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

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

A novel compound alleviates oxidative stress via PKA/CREB1-mediated DJ-1 upregulation.

Oxidative stress is one of the major culprits causing dopaminergic neuron loss in Parkinson's disease (PD). DJ-1 is a protein with multiple actions against oxidative stress, apoptosis, neuroinflammation, etc. DJ-1 expression is decreased in sporadic PD, therefore increasing DJ-1 expression might be beneficial in PD treatment. However, drugs known to upregulate DJ-1 are still lacking. In this study, we identified a novel DJ-1-elevating compound called ChemJ through luciferase assay-based high-throughput compound screening in SH-SY5Y cells and confirmed that ChemJ upregulated DJ-1 in SH-SY5Y cell line and primary cortical neurons. DJ-1 upregulation by ChemJ alleviated MPP+-induced oxidative stress. In exploring the underlying mechanisms, we found that the transcription factor CREB1 bound to DJ-1 promoter and positively regulated its expression under both unstressed and 1-methyl-4-phenylpyridinium-induced oxidative stress conditions and that ChemJ promoted DJ-1 expression via activating PKA/CREB1 pathway in SH-SY5Y cells. Our results demonstrated that ChemJ alleviated the MPP+-induced oxidative stress through a PKA/CREB1-mediated regulation of DJ-1 expression, thus offering a novel and promising avenue for PD treatment.

Effect of long-term Tai Chi training on Parkinson's disease: a 3.5-year follow-up cohort study.

BACKGROUND: Tai Chi has shown beneficial effects on the motor and non-motor symptoms of Parkinson's disease (PD), but no study has reported the effect of long-term Tai Chi training. OBJECTIVE: To examine whether long-term Tai Chi training can maintain improvement in patients with PD. METHODS: Cohorts of patients with PD with Tai Chi training (n=143) and patients with PD without exercise as a control group (n=187) were built from January 2016. All subjects were assessed at baseline and in November 2019, October 2020 and June 2021. A logarithmic linear model was used to analyse rating scales for motor and non-motor symptoms. The need to increase antiparkinsonian therapies was presented as a Kaplan-Meier plot and as a box plot. The bootstrap method was used to resample for statistical estimation. RESULTS: Tai Chi training reduced the annual changes in the deterioration of the Unified Parkinson's Disease Rating Scale and delayed the need for increasing antiparkinsonian therapies. The annual increase in the levodopa equivalent daily dosage was significantly lower in the Tai Chi group. Moreover, patients benefited from Tai Chi training in motor symptoms, non-motor symptoms and complications. CONCLUSION: Tai Chi training has a long-term beneficial effect on PD, with an improvement in motor and non-motor symptoms and reduced complications. TRIAL REGISTRATION NUMBER: NCT05447975.

Idiopathic Rapid Eye Movement Sleep Behavior Disorder (iRBD) Shares Similar Fecal Short-Chain Fatty Acid Alterations with Multiple System Atrophy (MSA) and Parkinson's Disease (PD).

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is considered as a prodromal stage of synucleinopathies. Fecal short-chain fatty acid (SCFA) changes in iRBD and the relationships with synucleinopathies have never been investigated. OBJECTIVES: To investigate fecal SCFA changes among iRBD, multiple system atrophy (MSA), and Parkinson's disease (PD), and evaluate their relationships. METHODS: Fecal SCFAs and gut microbiota were measured in 29 iRBD, 42 MSA, 40 PD, and 35 normal controls (NC) using gas chromatography-mass spectrometry and 16S rRNA gene sequencing. RESULTS: Compared with NC, fecal SCFA levels (propionic, acetic, and butyric acid) were lower in iRBD, MSA, and PD. Combinations of these SCFAs could differentiate NC from iRBD (AUC 0.809), MSA (AUC 0.794), and PD (AUC 0.701). Decreased fecal SCFAs were associated with the common reducing SCFA-producing gut microbiota in iRBD, MSA, and PD. CONCLUSIONS: iRBD shares similar fecal SCFA alterations with MSA and PD, and the combination of these SCFAs might be a potential synucleinopathies-related biomarker. © 2024 International Parkinson and Movement Disorder Society.

