The role of signal preprocessing on the discriminability of canonical time-series characteristics and classification among individuals with and without Parkinson’s disease during serious game interaction

Redefining Bradykinesia.

Universidade Federal de São Paulo (EPM/UNIFESP), Escola Paulista de Medicina, Disciplina de Neurociência, São Paulo/SP, Brazil

Recent studies demonstrated that individuals with Parkinson´s disease (PD) require 1.5 times more likely hospitalization than controls. Additionally, duration of hospitalisation and rate of complications, particularly infections and delirium, are increased in PD patients. Unfortunately, there is evidence that inpatients with PD may have a higher mortality rate than outpatients with PD [1]. Based on these facts, we enjoyed reading the recent article entitled, “Description of multimorbidity clusters of admitted patients in medical departments of a general hospital” by Matesanz-Fernández and colleagues published in the Intern Med J [2]. The authors identified for the first time some clusters of comorbidities among inpatients with PD. Considering the strong clinical relevance of these results, what are the repercussions on cardiac events in PD? Really, PD is one of the most frequent age-related neurodegenerative disorders, affects millions of people globally, has no cure, and several studies demonstrated that patients with PD have an increased mortality compared to the general population. The predominant causes of death in PD are pneumonia and cardiovascular diseases [3-5]. Besides that, sudden unexpected death in PD (SUDPAR), a rare but fatal event, is increasingly discussed as a contributor to mortality in PD. SUDPAR has been defined as unexpected death of a patient with PD without any satisfactory explanation of death as determined by autopsy [5,6]. So far there are no epidemiological studies that precisely demonstrate the possible distribution of SUDPAR among main research centres for movement disorders, but relevant data that evaluated SUDPAR cases found that an average of 14% of PD patients dies suddenly. Although causes of SUDPAR are not yet entirely identified [5,6], translational studies suggest that cardiac abnormalities and autonomic dysfunction play a possible "direct" role in SUDPAR, even because ~60% of PD patients have cardiovascular comorbidities and because of the frequent autonomic disturbances in PD [5]. Moreover, some determinants may be directly related to SUDPAR, such as age at onset, duration of PD, gender, motor severity and drug treatment (polypharmacy) [5,6]. However, these risk factors of SUDPAR need to be further investigated. Considering these clinical aspects, a current question could be: How to follow the news about SUDPAR? In fact, a fundamental practical problem in studying SUDPAR risk factors, mechanisms, and prevention is that it is relatively uncommon [5,6]. Thus, crucial questions are whether and when to talk about SUDPAR to individuals and family members. To answer these questions, it would be appropriate to establish a task force that discusses issues related to SUDPAR. Furthermore, a close convergence of clinical research and clinical care (e.g., neurologists, cardiologists, and other multidisciplinary team members) is extremely important to assess and establish the state of knowledge of SUDPAR [6]. Moreover, another point suggested in the literature is the importance of focusing also on dietary habits and food preferences in PD patients, facts related to the prevention of possible cases of SUDPAR [7,8]. In view of the complex needs of people with PD, a very recent study verified the reason for admission, specialist team interventions, length of stay, frequency of readmission, discharge destination, mortality and the bed cost per unplanned emergency department (ED) attendance or hospital admission episode [9]. It was found that the mortality of PDs admitted via the emergency department was twice as much as those of non-PD patients [9]. On the whole, PD is a heterogeneous, multifactorial, and systemic neurodegenerative disorder. To reduce mortality rates in PD individuals, a multidisciplinary team should perform routine cardiovascular screening (ECG, Holter-monitoring, and echocardiography [5,6]. Explanations for increased mortality rates in PD patients and for the occurrence of SUDPAR are warranted.

Anxiety affects 25-49% of Parkinson's disease (PD) patients, exacerbating non-motor symptoms and significantly reducing quality of life. Growing evidence suggests that gut microbiota plays a role in anxiety, but whether its impact differs between PD and non-PD populations remains unclear. This study explores the heterogeneity of gut microbiota-associated anxiety in PD and non-PD individuals. Participants from the NeuroGenetics Research Consortium provided clinical data, including PD status, anxiety status, and stool samples analyzed via 16S rRNA sequencing. After excluding nine participants with missing anxiety data, 322 individuals were included (193 PD, 129 non-PD). We assessed α-diversity, β-diversity, taxonomic composition, and functional pathways to compare microbial differences between anxious and non-anxious individuals within and across PD and non-PD groups. Beta diversity analysis revealed significant microbial differences between anxious and non-anxious PD patients (p = 0.043 in Bray-Curtis index) but not in the non-PD group. Escherichia-Shigella was significantly enriched in non-anxious PD patients (p = 0.011). Functional pathway analysis identified distinct metabolic alterations associated with anxiety in PD and non-PD individuals. In non-PD participants, anxiety was linked to increased activity in glycosphingolipid biosynthesis, sphingolipid metabolism, other glycan degradation, glycosphingolipid biosynthesis, and glycosaminoglycan degradation. In contrast, PD patients with anxiety exhibited enrichment in indole alkaloid biosynthesis, linoleic acid metabolism, and polyketide sugar unit biosynthesis. Gut microbiota-associated anxiety differs between PD and non-PD populations, suggesting distinct pathophysiological mechanisms. These findings underscore the potential of microbiome-targeted interventions as novel therapeutic strategies for anxiety in PD patients.

