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For decades the greatest goal of Parkinson's disease (PD) research has often been distilled to the discovery of treatments that prevent the disease or its progression. However, until recently only the latter has been realistically pursued through randomized clinical trials of candidate disease-modifying therapy (DMT) conducted on individuals after they received traditional clinical diagnosis of PD (i.e., tertiary prevention trials). Now, in light of major advances in our understanding of the prodromal stages of PD, as well as its genetics and biomarkers, the first secondary prevention trials for PD are beginning. In this review, we take stock of DMT trials to date, summarize the breakthroughs that allow the identification of cohorts at high risk of developing a traditional diagnosis of PD, and describe key design elements of secondary prevention trials and how they depend on the prodromal stage being targeted. These elements address whom to enroll, what interventions to test, and how to measure secondary prevention (i.e., slowed progression during the prodromal stages of PD). Although these design strategies, along with the biological definition, subtype classification, and staging of the disease are evolving, all are driven by continued progress in the underlying science and integrated by a broad motivated community of stakeholders. While considerable methodological challenges remain, opportunities to move clinical trials of DMT to earlier points in the disease process than ever before have begun to unfold, and the prospects for PD prevention are nowtangible. [ABSTRACT FROM AUTHOR]

Internationalization is known to enhance university capacities in cross‐border learning and encourage institutional transformations for improved quality of scholarship and education. Studies on internationalization of research and teaching are, however, under‐problematized with regard to asymmetries that pervade different collaborating systems and cultures. This paper addresses this gap by elucidating asymmetries in the Greater Bay Area of China (GBA), which is dealing with differences in legacies and experiences of internationalization in university research and teaching. At a time when the governments in the three constituent jurisdictions of GBA—Guangdong Province, Hong Kong Special Administrative Region (SAR), and Macao SAR—encourage universities to collaborate across jurisdictional borders, this study applies a bibliographic analysis to shed light on asymmetries and mitigation strategies in internationalization of research and teaching. [ABSTRACT FROM AUTHOR]

Background: The term rapidly progressive dementia (RPD) with Lewy bodies (rpDLB) is used for DLB patients who develop a rapidly progressive neurological syndrome and have reduced survival. Here, we characterise the clinical, neuropathological, and molecular characteristics of a large rpDLB neuropathological series. Methods: We included all RPD patients with a disease duration < 4 years submitted to our prion disease referral centre between 2003 and 2022 who showed Lewy body pathology (LBP) in limbic or neocortical stages as primary neuropathological diagnosis, had no systemic condition justifying the rapid deterioration and were previously neurologically unimpaired. Clinical features were retrieved and compared with Creutzfeldt-Jakob disease (CJD) and rapidly progressive Alzheimer's disease (rpAD) cohorts. Neuropathological and genetic (whole exome sequencing, APOE genotyping, and C9orf72 repeat expansion analysis) characteristics of rpDLB patients were systematically investigated. We scored semi-quantitatively the LBP load and performed a α-synuclein (αSyn) RT-QuIC seeding amplification assay (SAA) on cerebrospinal fluid (CSF) and tenfold serially diluted brain homogenates from different brain areas in rpDLB patients and typical long-lasting Lewy body disease (LBD) with dementia patients as control group. Results: RpDLB patients were older (p = 0.047) and presented more cognitive fluctuations (p = 0.005), visual hallucinations (p = 0.020), neuropsychiatric symptoms (p = 0.006) and seizures (p = 0.032), and fewer cerebellar (p < 0.001) and visual (p = 0.004) signs than CJD ones. Delirium onset was more common than in both CJD (p < 0.001) and rpAD (p = 0.008). Atypical LBD signs (pyramidal, myoclonus, akinetic mutism) were common. All tested patients were positive by CSF αSyn SAA. Concomitant pathologies were common, with only four cases showing relatively "pure" LBP. LBP load and αSyn seeding activity measured through αSyn RT-QuIC SAA were not significantly different between rpDLB patients and typical LBD. We found a likely pathogenic variant in GBA in one patient. Conclusions: Our results indicate that: 1) rpDLB exhibits a distinct clinical signature (2) CSF αSyn SAA is a reliable diagnostic test; 3) rpDLB is a heterogeneous neuropathological entity that can be underlain by both widespread pure LBP, or multiple copathologies 4) rpDLB is likely not sustained by distinct αSyn conformational strains; 5) genetic defects may, at least occasionally, contribute to the poor prognosis in these patients. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a complex disorder that is influenced by multiple genetic risk factors. There is a significant heterogeneity in PD presentation, both pathologically and clinically. Some of the most common and important symptoms affecting the patient are cognitive impairment and dementia. However, the genetic and biological basis underlying the differences in cognitive profiles, including the development of dementia in PD, is not yet well understood. Understanding the role of genes in cognitive outcomes is crucial for effective patient counseling and treatment. Research on familial PD has discovered more than 20 genes that can cause the disease. The identified genes responsible for familial cases of PD are LRRK2, PARK7, PINK1, PRKN, or SNCA gene, although theremay be other genes that also contribute. Additionally, some of these genes may also play a role in cases that were previously thought to be sporadic. Currently, numerous well-described genes increase the risk of cognitive decline in PD, each with varying levels of penetrance. The aim of this review is to identify the relevant genetic factors that contribute to differences in cognition. We discuss the genes thatmay affect cognition and the challenges in establishing a clear genetic diagnostic and prognostic assessment. This article aims to demonstrate the complexity of the genetic background of cognition in PD and to present the different types of genotype changes that can impact cognition through various neurobiological mechanisms. [ABSTRACT FROM AUTHOR]

Background and purpose: Subtle executive dysfunction is common in people newly diagnosed with Parkinson disease (PD), even when general cognitive abilities are intact. This study examined the Short Weekly Calendar Planning Activity (WCPA‐10)'s known‐group construct validity, comparing persons with PD to healthy controls (HCs) and nonmanifesting carriers of LRRK2 and GBA gene mutations to HCs. Additionally, convergent and ecological validity was examined. Methods: The study included 73 participants: 22 with idiopathic PD (iPD) who do not carry any of the founder GBA mutations or LRRK2‐G2019S, 29 nonmanifesting carriers of the G2019S‐LRRK2 (n = 14) and GBA (n = 15) mutations, and 22 HCs. Known‐group validity was determined using the WCPA‐10, convergent validity by also using the Montreal Cognitive Assessment (MoCA) and Color Trails Test (CTT), and ecological validity by using the WCPA‐10, Schwab and England Activities of Daily Living Scale (SE ADL), and Physical Activity Scale for the Elderly (PASE). Results: Known‐group validity of the WCPA‐10 was established for the iPD group only; they followed fewer rules (p = 0.020), were slower (p = 0.003) and less efficient (p = 0.001), used more strategies (p = 0.017) on the WCPA‐10, and achieved significantly lower CTT scores (p < 0.001) than the HCs. The nonmanifesting carriers and HCs were similar on all cognitive tests. Convergent and ecological validity of the WCPA‐10 were partially established, with few correlations between WCPA‐10 outcome measures and the MoCA (r = 0.50, r = 0.41), CTT‐2 (r = 0.43), SE ADL (r = 0.41), and PASE (r = 0.54, r = 0.46, r = 0.31). Conclusions: This study affirms the known‐group validity for most (four) WCPA‐10 scores and partially confirms its convergent and ecological validity for PD. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second-most common neurodegenerative disease, affecting 1% of people aged over 60. Currently, there is only symptomatic relief for PD patients, with levodopa being the gold standard of PD treatment. Deep brain stimulation (DBS) is a surgical option to treat PD patients. DBS improves motor functions and may also allow a significant reduction in dopaminergic medication. Important parameters for DBS outcomes are the disease duration, the age of disease onset, responsiveness to levodopa and cognitive or psychiatric comorbidities. Emerging data also highlight the need to carefully consider the genetic background in the preoperative assessment of PD patients who are candidates for DBS, as genetic factors may affect the effectiveness of DBS in these patients. This review article discusses the role of genetics in DBS for PD patients, in an attempt to better understand inter-individual variability in DBS response, control of motor PD symptoms and appearance of non-motor symptoms, especially cognitive decline. [ABSTRACT FROM AUTHOR]