Enhancing Nigrosome-1 Sign Identification via Interpretable AI using True Susceptibility Weighted Imaging.

BACKGROUND: Nigrosome 1 (N1), the largest nigrosome region in the ventrolateral area of the substantia nigra pars compacta, is identifiable by the "N1 sign" in long echo time gradient echo MRI. The N1 sign's absence is a vital Parkinson's disease (PD) diagnostic marker. However, it is challenging to visualize and assess the N1 sign in clinical practice. PURPOSE: To automatically detect the presence or absence of the N1 sign from true susceptibility weighted imaging by using deep-learning method. STUDY TYPE: Prospective. POPULATION/SUBJECTS: 453 subjects, including 225 PD patients, 120 healthy controls (HCs), and 108 patients with other movement disorders, were prospectively recruited including 227 males and 226 females. They were divided into training, validation, and test cohorts of 289, 73, and 91 cases, respectively. FIELD STRENGTH/SEQUENCE: 3D gradient echo SWI sequence at 3T; 3D multiecho strategically acquired gradient echo imaging at 3T; NM-sensitive 3D gradient echo sequence with MTC pulse at 3T. ASSESSMENT: A neuroradiologist with 5 years of experience manually delineated substantia nigra regions. Two raters with 2 and 36 years of experience assessed the N1 sign on true susceptibility weighted imaging (tSWI), QSM with high-pass filter, and magnitude data combined with MTC data. We proposed NINet, a neural model, for automatic N1 sign identification in tSWI images. STATISTICAL TESTS: We compared the performance of NINet to the subjective reference standard using Receiver Operating Characteristic analyses, and a decision curve analysis assessed identification accuracy. RESULTS: NINet achieved an area under the curve (AUC) of 0.87 (CI: 0.76-0.89) in N1 sign identification, surpassing other models and neuroradiologists. NINet localized the putative N1 sign within tSWI images with 67.3% accuracy. DATA CONCLUSION: Our proposed NINet model's capability to determine the presence or absence of the N1 sign, along with its localization, holds promise for enhancing diagnostic accuracy when evaluating PD using MR images. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Diagnosing Parkinson's disease by combining neuromelanin and iron imaging features using an automated midbrain template approach.

