PD Subjects Research Articles

Prevalence and clinical correlates of nonmotor symptoms in Parkinson's disease in a tertiary health-care center in Turkey.

The objective was to determine the prevalence and clinical correlates of nonmotor symptoms in Parkinson's disease patients in movement disorders outpatient clinics. We enrolled all consecutive PD patients who visited our movement disorders outpatient clinics between January and December 2023; and agreed to participate in the study. In addition to the evaluation of demographic and clinical features, clinical scales, including the MDS-UPDRS, NMSS, and FOOGQ, were performed. Overall, we enrolled 163 PD subjects with a mean age of 63.9 ± 10.4 (F/M = 27/136). The disease duration was 3.5 (20) y [median (range)]. The median score of the NMSS was 41 points. The NMSs burden levels were severe in 25.2%, and very severe in 25.2% of the subjects. The subitems with the highest scores were sleep/fatigue, mood/cognition, urinary, and miscellaneous. The analyses within the patient group with newly diagnosed PD also revealed high NMSS scores. Comparisons of the NMSS between distinct PD stages revealed greater NMSS scores in the severe stage than in the mild stage (p = 0.001). Correlation analyses between the clinical scores and the NMSS scores revealed positive correlations between the NMSS scores and the scores on all the clinical scales including the MDS-UPDRS 1-4, and FOGQ. We reported the first data regarding the NMS burden in PD patients from Turkey. We found a high prevalence and severity of various domains of NMSs, most of which were sleep/fatigue, mood/cognition, urinary, and miscellaneous. More than half of the patients had severe to very severe NMS burden. Although NMSs were more common severe-stage disease, they were also prevalent in the subgroup with newly diagnosed patients.

Capacitive Neuromodulation via Material-Based Passive Interaction: Efficacy in Motor Function Improvement in Parkinson Disease.

A non-invasive and non-pharmacological approach is evaluated for the proprioceptive and postural improvement of PD subjects. The authors evaluated the effectiveness of a class I medical device according to EU regulation 745/2017 designed to develop the mechanism of action based on the modulation of action potentials, which occurs in prevalent pathways of the afferent peripheral nervous system efferent in subjects with spasticity. The present observational study, structured in a double-blind randomized manner, therefore, had the main aim of evaluating the ability of the device to improve on the motor and proprioceptive function of PD patients. This study was based on the instrumented gait analysis performed according to the Timed Up and Go (TUG) test procedure, as well as using a fall risk assessment in accordance with the Berg Balance Scale (BBS) procedures. This study involved 25 participants in the active group (no placebo) and 25 in the non-active group (placebo), the latter to whom non-functional devices were applied, but in every respect identical to the functional devices applied to the 25 patients in the no placebo group. Data analysis was conducted using statistical methodologies for statistics, the statistical significance of the results for the observed samples and the interdependence between the measured variables. The study of the mechanism of action based on the remodulation of action potentials was preliminary conducted through numerical modeling of the Hodgkin-Huxley axon, modified by introducing the influence of the capacitive device applied in clinical tests into the validated model to target the dielectric properties of materials constituting the passive sensor. The use of the neuromodulation device promises observable improvements in motor function among PD patients, including increased limb mobility and greater postural stability.

Dysrhythmia as a prominent feature of Parkinson's disease: An app-based tapping test

IntroductionSmartphone applications (apps) are instruments that assist with objective measurements during the clinical assessment of patients with movement disorders. We aim to test the hypothesis that Parkinson's disease (PD) patients will exhibit an increase in tapping variability and a decrease in tapping speed over a one-year period, compared to healthy controls (HC). MethodsData was prospectively collected from participants enrolled in our Cincinnati Cohort Biomarker Program, in 2021–2023. Participants diagnosed with PD and age-matched HC were examined over a one-year-interval with a tapping test performed with customized smartphone app. Tapping speed (taps/s), inter-tap intervals and variability (movement regularity), and sequence effect were measured. ResultsWe included 295 PD patients and 62 HC. At baseline, PD subjects showed higher inter-tap variability than HC (coefficient-of-variation-CV, 37 ms [22–64] vs 26 ms [8–51]) (p = 0.007). Conversely, there was no difference in inter-tap intervals (411 ms [199–593] in PD versus 478 ms [243–618] in HC) and tapping speed (3.42[2.70–4.76] taps/s in PD versus 3.21 taps/s [2.57–4.54] in HC) (p > 0.05). Only PD subjects (n = 135), at the one-year follow-up, showed a decreased tapping speed vs baseline (3.44 taps/s [2.86–4.81] versus 3.39 taps/s [2.58,4.30]) (p = 0.036), without significant changes in inter-tap variability (CV, 32 ms [18,55] baseline versus 34 ms [22,59] follow-up) (p = 0.142). No changes were found in HC at the one-year follow up (all p values>0.05). ConclusionsInter-tap variability (dysrhythmia) but no inter-tap intervals or tapping speed are reliably distinctive feature of an app-based bradykinesia assessment in PD.