Neurosteroids are pleiotropic molecules involved in various neurodegenerative diseases with neuroinflammation. We assessed neurosteroids' serum levels in a cohort of Parkinson's Disease (PD) patients with heterozygous glucocerebrosidase (GBA) mutations (GBA-PD) compared with matched cohorts of consecutive non-mutated PD (NM-PD) patients and healthy subjects with (GBA-HC) and without (NM-HC) GBA mutations. A consecutive cohort of GBA-PD was paired for age, sex, disease duration, Hoehn and Yahr stage, and comorbidities with a cohort of consecutive NM-PD. Two cohorts of GBA-HC and HC were also considered. Clinical assessment included the Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the Montreal Cognitive Assessment (MoCA). Serum samples were processed and analyzed by liquid chromatography coupled with the triple quadrupole mass spectrometry. Twenty-two GBA-PD (males: 11, age: 63.68), 22 NM-PD (males: 11, age: 63.05), 14 GBA-HC (males: 8; age: 49.36), and 15 HC (males: 4; age: 60.60) were studied. Compared to NM-PD, GBA-PD showed more hallucinations and psychosis (p < 0.05, Fisher's exact test) and higher MDS-UPDRS part-II (p < 0.05). Most of the serum neurosteroids were reduced in both GBA-PD and NM-PD compared to the respective control cohorts, except for 5α-dihydroprogesterone. Allopregnanolone was the only neurosteroid significantly lower (p < 0.01, Dunn's test) in NM-PD compared to GBA-PD patients. Only in GBA-PD, allopregnanolone, and pregnanolone levels correlated (Spearman) with a more severe MDS-UPDRS part-III. Allopregnanolone levels also negatively correlated with MoCA scores, and pregnanolone levels correlated with more pronounced bradykinesia. This pilot study provides the first observation of changes in neurosteroid peripheral levels in GBA-PD. The involvement of the observed changes in the development of neuropsychological and motor symptoms of GBA-PD deserves further attention. [ABSTRACT FROM AUTHOR]

Introduction: Gaucher disease (GD) is classically divided into three types, based on the presence or absence of neurological signs and symptoms. However, presentation can be highly variable in adulthood, and this aspect has not been adequately addressed in the literature so far. We performed a systematic literature review to analyze the entire spectrum of neurological manifestations in adult patients previously classified as GD type I, II, or III, evaluating the role of variants in different neurological manifestations. Methods: We searched databases for studies reporting clinical data of adult GD patients (age ≥ 18). Data extraction included GD types, GBA1 variants, age at disease onset and diagnosis, duration of GD, and age at onset and type of neurological symptoms reported. Results: Among 4190 GD patients from 85 studies, 555 exhibited neurological symptoms in adulthood. The median age at evaluation was 46.8 years (IQR 26.5), age at neurological symptoms onset was 44 years (IQR 35.1), and age at GD clinical onset was 23 years (IQR 23.4). Parkinsonism, including Parkinson's disease and Lewy Body dementia, was the most reported neurological manifestation. Other symptoms and signs encompassed oculomotor abnormalities, peripheral neuropathy, seizures, myoclonus, and cerebellar, cognitive and psychiatric symptoms. The genotype N370S/N370S mostly presented with Parkinsonism and the L444P variant with severe and earlier neurological symptoms. Conclusion: The findings of this systematic review highlight: (1) the relevance of a comprehensive neurological assessment in GD patients, and (2) the importance of considering possible undiagnosed GD in adult patients with mild systemic symptoms presenting unexplained neurological symptoms. [ABSTRACT FROM AUTHOR]

Introduction: Prodromal Parkinson's disease (PD) carriers of dual leucine‐rich repeat kinase 2 (LRRK2) and glucosylceramidase β (GBA) variants are rare, and their biomarkers are less well developed. Objective: This study aimed to investigate the biomarkers for diagnosing the prodromal phase of LRRK2‐GBA‐PD (LRRK2‐GBA‐prodromal). Methods: We assessed the clinical and whole‐brain white matter microstructural characteristics of 54 prodromal PD carriers of dual LRRK2 (100% M239T) and GBA (95% N409S) variants, along with 76 healthy controls (HCs) from the Parkinson's Progression Markers Initiative (PPMI) cohort. Results: By analyzing the four values of 100 nodes on 20 fiber bundles, totaling 8000 data points, we identified the smallest p value in the fractional anisotropy (FA) value of the 38th segment of left corticospinal tract (L‐CST) with differences between LRRK2‐GBA‐prodromal and HCs (p = 8.94 × 10−9). The FA value of the 38th node of the L‐CST was significantly lower in LRRK2‐GBA‐prodromal (FA value, 0.65) compared with HCs (FA value, 0.71). The receiver‐operating characteristic curve showed a cut‐off value of 0.218 for the FA value of L‐CST, providing sufficient sensitivity (79.2%) and specificity (72.2%) to distinguish double mutation prodromal PD from the healthy population. Conclusion: L‐CST, especially the 38th node, may potentially serve as a biomarker for distinguishing individuals with double mutation prodromal PD from the healthy population. [ABSTRACT FROM AUTHOR]

Background: The GPNMB single‐nucleotide polymorphism rs199347 and GBA1 variants both associate with Lewy body disorder (LBD) risk. GPNMB encodes glycoprotein nonmetastatic melanoma protein B (GPNMB), a biomarker for GBA1‐associated Gaucher's disease. Objective: The aim of this study was to determine whether GPNMB levels (1) differ in LBD with and without GBA1 variants and (2) associate with rs199347 genotype. Methods: We quantified GPNMB levels in plasma and cerebrospinal fluid (CSF) from 124 individuals with LBD with one GBA1 variant (121 plasma, 14 CSF), 631 individuals with LBD without GBA1 variants (626 plasma, 41 CSF), 9 neurologically normal individuals with one GBA1 variant (plasma), and 2 individuals with two GBA1 variants (plasma). We tested for associations between GPNMB levels and rs199347 or GBA1 status. Results: GPNMB levels associate with rs199347 genotype in plasma (P = 0.022) and CSF (P = 0.007), but not with GBA1 status. Conclusions: rs199347 is a protein quantitative trait locus for GPNMB. GPNMB levels are unaltered in individuals carrying one GBA1 variant. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Levodopa-carbidopa intestinal gel infusion (LCIG) is a therapeutic option for advanced Parkinson disease (PD) patients with troublesome motor complications, unresponsive to conventional oral treatment. There is some evidence to suggest that the genetic background may influence the clinical presentation and rate of progression of PD. Whether the genetic background influences the outcome of device-assisted therapies is currently debated. Some studies have investigated the effectiveness of deep brain stimulation (DBS) in PD patients with different genetic background, while evidence is lacking regarding LCIG. Methods: A cohort of LCIG patients underwent genetic testing. The motor and neuropsychological outcomes of LCIG were retrospectively analyzed. Results: Fifty-six patients were analyzed, nine of them (15%) had at least one mutation/variant in a PD-associated gene: five GBA1, two SNCA, one LRRK2, one PRKN; 13 (23%) carried the BDNF Val66Met polymorphism. The mean duration of follow-up was 4.9 ± 2.6 years. There were no significant differences in motor or neuropsychological outcomes between patients with and without these gene mutations/variants. No cognitive worsening was observed at follow-up among GBA-PD patients, and they responded well to LCIG in terms of motor symptoms. Conclusions: Overall, we observed a significant benefit in terms of motor complications in our cohort, including patients carrying genetic mutations/variants. Due to the small sample and limited number of patients carrying genetic mutations/variants, no definitive conclusions can be drawn yet on the genotype impact on LCIG outcome. A careful selection of patients, regardless of the genetic background, is pivotal for an optimal outcome of LCIG. [ABSTRACT FROM AUTHOR]

A significant rise in metabolic disorders, frequently brought on by lifestyle choices, is alarming. A wide range of preliminary studies indicates the significance of the gut-brain axis, which regulates bidirectional signaling between the gastrointestinal tract and the cognitive system, and is crucial for regulating host metabolism and cognition. Intimate connections between the brain and the gastrointestinal tract provide a network of neurohumoral transmission that can transmit in both directions. The gut-brain axis successfully establishes that the wellness of the brain is always correlated with the extent to which the gut operates. Research on the gut-brain axis has historically concentrated on how psychological health affects how well the gastrointestinal system works. The latest studies, however, revealed that the gut microbiota interacts with the brain via the gut-brain axis to control phenotypic changes in the brain and in behavior. This study addresses the significance of the gut microbiota, the role of the gut-brain axis in management of various metabolic disorders, the hormonal and neural signaling pathways and the therapeutic treatments available. Its objective is to establish the significance of the gut-brain axis in metabolic disorders accurately and examine the link between the two while evaluating the therapeutic strategies to be incorporated in the future. Deciphering the intricate communication of the GBA reveals its pivotal role in regulating metabolic disorders and cognition. This exploration underscores the dynamic interplay between gut microbiota, neurohumoral signaling, and potential therapeutic interventions, highlighting new avenues for holistic metabolic management. [ABSTRACT FROM AUTHOR]

