Distinctive Pattern of Metal Deposition in Neurologic Wilson Disease: Insights From 7T Susceptibility-Weighted Imaging.

BACKGROUND AND OBJECTIVES: Noninvasive and accurate biomarkers of neurologic Wilson disease (NWD), a rare inherited disorder, could reduce diagnostic error or delay. Excessive subcortical metal deposition seen on susceptibility imaging has suggested a characteristic pattern in NWD. With submillimeter spatial resolution and increased contrast, 7T susceptibility-weighted imaging (SWI) may enable better visualization of metal deposition in NWD. In this study, we sought to identify a distinctive metal deposition pattern in NWD using 7T SWI and investigate its diagnostic value and underlying pathophysiologic mechanism. METHODS: Patients with WD, healthy participants with monoallelic ATP7B variant(s) on a single chromosome, and health controls (HCs) were recruited. NWD and non-NWD (nNWD) were defined according to the presence or absence of neurologic symptoms during investigation. Patients with other diseases with comparable clinical or imaging manifestations, including early-onset Parkinson disease (EOPD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and neurodegeneration with brain iron accumulation (NBIA), were additionally recruited and assessed for exploratory comparative analysis. All participants underwent 7T T1, T2, and high-resolution SWI scanning. Quantitative susceptibility mapping and principal component analysis were performed to illustrate metal distribution. RESULTS: We identified a linear signal intensity change consisting of a hyperintense strip at the lateral border of the globus pallidus in patients with NWD. We termed this feature "hyperintense globus pallidus rim sign." This feature was detected in 38 of 41 patients with NWD and was negative in all 31 nNWD patients, 15 patients with EOPD, 30 patients with MSA, 15 patients with PSP, and 12 patients with NBIA; 22 monoallelic ATP7B variant carriers; and 41 HC. Its sensitivity to differentiate between NWD and HC was 92.7%, and specificity was 100%. Severity of the hyperintense globus pallidus rim sign measured by a semiquantitative scale was positively correlated with neurologic severity (ρ = 0.682, 95% CI 0.467-0.821, p < 0.001). Patients with NWD showed increased susceptibility in the lenticular nucleus with high regional weights in the lateral globus pallidus and medial putamen. DISCUSSION: The hyperintense globus pallidus rim sign showed high sensitivity and excellent specificity for diagnosis and differential diagnosis of NWD. It is related to a special metal deposition pattern in the lenticular nucleus in NWD and can be considered as a novel neuroimaging biomarker of NWD. CLASSIFICATION OF EVIDENCE: The study provides Class II evidence that the hyperintense globus pallidus rim sign on 7T SWI MRI can accurately diagnose neurologic WD.

Machine-learning model for the prediction of acute orthostatic hypotension after levodopa administration.

BACKGROUND: Levodopa could induce orthostatic hypotension (OH) in Parkinson's disease (PD) patients. Accurate prediction of acute OH post levodopa (AOHPL) is important for rational drug use in PD patients. Here, we develop and validate a prediction model of AOHPL to facilitate physicians in identifying patients at higher probability of developing AOHPL. METHODS: The study involved 497 PD inpatients who underwent a levodopa challenge test (LCT) and the supine-to-standing test (STS) four times during LCT. Patients were divided into two groups based on whether OH occurred during levodopa effectiveness (AOHPL) or not (non-AOHPL). The dataset was randomly split into training (80%) and independent test data (20%). Several models were trained and compared for discrimination between AOHPL and non-AOHPL. Final model was evaluated on independent test data. Shapley additive explanations (SHAP) values were employed to reveal how variables explain specific predictions for given observations in the independent test data. RESULTS: We included 180 PD patients without AOHPL and 194 PD patients with AOHPL to develop and validate predictive models. Random Forest was selected as our final model as its leave-one-out cross validation performance [AUC_ROC 0.776, accuracy 73.6%, sensitivity 71.6%, specificity 75.7%] outperformed other models. The most crucial features in this predictive model were the maximal SBP drop and DBP drop of STS before medication (ΔSBP/ΔDBP). We achieved a prediction accuracy of 72% on independent test data. ΔSBP, ΔDBP, and standing mean artery pressure were the top three variables that contributed most to the predictions across all individual observations in the independent test data. CONCLUSIONS: The validated classifier could serve as a valuable tool for clinicians, offering the probability of a patient developing AOHPL at an early stage. This supports clinical decision-making, potentially enhancing the quality of life for PD patients.

