Imaging analysis of Parkinson's disease patients using SPECT and tractography.
ABSTRACT: Parkinson's disease (PD) is a degenerative disorder that affects the central nervous system. PD-related alterations in structural and functional neuroimaging have not been fully explored. This study explored multi-modal PD neuroimaging and its application for predicting clinical scores on the Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Multi-modal imaging that combined 123I-Ioflupane single-photon emission computed tomography (SPECT) and diffusion tensor imaging (DTI) were adopted to incorporate complementary brain imaging information. SPECT and DTI images of normal controls (NC; n?=?45) and PD patients (n?=?45) were obtained from a database. The specific binding ratio (SBR) was calculated from SPECT. Tractography was performed using DTI. Group-wise differences between NC and PD patients were quantified using SBR of SPECT and structural connectivity of DTI for regions of interest (ROIs) related to PD. MDS-UPDRS scores were predicted using multi-modal imaging features in a partial least-squares regression framework. Three regions and four connections within the cortico-basal ganglia thalamocortical circuit were identified using SBR and DTI, respectively. Predicted MDS-UPDRS scores using identified regions and connections and actual MDS-UPDRS scores showed a meaningful correlation (r?=?0.6854, p?
Project description:BACKGROUND:Improved prediction of Parkinson's disease (PD) progression is needed to support clinical decision-making and to accelerate research trials. OBJECTIVES:To examine whether baseline measures and their 1-year change predict longer-term progression in early PD. METHODS:Parkinson's Progression Markers Initiative study data were used. Participants had disease duration ?2 years, abnormal dopamine transporter (DAT) imaging, and were untreated with PD medications. Baseline and 1-year change in clinical, cerebrospinal fluid (CSF), and imaging measures were evaluated as candidate predictors of longer-term (up to 5 years) change in Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score and DAT specific binding ratios (SBR) using linear mixed-effects models. RESULTS:Among 413 PD participants, median follow-up was 5 years. Change in MDS-UPDRS from year-2 to last follow-up was associated with disease duration (?=?0.351; 95% CI?=?0.146, 0.555), male gender (?=?3.090; 95% CI?=?0.310, 5.869), and baseline (?=?-0.199; 95% CI?=?-0.315, -0.082) and 1-year change (?=?0.540; 95% CI?=?0.423, 0.658) in MDS-UPDRS; predictors in the model accounted for 17.6% of the variance in outcome. Predictors of percent change in mean SBR from year-2 to last follow-up included baseline rapid eye movement sleep behavior disorder score (?=?-0.6229; 95% CI?=?-1.2910, 0.0452), baseline (?=?7.232; 95% CI?=?2.268, 12.195) and 1-year change (?=?45.918; 95% CI?=?35.994,55.843) in mean striatum SBR, and 1-year change in autonomic symptom score (?=?-0.325;95% CI?=?-0.695, 0.045); predictors in the model accounted for 44.1% of the variance. CONCLUSIONS:Baseline clinical, CSF, and imaging measures in early PD predicted change in MDS-UPDRS and dopamine-transporter binding, but the predictive value of the models was low. Adding the short-term change of possible predictors improved the predictive value, especially for modeling change in dopamine-transporter binding.
Project description:No disease modifying therapies for Parkinson's disease (PD) have been found effective to date. To properly power clinical trials for discovery of such therapies, the ability to predict outcome in PD is critical, and there is a significant need for discovery of prognostic biomarkers of PD. Dopamine transporter (DAT) SPECT imaging is widely used for diagnostic purposes in PD. In the present work, we aimed to evaluate whether longitudinal DAT SPECT imaging can significantly improve prediction of outcome in PD patients. In particular, we investigated whether radiomics analysis of DAT SPECT images, in addition to use of conventional non-imaging and imaging measures, could be used to predict motor severity at year 4 in PD subjects. We selected 64 PD subjects (38 male, 26 female; age at baseline (year 0): 61.9 ± 7.3, range [46,78]) from the Parkinson's Progressive Marker Initiative (PPMI) database. Inclusion criteria included (i) having had at least 2 SPECT scans at years 0 and 1 acquired on a similar scanner, (ii) having undergone a high-resolution 3 T MRI scan, and (iii) having motor assessment (MDS-UPDRS-III) available in year 4 used as outcome measure. Image analysis included automatic region-of-interest (ROI) extraction on MRI images, registration of SPECT images onto the corresponding MRI images, and extraction of radiomic features. Non-imaging predictors included demographics, disease duration as well as motor and non-motor clinical measures in years 0 and 1. The image predictors included 92 radiomic features extracted from the caudate, putamen, and ventral striatum of DAT SPECT images at years 0 and 1 to quantify heterogeneity and texture in uptake. Random forest (RF) analysis with 5000 trees was used to combine both non-imaging and imaging variables to predict motor outcome (UPDRS-III: 27.3 ± 14.7, range [3,77]). The RF prediction was evaluated using leave-one-out cross-validation. Our results demonstrated that addition of radiomic features to conventional measures significantly improved (p < 0.001) prediction of outcome, reducing the absolute error of predicting MDS-UPDRS-III from 9.00 ± 0.88 to 4.12 ± 0.43. This shows that radiomics analysis of DAT SPECT images has a significant potential towards development of effective prognostic biomarkers in PD.
