Early Parkinson's Disease Patients Research Articles

A prediction model for the walking and balance milestone in Parkinson's disease

BackgroundWalking and balance impairments, represented by freezing of gait and falls, are significant contributors to disability in advanced Parkinson's disease (PD) patients. However, the composite measure of the Walking and Balance Milestone (WBMS) has not been thoroughly investigated. MethodsThis study included 606 early-stage PD patients from the Parkinson's Progression Markers Initiative (PPMI) database, with a disease duration of less than 2 years and no WBMS at baseline. Patients were divided into a model development cohort (70 %) and a validation cohort (30 %) according to the enrollment site. Longitudinal follow-up data over a period of 12 years were analyzed. ResultsAmong all 606 patients, the estimated probability of being WBMS-free at the 5th and 10th year was 88 % and 60 %, respectively. Five clinical variables (Age, Symbol Digit Modalities Test (SDMT), postural instability and gait difficulty (PIGD) score, Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part I (MDS-UPDRS-I) score, and REM Sleep Behavior Disorder (RBD) were used to construct the Cox predictive model. The C-index of the model was 0.75 in the development cohort and 0.76 in the validation cohort. By optimizing the PIGD and MDS-UPDRS-I variables, an easy-to-use model was achieved with comparable predictive performance. ConclusionA predictive model based on five baseline clinical measures (Age, SDMT, PIGD score, MDS-UPDRS-I score, RBD) could effectively estimate the risk of the WBMS in early PD patients. This model is valuable for prognostic counseling and clinical intervention trials for gait and balance impairment.

Rest Tremor in Parkinson's Disease Is Associated with Ipsilateral Striatal Dopamine Transporter Binding.

The cardinal motor symptoms of Parkinson's disease (PD) include rigidity, bradykinesia, and rest tremor. Rigidity and bradykinesia correlate with contralateral nigrostriatal degeneration and striatal dopamine deficit, but association between striatal dopamine function and rest tremor has remained unclear. The aim of this study was to investigate the possible link between dopamine function and rest tremor using Parkinson's Progression Markers Initiative dataset, the largest prospective neuroimaging cohort of patients with PD. Clinical, [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([123I]FP-CIT) single photon emission computed tomography (SPECT), and structural magnetic resonance imaging data from 354 early PD patients and 166 healthy controls were included in this study. We employed a novel approach allowing nonlinear registration of individual scans accurately to a standard space and voxelwise analyses of the association between motor symptoms and striatal dopamine transporter (DAT) binding. Severity of both rigidity and bradykinesia was negatively associated with contralateral striatal DAT binding (PFWE < 0.05 [FWE, family-wise error corrected]). However, rest tremor amplitude was positively associated with increased ipsilateral DAT binding (PFWE < 0.05). The association between rest tremor and binding remained the same controlling for Hoehn & Yahr stage, Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score, bradykinesia-rigidity score, or motor phenotype. The association between rest tremor and binding was independent of bradykinesia-rigidity and replicated using 2-year follow-up data (PFWE < 0.05). In agreement with the existing literature, we did not find a consistent association between rest tremor and contralateral dopamine defect. However, our results demonstrate a link between rest tremor and increased or less decreased ipsilateral DAT binding. Our findings provide novel information about the association between dopaminergic function and parkinsonian rest tremor. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Silent Threat: Deep Vein Thrombosis in Early-Stage Parkinson's Disease.

