Scans Without Evidence Of Dopaminergic Deficit Research Articles

Cerebrospinal fluid biomarkers profile in scans without evidence of dopaminergic deficits (SWEDD)

BackgroundA small proportion of patients with clinical parkinsonism have normal transporter-single photon emission computed tomography (DaTSPECT) which is commonly defined as scans without evidence of dopaminergic deficits (SWEDD). A better understanding of SWEDD can improve the current therapeutic options and appropriate disease monitoring. AimWe aimed to assess CSF biomarkers levels including α-synuclein (α-syn), amyloid βeta (Aβ1–42), total tau (t-tau), and phosphorylated tau (p-tau) in SWEDD and investigate the longitudinal alteration in the CSF profile. MethodsIn total, 406 early-stage PD, 58 SWEDD, and 187 healthy controls (HCs) were entered into our study from PPMI. We compared the level of CSF biomarkers at baseline, six months, one year, and two years. Furthermore, the longitudinal alteration of CSF biomarkers was explored in each group using linear mixed models. ResultsThere was no significant difference in the level of CSF α-syn Aβ1–42, t-tau, and p-tau between HCs and SWEDD at different time points. Investigating the level of CSF α-syn in PD and SWEDD showed a significant difference at one (p = 0.016) and two years (p = 0.006). Also, we observed a significant difference in the level of CSF Aβ1–42 between SWEDD and PD at one year (p = 0.012). Moreover, there was a significant difference in the level of CSF t-tau between SWEDD and PD subjects at one (p = 0.013) and two years (p = 0.017). Furthermore, there was a significant difference in the level of CSF p-tau between SWEDD and PD groups at two years visits (p = 0.030). Longitudinal analysis showed a significant decrease after one (p = 0.029) and two years (p = 0.002) from baseline in the level of CSF α-syn only in the PD group. Also, we observed that the level of CSF Aβ1–42 significantly increased after one year in SWEDD (p = 0.031) and decreased after two years from baseline in PD subjects (p = 0.005). Moreover, there was a significant increase in the level of CSF t-tau after two years (p = 0.036) and CSF p-tau after six months from baseline in SWEDD subjects (p = 0.011). ConclusionThis finding suggests a faster neurodegeneration process in PD patients compared to SWEDD at least based on these biomarkers. Future studies with longer follow-up duration and more sample sizes are necessary to validate our results.

Comparison of resting tremor at the upper limb joints between patients with Parkinson's disease and scans without evidence of dopaminergic deficit.

A representative symptom of Parkinson's disease (PD) is resting tremor. The clinical manifestation of scans without evidence of dopaminergic deficit (SWEDD) is similar to it of PD, though the phenomenology of SWEDD is not well known. In the present study, the resting tremor of 9 SWEDD patients was quantitatively compared with that of 11 PD patients. Four 3-axis gyro sensors were attached on the index finger, thumb, dorsum of the hand, and arm of the more tremulous side. Root mean square (RMS) angular speed and angular displacement as well as irregularity of angular speed and displacement were derived from the sensor data. Although disease duration and Hoehn and Yahr stages were comparable, SWEDD patients exhibited different tremor features from PD patients. Significantly faster RMS angular speed and greater RMS angular displacement (p< 0.05) were observed in PD patients than in SWEDD patients. The irregularity of angular displacement of pitch direction at the dorsum of the hand was greater in SWEDD patients than in PD patients (p< 0.05). These results indicate that quantitative indices obtained from resting tremor task could be important biomarkers for identifying potential patients with SWEDD among patients diagnosed with PD.

Nigral volumetric and microstructural measures in individuals with scans without evidence of dopaminergic deficit.