Project description:Objective:The Parkinson's Progression Markers Initiative (PPMI) is an observational, international study designed to establish biomarker-defined cohorts and identify clinical, imaging, genetic, and biospecimen Parkinson's disease (PD) progression markers to accelerate disease-modifying therapeutic trials. Methods:A total of 423 untreated PD, 196 Healthy Control (HC) and 64 SWEDD (scans without evidence of dopaminergic deficit) subjects were enrolled at 24 sites. To enroll PD subjects as early as possible following diagnosis, subjects were eligible with only asymmetric bradykinesia or tremor plus a dopamine transporter (DAT) binding deficit on SPECT imaging. Acquisition of data was standardized as detailed at www.ppmi-info.org. Results:Approximately 9% of enrolled subjects had a single PD sign at baseline. DAT imaging excluded 16% of potential PD subjects with SWEDD. The total MDS-UPDRS for PD was 32.4 compared to 4.6 for HC and 28.2 for SWEDD. On average, PD subjects demonstrated 45% and 68% reduction in mean striatal and contralateral putamen Specific Binding Ratios (SBR), respectively. Cerebrospinal fluid (CSF) was acquired from >97% of all subjects. CSF (PD/HC/SWEDD pg/mL) ?-synuclein (1845/2204/2141) was reduced in PD vs HC or SWEDD (P < 0.03). Similarly, t-tau (45/53) and p-tau (16/18) were reduced in PD versus HC (P < 0.01). Interpretation:PPMI has detailed the biomarker signature for an early PD cohort defined by clinical features and imaging biomarkers. This strategy provides the framework to establish biomarker cohorts and to define longitudinal progression biomarkers to support future PD treatment trials.
Project description:Background:The Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UDPRS) is a commonly used tool to measure Parkinson disease (PD) progression. Longitudinal changes in MDS-UPDRS scores in de novo PD have not been established. Objective:Determine progression rates of MDS-UPDRS scores in de novo PD. Methods:362 participants from the Parkinson's Progression Markers Initiative, a multicenter longitudinal cohort study of de novo PD, were included. Longitudinal progression of MDS-UPDRS total and subscale scores were modeled using mixed model regression. Results:MDS-UPDRS scores increased in a linear fashion over five years in de novo PD. MDS-UPDRS total score increased an estimated 4.0 points/year, Part I 0.25 points/year, Part II 1.0 points/year, and Part III 2.4 points/year. Conclusions:The expected average progression of MDS-UPDRS scores in de novo PD from this study can assist in clinical monitoring and provide comparative data for detection of disease modification in treatment trials.
