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A Novel Mutation in the Deoxyguanosine Kinase Gene

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A Novel Mutation in the Deoxyguanosine Kinase Gene BRIEFCOMMUNICATIONS decreasedinnervation.13 Thelatterfindingaffordedan ProgressiveLossofCardiac opportunitytodeterminewhetherthelossofcardiac SympatheticInnervationin sympathetic innervation in Parkinson’s disease progressesovertimeand,ifso,withwhattiming,pat- Parkinson’sDisease tern,andconsistencyacrosspatients.Thisreportde- scribestheresultsofretestingsuchpatientswith Sheng-TingLi,MD,PhD,RaghuveerDendi,MD, 6-[18F]fluorodopaminepositronemissiontomography CourtneyHolmes,CMT, scanningafteranaverageof2years. andDavidS.Goldstein,MD,PhD PatientsandMethods Thisstudyaddressedwhethercardiacsympathetic denervationprogressesovertimeinParkinson’sdis- ThestudyprotocolwasapprovedbytheIntramuralResearch ease.In9patientswithoutorthostatichypotension, BoardoftheNationalInstituteofNeurologicalDisorders 6-[18F]fluorodopaminepositronemissiontomography andStroke.Eachpatientgaveinformed,writtenconsent. scanningwasrepeatedafterameanof2yearsfromthe firstscan.6-[18F]fluorodopamine-derivedradioactivity waslessinthesecondscanthaninthefirstscan,by Patients 31%intheleftventricularfreewalland16%inthe Thoracicpositronemissiontomographyscanningwasper- septum.InParkinson’sdisease,lossofcardiacsympa- formedafterintravenousinjectionof6-[18F]fluoro- theticdenervationprogressesinapatternoflosssug- dopaminein9patientswithParkinson’sdisease(age: gestingadying-backmechanism. mean,60years;SEM,3years).Noneofthepatientshad orthostatichypotension,whichwasdefinedasadecreasein AnnNeurol2002;52:220–223 systolicbloodpressuregreaterthan20mmHganddecrease indiastolicpressuregreaterthan5mmHgbetweenthesu- pinepositionandstandingfor5minutes.Caffeine- containingbeverages,cigarettes,andalcoholwerenotal- Allofatleastadozenstudieshaveagreedthatpatients lowedforatleast24hoursbeforethescanning.Patients withParkinson’sdiseasehaveahighprevalenceofneu- wereallowedtotaketheirusualmedications,including roimagingevidencefordecreasedsympatheticinnerva- L-dopa,exceptformedicationsknowntoinhibitneuronal tionoftheheart.Lowmyocardialconcentrationsofra- uptakeofcatecholamines. dioactivityhavebeennotedafterinjectionofthe sympathoneuralimagingagents 123I-metaiodobenzyl- guanidine1–12 and6-[18F]fluorodopamine.13 Neuro- PositronEmissionTomographyScanning 18 14 chemicalassessmentsduringrightheartcatheterization 6-[ F]fluorodopamine,synthesizedasdescribedpreviously, haveconfirmedthatlowconcentrationsofradioactivity wasinfusedintravenouslyataconstantratefor3minutes. resultfromlossoffunctionalcardiacsympatheticnerve Tomographyimages(35contiguoustransaxialslices4.25mm 13 apart)wereacquiredforupto30minutes.Three- terminals. dimensionalpositronemissiontomographyscanswereob- AlthoughallpatientswithParkinson’sdiseaseand tainedwithanAdvancewhole-bodyscanner(GeneralElec- orthostatichypotensionhavediffuselydecreasedsym- tric,Milwaukee,WI).Transmissionscansof2minutesand patheticinnervationthroughouttheleftventricular 8minutes,withrotating 68Ge/68Gapinsources,wereob- myocardium,amongpatientswhodonothaveortho- tainedforattenuationcorrectionandforconfirmingproper statichypotension,abouthalfhavediffuselydecreased positioninginthescanner. innervationandabouthalfhavenormaloronlylocally Follow-upscanningwasperformed1to4years(mean, 2.0years;SEM,0.3years)afterthefirstscan,withtheiden- ticalscanningprocedure.Noneofthepatientshadortho- statichypotensionatthetimeofeithertest.Ofthe9pa- FromtheClinicalNeurocardiologySection,NationalInstituteof tients, 2 had normal 6-[18F]fluorodopamine-derived NeurologicalDisordersandStroke,NationalInstitutesofHealth, 18 Bethesda,MD. radioactivity and 7 had locally decreased 6-[ F]- fluorodopamine-derivedradioactivityintheleftventricular ReceivedNov28,2001,andinrevisedformFeb28andMar7, myocardiumatthetimeofthefirsttest. 2002.AcceptedforpublicationMar7,2002. Published online Jun 23, 2002, in Wiley InterScience (www.interscience.wiley.com).DOI:10.1002/ana.10236 DataAnalysisandStatistics AddresscorrespondencetoDrLi,Building10,Room6N252,Na- Tomographyimageswerereconstructedaftercorrectionfor tionalInstituteofNeurologicalDisordersandStroke,NationalIn- 18 stitutesofHealth,10CenterDrive,MSC-1620,Bethesda,MD attenuationandforphysicaldecayof F.Cardiacimages 20892-1620.E-mail:[email protected] wereanalyzedasdescribedpreviously.14 Briefly,circularre- ThisarticleisaUSGovernmentworkand,assuch,isinthepublicdo- gionsofinterestapproximatelyhalftheventricularwall mainintheUnitedStatesofAmerica. thicknesswereplacedonimagesoftheseptum,withtime- 220 Published2002byWiley-Liss,Inc. averaged pictures of a single slice. Left ventricular septal urinary frequency. None of the patients developed or- radioactivity was averaged from two regions of interest for thostatic hypotension between the first and second the 5-minute scanning interval with a midpoint about scans. 