The movement toward prevention trials in people at-risk for Parkinson's disease (PD) is rapidly becoming a reality. The authors of this article include a genetically at-risk advocate with the LRRK2 G2019 S variant and two patients with rapid eye movement sleep behavior disorder (RBD), one of whom has now been diagnosed with PD. These authors participated as speakers, panelists, and moderators in the "Planning for Prevention of Parkinson's: A Trial Design Forum" hosted by Massachusetts General Hospital in 2021 and 2022. Other authors include a young onset person with Parkinson's (PwP) and retired family physician, an expert in patient engagement in Parkinson's, and early career and veteran movement disorders clinician researchers. Several themes emerged from the at-risk participant voice concerning the importance of early intervention, the legitimacy of their input in decision-making, and the desire for transparent communication and feedback throughout the entire research study process. Challenges and opportunities in the current environment include lack of awareness among primary care physicians and general neurologists about PD risk, legal and psychological implications of risk disclosure, limited return of individual research study results, and undefined engagement and integration of individuals at-risk into the broader Parkinson's community. Incorporating the perspectives of individuals at-risk as well as those living with PD at this early stage of prevention trial development is crucial to success. [ABSTRACT FROM AUTHOR]

This research selects art museums in four cities in the Guangdong-Hong Kong-Macao Greater Bay Area (GBA) region for relevant research, namely Guangzhou, Hong Kong, Macao and Shenzhen, which are important representatives of the artistic, cultural, economic and technological development of the GBA. It examines the digital technology strategies used by six selected art museums within the four GBA cities to promote the co-development of collections, exhibitions and audience engagement. The objective of the study has been approached through the following research question: How are art museums using digital technology to improve the relationship among collections, exhibitions and audience engagement from the perspective of online exhibitions? In this article, online exhibitions are seen as an invaluable virtual platform for art museums to display art to the public during the COVID-19 pandemic. The necessity for art museums to use digital technology to develop online exhibitions in the face of the plight of the COVID-19 pandemic is first introduced in this article. It then addresses how online exhibitions and online technologies in art museums have influenced the development of collections from offline to online, as well as how to further strengthen the relationship between collections, exhibitions and the audience. Some of the key challenges for art museums in developing online exhibitions using digital technology are also mentioned, and possible future developments of online exhibitions in art museums are discussed. At the same time, there is a need to consider the issues faced by art museums in the Guangdong-Hong Kong-Macao Greater Bay Area as they continue to use digital technology to develop collections, exhibitions and audiences in the post-COVID-19 pandemic period. [ABSTRACT FROM AUTHOR]

The most common genetic risk factors for Parkinson's disease are GBA1 mutations, encoding the lysosomal enzyme glucocerebrosidase. Patients with GBA1 mutations (GBA-PD) exhibit earlier age of onset and faster disease progression with more severe cognitive impairments, postural instability and gait problems. These GBA-PD features suggest more severe cholinergic system pathologies. PET imaging with the vesicular acetylcholine transporter ligand 18F-F-fluoroethoxybenzovesamicol (18F-FEOBV PET) provides the opportunity to investigate cholinergic changes and their relationship to clinical features in GBA-PD. The study investigated 123 newly diagnosed, treatment-naïve Parkinson's disease subjects—with confirmed presynaptic dopaminergic deficits on PET imaging. Whole-gene GBA1 sequencing of saliva samples was performed to evaluate GBA1 variants. Patients underwent extensive neuropsychological assessment of all cognitive domains, motor evaluation with the Unified Parkinson's Disease Rating Scale, brain MRI, dopaminergic PET to measure striatal-to-occipital ratios of the putamen and 18F-FEOBV PET. We investigated differences in regional cholinergic innervation between GBA-PD carriers and non- GBA1 mutation carriers (non-GBA-PD), using voxel-wise and volume of interest-based approaches. The degree of overlap between t-maps from two-sample t -test models was quantified using the Dice similarity coefficient. Seventeen (13.8%) subjects had a GBA1 mutation. No significant differences were found in clinical features and dopaminergic ratios between GBA-PD and non-GBA-PD at diagnosis. Lower 18F-FEOBV binding was found in both the GBA-PD and non-GBA-PD groups compared to controls. Dice (P < 0.05, cluster size 100) showed good overlap (0.7326) between the GBA-PD and non-GBA-PD maps. GBA-PD patients showed more widespread reduction in 18F-FEOBV binding than non-GBA-PD when compared to controls in occipital, parietal, temporal and frontal cortices (P < 0.05, FDR-corrected). In volume of interest analyses (Bonferroni corrected), the left parahippocampal gyrus was more affected in GBA-PD. De novo GBA-PD show a distinct topography of regional cholinergic terminal ligand binding. Although the Parkinson's disease groups were not distinguishable clinically, in comparison to healthy controls, GBA-PD showed more extensive cholinergic denervation compared to non-GBA-PD. A larger group is needed to validate these findings. Our results suggest that de novo GBA-PD and non-GBA-PD show differential patterns of cholinergic system changes before clinical phenotypic differences between carriers versus non-carrier groups are observable. [ABSTRACT FROM AUTHOR]

Objective: Glucosylceramidase (GBA) variants and onset age significantly affect clinical phenotype and progression in Parkinson's disease (PD). The current study compared clinical characteristics at baseline and cognitive and motor progression over time among patients having GBA‐related PD (GBA‐PD), early‐onset idiopathic PD (early‐iPD), and late‐onset idiopathic PD (late‐iPD). Methods: We recruited 88 GBA‐PD, 167 early‐iPD, and 488 late‐iPD patients in this study. A subset of 50 GBA‐PD, 81 early‐iPD, and 223 late‐iPD patients was followed up at least once, with a 3.0‐year mean follow‐up time. Linear mixed‐effects models helped evaluate the rate of change in the Unified Parkinson's Disease Rating Scale motor and Montreal Cognitive Assessment scores. Results: At baseline, the GBA‐PD group showed more severe motor deficits and non‐motor symptoms (NMSs) than the early‐iPD group and more NMSs than the late‐iPD group. Moreover, the GBA‐PD group had more significant cognitive and motor progression, particularly bradykinesia and axial impairment, than the early‐iPD and late‐iPD groups at follow‐up. However, the early‐onset GBA‐PD (early‐GBA‐PD) group was similar to the late‐onset GBA‐PD (late‐GBA‐PD) group in baseline clinical features and cognitive and motor progression. Conclusion: GBA‐PD patients exhibited faster cognitive and motor deterioration than early‐iPD and late‐iPD patients. Thus, subtype classification based on genetic characteristics rather than age at onset could enhance the prediction of PD disease progression. [ABSTRACT FROM AUTHOR]

While multiple system atrophy (MSA) has been considered a sporadic disease, there were previously reported multiplex families with MSA. Furthermore, several families with multiple patients with MSA and Parkinson's disease (PD) have been reported. As genetic risk factors for MSA, functionally impaired variants in COQ2 and Gaucher-disease-causing GBA variants have been reported. While it has been established that GBA variants are associated with PD, COQ2 may also be associated with PD. In 672 patients with MSA, we identified 12 multiplex families of patients with MSA and PD in first-degree relatives. We conducted a detailed analysis of the clinical presentations of these patients and genetic analyses of GBA and COQ2. In the multiplex families, a patient with MSA with predominant parkinsonism (MSA-P) was observed in nine families, while a patient with MSA cerebellar subtype (MSA-C) was observed in three families. Six families had siblings with MSA and PD, five families had a parent–offspring pair with MSA and PD, and in one family, a sibling and a parent of an MSA patient had PD. In genetic analyses of these patients, GBA variants were identified in one of the 12 MSA patients and two of the seven PD patients. Functionally impaired variants of COQ2 were identified in two of the 12 MSA patients and not identified in the seven PD patients. This study further emphasizes the occurrence of MSA and PD in first-degree relatives, raising the possibility that a common genetic basis underlies MSA and PD. Even though variants of COQ2 and GBA were identified in some patients in multiplex families with MSA and PD, it is necessary to further explore as yet unidentified genetic risk factors shared by MSA and PD. [ABSTRACT FROM AUTHOR]