Acute effect of levodopa on orthostatic hypotension and its association with motor responsiveness in Parkinson's disease: Results of acute levodopa challenge test.

OBJECTIVE: Levodopa administration can induce or worsen orthostatic hypotension (OH) in patients with Parkinson's disease (PD). Understanding of acute OH post levodopa (AOHPL) is important for rational drug use in PD patients. Primary objective of this study was to investigate the incidence of AOHPL in PD patients. The secondary objectives were a) hemodynamic character of AOHPL; b) risk factors of AOHPL; c) relationship between motor responsiveness and blood pressure (BP) change. METHODS: 490 PD inpatients underwent acute levodopa challenge test (LCT). Supine-to-standing test (STS) was done 4 times during LCT, including before levodopa and every hour post levodopa intake within 3 h. Patients were classified into two groups, AOHPL and non-AOHPL. A comprehensive set of clinical features scales was assessed, including both motor (e.g., motor response, wearing-off) and nonmotor symptoms (e.g., autonomic dysfunction, neuropsychology). RESULTS: 33.1% PD patients had OH before drug, 50.8% the same subjects had AOHPL during levodopa effectiveness. PD patients who had better response to levodopa likely to have lower standing mean artery pressure (MAP) and severer systolic BP drop after levodopa intake. BP increased when the motor performance worsened and vice versa. Beneficial response was a risk factors of AOHPL (OR = 1.624, P = 0.017). CONCLUSIONS: AOHPL was very common in PD patients. We suggested that PD patients with risk factors should monitor hemodynamic change during LCT to avoid AOHPL following the introduction or increase of oral levodopa. The fluctuations of BP were complicated and multifactorial, likely caused by the process of PD and levodopa both.

Microstructural and functional impairment of the basal ganglia in Wilson's disease: a multimodal neuroimaging study.

Objectives: Magnetic susceptibility changes in brain MRI of Wilson's disease (WD) patients have been described in subcortical nuclei especially the basal ganglia. The objectives of this study were to investigate its relationship with other microstructural and functional alterations of the subcortical nuclei and the diagnostic utility of these MRI-related metrics. Methods: A total of 22 WD patients and 20 healthy controls (HCs) underwent 3.0T multimodal MRI scanning. Susceptibility, volume, diffusion microstructural indices and whole-brain functional connectivity of the putamen (PU), globus pallidus (GP), caudate nucleus (CN), and thalamus (TH) were analyzed. Receiver operating curve (ROC) was applied to evaluate the diagnostic value of the imaging data. Correlation analysis was performed to explore the connection between susceptibility change and microstructure and functional impairment of WD and screen for neuroimaging biomarkers of disease severity. Results: Wilson's disease patients demonstrated increased susceptibility in the PU, GP, and TH, and widespread atrophy and microstructural impairments in the PU, GP, CN, and TH. Functional connectivity decreased within the basal ganglia and increased between the PU and cortex. The ROC model showed higher diagnostic value of isotropic volume fraction (ISOVF, in the neurite orientation dispersion and density imaging model) compared with susceptibility. Severity of neurological symptoms was correlated with volume and ISOVF. Susceptibility was positively correlated with ISOVF in GP. Conclusion: Microstructural impairment of the basal ganglia is related to excessive metal accumulation in WD. Brain atrophy and microstructural impairments are useful neuroimaging biomarkers for the neurological impairment of WD.

CRISPR/Cas12a-mediated Enzymatic recombinase amplification for rapid visual quantitative authentication of halal food.

