# paper.pdf ## Metadata - PDFFormatVersion=1.4 - Language=en-US - IsLinearized=false - IsAcroFormPresent=false - IsXFAPresent=false - IsCollectionPresent=false - IsSignaturesPresent=false - Creator=Arbortext Advanced Print Publisher 9.1.510/W Unicode - ModDate=D:20260319141144+05'30' - Title=WNL-2025-205701 1..12 - Producer=Acrobat Distiller 7.0 (Windows) - CreationDate=D:20260319120546+05'30' - xmp:modifydate=2026-03-19T14:11:44+05:30 - xmp:metadatadate=2026-03-19T14:11:44+05:30 - xmp:createdate=2026-03-19T12:05:46+05:30 - xmp:creatortool=Arbortext Advanced Print Publisher 9.1.510/W Unicode - pdf:producer=Acrobat Distiller 7.0 (Windows) - dc:title=WNL-2025-205701 1..12 ## Contents ### Page 1 ![Figure]() RESEARCH ARTICLE OPEN ACCESS # Striatal Dopamine Transporter and Rest Tremor inParkinson Disease A Clinical Validation Kalle J. Niemi,1,2,3 Elina Jaakkola,1,2,3,4 Elina Maaria Myller,1 Mikael R.E. Eklund,1,2 Simo Nuuttila,2Tuomas Mertsalmi,5 Kirsi-Marja Murtom¨aki,5 Reeta Levo,5 Tomm Noponen,6 Toni Ihalainen,7Filip Scheperjans,5 Juho Joutsa,1,2,3,8,* and Valtteri Kaasinen2,3,* Neurology® 2026;106:e214811. doi:10.1212/WNL.0000000000214811 ## Abstract ### Background and Objectives The mechanisms underlying tremor generation in Parkinson disease (PD) remain unclear.Previously, we demonstrated a connection between rest tremor amplitude and higher dopamine transporter (DAT) binding in the ipsilateral striatum among the Parkinson ProgressionMarkers Initiative cohort. Here, we investigated the association of parkinsonian motorsymptoms with striatal DAT binding in a sizable and clinically representative sample of patientswith parkinsonian signs to validate the previously observed ipsilateral relationship in PD. ### Methods This observational cross-sectional study included right-handed patients referred for [123I]FPCIT SPECT because of clinically uncertain parkinsonism or tremor at Turku UniversityHospital and the Helsinki and Uusimaa Hospital District, Finland. Each patient underwenta comprehensive clinical evaluation and follow-up (median 3.0 years [interquartile range (IQR)2.5]). Associations between striatal tracer binding and symptoms were investigated using voxelwise linear models, adjusting for age, sex, motor symptom severity, and medication. Theprimary outcome measure was the association between rest tremor amplitude and striatal DATbinding. ### Results At the end of the follow-up period, of the 414 patients included (median age 68 years [IQR 14],49.4% female), 148 were evaluated to have PD and 79 other forms of parkinsonism with striatalDAT deficit. In total, 187 patients had normal binding. Among the patients with PD, left andright rest tremor amplitudes were positively associated with ipsilateral striatal DAT binding (β =+0.12 [95% CI +0.05, +0.19] and +0.10 [+0.05, +0.15] specific binding ratio [SBR] per point;pFWE + Bonf. < 0.05, respectively). Left and right bradykinesia (β = −0.16 [−0.22, −0.09]and −0.18 [−0.25, −0.10] SBR per 5 points, pFWE + Bonf. < 0.05, respectively) and rigidity(β = −0.07 [−0.08, −0.04] and −0.08 [−0.11, −0.05] SBR per point, pFWE + Bonf. < 0.05,respectively) mainly showed a negative association with contralateral striatal DAT binding. Noconsistent associations were observed in non-PD groups. ### Discussion These findings confirm the positive association between rest tremor amplitude and ipsilateralstriatal DAT binding in a clinical sample of PD patients. However, the non-PD groups werediagnostically heterogeneous, limiting conclusions about disease specificity. CorrespondenceDr. Niemi MORE ONLINE #### Supplementary Material *These authors contributed equally to this work as co-senior authors. - 1Turku Brain and Mind Center, University of Turku, Finland;2Clinical Neurosciences, University of Turku, Finland;3Neurocenter, Turku University Hospital, Finland;4Department ofPsychiatry, University of Helsinki and Helsinki University Hospital, Finland;5Department of Neurology, Helsinki University Hospital, and Clinicum, University of Helsinki, Finland; - 6Department of Clinical Physiology, Nuclear Medicine, Turku PET Centre and Medical Physics, Turku University Hospital and Wellbeing Services County of Southwest Finland; - 7Department of Clinical Physiology and Nuclear Medicine, Helsinki University Hospital and University of Helsinki, Finland; and8Turku PET Centre, Turku University Hospital, Finland. The Article Processing Charge was funded by Varha (the wellbeing services county of Southwest Finland)/Turku University Hospital (project 38003). This is an open access article distributed under the terms of the, where it is permissible todownload and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2026 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. e214811(1) ### Page 2 ## Glossary 3D = 3-dimensional; DAT = dopamine transporter; FWE = family-wise error; FWHM = full-width-at-half-maximum; IQR =interquartile range; LEDD = levodopa-equivalent daily dose; MDS-UPDRS-III = Movement Disorders Society UnifiedParkinson’s Disease Rating Scale, part III; MNI = Montreal Neurological Institute; PD = Parkinson disease; PPMI =Parkinson’s Progression Markers Initiative; ROI = region of interest; SBR = specific binding ratio. ## Introduction Parkinson disease (PD) manifests clinically through the presentation of 3 cardinal motor symptoms: rigidity, bradykinesia,and rest tremor.1 While rigidity and bradykinesia are wellestablished to associate with contralateral striatal dopaminergicdeficit2,3 and overall motor severity with progression of dopamine transporter (DAT) deficit in the less affected hemisphere,4 the connection between dopaminergic function andrest tremor remains unclear.2,3,5-7 Notably, existing studies haveoften examined the association between tremor and dopaminergic function in PD by aggregating all tremor subtypes,2,3,5whereas rest tremor may warrant separate investigation, owingto its potentially unique pathophysiology among tremor subtypes.6-8 Rest tremor in PD is believed to be generated within thecerebello-thalamo-cortical circuit and its expression regulated by the basal ganglia.9 However, this conventionaltheory fails to fully explain the observed phenomenon,wherein unilateral deep brain stimulation (DBS) not onlyhas efficacy for contralateral tremor symptoms but alsoalleviates ipsilateral tremor,10 implying the involvement ofless dominant interhemispheric or crossing pathways.11-14Nevertheless, the observed therapeutic response of resttremor to dopaminergic treatment suggests a potential,partial link with dopaminergic dysfunction.8,15 In a previous study, we identified a robust association betweenrest tremor amplitude and higher ipsilateral DAT bindingwithin the Parkinson’s Progression Markers Initiative (PPMI)neuroimaging cohort.16 This association was observed both atbaseline and at 2-year follow-up, including patients with various levels of dexterity, and those expressing rest tremor exclusively. However, it is noteworthy that the PPMI cohortpredominantly comprises selected tremor-dominant early PDpatients (approximately 70%),17 and a substantial numbermay have undergone DAT imaging without typical clinicalindications. Consequently, the generalizability of these findings to a broader clinical PD population may be limited, giventhe distinct characteristics of the PPMI cohort. Therefore, in this study, our aim was to investigate thepotential link between rest tremor amplitude and increasedipsilateral dopaminergic activity in a real-world clinicalcohort of patients presenting with parkinsonian symptoms,who underwent DAT imaging as a part of their diagnosticevaluation. ## Methods ### Study Sample The