Clinical features, disease progression, and nuclear imaging in ATXN2-related parkinsonism in a longitudinal cohort.

BACKGROUND: Spinocerebellar ataxia 2 (SCA2) with a low range of CAG repeat expansion of ATXN2 gene can present with predominant or isolated parkinsonism that closely resembles Parkinson's disease (PD). This study is aimed at comparing clinical features, disease progression, and nuclear imaging between ATXN2-related parkinsonism (ATXN2-P) and PD. METHODS: Three hundred and seventy-seven clinically diagnosed PD with family history were screened by multiplex ligation-dependent probe amplification, whole-exome sequencing or target sequencing, and dynamic mutation testing of 10 SCA subtypes. The baseline and longitudinal clinical features as well as the dual-tracer positron emission tomography (PET) imaging were compared between ATXN2-P and genetically undefined familial PD (GU-fPD). RESULTS: Fifteen ATXN2-P patients from 7 families and 50 randomly selected GU-fPD patients were evaluated. Significantly less resting tremor and more symmetric signs were observed in ATXN2-P than GU-fPD. No significant difference was found in motor progression and duration from onset to occurrence of fluctuation, dyskinesia, and recurrent falls between the two groups. Cognitive impairment and rapid-eye-movement sleep behavior disorder were more common in ATXN2-P. During follow-up, olfaction was relatively spared, and no obvious progression of cognition dysfunction evaluated by Mini-Mental State Examination scores was found in ATXN2-P. PET results of ATXN2-P demonstrated a symmetric, diffuse, and homogenous dopamine transporter loss of bilateral striatum and a glucose metabolism pattern inconsistent with that in PD. CONCLUSIONS: Symmetric motor signs and unique nuclear imaging might be the clues to distinguish ATXN2-P from GU-fPD.

18F-Florzolotau PET imaging captures the distribution patterns and regional vulnerability of tau pathology in progressive supranuclear palsy.

PURPOSE: Human post mortem studies have described the topographical patterns of tau pathology in progressive supranuclear palsy (PSP). Recent advances in tau PET tracers are expected to herald the next era of PSP investigation for early detection of tau pathology in living brains. This study aimed to investigate whether 18F-Florzolotau PET imaging may capture the distribution patterns and regional vulnerability of tau pathology in PSP, and to devise a novel image-based staging system. METHODS: The study cohort consisted of 148 consecutive patients with PSP who had undergone 18F-Florzolotau PET imaging. The PSP rating scale (PSPrs) was used to measure disease severity. Similarities and differences of tau deposition among different clinical phenotypes were examined at the regional and voxel levels. An 18F-Florzolotau pathological staging system was devised according to the scheme originally developed for post mortem data. In light of conditional probabilities for the sequence of events, an 18F-Florzolotau modified staging system by integrating clusters at the regional level was further developed. The ability of 18F-Florzolotau staging systems to reflect disease severity in terms of PSPrs score was assessed by analysis of variance. RESULTS: The distribution patterns of 18F-Florzolotau accumulation in living brains of PSP showed a remarkable similarity to those reported in post mortem studies, with the binding intensity being markedly higher in Richardson's syndrome. Moreover, 18F-Florzolotau PET imaging allowed detecting regional vulnerability and tracking tau accumulation in an earlier fashion compared with post mortem immunostaining. The 18F-Florzolotau staging systems were positively correlated with clinical severity as reflected by PSPrs scores. CONCLUSIONS: 18F-Florzolotau PET imaging can effectively capture the distribution patterns and regional vulnerability of tau pathology in PSP. The 18F-Florzolotau modified staging system holds promise for early tracking of tau deposition in living brains.

18 F-Florzolotau Positron Emission Tomography Imaging of Tau Pathology in the Living Brains of Patients with Corticobasal Syndrome.