18F-labeled fluoropropyl-carbomethoxylodopropyl-nor-ß-tropane ([18F]FP-CIT) positron emission tomography (PET) is a useful tool for evaluating disease progression in Parkinson's disease (PD) patients. We evaluated the test-retest reproducibility of [18F]FP-CIT PET measures in essential tremor (ET) and PD patients. Fifteen ET (68.9 ± 6.6years) and 10 PD patients (70.5 ± 6.3years; Hoehn and Yahr stage, 2.3 ± 0.8) underwent two [18F]FP-CIT PET/CT scans with an interval of 48 ± 7day. For both the test and retest studies, standardized uptake value ratios were estimated for 90-min and 3-h acquisitions for the caudate, anterior putamen, and posterior putamen using T1-MRI-based normalization (automatic) and fixed-VOI (manual) methods, with the occipital lobe as a reference. Reproducibility was evaluated by the bias, variability, percent test-retest, within-subject coefficient of variation, repeatability coefficient, and intraclass correlation coefficient (ICC). Reproducibility was excellent, with low variability (ET: 6.99-8.02%, PD: 3.51-6.94%) and high reliability (ICC; ET: 0.88-0.96, PD: 0.98-0.99). The ET group showed higher variability and lower ICCs than the PD group. The variability in the 90-min images (ET: 7.85-8.59%, PD: 1.52-2.75%) was comparable to that in the 3-h images (ET: 6.99-8.02%, PD: 3.51-6.94%). There were no differences in variability among the subregions in the ET group. In the PD group, the variability was high in the posterior putamen (automatic method: 6.94%, manual method: 11.80%). The test-retest variability and ICCs were similar for the manual and automatic methods. [18F]FP-CIT PET is reproducible for the quantitative measurement of DAT binding in both ET and PD individuals, independent of the acquisition time or analysis method. Also, the automaticmethod is more suitable for evaluating early loss of DAT binding inpatients with PD.

Background: It has been proposed that physical exercise can help improve upper limb functions in Parkinson’s disease (PD) patients; yet evidence for this hypothesis is limited.Objective: To assess the effects of aerobic exercise training (AET) on general upper limb functions in sedentary people with PD and healthy adults (HA).Methods: Two groups, 19 PD patients (Hoehn & Yahr ≤ 2) and 20 HA, matched on age and sedentary level, followed a 3-month stationary bicycle AET regimen. We used the kinematic theory framework to characterize and quantify the different motor control commands involved in performing simple upper-limb movements as drawing lines. Repeated measures ANCOVA models were used to assess the effect of AET in each group, as well as the difference between groups following the training regimen.Results: At baseline, PD individuals had a larger antagonist response, a longer elapsed time between the visual stimulus and the end of the movement, and a longer time of displacement of the stylus than the HA. Following the 12-week AET, PD participants showed significant decreases of the agonist and antagonist commands, as well as the antagonist response spread. A significant group ∗ session interaction effect was observed for the agonist command and the response spread of the antagonist command, suggesting a significant change for these two parameters only in PD patients following the AET. Among the differences observed at baseline, only the difference for the time of movement remained after AET.Conclusion: A 3-month AET has a significant positive impact on the capacity to draw lines in a more efficiency way, in PD patients, indicating an improvement in the upper limb motor function.

