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.

Temporal trends in the prevalence of Parkinson's disease from 1980 to 2023: a systematic review and meta-analysis.

BACKGROUND: Parkinson's disease is the second most common neurodegenerative disorder, exhibiting an upward trend in prevalence. We aimed to investigate the prevalence of Parkinson's disease, temporal trends between 1980 and 2023, and variations in prevalence by location, age, sex, survey period, sociodemographic index (SDI), human development index (HDI), and study characteristics (sample size, diagnostic criteria, and data source). METHODS: In this systematic review and meta-analysis we searched PubMed, Cochrane, Web of Science, Embase, Scopus, and Global Health for observational studies that reported Parkinson's disease prevalence in the general population from database inception to Nov 1, 2023. We included studies if they were original observational investigations, had participants from the general population or community-based datasets, and provided numerical data on the prevalence of Parkinson's disease either with 95% CIs or with sufficient information to calculate 95% CIs. Studies were excluded if they were conducted in a specific population, had a sample size smaller than 1000, or were review articles, case reports, protocols, meeting abstracts, letters, comments, short communications, posters, and reports. The publication characteristics (first author and publication year), study location (countries, WHO regions, SDI, and HDI), survey period, study design, diagnostic criteria, data source, participant information, and prevalence data were extracted from articles using a standard form. Two authors independently evaluated eligibility, and discrepancies were resolved through discussion with the third author. We used random effect models to pool estimates with 95% CIs. Estimated annual percentage change (EAPC) was calculated to assess the temporal trend in prevalence of Parkinson's disease. The study was registered with PROSPERO, CRD42022364417. FINDINGS: 83 studies from 37 countries were eligible for analysis, with 56 studies providing all-age prevalence, 53 studies reporting age-specific prevalence, and 26 studies providing both all-age and age-specific prevalence. Global pooled prevalence of Parkinson's disease was 1·51 cases per 1000 (95% CI 1·19-1·88), which was higher in males (1·54 cases per 1000 [1·17-1·96]) than in females (1·49 cases per 1000 [1·12-1·92], p=0·030). During different survey periods, the prevalence of Parkinson's disease was 0·90 cases per 1000 (0·48-1·44; 1980-89), 1·38 cases per 1000 (1·17-1·61; 1990-99), 1·18 cases per 1000 (0·77-1·67; 2000-09), and 3·81 cases per 1000 (2·67-5·14; 2010-23). The EAPC of Parkinson's disease prevalence was significantly higher in the period of 2004-23 (EAPC 16·32% [95% CI 6·07-26·58], p=0·0040) than in the period of 1980-2003 (5·30% [0·82-9·79], p=0·022). Statistically significant disparities in prevalence were observed across six WHO regions. Prevalence increased with HDI or SDI. Considerable variations were observed in the pooled prevalence of Parkinson's disease based on different sample sizes or diagnostic criteria. Prevalence also increased with age, reaching 9·34 cases per 1000 (7·26-11·67) among individuals older than 60 years. INTERPRETATION: The global prevalence of Parkinson's disease has been increasing since the 1980s, with a more pronounced rise in the past two decades. The prevalence of Parkinson's disease is higher in countries with higher HDI or SDI. It is necessary to conduct more high-quality epidemiological studies on Parkinson's disease, especially in low SDI countries. FUNDING: National Nature Science Foundation of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Iron deposition in subcortical nuclei of Parkinson's disease: A meta-analysis of quantitative iron-sensitive magnetic resonance imaging studies.