BACKGROUND AND PURPOSE: Early diagnosis of Parkinson's disease (PD) is still a clinical challenge. Most previous studies using manual or semi-automated methods for segmenting the substantia nigra (SN) are time-consuming and, despite raters being well-trained, individual variation can be significant. In this study, we used a template-based, automatic, SN subregion segmentation pipeline to detect the neuromelanin (NM) and iron features in the SN and SN pars compacta (SNpc) derived from a single 3D magnetization transfer contrast (MTC) gradient echo (GRE) sequence in an attempt to develop a comprehensive imaging biomarker that could be used to diagnose PD. MATERIALS AND METHODS: A total of 100 PD patients and 100 age- and sex-matched healthy controls (HCs) were imaged on a 3T scanner. NM-based SN (SNNM) boundaries and iron-based SN (SNQSM) boundaries and their overlap region (representing the SNpc) were delineated automatically using a template-based SN subregion segmentation approach based on quantitative susceptibility mapping (QSM) and NM images derived from the same MTC-GRE sequence. All PD and HC subjects were evaluated for the nigrosome-1 (N1) sign by two raters independently. Receiver Operating Characteristic (ROC) analyses were performed to evaluate the utility of SNNM volume, SNQSM volume, SNpc volume and iron content with a variety of thresholds as well as the N1 sign in diagnosing PD. Correlation analyses were performed to study the relationship between these imaging measures and the clinical scales in PD. RESULTS: In this study, we verified the value of the fully automatic template based midbrain deep gray matter mapping approach in differentiating PD patients from HCs. The automatic segmentation of the SN in PD patients led to satisfactory DICE similarity coefficients and volume ratio (VR) values of 0.81 and 1.17 for the SNNM, and 0.87 and 1.05 for the SNQSM, respectively. For the HC group, the average DICE similarity coefficients and VR values were 0.85 and 0.94 for the SNNM, and 0.87 and 0.96 for the SNQSM, respectively. The SNQSM volume tended to decrease with age for both the PD and HC groups but was more severe for the PD group. For diagnosing PD, the N1 sign performed reasonably well by itself (Area Under the Curve (AUC) = 0.783). However, combining the N1 sign with the other quantitative measures (SNNM volume, SNQSM volume, SNpc volume and iron content) resulted in an improved diagnosis of PD with an AUC as high as 0.947 (using an SN threshold of 50ppb and an NM threshold of 0.15). Finally, the SNQSM volume showed a negative correlation with the MDS-UPDRS III (R2 = 0.1, p = 0.036) and the Hoehn and Yahr scale (R2 = 0.04, p = 0.013) in PD patients. CONCLUSION: In summary, this fully automatic template based deep gray matter mapping approach performs well in the segmentation of the SN and its subregions for not only HCs but also PD patients with SN degeneration. The combination of the N1 sign with other quantitative measures (SNNM volume, SNQSM volume, SNpc volume and iron content) resulted in an AUC of 0.947 and provided a comprehensive set of imaging biomarkers that, potentially, could be used to diagnose PD clinically.

Visualizing the deep cerebellar nuclei using quantitative susceptibility mapping: An application in healthy controls, Parkinson's disease patients and essential tremor patients.

The visualization and identification of the deep cerebellar nuclei (DCN) (dentate [DN], interposed [IN] and fastigial nuclei [FN]) are particularly challenging. We aimed to visualize the DCN using quantitative susceptibility mapping (QSM), predict the contrast differences between QSM and T2* weighted imaging, and compare the DCN volume and susceptibility in movement disorder populations and healthy controls (HCs). Seventy-one Parkinson's disease (PD) patients, 39 essential tremor patients, and 80 HCs were enrolled. The PD patients were subdivided into tremor dominant (TD) and postural instability/gait difficulty (PIGD) groups. A 3D strategically acquired gradient echo MR imaging protocol was used for each subject to obtain the QSM data. Regions of interest were drawn manually on the QSM data to calculate the volume and susceptibility. Correlation analysis between the susceptibility and either age or volume was performed and the intergroup differences of the volume and magnetic susceptibility in all the DCN structures were evaluated. For the most part, all the DCN structures were clearly visualized on the QSM data. The susceptibility increased as a function of volume for both the HC group and disease groups in the DN and IN (p < .001) but not the FN (p = .74). Only the volume of the FN in the TD-PD group was higher than that in the HCs (p = .012), otherwise, the volume and susceptibility among these four groups did not differ significantly. In conclusion, QSM provides clear visualization of the DCN structures. The results for the volume and susceptibility of the DCN can be used as baseline references in future studies of movement disorders.

An automatic interpretable deep learning pipeline for accurate Parkinson's disease diagnosis using quantitative susceptibility mapping and T1-weighted images.