Striatal dopamine transporter (DAT) imaging using 123I-ioflupane single photon positron emitted computed tomography (SPECT) (DaTScan, GE) identifies 5-20% of newly diagnosed Parkinson's disease (PD) subjects enrolling in clinical studies to have scans without evidence of dopaminergic deficit (SWEDD). These individuals meet diagnostic criteria for PD, but do not clinically progress as expected, and they are not believed to have neurodegenerative Parkinsonism. Inclusion of SWEDD participants in PD biomarker studies or therapeutic trials may therefore cause them to fail. DaTScan can identify SWEDD individuals, but it is expensive and not widely available; an alternative imaging approach is needed. Here, we evaluate the use of neuromelanin-sensitive, iron-sensitive, and diffusion contrasts in substantia nigra pars compacta (SNpc) to differentiate SWEDD from PD individuals. Neuromelanin-sensitive, iron-sensitive, and diffusion imaging data for SWEDD, PD, and control subjects were downloaded from the Parkinson's progression markers initiative (PPMI) database. SNpc volume, SNpc iron (R 2), and SNpc free water (FW) were measured for each participant. Significantly smaller SNpc volume was seen in PD as compared to SWEDD (P < 10-3) and control (P < 10-3) subjects. SNpc FW was elevated in the PD group relative to controls (P = 0.017). No group difference was observed in SNpc R 2. In conclusion, nigral volume and FW in the SWEDD group were similar to that of controls, while a reduction in nigral volume and increased FW were observed in the PD group relative to SWEDD and control participants. These results suggest that these MRI measures should be explored as a cost-effective alternative to DaTScan for evaluation of the nigrostriatal system.

Advancement of biomolecular engineering in Parkinson disease

Parkinson's Condition (PD) is the second most common degenerative neurological disease, affecting 10 million people globally. Nigrostriatal degeneration is linked to decreased motor and non-motor functioning in this chronic illness. Resting tremor, stiffness, akinesia (or bradykinesia), and postural instability are the four cardinal symptoms of Parkinson's disease. Because the symptoms of Parkinson's disease are similar to those of other age-related disorders like SWEDD (scans without evidence of dopaminergic deficit), essential tremors, and Parkinson's disease, early diagnosis is difficult. A synucleinopathy is Parkinson's disease (PD) with Lewy Bodies (DLB).Although both genetic and environmental variables are assumed to play a role in Parkinson's disease (PD), there was no direct evidence to support either as a causal component until recently. Six distinct genes have been discovered as producing familial PD in the last eight years. They back up the idea that similar pathogenetic pathways exist across the spectrum of Parkinson's disease etiologies. Mutations in α-synuclein, parkin, UCHL1, DJ1, PINK1, and LRRK2 cause.Parkinson's disease, which is inherited in a Mendelian form. Overexpression of α- synuclein and parkin causes mitochondrial issues, but DJ1 and PINK1 are mitochondrial proteins. These same proteins regulate proteasomal function and play a role in the oxidative stress response.Doped carbon nanotubes, especially phosphorus-doped carbon nanotubes, can efficiently prevent the formation of α- synuclein amyloid, suggesting that they could be utilized to treat Parkinson's disease. More in vitro and clinical research is, however, necessary. As previously stated, αsynuclein could be a therapeutic target for Parkinson's disease and other synucleinopathies. The most promising option would be small chemicals that may modify the structure of protofibrillar forms of α-synuclein and render them nonpathogenic. Given the pathogenic consequences of αsynuclein's feed-forward amplification loops, a range of therapeutic options will almost certainly be required.

Studying cognitive function in patients with a long-standing diagnosis of SWEDD

IntroductionThe cognitive profile of patients with longstanding clinical Parkinsonism possessing scans without evidence of dopaminergic deficit (SWEDD) remains unclear from previous studies. MethodsWe studied 47 patients recruited in the Parkinson's Progression Markers Initiative with SWEDD as baseline diagnosis. They were subdivided by final clinical diagnoses after a 2-year follow-up period into 25 patients with either clinical evidence of Parkinson's Disease (PD) or unclassified parkinsonism and normal SPECT imaging (“true SWEDDs”), 6 patients with a psychogenic illness exhibiting Parkinsonism, 6 patients who had phenoconverted to PD based on reduced striatal dopaminergic activity on imaging, and 10 patients with another tremulous condition. Cognitive symptoms were compared between these subgroups, as well as with 62 PD patients and 195 healthy controls (HCs), at baseline and follow-ups. ResultsA significant difference in working memory was found between true SWEDDs and HCs (P = 0.009), but not true SWEDDs and PD patients (P = 0.432), nor PD patients and HCs (P = 0.154). The prevalence of attentional impairment was also significantly different between the three groups (P < 0.001). SWEDD subgroups possessed similar cognitive symptoms irrespective of their final clinical diagnosis. Psychogenic, phenoconverted and tremulous SWEDDs also possessed stable cognitive symptoms over the 2-year period whilst true SWEDDs, PD patients and HCs experienced significant changes in working memory. ConclusionsOur results, particularly relating to working memory and attention, add to the knowledge of other true SWEDD non-motor symptoms to facilitate earlier diagnosis and improved management strategies for these patients.