Objective: Parkinson's disease (PD) patients are known to suffer from pain, anxiety, and depression, but the exact degree of association between the two is unknown. As many PD patients also suffer from physical impairments, this cross-sectional case-control study sets out to compare and determine the case-ness of pain, anxiety and depression in PD patients that suffer with or without symptomatic osteoarthritis (OA). The goal of this study, therefore, was to observe if additional pain associated with comorbid OA in PD patients is correlated with greater depression and anxiety rates. The importance of understanding the burden of pain and increased depression severity of PD and OA patients is so that they may be screened appropriately based on the symptoms, which may increase their overall quality of life.Methods:This cross-sectional case-control study included 3 groups of 34 patients and 78 healthy age and gender-matched control participants. PD patients with symptomatic OA (PD+OA), PD patients without symptomatic OA (PD), patients with symptomatic OA but no PD (OA), and healthy control participants (Control). A PD patient group with Restless Legs Syndrome (PD+RLS) of 27 patients was also included. All participants completed questionnaires to assess for pain, depression, and anxiety.Results:PD+OA and PD patients had worsened depression severity and were more likely to report anxiety and depression case-ness than OA patients. PD+OA patients were more likely to complain about paresthestic and akasthisic pain, but less likely to complain about aching pain compared to PD patients and OA patients. PD+OA patients were more likely to have greater pain severity, and were more likely to report radiating and sharp pain than PD+RLS patients. PD+OA patients were also more likely to report higher depression case-ness than PD+RLS patients.Conclusion:PD with OA seems to be linked with specific pain characteristics (akathisia and paraesthesia) as well as heightened overall pain severity and pain interference in comparison to OA alone, PD alone and PD with RLS. PD is also correlated with depression severity and anxiety case-ness in OA when compared to the OA alone, PD alone and PD with RLS.

Blood biomarkers associated with cognitive decline in early stage and drug-naive Parkinson's disease patients

Goal: This study aims to develop an innovative gait analysis framework using recurrence plots (RPs) to differentiate gait patterns between Parkinson's disease (PD) patients under varying treatment regimes and healthy individuals. Methods: Pressure sensor data were transformed into RPs and analyzed using a Vision Transformer (ViT) model with multiple fusion strategies. To address class imbalance, a conditional Deep Convolutional Generative Adversarial Network (DC-GAN) was employed to generate synthetic gait data. Four ViT-based fusion architectures were investigated and evaluated across multi-class and binary classification tasks. Results: The dual ViT stream with late fusion achieved the highest accuracy in multi-class classification (94.58%), while the cross-attention fusion model outperformed others in binary classification tasks. Conclusions: The findings indicate that gait characteristics captured via RPs can effectively distinguish between PD patients under different treatments and healthy controls. This approach provides a data-driven pathway for objective and individualized assessment of PD therapies, potentially supporting improved clinical decision-making.

Bradykinesia is the hallmark feature of Parkinson's disease (PD); however, it can manifest in other conditions, including essential tremor (ET), and in healthy elderly individuals. Here we assessed whether bradykinesia features aid in distinguishing PD, ET, and healthy elderly individuals. We conducted simultaneous video and kinematic recordings of finger tapping in 44 PD patients, 69 ET patients, and 77 healthy elderly individuals. Videos were evaluated blindly by expert neurologists. Kinematic recordings were blindly analyzed. We calculated the inter-raters agreement and compared data among groups. Density plots assessed the overlapping in the distribution of kinematic data. Regression analyses and receiver operating characteristic curves determined how the kinematics influenced the likelihood of belonging to a clinical score category and diagnostic group. The inter-rater agreement was fair (Fleiss K = 0.32). Rater found the highest clinical scores in PD, and higher scores in ET than healthy elderly individuals (p < 0.001). In regard to kinematic analysis, the groups showed variations in movement velocity, with PD presenting the slowest values and ET displaying less velocity than healthy elderly individuals (all ps < 0.001). Additionally, PD patients showed irregular rhythm and sequence effect. However, kinematic data significantly overlapped. Regression analyses showed that kinematic analysis had high specificity in differentiating between PD and healthy elderly individuals. Nonetheless, accuracy decreased when evaluating subjects with intermediate kinematic values, i.e., ET patients. Despite a considerable degree of overlap, bradykinesia features vary to some extent in PD, ET, and healthy elderly individuals. Our findings have implications for defining bradykinesia and categorizing patients.

Polymorphisms in immune/inflammatory cytokine genes are related to Parkinson's disease with cognitive impairment in the Han Chinese population