main data used in this cross-sectional observational multicenter study consisted of clinical, medication, and [123I]FP-CITSPECT imaging data of patients who had undergone diagnostic [123I]FP-CIT SPECT imaging in Turku UniversityHospital and Helsinki and Uusimaa Hospital District duringyears 2014–2020 to evaluate suspected parkinsonism, inwhich assessment of potential nigrostriatal involvement wasclinically indicated. Inclusion criteria were age 18–100 yearsand referral for clinical [123I]FP-CIT SPECT imaging atTurku University Hospital or the Helsinki and UusimaaHospital District. Recruitment was consecutive, apart frompatients who opted not to participate. All clinical data werereviewed in August 2022 by 2 movement disorder specialists,who reassessed the diagnoses according to the MovementDisorders Society clinical criteria for PD,1 based on symptoms, signs, progression, levodopa response, and imagingfindings. Left-handed and ambidextrous patients were excluded to minimize the confounding effects of brain lateralization. All analyses were conducted using baseline data only.Follow-up clinical information and patient records were usedexclusively for diagnostic confirmation. To investigate the similarity of striatal findings betweencohorts, previously identified region of interest (ROIs)with statistically significant effects were acquired from thePPMI baseline cohort used in the earlier study,16 examinedoff medication, with equivalent preprocessing steps. Dataused in the preparation of this article were obtained onApril 12, 2019, from the PPMI database,18 RRID:SCR_006431. For up-to-date information on the study, visit thePPMI website.19 ### Standard Protocol Approvals, Registrations,and Patient Consents The study protocol was registered in 2015 (identifier: NCT02650843). The study was approved by theEthics Committees of the Hospital Districts and was conducted according to the principles of the Declaration ofHelsinki. Informed consent was obtained from all participantsincluded in the study. The PPMI study protocol was registered on June 8, 2010( identifier: NCT01141023). The study wasapproved by the institutional review board at each researchsite. All participants provided written informed consent. Neurology | Volume 106, Number 7 | April 14, 2026 e214811(2) ### Page 3 ### Measures of the Motor Symptoms The motor symptom measures used in the analysis were defined as composite scores derived from specific MovementDisorders Society Unified Parkinson’s Disease Rating Scale,part III (MDS-UPDRS-III) items, as presented in eTable 1.Sidewise total rest tremor amplitude scores (i.e., the sums ofeither left or right rest tremor amplitude scores in the upperand lower extremity) were used as the primary measures ofrest tremor. ### SPECT Imaging Participants were injected with 185 MBq of the radiopharmaceutical [123I]FP-CIT 3 hours before SPECT imaging. Toprotect the thyroid from radiation exposure, participants wereadministered either 250–300 mg of potassium perchlorate orpotassium iodide tablets (130 mg) 30–60 minutes before theradiopharmaceutical injection. SPECT imaging acquisition wasperformed using 1 of 6 SPECT/CT devices. Before the study, allSPECT/CT devices were calibrated using a striatal phantom(RSD, Radiology Support Devices, Inc., Long Beach, CA) following a recommended calibration procedure.20,21 ### ROI Value Acquisition and Image Preprocessing SPECT images were reconstructed using a 3-dimensional(3D) ordered-subsets expectation maximization reconstruction algorithm (HybridRecon Neurology, version1.3, Hermes Medical Solutions AB, Stockholm, Sweden), with16 iterations, 4 subsets, uniform attenuation correction withthe attenuation coefficient of 0.146 1/cm, collimator responsecorrection using Gaussian diffusion model, Monte-Carlobased scatter correction for the123I isotope and 3D Gaussianpostfiltering with a full-width-at-half-maximum (FWHM) of0.7 cm. The reconstructed images were originally analyzedusing the BRASS analysis software (Hermes Medical Solutions AB, Stockholm, Sweden) in the clinical context. The camera-specific calibration coefficients were implemented into BRASS software. With BRASS software, thespecific binding ratios (SBRs) of DAT binding were calculated over 6 striatal ROIs (the right and left anterior putamen,the right and left posterior putamen, and the right and leftcaudate nucleus), which were automatically segmented. Theoccipital cortex was used as the reference region, and the SBRswere calculated as: SBR = ROI − ROIoccipital ROIoccipital (1) An [123I]FP-CIT scan was classified as abnormal if SBR of atleast 1 anatomical ROI was more than 2 SDs below thenormative reference mean.22-24 ROI SBR values were nonnormally distributed (Shapiro-Wilk test p < 0.001 for allROIs), with marked right-skewness; therefore, naturallogarithm-transformed values were used in the regressionanalyses. The preprocessing of the imaging data for the voxel-wiseanalyses involved the registration of [123I]FP-CIT SPECT images to the same standard space (2 × 2 × 2 mm3 voxel size)with BRASS software using the built-in template, with consequent registration to Montreal Neurological Institute(MNI) standard space and smoothing with a Gaussian kernel(FWHM 4 mm). Voxel-wise SBR values were defined analogically to the ROI SBR values: SBR i;j;k = Intensityi;j;k − ROIoccipital ROIoccipital (2) The voxel-wise SBR values were log-transformed in the samemanner as the ROI values, resulting in voxel-wise distributionswithin the striatum that more closely approximated normality(eFigure 1). For further analyses, DAT asymmetry indices were calculatedfor each patient based on the ROI data. DAT asymmetryindex was defined as: DAT − AI = SBR mean;R −SBR mean;L SBR mean;R +SBR mean;L ; (3) where SBRmean ; L =R = SBR Caudate L =R + SBR Anterior Putamen L =R + SBR Posterior Putamen L =R : ### PPMI Data: Image Preprocessing To acquire applicable external ROIs for the validation of therest tremor amplitude findings in the PPMI data,16 the PPMIdata were reanalyzed without partial volume effect correction,with registration to MNI standard space based on the structural imaging data, and with FWHM 4-mm Gaussian kernelsmoothing. SBR values were log-transformed identically tothe main analyses of this study. Other steps of the PPMI datapreprocessing and analysis workflow have been describedearlier.16 ### Voxel-Wise Analyses The voxel-wise analyses were conducted with StatisticalParametric Mapping 1225 (Functional Imaging Laboratory,UCL Queen Square Institute of Neurology, London, theUnited Kingdom) using generalized linear model running onMATLAB R2021b (MathWorks Inc., Natick, MA). The mainanalyses of the association between striatal [123I]FP-CITbinding and the clinical motor evaluation subscores wereconducted adjusting for age, sex, medication state, andlevodopa-equivalent daily dose (LEDD) (only for medicatedpatients; interaction medication state × LEDD). Additionalanalyses were conducted with MDS-UPDRS-III total score asan additional covariate (interaction medication state × MDSUPDRS-III). A 3-mm dilated striatal mask from HarvardOxford Subcortical Atlas (eFigure 2) was used to restrict allthe voxel-wise analyses to the striatum where SBR almostselectively reflects DAT binding, in contrast to other brainregions where SBR is influenced by binding to other monoamine transporters.26 Similar analyses were also conducted in 2 non-PD subgroups:(1) patients with normal striatal DAT binding (all ROIZ-scores ≥−2 SD) and (2) patients with abnormal binding (at Neurology.org/N Neurology | Volume 106, Number 7 | April 14, 2026 e214811(3) ### Page 4 least 1 ROI Z-score <−2 SD). The imaging