Convolutional Neural Network-Based Parkinson Disease Classification Using SPECT Imaging Data

In this paper, we used the single-photon emission computerized tomography (SPECT) imaging technique to visualize the deficiency of dopamine-generated patterns inside the brain. These patterns are used to establish a patient’s disease progression, which helps distinguish the patients into different categories. Furthermore, we used a convolutional neural network (CNN) model to classify the patients based on the dopamine level inside the brain. The dataset used throughout this paper is the Parkinson’s progressive markers initiative (PPMI) dataset. The collected dataset was pre-processed and data amplification was performed to balance the imbalanced dataset. A CNN-based neural network was defined to classify input SPECT images into four categories. The motivation behind the proposed model is to reduce the number of resources consumed while maintaining the performance of the classification model. This will help the healthcare ecosystem run the classification model on mobile devices. The proposed model contains 14 layers with input layers, convolutional layers, max-pool layers, flatten layers, and dense layers with different dimensions. The dense layer classifies the patients into four different categories, including PSD, healthy control, scans without evidence of dopaminergic deficit (SWEDD), and GenReg PSD from the entire SPECT imaging dataset, which is used to establish the disease progression of different patients using SPECT images. The proposed model is trained with a large dataset with 58,692 images for training and 11,738 images for validation, and 7826 for testing. The proposed model outperforms the classification models from the surveyed papers. The proposed model’s accuracy is 0.889, recall is 0.9012, the precision is 0.9104, and the F1-score is 0.9057.

Structural connectivity alterations in the motor network of patients with scans without evidence of dopaminergic deficit (SWEDD).

Approximatively, 10% of patients initially diagnosed with Parkinson's disease (PD) show preserved presynaptic dopaminergic function in the nigrostriatal pathway on DAT-SPECT imaging. This syndrome is not compatible with PD diagnosis, and is known as scans without evidence of dopaminergic deficit (SWEDD). To investigate structural connectivity of cerebello-subcortico-cortical networks, including the nigrostriatal pathway, in an international cohort of subjects with SWEDD compared to normal controls using probabilistic tractography. Twenty-eight patients with SWEDD and 21 age- and sex-matched healthy controls (HC) were selected from the Parkinson's Progression Markers Initiative (PPMI) database. All participants underwent whole-brain 3D T1-weighted and diffusion-weighted MRI, as well as DAT-SPECT. Probabilistic tractography was performed in network-mode between regions of the cerebello-thalamo-basal ganglia-cortical circuits, to extract the connectivity strength between pairs of nodes of the circuit, as well as volumetric and diffusion measures of each reconstructed tract. Analysis of covariance with age and sex as covariates of non-interest was performed to assess group differences. Statistical significance was set at p < 0.05 after false-discovery-rate correction for multiple comparisons. Compared to HC, patients with SWEDD showed increased fractional anisotropy in bilateral thalamo-putamen-precentral, left nigro-putaminal and left thalamo-pallidal pathways. Furthermore, we found decreased mean streamline length in bilateral thalamo-nigro-cerebellar pathways and in the left nigro-caudate connection. Clinical heterogeneity of SWEDD syndrome may account for involvement of different brain circuits, such as the cerebello-thalamo-cortical and the nigrostriatal pathways, characteristic of different tremulous disorders.

Explainable machine learning with pairwise interactions for the classification of Parkinson's disease and SWEDD from clinical and imaging features.