Rare and common GBA variants are risk factors for both Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). However, the degree to which GBA variants are associated with neuropathological features in Lewy body disease (LBD) is unknown. Herein, we assessed 943 LBD cases and examined associations of 15 different neuropathological outcomes with common and rare GBA variants. Neuropathological outcomes included LBD subtype, presence of a high likelihood of clinical DLB (per consensus guidelines), LB counts in five cortical regions, tyrosine hydroxylase immunoreactivity in the dorsolateral and ventromedial putamen, ventrolateral substantia nigra neuronal loss, Braak neurofibrillary tangle (NFT) stage, Thal amyloid phase, phospho-ubiquitin (pS65-Ub) level, TDP-43 pathology, and vascular disease. Sequencing of GBA exons revealed a total of 42 different variants (4 common [MAF > 0.5%], 38 rare [MAF < 0.5%]) in our series, and 165 cases (17.5%) had a copy of the minor allele for ≥ 1 variant. In analysis of common variants, p.L483P was associated with a lower Braak NFT stage (OR = 0.10, P < 0.001). In gene-burden analysis, presence of the minor allele for any GBA variant was associated with increased odds of a high likelihood of DLB (OR = 2.00, P < 0.001), a lower Braak NFT stage (OR = 0.48, P < 0.001), a lower Thal amyloid phase (OR = 0.55, P < 0.001), and a lower pS65-Ub level (β: −0.37, P < 0.001). Subgroup analysis revealed that GBA variants were most common in LBD cases with a combination of transitional/diffuse LBD and Braak NFT stage 0-II or Thal amyloid phase 0–1, and correspondingly that the aforementioned associations of GBA gene-burden with a decreased Braak NFT stage and Thal amyloid phase were observed only in transitional or diffuse LBD cases. Our results indicate that in LBD, GBA variants occur most frequently in cases with greater LB pathology and low AD pathology, further informing disease–risk associations of GBA in PD, PD dementia, and DLB. [ABSTRACT FROM AUTHOR]

Multi-scale landscape functions play a critical role in revealing intricate functional structures within large regions. However, previous studies on landscape functions have predominantly focused on a single macro or micro scale, impeding a holistic multi-scale understanding of the spatial distribution and heterogeneity of landscape functions. To address this gap, this study proposes a framework leveraging the power of big geodata to mine multi-scale landscape functions from parcel to entire urban agglomerations, as well as non-administrative divisions. Our study focuses on the Guangdong-Hong Kong-Macao Greater Bay Area (GBA) in China. Firstly, we integrated multi-source big geodata to derive parcel-scale landscape functions. Subsequently, we employed the Normalized Revealed Comparative Advantage index to derive landscape functions at broader scales, including towns, counties and cities. The effectiveness of our approach is validated through in-field investigations and comparisons with established policy planning positions. The outcomes not only offer distinctive planning insights at various scales but also highlight the versatility of big geodata in extracting landscape functions across scales. This study demonstrates that big geodata is adept at uncovering multi-scale landscape functions irrespective of administrative boundaries, providing valuable insights for fostering multi-scale regional coordinated development. [ABSTRACT FROM AUTHOR]

Parknson's disease (PD) is the second most common neurodegenerative disease, affecting 1% of people aged over 60. PD is characterized by a wide range of motor symptoms, however the clinical spectrum of PD covers a wide range of non-motor symptoms, as well. Sleep disorders are among the most common non-motor symptoms of PD, can occur at any stage of the disease and significantly affect quality of life. These include rapid eye movement sleep behavior disorder (RBD), restless legs syndrome (RLS), excessive daytime sleepiness (EDS), insomnia, obstructive sleep apnea (OSA) and circadian rhythm disturbances. One of the main challenges in PD research is identifying individuals during the prodromal phase of the disease. Combining genetic and prodromal data may aid the early identification of individuals susceptible to PD. This review highlights current data regarding the genetic component of sleep disorders in PD patients, focusing on genes that have currently been associated with this PD co-morbidity. [ABSTRACT FROM AUTHOR]

Introduction: The extensive clinical variations observed in Parkinson’s disease (PD) pose challenges in early diagnosis and treatment initiation. However, genetic research in PD has significantly transformed the clinical approach to its treatment. Moreover, researchers have adopted a subtyping strategy based on homogeneous clinical symptoms to improve clinical diagnosis and treatment approaches. We conducted a study to explore clinical characteristics in genetic PD groups with motor symptom subtyping. Methods: Data was driven from the Parkinson’s Progression Markers Initiative (PPMI) database. The sporadic PD (sPD) group and the genetic PD group including patients with leucine-rich kinase 2 (LRRK2) or glucosylceramidase β (GBA) mutations were analyzed. Motor subtyping was performed using Movement Disorder Society-Unified Parkinson’s disease rating scale (MDS-UPDRS) scores. I-123 FP-CIT SPECT scans were used to calculate specific binding ratios (SBRs) in the caudate and putamen. Clinical symptoms of each group were also compared. Results: MDS-UPDRS III scores were lower in the LRRK2 group, compared with the GBA and SPD group (P < 0.001), but no significant differences in striatal SBRs. The putaminal SBR value of the LRRK2 group was higher than the sPD group (P < 0.05). Within the GBA group, we observed lower SBR values in the postural instability/gait difficulty (PIGD) subtype GBA group compared to the tremor-dominant (TD) subtype GBA group (P < 0.05). The TD subtype GBA group exhibited superior putaminal SBRs compared to the TD subtype sPD group (P < 0.05). The TD subtype LRRK2 group had better putaminal SBR values (P < 0.001) and MDS-UPDRS Part III scores (P < 0.05) compared to the TD SPD group. Discussions: Our subtyping approach offers valuable insights into the clinical characteristics and progression of different genetic PD subtypes. To further validate and expand these findings, future research with larger groups and long- term follow-up data is needed. The subtyping strategy based on motor symptoms holds promise in enhancing the diagnosis and treatment of genetic PD. [ABSTRACT FROM AUTHOR]

Background: Patients with Parkinson's disease (PD) and GBA gene mutations (GBA‐PD) develop nonmotor complications more frequently than noncarriers. However, an objective characterization of both cardiovascular and sudomotor autonomic dysfunction using extensive clinical and instrumental measures has never been provided so far. Survival is reduced in GBA‐PD regardless of age and dementia, suggesting that other hitherto unrecognized factors are involved. Objectives: To provide instrumental measures of pattern and severity of autonomic dysfunction in GBA‐PD and explore their correlation with other non‐motor symptoms and implications for clinical practice. Methods: In this cross‐sectional study, 21 GBA‐PD and 24 matched PD noncarriers underwent extensive assessment of motor and non‐motor features, including neuropsychological testing. Cardiovascular autonomic function was explored through a comprehensive battery of indexes, including power spectral analysis of the R‐R intervals and blood pressure short‐term variability during resting state and active maneuvers. Dynamic Sweat Test was used to assess post‐ganglionic sudomotor dysfunction. Results: Despite minimal or absent clinical correlates, cardiovagal and sympathetic indexes, heart rate variability parameters and sudomotor postganglionic function were more severely impaired in GBA‐PD than noncarriers (overcoming relatively preserved compensatory peripheral sympathetic function), suggesting more prominent cardiac sympatho‐vagal demodulation, efferent baroreflex failure and peripheral sympathetic dysfunction in GBA‐PD. Cardiovascular dysautonomia showed marginal correlations with cognitive impairment. Conclusions: Compared to PD noncarriers, GBA‐PD display more severe instrumental autonomic abnormalities, which may be underestimated by purely clinical measures, despite their relevance on morbidity and mortality. This supports the necessity of implementing instrumental autonomic assessment in all GBA‐PD, regardless of clinically overt symptoms. [ABSTRACT FROM AUTHOR]

