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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.

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., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

The GBA1 gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis and regulates the autophagy process. Genomic variants of GBA1 are associated with Goucher disease; however, several heterozygous variants of GBA (E326K, T369M, N370S, L444P) are frequent high-risk factors for Parkinson's disease (PD). The underlying mechanism of these variants has been revealed through functional and patient-centered research, but the structural and dynamical aspects of these variants have not yet been thoroughly investigated. In the current study, we used a thorough computational method to pinpoint the structural changes that GBA underwent because of genomic variants and drug binding mechanisms. According to our findings, PD-linked nsSNP variants of GBA showed structural variation and abnormal dynamics when compared to wild-typ. The docking analysis demonstrated that the mutants E326K, N370S, and L444P have higher binding affinities for Ambroxol. Root means square deviation (RMSD), Root mean square fluctuation analysis (RMSF), and MM-GBSA analysis confirmed that the Ambroxol are more stable in the binding site of N370S and L444P, and that their binding affinities are stronger as compared to the wild-type and T369M variants of GBA. The evaluation of hydrogen bonds and the calculation of the free binding energy provided additional evidence in favor of this conclusion. When docked with Ambroxol, GBA demonstrated an increase in binding affinity and catalytic activity. Understanding the therapeutic efficacy and potential against the aforementioned changes in the GBA will be beneficial in order to use more efficient methods for developing novel drugs.

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., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

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., (© 2023. Fondazione Società Italiana di Neurologia.)

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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

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.

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.

Background: Variants in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD). They are also risk factors for Parkinson's disease (PD), and modify the expression of the PD phenotype. The penetrance of GBA1 variants in PD is incomplete, and the ability to determine who among GBA1 variant carriers are at higher risk of developing PD, would represent an advantage for prognostic and trial design purposes., Objectives: To compare the motor and non-motor phenotype of GBA1 carriers and non-carriers., Methods: We present the cross-sectional results of the baseline assessment from the RAPSODI study, an online assessment tool for PD patients and GBA1 variant carriers. The assessment includes clinically validated questionnaires, a tap-test, the University of Pennsyllvania Smell Identification Test and cognitive tests. Additional, homogeneous data from the PREDICT-PD cohort were included., Results: A total of 379 participants completed all parts of the RAPSODI assessment (89 GBA1-negative controls, 169 GBA1-negative PD, 47 GBA1-positive PD, 47 non-affected GBA1 carriers, 27 GD). Eighty-six participants were recruited through PREDICT-PD (43 non-affected GBA1 carriers and 43 GBA1-negative controls). GBA1-positive PD patients showed worse performance in visual cognitive tasks and olfaction compared to GBA1-negative PD patients. No differences were detected between non-affected GBA1 carriers carriers and GBA1-negative controls. No phenotypic differences were observed between any of the non-PD groups., Conclusions: Our results support previous evidence that GBA1-positive PD has a specific phenotype with more severe non-motor symptoms. However, we did not reproduce previous findings of more frequent prodromal PD signs in non-affected GBA1 carriers., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest or financial issues to declare in relation to this manuscript., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Presently, neurotransmitter deficits in GBA-related Parkinson's disease (GBA-PD) and relationships with cognitive impairment are poorly understood. A better understanding of neurotransmitter impairments in GBA-PD - particularly in the newly diagnosed drug-naïve phase - may support developing targeted intervention strategies. We aimed to investigate patterns of neurotransmitter deficits in GBA-PD and idiopathic PD (iPD) and cognitive performance correlations., Methods: We recruited 189 newly diagnosed PD patients for GBA sequencing. Voxel-wise gray matter volume (GMV) was evaluated in a subgroup of 17 GBA-PD, 100 iPD, and 32 age- and sex-matched healthy controls (HCs). The JuSpace toolbox covering various neurotransmitter maps helped assess whether the spatial patterns of GMV alterations in GBA-PD or iPD patients (relative to HCs) were associated with specific neurotransmitter systems., Results: GBA-PD patients indicated widespread GM atrophy in the fronto-temporal-occipital region compared with HCs. GMV atrophy was spatially correlated in GBA-PD and iPD with serotonergic, dopaminergic, and acetylcholinergic pathway distributions (p < 0.05, false discovery rate corrected). Executive function and language in cognitive domains were also associated with the strength of GMV colocalization of serotonergic, dopaminergic, and acetylcholinergic circuits., Conclusions: Regional GM atrophy related to specific neurotransmitter deficits in de novo GBA-PD and iPD patients could provide new insights into pathophysiological processes, facilitating potential therapeutic targets to support PD management., Competing Interests: Declaration of Competing Interest The authors do not have any conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Genetic risk factors impact around 15% of Parkinson's disease (PD) patients and at least 23 variants have been identified including Glucocerebrosidase (GBA) gene variants. Using different clinical and instrumental qualitative-based data, various studies have been published on GBA-PD cohorts which suggested possible differences in dopaminergic nigrostriatal denervation pattern, particularly in caudate and putamen nuclei., Methods: This retrospective study included two consecutive homogenous cohorts of GBA-PD and idiopathic (I-PD) patients. Each consecutive GBA-PD patient has been matched with a 1:1 pairing method with a consecutive I-PD subject according to age, age at disease onset, sex, Hoehn & Yahr (H&Y) staging scale and comorbidity level (CCI). Semiquantitative volumetric data by the DaTQUANT TM software integrated in the DaTSCAN exam performed at time of the diagnosis (SPECT imaging performed according to current guidelines of I-123 FPCIT SPECT imaging) were extrapolated. Bilateral specific binding ratios (SBR) at putamen and caudate levels were calculated, using the occipital lobes uptake. The Mann-Whitney test was performed to compare the two cohorts while the Spearman's test was used to find correlations between motor and volumetric data in each group. Bonferroni correction was used to account for multiple comparisons., Results: Two cohorts of 25 patients each (GBA-PD and I-PD), were included. By comparing GBA-PD and I-PD patients, lower SBR values were found in the most affected anterior putamen and left caudate of the GBA-PD cohort. Furthermore, in the GBA-PD cohort the SBR of the most affected posterior putamen negatively correlated with the H&Y scale. However, none of these differences or correlations remained significant after Bonferroni correction for multiple comparisons., Conclusions: We observed differences in SBR values in GBA-PD patients compared with I-PD. However, these differences were no longer significant after Bonferroni multiple comparisons correction highlighting the need for larger, longitudinal studies., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