outcomes wereclassified as normal or abnormal according to the primarysemiquantitative analysis with BRASS software combinedwith confirmatory visual evaluation made by a nuclear medicine physician. The classifications were reviewed, and borderline cases were carefully re-evaluated by the investigatorswho were blinded to the clinical diagnoses, as describedpreviously.27,28 Separate voxel-wise analyses for patients with rest tremor(i.e., MDS-UPDRS-III lateralized rest tremor items >0) werenot conducted due to the limited sample size (n = 69 for PDwith left and n = 69 for PD with right rest tremor), as samplesize of 125 would be required to observe the effects with 80%power. Clusters with cluster-wise familywise error (FWE) corrected pvalues (pFWE) < 0.05 (with voxel-wise height threshold set top < 0.005) were considered potentially significant. For themain analysis models, pFWE values were further post hocBonferroni-corrected across all tested nonsignificant contrasts(positive and negative) and all potentially significant clusters(211 in total), yielding pFWE +Bonf. To test the robustness ofvoxel-wise findings against remaining heteroscedasticity, logtransformed cluster mean values were analyzed using multivariable robust regression (with optimal Ψ function).29,30Clusters with pFWE +Bonf. < 0.05 and significant associations inthe corresponding robust regression models (p < 0.05) wereconsidered significant. ### ROI Analyses First, associations between clinical characteristics and 6 automatically segmented ROI SBR values were evaluated usingrobust regression, with identical sets of covariates asemployed in the voxel-wise analyses. Robust regression wasselected to accommodate residual heteroscedasticity and occasional outliers not tolerated by ordinary least squares linearregression. Second, to further validate these association in relation to thePPMI, significant clusters identified in earlier PPMI analyseswere resampled to match the resolution of the present study’sdata, using nearest neighbor interpolation. Given the unmedicated status of PPMI patients during baseline imaging,SBR values for these areas were extracted exclusively fromSPECT imaging data of unmedicated patients with PD in thisstudy and were subsequently used in multivariable robustregression analyses identical to those in the voxel-wise analyses. As the regression models describe a slightly nonlinear(exponential) relationship between raw SBR values and thestudied symptoms, the beta coefficients reported (βmean) referto local slopes at the mean of the symptom severity score ina group of interest. ### Statistics Analyses with the clinical, cluster, and ROI data were performed with R 4.1.2 (R Foundation for Statistical Computing, Austria) running on macOS 10.15 (Apple Inc., Cupertino,CA). The between-group comparisons were conducted using2-sided Mann-Whitney U tests or Fisher exact tests, as appropriate. Diagnostic measures to assess the validity of robustregression models were tested with Shapiro-Wilk (residualnormality), Breusch-Pagan (homoscedasticity), and varianceinflation factor (absence of marked multicollinearity) analyses. These tests showed that the key assumptions of thechosen analysis methods were met consistently. The use ofmotor symptom severity scores as continuous (rather thancategorical) variables was supported by likelihood ratio,Akaike information criteria, and Bayes information criteriatests.31 The statistical significance of in-sample proportionswas tested with 2-sided Z test. p Values <0.05 were consideredstatistically significant. ### Data Availability The data that support the findings of this study are availablefrom the corresponding author on reasonable request, subjectto the national and institutional regulations. The data of thePPMI cohort were downloaded from the publicly availablePPMI database.18 For up-to-date information on the studyand the data handling protocol, visit the PPMI website.19 AsPPMI manages the use of the original data, the processed dataare not publicly available. ## Results ### Clinical Characteristics In total, 414 right-handed patients who had undergone [123I]FP-CIT SPECT imaging for clinical diagnostic purposeswere included in this study. At the conclusion of the follow-upperiod, 148 patients received a clinical diagnosis of PD, while79 individuals were diagnosed with other movement disorderswith abnormal [123I]FP-CIT SPECT imaging results, and 187patients had normal [123I]FP-CIT SPECT imaging resultswith varying diagnoses. The specific diagnoses of the non-PDgroups are presented in eTable 2. Across the entire sample,the median age was 68 years (interquartile range [IQR] 14),with a median follow-up duration of 3.0 years (IQR 2.5).Among all patients, 215 (50.6%) were male and the medianmotor symptom severity, as evaluated on the MDS-UPDRSIII scale, was 34 points (IQR 22) (Table 1). Limb rest tremorwas most frequent in patients diagnosed with PD (n = 101[68.2%]) (Fisher test, p = 1.8 × 10−5) but was also observed inpatients with other movement disorders, both those withabnormal DAT binding (n = 31 [39.2%]), and those withnormal imaging (n = 90 [48.1%]). ### Patients With PD In the patients with PD, both left-sided and right-sided totalrest tremor amplitude scores were associated with higher ipsilateral striatal [123I]FP-CIT binding (βmean = +0.12 [95% CI+0.05, +0.19] and +0.10 [95% CI +0.05, +0.15] SBR units per 1 point, pFWE + Bonf. < 2.1 × 10−14 and <2.1 × 10−14, respectively) (Figure 1A). Left-sided rest tremor amplitude Neurology | Volume 106, Number 7 | April 14, 2026 e214811(4) ### Page 5 | Patients withPD (n = 148) | Patients with any other diagnosisthan PD: Normal SPECT (n = 187) | Patients with any other diagnosisthan PD: Abnormal SPECT (n = 79) | | - | - | - | | Age (y) | 67 [59, 72] | 67 [57, 74] | 69 [63.5, 73] | | Sex (male/female [male %]) | 71/77 [48] | 90/97 [48.1] | 46/33 [58.2] | | MMSE | 28 [26, 29]†‡ | 27 [25, 28.75] | 27 [24, 28] | | Predominant side of symptom onset (R/L/S) | 65/58/21a†‡ | 81/46/56a | 25/25/28a | | Predominant side of limb rest tremor (R/L/S/N) | 44/37/20/47†‡ | 49/17/24/97* | 13/10/8/48 | | Disease duration from symptom onset (mo) | 18 [11, 36]† | 27 [16.5, 72]* | 24 [12, 30] | | Unmedicated/medicated [medicated %]b | 108/40 [27.0]† | 165/22 [11.8]* | 60/19 [24.1] | | LEDD (medicated) | 300 [103.75, 429.8] | 265 [150, 300] | 300 [175, 375] | | MDS-UPDRS-III score | 34 [25.75, 46]‡ | 33 [23, 45]* | 40 [31.5, 51.5] | | MDS-UPDRS-III score, unmedicated | 33.5 [24.2, 43.2]‡ | 32 [23, 43]* | 38.5 [32, 51.2] | | MDS-UPDRS-III score, medicated | 35 [26, 48.2] | 44 [25, 47.8]* | 42 [26, 55.5] | | MDS-UPDRS-III bradykinesia-rigidity | 21 [14, 31]‡ | 19 [13, 27]* | 26 [19.25, 33] | | MDS-UPDRS-III bradykinesia-rigidity, unmedicated | 19.5 [13, 30]‡ | 19 [13, 26]* | 28 [20.5, 32.5] | | MDS-UPDRS-III Bradykinesia-rigidity, medicated | 23.5 [17.75, 35] | 26 [19, 32] | 24 [12.5, 37] | | MDS-UPDRS-III total tremor | 6.5 [3, 10]‡ | 6 [3, 9]* | 5 [3, 8] | | MDS-UPDRS-III total tremor, unmedicated | 7 [3, 11]‡ | 6 [3, 9]* | 4 [3, 7.2] | | MDS-UPDRS-III total tremor, medicated | 4.5 [3, 8] | 4.5 [2, 10.5] | 7 [2.5, 10.5] | | Hoehn & Yahr stage†‡ | | 0 | 1 [0.7] | 6 [3.2] | 1 [1.3] | | 1 | 32 [21.6] | 16 [8.6] | 6 [7.6] | | 2 | 82 [55.4] | 109 [58.3] | 45 [57] | | 3 | 25 [16.9] | 38 [20.3] | 17 [21.5] | | 4 | 8 [5.4] | 14 [7.5] | 5 [6.3] | | 5 | — 4 [2.1] | 5 [6.3] | | Mean (L&R) caudate Z-score | −2.34 [−2.89, −1.67]† | −0.54 [−1.14, 0.48]* | −2.49 [−3.14, −1.64] | | Mean (L&R) anterior putamen Z-score | −2.84 [−3.60, −2.26]† | −0.46 [−0.95, 0.41]* | −2.73 [−3.58, −1.94] | | Mean (L&R) posterior putamen Z-score | −3.76 [−4.28, −3.22]†‡ | −0.45 [−1.02, 0.32]* | −3.20 [−3.82, −2.38] | Abbreviations: L = left; LEDD = levodopa-equivalent daily dose; MDS-UPDRS-III = Movement Disorders Society Unified Parkinson’s Disease Rating Scale, part III;MMSE = Mini-Mental State Examination; N = none; PD = Parkinson disease; R = right; S = symmetrical. For the scalar variables, the median with 25th and 75th percentiles [in square brackets] are reported. Percentages of categorical variables are reported [insquare brackets]. Differences of scalar variables were evaluated with 2-tailed Mann-Whitney U test and categorical variables with Fisher exact test. Statisticallysignificant (p < 0.05) difference † between PD group and non-PD normal imaging group; ‡ between PD group and non-PD abnormal imaging group; * betweennon-PD normal imaging and non-PD abnormal imaging groups. a Data missing. b Terms “medicated” and “unmedicated” refer to patients receiving antiparkinsonian dopaminergic drugs. additionally showed a limited region of negative association inthe contralateral striatum and claustrum (βmean = −0.11 [95%CI −0.16, −0.04] SBR units per 1 point, pFWE + Bonf. = 9.1 ×10−7). Left-sided and right-sided bradykinesia showed associations with contralateral binding deficits (βmean = −0.16[95% CI −0.22, −0.09] and −0.18 [95% CI −0.25, −0.10] SBR units per 5 points, pFWE + Bonf. < 2.1 × 10−14 and <2.1 × 10−14, respectively) (Figure 1B). Right-sided bradykinesia also showed an association with higher ipsilateral binding (βmean =+0.12 [95% CI +0.02, +0.23] SBR units per 5 points, pFWE +Bonf. = 2.3 × 10−14). Left-sided and right-sided rigidity hadassociations with contralateral tracer binding deficit(βmean = −0.07 [95% CI −0.08, −0.04] and −0.08 [95%CI −0.11, −0.05] SBR units per 1 point, pFWE + Bonf. 3.6 × 10−9and <2.1 × 10−14, respectively) (Figure 1C). These resultsremained consistent when adjusting for overall motor Neurology | Volume 106, Number 7 | April 14, 2026 e214811(5) ### Page 6 symptom severity, as assessed by the MDS-UPDRS-III totalscore (eFigure 3, A–C), but negative association with left resttremor became insignificant (eFigure 3A). The compositebradykinesia-rigidity scores showed similar findings as bradykinesia alone (eFigure 3, D and E). In addition, comparisonof the clusters associated with left and right rest tremor amplitude in this study with those identified in the PPMI data setrevealed a substantial overlap volumes of 4096 mm3 and3504 mm3, respectively (eFigure 4A). The key associations between rest tremor amplitude and ipsilateral binding remained significant after additionally adjusting for DAT asymmetry index and MDS-UPDRS-III total score(eFigure 5, A and B). Only including unmedicated PD patients(n = 108), left-sided and right-sided rest tremor amplitudescores were significantly associated with higher [123I]FP-CITbinding in the ipsilateral striatum (pFWE < 1 × 10−16 and pFWE < 1 × 10−16; with MDS-UPDRS-III as an additional covariate,pFWE < 1 × 10−16 and pFWE < 1 × 10−16, respectively) (eFigure 6, A and B). Furthermore, left-sided and right-sided rest tremor severityindex, calculated as the product of amplitude and constancy,had a significant association with ipsilateral DAT binding ![Figure]() The association of sidewise (A) total rest tremor amplitude, (B) total bradykinesia, and (C) total rigidity with voxel-wise [123I]FP-CIT SBR in the right-handedpatients with PD. The analyses of the association between binding and the clinical motor evaluation subscores were conducted adjusting for age, sex, themedication state, and levodopa-equivalent daily dose (only for medicated patients; interaction with medication state), with log-transformed SBR values. Resttremor amplitude (A) showed a positive association with ipsilateral binding (left side rest tremor amplitude also a negative association with contralateralbinding in a limited region), while bradykinesia showed (B) negative associations with contralateral binding (right side bradykinesia also a positive associationwith ipsilateral binding) and rigidity (C) showed negative associations with contralateral binding. Cluster-level FWE corrected p values, further correctedamong all the contrasts and clusters tested (pFWE +Bonf.) are shown below each image. βmean, cluster = the local strength of association between the clusterregion mean SBR and the subscore at the score level nearest to mean symptom severity in the PD group. Negative association is indicated with blue-greencolor scale, and positive association with red-yellow color scale. BK = bradykinesia; FWE = family-wise error; PD = Parkinson disease; R = right; RGD = rigidity;RTA = rest tremor amplitude; SBR = specific binding ratio. Neurology | Volume 106, Number 7 | April 14, 2026 e214811(6) ### Page 7 (βmean = +0.13 [95% CI +0.06, +0.21] and +0.05 [95% CI+0.02, +0.08] SBR units per 4 points, pFWE + Bonf. = 2.1 ×10−14 and 2.1 × 10−14, respectively, with MDS-UPDRS-III asan additional covariate, pFWE + Bonf. < 2.1 × 10−14 and pFWE +Bonf. < 2.1 × 10−14) (Figure 2, eFigure 7). Left-sided resttremor severity index was also associated with lower bindingin a narrow region in the contralateral striatum (βmean = −0.05[95% CI −0.10, −0.004], pFWE + Bonf. = 0.017) (Figure 2), butthis association was not significant when the model was additionally adjusted for MDS-UPDRS-III-score (eFigure 7). Overall rest tremor severity index was associated with higherbinding in the right anterior striatum (βmean = +0.11 [95% CI+0.06, +0.16] SBR per 4 points, pFWE + Bonf. < 2.1 × 10−14;with MDS-UPDRS-III as an additional covariate, pFWE +Bonf. < 2.1 × 10−14) (eFigure 8A). Overall rest tremor constancy was associated with higher binding in the left caudate(βmean = +0.07 [95% CI +0.02, +0.12] SBR per point; pFWE =0.006) and with MDS-UPDRS-III as an additional covariate,with higher binding in the left and right caudates (βmean =+0.10 [95% CI +0.03, +0.18] and βmean = +0.07 [95% CI+0.03, +0.12] SBR per point; pFWE + Bonf. = 4.0 × 10−4 andpFWE + Bonf. = 0.007) (eFigure 8B). Of other tremor measures, left postural tremor of the handwas associated with higher ipsilateral and lower contralateralbinding (βmean = +0.18 [95% CI +0.09, +0.30] and −0.19[95% CI −0.25, −0.12] SBR per point; pFWE + Bonf. = 1.1 ×10−4 and <2.1 × 10−14, respectively; with MDS-UPDRS-III asan additional covariate, pFWE + Bonf. = 2.0 × 10−6 and pFWE +Bonf. = 7.0 × 10−14) (eFigure 9, A and B). Right posturaltremor was not significantly associated with binding. Left kinetic tremor and right kinetic tremor of the hands were associated with higher ipsilateral binding in the striatum(βmean = +0.21 [95% CI +0.10, +0.35] and +0.12 [95% CI+0.004, +0.25] SBR per point; pFWE + Bonf. = 1.3 × 10−11 and <2.1 × 10−14, respectively; with MDS-UPDRS-III as anadditional covariate, pFWE + Bonf. < 2.1 × 10−14 and pFWE +Bonf. < 2.1 × 10−14) (eFigure 9, C and D). However, thesefindings did not replicate in the PPMI data, as only posturaltremor was consistently associated with higher ipsilateralbinding on both sides and only when adjusted with MDSUPDRS-III total score (eFigure 10). In the ROI analyses, scores of rest tremor amplitude on bothsides were significantly associated with higher ipsilateralstriatal DAT binding (Table 2), whereas scores of bradykinesia and rigidity on both sides correlated with contralateralstriatal binding deficits (Table 2). In the analyses with ROISBR values extracted from the PPMI analysis cluster areasadjusted for age, sex, and MDS-UPDRS-III total score, significant associations were observed for both left-sided andright-sided rest tremor amplitude scores (βmean = +0.16 [95%CI +0.06, +0.26] and +0.15 [95% CI +0.07, +0.24], respectively; p < 0.001 for both). Excluding patients without rest tremor on the side of interest,the associations of left-sided and right-sided rest tremor amplitude scores with binding in the associated areas were stillstatistically significant (n = 49, βmean = +0.20 [95% CI +0.03,+0.40], p = 0.018, and n = 52, βmean = +0.17 [95% CI +0.02,+0.33], p = 0.021, respectively) (Figure 3). The results of leftsided and right-sided rest tremor amplitude also remainedsignificant when also DAT asymmetry index was added asa covariate in the model (βmean = +0.18 [95% CI +0.03,+0.35], p = 0.011, and βmean = +0.12 [95% CI +0.02, +0.22],p = 0.015, respectively). ### Non-PD Patients Among the patients with abnormal DAT SPECT imagingresults and diagnosis other than PD, no significant associations were observed between left-sided or right-sided rest ![Figure]() The association of side-wise rest tremor severity index with voxel-wise [123I]FP-CIT SBR in the right-handed patients with PD. The analyses of the associationwere conducted adjusting for age, sex, the medication state, and levodopa-equivalent daily dose (only for medicated patients; interaction with medicationstate), with log-transformed SBR values. Cluster-level FWE corrected p values, further corrected among all the contrasts and clusters tested (pFWE +Bonf.), areshown below each image. β = the local strength of association between the cluster region mean SBR and the subscore at the score level nearest to meansymptom severity in the PD group. Negative association is indicated with blue-green color scale and positive association with red-yellow color scale. FWE =family-wise error; PD = Parkinson disease; R = right; SBR = specific binding ratio. Neurology | Volume 106, Number 7 | April 14, 2026 e214811(7) ### Page 8 | Left totalbradykinesia | Left totalrigidity | Left total resttremor amplitude | Right totalbradykinesia | Right totalrigidity | Right total resttremor amplitude | | - | - | - | - | - | - | | Region-of-interest SBR values fromthe original imaging evaluation | β coefficient(SBR/5 points) | β coefficient(SBR/point) | β coefficient(SBR/point) | β coefficient(SBR/5 points) | β coefficient(SBR/point) | β coefficient(SBR/point) | | Caudate (left) | −0.05[−0.15, 0.05] | −0.04[−0.09, 0.02] | 0.10 | −0.20 | −0.09 | 0.06 | | [0.02, 0.20]† | [−0.30, −0.09]‡ | [−0.13, −0.04]‡ | [−0.00, 0.13] | | Anterior putamen (left) | −0.04[−0.15, 0.08] | −0.03[−0.08, 0.03] | 0.08 | −0.20 | −0.08 | 0.06 | | [0.02, 0.16]† | [−0.31, −0.08]† | [−0.13, −0.03]† | [0.01, 0.12]* | | Posterior putamen (left) | −0.00[−0.08, 0.08] | −0.02[−0.05, 0.01] | 0.08 | −0.18 | −0.08 | −0.01[−0.05, 0.03] | | [0.03, 0.13]‡ | [−0.27, −0.09]‡ | [−0.10, −0.04]‡ | | Caudate (right) | −0.18 | −0.09 | −0.03[−0.09, 0.04] | 0.00 | −0.02[−0.08, 0.05] | 0.14 | | [−0.28, −0.07]† | [−0.15, −0.02]* | [−0.09, 0.10] | [0.08, 0.20]‡ | | Anterior putamen (right) | −0.28 | −0.09 | −0.08 | 0.04 | −0.02[−0.07, 0.04] | 0.15 | | [−0.40, −0.14]‡ | [−0.14, −0.04]‡ | [−0.13, −0.01]* | [−0.08, 0.16] | [0.08, 0.23]‡ | | Posterior putamen (right) | −0.23 | −0.09 | −0.05 | 0.02 | −0.01[−0.04, 0.03] | 0.11 | | [−0.33, −0.12]‡ | [−0.11, −0.06]‡ | [−0.09, −0.00]* | [−0.05, 0.10] | [0.06, 0.17]‡ | Abbreviations: LEDD = levodopa-equivalent daily dose; PD = Parkinson disease; RTA = rest tremor amplitude; SBR = specific binding ratio. Robust regression models, age, sex, medication state during examination (medicated/unmedicated) and LEDD (if medicated) as additional covariates. Localslope of the association, confidence intervals [in brackets] at the mean symptom score level in the PD group, and their statistical significance in robustregression models of log-transformed original region-of-interest SBR values and main parkinsonian motor symptoms (left and right total bradykinesia,rigidity and rest tremor amplitude) in the PD group, with age, sex, medication state during examination (medicated/unmedicated), and LEDD (if medicated) asadditional covariates. Uncorrected *p < 0.05, †p < 0.01, ‡p < 0.001. tremor amplitude, rest tremor consistency, rest tremor severity indices, bradykinesia, or rigidity, and striatal tracerbinding in any of the voxel-wise analyses. Left kinetic tremorshowed an association with stronger binding in the contralateral anterior striatum (βmean = +0.25 [95% CI +0.06, +0.48]SBR per 1 point; pFWE + Bonf. = 0.002; with MDS-UPDRS-IIIas an additional covariate, pFWE + Bonf. = 0.006) (eFigure 11). Among the patients with normal DAT SPECT imagingresults, right-sided total rest tremor amplitude showed anassociation with increased binding in the contralateral anterior striatum (βmean = +0.13 [95% CI +0.04, +0.23] SBR per 1point; pFWE + Bonf. = 0.019; with MDS-UPDRS-III as an additional covariate, pFWE + Bonf. = 1.5 × 10−6) (eFigure 12A). Inaddition, several rest tremor measures had associations withbinding but only when adjusted for MDS-UPDRS-III totalscore: left-sided rest tremor amplitude was associated withweaker binding in the contralateral posterior striatum(βmean = −0.07 [95% CI −0.12, −0.01]; pFWE + Bonf. = 0.049)(eFigure 12B). Right-sided rest tremor severity index had anassociation with stronger binding in the left caudate andpallidofugal areas (βmean = +0.15 [95% CI +0.07, +0.23] SBRper 4 points; pFWE +Bonf. = 9.6 × 10−6) (eFigure 12C). Overallrest tremor severity index was also associated with strongerbinding in the left caudate (βmean = +0.15 [95% CI +0.07,+0.24] SBR per 4 points; pFWE + Bonf. < 2.1 × 10−14)(eFigure 12D). Considering other measures than those of rest tremor, leftpostural tremor was associated with increased binding in theleft striatum and globus pallidum and right striatum (βmean = +0.23 [95% CI +0.09, +0.38] and +0.27 [95% CI +0.10,+0.46], pFWE + Bonf. = 5.6 × 10−5 and 0.006), but when adjusted for MDS-UPDRS-III total score, only in the left globuspallidum (βmean = +0.21 [95% CI +0.07, +0.36], pFWE + Bonf =0.006) (eFigure 12E). In addition, left-sided rigidity waslinked to lower binding in the contralateral caudate and pallidum (βmean = −0.10 [95% CI −0.16, −0.01]; pFWE + Bonf. =0.006), but not if corrected for MDS-UPDRS-III total score(eFigure 12F). Instead, left-sided bradykinesia-rigidity composite score was associated with lower binding in the contralateral anterior striatum (βmean = −0.21 [95%CI −0.27, −0.14], pFWE = 1.2 × 10−8) and, when adjusted forMDS-UPDRS-III total score, showed a stronger associationwith lower binding bilaterally in the pallidofugal areas(βmean = −0.22 [95% CI −0.27, −0.14], pFWE < 2.1 × 10−14)(eFigure 12 G). No significant associations with the examinedmotor symptoms were observed otherwise. ## Discussion In this study, we validated the association between rest tremoramplitude and higher ipsilateral striatal DAT binding in anindependent, clinical sample of patients with PD. This association was not observed in non-PD patients with eithernormal or abnormal striatal dopaminergic function, demonstrating robustness of the link between rest tremor amplitudeand ipsilateral DAT binding in PD. Previous evidence suggests that the emergence of rest tremormay be associated with preceding changes in integrative brainstates affecting both hemispheres, which may fluctuate under Neurology | Volume 106, Number 7 | April 14, 2026 e214811(8) ### Page 9 ![Figure]() The association of sidewise total rest tremor amplitude with mean [123I]FP-CIT SBR in the regions derived from the PPMI, with robust regression modelsadjusting for age, sex and MDS-UPDRS-III total score. Only unmedicated, right-handed patients with PD were included in these analyses, corresponding to theregion-defining analyses, and