BACKGROUND: Iron deposition plays a crucial role in the pathophysiology of Parkinson's disease (PD), yet the distribution pattern of iron deposition in the subcortical nuclei has been inconsistent across previous studies. We aimed to assess the difference patterns of iron deposition detected by quantitative iron-sensitive magnetic resonance imaging (MRI) between patients with PD and patients with atypical parkinsonian syndromes (APSs), and between patients with PD and healthy controls (HCs). METHODS: A systematic literature search was conducted on PubMed, Embase, and Web of Science databases to identify studies investigating the iron content in PD patients using the iron-sensitive MRI techniques (R2* and quantitative susceptibility mapping [QSM]), up until May 1, 2023. The quality assessment of case-control and cohort studies was performed using the Newcastle-Ottawa Scale, whereas diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies-2. Standardized mean differences and summary estimates of sensitivity, specificity, and area under the curve (AUC) were calculated for iron content, using a random effects model. We also conducted the subgroup-analysis based on the MRI sequence and meta-regression. RESULTS: Seventy-seven studies with 3192 PD, 209 multiple system atrophy (MSA), 174 progressive supranuclear palsy (PSP), and 2447 HCs were included. Elevated iron content in substantia nigra (SN) pars reticulata (P <0.001) and compacta (P <0.001), SN (P <0.001), red nucleus (RN, P <0.001), globus pallidus (P <0.001), putamen (PUT, P = 0.009), and thalamus (P = 0.046) were found in PD patients compared with HCs. PD patients showed lower iron content in PUT (P <0.001), RN (P = 0.003), SN (P = 0.017), and caudate nucleus (P = 0.027) than MSA patients, and lower iron content in RN (P = 0.001), PUT (P <0.001), globus pallidus (P = 0.004), SN (P = 0.015), and caudate nucleus (P = 0.001) than PSP patients. The highest diagnostic accuracy distinguishing PD from HCs was observed in SN (AUC: 0.85), and that distinguishing PD from MSA was found in PUT (AUC: 0.90). In addition, the best diagnostic performance was achieved in the RN for distinguishing PD from PSP (AUC: 0.84). CONCLUSION: Quantitative iron-sensitive MRI could quantitatively detect the iron content of subcortical nuclei in PD and APSs, while it may be insufficient to accurately diagnose PD. Future studies are needed to explore the role of multimodal MRI in the diagnosis of PD. REGISTRISION: PROSPERO; CRD42022344413.

Dopaminergic versus anticholinergic treatment effects on physiologic complexity of hand tremor in Parkinson's disease: A randomized crossover study.

AIMS: Parkinsonian tremor (PT) is regulated by numerous neurophysiological components across multiple temporospatial scales. The dynamics of tremor fluctuation are thus highly complex. This study aimed to explore the effects of different medications on tremor complexity, and how the underlying factors contribute to such tremor complexity. METHODS: In this study, 66 participants received a 2-mg dose of benzhexol or a pre-determined dose of levodopa at two study visits in a randomized order. Before and after taking the medications, tremor fluctuation was recorded using surface electromyography electrodes and accelerometers in resting, posture, and weighting conditions with and without a concurrent cognitive task. Tremor complexity was quantified using multiscale entropy. RESULTS: Tremor complexity in resting (p = 0.002) and postural condition (p < 0.0001) was lower when participants were performing a cognitive task compared to a task-free condition. After taking levodopa and benzhexol, participants had increased (p = 0.02-0.03) and decreased (p = 0.03) tremor complexity compared to pre-medication state, respectively. Tremor complexity and its changes as induced by medications were significantly correlated with clinical ratings and their changes (ß = -0.23 to -0.39; p = 0.002-0.04), respectively. CONCLUSION: Tremor complexity may be a promising marker to capture the pathophysiology underlying the development of PT, aiding the characterization of the effects medications have on PT regulation.

Microstructural and functional alterations of the ventral pallidum are associated with levodopa-induced dyskinesia in Parkinson's disease.