A minimally Invasive Biomarker for Sensitive and Accurate Diagnosis of Parkinson's Disease.

ImportanceParkinson′s disease (PD), the second most common neurodegenerative disease, is pathologically characterized by intraneuronal deposition of misfolded alpha-synuclein aggregates (αSynD). αSynDseeding activities in CSF and skin samples have shown great promise in PD diagnosis, but they require invasive procedures. Sensitive and accurate αSynDseed amplification assay (αSyn-SAA) for more accessible and minimally invasive samples (such as blood and saliva) are urgently needed for PD pathological diagnosis in routine clinical practice.ObjectiveTo develop a sensitive and accurate αSyn-SAA biomarker using blood and saliva samples for sensitive, accurate and minimally invasive PD diagnosis.Design, Setting, and ParticipantsThis prospective diagnostic study evaluates serum and saliva samples collected from patients clinically diagnosed with PD or healthy controls (HC) without PD at an academic Parkinson′s and Movement Disorders Center from February 2020 to March 2024. Patients diagnosed with non-PD parkinsonism were excluded from this analysis. A total of 124 serum samples (82 PD and 42 HC) and 131 saliva samples (83 PD and 48 HC) were collected and examined by αSyn-SAA. Out of the 124 serum donors, a subset of 74 subjects (48 PD and 26 HC) also donated saliva samples during the same visits. PD patients with serum samples had a mean age of 69.21 years (range 44-88); HC subjects with serum samples had a mean age of 66.55 years (range 44-81); PD patients with saliva samples had a mean age of 69.58 years (range 49-87); HC subjects with saliva samples had a mean age of 64.71 years (range 30-81).Main Outcomes and MeasuresSerum and/or saliva αSynDseeding activities from PD and HC subjects were measured by αSyn-SAA using the Real-Time Quaking-Induced Conversion (RT-QuIC) platform. These PD patients had extensive clinical assessments including MDS-UPDRS. For a subset of PD and HC subjects whose serum and saliva samples were both collected during the same visits, the αSynDseeding activities in both samples from the same subjects were examined, and the diagnostic accuracies for PD based on the seeding activities in either sample alone or both samples together were compared.ResultsRT-QuIC analysis of αSynDseeding activities in the 124 serum samples revealed a sensitivity of 80.49%, a specificity of 90.48%, and an accuracy of 0.9006 (AUC of ROC, 95% CI, 0.8472-0.9539, p<0.0001) for PD diagnosis. RT-QuIC analysis of αSynDseeding activity in 131 saliva samples revealed a sensitivity of 74.70%, a specificity of 97.92%, and an accuracy of 0.8966 (AUC of ROC, 95% CI, 0.8454-0.9478, p<0.0001). When aSynDseeding activities in the paired serum-saliva samples from the subset of 48 PD and 26 HC subjects were considered together, sensitivity was 95.83%, specificity was 96.15%, and the accuracy was 0.98 (AUC of ROC, 95% CI, 0.96-1.00, p<0.001), which are significantly better than when αSynDseeding activities in either serum or saliva were used alone. For the paired serum-saliva samples, when specificity was set at 100% by elevating the αSyn-SAA cutoff values, a sensitivity of 91.7% and an accuracy of 0.9457 were still attained. Detailed correlation analysis revealed that αSynDseeding activities in the serum of PD patients were correlated inversely with Montreal Cognitive Assessment (MoCA) score (p=0.04), positively with Hamilton Depression Rating Scale (HAM-D) (p=0.03), and weakly positively with PDQ-39 cognitive impairment score (p=0.07). Subgroup analysis revealed that the inverse correlation with MoCA was only seen in males (p=0.013) and weakly in the ≥70 age group (p=0.07), and that the positive correlation with HAM-D was only seen in females (p=0.04) and in the <70 age group (p=0.01). In contrast, αSynDseeding activities in the saliva of PD patients were inversely correlated with age at diagnosis (p=0.02) and the REM sleep behavior disorder (RBD) status (p=0.04), but subgroup analysis showed that the inverse correlation with age at diagnosis was only seen in males (p=0.04) and in the <70 age group (p=0.01).Conclusion and RelevanceOur data show that concurrent RT-QuIC assay of αSynDseeding activities in both serum and saliva can achieve high diagnostic accuracies comparable to that of CSF αSyn-SAA, suggesting that αSynDseeding activities in serum and saliva together can potentially be used as a valuable biomarker for highly sensitive, accurate, and minimally invasive diagnosis of PD in routine clinical practice. αSynDseeding activities in serum and saliva of PD patients correlate differentially with some clinical characteristics and in an age and sex-dependent manner.