additionally patients with no rest tremor on the side of interest were excluded (leaving 49 patients with left (A) and 52 patientswith right (B) rest tremor). β = the strength of association between the region mean SBR and the subscore at rest tremor amplitude score 1; MDS-UPDRS-III =Movement Disorders Society Unified Parkinson’s Disease Rating Scale, part III; PD = Parkinson disease; PPMI = Parkinson’s Progression Markers Initiative;SBR = specific binding ratio. cognitive load.32 However, earlier studies attempting to unravel the connection between tremor and dopaminergicfunction in PD have often investigated multiple tremor typestogether, yielding incongruous results.2,3,5-7,33 The diverseneurobiological mechanisms underlying different tremorsubtypes may explain why the dopaminergic correlates of resttremor have remained partially unrecognized. Recent independent findings in a separate cohort of 60 PD patientsusing another presynaptic dopaminergic tracer targeting thevesicular monoamine transporter 2 support the specific association between rest tremor and increased striatal dopaminefunction.34 Thus, the positive link between rest tremor andpresynaptic ipsilateral dopaminergic function has now beenobserved in 3 distinct PD patient populations. The paradox regarding rest tremor and dopaminergic functionin PD arises from the fact that while nigrostriatal dopaminedepletion may be a prerequisite for developing rest tremor, theexpression of tremor appears to occur independently of thisdegeneration.9 Instead of the striatum, there are indicationsthat pallidal dopaminergic depletion may play a significant rolein rest tremor generation.7 Our findings further complicate this picture by revealing links between dopaminergic function in theipsilateral striatum. Notably, pallidal neurons exert distinct androbust effects on the striatum, with over 25% of striatal interneurons receiving direct synaptic input from arkypallidal cellsin the pallidum.35 Thus, it is possible that the previously observed findings related to pallidal dysfunction in tremulous PDpatients are associated with the present results, warrantingfurther investigation. We interpret increased ipsilateral DAT binding not as evidence of an increased number of dopaminergic neurons, butrather as a possible functional activity change, possibly due tocompensatory activation. The mechanism underlying theobserved association between ipsilateral higher DAT bindingand greater rest tremor amplitude in PD remains unclearbased on this study alone. However, potential pathways thatcould contribute to this association include interhemisphericcortical,11 crossing cortico-striatal11 and nondecussatingdentatorubrothalamic14 connections, while tremor oscillations themselves may originate within the striato-pallidaland cerebello-thalamo-cortical circuits.9 Similar connection ofbilateral cortical activity with unilaterally manifesting tremor Neurology | Volume 106, Number 7 | April 14, 2026 e214811(9) ### Page 10 in essential tremor has been recognized recently.36 Previousobservations of ipsilateral tremor alleviation with unilateralDBS also support the involvement of both hemispheres in theemergence of rest tremor,10 while the beneficial effects ofdopaminergic medications on parkinsonian tremor supportthe involvement of the dopaminergic system.8,15 Nevertheless, it is vital to note that no functional imaging data beyondDAT SPECT were used in this study. In the non-PD patients with normal scans, we observeda negative association between [123I]FP-CIT binding and rigidity, particularly in the caudate nucleus. These additionalresults suggest that even in symptomatic patients with striatalDAT binding in normal range, motor symptoms may be relevantly linked to dopaminergic function, especially in thecaudate nucleus, which has a role in de novo motor learning,goal-directed motor behavior,37 and gait.38 Further research iswarranted to investigate the association between motorsymptom severity and dopamine function in individuals withmotor symptoms but normal striatal DAT binding. [123I]FP-CIT SPECT is the most common molecular imagingmethod used in the differential diagnostics of unclear parkinsonism,39 with the best diagnostic predictive value achieved indistinguishing individuals with striatal dopaminergic degeneration from those with essential tremor,40 drug-inducedparkinsonism, and vascular parkinsonism.41,42 However, itsdiagnostic utility is weaker in atypical parkinsonism syndromeswith nigrostriatal defects, such as multiple system atrophy andprogressive supranuclear palsy, which may be clinically indistinguishable from PD in the early stages.43 Although therelationship between motor features and molecular imagingmarkers could, in principle, inform diagnostic evaluation, suchapplications would require substantially more evidence acrossdifferent movement disorders. At present, our findings primarily support a pathophysiologic link between tremor amplitude and dopaminergic function. This study has certain limitations that should be acknowledged. First, the image registration workflow did not incorporate separate anatomical imaging, and the number ofpatients with PD was smaller than in our previous study usingPPMI data. Because [123I]FP-CIT SPECT has limited anatomical resolution, inherently smooth signal characteristics,and relatively low signal-to-noise ratio, the combination ofthese technical limitations with the commonly appliedsmoothing procedure results in some spillover into adjacentwhite matter areas, which must be considered when interpreting the results. If these limitations had affected the resultsrelevantly, their effect would most likely have been to bias theanalysis toward false-negative findings or to produce spatialmisalignments. The latter possibility is unlikely, however,given the accurate alignment observed with the PPMI data.Second, the spectrum of diagnoses other than PD was varied,and no definitive conclusions regarding the specific differences between PD and other, separate types of parkinsonismsyndromes in terms of the association of molecular imaging Neurology | Volume 106, Number 7 | April 14, 2026 and clinical findings, can be drawn based on the data. Third,a selection bias is possible since the patients represent thosewho were referred for SPECT imaging due to diagnosticdifficulties. Thus, although the sample was derived froma clinical population, it may not fully represent the generalpatient population with parkinsonism. Fourth, in the non-PDgroups, rest tremor was less frequent, reducing sensitivity todetect tremor-binding associations. Moreover, referral-basedselection and diagnostic heterogeneity in these groups limitconclusions about the specificity of the tremor-DAT association for PD. Our study provides evidence supporting the association between rest tremor amplitude and greater ipsilateral striatalDAT binding in PD within a clinical sample. Further electrophysiologic, functional MRI, molecular imaging, and connectivity studies are needed to elucidate the mechanismsunderlying this finding and to clarify its relevance for thepathophysiology of rest tremor in PD. ### Author Contributions K.J. Niemi: drafting/revision of the manuscript for content,including medical writing for content; study concept or design; analysis or interpretation of data. E. Jaakkola: drafting/revision of the manuscript for content, including medicalwriting for content; major role in the acquisition of data. E.M.Myller: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data. M.R.E. Eklund: drafting/revision of themanuscript for content, including medical writing for content;major role in the acquisition of data. S. Nuuttila: drafting/revision of the manuscript for content, including medicalwriting for content; major role in the acquisition of data. T.Mertsalmi: drafting/revision of the manuscript for content,including medical writing for content; major role in the acquisition of data. K.