BACKGROUND: Recent development in tau-sensitive tracers has sparkled significant interest in tracking tauopathies using positron emission tomography (PET) biomarkers. However, the ability of 18 F-florzolotau PET imaging to topographically characterize tau pathology in corticobasal syndrome (CBS) remains unclear. Further, the question as to whether disease-level differences exist with other neurodegenerative tauopathies is still unanswered. OBJECTIVE: To analyze the topographical patterns of tau pathology in the living brains of patients with CBS using 18 F-florzolotau PET imaging and to examine whether differences with other tauopathies exist. METHODS: 18 F-florzolotau PET imaging was performed in 20 consecutive patients with CBS, 20 cognitively healthy controls (HCs), 20 patients with Alzheimer's disease (AD), and 16 patients with progressive supranuclear palsy-Richardson's syndrome (PSP-RS). Cerebrospinal fluid (CSF) levels of ß-amyloid biomarkers were quantified in all patients with CBS. 18 F-florzolotau uptake was quantitatively assessed using standardized uptake value ratios. RESULTS: Of the 20 patients with CBS, 19 (95%) were negative for CSF biomarkers of amyloid pathology; of them, three had negative 18 F-florzolotau PET findings. Compared with HCs, patients with CBS showed increased 18 F-florzolotau signals in both cortical and subcortical regions. In addition, patients with CBS were characterized by higher tracer retentions in subcortical regions compared with those with AD and showed a trend toward higher signals in cortical areas compared with PSP-RS. An asymmetric pattern of 18 F-florzolotau uptake was associated with an asymmetry of motor severity in patients with CBS. CONCLUSIONS: In vivo 18 F-florzolotau PET imaging holds promise for distinguishing CBS in the spectrum of neurodegenerative tauopathies. © 2023 International Parkinson and Movement Disorder Society.

Comparison of comfort and complications of Implantable Venous Access Port (IVAP) with ultrasound guided Internal Jugular Vein (IJV) and Axillary Vein/Subclavian Vein (AxV/SCV) puncture in breast cancer patients: a randomized controlled study.

BACKGROUND: Axillary vein/subclavian vein (AxV/SCV) and Internal jugular vein (IJV) are commonly used for implantable venous access port (IVAP) implantation in breast cancer patients for chemotherapy. Previous research focused on comparison of complications while patient comfort was ignored. This study aims to compare patient comfort, surgery duration and complications of IVAP implantation between IJV and AxV/SCV approaches. METHODS: Two hundred forty-eight breast cancer patients were enrolled in this randomized controlled study from August 2020 to June 2021. Patients scheduled to undergo IVAP implantation were randomly and equally assigned to receive central venous catheters with either AxV /SCV or IJV approaches. All patients received comfort assessment using a comfort scale table at day 1, day 2 and day 7 after implantation. Patient comfort, procedure time of operation as well as early complications were compared. RESULTS: Patient comfort was significantly better in the AxV/SCV group than that of IJV group in day 1 (P < 0.001), day 2 (P < 0.001) and day 7(P = 0.023). Procedure duration in AxV/SCV group was slightly but significantly shorter than IJV group (27.14 ± 3.29 mins vs 28.92 ± 2.54 mins, P < 0.001). More early complications occurred in AxV/SCV group than IJV group (11/124 vs 2/124, P = 0.019). No difference of complications of artery puncture, pneumothorax or subcutaneous hematoma between these two groups but significantly more catheter misplacement in AxV/SCV group than IJV group (6/124 vs 0/124, P = 0.029). Absolutely total risk of complications was rather low in both groups (8.87% in AxV/SCV group and 1.61% in IJV group). CONCLUSIONS: Our study indicates that patients with AxV/SCV puncture have higher comfort levels than IJV puncture. AxV/SCV puncture has shorter procedure duration but higher risk of early complications, especially catheter misplacement. Both these two approaches have rather low risk of complications. Consequently, our study provides an alternative choice for breast cancer patients to reach better comfort.