The primary clinical manifestation of venous thrombosis is discomfort in the lower extremities. Some early Parkinson's disease (PD) patients feel discomfort in the lower limbs. Venous thrombosis can risk lives by causing pulmonary embolism. This study examines the incidence of DVT in early PD patients and its correlation with different clinical and lab features. A cross-sectional study was conducted on 117 patients with early-stage PD. Ultrasonography was employed to detect the presence of DVT. Factors such as age, gender, body mass index, lifestyle habits (smoking and drinking), medical history (hypertension, diabetes, atrial fibrillation, and tumor), and other lab tests linked to thrombosis were analyzed. In 117 patients, 11 (9.4%) had DVT, while 106 (90.6%) did not. There were no significant differences in gender, BMI, habits, medical history, or other thrombosis-related tests between both groups. However, DVT patients were older with higher d-dimer levels. They also showed an increased right substantia nigra ultrasound echo area, higher HY grades, higher UPDRS 3 scores, less improvement in UPDRS 3 scores and levodopa response. The primary risk factors for lower extremity venous thrombosis were found to be age, d-dimer levels, and low-dose levodopa. Therefore, for elderly patients with early-stage PD, it is crucial to conduct d-dimer and lower extremity vascular ultrasound tests. The prevention of venous thrombosis in the lower extremities of early PD patients is of utmost importance.

Disease progression in Parkinson's disease patients with mild cognitive impairment: 5-year longitudinal study from the early Parkinson's disease longitudinal Singapore (PALS) cohort.

To investigate motor, non-motor and cognitive progression in early Parkinson's disease (PD) patients with Mild Cognitive Impairment (MCI). PD patients were recruited within 1 year of diagnosis and were classified into PD-MCI group and PD with normal cognition (PD-NC) group. H&Y staging scale, MDS-UPDRS part III were used to assess disease severity and motor progression. Non-motor symptom scale (NMSS) was used to evaluate the NMS progression. Cognitive progression was assessed from 5 cognitive domains. Annual progression changes in the longitudinal outcomes were examined via linear mixed model with random intercept effect. False discovery rate (FDR) method was performed to control for multiple testing comparison and q-value was calculated. We set the threshold of q-values as 0.1. A total of 205 PD patients, including 107 PD-MCI and 98 PD-NC patients were assessed prospectively over a 5-year period. PD-MCI patients, compared to PD-NC group, had a significantly higher progression rate in H&Y score (0.11 vs. 0.06, p=0.03, q=0.08), MDS-UPDRS motor score (3.11 vs. 1.90 p<0.001, q=0.06) and postural instability gait difficulty (PIGD) score (0.40 vs. 0.20, p=0.02, q=0.07). PD-MCI group also exhibited significantly faster deterioration in NMSS perceptual domain (PD-MCI vs. PD-NC: 0.38 vs. -0.04, p=0.01, q=0.06) and cognitive visuospatial domain (PD-MCI vs. PD-NC: 0.13 vs. -0.06, p=0.048, q=0.09) after adjustment for confounders and multiple comparisons. PD-MCI patients had faster decline in motor functions, visuo-perceptual and visuospatial performance. These findings provide a more comprehensive prognosis of PD-MCI, which could be helpful for clinician to manage PD-MCI patients.

The impact of combined aerobic and resistance exercise on the prognosis of early Parkinson's disease patients.

Although literature suggests that exercise can improve symptoms in Parkinson's Disease (PD) patients, research on the effects of aerobic exercise and resistance training (AE&RT) in early-stage PD remains limited. Understanding the synergistic effects of these exercise modalities can provide valuable insights for optimizing exercise interventions for PD patients, particularly in the early stages of the disease, where interventions may have the greatest impact on long-term functional outcomes. This study aimed to investigate the effects of a combined AE&RT program on motor function, postural stability, and cognitive processing speed in early stage PD patients. A total of 236 participants with early-stage PD were assigned to either the Aerobic Exercise Group (AE group) (n= 112) or the AE&RT Group (n= 124) inthis controlled randomized trial. The study employed a one-year supervised exercise program, with the AE Group participating in aerobic activities and the AE&RT Group engaging in combined AE&RT. Outcome measures included symptom improvement, motor function, postural stability, cognitive processing speed, peak oxygen consumption, quality of life evaluation, and the incidence of adverse events. The AE&RT Group demonstrated greater improvements in tremor, muscle rigidity, gait instability, sleep problems, and hyposmia compared to the AE Group. Additionally, the combined exercise group exhibited better cognitive processing speed, as well as enhanced motor function and postural stability. Peak oxygen consumption was significantly higher in the AE&RT Group. However, the quality of life evaluation indicated a statistically higher quality of life in the AE Group. There was no significant difference in the incidence of adverse events between the two groups. The findings suggest that the integration of AE&RT in early-stage PD patients leads to more comprehensive improvements in motor symptoms, cognitive function, postural stability, and cardiovascular fitness compared to aerobic exercise alone. These results have important implications for developing tailored exercise interventions to enhance the physical and cognitive well-being of individuals with early-stage PD.