8 minutes after initiation of the infusion. The same At the time of the first scan, 2 patients had normal time interval was used for radioactivity in the liver and kid- myocardial 6-[18F]fluorodopamine-derived radioactiv- ney. For radioactivity in structures of the head and neck, 18 static three-dimensional data were obtained for 10 to 15 ity, and 7 had decreased myocardial 6-[ F]- minutes. Images of noncardiac structures, including the fluorodopamine-derived radioactivity confined to the liver, spleen, renal cortex, renal pelvis, salivary glands, na- lateral wall or apex, so that no patient had sopharyngeal mucosa, and thyroid, were reconstructed and 6-[18F]fluorodopamine-derived radioactivity more than analyzed by manual drawing of the regions of interest out- two standard deviations below the normal mean in lining the structures. Radioactivity concentrations were both the lateral wall and interventricular septum. normalized by correction for the radioactivity concentration All 9 patients had lower lateral wall concentrations for the administered dose of radioactive drug per unit of of 6-[18F]fluorodopamine-derived radioactivity in body mass of the subject and were expressed as nCi-kg/cc- mCi.14 the second scan than in the first scan (Fig 1). Mean values for 6-[18F]fluorodopamine-derived radioac- Left ventricular myocardial mean concentrations of 18 tivity were compared with paired t tests. Differences between 6-[ F]fluorodopamine-derived radioactivity decreased groups in trends over time of 6-[18F]fluorodopamine-derived by 23% between the first scans (mean, 5,122nCi-kg/ radioactivity were assessed by analyses of variance for re- cc-mCi; SEM, 564nCi-kg/cc-mCi) and second scans peated measures. A p value of less than 0.05 defined statis- (mean, 6,634nCi-kg/cc-mCi; SEM, 447nCi-kg/cc-mCi; tical significance. p ϭ 0.003). Lateral wall radioactivity decreased by 31% between the first scans (mean, 4,107nCi-kg/ cc-mCi; SEM, 535nCi-kg/cc-mCi) and second scans (mean, 5,991nCi-kg/cc-mCi; SEM, 537nCi-kg/cc-mCi; Results ϭ At the time of the first scan, patients had had Parkin- p 0.003), and septal radioactivity decreased by 16% son’s disease for 5.7 Ϯ 1.2 years (range, 0.3–13 years). between the first scans (mean, 6,137nCi-kg/cc-mCi; Disease severity averaged 2.2 Ϯ 0.2 (range, 1–3) of a SEM, 716nCi-kg/cc-mCi) and second scans (mean, ϭ maximum of 5. Heart rate and beat-to-beat systolic 7,278nCi-kg/cc-mCi; SEM, 385nCi-kg/cc-mCi; p blood pressure changes during phase II of the Valsalva 0.05; Fig 2, Table). In 1 patient, the lateral ventricular maneuver averaged 11 Ϯ 2bpm and Ϫ43 Ϯ 5mm Hg wall was not visualized in the second scan, and the tis- for a mean arterial baroreflex-cardiovagal gain of 2.3 Ϯ sue concentration was assumed to be equal to the left 0.4ms/mm Hg (normal: mean, 8.5ms/mm Hg; SEM, ventricular chamber concentration. 2.2ms/mm Hg). Plasma catecholamine levels (norepi- With the exclusion of data from the patient for nephrine: mean, 2.34nmol/L; SEM, 0.37nmol/L; epi- whom the left ventricular wall was not visualized in the nephrine: mean, 0.23nmol/L; SEM, 10nmol/L) were second scan, the percentage decrease in lateral wall ra- approximately normal. Most patients had tremor and dioactivity between the first and second scans (mean, Fig 1. Progressive loss of myocardial 6-[18F]fluorodopamine-derived radioactivity in a patient with Parkinson’s disease. Li et al: Sympathetic Innervation in Parkinson’s Disease 221 years. This rate of loss of sympathetic terminals appears to be at least as high as the rate of loss of nigrostriatal dopamine terminals.15 So far in our ongoing series, all patients with Par- kinson’s disease and orthostatic hypotension have had evidence of diffuse loss of cardiac sympathetic inner- vation at the time of initial testing.13 About half of patients with Parkinson’s disease without orthostatic hypotension have also had evidence of diffuse cardiac sympathetic denervation, and because of the likeli- hood of a floor effect, data from these patients were not included in this study. Given these results, and the present findings, based on the remaining patients with Parkinson’s disease who did not have either or- thostatic hypotension or diffuse cardiac sympathetic denervation at the time of initial testing, indicate that progressive loss of cardiac sympathetic innervation characterizes the disease. As of the time of the second scan, none of the patients developed orthostatic hy- potension. The sympathetic innervation of the myocardium travels with the coronary arteries. The finding of more severely decreased 6-[18F]fluorodopamine-derived ra- Fig 2. Concentrations (mean Ϯ standard error of the mean) of dioactivity in the lateral wall than in the interventric- 6-[18F]fluorodopamine-derived radioactivity in the (top) lateral ular septal wall
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