18 F-Florzolotau Tau Positron Emission Tomography Imaging in Patients with Multiple System Atrophy-Parkinsonian Subtype.

BACKGROUND: Anecdotal evidence suggests that patients diagnosed with the parkinsonian subtype of multiple system atrophy (MSA-P) may show uptake of the second-generation tau positron emission tomography (PET) tracer 18 F-Florzolotau (previously known as 18 F-APN-1607) in the putamen. OBJECTIVES: This study systematically investigated the localization and magnitude of 18 F-Florzolotau uptake in a relatively large cohort of patients with MSA-P. METHODS: 18 F-Florzolotau PET imaging was performed in 31 patients with MSA-P, 24 patients with Parkinson's disease (PD), and 20 age-matched healthy controls. 18 F-Florzolotau signal in the striatum was analyzed by visual inspection and classified as either positive or negative. Regional 18 F-Florzolotau binding was also expressed as standardized uptake value ratio (SUVR) to assess whether it was associated with core symptoms of MSA-P after adjustment for potential confounders. RESULTS: By visual inspection and semiquantitative SUVR comparisons, patients with MSA-P showed elevated 18 F-Florzolotau uptake in the putamen, globus pallidus, and dentate-a finding that was not observed in PD. This increased signal was significantly associated with the core symptoms of MSA-P. In addition, patients with MSA-P with cerebellar ataxia showed an elevated 18 F-Florzolotau uptake in the cerebellar dentate. CONCLUSIONS: 18 F-Florzolotau tau PET imaging findings may reflect the clinical severity of MSA-P and can potentially discriminate between this condition and PD. © 2022 International Parkinson and Movement Disorder Society.

In Vivo 18 F-APN-1607 Tau Positron Emission Tomography Imaging in MAPT Mutations: Cross-Sectional and Longitudinal Findings.

BACKGROUND: Frontotemporal lobar degeneration with tauopathy caused by MAPT (microtubule-associated protein tau) mutations is a highly heterogenous disorder. The ability to visualize and longitudinally monitor tau deposits may be beneficial to understand disease pathophysiology and predict clinical trajectories. OBJECTIVE: The aim of this study was to investigate the cross-sectional and longitudinal 18 F-APN-1607 positron emission tomography/computed tomography (PET/CT) imaging findings in MAPT mutation carriers. METHODS: Seven carriers of MAPT mutations (six within exon 10 and one outside of exon 10) and 15 healthy control subjects were included. All participants underwent 18 F-APN-1607 PET/CT at baseline. Three carriers of exon 10 mutations received follow-up 18 F-APN-1607 PET/CT scans. Standardized uptake value ratio (SUVR) maps were obtained using the cerebellar gray matter as the reference region. SUVR values observed in MAPT mutation carriers were normalized to data from healthy control subjects. A regional SUVR z score ≥ 2 was used as the criterion to define positive 18 F-APN-1607 PET/CT findings. RESULTS: Although the seven study patients had heterogenous clinical phenotypes, all showed a significant 18 F-APN-1607 uptake characterized by high-contrast signals. However, the anatomical localization of tau deposits differed in patients with distinct clinical symptoms. Follow-up imaging data, which were available for three patients, demonstrated worsening trends in patterns of tau accumulation over time, which were paralleled by a significant clinical deterioration. CONCLUSIONS: Our data represent a promising step in understanding the usefulness of 18 F-APN-1607 PET/CT imaging for detecting tau accumulation in MAPT mutation carriers. Our preliminary follow-up data also suggest the potential value of 18 F-APN-1607 PET/CT for monitoring the longitudinal trajectories of frontotemporal lobar degeneration caused by MAPT mutations. © 2021 International Parkinson and Movement Disorder Society.

Dopamine transporter imaging in progressive supranuclear palsy: Severe but nonspecific to subtypes.

BACKGROUND: Previous studies with a limited sample size suggested more severe dopaminergic transporter (DAT) lesions in the striatum of progressive supranuclear palsy (PSP) than those in Parkinson's disease (PD) and multiple system atrophy-parkinsonism (MSA-P). However, few studies had taken various subtypes of PSP into consideration, making the reanalysis of DAT imaging in larger PSP cohort with various subtypes in need. OBJECTIVES: To compare the dopaminergic lesion patterns of PSP with MSA-P and PD, and to explore the specific striatal subregional patterns of different PSP subtypes. METHODS: 11 C-CFT positron emission tomography (PET) imaging was conducted in 83 PSP patients consisting of different subtypes, 61 patients with PD, 41 patients with MSA-P, and 43 healthy volunteers. Demographic and clinical data were compared by the chi-squared test or one-way analysis of variance. A generalized linear model was used to examine intergroup differences in tracer uptake values after adjusting for age, disease duration, and disease severity. Areas under the receiver operating characteristic curve were calculated to assess the diagnostic accuracy of subregional DAT binding patterns. RESULTS: The patients with PSP presented more severe DAT loss in the striatum than in PD and MSA-P, especially in caudate. In PSP, the subregional lesion was still more severe in putamen than in caudate, similar to that in PD and MSA-P. Among detailed subtypes, no significant difference was detected. CONCLUSION: The dopaminergic lesions were more severe in PSP, and no difference was detected among subtypes.