Clinically established early Parkinson's disease patients do not show impaired use of priors in conditions of perceptual uncertainty

The ability to use past learned experiences to guide decisions is an important component of adaptive behavior, especially when decision-making is performed under time pressure or when perceptual information is unreliable. Previous studies using visual discrimination tasks have shown that this prior-informed decision-making ability is impaired in Parkinson's disease (PD), but the mechanisms underlying this deficit and the precise impact of dopaminergic denervation within cortico-basal circuits remain unclear. To shed light on this problem, we evaluated prior-informed decision-making under various conditions of perceptual uncertainty in a sample of 13 clinically established early PD patients, and compared behavioral performance with healthy control (HC) subjects matched in age, sex and education. PD patients and HC subjects performed a random dot motion task in which they had to decide the net direction (leftward vs. rightward) of a field of moving dots and communicate their choices through manual button presses. We manipulated prior knowledge by modulating the probability of occurrence of leftward vs. rightward motion stimuli between blocks of trials, and by explicitly giving these probabilities to subjects at the beginning of each block. We further manipulated stimulus discriminability by varying the proportion of dots moving coherently in the signal direction and speed-accuracy instructions. PD patients used choice probabilities to guide perceptual decisions in both speed and accuracy conditions, and their performance did not significantly differ from that of HC subjects. An additional analysis of the data with the diffusion decision model confirmed this conclusion. These results suggest that the impaired use of priors during visual discrimination observed at more advanced stages of PD is independent of dopaminergic denervation, though additional studies with larger sample sizes are needed to more firmly establish this conclusion.

Prokineticin-2 Is Highly Expressed in Colonic Mucosa of Early Parkinson's Disease Patients.

Elevated levels of prokineticin-2 (PK2), regarded as a protein involved in modulating immune/inflammatory responses, have been detected in the substantia nigra, serum, and olfactory neurons of Parkinson's disease (PD) patients. Of note, emerging evidence suggests that gut alterations, including dysbiosis and enteric inflammation, play a role in PD via the gut-brain axis. Our goal was to investigate the expression of PK2 in colonic biopsies of PD patients. Mucosal biopsies from the descending colon were obtained in 11 PD patients and five asymptomatic subjects. Biopsy samples were processed for PK2 immunofluorescence and western blot. We revealed an increased PK2 expression in colonic mucosa from PD patients in the early stages compared to controls. In addition, we found that PK2 was expressed by activated enteric glial cells and macrophages. PK2 is highly expressed within neurogenic/inflammatory cells of colonic mucosa from early PD patients, suggesting a potential role of PK2 in gut inflammation, especially in the early stages of PD. © 2024 International Parkinson and Movement Disorder Society.

Unraveling olfactory subtypes in Parkinson's disease and their effect on the natural history of the disease.

Hyposmia in Parkinson's disease (PD) had been studied before but had not been detailed by its temporal progression. This study observed how each olfactory subtype evolved in terms of motor symptoms, cardiac sympathetic innervation, and cognition. Two hundred and three early PD patients were classified as normosmia, hyposmia-converter (hypo-converter), and hyposmia. Their presynaptic monoamine availability at the time of diagnosis was assessed by positron emission tomography imaging using 18F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane and compared across the subtypes. Motor symptoms were evaluated in all patients, cardiac denervation was examined in 183 patients, and cognition in 195 patients were assessed using a neuropsychological battery. The domains were re-assessed 2-4 times, and the longitudinal data were analyzed to discern the natural course of each subtype. Twenty-nine (14.3%) patients belonged to the normosmia group, 34 (16.7%) to the hypo-converter group, and the rest to the hyposmia (69.0%) group. 85.7% of the total population became hyposmic during an average 3years of follow-up. The baseline motor symptoms, cardiac denervation, and cognition were comparable across the olfactory subtypes. Across the subtypes, a decline in the presynaptic monoamine densities of the caudate, especially the ventral-anterior subdivisions, correlated inversely with olfaction dysfunction. Over time, motor and cardiac denervation burdens worsened regardless of olfactory subtypes, but hypo-converters experienced faster cognitive deterioration than the other two groups. The results suggest that the olfactory subtypes have differential significance along the disease course, which might reflect the involvement of different neuro-biochemical circuitries.