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., (© 2023. The Author(s).)

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., (© 2023. The Author(s).)

Introduction: Recent studies found an association between Parkinson's disease (PD) and alterations in the innate immune system. However, whether the involvement of this system in two of the known genetic forms of PD, GBA-PD and LRRK2-PD, and in patients who do not carry these mutations is different, is yet to be determined. We aimed to test if genetic variations in the innate immune genes are differentially associated with PD in these subgroups., Methods: Innate immune genes were identified and classified into sub-lists according to Reactome pathways. Whole-genome-sequencing (WGS) was performed on 201 unrelated Ashkenazi-Jewish (AJ) PD patients including 104 GBA-PD, 32 LRRK2-PD, and 65 non-carriers-PD (NC-PD). To identify genes with different burden between these subgroups of PD, gene-based Sequence kernel association optimal unified test (SKAT-O) analysis was performed on innate immune pathways. Candidate variants within the significant genes were further genotyped in a cohort of 1200 unrelated, consecutively recruited, AJ-PD patients, and to evaluate their association with PD-risk their allele frequencies were compared to AJ-non-neuro cases in gnomAD database, in a stratified and un-stratified manner., Results: SKAT-O analysis showed significantly different burden for PSMB9 (GBA-PD versus NC-PD) and FGR (GBA-PD versus LRRK2-PD). Two candidate variants in PSMB9 showed an association with GBA-PD-risk and NC-PD-risk while one FGR variant showed an association with LRRK2-PD-risk., Conclusion: Our data supports differential involvement of innate immunity risk alleles in PD and emphasizes the differences between the GBA- and LRRK2-PD subgroups., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., (© 2023 International Parkinson and Movement Disorder Society.)

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.

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 [ 18 F]-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane ( 1 8 F-FP-CIT) positron emission tomography (PET) and cardiac 123 I-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 18 F-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 123 I-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., (© 2022 European Academy of Neurology.)

Parkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected individual develops a virtually unique form of Parkinson's syndrome. Clinical manifestations consist of variable motor and nonmotor features, and myriad overlaps are recognized with other neurodegenerative conditions. Although most commonly characterized by alpha-synuclein protein pathology throughout the central and peripheral nervous systems, the distribution varies and other pathologies commonly modify PD or trigger similar manifestations. Nearly all PD is genetically influenced. More than 100 genes or genetic loci have been identified, and most cases likely arise from interactions among many common and rare genetic variants. Despite its complex architecture, insights from experimental genetic dissection coalesce to reveal unifying biological themes, including synaptic, lysosomal, mitochondrial, andimmune-mediated mechanisms of pathogenesis. This emerging understanding of Parkinson's syndrome, coupled with advances in biomarkers and targeted therapies, presages successful precision medicine strategies.