BACKGROUND AND PURPOSE: The ventral pallidum (VP) regulates involuntary movements, but it is unclear whether the VP regulates the abnormal involuntary movements in Parkinson's disease (PD) patients who have levodopa-induced dyskinesia (LID). To further understand the role of the VP in PD patients with LID (PD-LID), we explored the structural and functional characteristics of the VP in such patients using multimodal magnetic resonance imaging (MRI). METHODS: Thirty-one PD-LID patients, 39 PD patients without LID (PD-nLID), and 28 healthy controls (HCs) underwent T1-weighted MRI, quantitative susceptibility mapping, multi-shell diffusion MRI, and resting-state functional MRI (rs-fMRI). Different measures characterizing the VP were obtained using a region-of-interest-based approach. RESULTS: The left VP in the PD-LID group showed significantly higher intracellular volume fraction (ICVF) and isotropic volume fraction (IsoVF) compared with the PD-nLID and HC groups. Rs-MRI revealed that, compared with the PD-nLID group, the PD-LID group in the medication 'off' state had higher functional connectivity (FC) between the left VP and the left anterior caudate, left middle frontal gyrus and left precentral gyrus, as well as between the right VP and the right posterior ventral putamen and right mediodorsal thalamus. In addition, the ICVF values of the left VP, the FC between the left VP and the left anterior caudate and left middle frontal gyrus were positively correlated with Unified Dyskinesia Rating Scale scores. CONCLUSION: Our multimodal imaging findings show that the microstructural changes of the VP (i.e., the higher ICVF and IsoVF) and the functional change in the ventral striatum-VP-mediodorsal thalamus-cortex network may be associated with pathophysiological mechanisms of PD-LID.

Novel voxelwise residual analysis of [11C]raclopride PET data improves detection of low-amplitude dopamine release.

Existing methods for voxelwise transient dopamine (DA) release detection rely on explicit kinetic modeling of the [11C]raclopride PET time activity curve, which at the voxel level is typically confounded by noise, leading to poor performance for detection of low-amplitude DA release-induced signals. Here we present a novel data-driven, task-informed method-referred to as Residual Space Detection (RSD)-that transforms PET time activity curves to a residual space where DA release-induced perturbations can be isolated and processed. Using simulations, we demonstrate that this method significantly increases detection performance compared to existing kinetic model-based methods for low-magnitude DA release (simulated +100% peak increase in basal DA concentration). In addition, results from nine healthy controls injected with a single bolus of [11C]raclopride performing a finger tapping motor task are shown as proof-of-concept. The ability to detect relatively low magnitudes of dopamine release in the human brain using a single bolus injection, while achieving higher statistical power than previous methods, may additionally enable more complex analyses of neurotransmitter systems. Moreover, RSD is readily generalizable to multiple tasks performed during a single PET scan, further extending the capabilities of task-based single-bolus protocols.

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.

Tau-PET imaging in Parkinson's disease: a systematic review and meta-analysis.

Background: Pathological tau accumulates in the cerebral cortex of Parkinson's disease (PD), resulting in cognitive deterioration. Positron emission tomography (PET) can be used for in vivo imaging of tau protein. Therefore, we conducted a systematic review and meta-analysis of tau protein burden in PD cognitive impairment (PDCI), PD dementia (PDD), and other neurodegenerative diseases and explored the potential of the tau PET tracer as a biomarker for the diagnosis of PDCI. Methods: PubMed, Embase, the Cochrane Library, and Web of Science databases were systematically searched for studies published till 1 June 2022 that used PET imaging to detect tau burden in the brains of PD patients. Standardized mean differences (SMDs) of tau tracer uptake were calculated using random effects models. Subgroup analysis based on the type of tau tracers, meta-regression, and sensitivity analysis was conducted. Results: A total of 15 eligible studies were included in the meta-analysis. PDCI patients (n = 109) had a significantly higher tau tracer uptake in the inferior temporal lobe than healthy controls (HCs) (n = 237) and had a higher tau tracer uptake in the entorhinal region than PD with normal cognition (PDNC) patients (n = 61). Compared with progressive supranuclear palsy (PSP) patients (n = 215), PD patients (n = 178) had decreased tau tracer uptake in the midbrain, subthalamic nucleus, globus pallidus, cerebellar deep white matter, thalamus, striatum, substantia nigra, dentate nucleus, red nucleus, putamen, and frontal lobe. Tau tracer uptake values of PD patients (n = 178) were lower than those of patients with Alzheimer's disease (AD) (n = 122) in the frontal lobe and occipital lobe and lower than those in patients with dementia with Lewy bodies (DLB) (n = 55) in the occipital lobe and infratemporal lobe. Conclusion: In vivo imaging studies with PET could reveal region-specific binding patterns of the tau tracer in PD patients and help in the differential diagnosis of PD from other neurodegenerative diseases. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/.