Clinical Utility of 18 F-APN-1607 Tau PET Imaging in Patients with Progressive Supranuclear Palsy.

BACKGROUND: 18 F-APN-1607 is a novel tau PET tracer characterized by high binding affinity for 3- and 4-repeat tau deposits. Whether 18 F-APN-1607 PET imaging is clinically useful in PSP remains unclear. OBJECTIVES: The objective of this study was to investigate the clinical utility of 18 F-APN-1607 PET in the diagnosis, differential diagnosis, and assessment of disease severity in patients with PSP. METHODS: We enrolled 3 groups consisting of patients with PSP (n = 20), patients with α-synucleinopathies (MSA with predominant parkinsonism, n = 7; PD, n = 10), and age- and sex-matched healthy controls (n = 13). The binding patterns of 18 F-APN-1607 in PET/CT imaging were investigated. Regional standardized uptake ratios were compared across groups and examined in relation to their utility in the differential diagnosis of PSP versus α-synucleinopathies. Finally, the relationships between clinical severity scores and 18 F-APN-1607 uptake were investigated after adjustment for age, sex, and disease duration. RESULTS: Compared with healthy controls, patients with PSP showed increased 18 F-APN-1607 binding in several subcortical regions, including the striatum, putamen, globus pallidus, thalamus, subthalamic nucleus, midbrain, tegmentum, substantia nigra, pontine base, red nucleus, raphe nuclei, and locus coeruleus. We identified specific regions that were capable of distinguishing PSP from α-synucleinopathies. The severity of PSP was positively correlated with the amount of 18 F-APN-1607 uptake in the subthalamic nucleus, midbrain, substantia nigra, red nucleus, pontine base, and raphe nuclei. CONCLUSIONS: 18 F-APN-1607 PET imaging holds promise for the diagnosis, differential diagnosis, and assessment of disease severity in patients with PSP. © 2021 International Parkinson and Movement Disorder Society.

Disease Progression in Patients with Parkin-Related Parkinson's Disease in a Longitudinal Cohort.

BACKGROUND: There was a paucity of follow-up studies in the disease progression of early-onset PD patients with Parkin mutations (Parkin-EOPD). Here we conducted a longitudinal study to investigate the progression of motor and cognitive features of Parkin-EOPD patients. METHODS: Genetic analysis was performed via target sequencing and multiplex ligation-dependent probe amplification. Thirty patients carrying homozygous or compound heterozygous Parkin mutations with at least 2 follow-up revisions were investigated as the Parkin-EOPD group. Fifty-two patients with at least 2 follow-up revisions, who did not have any known causative PD mutations, GBA or LRRK2 risk variants, a heterozygous Parkin mutation or 2 Parkin mutations without a segregation test, were defined as the genetically undefined EOPD (GU-EOPD) group. A linear mixed-effect model was implemented to evaluate longitudinal changes in motor symptoms and cognition. RESULTS: At baseline, the Parkin-EOPD group had a lower Unified Parkinson's Disease Rating Scale score (UPDRS-III) (off-medication) than the GU-EOPD group, without significant differences in cognition. A longitudinal study showed the estimated progression rate per year (standard error) of the UPDRS-III score (off-medication) was lower in the Parkin-EOPD group (0.203 [0.3162] points per year) than in the GU-EOPD group (1.056 [0.3001] points per year). The difference in the UPDRS-III score rate between the 2 groups was 0.853 (0.4183) (P = 0.042). The Parkin-EOPD group showed better maintenance of spatial processing ability compared with the GU-EOPD group (P = 0.027). CONCLUSION: Parkin-EOPD patients showed a slower deterioration of motor symptoms and a better spatial processing ability than GU-EOPD patients, which suggests that subtyping according to genetic features can help predict PD progression. © 2020 International Parkinson and Movement Disorder Society.

Propagated α-synucleinopathy recapitulates REM sleep behaviour disorder followed by parkinsonian phenotypes in mice.