Project description:The aim of this study was to evaluate associations of motor and non-motor symptoms with dopamine transporter binding in prodromal stage of synucleinopathies. We examined 74 patients with idiopathic REM sleep behavior disorder (RBD), which is a prodromal synucleinopathy, and 39 controls using Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Montreal Cognitive Assessment, University of Pennsylvania Smell Identification Test (UPSIT), Farnsworth-Munsell 100 hue test, orthostatic test, Scales for Outcomes in PD-Autonomic, Beck depression inventory-II, State-Trait Anxiety Inventory, and video-polysomnography. Electromyographic muscle activity during REM sleep was quantified according to Sleep Innsbruck-Barcelona criteria. In 65 patients, dopamine transporter single-photon emission computed tomography (DAT-SPECT) imaging was performed, putaminal binding ratio was calculated and scans were classified as normal, borderline, or abnormal. Compared to controls, RBD patients had significantly more severe scores in all examined tests. Patients with abnormal DAT-SPECT had higher MDS-UPDRS motor score (p = 0.006) and higher prevalence of orthostatic hypotension (p = 0.008). Putaminal binding ratio was positively associated with UPSIT score (p = 0.03) and negatively associated with tonic (p = 0.003) and phasic (p = 0.01) muscle activity during REM sleep. These associations likely reflect simultaneous advancement of underlying pathology in substantia nigra and susceptible brainstem and olfactory nuclei in prodromal synucleinopathy.
Project description:Background:Nonmotor symptoms (NMSs) of Parkinson's disease (PD) impair health-related quality of life. Objectives:To identify changes in NMSs during 52?weeks in Japanese PD patients exhibiting motor fluctuations. Methods:In PD patients with ?1 NMS and wearing-off, changes in total/subscore of the Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) Part I and 8-item PD Questionnaire were assessed. Group-based trajectory models were used to characterize longitudinal patterns of MDS-UPDRS Part I. Results:Data from 996 patients were analyzed. MDS-UPDRS Part I subscores for cognitive function decreased linearly over time. Total and subscores for apathy and lightheadedness on standing significantly deteriorated with fluctuations, whereas other subscores fluctuated without significant deterioration. Changes in the MDS-UPDRS Part I total score correlated with changes in the 8-item PD Questionnaire total score. Based on group-based trajectory models, longitudinal pattern analysis of MDS-UPDRS Part I scores yielded the following 3 separate groups: unchanged (63.8%), deteriorated (20.1%), and improved (16.2%). The improved group had significantly more NMSs at baseline, significantly higher MDS-UPDRS Part I/8-item PD Questionnaire total scores, and modified Hoehn and Yahr scores, and had received treatment for NMSs. The multivariate analysis revealed significant associations between severe motor disability and receiving any treatment for NMSs at baseline and improvement of MDS-UPDRS Part I total scores. Conclusions:Changes in MDS-UPDRS Part I scores were variable and related to changes in health-related quality of life in PD patients with motor fluctuations.
Project description:Cardiovascular comorbidities associate with neurodegeneration in the elderly and may contribute to extranigral pathologies and medically refractory axial motor features in Parkinson disease (PD).We explored differences in the estimated rate of axial motor feature accrual between patients with PD with and without elevated cardiovascular risk factors as estimated by the Framingham General Cardiovascular Disease risk-scoring algorithm in a cross-sectional cohort study. All participants underwent motor evaluations with the Movement Disorders Society revised Unified Parkinson's Disease Rating Scale (MDS-UPDRS), [(11)C]dihydrotetrabenazine (DTBZ) monoaminergic brain PET imaging, and MRI.Participants with PD with elevated Framingham risk (FR) scores (n = 63, 74.1%) showed higher unadjusted rates of total MDS-UPDRS (t = 3.60, p = 0.0006) and axial motor scores (t = 3.98, p = 0.0001) per estimated year of motor symptoms compared to participants with normal-range risk scores (n = 22, 25.9%). After controlling for sex, Montreal Cognitive Assessment score, frontal leukoaraiosis severity, and striatal DTBZ activity, elevated risk factor status was associated with the rate of accrual of axial motor impairments (R(2) = 0.206; t = 2.62, p = 0.011) but not with total MDS-UPDRS motor score (R(2) = 0.198; t = 1.51, p = 0.135). Frontal leukoaraiosis was associated with the rate of axial and total MDS-UPDRS scores per year of symptoms and also with elevated systolic blood pressure (R(2) = 0.291; t = 2.30, p = 0.024) in a separate risk-factor model.Cardiovascular risk factors may contribute to axial motor features in PD. Early modification of cardiovascular risk factors, including hypertension, deserves further study as a novel disease-modifying strategy in PD.