Parkinson's disease (PD) diagnosis based on magnetic resonance imaging (MRI) is still challenging clinically. Quantitative susceptibility maps (QSM) can potentially provide underlying pathophysiological information by detecting the iron distribution in deep gray matter (DGM) nuclei. We hypothesized that deep learning (DL) could be used to automatically segment all DGM nuclei and use relevant features for a better differentiation between PD and healthy controls (HC). In this study, we proposed a DL-based pipeline for automatic PD diagnosis based on QSM and T1-weighted (T1W) images. This consists of (1) a convolutional neural network model integrated with multiple attention mechanisms which simultaneously segments caudate nucleus, globus pallidus, putamen, red nucleus, and substantia nigra from QSM and T1W images, and (2) an SE-ResNeXt50 model with an anatomical attention mechanism, which uses QSM data and the segmented nuclei to distinguish PD from HC. The mean dice values for segmentation of the five DGM nuclei are all >0.83 in the internal testing cohort, suggesting that the model could segment brain nuclei accurately. The proposed PD diagnosis model achieved area under the the receiver operating characteristic curve (AUCs) of 0.901 and 0.845 on independent internal and external testing cohorts, respectively. Gradient-weighted class activation mapping (Grad-CAM) heatmaps were used to identify contributing nuclei for PD diagnosis on patient level. In conclusion, the proposed approach can potentially be used as an automatic, explainable pipeline for PD diagnosis in a clinical setting.

Iron accumulation and axonal damage of cerebellum in idiopathic cervical dystonia.

BACKGROUND AND PURPOSE: Postmortem brain study indicated that cerebellar Purkinje cell (PC) loss might be a pathological finding in patients with inherited and idiopathic cervical dystonia (ICD). The analysis of conventional magnetic resonance imaging brain scans failed to yield support for this finding. Previous studies have identified that iron overload can be the consequence of neuron death. The objectives of this study were to investigate iron distribution and demonstrate changes in axons in the cerebellum, providing evidence for PC loss in patients with ICD. METHODS: Twenty-eight patients with ICD (20 females) and 28 age- and sex-matched healthy controls were recruited. A spatially unbiased infratentorial template was applied to perform cerebellum optimized quantitative susceptibility mapping and diffusion tensor analysis based on magnetic resonance imaging. Voxel-wise analysis was performed to assess cerebellar tissue magnetic susceptibility and fractional anisotropy (FA) alterations, and the clinical relevance of these findings was investigated in the patients with ICD. RESULTS: Increased susceptibility values revealed by quantitative susceptibility mapping in the right lobule CrusI, CrusII, VIIb, VIIIa, VIIIb and IX were found in the patients with ICD. A reduced FA value was found across almost all the cerebellum; an FA value of the significant clusters within the right lobule VIIIa significantly correlated with the motor severity of patients with ICD (r = -0.575, p = 0.002). CONCLUSIONS: Our study provided evidence for cerebellar iron overload and axonal damage in patients with ICD, which may indicate PC loss and related axonal changes. These results provide evidence for the neuropathological findings in patients with ICD and further highlight the cerebellar involvement in the pathophysiology of dystonia.

Tai Chi enhances cognitive training effects on delaying cognitive decline in mild cognitive impairment.

INTRODUCTION: Cognitive training and physical exercise have shown positive effects on delaying progression of mild cognitive impairment (MCI) to dementia. METHODS: We explored the enhancing effect from Tai Chi when it was provided with cognitive training for MCI. In the first 12 months, the cognitive training group (CT) had cognitive training, and the mixed group (MixT) had additional Tai Chi training. In the second 12 months, training was only provided for a subgroup of MixT. RESULTS: In the first 12 months, MixT and CT groups were benefited from training. Compared to the CT group, MixT had additional positive effects with reference to baseline. In addition, Compared to short-time training, prolonged mixed training further delayed decline in global cognition and memory. Functional magnetic resonance imaging showed more increased regional activity in both CT and MixT. DISCUSSION: Tai Chi enhanced cognitive training effects in MCI. Moreover, Tai Chi and cognitive mixed training showed effects on delaying cognitive decline.

Dietary ß-Hydroxy-ß-Methylbutyrate Supplementation Affects Growth Performance, Digestion, TOR Pathway, and Muscle Quality in Kuruma Shrimp (Marsupenaeus japonicas) Fed a Low Protein Diet.