Dynamic channelwise functional-connectivity states extracted from resting-state EEG signals of patients with Parkinson’s disease

BackgroundParkinson’s disease (PD) is a progressive neurodegenerative disease that usually happens to elderly people, with a wide range of motor and dementia symptoms. An objective and convenient biomarker for PD detection is extremely valuable, especially one that could be acquired non-invasively and low-costly. To this end, this study used resting-state scalp electroencephalography (EEG) signals to explore dynamic functional-connectivity (dFC) states between each pair of EEG recording channels, without source localization.MethodsdFC refers to synchronization patterns over time between each pair of EEG channels. First, five frequency bands were extracted from EEG signals with fourth-order Butterworth bandpass filter, including delta (0.5–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), beta (8–30 Hz) and gamma (30–50 Hz). Then, after non-random joint fluctuation was measured with weighted symbolic mutual information (wSMI) algorithm, whole-brain dynamic channelwise dFC states were estimated, and classified with k-means clustering. At last, FC state occurrences were calculated, and ANOVA analyses were performed for each state. Two open-source resting-state EEG data sets (https://doi.org/10.18112/openneuro.ds002778.v1.0.4: 32 channels, 16 health controls and 15 PD subjects. https://doi.org/10.18112/openneuro.ds003490.v1.1.0: 64 channels, 25 health controls and 25 PD subjects) were used to test our methods.ResultsSignificant changes in proportions of various dFC states within beta frequency-band were consistently observed in these both data sets (p value < 0.05).ConclusionsOur findings suggest that channelwise dFC states within beta frequency-band directly extracted from resting-state scalp–EEG recordings could potentially serve as a biomarker of PD.

Investigation of the nonmotor symptoms in patients with STN-DBS therapy in comparison with those without STN-DBS.

The impact of STN-DBS on NMS remains rather as an underestimated topic. Besides, the significance of NMSs in QOL indexes of PD subjects with STN-DBS is unknown. We primarily aimed to evaluate the NMSs and their significance in QOL indexes in PD subjects comparatively with and without STN-DBS therapy. We enrolled all consecutive PD subjects with and without STN-DBS who applied to our movement disorders outpatient clinics between January/2023 and September/2023. We performed comprehensive assessments of the motor and nonmotor features including the clinical scales of Movement Disorder Society-sponsored revisionof the MDS-UPDRS, NMSS, HAM-A, HAM-D, and the PDQ-39. Overall, 48 PD subjects with STN-DBS and 161 without STN-DBS treatment were included. The comparative analyses revealed that the sub-scores of the MDS-UPDRS-2, -3 and -4 were higher in the STN-DBS group. However, the MDS-UDPRS-1 and the total scores of the NMSS were similar between groups. Among eight subitems of the NMSS, only, the sub scores of the mood/cognition and the gastrointestinal tract differed. Remarkably, the significant correlations between the scores of the QOL and the NMSS scores in the STN-DBS (-) group, did not persist within the STN-DBS group. Remarkably, the correlations between the NMSS and PQQ-39 disappeared for most of the sub scores within the STN-DBS group. We found indirect evidence regarding the benefit of STN-DBS therapy on NMSs in our cross-sectional study. Besides, we found weaker impact of NMSs in QOL indexes in PD subjects with STN-DBS therapy.

PENCIL imaging: A novel approach for neuromelanin sensitive MRI in Parkinson's disease

BackgroundParkinson's disease (PD) is associated with the loss of neuromelanin (NM) and increased iron in the substantia nigra (SN). Magnetization transfer contrast (MTC) is widely used for NM visualization but has limitations in brain coverage and scan time. This study aimed to develop a new approach called Proton-density Enhanced Neuromelanin Contrast in Low flip angle gradient echo (PENCIL) imaging to visualize NM in the SN. MethodsThis study included 30 PD subjects and 50 healthy controls (HCs) scanned at 3T. PENCIL and MTC images were acquired. NM volume in the SN pars compacta (SNpc), normalized image contrast (Cnorm), and contrast-to-noise ratio (CNR) were calculated. The change of NM volume in the SNpc with age was analyzed using the HC data. A group analysis compared differences between PD subjects and HCs. Receiver operating characteristic (ROC) analysis and area under the curve (AUC) calculations were used to evaluate the diagnostic performance of NM volume and CNR in the SNpc. ResultsPENCIL provided similar visualization and structural information of NM compared to MTC. In HCs, PENCIL showed higher NM volume in the SNpc than MTC, but this difference was not observed in PD subjects. PENCIL had higher CNR, while MTC had higher Cnorm. Both methods revealed a similar pattern of NM volume in SNpc changes with age. There were no significant differences in AUCs between NM volume in SNpc measured by PENCIL and MTC. Both methods exhibited comparable diagnostic performance in this regard. ConclusionsPENCIL imaging provided improved CNR compared to MTC and showed similar diagnostic performance for differentiating PD subjects from HCs. The major advantage is PENCIL has rapid whole-brain coverage and, when using STAGE imaging, offers a one-stop quantitative assessment of tissue properties.