Idiopathic rapid eye movement sleep behaviour disorder (RBD) is now recognized as an early manifestation of α-synucleinopathies. Increasing experimental studies demonstrate that manipulative lesion or inactivation of the neurons within the sublaterodorsal tegmental nucleus (also known as the subcoeruleus nucleus in humans) can induce RBD-like behaviours in animals. As current RBD animal models are not established on the basis of α-synucleinopathy, they do not represent the pathological substrate of idiopathic RBD and thus cannot model the phenoconversion to Parkinson's disease. The purpose of this study was therefore to establish an α-synucleinopathy-based RBD animal model with the potential to convert to parkinsonian disorder. To this end, we first determined the functional neuroanatomical location of the sublaterodorsal tegmental nucleus in wild-type C57BL/6J mice and then validated its function by recapitulating RBD-like behaviours based on this determined nucleus. Next, we injected preformed α-synuclein fibrils into the sublaterodorsal tegmental nucleus and performed regular polysomnographic recordings and parkinsonian behavioural and histopathological studies in these mice. As a result, we recapitulated RBD-like behaviours in the mice and further showed that the α-synucleinopathy and neuron degeneration identified within the sublaterodorsal tegmental nucleus acted as the neuropathological substrates. Subsequent parkinsonian behavioural studies indicated that the α-synucleinopathy-based RBD mouse model were not stationary, but could further progress to display parkinsonian locomotor dysfunction, depression-like disorder, olfactory dysfunction and gastrointestinal dysmotility. Corresponding to that, we determined α-synuclein pathology in the substantia nigra pars compacta, olfactory bulb, enteral neuroplexus and dorsal motor nucleus of vagus nerve, which could underlie the parkinsonian manifestations in mice. In conclusion, we established a novel α-synucleinopathy-based RBD mouse model and further demonstrated the phenoconversion of RBD to Parkinson's disease in this animal model.

Diagnosis and surgical treatment of non-lesional temporal lobe epilepsy with unilateral amygdala enlargement.

OBJECTIVE: Exploring the role of amygdala enlargement (AE) in temporal lobe epilepsy (TLE) without ipsilateral mesial temporal sclerosis (MTS) using comprehensive presurgical workup tools including traditional tools, automatically volumetric analysis, high-density EEG (HD-EEG) source imaging (HD-ESI), and stereoelectroencephalography (SEEG). METHODS: Nine patients diagnosed with TLE-AE who underwent resective surgeries encompassing the amygdala were retrospectively studied. HD-ESI was obtained using 256-channel HD-EEG on the individualized head model. For automatic volumetric analysis, 48 matched controls were enrolled. Diagnosis and surgical strategies were based on a comprehensive workup following the anatomo-electro-clinical principle. RESULTS: At post-operative follow-up (average 30.9 months), eight patients had achieved Engel class I and one Engel class II recovery. HD-ESI yielded unifocal source estimates in anterior mesial temporal region in 85.7% of cases. Automatic volumetric analysis showed the AE sides were consistent with the values determined through other preoperative workup tools. Furthermore, the amygdala volume of the affected sides in AE was significantly greater than that of the larger sides in controls (p < 0.001). Meanwhile, the amygdala volume lateral index (LI) of AE was significantly higher than in controls (p < 0.001). SEEG analysis showed that ictal onsets arose from the enlarged amygdala (and hippocampus) in all cases. CONCLUSION: In addition to traditional workup tools, automatic volumetric analysis, HD-ESI on individualized head model, and invasive SEEG can provide evidence of epileptogenicity in TLE-AE. Resective surgical strategies encompassing the amygdala result in better prognosis. In suspected TLE cases, more attention should be focused on detecting enlargement of amygdala which sometimes is "hidden" in "MR-negative" non-MTS cases.

Short-echo-time magnitude image derived from quantitative susceptibility mapping could resemble neuromelanin-sensitive MRI image in substantia nigra.