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.

Multimodal Imaging of Substantia Nigra in Parkinson's Disease with Levodopa-Induced Dyskinesia.

BACKGROUND: Degeneration of the substantia nigra (SN) may contribute to levodopa-induced dyskinesia (LID) in Parkinson's disease (PD), but the exact characteristics of SN in LID remain unclear. OBJECTIVE: To further understand the pathogenesis of patients with PD with LID (PD-LID), we explored the structural and functional characteristics of SN in PD-LID using multimodal magnetic resonance imaging (MRI). METHODS: Twenty-nine patients with PD-LID, 37 patients with PD without LID (PD-nLID), and 28 healthy control subjects underwent T1-weighted MRI, quantitative susceptibility mapping, neuromelanin-sensitive MRI, multishell diffusion MRI, and resting-state functional MRI. Different measures characterizing the SN were obtained using a region of interest-based approach. RESULTS: Compared with patients with PD-nLID and healthy control subjects, the quantitative susceptibility mapping values of SN pars compacta (SNpc) were significantly higher (P = 0.049 and P = 0.00002), and the neuromelanin contrast-to-noise ratio values in SNpc were significantly lower (P = 0.012 and P = 0.000002) in PD-LID. The intracellular volume fraction of the posterior SN in PD-LID was significantly higher compared with PD-nLID (P = 0.037). Resting-state fMRI indicated that PD-LID in the medication off state showed higher functional connectivity between the SNpc and putamen compared with PD-nLID (P = 0.031), and the functional connectivity changes in PD-LID were positively correlated with Unified Dyskinesia Rating Scale total scores (R = 0.427, P = 0.042). CONCLUSIONS: Our multimodal imaging findings highlight greater neurodegeneration in SN and the altered nigrostriatal connectivity in PD-LID. These characteristics provide a new perspective into the role of SN in the pathophysiological mechanisms underlying PD-LID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Tau PET imaging in progressive supranuclear palsy: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the difference of tau burden between patients with progressive supranuclear palsy (PSP) and healthy controls (HCs) or other neurodegenerative diseases using tau-positron emission tomography (PET) imaging. METHODS: A systematic search on PubMed, Embase, and Web of Science databases was performed for tau-PET studies in PSP patients, up to April 1, 2022. Standardized mean differences (SMDs) of tau tracer uptake were calculated using random-effects models. Subgroup analysis based on the type of tau tracers, meta-regression, and sensitivity analysis were conducted. RESULTS: Twenty-seven studies comprising 553 PSP, 626 HCs, and 406 other neurodegenerative diseases were included. Compared with HCs, PSP patients showed elevated tau binding in basal ganglia, midbrain, dentate nucleus, cerebellar white matter, and frontal lobe with decreasing SMD (SMD: 0.390-1.698). Compared with Parkinson's disease patients, increased tau binding was identified in the midbrain, basal ganglia, dentate nucleus, and frontal and parietal lobe in PSP patients with decreasing SMD (SMD: 0.503-1.853). PSP patients showed higher tau binding in the subthalamic nucleus (SMD = 1.351) and globus pallidus (SMD = 1.000), and lower binding in the cortex and parahippocampal gyrus than Alzheimer's disease patients (SMD: - 2.976 to - 1.018). PSP patients showed higher midbrain tau binding than multiple system atrophy patients (SMD = 1.269). CONCLUSION: Tau PET imaging indicates different topography of tau deposition between PSP patients and HCs or other neurodegenerative disorders. The affinity and selectivity of tracers for 4R-tau and the off-target binding of tracers should be considered when interpreting the results.