Evaluation of bidirectional gut-brain axis and anorectal function in Parkinson's disease with constipation.

Parkinson's disease (PD) is a neurodegenerative movement disorder with prodromal and highly prevalent gastrointestinal (GI) symptoms, especially constipation. Although PD models suggest gut-brain axis dysfunction, the mechanistic underpinnings and their correlation with GI symptoms are poorly understood. To examine the bidirectional gut-brain axis function in PD and correlate it with constipation severity, PD duration, and severity. Rectal sensory thresholds and afferent cortical evoked potentials (CEP) were assessed using a 4-ring EMG electrode probe. Efferent anal and rectal motor evoked potentials (MEPs) were obtained following transcranial and lumbosacral magnetic stimulation. Bowel symptoms were assessed by prospective stool diary. The CEP and MEP latencies, rectal sensory thresholds, and anorectal sensorimotor data were compared between PD subjects and age-adjusted healthy subjects. Twenty-five PD subjects with constipation (F/M = 6/19) and 20 healthy subjects (F/M = 14/6) were enrolled. The first and pain sensation thresholds were higher in PD subjects than healthy subjects (p < 0.002) but lost significance after adjustment for age. Age-adjusted rectal CEP and right-sided cortico-anal MEP latencies were prolonged in PD subjects compared to healthy subjects (p < 0.04). Also, half (4 of 8) age-adjusted spino-anal and rectal MEP latencies in PD subjects were significantly longer. In multivariate linear analysis, first rectal sensation and right-sided MEP latencies showed moderate correlation with constipation severity. Parkinson's disease is associated with significant bidirectional gut-brain axis dysfunction as evidenced by prolonged afferent and efferent neuronal signaling. Constipation severity in PD is correlated to abnormal rectal sensation and lateralized disturbance of efferent brain-gut signaling.

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.

Analyses of the clinical factors and freezing of gait in association with the quality-of-life indexes in Parkinson’s disease subjects with and without STN-DBS therapy

ABSTRACT Introduction In this research, paying particular attention to freezıng of gait (FOG), we aimed to investigate the associations between the clinical features and quality of lilfe (QOL) indexes comparatively in our PD subjects with and without STN-DBS therapy. Methods All consecutive PD subjects with and without STN-DBS who applied to our movement disorders outpatient clinics between January/2022 and September/2022; and accepted to participate in the study were enrolled. The demographic data and clinical features were noted. Besides, the MDS-UPDRS, the FOG Questionnaire (FOGQ) and the Parkinson’s Disease Questionnaire (PDQ-39) have also been performed on all individuals. Results Overall, 105 patients with PD participated in this study (34 patients with STN-DBS, 71 patients without STN-DBS). No difference was found in the PDQ-39 scores between patients with and without STN-DBS. The correlation analyses between the PQQ-39 scores and the clinical parameters revealed significant moderate correlations with the FOGQ score and low correlations with MDS-UPDRS scores. The analyses repeated in either patient group showed that there were no correlations between the MDS-UPDRS scores and PDQ-39 indexes in the DBS group. Besides, the correlations between the PDQ-39 scores and the FOG scores were more prominent in patients without DBS therapy. Conclusion FOG was found to be associated with worse QOL status in both patients with and without STN-DBS therapy. However, the correlations analyses in either group showed that FOG was a more significant determinant in the QOL indexes in patients without DBS. Future studies evaluating the impact of other clinical features such as falls and gait impairment in QOL of patients with STN-DBS may provide contributions to the current evidence.

Serum Uric Acid as a Putative Biomarker in Prodromal Parkinson's Disease: Longitudinal Data from the PPMI Study.

The role of blood uric acid as a biomarker in symptomatic motor PD has been increasingly established in the literature. Our present study assessed the role of serum uric acid as a putative biomarker in a prodromal PD cohort [REM Sleep Behavior disorder (RBD) and Hyposmia] followed longitudinally. Longitudinal 5-year serum uric acid measurement data of 39 RBD patients and 26 Hyposmia patients with an abnormal DATSCAN imaging were downloaded from the Parkinson's Progression Markers Initiative database. These cohorts were compared with 423 de novo PD patients and 196 healthy controls enrolled in the same study. After adjusting for age, sex, body mass index, and concomitant disorders (hypertension/gout), baseline and longitudinal serum uric acid levels were higher in the RBD subgroup as compared to the established PD cohort (p = 0.004 and p = 0.001). (Baseline RBD 6.07±1.6 vs. Baseline PD 5.35±1.3 mg/dL and Year-5 RBD 5.7±1.3 vs. Year-5 PD 5.26±1.33). This was also true for longitudinal measurements in the Hyposmic subgroup (p = 0.008) (Baseline Hyposmic 5.7±1.6 vs. PD 5.35±1.3 mg/dL and Year-5 Hyposmic 5.58±1.6 vs. PD 5.26±1.33). Our results indicate that serum uric acid levels are higher in prodromal PD subjects with ongoing dopaminergic degeneration compared to those with manifest PD. These data indicate that the well-established decrease in the levels of serum uric acid occurs with the transition from prodromal to clinical PD. Whether the higher levels of serum uric acid observed in prodromal PD may provide protection against conversion to full-blown clinical PD will require further study.