BACKGROUND: In this study, we explored whether the proposed short-echo-time magnitude (setMag) image derived from quantitative susceptibility mapping (QSM) could resemble NM-MRI image in substantia nigra (SN), by quantitatively comparing the spatial similarity and diagnosis performances for Parkinson's disease (PD). METHODS: QSM and NM-MRI were performed in 18 PD patients and 15 healthy controls (HCs). The setMag images were calculated using the short-echo-time magnitude images. Bilateral hyperintensity areas of SN (SNhyper) were manually segmented on setMag and NM-MRI images by two raters in a blinded manner. The inter-rater reliability was evaluated by the intraclass correlation coefficients (ICC) and the Dice similarity coefficient (DSC). Then the inter-modality (i.e. setMag and NM-MRI) spatial similarity was quantitatively assessed using DSC and volume of the consensual voxels identified by both of two raters. The performances of mean SNhyper volume for PD diagnosis on setMag and NM-MRI images were evaluated using receiver operating characteristic (ROC) analysis. RESULTS: The SNhyper segmented by two raters showed substantial to excellent inter-rater reliability for both setMag and NM-MRI images. The DSCs of SNhyper between setMag and NM-MRI images showed substantial to excellent voxel-wise overlap in HCs (0.80 ~ 0.83) and PD (0.73 ~ 0.76), and no significant difference was found between the SNhyper volumes of setMag and NM-MRI images in either HCs or PD (p > 0.05). The mean SNhyper volume was significantly decreased in PD patients in comparison with HCs on both setMag images (77.61 mm3 vs 95.99 mm3, p < 0.0001) and NM-MRI images (79.06 mm3 vs 96.00 mm3, p < 0.0001). Areas under the curve (AUCs) of mean SNhyper volume for PD diagnosis were 0.904 on setMag and 0.906 on NM-MRI images. No significant difference was found between the two curves (p = 0.96). CONCLUSIONS: SNhyper on setMag derived from QSM demonstrated substantial spatial overlap with that on NM-MRI and provided comparable PD diagnostic performance, providing a new QSM-based multi-contrast imaging strategy for future PD studies.

Modifiable risk factors for cognitive impairment in Parkinson's disease: A systematic review and meta-analysis of prospective cohort studies.

BACKGROUND: Cognitive impairment is a common and devastating manifestation in Parkinson's disease (PD). We aimed to identify modifiable risk factors for PD with cognitive impairment. METHODS: We systematically searched PubMed and the Cochrane Library from June 1937 to September 2018 and included prospective cohort studies with random-effects model used to combine estimates. Primary analyses for all types of cognitive impairments and subgroup analyses for separate outcomes were conducted. RESULTS: A total of 31,298 articles were identified, of which 32 articles with 18 factors met the inclusion criteria for meta-analysis. In the primary analysis, 9 modifiable risk factors were found to increase the risk of PD with cognitive impairment, including postural-instability-gait disorder (relative risk = 3.76, 95% confidence interval = 1.36-10.40), hallucinations (relative risk = 3.09, 95% confidence interval = 1.61-5.93), orthostatic hypotension (relative risk = 2.98, 95% confidence interval = 1.41-6.28), cerebrovascular disease (relative risk = 1.52, 95% confidence interval = 1.01-2.28), diabetes mellitus (relative risk = 1.47, 95% confidence interval = 1.13-1.92), obesity (relative risk = 1.38, 95% confidence interval = 1.15-1.65), cardiac disease (relative risk = 1.35, 95% confidence interval = 1.17-1.56), alcohol consumption (relative risk = 1.32, 95% confidence interval = 1.15-1.52), and smoking (relative risk = 1.31, 95% confidence interval = 1.14-1.50). In the subgroup analysis, postural-instability-gait disorder subtype, orthostatic hypotension and hallucinations may increase the risk of dementia in PD. A total of 37 articles were included in the systematic review, in which 9 risk factors and 1 protective factor were additionally associated in single studies with the risk of PD with cognitive impairment, and 5 factors were associated with specific cognition domains. CONCLUSIONS: Effective interventions in the management of PD symptoms, comorbidities, and lifestyles may be promising to reduce PD with cognitive impairment risk. © 2019 International Parkinson and Movement Disorder Society.

Predictors to quality of life improvements after subthalamic stimulation in Parkinson's disease.

