsrisk and our current data suggest that serotonergic

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Brain MRI, lumbar CSF monoamine concentrations, and clinical descriptors ofpatients with spinocerebellar ataxia mutations

abnormalities in patients with mutSCAl andmutSCA3 may reflect a functional variation ofthe serotonergic system under abnormaldopaminergic control. We suggest that this isthe reason why patients with dominantlyinherited ataxia do not respond to agentswhich alter serotonin metabolism.To our knowledge, this is the first report

describing serial measurements of biochemi-cal, clinical, and radiological variables inpatients with dominantly inherited ataxia. Wehave found by MRI that the degree of atrophyof the cerebellum, pons, and cervical spinalcord do not change over a one year period. Itseems that lumbar CSF HVA concentrationsand the total ACRS-rev scores could serve asmeaningful biological markers to monitor pro-gression of disease during therapeutic trials.Until the underlying pathogenetic mechanismof the CAG trinucleotide repeat expansion isunravelled, symptomatic treatment is cur-rently the only option. Our data support thenotion that combined treatment with seroton-ergic and dopaminergic agonists may improvethe monoaminergic imbalance present inpatients with mutSCAl or mutSCA3.Interestingly, the MRI findings in those at riskfor mutSCA3 indicates that the cerebellummay be the first neuroanatomical structureinvolved in the disease process. However, therelative paucity of abnormal histological find-ings in the cerebellum of patients with themutSCA3 implies that the cerebellar afferentsoriginating in the brainstem are the first areastargeted by the disease.9'3 The distinct topog-raphy of radiological and biochemical lesionsin patients with various SCA mutations alsosuggests that there may be developmentallyregulated injuries to the metencephalon by dif-ferent genes, gene products, or modifier genes.

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