Scans without evidence of dopaminergic deficit (SWEDD) refers to patients who mimics motor and non-motor symptoms of Parkinson’s disease (PD) but showing integrity of dopaminergic system. For this reason, the differential diagnosis between SWEDD and PD patients is often not possible in absence of dopamine imaging. Machine Learning (ML) showed optimal performance in automatically distinguishing these two diseases from clinical and imaging data. However, the most common applied ML algorithms provide high accuracy at expense of findings intelligibility. In this work, a novel ML glass-box model, the Explainable Boosting Machine (EBM), based on Generalized Additive Models plus interactions (GA2Ms), was employed to obtain interpretability in classifying PD and SWEDD while still providing optimal performance. Dataset (168 healthy controls, HC; 396 PD; 58 SWEDD) was obtained from PPMI database and consisted of 178 among clinical and imaging features. Six binary EBM classifiers were trained on feature space with (SBR) and without (noSBR) dopaminergic striatal specific binding ratio: HC-PDSBR, HC-SWEDDSBR, PD-SWEDDSBR and HC-PDnoSBR, HC-SWEDDnoSBR, PD-SWEDDnoSBR. Excellent AUC-ROC (1) was reached in classifying HC from PD and SWEDD, both with and without SBR, and by PD-SWEDDSBR (0.986), while PD-SWEDDnoSBR showed lower AUC-ROC (0.882). Apart from optimal accuracies, EBM algorithm was able to provide global and local explanations, revealing that the presence of pairwise interactions between UPSIT Booklet #1 and Epworth Sleepiness Scale item 3 (ESS3), MDS-UPDRS-III pronation-supination movements right hand (NP3PRSPR) and MDS-UPDRS-III rigidity left upper limb (NP3RIGLU) could provide good performance in predicting PD and SWEDD also without imaging features.

Unexpected (123I)FP-CIT SPECT findings: SWIDD, SWEDD and all DAT.

Although the diagnosis of Parkinson's disease (PD) is essentially clinical, the implementation of imaging techniques can improve diagnostic accuracy. While some techniques (e.g. magnetic resonance imaging-MRI, computerized tomography-CT) are used to exclude secondary syndromes, presynaptic dopaminergic imaging including imaging of dopamine transporter (DAT)-can help the Neurologist in the differential diagnosis between neurodegenerative parkinsonian syndromes and parkinsonism without dopamine deficiency. DAT imaging can be useful in cases in which the clinical picture is not univocal, as in case of overlapping clinical features in patients with early disease, atypical syndromes or unsatisfying response to therapy. Currently, (123I)FP-CIT ([123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane) (trade name DaTSCAN) is the only agent approved by international regulatory agencies for this purpose. With the increasing use of this technique, some unexpected findings have been reported, including patients clinically diagnosed with PD with a normal SPECT scan [e.g. Scans Without Evidence of Dopaminergic Deficit (SWEDD)]; PD patients with a greater dopaminergic deficit in the striatum ipsilateral to the clinicallymore affected side [e.g. Scans With Ipsilateral Dopaminergic Deficit (SWIDD)]; as well as some artifacts. Moreover, the neurologist must remember that structural lesions and administration of some drugs might alter the result of DAT imaging. Unexpected findings, artifacts, and misinterpretation of imaging findings can lead to an erroneous diagnosis and inappropriate therapy, neglect of other medical conditions that might explain the clinical picture, and undermine the selection phase in clinical trials. The aim of the present review is to bring clarity on these controversial (and sometimes erroneous) results, in order to informof these possibilities the clinicians requesting a DaTSCAN in clinical practice.

An Integrative Nomogram for Identifying Early-Stage Parkinson's Disease Using Non-motor Symptoms and White Matter-Based Radiomics Biomarkers From Whole-Brain MRI.