Disease Progression of Data-Driven Subtypes of Parkinson's Disease: 5-Year Longitudinal Study from the Early Parkinson's Disease Longitudinal Singapore (PALS) Cohort.

The detailed trajectory of data-driven subtypes in Parkinson's disease (PD) within Asian cohorts remains undisclosed. To evaluate the motor, non-motor symptom (NMS) progression among the data-driven PD clusters. In this 5-year longitudinal study, NMS scale (NMSS), Hospital Anxiety Depression Scale (HADS), and Epworth sleepiness scale (ESS) were carried out annually to monitor NMS progression. H& Y staging scale, MDS-UPDRS part III motor score, and postural instability gait difficulty (PIGD) score were assessed annually to evaluate disease severity and motor progression. Five cognitive standardized scores were used to assess detailed cognitive progression. Linear mixed model was performed to assess the annual progression rates of the longitudinal outcomes. Two hundred and six early PD patients, consisting of 43 patients in cluster A, 98 patients in cluster B and 65 subjects in cluster C. Cluster A (severe subtype) had significantly faster progression slope in NMSS Domain 3 (mood/apathy) score (p = 0.01), NMSS Domain 4 (perceptual problems) score (p = 0.02), NMSS Domain 7 (urinary) score (p = 0.03), and ESS Total Score (p = 0.04) than the other two clusters. Cluster A also progressed significantly in PIGD score (p = 0.04). For cognitive outcomes, cluster A deteriorated significantly in visuospatial domain (p = 0.002), while cluster C (mild subtype) deteriorated significantly in executive domain (p = 0.04). The severe cluster had significantly faster progression, particularly in mood and perceptual NMS domains, visuospatial cognitive performances, and postural instability gait scores. Our findings will be helpful for clinicians to stratify and pre-emptively manage PD patients by developing intervention strategies to counter the progression of these domains.

Smartphone Voice Calls Provide Early Biomarkers of Parkinsonism in Rapid Eye Movement Sleep Behavior Disorder.

Speech dysfunction represents one of the initial motor manifestations to develop in Parkinson's disease (PD) and is measurable through smartphone. The aim was to develop a fully automated and noise-resistant smartphone-based system that can unobtrusively screen for prodromal parkinsonian speech disorder in subjects with isolated rapid eye movement sleep behavior disorder (iRBD) in a real-world scenario. This cross-sectional study assessed regular, everyday voice call data from individuals with iRBD compared to early PD patients and healthy controls via a developed smartphone application. The participants also performed an active, regular reading of a short passage on their smartphone. Smartphone data were continuously collected for up to 3 months after the standard in-person assessments at the clinic. A total of 3525 calls that led to 5990 minutes of preprocessed speech were extracted from 72 participants, comprising 21 iRBD patients, 26 PD patients, and 25 controls. With a high area under the curve of 0.85 between iRBD patients and controls, the combination of passive and active smartphone data provided a comparable or even more sensitive evaluation than laboratory examination using a high-quality microphone. The most sensitive features to induce prodromal neurodegeneration in iRBD included imprecise vowel articulation during phone calls (P = 0.03) and monopitch in reading (P = 0.05). Eighteen minutes of speech corresponding to approximately nine calls was sufficient to obtain the best sensitivity for the screening. We consider the developed tool widely applicable to deep longitudinal digital phenotyping data with future applications in neuroprotective trials, deep brain stimulation optimization, neuropsychiatry, speech therapy, population screening, and beyond. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Insular and limbic abnormal functional connectivity in early-stage Parkinson's disease patients with autonomic dysfunction.