Economically motivated adulteration (EMA) has become a concern in food safety. We propose a CRISPR/Cas12a Mediated Enzymatic Recombinase Amplification detection system (CAMERA) that integrates Enzymatic Recombinase Amplification (ERA) and Cas12a cleavage to detect halal food adulteration. We designed and screened crRNA targeting CLEC, a porcine-specific nuclear single-copy gene, and optimized the reagent concentrations and incubation times for the ERA and Cas12a cleavage steps. CAMERA was highly specific for pork ingredients detection. The DNA concentration and fluorescence signal intensity relationship was linear at DNA concentrations of 20-0.032 ng/µL. CAMERA detected as few as two CLEC copies and quantified samples with porcine DNA content as low as 5% within 25 min. The system could be operated in a miniaturized working mode that requires no technical expertise or professional equipment, making CAMERA a valuable tool in resource-limited areas for the qualitative and quantitative detection of pork ingredients in halal food.

Alterations of structure and functional connectivity of visual brain network in patients with freezing of gait in Parkinson's disease.

Freezing of gait (FOG) is a disabling gait disorder common in advanced stage of Parkinson's disease (PD). The gait performance of PD-FOG patients is closely linked with visual processing. Here, we aimed to investigate the structural and functional change of visual network in PD-FOG patients. Seventy-eight PD patients (25 with FOG, 53 without FOG) and 29 healthy controls (HCs) were included. All the participants underwent structural 3D T1-weighted magnetic resonance imaging (MRI) and resting state functional MRI scan. Our results demonstrated a significant decrease of right superior occipital gyrus gray matter density in PD-FOG relative to non-FOG (NFOG) patients and healthy controls (PD-FOG vs. PD-NFOG: 0.33 ± 0.04 vs. 0.37 ± 0.05, p = 0.005; PD-FOG vs. HC: 0.37 ± 0.05 vs. 0.39 ± 0.06, p = 0.002). Functional MRI revealed a significant decrease of connectivity between right superior occipital gyrus and right paracentral lobule in PD-FOG compared to PD-NFOG (p = 0.045). In addition, the connectivity strength was positively correlated with gray matter density of right superior occipital gyrus (r = 0.471, p = 0.027) and negatively associated with freezing of gait questionnaire (FOGQ) score (r = -0.562, p = 0.004). Our study suggests that the structural and functional impairment of visual-motor network might underlie the neural mechanism of FOG in PD.

Altered Brain Activity in Depression of Parkinson's Disease: A Meta-Analysis and Validation Study.

Background: The pathophysiology of depression in Parkinson's disease (PD) is not fully understood. Studies based upon functional MRI (fMRI) showed the alterations in the blood-oxygen-level-dependent (BOLD) fluctuations in multiple brain regions pertaining to depression in PD. However, large variance was observed across previous studies. Therefore, we conducted a meta-analysis to quantitatively evaluate the results in previous publications and completed an independent regions-of-interests (ROIs)-based analysis using our own data to validate the results of the meta-analysis. Methods: We searched PubMed, Embase, and Web of Science to identify fMRI studies in PD patients with depression. Using signed differential mapping (SDM) method, we performed a voxel-based meta-analysis. Then, a validation study by using multiscale entropy (MSE) in 28 PD patients with depression and 25 PD patients without depression was conducted. The fMRI scan was completed in anti-depression-medication-off state. The ROIs of the MSE analysis were the regions identified by the meta-analysis. Results: A total of 126 PD patients with depression and 153 PD patients without depression were included in meta-analysis. It was observed that the resting-state activities within the posterior cingulate gyrus, supplementary motor area (SMA), and cerebellum were altered in depressed patients. Then, in the validation study, these regions were used as ROIs. PD patients with depression had significantly lower MSE of the BOLD fluctuations in these regions (posterior cingulate gyrus: F = 0.856, p = 0.049; SMA: F = 0.914, p = 0.039; cerebellum: F = 0.227, p = 0.043). Conclusion: Our study revealed that the altered BOLD activity in cingulate, SMA, and cerebellum of the brain were pertaining to depression in PD.

Risk factors for motor complications in female patients with Parkinson's disease.