An 8-week feeding trial was performed to evaluate the effects of dietary ß-hydroxy-ß-methylbutyrate (HMB) supplementation on growth performance and muscle quality of kuruma shrimp (Marsupenaeus japonicas) (initial weight: 2.00 ± 0.01 g) fed a low protein diet. The positive control diet (HP) with 490 g/kg protein and negative control diet (LP) with 440 g/kg protein were formulated. Based on the LP, 0.25, 0.5, 1, 2 and 4 g/kg ß-hydroxy-ß-methylbutyrate calcium were supplemented to design the other five diets named as HMB0.25, HMB0.5, HMB1, HMB2 and HMB4, respectively. Results showed that compared with the shrimp fed LP, the HP, HMB1 and HMB2 groups had significantly higher weight gain and specific growth rate, while significantly lower feed conversion ratio (p < 0.05). Meanwhile, intestinal trypsin activity was significantly elevated in the above three groups than that of the LP group. Higher dietary protein level and HMB inclusion upregulated the expressions of target of rapamycin, ribosomal protein S6 kinase, phosphatidylinositol 3-kinase, and serine/threonine-protein kinase in shrimp muscle, accompanied by the increases in most muscle free amino acids contents. Supplementation of 2 g/kg HMB in a low protein diet improved muscle hardness and water holding capacity of shrimp. Total collagen content in shrimp muscle increased with increasing dietary HMB inclusion. Additionally, dietary inclusion of 2 g/kg HMB significantly elevated myofiber density and sarcomere length, while reduced myofiber diameter. In conclusion, supplementation of 1-2 g/kg HMB in a low protein diet improved the growth performance and muscle quality of kuruma shrimp, which may be ascribed to the increased trypsin activity and activated TOR pathway, as well as elevated muscle collagen content and changed myofiber morphology caused by dietary HMB.

Speech silence character as a diagnostic biomarker of early cognitive decline and its functional mechanism: a multicenter cross-sectional cohort study.

BACKGROUND: Language deficits frequently occur during the prodromal stages of Alzheimer's disease (AD). However, the characteristics of linguistic impairment and its underlying mechanism(s) remain to be explored for the early diagnosis of AD. METHODS: The percentage of silence duration (PSD) of 324 subjects was analyzed, including patients with AD, amnestic mild cognitive impairment (aMCI), and normal controls (NC) recruited from the China multi-center cohort, and the diagnostic efficiency was replicated from the Pitt center cohort. Furthermore, the specific language network involved in the fragmented speech was analyzed using task-based functional magnetic resonance. RESULTS: In the China cohort, PSD increased significantly in aMCI and AD patients. The area under the curve of the receiver operating characteristic curves is 0.74, 0.84, and 0.80 in the classification of NC/aMCI, NC/AD, and NC/aMCI+AD. In the Pitt center cohort, PSD was verified as a reliable diagnosis biomarker to differentiate mild AD patients from NC. Next, in response to fluency tasks, clusters in the bilateral inferior frontal gyrus, precentral gyrus, left inferior temporal gyrus, and inferior parietal lobule deactivated markedly in the aMCI/AD group (cluster-level P < 0.05, family-wise error (FWE) corrected). In the patient group (AD+aMCI), higher activation level of the right pars triangularis was associated with higher PSD in in both semantic and phonemic tasks. CONCLUSIONS: PSD is a reliable diagnostic biomarker for the early stage of AD and aMCI. At as early as aMCI phase, the brain response to fluency tasks was inhibited markedly, partly explaining why PSD was elevated simultaneously.