Camostat mesylate is expected to be promising as a treatment option for COVID-19, in addition to other indications for which it is currently used. Furthermore, in vitro experiments have confirmed the potential of camostat and its metabolites to be effective against COVID-19. Therefore, clinical trials were conducted to evaluate the safety and pharmacokinetic characteristics of camostat after single-dose administration. Additionally, we aim to predict the pharmacokinetics of repeated dosing through modeling and simulation based on clinical trials. Clinical trials were conducted on healthy Korean adults, and an analysis was carried out of the metabolites of camostat, GBPA, and GBA. Pharmacokinetic modeling and simulation were performed using Monolix. There were no safety issues (AEs, physical examinations, clinical laboratory tests, vital sign measurements, and ECG) during the clinical trial. The pharmacokinetic characteristics at various doses were identified. It was confirmed that AUC last and Cmax increased in proportion to dose in both GBPA and GBA, and linearity was also confirmed in log-transformed power model regression. Additionally, the accumulation index was predicted (1.12 and 1.08 for GBPA and GBA). The pharmacokinetics of camostat for various dose administrations and indications can be predicted prior to clinical trials using the developed camostat model. Furthermore, it can be used for various indications by connecting it with pharmacodynamic information. [ABSTRACT FROM AUTHOR]

The study of the formation and development of urban agglomerations is of great significance, and the connection between cities is the critical foundation for shaping these agglomerations. However, the mechanism behind spatial connection between cities in the formation of urban agglomerations remains unclear. Using the Greater Bay Area (GBA) as a case study, we proposed a Bayesian network framework that integrated the spatial connection index and land use intensity. We constructed a dependency network of land use intensity from the perspective of spatial connection, and summarized the spatiotemporal evolution patterns of urban agglomeration combined with social network analysis methods. The results indicate that: (1) From 1980 to 2020, both land use intensity and spatial connection strength in the GBA have significantly increased, though the characteristics of different cities varied noticeably; (2) The spatial connection center of the urban agglomeration has shifted geographically from Hong Kong and Macao to the Pearl River Delta, and then to the east bank of the Pearl River. Hong Kong, Guangzhou, and Shenzhen are the three core cities in the spatial connection network, each with different development trajectories. (3) A dependency network of changes in land use intensity among cities at different stages from the perspective of spatial connection was constructed, identifying the evolving roles of each city in the development of the urban agglomeration. The study discussed a three-stage development model of urban agglomerations from the perspective of spatial connection, providing a new perspective for exploring the formation mechanism of urban agglomerations. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder among elderly individuals, after Alzheimer's disease. This complex disorder manifests with multiple motor and non-motor features and is often diagnosed only after the onset of significant pathological symptoms. Based on the presumption that epigenetic mechanisms are involved in neurodevelopment and synaptic transmission, it is hypothesized that epigenetic alterations are closely connected to the development of PD. Several studies have reported that genetic risk factors are involved in PD susceptibilities. These factors play a prominent role in the predisposition and development of PD and may be closely linked to different metabolic pathways. In this review, we revise associations between single nucleotide polymorphisms (SNPs) and PD pathogenesis. [ABSTRACT FROM AUTHOR]

Background: GBA1 variants are the strongest genetic risk factor for Parkinson's disease (PD). However, the pathogenicity of GBA1 variants concerning PD is still not fully understood. Additionally, the frequency of GBA1 variants varies widely across populations. Objectives: To evaluate Oxford Nanopore sequencing as a strategy, to determine the frequency of GBA1 variants in Norwegian PD patients and controls, and to review the current literature on newly identified variants that add to pathogenicity determination. Methods: We included 462 Norwegian PD patients and 367 healthy controls. We sequenced the full-length GBA1 gene on the Oxford Nanopore GridION as an 8.9 kb amplicon. Six analysis pipelines were compared using two aligners (NGMLR, Minimap2) and three variant callers (BCFtools, Clair3, Pepper-Margin-Deepvariant). Confirmation of GBA1 variants was performed by Sanger sequencing and the pathogenicity of variants was evaluated. Results: We found 95.8% (115/120) true-positive GBA1 variant calls, while 4.2% (5/120) variant calls were false-positive, with the NGMLR/Minimap2-BCFtools pipeline performing best. In total, 13 rare GBA1 variants were detected: two were predicted to be (likely) pathogenic and eleven were of uncertain significance. The odds of carrying one of the two common GBA1 variants, p.L483P or p.N409S, in PD patients were estimated to be 4.11 times the odds of carrying one of these variants in controls (OR = 4.11 [1.39, 12.12]). Conclusions: In conclusion, we have demonstrated that Oxford long-read Nanopore sequencing, along with the NGMLR/Minimap2-BCFtools pipeline is an effective tool to investigate GBA1 variants. Further studies on the pathogenicity of GBA1 variants are needed to assess their effect on PD. [ABSTRACT FROM AUTHOR]

Background: The glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 (LRRK2) genes are associated with the risk of sporadic Parkinson's disease (PD). As an environmental factor, hypoxic insults may impair dopamine neurons in the substantia nigra and exacerbate PD symptoms. However, covariants of GBA and LRRK2 combined with hypoxic insults in clinical cases of Parkinsonism have not yet been reported. Case presentation: A 69-year-old male patient with PD and his relatives were clinically characterized and sequenced using the whole-exome technique. A novel covariant, c.1448 T > C (p. L483P, rs421016) on GBA and c.691 T > C (p. S231P, rs201332859) on LRRK2 were identified in this patient who first developed bradykinesia and rigidity in the neck at one month after an acute hypoxic insult during mountaineering. The patient presented with a mask-like face, festinating gait, asymmetric bradykinesia, and moderate rigidity. These symptoms were treated with levodopa and pramipexole, resulting in a 65% improvement in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score. These parkinsonian symptoms persisted and developed with hallucinations, constipation, and rapid eye movement sleep behavior disorder. After 4 years, the patient exhibited a wearing-off phenomenon and died from pulmonary infection 8 years after disease onset. His parents, wife, and siblings were not diagnosed with PD, and his son carried p. L483P without Parkinsonism-like symptoms. Conclusions: This is a case report of PD after hypoxic insult in a patient carrying a covariant of GBA and LRRK2. This study may help us understand the interaction between genetic and environmental factors in clinical PD. [ABSTRACT FROM AUTHOR]

Background: ship emissions have an adverse effect on air quality in coastal regions, and this effect can be exacerbated by onshore winds. Objectives and methods: to investigate the impact of ship emissions on air pollutant concentrations during the onshore wind period in a low-latitude region in China, this study applied the WRF/Chem model to simulate the contribution of ship emissions to PM2.5 and O3 by "zero-out" in 2018, in the Guangdong-Hong Kong-Macao Greater Bay Area (GBA). Results/findings: results show that the onshore winds facilitated the transport of ship-emitted pollutants to inland areas, causing the contribution of ship emissions to PM2.5 exceeding 4 μg/m3 to areas north of Guangzhou in April and west of the GBA in October. The impact of onshore winds on the ship contribution to the O3 concentration shows a bidirectional trend both spatially and monthly. The onshore winds raised the ship contribution to O3 concentrations in April by 1.54 μg/m3, while exacerbated the decreasing contribution in other months. In VOC-sensitive cities such as Foshan, onshore winds exacerbated the negative contribution of ship emissions to O3 concentrations; while in NOx-sensitive cities such as Huizhou, they enhanced the contribution of ship-induced O3. Novelty/Improvement: this paper fills a gap in the study of pollutants transportation characteristics from ship emissions under the influence of onshore winds in the GBA. Our results demonstrate the importance of considering meteorological conditions and atmospheric chemical mechanisms regarding the coastal air pollution prevention caused by ship emissions. [ABSTRACT FROM AUTHOR]

Listening is a skill that is sometimes forgotten when learning a language. Although it may appear challenging, listening abilities can be improved over time if practiced regularly. This study aimed to see if the genre-based approach (GBA) could be used to teach listening. This study employed a qualitative design. The participants of this study were a teacher and 15 students of grade 11 (eleven) of Senior High school in Medan, Indonesia, consisting of nine males and six female students. The English teacher was chosen because she is a senior teacher who has applied 2013 curriculum and used genre-based English learning in grade eleven (11) students of an old high school in Medan. This study applied the data collection techniques by conducting classroom observation and interviews. The findings presented that the GBA with four cycles of learning model applied by the teacher was considered capable of helping students in listening learning. It can help students recognize text variations, vocabulary, and structures in the text, which were also students' provisions in the listening process. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) patients who are carriers of glucosylceramidase β1 (GBA1) gene mutations typically have an earlier age at onset and a more aggressive disease course, with a higher burden of neuropsychological issues. The use of deep brain stimulation (DBS) in PD patients with disabling motor fluctuations and absence of dementia is a widespread therapeutic option, often with good results in terms of improvement in activities of daily living and quality of life. Although all PD patients, when fulfilling the common selection criteria for DBS, can benefit from this intervention, some studies have raised attention toward the fact that PD patients who are carriers of GBA1 variants may have a worse DBS outcome possibly due to an accelerated progression of cognitive decline. From this viewpoint, we summarize the current literature, highlighting the knowledge gaps and proposing suggestions for further research as well as for clinical practice in this timeframe of uncertainty related to using DBS in PD patients who are carriers of GBA1 variants. [ABSTRACT FROM AUTHOR]