OBJECTIVE: To investigate the risk factors of motor complications in female patients with Parkinson's disease (PD) and the correlation between the occurrence of motor complications and sex hormone levels. METHODS: According to the occurrence and types of motor complications, 103 female PD patients were divided into two groups: patients with or without the wearing-off phenomenon, patients with or without dyskinesia. Binary logistic regression analysis was performed respectively to screen for the risk factors of the wearing-off phenomenon and dyskinesia in female PD patients. RESULTS: Among 103 female PD patients, 44 (42.72%) had motor complications. Patients with the wearing-off phenomenon and patients with dyskinesia had higher prolactin levels than patients without the wearing-off phenomenon and patients without dyskinesia, respectively. However, the difference was no longer significant when the two groups were corrected for multiple comparisons (P < 0.0028). Multivariate analysis found that younger age at onset and higher Hoehn-Yahr (H&Y) stage were identified as independent risk factors for the wearing-off phenomenon and younger age of onset was an independent risk factor for dyskinesia in female PD patients (P < 0.05). CONCLUSION: Female PD patients have a higher incidence of motor complications. Younger age of onset and higher H&Y stage were the risk factors of the wearing-off phenomenon, and younger onset age was the risk factor of dyskinesia in female PD patients. There may be a certain correlation between the occurrence of motor complications and sex hormone levels in female PD patients, which requires further verification.

The altered multiscale dynamics of spontaneous brain activity in depression with Parkinson's disease.

BACKGROUND: Depression is one typical mood disorder in Parkinson's disease (DPD). The alterations in the resting-state brain activities are believed to be associated with DPD. These resting-state activities are regulated by neurophysiological components over multiple temporal scales. The multiscale dynamics of these spontaneous fluctuations are thus complex, but not well-characterized. OBJECTIVE: To characterize the complexity of the spontaneous blood-oxygen-level-dependent (BOLD) of fMRI in DPD. We hypothesized that (1) compared to non-depression PD (NDPD), the complexity in DPD would be lower; and (2) the diminished complexity would be associated with lower connections/communications between brain regions. METHODS: Twenty-nine participants (10 in DPD and 19 in NDPD) who were naïve to medications completed a resting-sate functional MRI scan. The BOLD complexity within each voxel was calculated by using multiscale entropy (MSE). The complexity of the whole brain and each of the 90 regions parcellated following automated-anatomical-labeling template was then obtained by averaging voxel-wised complexity across all brain regions or within each region. The level of connections of regions with diminished complexity was measured by their own global functional connectivity (FC). RESULTS: As compared to NDPD patients, the whole-brain complexity and complexity in 18 regions were significantly lower in DPD (F > 16.3, p < 0.0005). Particularly, in eight of the 18 regions, lower complexity was associated with lower global FC (Beta = 0.333 ~ 0.611, p = 0.000 ~ 0.030). CONCLUSION: The results from this pilot study suggest that the resting-state BOLD complexity may provide critical knowledge into the pathology of DPD. Future studies are thus warranted to confirm the findings of this study.

Effect of onset age on the levodopa threshold dosage for dyskinesia in Parkinson's disease.

INTRODUCTION: With the levodopa threshold effect for dyskinesia observed, threshold dosage of levodopa was identified in the general Parkinson's disease (PD) population. While early-onset PD (EOPD) and late-onset PD (LOPD) differ in the pathogenesis and clinical manifestations, threshold dosage of levodopa for individualized treatment remains unestablished. The objective of this study was to propose threshold dosage of levodopa in EOPD and LOPD patients, respectively. METHODS: Data on demographic and clinical and treatment measures were collected in 539 PD patients. Patients were divided into different onset groups using 50 as the cut-off age. We used univariable and multivariable analysis to screen for risk factors for dyskinesia. Receiver operating characteristic curve was used to determine the levodopa threshold dosages for dyskinesia. RESULTS: The prevalence of dyskinesia was 47.7% (53/111) in the EOPD group and 24.1% (103/428) in the LOPD group. Risk factors identified for dyskinesia include high levodopa daily dose and levodopa responsiveness for EOPD patients and high levodopa daily dose, long levodopa treatment duration, low body weight, use of entacapone, and high Hoehn-Yahr stage in off state for LOPD patients. The daily levodopa threshold dosages were 400 mg or 5.9 mg/kg for EOPD and 450 mg or 7.2 mg/kg for LOPD. CONCLUSION: EOPD patients had lower levodopa threshold dosage comparing with LOPD patients. Treatment of EOPD requires stricter levodopa dose control to delay the onset of dyskinesia.

Hyper- and hypo-connectivity in sensorimotor network of drug-naïve patients with cervical dystonia.