Comparative efficacy and safety of monoamine oxidase type B inhibitors plus channel blockers and monoamine oxidase type B inhibitors as adjuvant therapy to levodopa in the treatment of Parkinson's disease: a network meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: The monoamine oxidase type B inhibitors plus channel blockers (MAO-BIs plus) are a new class of antiparkinsonian drug with additional mechanisms of action for their property as ion channel blockers. The present study aimed to compare the efficacy and safety of MAO-BIs plus and conventional MAO-BIs, as well as their corresponding doses, as adjuvant therapy to levodopa in the treatment of Parkinson's disease (PD). METHOD: Randomized controlled trials enrolling PD patients treated with selegiline, rasagiline, safinamide or zonisamide as adjuvant therapy to levodopa were identified. Bayesian network meta-analysis was conducted. RESULTS: Thirty-one randomized controlled trials comprising 7142 PD patients were included. Compared with levodopa monotherapy, the combination therapy of MAO-BIs and levodopa was significantly more effective, with a mean difference of 2.74 (1.26-4.18) on the Unified Parkinson's Disease Rating Scale (UPDRS) III score change for selegiline, 2.67 (1.45-3.87) for safinamide, 2.2 (0.98-3.64) for zonisamide and 2.04 (1.24-2.87) for rasagiline. No significant difference was detected amongst MAO-BIs. The surface under the cumulative ranking results showed that safinamide 100 mg and rasagiline 1 mg ranked first in improving UPDRS III and UPDRS II, respectively. Zonisamide 100 mg ranked first in reducing OFF time. For safety outcomes, rasagiline was associated with a higher incidence of adverse events than placebo and safinamide. MAO-BIs plus had a higher probability of being safer agents compared to conventional MAO-BIs. CONCLUSIONS: Monoamine oxidase type B inhibitors plus, conventional MAO-BIs and the corresponding doses are similar in efficacy in PD treatment. MAO-BIs plus might be safer than conventional MAO-BIs. Head-to-head comparisons are needed for further investigation.

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.

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.

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.

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.

Risk thresholds of levodopa dose for dyskinesia in Chinese patients with Parkinson's disease: a pilot study.

Levodopa is widely used to treat Parkinson's disease (PD), and its long-term therapy may induce dyskinesia in a dose-dependent manner. However, the threshold dose with a relatively low risk for dyskinesia has not been determined. Demographic, clinical profiles and detailed information of dopaminergic drugs were recorded for 403 PD patients in treatment with levodopa. Variables were compared between dyskinesia and non-dyskinesia groups. Logistic regression analysis was used to assess the association between levodopa dose-related variables and dyskinesia. Receiver operating characteristic curve and decision tree classification model were used to investigate the cut-off value of levodopa dose to best separate the dyskinesia group from the non-dyskinesia group. Patients with dyskinesia tended to have a lower weight and age at onset, higher percentage of female and wearing-off, longer duration of disease and levodopa treatment, higher H-Y stage and MDS-UPDRS Part III score, and higher levodopa dose and levodopa equivalent dose than those without dyskinesia. After adjusted for demographical and clinical variables, levodopa dose-related factors (daily dose, cumulative dose, and weight-adjusted dose) were still associated with dyskinesia. Both the receiver operating characteristic and decision tree classification analysis indicated that patients who have taken levodopa dose ≤ 400 mg per day may be associated with a reduced risk for dyskinesia. In conclusion, we evaluated the thresholds of levodopa treatment with a relatively low risk for dyskinesia. These data should be considered for prevention and management of dyskinesia in patients with PD.