Pathogenesis, therapeutic strategies and biomarker development based on "omics" analysis related to microglia in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease and the most common cause of dementia. Among various pathophysiological aspects, microglia are considered to play important roles in the pathogenesis of AD. Genome wide association studies (GWAS) showed that the majority of AD risk genes are highly or exclusively expressed in microglia, underscoring the critical roles of microglia in AD pathogenesis. Recently, omics technologies have greatly advanced our knowledge of microglia biology in AD. Omics approaches, including genomics, epigenomics, transcriptomics, proteomics, and metabolomics/lipidomics, present remarkable opportunities to delineate the underlying mechanisms, discover novel diagnostic biomarkers, monitor disease progression, and shape therapeutic strategies for diseases. In this review, we summarized research based on microglial "omics" analysis in AD, especially the recent research advances in the identification of AD-associated microglial subsets. This review reinforces the important role of microglia in AD and advances our understanding of the mechanism of microglia in AD pathogenesis. Moreover, we proposed the value of microglia-based omics in the development of therapeutic strategies and biomarkers for AD.

Injection of amyloid-ß to lateral ventricle induces gut microbiota dysbiosis in association with inhibition of cholinergic anti-inflammatory pathways in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease and its pathogenesis is still unclear. There is dysbiosis of gut microbiota in AD patients. More importantly, dysbiosis of the gut microbiota has been observed not only in AD patients, but also in patients with mild cognitive impairment (MCI). However, the mechanism of gut microbiota dysbiosis in AD is poorly understood. Cholinergic anti-inflammatory pathway is an important pathway for the central nervous system (CNS) regulation of peripheral immune homeostasis, especially in the gut. Therefore, we speculated that dysfunction of cholinergic anti-inflammatory pathway is a potential pathway for dysbiosis of the gut microbiota in AD. METHODS: In this study, we constructed AD model mice by injecting Aß1-42 into the lateral ventricle, and detected the cognitive level of mice by the Morris water maze test. In addition, 16S rDNA high-throughput analysis was used to detect the gut microbiota abundance of each group at baseline, 2 weeks and 4 weeks after surgery. Furthermore, immunofluorescence and western blot were used to detect alteration of intestinal structure of mice, cholinergic anti-inflammatory pathway, and APP process of brain and colon in each group. RESULTS: Aß1-42 i.c.v induced cognitive impairment and neuron damage in the brain of  mice. At the same time, Aß1-42 i.c.v induced alteration of gut microbiota at 4 weeks after surgery, while there was no difference at the baseline and 2 weeks after surgery. In addition, changes in colon structure and increased levels of pro-inflammatory factors were detected in Aß1-42 treatment group, accompanied by inhibition of cholinergic anti-inflammatory pathways. Amyloidogenic pathways in both the brain and colon were accelerated in Aß1-42 treatment group. CONCLUSIONS: The present findings suggested that Aß in the CNS can induce gut microbiota dysbiosis, alter intestinal structure and accelerate the amyloidogenic pathways, which were related to inhibiting cholinergic anti-inflammatory pathways.

A 10-Year Community-Based Study of Leucine-Rich Repeat Kinase 2 G2385R Carriers' Conversion to Parkinson's Disease.

BACKGROUND: The G2385R variant of leucine-rich repeat kinase 2 (LRRK2) is mainly associated with Parkinson's disease(PD) in Asian populations. OBJECTIVE: The aim of this study was to investigate the PD conversion rate and clinical characteristics of LRRK2 G2385R nonmanifesting carriers. METHODS: All participants were from the community-based longitudinal cohort of Shanghai Ruijin Hospital. The G2385R carriers and noncarriers were screened by Sanger sequencing and received face-to-face interviews at baseline and follow-up assessments. The Kaplan-Meier method was used to compare the conversion rate of PD. Cox regression models were used to estimate the risk of G2385R variant for PD. RESULTS: In the combined cohort, 26 (7.9%) people developed PD in 329 carriers versus 9 (2.6%) in 345 noncarriers (P = 0.0016). Cox regression model confirmed that the G2385R variant was a strong risk factor for PD in a Chinese population older than 50 years (hazard ratio, 3.314; 95% confidence interval, 1.551-7.078; P = 0.002). No difference was found in clinical symptoms between carriers and noncarriers. CONCLUSIONS: We confirmed an increased conversion of PD in leucine-rich repeat kinase 2 G2385R carriers during a 10-year follow-up. © 2022 International Parkinson and Movement Disorder Society.