Immune profiling in patients with glioblastoma treated with VT1021 in a phase I/II expansion study.

2021 Background: The cyclic peptide VT1021 is a first-in-class therapeutic agent that has been shown to inhibit tumor growth via stimulation of thrombospondin-1 (TSP-1) and reprogramming the immune tumor microenvironment (TME) in preclinical models. Subsequently, VT1021 has been tested in a phase I/II clinical study in solid tumors (NCT03364400) and has advanced to a phase II/III clinical study in glioblastoma (NCT03970447). VT1021 has demonstrated promising single-agent clinical activity against recurrent glioblastoma (rGBM) in a phase I/II expansion study. Among 22 evaluable subjects with rGBM, 3 had complete response (CR), 1 had partial response (PR), and 6 had stable disease (SD) with an average study duration of over 120 days. One subject has been on VT1021 treatment for &gt; 900 days with no measurable lesion left. The overall disease control rate (DCR) was 45%. Here, we sought to examine the peripheral immune cell profile(s) in response to VT1021 and explore the association between these profiles and clinical responses in rGBM subjects. Methods: In the phase I/II expansion study, 22 evaluable rGBM subjects received VT1021 at a dose of 11.8 mg/kg (twice per week intravenously) until disease progression. Peripheral blood samples were collected from all evaluable subjects; immune cell profiles were analyzed by flow cytometry. Results: The immune profiles following VT1021 treatment on day 1 did not vary significantly among rGBM subjects, regardless of response. Intriguingly, after long-term VT1021 treatment (day 53), our analysis of the immune profiles revealed beneficial and sustained changes in three cytotoxic T Cell (CTL) parameters and PD-L1+ MDSCs that correlated with response. Specifically, CR/PR subjects showed a 20% increase in total CTLs (Pre 33.79% vs. 6hr 40.42%), a 66% increase in proliferating CTLs (Pre 1.37% vs. 6hr 2.28%) and a 63% increase in CTL/Treg ratio (Pre 7.85 vs. 6hr 12.81) on day 53 of VT1021 treatment. In contrast, SD and PD subjects exhibited no change or decrease in these three CTL parameters, respectively. We also observed that CR/PR subjects experienced a sustained decrease in PD-L1+ MDSCs after VT1021 treatment (day 1 Pre 95.96% vs. day 53 Pre 92.66% and day 53 6hr 88.06%). Conversely, the sustained decrease of PD-L1+ MDSCs after VT1021 treatment was not observed in SD and PD subjects. Conclusions: Here we report that the durable responses of peripheral immune cells to VT1021 may be associated with better clinical outcomes in rGBM subjects. These findings are consistent with the MOA of TSP-1 to reprogram the TME by stimulating immune and inflammatory cell functions. While the interpretation of our data is limited by the lack of a control arm and the small sample size, the results provide a signal and warrant continued analysis of these parameters in the ongoing phase II/III trial.

Isolating the speed factor is crucial in gait analysis for Parkinson's disease.

Parkinson's disease (PD) is characterized by an alteration of the walking gait, frequently including a slower self-selected walking speed (SSWS). Although the reduction of walking speed is inherent to people with PD, such speed reduction also represents a potential confounding factor that might partly explain the observed gait differences between PD and control participants. In this study, each participant walked along a 25 m level corridor during which vertical ground reaction force signals were recorded using shoes equipped with eight pressure sensors. Vertical ground reaction force signals (using statistical parametric mapping) and temporal and kinetic variables as well as their related variability and asymmetry (using Student's t-test) were compared between PD (n = 54) and walking-speed-matched control subjects (n = 39). Statistical parametric mapping did not yield significant differences between PD and control groups for the vertical ground reaction force signal along the walking stance phase. Stride time and single support time (equivalent to swing time) were shorter and peak vertical ground reaction force was larger in PD patients compared to controls (p ≤ 0.05). However, the single support time was no longer different between people with PD and healthy subjects when expressed relatively to stride time (p = 0.07). While single support, double support, and stance times were significantly more variable and asymmetric for PD than for the control group (p ≤ 0.05), stride time was similar (p ≥ 0.07). These results indicate that at matched SSWS, PD patients adopt a higher cadence than control participants. Moreover, the temporal subdivision of the walking gait of people with PD is similar to healthy individuals but the coordination during the double support phase is different. Hence, this study indicates that isolating the speed factor is crucial in gait analysis for PD.