Purpose: To develop and validate an integrative nomogram based on white matter (WM) radiomics biomarkers and nonmotor symptoms for the identification of early-stage Parkinson's disease (PD).Methods: The brain magnetic resonance imaging (MRI) and clinical characteristics of 336 subjects, including 168 patients with PD, were collected from the Parkinson's Progress Markers Initiative (PPMI) database. All subjects were randomly divided into training and test sets. According to the baseline MRI scans of patients in the training set, the WM was segmented to extract the radiomic features of each patient and develop radiomics biomarkers, which were then combined with nonmotor symptoms to build an integrative nomogram using machine learning. Finally, the diagnostic accuracy and reliability of the nomogram were evaluated using a receiver operating characteristic curve and test data, respectively. In addition, we investigated 58 patients with atypical PD who had imaging scans without evidence of dopaminergic deficit (SWEDD) to verify whether the nomogram was able to distinguish patients with typical PD from patients with SWEDD. A decision curve analysis was also performed to validate the clinical practicality of the nomogram.Results: The area under the curve values of the integrative nomogram for the training, testing and verification sets were 0.937, 0.922, and 0.836, respectively; the specificity values were 83.8, 88.2, and 91.38%, respectively; and the sensitivity values were 84.6, 82.4, and 70.69%, respectively. A significant difference in the number of patients with PD was observed between the high-risk group and the low-risk group based on the nomogram (P < 0.05).Conclusion: This integrative nomogram is a new potential method to identify patients with early-stage PD.

Difference of static postural balance in patients with Parkinson's Disease and scans without evidencec of dopaminergic deficits

Differentiating scans without evidence of dopaminergic deficit (SWEDD) from Parkinson's disease (PD) is very important to avoid costly and inappropriate interventions. Little is known of postural balance strategy of SWEDD patients. The purpose of this study was investigate difference of static postural balance between SWEDD and PD patients. Eleven patients with SWEDD, 11 patients with PD and normal subjects were instructed to quietly stand on a force plate in a comfortable self selected stance width. Center of pressure (COP) was measured for quantitative evaluation during static standing. As outcome measure, mean distance, mean velocity, 95% confidence ellipse area, mean frequency, peak frequency and peak power were derived from the COP time series in overall, anterio-posterior (AP) and medio-lateral (ML) directions. ANOVA and post hoc test were evaluated for comparison between SWEDD patients and PD patients. SWEDD patients presented a smaller postural sway size and a more frequent postural sway manly in ML direction (p< 0.05). In contrast, there was no significant differences in mean velocity and peak power (p>0.05). There were no significant difference between SWEDD patients and normal subjects (p>0.05). These results indicate that some COP-based outcome variables might be useful to distinguish SWEDD patients with PD patients. This study suggests that static postural balance test could aid clinicians in the identification of potential SWEDD.

DIFFERENCES IN GAIT PATTERNS BETWEEN PATIENTS WITH SWEDD AND NORMAL SUBJECTS

Whether gait assessment can distinguish patients with scans without evidence of dopaminergic deficit (SWEDD) from normal individuals remains unclear. In the present study, the gait patterns in SWEDD patients and normal individuals were investigated. 10 patients with SWEDD and 10 healthy normal subjects were recruited. A GaitRite linear walkway was used to quantitatively assess level walking. Eight spatiotemporal variables were selected for comparison between two groups. For statistical analysis, independent sample [Formula: see text]-tests were performed to compare between normal individuals and SWEDD patients. Compared with normal individuals, SWEDD patients exhibited a shorter step length ([Formula: see text]). In addition, SWEDD patients showed a wider distribution of heel-to-heel (HH) base of support compared with normal individuals ([Formula: see text]). SWEDD patients had a tendency to deteriorated gait speed ([Formula: see text]) and double-limb support cycle ([Formula: see text]). These results indicate that SWEDD patients adopted a walking strategy that utilized increased step length and width to compensate for deteriorated dynamic balance. These results indicate that quantitative gait assessment could be useful for more accurate diagnosis of SWEDD patients. In addition, understanding clinical features of SWEDD patients might contribute to efficient interventions.