Autonomic symptoms in Parkinson's disease result from variable involvement of the central and peripheral systems, but many aspects remain unclear. The analysis of functional connectivity has shown promising results in assessing the pathophysiology of Parkinson's disease. This study aims to investigate the association between autonomic symptoms and cortical functional connectivity in early Parkinson's disease patients using high-density EEG. 53 early Parkinson's disease patients (F/M 18/35) and 49 controls (F/M 20/29) were included. Autonomic symptoms were evaluated using the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score. Data were recorded with a 64-channel EEG system. We analyzed cortical functional connectivity, based on weighted phase-lag index, in θ-α-β-low-γ bands. A network-based statistic was used to perform linear regression between Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and functional connectivity in Parkinson's disease patients. We observed a positive relation between the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and α-functional connectivity (network τ = 2.8, P = 0.038). Regions with higher degrees were insula and limbic lobe. Moreover, we found positive correlations between the mean connectivity of this network and the gastrointestinal, cardiovascular, and thermoregulatory domains of Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction. Our results revealed abnormal functional connectivity in specific areas in Parkinson's disease patients with greater autonomic symptoms. Insula and limbic areas play a significant role in the regulation of the autonomic system. Increased functional connectivity in these regions might represent the central compensatory mechanism of peripheral autonomic dysfunction in Parkinson's disease.

Understanding the role of cerebellum in early Parkinson’s disease: a structural and functional MRI study

Increasing evidence suggests that the cerebellum may have a role in the pathophysiology of Parkinson’s disease (PD). Hence, the scope of this study was to investigate whether there are structural and functional alterations of the cerebellum and whether they correlate with motor and non-motor symptoms in early PD patients. Seventy-six patients with early PD and thirty-one age and sex-matched healthy subjects (HS) were enrolled and underwent a 3 T magnetic resonance imaging (MRI) protocol. The following MRI analyses were performed: (1) volumes of 5 cerebellar regions of interest (sensorimotor and cognitive cerebellum, dentate, interposed, and fastigial nuclei); (2) microstructural integrity of the cerebellar white matter connections (inferior, middle, and superior cerebellar peduncles); (3) functional connectivity at rest of the 5 regions of interest already described in point 1 with the rest of brain. Compared to controls, early PD patients showed a significant decrease in gray matter volume of the dentate, interposed and fastigial nuclei, bilaterally. They also showed abnormal, bilateral white matter microstructural integrity in all 3 cerebellar peduncles. Functional connectivity of the 5 cerebellar regions of interest with several areas in the midbrain, basal ganglia and cerebral cortex was altered. Finally, there was a positive correlation between abnormal functional connectivity of the fastigial nucleus with the volume of the nucleus itself and a negative correlation with axial symptoms severity. Our results showed that structural and functional alterations of the cerebellum are present in PD patients and these changes contribute to the pathophysiology of PD in the early phase.

Parkinson's Disease Risk Variant rs9638616 is Non-Specifically Associated with Altered Brain Structure and Function.

A genome-wide association study (GWAS) variant associated with Parkinson's disease (PD) risk in Asians, rs9638616, was recently reported, and maps to WBSCR17/GALNT17, which is involved in synaptic transmission and neurite development. To test the association of the rs9638616 T allele with imaging-derived measures of brain microstructure and function. We analyzed 3-Tesla MRI and genotyping data from 116 early PD patients (aged 66.8±9.0 years; 39% female; disease duration 1.25±0.71 years) and 57 controls (aged 68.7±7.4 years; 54% female), of Chinese ethnicity. We performed voxelwise analyses for imaging-genetic association of rs9638616 T allele with white matter tract fractional anisotropy (FA), grey matter volume and resting-state network functional connectivity. The rs9638616 T allele was associated with widespread lower white matter FA (t = -1.75, p = 0.042) and lower functional connectivity of the supplementary motor area (SMA) (t = -5.05, p = 0.001), in both PD and control groups. Interaction analysis comparing the association of rs9638616 and FA between PD and controls was non-significant. These imaging-derived phenotypes mediated the association of rs9638616 to digit span (indirect effect: β= -0.21 [-0.42,-0.05], p = 0.031) and motor severity (indirect effect: β= 0.15 [0.04,0.26], p = 0.045). We have shown that a novel GWAS variant which is biologically linked to synaptic transmission is associated with white matter tract and functional connectivity dysfunction in the SMA, supported by changes in clinical motor scores. This provides pathophysiologic clues linking rs9638616 to PD risk and might contribute to future risk stratification models.