BACKGROUND: Cervical dystonia (CD) is the most common form of focal dystonia with involuntary movements and postures of the head. The pathogenesis and neural mechanisms underlying CD have not been fully elucidated. METHODS: Twenty-seven newly drug-naïve patients with CD and 21 healthy controls (HCs) were recruited with clinical assessment and resting-state functional magnetic resonance imaging (rs-fMRI) scanning. Severity of CD was measured by Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and Tsui scores. Whole-brain voxel-wise intrinsic connectivity (IC) and seed-based functional connectivity (FC) analyses were performed for detection of changes in the CD group relative to HCs, controlling for age, gender, and global time series correlation, followed by correlation analyses of IC, seed-based FC and clinically relevant features, respectively. RESULTS: In comparison with HCs, CD patients showed significantly increased IC measurement in the anterior part of the left supramarginal gyrus and extended to the inferior left postcentral gyrus (AL-SMG/IL-PCG). With this cluster as a seed, decreased FC was found in the right precentral and postcentral gyrus. Moreover, the regional IC value in the AL-SMG/IL-PCG was significantly positively correlated with TWSTRS-1 (severity) score, and significantly negatively correlated with the associated seed-based FC strength. CONCLUSIONS: Our results showed signs of both hyper- and hypo-connectivity in bilateral regions of the sensorimotor network related to CD. The imbalance of functional connectivity (both hyper- and hypo-) may hint both overloading and disrupted somatosensory or sensorimotor integration dysfunction within the sensorimotor network underlying the pathophysiology of CD, thus providing a network target for future therapies.

Quantitative Evaluation of Gastrocnemius Medialis Stiffness During Passive Stretching Using Shear Wave Elastography in Patients with Parkinson's Disease: A Prospective Preliminary Study.

OBJECTIVE: To prospectively investigate the feasibility of shear wave elastography (SWE) as a new quantitative and objective method for evaluating the stiffness of the gastrocnemius medialis (GM) muscle during passive stretching in patients with Parkinson's disease (PD). MATERIALS AND METHODS: SWE of the GM muscle was performed in 28 patients with PD [13 female and 15 male; mean age ± standard deviation (SD): 63.0 ± 8.5 years] and 12 healthy controls (5 female and 7 male; mean age ± SD: 59.3 ± 6.4 years) during passive ankle rotation. A Young's modulus-ankle angle curve was constructed. The GM slack angle and baseline Young's modulus (E0) were compared between the markedly symptomatic and mildly symptomatic sides of patients with PD, and healthy controls. Additionally, the correlation between the GM slack angle and the severity of rigidity, and the observer reproducibility of SWE in determining the GM slack angle were evaluated. RESULTS: The GM slack angle was smaller on both the markedly and mildly symptomatic sides in patients with PD than in healthy controls (mean ± SD of -29.13° ± 3.79° and -25.65° ± 3.39°, respectively, vs. -21.22° ± 3.52°; p < 0.001 and p = 0.006, respectively). Additionally, in patients with PD, the GM slack angle on the markedly symptomatic side was smaller than that on the mildly symptomatic side (p = 0.003). The E0 value was lower on both the markedly and mildly symptomatic sides in patients with PD than in healthy controls (mean ± SD of 10.11 ± 2.85 kPa and 10.08 ± 1.88 kPa, respectively, vs. 12.23 ± 1.02 kPa; p = 0.012 and p < 0.001, respectively). However, no significant difference was found between the markedly and mildly symptomatic sides in patients with PD (p = 0.634). A negative linear relationship was observed between the GM slack angle and lower limb rigidity score on the markedly symptomatic side in patients with PD (r = -0.719; p < 0.001). The intraclass correlation coefficients for observer reproducibility of SWE ranged from 0.880 to 0.951. CONCLUSION: The slack angle determined by SWE may be a useful quantitative and reproducible method for evaluating muscle stiffness in patients with PD.

Different effects of essential tremor and Parkinsonian tremor on multiscale dynamics of hand tremor.