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.

Genetic variants in GBA, encoding the lysosomal enzyme glucocerebrosidase (GCase), are common risk factors for Parkinson's disease (PD). Genotype-phenotype studies have demonstrated that different types of GBA variants have differential effects on the phenotype. Variants could be classified as mild or severe depending on the type of Gaucher disease they cause in the biallelic state. It was shown that severe GBA variants, as compared to mild variants, are associated with higher risk of PD, earlier age at onset, and faster progression of motor and nonmotor symptoms. The observed difference in phenotype might be caused by a diversity of cellular mechanisms related to the particular variants. The lysosomal function of GCase is thought to play a significant role in the development of GBA-associated PD, and other mechanisms such as endoplasmic reticulum retention, mitochondrial dysfunction, and neuroinflammation have also been suggested. Moreover, genetic modifiers such as LRRK2, TMEM175, SNCA, and CTSB can either affect GCase activity or modulate risk and age at onset of GBA-associated PD. To achieve ideal outcomes with precision medicine, therapies will have to be tailored to individuals with specific variants, potentially in combination with known modifiers., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To analyze mutations and polymorphisms in exons 2, 7, 8, 9, 10 and 11 of the glucocerebrosidase ( GBA ) gene in patients of the Krasnoyarsk region diagnosed with Parkinson's disease (PD)., Material and Methods: Seventy-five patients with sporadic and familial forms of PD were examined. Genomic DNA was isolated from the whole blood of patients. The above mentioned exons of GBA were analyzed using Sanger sequencing., Results: Various changes in the DNA structure of GBA were detected in 11 patients, thus, the overall frequency of variants was 14.7%, and the frequency of pathologically significant mutations (p.L444P, p.D409H, p.H255Q) was 5.3%., Conclusion: The frequencies of variants in GBA , one of the most common high-risk factors for PD, in patients of the Krasnoyarsk region turned out to be quite high and comparable to that in patients in other populations of the world. Thus, screening for GBA mutations is relevant for PD patients living in the Krasnoyarsk region as part of genetic counseling at present, and in the future it may be necessary for personalized treatment.

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 &lt; 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., (© 2022 International Parkinson and Movement Disorder Society.)

Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. The median age of disease onset is around 60 years. From a genetic point of view, PD is basically considered a sporadic, idiopathic disease, however, hereditary components can be detected in 5-10% of patients. Expanding data are available regarding the targeted molecular therapy of the disease., Areas Covered: The aim of this current review article is to provide brief clinical and molecular insight into three important genetic forms (LRRK2, SNCA, GBA) of hereditary PD subtypes and to present the human clinical trials in relation to these forms of the disease., Expert Opinion: These small hereditary subgroups are crucially important in drug development, because the general trend is that clinical trials that treat PD patients as a large group, without any separation, do not meet expectations. As a result, no long term conclusions can currently be drawn regarding the effectiveness of the molecules tested in these phase 1 and 2 studies. Further precise studies are needed in the near future.

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., (© 2022. The Author(s).)

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., Competing Interests: The authors report no competing interests.

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., (© 2022. The Author(s).)

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. Among its pathologies, progressive loss of dopaminergic (DA) neurons in the substantia nigra is characteristic and contributes to many of the most severe symptoms of PD. Recent advances in induced pluripotent stem cell (iPSC) technology have made it possible to generate patient-derived DA neuronal cell culture and organoid models of PD. These models have contributed to understanding disease mechanisms and the identification of novel targets and therapeutic candidates. Still needed are better ways to model the age-related aspects of PD, as well as a deeper understanding of the interactions among disease-modifying genes and between genetic and environmental contributions to the etiology and progression of PD., Competing Interests: Declaration of interests L.S. is a co-founder and paid consultant of BlueRock Therapeutics. G.A.P. is a co-founder of Retromer Therapeutics, and is a paid consultant for MeiraGTx, Amicus Therapeutics, Proclara Biosciences, and Annovis Bio., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Genetic variants in the Beta-glucocerebrosidase gene (GBA1) is a known risk factor for Parkinson's disease. The GBA1 mutations L444P, N370S and many other have been shown to associate with the disease in populations with diverse background. Some GBA1 polymorphisms have a less pronounced effect, and their pathogenicity has been debated. We have previously found associations with L444P, N370S and E326K and Parkinson's disease in Sweden., Method: In this study we used pyrosequencing to genotype the T369M variant in a large Swedish cohort consisting of 1,131 patients with idiopathic Parkinson's disease, and 1,594 control subjects to evaluate the possibility of this variant conferring an increased risk for Parkinson's disease., Results: The minor allele frequency was 2.15% in patients and 1.76% in controls. Statistical analysis showed that there was no significant difference in allele frequency between patients and control subjects, p-value 0.37, Odds Ratio 1.23 with a 95% confidence interval of 0.82-1.83., Conclusion: Our results suggest that T369M is not a risk factor for Parkinson's disease in the Swedish population., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: The authors declare no conflict of interest.