-M. Murtom¨aki: drafting/revision of themanuscript for content, including medical writing for content;major role in the acquisition of data. R. Levo: major role in theacquisition of data. T. Noponen: drafting/revision of themanuscript for content, including medical writing for content;major role in the acquisition of data. T. Ihalainen: drafting/revision of the manuscript for content, including medicalwriting for content; major role in the acquisition of data. F.Scheperjans: drafting/revision of the manuscript for content,including medical writing for content; major role in the acquisition of data. J. Joutsa: drafting/revision of the manuscriptfor content, including medical writing for content; major rolein the acquisition of data; study concept or design; analysis orinterpretation of data. V. Kaasinen: drafting/revision of themanuscript for content, including medical writing for content;major role in the acquisition of data; study concept or design;analysis or interpretation of data. ### Study Funding This study was funded by the Finnish Parkinson Foundation,the Finnish Cultural Foundation, the Turku University Foundation, TYKS Foundation, and Satakunta Wellbeing Services e214811(10) ### Page 11 County. PPMI—a public-private partnership—is funded bythe Michael J. Fox Foundation for Parkinson’s Research andfunding partners, including 4D Pharma, Abbvie Inc., AcureXTherapeutics, Allergan, Amathus Therapeutics, Aligning ScienceAcross Parkinson’s (ASAP), Avid Pharmaceuticals, Bial Biotech,Biogen, BioLegend, Bristol Myers Squibb, Calico Life SciencesLLC, Celgene Corporation, DaCapo Brainscience, DenaliTherapeutics, the Edmond J. Safra Foundation, Eli Lilly andCompany, GE Healthcare, GlaxoSmithKline, Golub Capital,Handl Therapeutics, Insitro, Janssen Pharmaceuticals, Lundbeck, Merck & Co. Inc., Meso Scale Diagnostics LLC, Pfizer Inc.,Piramal Imaging, Prevail Therapeutics, F. Hoffmann‐La RocheLtd. and its affiliated company Genentech Inc., Sanofi Genzyme,Servier, Takeda Pharmaceutical Company, Teva NeuroscienceInc., UCB, Vanqua Bio, Verily Life Sciences, Voyager Therapeutics Inc., and Yumanity Therapeutics Inc. ### Disclosure K.J. Niemi has minor stock ownership in CareCloud, GlaxoSmithKline, Healthpeak Properties, Modulight, and Nightingale Health; reports research grants from the Finnish ParkinsonFoundation, the Finnish Cultural Foundation (Pertteli Aaltonen Fund), Sigrid Juselius Foundation, the Finnish Neurological Society, the University of Turku, the Turku UniversityFoundation, Turku University Hospital, TYKS Foundation,and Satakunta Wellbeing Services County; reports conferencetravel support from the Finnish Parkinson Foundation, theFinnish Neurological Society, the Finnish Society of NuclearMedicine, the Finnish Cultural Foundation (Pertteli AaltonenFund), the International Parkinson and Movement DisorderSociety, the Turku University Foundation, Turku UniversityHospital, the University of Turku, and Merck; and reportslecturer honoraria from Wellbeing Services County of NorthSavo. E. Jaakkola reports research grants from the FinnishMedical Foundation. E.M. Myller reports research grants fromthe Finnish Parkinson Foundation and the Turku UniversityFoundation, and conference travel support from the FinnishNeurological Society. M.R.E. Eklund reports research grantsfrom Turku University Hospital, the Finnish ParkinsonFoundation, the Finnish Medical Foundation, Maire TaponenFoundation, the Finnish Brain Foundation, and the OrionResearch Foundation. S. Nuuttila has stocks/stock options inHerantis Pharma, Faron Pharmaceuticals, Orion Pharmaceuticals, Nightingale Health, Modulight, Revenio Group, andTerveystalo. K.-M. Murtom¨aki reports grants from the FinnishParkinson Foundation and Maire Taponen Foundation, andconference support from Nordicinfu Care and Abbvie. T.Ihalainen acts as the President of the Nordic Association forClinical Physics (NACP). F. Scheperjans has stocks/stockoptions in NeuroInnovation, NeuroBiome, Axial Biotherapeutics, and MRM Health; reports advisory board memberships for Axial Biotherapeutics, MRM Health and AdamantHealth; reports royalties from MRM Health; reports consulting fees from Abbvie, CRST, MRM Health, Lundbeck,Adamant Health, and the Finnish Movement Disorders Association; reports lecturer honoraria from Abbvie, GE Healthcare,Merck, Teca, Bristo Myers Squibb, Sanofi, Biocodex, Biogen, Nordicinfu Care, the Finnish Medical Association, and theAlzheimer Society of Finland; reports conference support fromLundbeck, NordicInfu Care, and Abbvie; has planned, issued,or pending patents; reports research grants from the ResearchCouncil of Finland, the Hospital District of Helsinki andUusimaa, Renishaw, Orion Pharma, and Abbvie; and is a boardmember of Finnish Movement Disorders Association. J. Joutsahas stocks/stock options in Neurologic Finland and SuomenNeurolaboratorio; reports conference travel support fromInsightec, Abbvie, and Abbott; reports consulting for Summaryx and Adamant Health; reports lecturer honoraria fromLundbeck and Novartis; and reports research grants from theFinnish Medical Foundation, the Sigrid Juselius Foundation,the Finnish Foundation for Alcohol Studies, University ofTurku, and Turku University Hospital. V. Kaasinen reportsadvisory board memberships for Abbvie Finland and NordicInfucare AB; reports speaker’s honoraria from Orion Pharma,Teva, Abbvie Finland, Lundbeck, Nordic Infucare AB, andEisai; has planned, issued, or pending patents; has acted asthe President of the Finnish Neurological Society; andreports research funding from the Finnish ParkinsonFoundation, the Finnish Cultural Foundation, TurkuUniversity Hospital (VTR-funds), the Turku UniversityFoundation, and the P¨aivikki and Sakari Sohlberg Foundation. All other authors report no relevant disclosures. Goto for full disclosures. ### Publication History Received by Neurology® October 1, 2025. Accepted in final formJanuary 15, 2026. Submitted and externally peer reviewed. The handlingeditor was Associate Editor Peter Hedera, MD, PhD. ## References - 1. Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’sdisease: MDS-PD Clinical Diagnostic Criteria. Mov Disord. 2015;30(12):1591-1601.doi:10.1002/mds.26424 - 2. Seibyl JP, Marchek KL, Quinlan D, et al. Decreased single-photon emissioncomputed tomographic {123I}?-CIT striatal uptake correlates with symptomseverity in Parkinson’s disease. Ann Neurol. 1995;38(4):589-598. doi:10.1002/ana.410380407 - 3. Benamer HT, Patterson J, Wyper DJ, Hadley DM, Macphee GJ, Grosset DG. Correlation of Parkinson’s disease severity and duration with 123I-FP-CIT SPECTstriatal uptake. Mov Disord. 2000;15(4):692-698. doi:10.1002/1531-8257(200007)15:4<692::aid-mds1014>3.0.co;2-v - 4. Dzialas V, Bischof GN, M¨ollenhoff K, Drzezga A, van Eimeren T. Dopamine transporter imaging as objective monitoring biomarker in Parkinson’s disease. Ann Neurol.2025;98(1):120-135. doi:10.1002/ana.27223 - 5. Spiegel J, Hellwig D, Samnick S, et al. Striatal FP-CIT uptake differs in the subtypes ofearly Parkinson’s disease. J Neural Transm. 2007;114(3):331-335. doi:10.1007/s00702006-0518-2 - 6. Lee J-Y, Lao-Kaim NP, Pasquini J, Deuschl G, Pavese N, Piccini P. Pallidaldopaminergic denervation and rest tremor in early Parkinson’s disease: PPMIcohort analysis. Parkinsonism Relat Disord. 