Project description:Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with both underlying genetic factors and neuroimaging findings. Existing neuroimaging studies related to the genome in PD have mostly focused on certain candidate genes. The aim of our study was to construct a linear regression model using both genetic and neuroimaging features to better predict clinical scores compared to conventional approaches. We obtained neuroimaging and DNA genotyping data from a research database. Connectivity analysis was applied to identify neuroimaging features that could differentiate between healthy control (HC) and PD groups. A joint analysis of genetic and imaging information known as imaging genetics was applied to investigate genetic variants. We then compared the utility of combining different genetic variants and neuroimaging features for predicting the Movement Disorder Society-sponsored unified Parkinson's disease rating scale (MDS-UPDRS) in a regression framework. The associative cortex, motor cortex, thalamus, and pallidum showed significantly different connectivity between the HC and PD groups. Imaging genetics analysis identified PARK2, PARK7, HtrA2, GIGYRF2, and SNCA as genetic variants that are significantly associated with imaging phenotypes. A linear regression model combining genetic and neuroimaging features predicted the MDS-UPDRS with lower error and higher correlation with the actual MDS-UPDRS compared to other models using only genetic or neuroimaging information alone.
Project description:Background:The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a newly developed tool to assess Parkinson's disease (PD). Changes in scores on the scale over the course of PD, including increasing disease duration and Hoehn and Yahr (HY) stages, have not been described. The objectives of this study were to analyze MDS-UPDRS scores on Parts I through IV and their differences based on HY stage and disease duration in a large cohort of patients with PD. Methods:For this cross-sectional study, demographic data and MDS-UPDRS scores were collected, including HY stage. Subscores on MDS-UPDRS Parts I through IV were analyzed using 1-way analyses of variance for each HY stage and in 5-year increments of disease duration. Part III (motor assessment) scores were analyzed separately for on and off states. Results:The mean age of the 3206 patients was 65.8 ± 10.6 years, 53.3% were men, the mean disease duration was 11.5 ± 4.6 years, and the median HY stage was 2 (range, 0-5); 2156 patients were examined in an on state and 987 were examined in an off state. Scores for all MDS-UPDRS parts increased significantly through HY stages 1 through 5, with an average increase of 3.8, 7.7, 14.6, and 2.0 points consecutively for parts I through IV, respectively. For the 5-year increments of disease duration, MDS-UPDRS subscores increased by an average of 1.6, 3.3, 4.2, and 1.4 points consecutively for parts I through IV, respectively. This increase was significant only during the first 15 years of disease for all 4 parts, including part III scores evaluated in both on and off states. Conclusions:MDS-UPDRS scores for all 4 parts increase significantly with every HY stage and also with 5-year increments of disease duration in the first 15 years of the disease.
Project description:BACKGROUND AND PURPOSE:Whether the neuromelanin-positive substantia nigra pars compacta area (NM-SNc) on neuromelanin magnetic resonance imaging (NM-MRI) and the specific binding ratio (SBR) on 123 I-N-v-fluoropropyl-2b-carbomethoxy3b-(4-iodophenyl)nortropane single photon emission computed tomography (DaT-SPECT) can be correlated with motor fluctuations (MFs) in advanced Parkinson's disease (PD) was investigated. METHODS:Thirty-five PD patients (60 ± 13 years) and 23 healthy individuals as controls (59 ± 19 years) were enrolled. The relationships between NM-MRI and DaT-SPECT were prospectively examined in two subgroups divided according to the presence or absence of MFs. Multivariate analysis was performed using the Cox proportional hazard model to screen for association factors. RESULTS:The NM-SNc size was correlated with the SBR (Spearman's ? = 0.43, P < 0.05). The NM-SNc size was significantly reduced in PD with MFs compared with the subgroup without (P < 0.001), whereas the SBR did not significantly differ between the groups. NM-SNc size was a significant association factor for MFs (hazard ratio 0.94, P = 0.04). In receiver operating characteristic analysis of the factors for MF occurrence, the area under the receiver operating characteristic curve of the NM-SNc size showed a significant difference of 0.89 (P < 0.05) but no significant difference was found in the SBR. CONCLUSIONS:NM-SNc size was significantly correlated with the SBR in PD, but several factors in advanced PD were more closely associated with NM-SNc size than the SBR. NM-MRI might reflect the status of advanced PD more accurately than DaT-SPECT. Therefore, NM-MRI appears to provide a better marker for discriminating advanced PD than DaT-SPECT.