INTRODUCTION: Subthalamic deep brain stimulation (STN DBS) has been reported to improve the quality of life (QoL) related to Parkinson's disease (PD). However, not all subjects are satisfied with the postsurgical QoL outcome. We aimed to detect the related factors and possible predictors to QoL improvement for those PD patients one year after STN DBS. MATERIALS AND METHODS: A total of 45 PD patients with bilateral STN DBS surgery were included and followed up for 1 year. The Reliable Change Index (RCI) was adapted to determine the individual postsurgical QoL outcome. The changes of QoL were correlated with baseline parameters and the changes of progression parameters using Pearson's correlation. The exploratory stepwise regressions were adopted to detect the extents of baseline variables and progression parameters. The predictors to QoL outcome were detected using the logistic regression analysis. RESULTS: A total of 51.1% of the patients reported a better QoL, 40.0% of patients reported an unchanged QoL, while 8.9% of patients reported a worsening of QoL. The subdomains of mobility, activity of daily living, cognition, and bodily discomfort improved significantly after the surgery. The presurgical factors including QoL, dopaminergic medication burden, disease stages, depression scores, and postsurgical reductions in depression and nonmotor scores were found to correlate with QoL changes. Furthermore, the greater presurgical QoL burden, lesser dopaminergic medication exposure, and earlier disease stages were predictors to QoL improvements. CONCLUSION: The clinicians should carefully evaluate the nonmotor symptoms and life quality in those patients at relatively earlier stages and with lower medicine dosage to get more successful DBS outcomes.

Clinical characteristics of cognitive impairment in patients with Parkinson's disease and its related pattern in 18 F-FDG PET imaging.

This study aimed to characterize the clinical features and the related cerebral glucose metabolism pattern of cognitive impairments in Parkinson's disease (PD) with positron emission tomography (PET) imaging. We recruited 168 PD patients and 100 age-matched healthy controls of similar education and gender distribution. All of those enrolled underwent clinical assessment including the unified Parkinson's disease rating scale motor score, Hoehn and Yahr scale, and comprehensive neuropsychological tests including domains of executive function, attention, memory, visuospatial function, and language. Demographics and the results of cognitive measures were compared between patients and healthy controls. Cognition status was classified as PD patients with dementia (PD-D), PD patients with mild cognitive impairment (PD-MCI), or PD patients with normal cognition (PD-NC). In 53 PD patients who underwent 18 F-fluorodeoxyglucose (18 F-FDG) PET imaging, correlations between Z-score values of the different cognitive domains and cerebral 18 F-FDG uptake were assessed using statistical parametric mapping (SPM8) corrected for age and motor severity. A total of 23.2% of PD patients were PD-MCI and 8.9% were PD-D. In the group of PD-MCI, 96.3% showed multiple-domain deficits, with executive function and attention impairment most predominantly involved. All the cognitive domain scores with the exception of language correlated with 18 F-FDG metabolisms, primarily in posterior temporo-parieto-occipital association cortical areas. This study found that cognitive impairment in PD particularly encompasses frontal/executive deficits. Posterior cortical areas, containing multiple neurotransmitters and neural circuits, may play an important role in the pathogenesis of cognitive impairment in PD.

Design, synthesis and structure-activity relationship of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure as multi-target inhibitors against receptor tyrosine kinase.

Inspired by that the multi-target inhibitors against receptor tyrosine kinases (RTKs) have significantly improved the effect of clinical treatment for cancer, and based on the chemical structure of Linifanib (ABT-869, Abbott), two series of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure were designed and synthesized as multi-target inhibitors against RTKs. The preliminary biological evaluation showed that several compounds exhibited comparable potency with Linifanib. Compound S21 was identified as the most potent inhibitor against Fms-like tyrosine kinase 3 (FLT-3), kinase insert domain containing receptor (KDR) and platelet-derived growth factor receptor ß (PDGFR-ß) with its IC50 values were 4 nM, 3 nM and 8 nM respectively, it also showed potent inhibitory activities against several cancer cells.

Depressive Symptoms Are Associated With Color Vision but not Olfactory Function in Patients With Parkinson's Disease.