Patients with autonomic neuropathy associated with Parkinson's disease often show reverse dipping pattern/nocturnal hypertension at 24-h ambulatory blood pressure (BP) monitoring (24-h ABPM) and diurnal orthostatic hypotension. The aim of the study was to evaluate cardiac alterations in Parkinson's disease patients with reverse dipping, in comparison with non-reverse dippers Parkinson's disease and essential hypertensive patients. A total of 26 consecutive Parkinson's disease patients with reverse dipping at 24-h ABPM and no previous history of hypertension were compared with 26 non-reverse Parkinson's disease patients matched for age, sex and 24-h mean BP, and 26 essential hypertensive patients matched for nighttime mean BP. None of the Parkinson's disease patients suffered from cardiovascular diseases or were treated with antihypertensive or antihypotensive drugs. Reverse dipping was defined by a systolic day-night BP difference less than 0% at 24-h ABPM. Left ventricular (LV) hypertrophy was defined by a LV mass index at least 115 g/m in men and at least 95 g/m in women. LV mass, indexed for BSA, was significantly higher in reverse dipping than non-reverse Parkinson's disease patients (respectively 90.2 ± 25.3 vs. 77.4 ± 13.3 g/m, P = 0.04), and was similar to essential hypertensive patients (91.6 ± 24.8, P = 0.92). LV hypertrophy was detected in five reverse dipping Parkinson's disease patients and four hypertensive patients, but was not present in non-reverse Parkinson's disease patients (P = 0.046). Nocturnal BP values, nocturnal BP load, weighted BP variability and age were found to correlate with the increased LV mass index. Reverse dipping and nocturnal hypertension are related to higher LV mass and increased prevalence of LV hypertrophy in Parkinson's disease patients.

People with Parkinson’s Disease (PD) are associated with the presence of periodontitis. We aimed to compare blood and standard biochemical surrogates of PD patients diagnosed with periodontitis with PD individuals without periodontitis. This retrospective cohort study used a sample from the National Health and Nutrition Examination Survey (NHANES) 2011–2012 that underwent periodontal diagnosis (n = 3669). PD participants were identified through specific PD reported medications. Periodontitis was defined according to the 2012 case definition, using periodontal examination data provided. Then, we compared blood levels and standard chemical laboratory profiles of PD patients according to the presence of periodontitis. Multivariable regression was used to explore this dataset and identify relevant variables towards the presence of periodontitis. According to the medication report, 37 participants were eligible, 29 were secure and 8 were unsecure PD medications regimens. Overall, PD cases with periodontitis presented increased levels of White Blood Cells (WBC) (p = 0.002), Basophils (p = 0.045) and Segmented neutrophils (p = 0.009), and also, lower levels of Total Bilirubin (p = 0.018). In the PD secure medication group, a significant difference was found for WBC (p = 0.002) and Segmented neutrophils (p = 0.002) for the periodontitis group. Further, WBC might be a discriminating factor towards periodontitis in the global sample. In the secure PD medication, we found gender, segmented neutrophils and Vitamin D2 to be potential discriminative variables towards periodontitis. Thus, periodontitis showed association with leukocyte levels alterations in PD patients, and therefore with potential systemic changes and predictive value. Furthermore, Vitamin D2 and gender showed to be associated with periodontitis in with secure medication for PD. Future studies should assess in more detail the potential systemic repercussion of the presence of periodontitis in PD patients.

Objective: To analyze the content of α-synuclein oligomer(O-α-Syn) in erythrocytes in patients with Parkinson's disease (PD) and multiple system atrophy (MSA) and the correlation with clinical symptoms. Methods: Two hundred and ninety-six PD patients and 85 MSA patients were recruited from the Department of Functional Neurosurgery and Neurology of Xuanwu Hospital, Capital Medical University from July 2020 to October 2021. Four hundred and three healthy controls (HC) were recruited from the Beijing Longitudinal Study of Aging community cohort during the same period. The levels of RBC-O-α-Syn were measured by enzyme-linked immunosorbent assay (ELISA). Univariate linear regression model was used to analyze the correlation between the content of RBD-O-α-Syn and various motor and non-motor functional scores, such as Unified Parkinson Disease Rating Scale (UPDRS) Ⅲ, Unified Multiple System Atrophy Rating Scale (UMSARS) Ⅲ, Mini-Mental State Examination (MMSE), rapid eye movement sleep disorder questionnaire-HongKong(RBDQ-HK) and Montreal Cognitive Assessment (MoCA). Receiver operating characteristic (ROC) curves was used to evaluate the specificity, sensitivity, and the area under the curve (AUC) of RBC-O-α-Syn in distinguishing PD and MSA patients from HC subjects. Results: The average age of HC subjects was (70±8) years old, the average age of PD patients was (64±9) years old, including 115 (38.9%) cases with tremor dominant PD (TD-PD), 132 cases (44.6%) of postural instability disorder predominant PD (PIGD-PD), and 142 cases (48.0%) of patients with H-Y stage 2. UPDRS Ⅲ score was 31.2±17.8. The mean age of MSA patients was (64±9) years, with the mean UMSARS Ⅱ score of 18.9±10.3. The non-motor symptoms of PD and MSA patients were significantly different from those of HC subjects (P<0.001). The levels of RBC-O-α-Syn in PD [(50±17) ng/mg] and MSA [(52±19) ng/mg] were significantly higher than those in HC subjects [(21±10) ng/mg] (P<0.001). The sensitivity and specificity of RBC-O-α-Syn in distinguishing PD patients and HC subjects were 87.16% (95%CI: 82.87%-90.50%) and 86.10% (95%CI: 82.38%-89.14%), with an AUC of 0.933 (95%CI: 0.914-0.951), and the sensitivity and specificity in distinguishing MSA patients and HC subjects were 85.88% (95%CI: 76.93%-91.74%) and 81.39% (95%CI: 77.30%-84.89%), with an AUC of 0.921 (95%CI: 0.884-0.957). The levels of RBC-O-α-Syn in PD patients with rapid eye movement sleep behavior disorder (RBD) were higher than that in PD patients without RBD [(53±16) ng/mg vs (48±17) ng/mg, P=0.029].The content of RBC-O-α-Syn in female PD patients and HC subjects was higher than that in male, but there was no significant difference between subjects of different ages and disease duration (P>0.05). In addition, RBC-O-α-Syn content was positively correlated with UPDRS Ⅲ (r=0.18, P=0.002) and the score of rapid eye movement sleep behavior disorder questionnaire(Hong Kong) (RBDQ-HK)(r=0.19, P<0.001). But there was no correlation with H-Y stage, non-motor symptoms scale (NMSS), MMSE, Moca, Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA) scores (all P>0.05). There was no correlation between RBC-O-α-Syn content and UMSARS Ⅱ, NMSS, MMSE, MoCA, HAMD, HAMA in patients with MSA (all P>0.05). Conclusions: Levels of RBC-O-α-Syn are significantly increased in PD and MSA patients. There are positive correlations between levels of RBC-O-α-Syn and scores of UPDRS Ⅲ and RBDQ-HK.