Impaired Ocular Tracking and Cortical Atrophy in Idiopathic Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a prodromal stage of synucleinopathies. Patients with synucleinopathies frequently display eye movement abnormalities. However, whether patients with iRBD have eye movement abnormalities remains unknown. OBJECTIVE: The aim of this study was to assess eye movement abnormalities and related gray matter alterations and explore whether such abnormalities can serve as biomarkers to indicate phenoconversion to synucleinopathies in iRBD. METHODS: Forty patients with iRBD with early disease progression and 35 healthy control subjects participated in a 15-minute ocular-tracking task that evaluated their control of eye movement abilities. They also underwent clinical assessments for olfactory function, nonmotor symptoms, and autonomic symptoms, all of which are biomarkers to predict phenoconversion to synucleinopathies in iRBD. A subgroup of the participants (20 patients with iRBD and 20 healthy control subjects) also participated in structural magnetic resonance imaging. RESULTS: The ocular-tracking ability in patients with iRBD was inferior to that of healthy control subjects in two aspects: pursuit initiation and steady-state tracking. Cortical thinning in the right visual area V4 in patients with iRBD is coupled with impaired pursuit initiation. Furthermore, prolonged pursuit initiation in patients with iRBD exhibits a trend of correlation with olfactory loss, the earliest biomarker that develops prior to other prodromal biomarkers. CONCLUSIONS: We found ocular-tracking abnormalities in patients with iRBD even early in their disease progression that have not been reported before. These abnormalities are coupled with atrophy of brain areas involved in the perception of object motion and might indicate phenoconversion to synucleinopathies in iRBD. © 2022 International Parkinson and Movement Disorder Society.

Penetrance of Parkinson disease LRRK2 G2385R-associated variant in the Chinese population.

BACKGROUND AND PURPOSE: Penetrance estimates of the leucine-rich repeat kinase 2 (LRRK2) variants for Parkinson disease (PD) vary widely. G2385R is one of the most common LRRK2 variants in Asian populations, and its penetrance is currently unknown. We aimed to estimate the penetrance of G2385R in the Chinese population. METHODS: The G2385R variant was tested by Sanger sequencing in 6386 participants older than 50 years, all from the community cohort established by Shanghai Ruijin Hospital in 2009-2011. G2385R carriers and matched noncarriers underwent a brief questionnaire survey (including sex, current age, PD diagnosis, and age at onset) and face-to-face PD assessment during 2020-2021. The penetrance of PD was estimated by the Kaplan-Meier method. RESULTS: A total of 396 G2385R carriers and 415 noncarriers were included, after excluding those with a baseline diagnosis of PD or unwilling to participate. In G2385R carriers, the penetrance of PD was 1.64% at 70 years, 10.26% at 80 years, and 18.49% at 90 years, and reached 25.90% at 95 years. The penetrance of PD in G2385R carriers was higher than in noncarriers (p = 0.0071). In noncarriers, only 0%, 3.72%, and 9.66% developed parkinsonism by 70, 80, and 90 years of age. Among carriers and noncarriers, there were no statistically significant differences in penetrance comparisons between males and females, or between urban and rural. CONCLUSIONS: The lifetime penetrance of LRRK2 G2385R in the Chinese population was 25.9%. The penetrance modifier of G2385R in our study was age-related. Further investigation of genetic and environmental modifiers affecting G2385R penetrance is warranted.

Increased free water in the substantia nigra in idiopathic REM sleep behaviour disorder.