The utility of quantitative MRI parameters in discriminating progressive supranuclear palsy from Parkinson’s disease

ABSTRACT Objective We sought tore-evaluate the utility of all the quantitative neuroimaging parametersattributed to progressive supranuclear palsy (PSP) in discrimination betweenPSP and Parkinson’ s disease (PD) subjects in our cohort. We aimed to proposesome practical clinical remarks in this field. Methods In our retrospective study, 19 patients with‘probable’ PSP and 37 patients with PD were enrolled. The radiological measurements of PSP, describedin the previous reports, have been calculated in all subjects. The comparisonsbetween the groups were performed and the measures regarding the accuracy ofthese parameters in the differentiation of PSP from PD subjects were analyzed. Results We found that the values of magnetic resonance parkinsonism index-2 (MRPI-2), pontine-to-midbrain area (P/M) ratio, P/M 2 ratio, and 3rdV/bifrontal width ratio had high AUC values and very good discriminative powers. The analyses revealed that; for the discrimination of PSP from PD subjects, a 3rdvent/bifrontal width cut-off value of 0.30 had 42.1 % sensitivity and 97.3 % specificity; a P/M cut-off value of 6.03 had a 52.6 % sensitivity and 97.3 % specificity; and an MRPI-2 cut-off value of 7.43 had 57.9 % sensitivity and 97.3 % specificity. Remarkably, we also found that the presence of high values for both P/M and 3rdV/bifrontal ventricle rate had a positive predictive value of 100% for the diagnosis of PSP. Conclusion Our study results support the utility of previously defined neuroimaging parameters in distinguishing PSP and PD subjects. Besides, combined use of a high P/M ratio and 3rdV/bifrontal width may be practical and present strictly high evidence for the diagnosis of PSP.

Abstract CT089: Molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancers: a Beat Childhood Cancer Research Consortium trial

Abstract Background: Children with relapsed CNS tumors, neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. Here we describe a study to determine the feasibility of leveraging genomic profiling results within a molecular tumor board (MTB) to make real-time treatment decisions for children with relapsed/refractory solid tumors. Methods: Subjects were divided to 3 strata: Strata 1: Relapsed/refractory neuroblastoma, Strata 2: Relapsed/refractory CNS tumors, and Strata 3: Relapsed/refractory rare solid tumors. Samples were sent for tumor/normal whole exome (WES) and tumor whole transcriptome sequencing, and the genomic data were used in a MTB to make real-time treatment decisions. The MTB recommended plan allowed for a combination of up to 4 agents. Feasibility was measured by time to completion of genomic sequencing, MTB review and initiation of treatment. Response was assessed after every 2 cycles using Response Evaluation Criteria in Solid Tumors (RECIST). Patient benefit was calculated by the sum of the CR, PR, SD, and NED subjects divided by the sum of CR, PR, SD, NED, and PD subjects. Grade 3 and higher related and unexpected adverse events (AEs) were tabulated for safety evaluation. Results: 144 eligible subjects were enrolled with 144 evaluable for safety and 124 evaluable for response. Tumor types included neuroblastoma (n=31), CNS tumors (n=41), and rare tumors (n=72). Sarcomas (n=40) were the most common tumor type in the rare tumor stratum. The average time from biopsy to completion of DNA/RNA sequencing was 10 days (range 2-31 days); to completed analysis and drug prediction report, 17 days (8-41); 23 days (10-66) to MTB decisions; and 38 days (18-146) to initiation of the 4-drug combination agreed upon by the MTB. Treatments were selected on DNA and RNA findings in 19.5% of cases and in 80.5% on RNA alone. Patient benefit was exhibited in 70% of all subjects, 85% of neuroblastoma subjects, 73% of CNS tumor subjects, and 62% of rare tumor subjects. AEs occurred in &amp;lt;1% of the subject cohort. Grade 3 leukopenia was the only unexpected hematologic AE. There were 7 occurrences of unexpected non-hematologic AEs: grade 4 elevated ALT (1), grade 3 elevated AST (1), grade 3 dehydration (1), grade 3 infection (2), grade 3 oral mucositis (1), and grade 3 pancreatitis (1). Conclusions: It has been well-established that comprehensive genomic sequencing is the future of precision medicine. Here, we have demonstrated the feasibility, efficacy, and safety of a comprehensive sequencing model to guide targeted therapy for patients with any relapsed/refractory solid malignancies. Targeted therapy was well tolerated, and the response benefit rate of 70% in these heavily pretreated populations suggests that this treatment could be an effective option for relapsed and refractory pediatric cancers. Citation Format: Giselle L. Saulner Sholler, Jacqueline Kraveka, Genevieve Bergendahl, Elizabeth Lewis, William Ferguson, Abhinav Nagulapally, Karl Dykema, Valerie Brown, Michael Isakoff, Joseph Junewick, Deanna Mitchell, Don Eslin, Virginia Harrod, William Roberts, Javier Oesterheld, Randy Wada, Jawhar Rawwas, Devang Pastakia, Kevin Ginn, Raya Saab, Kevin Bielamowicz, Jason Glover, Eugenia Chang, Gina Hanna, Daniel Enriquez, Tyler Izatt, Rebecca Halperin, Sara Byron, William Hendricks, Jeffrey Trent. Molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancers: a Beat Childhood Cancer Research Consortium trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT089.