Depressive symptoms and sensory dysfunction, such as reduction in visual and olfactory function, are common in Parkinson's disease (PD). Previous studies have suggested that depressive symptoms are associated with visual impairments and potentially with hyposmia in several types of mood disorders. However, the relationship between depressive symptoms and sensory dysfunction remains unclear in PD. To examine the association of depressive symptoms with color vision and olfactory function in PD, the authors conducted a cross-sectional study in 159 patients with PD. Depressive symptoms were measured with the Beck Depression Inventory-II (BDI-II) and the 30-item Geriatric Depression Scale (GDS-30); color vision was tested with the Farnsworth-Munsell 100 Hue Test (FMT); and olfactory function was tested with the Sniffin' Sticks Screening 12 Test. Results showed that the total error score (TES) for the FMT was significantly and independently correlated with scores on both the BDI-II and GDS-30 in a positive manner, suggesting that more severe depressive symptoms are associated with poorer color vision in PD. In addition, both somatic and effective subscores for the BDI-II were correlated with the TES on the FMT, while no significant correlation was observed between total scores on the Sniffin' Sticks Screening 12 Test and BDI-II or GDS-30. The decrease in color vision but not olfactory function was found to be associated with the severity of depressive symptoms in PD patients, supporting the idea that the occurrence of depressive symptoms in PD is linked with disruption of the visual system.

A homozygous missense variant in HSD17B4 identified in a consanguineous Chinese Han family with type II Perrault syndrome.

BACKGROUND: Perrault syndrome is a rare multisystem disorder that manifests with sensorineural hearing loss in both sexes, primary ovarian insufficiency in females and neurological features. The syndrome is heterogeneous both genetically and phenotypically. CASE PRESENTATION: We reported a consanguineous family (two affected sisters) with Perrault syndrome. The proband had the characteristics of Perrault syndrome: ovarian dysgenesis, bilateral hearing loss and obvious neurological signs. Target genetic sequencing and triplet repeat primed PCR (TP-PCR) plus capillary electrophoresis was conducted to detect causative mutations in the proband. The detected variant was further confirmed in the proband and tested in other family members by Sanger sequencing. Both the proband and her sister were found homozygous for the novel variant HSD17B4 c.298G > T (p.A100S) with their parents heterozygous. Detected by western blot, the protein expression of HSD17B4 mutant was much lower than that of the wild type in SH-SY5Y cells transfected by HSD17B4 wild type or mutant plasmid, which indicated the pathogenicity of the HSD17B4 mutation. CONCLUSIONS: Our findings supported that HSD17B4 was one of the genes contributing to Perrault syndrome with the likely pathogenic variant c.298G > T (p.A100S). Special manifestations of cerebellar impairment were found in cases caused by HSD17B4 mutations. Besides, attention should be paid to distinguish Perrault syndrome from D-bifunctional protein deficiency and hereditary ataxia.

Evaluation of PDQ-8 and its relationship with PDQ-39 in China: a three-year longitudinal study.

BACKGROUND: Parkinson's disease is characterized by motor and non-motor symptoms with wide ranging impacts on the health-related quality of life. The 39-item Parkinson's disease Questionnaire (PDQ-39) is the most widely used PD-specific health-related quality-of-life questionnaire. The short-form 8-item Parkinson's disease Questionnaire (PDQ-8) was found to produce results similar to that of the PDQ-39 cross-culturally. However, there is no evaluation of the PDQ-8 in the mainland of China. METHODS: In this longitudinal study, 283 patients with Parkinson's disease were recruited. The PDQ-39, the PDQ-8 and other scales were administered. Patients attended the clinic once annually for three years to complete the scales. RESULTS: The PDQ-8 was found to have good validity and reliability. There was a strong correlation between the summary indices of the PDQ-8 and the PDQ-39 (r=0.93, P<0.001). Results suggested that the PDQ-8 was also associated with other clinical scales of mobility, depression and cognition. The convergent validity and discriminant validity of the PDQ-8 were demonstrated by item-to-dimension correlations. There was acceptable internal consistency of the PDQ-8 (Cronbach's α: 0.80; Item-scale correlation efficient: 0.56-0.72). The PDQ-8 replicated the results of the PDQ-39 well at all follow-up time points (intraclass correlation coefficient: 0.96-0.98). In addition, there was good test-retest reliability of the PDQ-8. CONCLUSION: The PDQ-8 is a valid and reliable instrument assessing health-related quality of life for PD patients in the mainland of China.