Background: Mood disorders have emerged as major non‐motor comorbidities in Parkinson's disease (PD) even at the prodromal stage of the disease. Mutations in the LRRK2 and GBA genes are common among Ashkenazi Jews, with more severe phenotype reported for GBA‐PD. Objective: To explore the association between genetic status and mood related disorders before and after diagnosis of PD and the association between mood‐related medications, phenotype, and genetic status. Methods: Participants were genotyped for mutations in the LRRK2 and GBA genes. State of depression, anxiety and non‐motor features were evaluated using validated questionnaires. History of mood disorders prior to diagnosis of PD and use of mood‐related medications were assessed. Results: The study included 105 idiopathic PD (iPD), 55 LRRK2‐PD and 94 GBA‐PD. Scores on mood related questionnaires and frequency of depression and anxiety before diagnosis were similar between the groups (p>0.05). However, more GBA‐PD patients used mood related medications before PD diagnosis than LRRK2‐PD and iPD (16.5% vs 7.1% and 8.2%, p=0.044). LRRK2‐PD and GBA‐PD receiving mood‐related medications at time of assessment had worse motor and non‐motor phenotype compared to those that did not (p<0.05). LRRK2‐PD receiving mood related‐medications at time of assessment, scored higher on mood‐related questionnaires compared to LRRK2‐PD not receiving such medications (p<0.04). Conclusions: Prodromal GBA‐PD are more frequently treated with mood related‐medications despite equal rates of reported mood‐related disorders, while LRRK2‐PD with mood‐related disorders experience high rates of anxiety and depression despite treatment, attesting to the need of more precise assessment and treatment of these genetic subgroups. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder among elderly individuals, after Alzheimer's disease. This complex disorder manifests with multiple motor and non-motor features and is often diagnosed only after the onset of significant pathological symptoms. Based on the presumption that epigenetic mechanisms are involved in neurodevelopment and synaptic transmission, it is hypothesized that epigenetic alterations are closely connected to the development of PD. Several studies have reported that genetic risk factors are involved in PD susceptibilities. These factors play a prominent role in the predisposition and development of PD and may be closely linked to different metabolic pathways. In this review, we revise associations between single nucleotide polymorphisms (SNPs) and PD pathogenesis. [ABSTRACT FROM AUTHOR]

An emergy analysis is used to assess the sustainability of urban agglomerations' eco-economic systems, which are generally measured by emergy–value sustainability indicators using a combination of several system indicators. However, this assessment approach is not applicable to economically developed high-density urban agglomerations. The application of the traditional entropy value evaluation method needs to be expanded to further strengthen the sustainability of the complex eco-economic–social relationships in megacity cluster regions. In this study, taking the Guangdong–Hong Kong–Macau Greater Bay Area (GBA) as a case study, we study a new evaluation method for evaluating the sustainable development capacity of cities. This method is based on the entropy power method and is used to construct the evaluation system of all indicators of the social–economic–natural subsystems of the eco-economic system, and it couples the development degree with the coordination degree. (1) This study shows that the new method is applicable for the sustainability assessment of high-density megacity clusters and is more accurate and comprehensive. The sustainability rankings are provided for Zhaoqing, Jiangmen, Huizhou, Guangzhou, Macau, Foshan, Zhongshan, Dongguan, Zhuhai, and Shenzhen. Hong Kong is the most representative, with a high sustainability index, but has the lowest level of coordination and a clear incoherence within the system. (2) The current emergy structure of the GBA city cluster is extremely unreasonable. The GBA city cluster is a resource-consuming city with a common characteristic of a low level of coordinated development. Although urban clusters have some potential in terms of renewable emergy and resources, the recycling rate of waste is low, and the consumption rate of nonrenewable resources is high. The effective use of land resources has become an important factor in the bottlenecking of sustainable development, and all other cities face such problems, except Zhaoqing, Jiangmen, and Huizhou. (3) The GBA city cluster can be divided into three categories according to the new method. Category 1 mainly includes Hong Kong, Shenzhen, Dongguan, and Zhuhai, which have coordinated development degrees ranging between 0.0 and 0.135 and the highest emergy density (ED) values but are extremely dependent on external emergy. They have high levels of emergy use per capita (EUC), high living standards, and high quality of life. The effective use of land resources severely restricts sustainable economic development, resulting in extreme ecological and environmental carrying pressure. Category 2 includes Guangzhou, Macau, Foshan, and Zhongshan, whose coordinated development degrees range from 0.143 to 0.179. The sustainable development capacity of these cities is at the middle level amongst the whole GBA. Their main emergy characteristics are emergy flow and subsystem evaluation indices that are between category 1 and category 3, but each has its own characteristics. The category 3 cities include Zhaoqing, Jiangmen, and Huizhou, whose coordinated development degrees are between 0.192 and 0.369. These cities are characterized by relatively low ED and EUC values, living standards, and quality, but their land resources have certain potential. These cities have a high emergy self-sufficiency rate (ESR) and natural environmental support capacity, but their environmental loading ratio (ELR) is still much higher than the national average. In terms of the economic development and innovation development levels, these cities are ranked as category 1 > category 2 > category 3. In terms of the ecological and environmental conditions and blue–green space protection, these cities are ranked as category 1 < category 2 < category 3. The results of this study can provide cities in the GBA with more scientific and consistent directions for the coordinated development of their ecological–economic–social systems to provide sustainable development decision-making services for megacity cluster systems. [ABSTRACT FROM AUTHOR]

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Background: GBA1 variants are among the most common genetic risk factors for Parkinson's disease (PD). GBA1 variants can be classified into three categories based on their role in Gaucher's disease (GD) or PD: severe, mild, and risk variant (for PD). Objective: This review aims to generate and share a comprehensive database for GBA1 variants reported in PD to support future research and clinical trials. Methods: We performed a literature search for all GBA1 variants that have been reported in PD. The data have been standardized and complemented with variant classification, odds ratio if available, and other data. Results: We found 371 GBA1 variants reported in PD: 22 mild, 84 severe, 3 risk variants, and 262 of unknown status. We created a browser containing up‐to‐date information on these variants (https://pdgenetics.shinyapps.io/GBA1Browser/). Conclusions: The classification and browser presented in this work should inform and support basic, translational, and clinical research on GBA1‐PD. © 2023 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a multifarious neurodegenerative disease. Its pathology is characterized by a prominent early death of dopaminergic neurons in the pars compacta of the substantia nigra and the presence of Lewy bodies with aggregated α-synuclein. Although the α-synuclein pathological aggregation and propagation, induced by several factors, is considered one of the most relevant hypotheses, PD pathogenesis is still a matter of debate. Indeed, environmental factors and genetic predisposition play an important role in PD. Mutations associated with a high risk for PD, usually called monogenic PD, underlie 5% to 10% of all PD cases. However, this percentage tends to increase over time because of the continuous identification of new genes associated with PD. The identification of genetic variants that can cause or increase the risk of PD has also given researchers the possibility to explore new personalized therapies. In this narrative review, we discuss the recent advances in the treatment of genetic forms of PD, focusing on different pathophysiologic aspects and ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Background and purpose: Parkinson's disease (PD) with glucocerebrosidase (GBA) gene mutation (GBA‐PD) is known to show more rapid clinical progression than sporadic PD without GBA mutation (sPD). This study was performed to delineate the specific patterns of cortical hypoperfusion, dopamine transporter uptake and cardiac meta‐iodobenzylguanidine (MIBG) uptake of GBA‐PD in comparison to sPD. Methods: Through next‐generation sequencing analysis targeting 41 genes, a total of 16 GBA‐PD and 24 sPD patients (sex, age matched) were enrolled in the study, and the clinical, dual‐phase [18F]‐N‐(3‐fluoropropyl)‐2β‐carboxymethoxy‐3β‐(4‐iodophenyl) nortropane (18F‐FP‐CIT) positron emission tomography (PET) and cardiac 123I‐MIBG scintigraphy results were compared between the two groups. Results: The GBA‐PD group had higher rates of rapid eye movement sleep behavior disorder, orthostatic hypotension and neuropsychiatric symptoms than the sPD group. Early‐phase 18F‐FP‐CIT PET showed significantly lower standard uptake value ratio on bilateral posterior parietal cortex (0.94 ± 0.05 vs. 1.02 ± 0.04, p = 0.011) and part of the occipital cortex (p < 0.05) in the GBA‐PD group than the sPD group. In striatal dopamine transporter uptake, the regional standard uptake value ratio, asymmetry index and caudate‐to‐putamen ratio were similar between the two groups. The GBA‐PD group had a lower heart‐to‐mediastinum uptake ratio in 123I‐MIBG scintigraphy than the sPD group. Conclusions: The GBA‐PD patients showed decreased regional perfusion in the bilateral posterior parietal and occipital cortex. Cardiac sympathetic denervation and non‐motor symptoms (orthostatic hypotension, rapid eye movement sleep behavior disorder) were more common in GBA‐PD than sPD. These findings suggest that GBA‐PD patients have more widespread peripheral (extranigral) α‐synuclein accumulation, representing a body‐first PD subtype. [ABSTRACT FROM AUTHOR]