OBJECTIVE: Essential tremor (ET) and Parkinsonian tremor (PT) are often clinically misdiagnosed due to the overlapping characteristics of their hand tremor. We aim to examine if ET and PT influence the multiscale dynamics of hand tremor, as quantified using complexity, differently, and if such complexity metric is of promise to help identify ET from PT. METHODS: Forty-eight participants with PT and 48 with ET performed two 30-second tests within each of the following conditions: sitting while resting arms or outstretching arms horizontally. The hand tremor was captured by accelerometers secured to the dorsum of each hand. The complexity was quantified using multiscale entropy. RESULTS: Compared to PT group, ET group had lower complexity of both hands across conditions (F > 34.2, p < 0.001). Lower complexity was associated with longer disease duration (r2 > 0.15, p < 0.009) in both PT and ET, and within PT, greater Unified Parkinson's Disease Rating Scale-III UPDRS-III scores (r2 > 0.18, p < 0.009). Receiver-operating-characteristic curves revealed that the complexity metric can distinguish ET from PT (area-under-the-curve > 0.77, cut-off value = 48 (postural), 49 (resting)), which was confirmed in a separate dataset with ET and PT that were clearly diagnosed in prior work. CONCLUSIONS: The PT and ET have different effects on hand tremor complexity, and this metric is promising to help the identification of ET and PT, which still needs to be confirmed in future studies. SIGNIFICANCE: The characteristics of multiscale dynamics of the hand tremor, as quantified by complexity, provides novel insights into the different pathophysiology between ET and PT.

Simple Smartphone-Based Assessment of Gait Characteristics in Parkinson Disease: Validation Study.

BACKGROUND: Parkinson disease (PD) is a common movement disorder. Patients with PD have multiple gait impairments that result in an increased risk of falls and diminished quality of life. Therefore, gait measurement is important for the management of PD. OBJECTIVE: We previously developed a smartphone-based dual-task gait assessment that was validated in healthy adults. The aim of this study was to test the validity of this gait assessment in people with PD, and to examine the association between app-derived gait metrics and the clinical and functional characteristics of PD. METHODS: Fifty-two participants with clinically diagnosed PD completed assessments of walking, Movement Disorder Society Unified Parkinson Disease Rating Scale III (UPDRS III), Montreal Cognitive Assessment (MoCA), Hamilton Anxiety (HAM-A), and Hamilton Depression (HAM-D) rating scale tests. Participants followed multimedia instructions provided by the app to complete two 20-meter trials each of walking normally (single task) and walking while performing a serial subtraction dual task (dual task). Gait data were simultaneously collected with the app and gold-standard wearable motion sensors. Stride times and stride time variability were derived from the acceleration and angular velocity signal acquired from the internal motion sensor of the phone and from the wearable sensor system. RESULTS: High correlations were observed between the stride time and stride time variability derived from the app and from the gold-standard system (r=0.98-0.99, P<.001), revealing excellent validity of the app-based gait assessment in PD. Compared with those from the single-task condition, the stride time (F1,103=14.1, P<.001) and stride time variability (F1,103=6.8, P=.008) in the dual-task condition were significantly greater. Participants who walked with greater stride time variability exhibited a greater UPDRS III total score (single task: ß=.39, P<.001; dual task: ß=.37, P=.01), HAM-A (single-task: ß=.49, P=.007; dual-task: ß=.48, P=.009), and HAM-D (single task: ß=.44, P=.01; dual task: ß=.49, P=.009). Moreover, those with greater dual-task stride time variability (ß=.48, P=.001) or dual-task cost of stride time variability (ß=.44, P=.004) exhibited lower MoCA scores. CONCLUSIONS: A smartphone-based gait assessment can be used to provide meaningful metrics of single- and dual-task gait that are associated with disease severity and functional outcomes in individuals with PD.

Cerebral small vessel disease may worsen motor function, cognition, and mood in Parkinson's disease.