An interpretable deep learning Bayesian optimized random forest framework for the diagnosis of Parkinson's disease in structural magnetic resonance images

AbstractAs one of the fastest‐growing neurological disorders, Parkinson's disease is a neurodegenerative, cardinally motor ailment. Associated with the late onset of symptoms and often misdiagnosed, it inflicts massive life handicaps. To aid in its early detection, the research community is seeking alternative in‐vivo biomarkers, mainly in the field of neuroimaging. This study aimed to build a computer‐aided diagnosis system to distinguish between healthy controls (HC) and early Parkinsonian patients (PD). Our classification paradigm encompasses a Convolutional Neural Network built from scratch to extract discriminatory features, followed by a Bayesian‐optimized Random Forest classifier (CNN_RF). We trained and validated our customized model on the MRI images of 178 PD and 124 HC, taken from the benchmark Parkinson's Progression Markers Initiative (PPMI) dataset, as well as their brain tissue segments and Jacobian determinant maps. The classification was evaluated using seven performance metrics. For visual interpretation, we employed Grad‐CAM to generate saliency maps. Our findings demonstrate the robustness of the proposed method, as it outperformed deep‐tuned ResNet18, VGG16, and SqueezeNet, implemented for comparison. Furthermore, it resulted in 98.9% accuracy, 98.6% specificity, 99.0% precision, 99.5% F1‐score, a 97.7% Matthews correlation coefficient (MCC), and an AUC of 99.6% for the classification of fused gray matter and Jacobian map features. This indicates that the tailored CNN_RF possesses superior adaptability to identify intrinsic characteristics linked to the disease, as highlighted in the salient maps showcasing pertinent regions in the striatum, thalamus, frontal, temporal, and insular cortices for Parkinson's disease classification. Moreover, it offers a single modality and cost‐effective CAD, which could pave the way for a feasible early PD diagnosis. As data availability and AI robustness increase, PD diagnosis will no longer be a challenging task in the future.

Olfactory Dysfunction and Long-Term Trajectories of Sleep Disorders among early Parkinson’s Disease: Findings from a Longitudinal Cohort

Background: Previous studies have suggested a connection between impaired olfactory function and an increased risk of rapid eye movement sleep behavior disorder (RBD) in individuals diagnosed with Parkinson’s disease (PD). However, there is a gap in knowledge regarding the potential impact of olfactory dysfunction on the long-term patterns of sleep disorders among early PD patients. Methods: Data from the Parkinson’s Progression Markers Initiative program included 589 participants with assessments of sleep disorders using the Epworth Sleepiness Scale (ESS) and RBD Screening Questionnaire (RBDSQ). Olfactory dysfunction at baseline was measured using the University of Pennsylvania Smell Identification Test. Trajectories of sleep disorders over a 5-year follow-up were identified using group-based trajectory modeling, and the relationship between olfactory dysfunction and sleep disorder trajectories was examined through binomial logistic regression. Results: Two distinct trajectories of sleep disorders over the 5-year follow-up period were identified, characterized by maintaining a low or high ESS score and a low or high RBDSQ score. An inversion association was observed between olfactory function measures and trajectories of excessive daytime sleepiness (odds ratio [OR] = 0.97, 95% confidence interval [CI] 0.95, 1.00, p = 0.038), after controlling for potential covariates. Similarly, olfactory function showed a significant association with lower trajectories of probable RBD (OR = 0.96, 95% CI 0.94, 0.98, p = 0.001) among early PD individuals. Consistent findings were replicated across alternative analytical models. Conclusions: Our findings indicated that olfactory dysfunction was associated with unfavorable long-term trajectories of sleep disorders among early PD.