The poor outcome of advanced ovarian cancer under conventional therapy necessitates new strategies to improve therapeutic efficacy. β-glucosidase (encoded by GBA) is a lysosomal enzyme and is involved in sphingolipids metabolism. Recent studies revealed that β-glucosidase plays a role in cancer development and chemoresistance. In this work, we systematically evaluated the expression and role of GBA in ovarian cancer. Our work demonstrates that inhibition of β-glucosidase has therapeutic potential for ovarian cancer. Gene Expression Profiling Interactive Analysis database, western blot and immunohistochemistry analyses of patient samples demonstrated that GBA mRNA and protein expression levels were significantly increased in ovarian cancer compared to normal tissues. Functional studies using gainof-function and loss-of-function approaches demonstrated that GBA overexpression did not affect growth and migration but alleviated cisplatin’s efficacy in ovarian cancer cells. In addition, GBA depletion resulted in growth inhibition, apoptosis induction, and enhancement of cisplatin’s efficacy. Of note, we found that GBA inhibition specifically decreased receptor tyrosine kinase AXL level, leading to the suppression of AXL-mediated signaling pathways. Our data suggest that GBA represents a promising target to inhibit AXL signaling and overcome cisplatin resistance in ovarian cancer. [ABSTRACT FROM AUTHOR]

GBA gene variants were the first genetic risk factor for Parkinson's disease. GBA encodes the lysosomal enzyme glucocerebrosidase (GBA), which is involved in sphingolipid metabolism. GBA exhibits a complex physiological function that includes not only the degradation of its substrate glucosylceramide but also the metabolism of other sphingolipids and additional lipids such as cholesterol, particularly when glucocerebrosidase activity is deficient. In the context of Parkinson's disease associated with GBA, the loss of GBA activity has been associated with the accumulation of α-synuclein species. In recent years, several hypotheses have proposed alternative and complementary pathological mechanisms to explain why lysosomal enzyme mutations lead to α-synuclein accumulation and become important risk factors in Parkinson's disease etiology. Classically, loss of GBA activity has been linked to a dysfunctional autophagy–lysosome system and to a subsequent decrease in autophagy-dependent α-synuclein turnover; however, several other pathological mechanisms underlying GBA-associated parkinsonism have been proposed. This review summarizes and discusses the different hypotheses with a special focus on autophagy-dependent mechanisms, as well as autophagy-independent mechanisms, where the role of other players such as sphingolipids, cholesterol and other GBA-related proteins make important contributions to Parkinson's disease pathogenesis. [ABSTRACT FROM AUTHOR]

Multiple lines of clinical and pre-clinical research support a pathogenic role for neuroinflammation and peripheral immune system dysfunction in Parkinson's disease. In this paper, we have reviewed and summarised the published literature reporting evidence of neuroinflammation and peripheral immune changes in cohorts of patients with isolated REM sleep behaviour disorder and non-manifesting carriers of GBA or LRRK2 gene mutations, who have increased risk for Parkinsonism and synucleinopathies, and could be in the prodromal stage of these conditions. Taken together, the findings of these studies suggest that the early stages of pathology in Parkinsonism involve activation of both the central and peripheral immune systems with significant crosstalk. We consider these findings with respect to those found in patients with clinical Parkinson's disease and discuss their possible pathological roles. Moreover, those factors possibly associated with the immune response, such as the immunomodulatory role of the affected neurotransmitters and the changes in the gut-brain axis, are also considered. [ABSTRACT FROM AUTHOR]

The protection of mangroves through nature reserves has been demonstrated to be effective. There were many studies evaluating the mangrove protection effect. However, the evaluation of mangrove growth quality with positive or negative growth trends, as well as restoration potential against disturbance in nature reserves, is still lacking. Thus, this study proposed a hierarchical evaluation framework for mangrove protection in nature reserves, which takes long-term metrics at three levels of loss and gain areas, patch pattern dynamics, and pixel growth trends into account. The continuous change detection and classification (CCDC) was utilized to identify the change condition of mangroves in six nature reserves of the Guangdong–Hong Kong–Macao Greater Bay Area. The Entropy Weight Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) was utilized for scores evaluation of protection effort comparison from 2000 to 2020. The study results had the following three main findings. Firstly, the mangrove forest area increased by about 294.66 ha in four reserves and slightly decreased by about 58.86 ha in two. Most reserves showed an improved patches intact pattern and more positive growth trends. Secondly, the establishment of nature reserves and afforestation were the main causes of mangrove area gain. Until 2010, aquaculture, agriculture, and urban development were the biggest threats to mangroves. Finally, the protection of the reserves was successful in the early decades, but the general evaluation scores showed a decline in recent years once we considered the growth trends for quality. The proposed hierarchical evaluation methods provide a new sight to research the impacts of abrupt change and protection resilience status of the gradual restoration of nature reserves. [ABSTRACT FROM AUTHOR]

Patients with Parkinson's disease (PD) carrying variants in the Glucocerebrosidase (GBA) gene (GBA-PD) suffer from orthostatic symptoms more frequently than idiopathic PD patients (IPD). Systematic measurements of the blood pressure have not yet been performed. In the present study, a prospective analysis of 33 GBA-PD and 313 IPD patients was carried out. Systolic blood pressure upon changing from the supine to the upright position dropped more strongly in GBA-PD compared to IPD patients. Diastolic blood pressure and heart rate did not differ between groups. This study provides further evidence for a pronounced involvement of the autonomic nervous system in GBA-PD. [ABSTRACT FROM AUTHOR]

Background: Although men and women with the LRRK2 G2019S variant appear to be equally likely to have Parkinson's disease (PD), the sex‐distribution among glucocerebrosidase (GBA) variant carriers with PD, including limited to specific variant severities of GBA, is not well understood. Further, the sex‐specific genetic contribution to PD without a known genetic variant is controversial. Objectives: To better understand sex differences in genetic contribution to PD, especially sex‐specific frequencies among GBA variant carriers with PD (GBA PD) and LRRK2‐G2019S variant carriers with PD (LRRK2 PD). Methods: We assess differences in the sex‐specific frequency in GBA PD, including in subsets of GBA variant severity, LRRK2 PD, and idiopathic PD in an Ashkenazi Jewish cohort with PD. Further, we expand prior work evaluating differences in family history of parkinsonism. Results: Both idiopathic PD (267/420 men, 63.6%) (P < 0.001) and GBA PD overall (64/107, 59.8%) (P = 0.042) were more likely to be men, whereas no difference was seen in LRRK2 PD (50/99, 50.5%) and LRRK2/GBA PD (5/10, 50%). However, among GBA PD probands, severe variant carriers were more likely to be women (15/19 women, 79.0%) (P = 0.005), whereas mild variant carriers (44/70 men, 62.9%) (P = 0.039) and risk‐variant carriers (15/17 men, 88.2%) (P = 0.001) were more likely to be men. Conclusions: Our study demonstrates that the male‐sex predominance present in GBA PD overall was not consistent across GBA variant severities, and a female‐sex predominance was present among severe GBA variant carriers. Therefore, research and trial designs for PD should consider sex‐specific differences, including across GBA variant severities. © 2022 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Understanding the pathophysiology and genetic background of Parkinson's disease (PD) increases the likelihood of developing effective disease-modifying therapeutic strategies. In particular, the discovery of genetic variants causing or increasing the risk for PD has contributed to refining the clinical, biological, and molecular classification of the disease and has offered new insights into sporadic forms. It is even more evident that specific genetic mutations can show different responses to pharmacological and device-aided therapies. To date, several agents acting on multiple PD-causing pathogenic pathways have been tested as disease-modifying strategies, with disappointing results. This may be caused by the recruitment of PD populations whose underlying molecular pathophysiology is heterogeneous. We believe that an effective model of personalized medicine must be prioritized in the near future. Here, we review the current therapeutic options under clinical and preclinical development for PD and discuss the key pending questions and challenges to face for successful clinical trials. Furthermore, we provide some insights into the role of genetics in guiding the decision-making process on symptomatic and device-aided therapies for PD in daily clinical practice. [ABSTRACT FROM AUTHOR]