INTRODUCTION: Emerging evidence has suggested that cerebral small vessel disease (CSVD) may worsen motor function and cognition in Parkinson's disease (PD). However, the effect of CSVD on anxiety and depression in patients with PD remains unknown. This study explored the multi-dimensional effects of CSVD on PD outcomes (motor, cognition, and depression/anxiety). METHODS: This cross-sectional study included 431 patients with PD from Beijing Tiantan Hospital from May 2016 to August 2019. CSVD imaging markers were assessed and the four-point CSVD burden score was calculated. Motor function (MDS-UPDRS III score and subscores), cognition (MMSE, MoCA), anxiety (HAMA), and depression (HAMD) were assessed in these patients. The associations of CSVD with these outcomes were analyzed using the Spearman's correlation and multivariable linear regression models. RESULTS: Motor dysfunction, cognitive impairment, depression, and anxiety were significantly worse in patients with severe CSVD than in those with mild CSVD. Multivariable linear regression showed that CSVD burden was significantly associated with motor dysfunction (MDS-UPDRS III score and rigidity and bradykinesia subscores), impaired cognition, and high levels of depression and anxiety. A marginally significant association was observed between CSVD burden and gait/postural instability in multivariable regression analysis. Among the CSVD imaging markers, white matter hyperintensity, number of lacunes, and microbleeds were positively correlated with the severity of motor, cognitive, and emotional impairments, while the perivascular space in the basal ganglia was only correlated with cognitive impairments. CONCLUSIONS: Comorbid CSVD may affect multiple functional domains in patients with PD. Management of cerebrovascular disease may improve PD outcomes.

The Complexity in Complete Graphic Characterizations of Multiagent Controllability.

Establishing the graph-based criterion for the selection of any location and any number of leaders is the main difficulty in the complete graphic characterization of multiagent controllability. This greatly increases the complexity of the study, compared with the results derived for only one or several classes of leaders. Through a detailed analysis of graphs of six nodes, this article presents a systematic design and identification process for the complete graphic characterization by taking advantage of controllability destructive nodes. The topologies obtained by the proposed method allow directly determining controllability at the network topology level. The results are not only applicable to any leader's selection but also reveal the difficulty and complexity in the study of complete controllability graphic characterizations. Moreover, by comparing graphs composed of five and six nodes, the results reveal the graph-theory-based controllability complexity caused by adding only one node. Finally, results are derived to show how to design topology structures to ensure the controllability under any selection of leaders.

Clinical Characteristics and Electrophysiological Biomarkers of Parkinson's Disease Developed From Essential Tremor.

Background and Objective: Parkinson's disease developed from essential tremor (ET-PD) is a distinct clinical syndrome that is different from essential tremor (ET) and Parkinson's disease (PD). There is currently a lack of research on ET-PD. Tremor characteristics (amplitude and frequency) are primary quantitative indexes for diagnosing and monitoring of tremors. In this study, we aimed to explore specific clinical and electrophysiological biomarkers for the identification of ET-PD. Methods: The study included patients with ET-PD (n = 22), ET (n = 42), and tremor-dominant PD (t-PD, n = 47). We collected demographic data, clinical characteristics (including motor and non-motor symptoms), and tremor analysis. The frequency, amplitude, contracting patterns of resting tremor and postural tremor were collected. The analysis of ET-PD and ET/t-PD was compared. The receiver operating characteristic (ROC) curve was used to analyze the electrophysiological features in distinguishing ET-PD from ET or t-PD. Results: Compared with ET, hyposmia, bradykinesia, rigidity, postural abnormality, and resting tremor were more common in the ET-PD group (P = 0.01, 0.003, 0.001, 0.001, 0.019, respectively). The postural tremor frequencies of the head, upper limbs, and lower limbs were significantly lower in the ET-PD than in the ET (P = 0.007, 0.003, 0.035, respectively), which were the most appropriate variables for distinguishing ET-PD from ET (AUC: 0.775, 0.727, and 0.701, respectively). Compared with t-PD, bradykinesia, rigidity, postural abnormality (both P < 0.001), and resting tremor (P = 0.024) were less common in the ET-PD. The postural tremor amplitudes of the head and upper limbs were significantly higher in the ET-PD than in the t-PD (P = 0.022, 0.001, respectively), which were the most appropriate variables for distinguishing ET-PD from t-PD (AUC: 0.793 and 0.716). Conclusions: Hyposmia and electrophysiological biomarkers (postural tremor frequencies and amplitudes) help early recognition of ET-PD.

The Characteristics of Tremor Motion Help Identify Parkinson's Disease and Multiple System Atrophy.