Tongue strength and clinical correlations in parkinson's disease.

Individuals with Parkinson's disease present affected lingual functioning at some stage of the progression of the disease. The objective was to determine the strength and endurance values of the tongue in PD subjects and whether weakness in tongue lift may be an indicator of disease progression. Sixty subjects performed tasks of tongue to palate maximum isometric pressure (MIP) and sustained 50% of MIP for endurance. The Iowa Oral Performance Instrument was used as evaluation tool. Selected domains of the Swallowing Quality of Life Questionnaire (SWAL-QOL) related to tongue pressure were considered. Variables of sex, age, disease duration, disease progression (Hoehn & Yahr stage), and body mass index were selected for association analysis RESULTS: Tongue MIP ranged from 16 kPa to 48 kPa (mean= 33.43 kPa), which was significantly lower than normal reference values. Likewise, tongue endurance was significantly diminished. Analysis of variance showed differences in tongue strength between stages of disease progression F(3) = 6.503, p = 0.001, but not for endurance. Subjects in stage IV exhibited the lowest values. No sex effect was found. Tongue strength showed significant correlations with SWAL-QOL domains such as Food selection, Symptoms Frequency, and Eating Duration. Tongue strength and endurance are significantly reduced in Parkinson's disease. Tongue strength is higher in early stage of the disease and significantly different from that of more severe stages, emerging the notion that tongue strength is a sensitive indicator of disease progression. Selected items regarding swallowing quality of life are strongly associated with tongue strength.

Explainable classification of Parkinson’s disease using deep learning trained on a large multi-center database of T1-weighted MRI datasets

IntroductionParkinson’s disease (PD) is a severe neurodegenerative disease that affects millions of people. Early diagnosis is important to facilitate prompt interventions to slow down disease progression. However, accurate PD diagnosis can be challenging, especially in the early disease stages. The aim of this work was to develop and evaluate a robust explainable deep learning model for PD classification trained from one of the largest collections of T1-weighted magnetic resonance imaging datasets. Materials and MethodsA total of 2,041 T1-weighted MRI datasets from 13 different studies were collected, including 1,024 datasets from PD patients and 1,017 datasets from age- and sex-matched healthy controls (HC). The datasets were skull stripped, resampled to isotropic resolution, bias field corrected, and non-linearly registered to the MNI PD25 atlas. The Jacobian maps derived from the deformation fields together with basic clinical parameters were used to train a state-of-the-art convolutional neural network (CNN) to classify PD and HC subjects. Saliency maps were generated to display the brain regions contributing the most to the classification task as a means of explainable artificial intelligence. ResultsThe CNN model was trained using an 85%/5%/10% train/validation/test split stratified by diagnosis, sex, and study. The model achieved an accuracy of 79.3%, precision of 80.2%, specificity of 81.3%, sensitivity of 77.7%, and AUC-ROC of 0.87 on the test set while performing similarly on an independent test set. Saliency maps computed for the test set data highlighted frontotemporal regions, the orbital-frontal cortex, and multiple deep gray matter structures as most important. ConclusionThe developed CNN model, trained on a large heterogenous database, was able to differentiate PD patients from HC subjects with high accuracy with clinically feasible classification explanations. Future research should aim to investigate the combination of multiple imaging modalities with deep learning and on validating these results in a prospective trial as a clinical decision support system.