Mitochondria, α-syn fibrils and the endo-lysosomal system are key players in the pathophysiology of Parkinson's disease. The toxicity of α-syn is amplified by cell-to-cell transmission and aggregation of endogenous species in newly invaded neurons. Toxicity of α-syn PFF was investigated using primary cultures of dopaminergic neurons or on aged mice after infusion in the SNpc and combined with mild inhibition of GBA. In primary dopaminergic neurons, application of α-syn PFF induced a progressive cytotoxicity associated with mitochondrial dysfunction, oxidative stress, and accumulation of lysosomes suggesting that exogenous α-syn reached the lysosome (from the endosome). Counteracting the α-syn endocytosis with a clathrin inhibitor, dopaminergic neuron degeneration was prevented. In vivo, α-syn PFF induced progressive neurodegeneration of dopaminergic neurons associated with motor deficits. Histology revealed progressive aggregation of α-syn and microglial activation and accounted for the seeding role of α-syn, injection of which acted as a spark suggesting a triggering of cell-to-cell toxicity. We showed for the first time that a localized SNpc α-syn administration combined with a slight lysosomal deficiency and aging triggered a progressive lesion. The cellular and animal models described could help in the understanding of the human disease and might contribute to the development of new therapies. [ABSTRACT FROM AUTHOR]

Beta-propeller protein-associated neurodegeneration (BPAN) is a subtype of neurodegeneration with brain iron accumulation (NBIA) caused by loss-of-function variants in WDR45. The underlying mechanism of iron accumulation in WDR45 deficiency remains elusive. We established a primary skin fibroblast culture of a new BPAN patient with a missense variant p.(Asn61Lys) in WDR45 (NM_007075.3: c.183C>A). The female patient has generalized dystonia, anarthria, parkinsonism, spasticity, stereotypies, and a distinctive cranial MRI with generalized brain atrophy, predominantly of the cerebellum. For the functional characterization of this variant and to provide a molecular link of WDR45 and iron accumulation, we looked for disease- and variant-related changes in the patient's fibroblasts by qPCR, immunoblotting and immunofluorescence comparing to three controls and a previously reported WDR45 patient. We demonstrated molecular changes in mutant cells comprising an impaired mitochondrial network, decreased levels of lysosomal proteins and enzymes, and altered autophagy, confirming the pathogenicity of the variant. Compared to increased levels of the ferritinophagy marker Nuclear Coactivator 4 (NCOA4) in control cells upon iron treatment, patients' cells revealed unchanged NCOA4 protein levels, indicating disturbed ferritinophagy. Additionally, we observed abnormal protein levels of markers of the iron-dependent cell death ferroptosis in patients' cells. Altogether, our data suggests that WDR45 deficiency affects ferritinophagy and ferroptosis, consequentially disturbing iron recycling. [ABSTRACT FROM AUTHOR]

Given the clear role of GBA in the pathogenesis of Parkinson's disease (PD) and its impact on phenotypical characteristics, this review provides an overview of the current knowledge of GBA-associated PD with a special focus on clinical trajectories and the underlying pathological mechanisms. Importantly, differences and characteristics based on mutation severity are recognized, and current as well as potential future treatment options are discussed. These findings will inform future strategies for patient stratification and cohort enrichment as well as suitable outcome measures when designing clinical trials. [ABSTRACT FROM AUTHOR]

Background: Genetic mutations in beta-glucocerebrosidase (GBA) represent the major genetic risk factor for Parkinson's disease (PD). GBA participates in both the endo-lysosomal pathway and the immune response, two important mechanisms involved in the pathogenesis of PD. However, modifiers of GBA penetrance have not yet been fully elucidated. Methods: We characterized the transcriptomic profiles of circulating monocytes in a population of patients with PD and healthy controls (CTRL) with and without GBA variants (n = 23 PD/GBA, 13 CTRL/GBA, 56 PD, 66 CTRL) and whole blood (n = 616 PD, 362 CTRL, 127 PD/GBA, 165 CTRL/GBA). Differential expression analysis, pathway enrichment analysis, and outlier detection were performed. Ultrastructural characterization of isolated CD14+ monocytes in the four groups was also performed through electron microscopy. Results: We observed hundreds of differentially expressed genes and dysregulated pathways when comparing manifesting and non-manifesting GBA mutation carriers. Specifically, when compared to idiopathic PD, PD/GBA showed dysregulation in genes involved in alpha-synuclein degradation, aging and amyloid processing. Gene-based outlier analysis confirmed the involvement of lysosomal, membrane trafficking, and mitochondrial processing in manifesting compared to non-manifesting GBA-carriers, as also observed at the ultrastructural levels. Transcriptomic results were only partially replicated in an independent cohort of whole blood samples, suggesting cell-type specific changes. Conclusions: Overall, our transcriptomic analysis of primary monocytes identified gene targets and biological processes that can help in understanding the pathogenic mechanisms associated with GBA mutations in the context of PD. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) patients show a higher prevalence of Lewy body disease than the general population. Additionally, parkinsonian features were found in about 30% of ALS patients. We aimed to explore the frequency of Parkinson's disease (PD)-causative genes in ALS patients, compared to AD and healthy controls (HCs). We used next-generation sequencing multigene panels by analyzing SNCA, LRRK2, PINK1, PARK2, PARK7, SYNJ1, CHCHD2, PLA2G6, GCH1, ATP13A2, DNAJC6 and FBXO genes. GBA gene, a risk factor for PD, was also analyzed. In total, 130 ALS and 100 AD patients were investigated. PD-related genes were found to be altered in 26.2% of ALS, 20% of AD patients and 19.2% of HCs. Autosomal recessive genes were significantly more involved in ALS as compared to AD and HCs (p = 0.021). PARK2 variants were more frequent in ALS than in AD and HCs, although not significantly. However, the p.Arg402Cys variant was increased in ALS than in HCs (p = 0.025). This finding is consistent with current literature, as parkin levels were found to be decreased in ALS animal models and patients. Our results confirm the possible role of PD-related genes as risk modifier in ALS pathogenesis. [ABSTRACT FROM AUTHOR]

Apart from I GBA i and I PRKRA i , a potential role of pseudogenes has not (yet) caught our attention in the field of movement disorders, although several well-established disease-linked genes also have pseudogenes. The definition of a pseudogene has now broadened to include any DNA sequence that is similar to a known gene and has lost some of its original functionality.25 Therefore, pseudogenes can be translated into proteins, as recently proven for 140 human pseudogenes, and also act at the protein level.26 For instance, pseudogene-derived proteins may have the same activity as the parental proteins, but function in different tissues, cellular compartments, or pathophysiological conditions. Pseudogenes can be divided into two major groups, that is, unprocessed pseudogenes and processed pseudogenes, with the latter representing the majority of pseudogenes in humans (~70%, https://www.gencodegenes.org/human/stats.html). Therefore, the sequence identity for these pseudogenes should be too less to seriously trouble sequence analyses.27 Overall, pseudogenes have emerged as a hot topic because they can challenge genetic testing and trigger mutational events even in biologically functional parental genes. [Extracted from the article]