Excessive daytime sleepiness is common in Parkinson's disease and has been associated with Parkinson's disease-related dementia. Narcoleptic features have been observed in Parkinson's disease patients with excessive daytime sleepiness and hypocretin cell loss has been found in the hypothalamus of Parkinson's disease patients, in association with advanced disease. However, studies on cerebrospinal fluid levels of hypocretin-1 (orexin A) in Parkinson's disease have been inconclusive. Reports of sleep studies in Parkinson's disease patients with and without excessive daytime sleepiness have also been disparate, pointing towards a variety of causes underlying excessive daytime sleepiness. In this study, we aimed to measure cerebrospinal fluid hypocretin-1 levels in Parkinson's disease patients with and without dementia and to study their relationship to dementia and clinical excessive daytime sleepiness, as well as to describe potentially related sleep architecture changes. Twenty-one Parkinson's disease patients without dementia and 20 Parkinson's disease patients with dementia, along with 22 control subjects without sleep complaints, were included. Both Epworth sleepiness scale, obtained with the help of the caregivers, and mini-mental state examination were recorded. Lumbar cerebrospinal fluid hypocretin-1 levels were measured in all individuals using a radio-immunoassay technique. Additionally, eight Parkinson's disease patients without dementia and seven Parkinson's disease patients with dementia underwent video-polysomnogram and multiple sleep latencies test. Epworth sleepiness scale scores were higher in Parkinson's disease patients without dementia and Parkinson's disease patients with dementia than controls (P < 0.01) and scores >10 were more frequent in Parkinson's disease patients with dementia than in Parkinson's disease patients without dementia (P = 0.04). Cerebrospinal fluid hypocretin-1 levels were similar among groups (controls = 321.15 +/- 47.15 pg/ml; without dementia = 300.99 +/- 58.68 pg/ml; with dementia = 309.94 +/- 65.95 pg/ml; P = 0.67), and unrelated to either epworth sleepiness scale or mini-mental state examination. Dominant occipital frequency awake was slower in Parkinson's disease patients with dementia than Parkinson's disease patients without dementia (P = 0.05). Presence of slow dominant occipital frequency and/or loss of normal non-rapid eye movement sleep architecture was more frequent among Parkinson's disease patients with dementia (P = 0.029). Thus, excessive daytime sleepiness is more frequent in Parkinson's disease patients with dementia than Parkinson's disease patients without dementia, but lumbar cerebrospinal fluid hypocretin-1 levels are normal and unrelated to severity of sleepiness or the cognitive status. Lumbar cerebrospinal fluid does not accurately reflect the hypocretin cell loss known to occur in the hypothalamus of advanced Parkinson's disease. Alternatively, mechanisms other than hypocretin cells dysfunction may be responsible for excessive daytime sleepiness and the sleep architecture alterations seen in these patients.