COMPARISON OF STATIC POSTURAL BALANCE IN PATIENTS WITH SWEDDS AND PARKINSON’S DISEASE

Differentiating scans without evidence of dopaminergic deficits (SWEDDs) from Parkinson’s disease (PD) is very important to avoid costly and inappropriate interventions. The postural balance strategy patients with SWEDDs are not clear. This study investigates the difference in static postural balance between patients with SWEDDs and PD. Twenty-two patients (11 SWEDDs and 11 PD groups) and 11 control groups were instructed to quietly stand on a custom-made force platform. The outcome measures were, mean distance, 95% confidence ellipse area, mean velocity, mean frequency, peak frequency and peak power derived from the center of pressure (COP) data in overall, medio-lateral (ML) and anterio-posterior (AP) directions. As statistical analysis, ANOVA and post hoc tests were conducted for comparison of patients with SWEDDs and PD. SWEDDs patients presented a smaller postural sway size and a more frequent postural sway mainly in the ML direction ([Formula: see text]). On the contrary, there were no significant differences in mean velocity and peak power. Also, no significant differences existed between SWEDDs and normal subjects ([Formula: see text]). The results reflect that a few COP-based outcome variables might be useful to distinguish SWEDDs patients from PD patients. This study suggests that a static postural balance test can be used for clinical screening and identification of potential SWEDDs.

Novel Nasal Epithelial Cell Markers of Parkinson's Disease Identified Using Cells Treated with α-Synuclein Preformed Fibrils.

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterized by olfactory dysfunction in the early stages. α-Synuclein pathologies in the olfactory organs are shown to spread to the brain through the nose-brain axis. We first developed a nasal epithelial PD cellular model by treating RPMI-2650 cells with α-synuclein preformed fibrils (PFF). Upon uptake of PFF, RPMI-2650 cells showed mitochondrial proteome alteration and downregulation of parkin, which has previously been identified as a nasal biomarker of PD. Functional cluster analysis of differentially expressed genes in RPMI-2650 cells revealed various pathways affected by α-synuclein pathology, including the detection of chemical stimulus involved in sensory perception, olfactory receptor activity, and sensory perception of smell. Among genes that were most affected, we validated, by real-time quantitative PCR, the downregulation of MAP3K8, OR10A4, GRM2, OR51B6, and OR9A2, as well as upregulation of IFIT1B, EPN1, OR1D5, LCN, and OTOL1 in PFF-treated RPMI-2650 cells. Subsequent analyses of clinical samples showed a downregulation of OR10A4 and OR9A2 transcripts and an upregulation of IFIT1B in cells isolated from the nasal fluid of PD patients, as compared to those from the controls (cutoff value = 0.5689 for OR9A2, with 72.4% sensitivity and 75% specificity, and 1.4658 for IFIT1B, with 81.8% sensitivity and 77.8% specificity). Expression levels of these nasal PD markers were not altered in nasal fluid cells from SWEDD (scans without evidence of dopaminergic deficits) patients with PD-like motor symptoms. These nasal markers were significantly altered in patients of PD with hyposmia compared to the control hyposmic subjects. Our results validated the α-synuclein-treated nasal epithelial cell model to identify novel biomarkers for PD and suggest the utility of olfactory transcripts, along with olfactory dysfunction, in the diagnosis of PD.

Preserved Extrastriatal 123I-FP-CIT Binding in Scans Without Evidence of Dopaminergic Deficit (SWEDD).

Scans without evidence of dopaminergic deficit (SWEDD) have been initially described in a minority of subjects with suspected Parkinson's disease (PD). Although a highly controversial entity, longitudinal studies showed that SWEDD cases mostly involve non-degenerative conditions mimicking PD or misattribution of scan images to normal status. Using the Parkinson's Progression Markers Initiative (PPMI) cohort, we undertook a case-controlled analysis of [123I]N-ω-fluoropropyl-2β-carbomethoxy-iodophenyl nortropane ([123I]FP-CIT) single photon emission computed tomography (SPECT) images to measure extrastriatal serotonergic transporter (SERT) density in SWEDD and PD. We included 37 SWEDD cases (mean age 60years, 33% female) with available [123I]FP-CIT SPECT imaging and high-resolution T1-weighted magnetic resonance imaging (MRI) for coregistration. Sixty-one controls and 62 similarly aged PD subjects were included for group comparisons. Regional [123I]FP-CIT was extracted with PETPVE12 using geometric transfer matrix and partial volume effect correction. PD subjects showed significantly lower [123I]FP-CIT binding in both striatal (caudate nucleus and putamen) and extrastriatal regions (pallidum and insula) compared with controls and SWEDD (all between-group p < 0.0001). PD group also showed lower binding in the thalamus relative to controls (p = 0.007). Receiver operating characteristics (ROC) area under the curve (AUC) did not show a significant difference when using extrastriatal region in addition to striatal ROIs for the separation of SWEDD and PD (95% ROC-AUC for both methods, p = 0.52). In addition, striatal [123I]FP-CIT binding contralateral to the clinically more affected side was usually lower for PD (> 75%) but not for SWEDD (< 49%, p < 0.002). No significant difference regarding [123I]FP-CIT binding was observed between SWEDD and controls. These findings corroborate the view that SWEDD cases represent a heterogeneous group of conditions not involving dopaminergic and serotonergic terminals. Further studies are warranted to be assessed whether using extrastriatal [123I]FP-CIT evaluation can be of help in the assessment of degenerative parkinsonism.