Energetic dysfunction and iron overload in early Parkinson's disease: Two distinct mechanisms?

IntroductionIdentifying biomarkers reflecting cellular dysfunctions in early Parkinson's disease patients (ePD) is needed to develop targeted therapeutic strategies. We aimed to determine if cellular energetic dysfunction related to increased brain sodium concentration would be co-located to microstructural alterations and iron deposition in ePD. MethodsWe prospectively included 12 ePD (mean disease duration 20.0 ± 10.2 months) and 13 healthy controls (HC), scanned with a 7 T 1H and 23Na MRI. Complementary voxel-based and region-based assessments were performed, the latter utilizing a high-resolution multimodal template we created (combining quantitative T1 maps (qT1), transverse relaxation rate (R2*), quantitative magnetic susceptibility mapping (QSM) images) from 200 subjects. This template allowed a precise multiparametric assessment of sodium concentration, QSM, R2*, qT1, mean diffusivity, and fractional anisotropy values. A two-sided p-value<0.05 was considered statistically significant after the Bonferroni correction. ResultsRelative to HC, ePD showed significantly higher sodium concentration in left Substantia nigra (SN) pars reticulata (46.13 mM ± 3.52 vs 38.60 mM ± 6.10, p = 0.038), a subpart of the SN pars compacta (SNc) and ventral tegmental area, Putamen, Globus Pallidum external, accumbens nucleus and claustrum. Significantly increased QSM and R2* values, and decreased T1 values, were limited to the Nigrosomes 1 (Nig) and right SNc (all p < 0.05). QSM values in the Nig were significantly correlated to UPDRS-III scores (r = 0.91,p < 0.001). ConclusionIn ePD, brain sodium accumulation was broad and dissociated from iron accumulation. As with iron accumulation, a sodium-related pathophysiological approach could lead to identifying potential new therapeutic agents and deserves further investigation.

ATST-Net: A method to identify early symptoms in the upper and lower extremities of PD

Bradykinesia, a core symptom of motor disorders in Parkinson's disease (PD), is a major criterion for screening early PD patients in clinical practice. Currently, many studies have proposed automatic assessment schemes for bradykinesia in PD. However, existing schemes suffer from problems such as dependence on professional equipment, single evaluation tasks, difficulty in obtaining samples and low accuracy. This paper proposes a manual feature extraction- and neural network-based method to evaluate bradykinesia, effectively solving the problem of a small sample size. This method can automatically assess finger tapping (FT), hand movement (HM), toe tapping (TT) and bilateral foot sensitivity tasks (LA) through a unified model. Data were obtained from 120 individuals, including 93 patients with Parkinson's disease and 27 age- and sex-matched normal controls (NCs). Manual feature extraction and Attention Time Series Two-stream Networks (ATST-Net) were used for classification. Accuracy rates of 0.844, 0.819, 0.728, and 0.768 were achieved for FT, HM, TT, and LA, respectively. To our knowledge, this study is the first to simultaneously evaluate the upper and lower limbs using a unified model that has significant advantages in both model training and transfer learning.

Nonlinear Relationship Between Homocysteine and Mild Cognitive Impairment in Early Parkinson's Disease: A Cross-Sectional Study.