2018;51:101-104. doi:10.1016/j.parkreldis.2018.02.039 - 7. Helmich RC, Janssen MJR, Oyen WJG, Bloem BR, Toni I. Pallidal dysfunction drivesa cerebellothalamic circuit into Parkinson tremor. Ann Neurol. 2011;69(2):269-281.doi:10.1002/ana.22361 - 8. Zach H, Dirkx MF, Roth D, Pasman JW, Bloem BR, Helmich RC. Dopamineresponsive and dopamine-resistant resting tremor in Parkinson disease. Neurology.2020;95(11):e1461-e1470. doi:10.1212/WNL.0000000000010316 - 9. Helmich RC, Hallett M, Deuschl G, Toni I, Bloem BR. Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits? Brain. 2012;135(pt11):3206-3226. doi:10.1093/brain/aws023 - 10. Shemisa K, Hass CJ, Foote KD, et al. Unilateral deep brain stimulation surgery inParkinson’s disease improves ipsilateral symptoms regardless of laterality. Parkinsonism Relat Disord. 2011;17(10):745-748. doi:10.1016/j.parkreldis.2011.07.010 - 11. Parent M, Parent A. Single-axon tracing study of corticostriatal projections arisingfrom primary motor cortex in primates. J Comp Neurol. 2006;496(2):202-213. doi:10.1002/cne.20925 Neurology | Volume 106, Number 7 | April 14, 2026 e214811(11) ### Page 12 - 12. Hazrati L-N, Parent A. Contralateral pallidothalamic and pallidotegmental projectionsin primates: an anterograde and retrograde labeling study. Brain Res. 1991;567(2):212-223. doi:10.1016/0006-8993(91)90798-z - 13. Douglas R, Kellaway L, Mintz M, van Wageningen G. The crossed nigrostriatalprojection decussates in the ventral tegmental decussation. Brain Res. 1987;418(1):111-121. doi:10.1016/0006-8993(87)90967-x - 14. Meola A, Comert A, Yeh F-C, Sivakanthan S, Fernandez-Miranda JC. The nondecussating pathway of the dentatorubrothalamic tract in humans: humanconnectome-based tractographic study and microdissection validation. J Neurosurg.2016;124(5):1406-1412. doi:10.3171/2015.4.JNS142741 - 15. Frequin HL, Schouten J, Verschuur CVM, et al. Levodopa response in patients withearly parkinson disease: further observations of the LEAP study. Neurology. 2023;100(4):e367-e376. doi:10.1212/WNL.0000000000201448 - 16. Niemi KJ, Sunikka J, Soltanian-Zadeh H, et al. Rest tremor in Parkinson’s disease isassociated with ipsilateral striatal DAT binding. Mov Disord. 2024;39(11):2014-2025.doi:10.1002/mds.29997 - 17. Pasquini J, Ceravolo R, Qamhawi Z, et al. Progression of tremor in early stages ofParkinson’s disease: a clinical and neuroimaging study. Brain. 2018;141(3):811-821.doi:10.1093/brain/awx376 - 18. Parkinson’s Progression Markers Initiative. Parkinson’s Progression Markers Initiative:Access Data. Accessed December 22, 2025. - 19. Parkinson’s Progression Markers Initiative. Accessed December 22, 2025. - 20. Diemling M. HERMES Instructions on Implementation of Phantom Based CameraCorrections for Enc-Dat BRASS. Hermes Medical Solutions; 2012. - 21. Tossici-Bolt L, Dickson JC, Sera T, et al. Calibration of gamma camera systems fora multicentre European 123I-FP-CIT SPECT normal database. Eur J Nucl Med MolImaging. 2011;38(8):1529-1540. doi:10.1007/s00259-011-1801-5 - 22. Albert NL, Unterrainer M, Diemling M, et al. Implementation of the Europeanmulticentre database of healthy controls for [123I]FP-CIT SPECT increases diagnostic accuracy in patients with clinically uncertain parkinsonian syndromes. Eur JNucl Med Mol Imaging. 2016;43(7):1315-1322. doi:10.1007/s00259-015-3304-2 - 23. M¨akinen E, Joutsa J, Jaakkola E, et al. Individual parkinsonian motor signs and striataldopamine transporter deficiency: a study with [I-123]FP-CIT SPECT. J Neurol. 2019;266(4):826-834. doi:10.1007/s00415-019-09202-6 - 24. Varrone A, Dickson JC, Tossici-Bolt L, et al. European multicentre database of healthycontrols for [123I]FP-CIT SPECT (ENC-DAT): age-related effects, gender differences and evaluation of different methods of analysis. Eur J Nucl Med Mol Imaging.2013;40(2):213-227. doi:10.1007/s00259-012-2276-8 - 25. Friston KJ, editor. Statistical Parametric Mapping: The Analysis of Functional BrainImages. 1st ed. Elsevier/Academic Press; 2007. - 26. Qamhawi Z, Towey D, Shah B, et al. Clinical correlates of raphe serotonergicdysfunction in early Parkinson’s disease. Brain. 2015;138(pt 10):2964-2973. doi:10.1093/brain/awv215 - 27. M¨akinen E, Joutsa J, Johansson J, M¨aki M, Sepp¨anen M, Kaasinen V. Visual versusautomated analysis of [I-123]FP-CIT SPECT scans in parkinsonism. J Neural Transm.2016;123(11):1309-1318. doi:10.1007/s00702-016-1586-6 - 28. Jaakkola E, Joutsa J, M¨akinen E, et al. Burden of non-motor symptoms in unclearparkinsonism and tremor: a study with [123I]FP-CIT SPECT. J Neurol Sci. 2019;404:124-127. doi:10.1016/j.jns.2019.07.025 - 29. Maechler M, Todorov V, Ruckstuhl A, et al. robustbase: basic robust statistics. Rpackage version 0.99-6. Updated September 4, 2025. Accessed November 16, 2025.= - 30. Wang J, Zamar R, Marazzi A, et al. robust: port of the S+ “robust library”. R packageversion 0.7-5. August 17, 2024. Accessed November 16, 2025.= - 31. Williams R. Ordinal independent variables. In: SAGE Research Methods Foundations.SAGE Publications Ltd.; 2020. - 32. Dirkx MF, Shine JM, Helmich RC. Integrative brain states facilitate the expression ofParkinson’s tremor. Mov Disord. 2023;38(9):1615-1624. doi:10.1002/mds.29506 - 33. Rossi C, Frosini D, Volterrani D, et al. Differences in nigro-striatal impairment inclinical variants of early Parkinson’s disease: evidence from a FP-CIT SPECT study:SPECT in clinical variants of Parkinson disease. Eur J Neurol. 2010;17(4):626-630.doi:10.1111/j.1468-1331.2009.02898.x - 34. Huang A-Q, Liu S-Y, Barret O, et al. 18F-FP-DTBZ PET/CT detectable associationsbetween monoaminergic depletion in the putamen with rigidity and the pallidus withtremor in Parkinson’s disease. Parkinsonism Relat Disord. 2024;120:105979. doi:10.1016/j.parkreldis.2023.105979 - 35. Fang LZ, Creed MC. Updating the striatal-pallidal wiring diagram. Nat Neurosci. 2024;27(1):15-27. doi:10.1038/s41593-023-01518-x - 36. He S, West TO, Plazas FR, et al. Cortico-thalamic tremor circuits and their associations with deep brain stimulation effects in essential tremor. Brain. 2025;148(6):2093-2107. doi:10.1093/brain/awae387 - 37. Choi Y, Shin EY, Kim S. Spatiotemporal dissociation of fMRI activity in the caudatenucleus underlies human de novo motor skill learning. Proc Natl Acad Sci USA. 2020;117(38):23886-23897. doi:10.1073/pnas.2003963117 - 38. Dumurgier J, Crivello F, Mazoyer B, et al. MRI atrophy of the caudate nucleus andslower walking speed in the elderly. Neuroimage. 2012;60(2):871-878. doi:10.1016/j.neuroimage.2012.01.102 - 39. Kaasinen V, Vahlberg T. Striatal dopamine in Parkinson disease: a meta‐analysis ofimaging studies. Ann Neurol. 2017;82(6):873-882. doi:10.1002/ana.25103 - 40. Benamer TS, Patterson J, Grosset DG, et al. Accurate differentiation of parkinsonismand essential tremor using visual assessment of [123I]-FP-CIT SPECT imaging: the[123I]-FP-CIT study group. Mov Disord. 2000;15(3):503-510. - 41. Catafau AM, Tolosa E; DaTSCAN Clinically Uncertain Parkinsonian SyndromesStudy Group. Impact of dopamine transporter SPECT using123I‐Ioflupane on diagnosis and management of patients with clinically uncertain parkinsonian syndromes. Mov Disord. 2004;19(10):1175-1182. doi:10.1002/mds.20112 - 42. Lorberboym M, Treves TA, Melamed E, Lampl Y, Hellmann M, Djaldetti R. [123I]-FP/CIT SPECT imaging for distinguishing drug-induced parkinsonism from Parkinson’s disease: [123I]-FP/CIT SPECT in drug-induced parkinsonism. Mov Disord.2006;21(4):510-514. doi:10.1002/mds.20748 - 43. Jin S, Oh M, Oh SJ, et al. Differential diagnosis of parkinsonism using dual-phase F-18FP-CIT PET imaging. Nucl Med Mol Imaging. 2013;47(1):44-51. doi:10.1007/s13139-012-0182-4 Neurology | Volume 106, Number 7 | April 14, 2026 e214811(12)