Local White Matter Fiber Clustering Differentiates Parkinson’s Disease Diagnoses

Scans without evidence of dopaminergic deficit (SWEDD) patients are often misdiagnosed with Parkinson’s disease (PD) but have normal dopamine transporter scans. We hypothesised that white matter tracts associated with motor and cognition functions may be affected differently by SWEDD and PD. Automatically annotated fibre clustering (AAFC) is a novel clustering method based on diffusion magnetic resonance imaging (dMRI) tractography that enables highly robust reconstruction of white matter tracts that are composed of corresponding clusters. This study aimed to investigate the white matter properties in the subdivisions of white matter tracts among SWEDD and PD groups. We applied AAFC to identify white matter tracts related to motion and cognition functions in the dataset consisting of SWEDD (n = 22), PD (n = 30) and normal control (NC) (n = 30). Then, we resampled 200 nodes along fibres of cluster, and the diffusion metric values corresponding to each node were calculated and used for comparison. Compared with NC, PD showed significant difference (p < 0.05) in two clusters in thalamo-frontal (TF), one cluster in thalamo-parietal (TP) and one cluster in thalamo-occipital (TO), whereas SWEDD presented no significant difference. Three clusters in cingulum bundle (CB) commonly exhibited significant differences in PD versus SWEDD and NC versus SWEDD. The support vector machine classifier achieved high accuracies in PD-NC, PD-SWEDD and NC-SWEDD classifications. This outcome validated these local white matter differences were useful to separate the three groups. These results suggest that PD exerts more significant effects on thalamo tracts than SWEDD, and unique microstructural changes occur in CB tract in SWEDD.

EFFECT OF SENSORY ELECTRICAL STIMULATION ON RESTING TREMORS IN PATIENTS WITH PARKINSON’S DISEASE AND SWEDDs

Patients with scans without evidence of dopaminergic deficits (SWEDDs) show symptoms (e.g., tremors) similar to those of Parkinson’s disease (PD) patients, so they are often misdiagnosed. Sensory electrical stimulation (SES) was reported to suppress essential tremor in patients, but SES was never applied to patients with PD and SWEDDs. As the pathophysiological mechanisms of PD and SWEDDs are likely to be different, we hypothesized that the effect of SES would also be different in the two patient groups. This study aimed to test that hypothesis. Fourteen patients with PD and nine with SWEDDs participated in this study. Three wrist muscles were stimulated for 15[Formula: see text]s using SES with a stimulation intensity lower than the motor threshold. Angular motion of the index finger was measured via a triaxial gyrosensor before, during, and after stimulation. Outcome measures included the amplitude and peak frequency of the angular motion of the index finger. Tremor amplitude decreased during and after SES in patients with PD ([Formula: see text]). However, tremor amplitudes during and after SES were not different from the base level in SWEDDs patients. The peak frequency of tremors temporarily decreased during stimulation in PD patients, but not in SWEDDs patients. SES suppressed tremors in patients with PD, but not with SWEDDs. The results could help understand the pathophysiological differences of tremors between PD and SWEDDs.