TV‐L1 Ordinal Logistic Regression Reveals New Morphometric Patterns Related to Parkinsonian Symptom Severity: An ENIGMA‐PD study

AbstractBackgroundParkinson’s disease (PD) is heterogeneous, both phenotypically and in terms of temporal progression. The Hoehn and Yahr (HY) scale is a well‐established PD staging approach, and identifies 5 stages of the disease. Morphometric effects in deep gray matter regions of the brain associated with HY stages are complex; a recent large‐scale ENIGMA‐PD study showed higher local subcortical volumes in early HY stages relative to controls, followed by a precipitous decrease after stage 2 [1]. This finding motivates a closer look at fine‐level morphometry beyond gross volume measures. Here, we developed and applied a novel machine learning algorithm to reveal the subcortical shape signatures of HY staging.MethodWe computed shape features in 7 bilateral subcortical regions [2] based on T1‐weighted MRI data from 2,322 PD subjects and 1,207 controls from 20 ENIGMA‐PD cohorts (HY stages in Table 1). We developed a sparse, spatially coherent (total variation/TV‐L1) ordinal linear logistic classifier [3] to predict HY stages with a single linear model. We applied the model to vertex‐wise medial thickness features. We optimized regularization parameters for balanced recall (sensitivity) and precision using a 4‐fold cross‐validation grid search. Very low numbers of HY4 and HY5 samples necessitated merging stages 3‐5 into one category. For comparison, we also trained 4 binary TV‐L1 logit models on the same features [4], discriminating (1) PD‐Control; (2) HY1‐HY2; (3) HY1‐HY345; (4) HY2‐HY345, using ROC area‐under‐the‐curve (AUC) evaluation.ResultAcross‐stage mean out‐of‐sample precision and recall were 0.43, and 0.393, respectively (chance=0.33). Table 2 shows the confusion matrix and precision/recall for each HY stage. All models’ linear coefficient maps are displayed in Figures 1,2. Binary classification ROC‐AUC was 0.66 for PD‐Control, and ranged from 0.62 to 0.73 for HY prediction (Figure 2).ConclusionWe developed an ordit machine learning model for morphometric shape‐based ordinal classification of disease stages, training it for Parkinson’s Disease Hoehn and Yahr stage prediction on a large MRI collection. Performance was substantially above chance. Model weight maps indicate early increased thalamic thickness, followed by a complex thinning pattern associated with later HY stages.

Gut microbiome and Parkinson's disease: Perspective on pathogenesis and treatment

BackgroundParkinson's disease (PD) is a disease of ⍺-synuclein aggregation-mediated dopaminergic neuronal loss in the substantia nigra pars compacta, which leads to motor and non-motor symptoms. Through the last two decades of research, there has been growing consensus that inflammation-mediated oxidative stress, mitochondrial dysfunction, and cytokine-induced toxicity are mainly involved in neuronal damage and loss associated with PD. However, it remains unclear how these mechanisms relate to sporadic PD, a more common form of PD. Both enteric and central nervous systems have been implicated in the pathogenesis of sporadic PD, thus highlighting the crosstalk between the gut and brain. Aimof Review: In this review, we summarize how alterations in the gut microbiome can affect PD pathogenesis. We highlight various mechanisms increasing/decreasing the risk of PD development. Based on the previous supporting evidence, we suggest how early interventions could protect against PD development and how controlling specific factors, including our diet, could modify our perspective on disease mechanisms and therapeutics. We explain the strong relationship between the gut microbiota and the brain in PD subjects, by delineating the multiple mechanisms involved inneuroinflammation and oxidative stress. We conclude that the neurodetrimental effects of western diet (WD) and the neuroprotective effects of Mediterranean diets should be further exploredin humans through clinical trials.Key Scientific Concepts of Review: Alterations in the gut microbiome and associated metabolites may contribute to pathogenesis in PD. In some studies, probiotics have been shown to exert anti-oxidative effects in PD via improved mitochondrial dynamics and homeostasis, thus reducing PD-related consequences. However, there is a significant unmet need for randomized clinical trials to investigate the effectiveness of microbial products, probiotic-based supplementation, and dietary intervention in reversing gut microbial dysbiosis in PD.

A new scheme for the development of IMU-based activity recognition systems for telerehabilitation.

Wearable human activity recognition systems (HAR) using inertial measurement units (IMU) play a key role in the development of smart rehabilitation systems. Training of a HAR system with patient data is costly, time-consuming, and difficult for the patients. This study proposes a new scheme for the optimal design of HARs with minimal involvement of the patients. It uses healthy subject data for optimal design for a set of activities used in the rehabilitation of PD¹ patients. It maintains its performance for individual PD subjects using a single session data collection and an adaptation procedure. In the optimal design, several classifiers (i.e. NM, k-NN, MLP with RBF as a hidden layer, and multistage RBF SVM) were investigated. Features were signal-based in the time, frequency, and time-frequency domains. Double-stage feature extraction by PCA and fisher technique was used. The optimal design reached a recall of 95% on healthy subjects using only two sensors on the left thigh and forearm. Implementing the adaptation procedure on two PD subjects, the performance was maintained above 80%. Post analysis on the performance of the adapted HAR showed a slight drop in precision (above 87% to above 81%) for activities that was performed in sitting condition.