Imaging markers sensitive to neurodegeneration in the substantia nigra are critically needed for future disease-modifying trials. Previous studies have demonstrated the utility of posterior substantia nigra free water as a marker of progression in Parkinson's disease. In this study, we tested the hypothesis that free water is elevated in the posterior substantia nigra of idiopathic REM sleep behaviour disorder, which is considered a prodromal stage of synucleinopathy. We applied free-water imaging to 32 healthy control subjects, 34 patients with idiopathic REM sleep behaviour disorder and 38 patients with Parkinson's disease. Eighteen healthy control subjects and 22 patients with idiopathic REM sleep behaviour disorder were followed up and completed longitudinal free-water imaging. Free-water values in the substantia nigra were calculated for each individual and compared among groups. We tested the associations between posterior substantia nigra free water and uptake of striatal dopamine transporter in idiopathic REM sleep behaviour disorder. Free-water values in the posterior substantia nigra were significantly higher in the patients with idiopathic REM sleep behaviour disorder patients than in the healthy control subjects, but were significantly lower in patients with idiopathic REM sleep behaviour disorder than in patients with Parkinson's disease. In addition, we observed significantly negative associations between posterior substantia nigra free-water values and dopamine transporter striatal binding ratios in the idiopathic REM sleep behaviour disorder patients. Longitudinal free-water imaging analyses were conducted with a linear mixed-effects model, and showed a significant Group × Time interaction in posterior substantia nigra, identifying increased mean free-water values in posterior substantia nigra of idiopathic REM sleep behaviour disorder over time. These results demonstrate that free water in the posterior substantia nigra is a valid imaging marker of neurodegeneration in idiopathic REM sleep behaviour disorder, which has the potential to be used as an indicator in disease-modifying trials.

Effects of Onabotulinum Toxin A on Gait in Parkinson's Disease Patients with Foot Dystonia.

We investigated the effects of botulinum toxin on gait in Parkinson's disease (PD) patients with foot dystonia. Six patients underwent onabotulinum toxin A injection and were assessed by Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), visual analog scale (VAS) of pain, Timed Up and Go (TUG), Berg Balance Test (BBT), and 3D gait analysis at baseline, 1 month, and 3 months. BFMDRS (p = 0.002), VAS (p = 0.024), TUG (p = 0.028), and BBT (p = 0.034) were improved. Foot pressures at Toe 1 (p = 0.028) and Midfoot (p = 0.018) were reduced, indicating botulinum toxin's effects in alleviating the dystonia severity and pain and improving foot pressures during walking in PD.

DJ-1 regulates the integrity and function of ER-mitochondria association through interaction with IP3R3-Grp75-VDAC1.

Loss-of-function mutations in DJ-1 are associated with autosomal recessive early onset Parkinson's disease (PD), yet the underlying pathogenic mechanism remains elusive. Here we demonstrate that DJ-1 localized to the mitochondria-associated membrane (MAM) both in vitro and in vivo. In fact, DJ-1 physically interacts with and is an essential component of the IP3R3-Grp75-VDAC1 complexes at MAM. Loss of DJ-1 disrupted the IP3R3-Grp75-VDAC1 complex and led to reduced endoplasmic reticulum (ER)-mitochondria association and disturbed function of MAM and mitochondria in vitro. These deficits could be rescued by wild-type DJ-1 but not by the familial PD-associated L166P mutant which had demonstrated reduced interaction with IP3R3-Grp75. Furthermore, DJ-1 ablation disturbed calcium efflux-induced IP3R3 degradation after carbachol treatment and caused IP3R3 accumulation at the MAM in vitro. Importantly, similar deficits in IP3R3-Grp75-VDAC1 complexes and MAM were found in the brain of DJ-1 knockout mice in vivo. The DJ-1 level was reduced in the substantia nigra of sporadic PD patients, which was associated with reduced IP3R3-DJ-1 interaction and ER-mitochondria association. Together, these findings offer insights into the cellular mechanism in the involvement of DJ-1 in the regulation of the integrity and calcium cross-talk between ER and mitochondria and suggests that impaired ER-mitochondria association could contribute to the pathogenesis of PD.