Cognitive impairment, a prevalent non-motor symptom in advanced Parkinson's disease (PD), has been associated with hyperhomocysteinemia, an important risk factor for PD progression and cognitive decline in PD. However, evidence regarding the association between homocysteine (Hcy) and cognitive function during early PD remains insufficient. Therefore, this study aims to examine the correlation between Hcy levels and cognitive function in the early stage of PD. The study included 218 individuals in the early stages of PD who were consecutively admitted to the Suining Central Hospital Neurology Department. All the individuals completed the Parkinson's Disease Cognitive Rating Scale (PD-CDR). The Unified Parkinson's Disease Rating Scale part III (UPDRS-III) was employed for measuring the severity of motor symptoms, while the Hoehn-Yahr scale was used to measure the clinical symptom stage. Fasting venous blood samples were also drawn to measure the Hcy concentration, red blood cell folate, and vitamin B12. In this cross-sectional study, 47 (21.5%) patients with PD showed cognitive dysfunction. The serum Hcy levels were significantly higher in the cognitive impairment PD (PDCI) group compared with the cognitive normal PD group (P<0.001). The Generalized Additive Model (GAM) analysis revealed a nonlinear relationship between Hcy and the risk of PDCI. Multiple logistic regression analyses demonstrated a positive relationship between elevated Hcy and the risk of PDCI in the fully adjusted model ([OR]:3.1, 95% CI, 1.1-8.5, P=0.028). Segmented linear regression analysis showed that when Hcy levels were above 17.7 umol/l, the risk of PDCI increased by 1.6 times for every 1 unit elevated in Hcy (95% CI:1.1-2.2, P=0.008). This study revealed a nonlinear positive correlation between the risk of PDCI and elevated serum Hcy levels in early PD patients, suggesting hyperhomocysteinemia as one of the treatable factors for cognitive impairment in the early stages of PD.

A New Wrist-Worn Tool Supporting the Diagnosis of Parkinsonian Motor Syndromes.

To date, clinical expert opinion is the gold standard diagnostic technique for Parkinson's disease (PD), and continuous monitoring is a promising candidate marker. This study assesses the feasibility and performance of a new wearable tool for supporting the diagnosis of Parkinsonian motor syndromes. The proposed method is based on the use of a wrist-worn measuring system, the execution of a passive, continuous recording session, and a computation of two digital biomarkers (i.e., motor activity and rest tremor index). Based on the execution of some motor tests, a second step is provided for the confirmation of the results of passive recording. In this study, fifty-nine early PD patients and forty-one healthy controls were recruited. The results of this study show that: (a) motor activity was higher in controls than in PD with slight tremors at rest and did not significantly differ between controls and PD with mild-to-moderate tremor rest; (b) the tremor index was smaller in controls than in PD with mild-to-moderate tremor rest and did not significantly differ between controls and PD patients with slight tremor rest; (c) the combination of the said two motor parameters improved the performances in differentiating controls from PD. These preliminary findings demonstrate that the combination of said two digital biomarkers allowed us to differentiate controls from early PD.

Morphometric similarity differences in drug-naive Parkinson's disease correlate with transcriptomic signatures.

Differences in cortical morphology have been reported in individuals with Parkinson's disease (PD). However, the pathophysiological mechanism of transcriptomic vulnerability in local brain regions remains unclear. This study aimed to characterize the morphometric changes of brain regions in early drug-naive PD patients and uncover the brain-wide gene expression correlates. The morphometric similarity (MS) network analysis was used to quantify the interregional structural similarity from multiple magnetic resonance imaging anatomical indices measured in each brain region of 170 early drug-naive PD patients and 123 controls. Then, we applied partial least squares regression to determine the relationship between regional changes in MS and spatial transcriptional signatures from the Allen Human Brain Atlas dataset, and identified the specific genes related to MS differences in PD. We further investigated the biological processes by which the PD-related genes were enriched and the cellular characterization of these genes. Our results showed that MS was mainly decreased in cingulate, frontal, and temporal cortical areas and increased in parietal and occipital cortical areas in early drug-naive PD patients. In addition, genes whose expression patterns were associated with regional MS changes in PD were involved in astrocytes, excitatory, and inhibitory neurons and were functionally enriched in neuron-specific biological processes related to trans-synaptic signaling and nervous system development. These findings advance our understanding of the microscale genetic and cellular mechanisms driving macroscale morphological abnormalities in early drug-naive PD patients and provide potential targets for future therapeutic trials.