The Qualification of an Enrichment Biomarker for Clinical Trials Targeting Early Stages of Parkinson’s Disease

As therapeutic trials target early stages of Parkinson's disease (PD), appropriate patient selection based purely on clinical criteria poses significant challenges. Members of the Critical Path for Parkinson's Consortium formally submitted documentation to the European Medicines Agency (EMA) supporting the use of Dopamine Transporter (DAT) neuroimaging in early PD. Regulatory documents included a comprehensive literature review, a proposed analysis plan of both observational and clinical trial data, and an assessment of biomarker reproducibility and reliability. The research plan included longitudinal analysis of the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) and the Parkinson's Progression Markers Initiative (PPMI) study to estimate the degree of enrichment achieved and impact on future trials in subjects with early motor PD. The presence of reduced striatal DAT binding based on visual reads of single photon emission tomography (SPECT) scans in early motor PD subjects was an independent predictor of faster decline in UPDRS Parts II and III as compared to subjects with scans without evidence of dopaminergic deficit (SWEDD) over 24 months. The EMA issued in 2018 a full Qualification Opinion for the use of DAT as an enrichment biomarker in PD trials targeting subjects with early motor symptoms. Exclusion of SWEDD subjects in future clinical trials targeting early motor PD subjects aims to enrich clinical trial populations with idiopathic PD patients, improve statistical power, and exclude subjects who are unlikely to progress clinically from being exposed to novel test therapeutics.

Comparison of quantitative analysis of hand movements with gyroscope between early stage Parkinson's disease and scans without evidence of dopaminergic deficit (SWEDD)

Scans without evidence of dopaminergic deficit (SWEDD) is a radiological nomenclature, which refers to patients with a normal dopamine transporter scan presumed to have parkinsonism. It is important to differentiate SWEDD from Parkinson's disease (PD) in the early stage of disease because they have similar clinical features. As bradykinesia is a cardinal clinical feature of parkinsonism, we quantitatively investigated detailed presentations of hand movement by using an angular measurement system in SWEDD and PD patients, and normal controls. Twenty-three patients with SWEDD, 23 patients with drug-naïve early stage PD, and 23 age-matched healthy controls participated in this study. Angular velocity was measured during finger-tapping and forearm-rotation movement for assessment of bradykinesia. RMS (root mean square) velocity and amplitude, and movement irregularity were derived from the gyro sensor signal. SWEDD patients presented a greater average speed, a larger average amplitude, and more irregular speed and amplitude only during forearm rotation compared to PD patients (p < .05). SWEDD patients also exhibited a smaller average speed and average amplitude, and a more irregular velocity usually during finger tapping compared to controls (p < .05). Quantitative variables of forearm rotation movement showed significant differences between SWEDD and PD patients, and quantitative variables of finger tapping movement showed a significant difference between SWEDD patients and the control group. These results suggest that quantitatively determined/assessed variables using biomedical engineering devices can distinguish SWEDD patients from PD patients as well as from normal subjects.

Diagnosis of Parkinson’s Disease at an Early Stage Using Volume Rendering SPECT Image Slices

The non-degenerative variant called scans without evidence of dopaminergic deficit (SWEDD) is clinically analyzed and wrongly understood as Parkinson’s disease (PD) that results ineffective diagnosis of PD in the early stage. The present work is designed to improve the diagnostic accuracy at the early stage of PD from SWEDD and healthy control (HC). The volume rendering image slices are used as a novel method to achieve better diagnostic accuracy. These image slices are chosen from the single-photon emission computed tomography (SPECT) images based on their striatal uptake region, which contributes appreciated information on the shape of the striatum. Features related to surface and the shape of the striatum are calculated from the segmented region of the chosen image slices to illustrate the good amount of variations among early PD, SWEDD, and HC. Among these feature sets, the most optimized feature is selected using genetic algorithm. The performance of the classifiers like linear, radial basis function-support vector machine (RBF-SVM), extreme learning machine (ELM) activation functions, and RBF-ELM are investigated and compared based on the most optimized feature. It is noted that the RBF-ELM offers better performance with an accuracy of 98.23% than the other classifiers. This also proves that the present work is better than the previous studies. Hence, the proposed approach could act as an aid in the detection of early stage of PD.