Background/Objectives: Distinguishing between Parkinson's disease (PD) and multiple system atrophy (MSA) is challenging in the clinic because patients with these two conditions present with similar symptoms in motor dysfunction. Here, we aimed to determine whether tremor characteristics can serve as novel markers for distinguishing the two conditions. Methods: Ninety-one subjects with clinically diagnosed PD and 93 subjects with MSA were included. Tremor of the limbs was measured in different conditions (such as resting, postural, and weight-holding) using electromyography (EMG) surface electrodes and accelerometers. The dominant frequency, tremor occurrence rate, and harmonic occurrence rate (HOR) of the tremor were then calculated. Results: Our results demonstrated that the tremor dominant frequency in the upper limbs of the MSA group was significantly higher than that in the PD group across all resting (F = 5.717, p = 0.023), postural (F = 13.409, p < 0.001), and weight-holding conditions (F = 9.491, p < 0.001) and that it was not dependent on the patient's age or disease course. The tremor occurrence rate (75.6 vs. 14.9%, χ2 = 68.487, p < 0.001) and HOR (75.0 vs. 4.5%, χ2 = 46.619, p < 0.001) in the resting condition were significantly lower in the MSA group than in the PD group. The sensitivity of the harmonic for PD diagnosis was 75.0% and the specificity was relatively high, in some cases up to 95.5%. The PPV and NPV were 95.2 and 75.9%, respectively. Conclusion: Our study confirmed that several tremor characteristics, including the dominant tremor frequency and the occurrence rate in different conditions, help detect PD and MSA. The presence of harmonics may serve as a novel marker to help distinguish PD from MSA with high sensitivity and specificity.

Differential functional dysconnectivity of caudate nucleus subdivisions in Parkinson's disease.

Caudate dopaminergic dysfunction is implied in the pathophysiology of patients with Parkinson's disease (PD). Still, connectivity specificities of the caudate nucleus (CN) subdivisions and the effect of dopamine are poorly understood. We collected MRI and neuropsychological data from 34 PD patients and 26 age- and sex-matched healthy elderly individuals (HEs) in this study. Resting-state functional connectivity analysis revealed that compared to the other CN subdivisions, the CN head was more strongly connected to the default mode network (DMN), the CN body to the frontoparietal network (FPN), and the CN tail to the visual network in HEs. PD patients off medication showed reduced connectivity within all these subdivision networks. In PD patients on medication, functional connectivity in the CN head network was significantly improved in the medial prefrontal cortex and in the body network it was improved in the dorsolateral prefrontal cortex. These improvements contributed to ameliorated motivation and cognitive function in PD patients. Our results highlighted the specific alterations and dopamine modulation in these CN subdivision networks in PD, which may provide insight into the pathophysiology and therapeutics of this disease.

Effect of small vessel disease burden and lacunes on gait/posture impairment in Parkinson's disease.

INTRODUCTION: The comorbidity of cerebral small vessel disease (CSVD) may worsen gait impairment of Parkinson's disease (PD). However, the evidence remains scarce and controversial, and the mechanism of their potential interaction remains largely unknown. The present study aimed to investigate the overall impact of quantity and location of CSVD on gait/posture function in PD. METHODS: This cross-sectional study included 315 consecutive eligible patients with PD from Beijing Tiantan Hospital from May 2016 to August 2018. Associations of gait/posture subscores with the burden score of CSVD and four CSVD imaging markers were assessed using multivariate linear regression models. RESULTS: Burden of CSVD was significantly associated with more severe gait/posture impairment in PD in the unadjusted model (ß = 0.521, P = 0.011, 95% CI 0.118-0.923) and in the model adjusted for age, hypertension, ischemic stroke, low-density lipoprotein level, cholesterol level, and cognitive statues (ß = 0.448, P = 0.047, 95% CI 0.006-0.891). The presence of lacunes, but not other CSVD markers, was significantly associated with higher gait/posture subscores after the adjustment (ß = 0.492, P = 0.041, 95% CI 0.021-0.964), and the number of lacunes in the basal ganglia significantly correlated with the gait/posture subscores in patients with PD (P = 0.012, Spearman r = 0.161). CONCLUSIONS: CSVD and lacunes in the basal ganglia may independently contribute to gait/posture dysfunction in PD. Promoting neurovascular health may preserve some gait/posture function of PD.