Parkinson's disease (PD) is a neurodegenerative disease characterized pathologically by the formation of Lewy bodies comprised mainly of α-synuclein. Assessment of skin synuclein has the potential as an excellent diagnostic method with high sensitivity, specificity, and reproducibility that is also convenient and acceptable to patients. In this review, we summarize findings regarding the characteristics of cutaneous nerve p-α-syn or α-syn deposits and their correlations with clinical phenotypes in PD patients with and without orthostatic hypotension and LRRK2, GBA, and SNCA gene mutations. This review can serve as a reference for the diagnosis and classification of PD based on α-syn deposit patterns and to deeply explore its pathogenesis. FUNDING STATEMENT: The work was partly supported by the National Natural Science Key Foundation of China (No. 81830040 and No 82130042) and the Program of Excellent Talents in Medical Science of Jiangsu Province (No. JCRCA2016006) ., Competing Interests: Declaration of interests The authors have declared that no competing interest exists., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Common genetic variance in apolipoprotein E (APOE), β-glucocerebrosidase (GBA), microtubule-associated protein tau (MAPT), and α-synuclein (SNCA) has been linked to cognitive decline in Parkinson's disease (PD), although studies have yielded mixed results., Objectives: To evaluate the effect of genetic variants in APOE, GBA, MAPT, and SNCA on cognitive decline and risk of dementia in a pooled analysis of six longitudinal, non-selective, population-based cohorts of newly diagnosed PD patients., Methods: 1002 PD patients, followed for up to 10 years (median 7.2 years), were genotyped for at least one of APOE-ε4, GBA mutations, MAPT H1/H2, or SNCA rs356219. We evaluated the effect of genotype on the rate of cognitive decline (Mini-Mental State Examanation, MMSE) using linear mixed models and the development of dementia (diagnosed using standardized criteria) using Cox regression; multiple comparisons were accounted for using Benjamini-Hochberg corrections., Results: Carriers of APOE-ε4 (n = 281, 29.7%) and GBA mutations (n = 100, 10.3%) had faster cognitive decline and were at higher risk of progression to dementia (APOE-ε4, HR 3.57, P < 0.001; GBA mutations, HR 1.76, P = 0.001) than non-carriers. The risk of cognitive decline and dementia (HR 5.19, P < 0.001) was further increased in carriers of both risk genotypes (n = 23). No significant effects were observed for MAPT or SNCA rs356219., Conclusions: GBA and APOE genotyping could improve the prediction of cognitive decline in PD, which is important to inform the clinical trial selection and potentially to enable personalized treatment © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Intraneuronal accumulation of aggregated α-synuclein is a pathological hallmark of Parkinson's disease. Therefore, mechanisms capable of promoting α-synuclein deposition bear important pathogenetic implications. Mutations of the glucocerebrosidase 1 (GBA) gene represent a prevalent Parkinson's disease risk factor. They are associated with loss of activity of a key enzyme involved in lipid metabolism, glucocerebrosidase, supporting a mechanistic relationship between abnormal α-synuclein-lipid interactions and the development of Parkinson pathology. In this study, the lipid membrane composition of fibroblasts isolated from control subjects, patients with idiopathic Parkinson's disease and Parkinson's disease patients carrying the L444P GBA mutation (PD-GBA) was assayed using shotgun lipidomics. The lipid profile of PD-GBA fibroblasts differed significantly from that of control and idiopathic Parkinson's disease cells. It was characterized by an overall increase in sphingolipid levels. It also featured a significant increase in the proportion of ceramide, sphingomyelin and hexosylceramide molecules with shorter chain length and a decrease in the percentage of longer-chain sphingolipids. The extent of this shift was correlated to the degree of reduction of fibroblast glucocerebrosidase activity. Lipid extracts from control and PD-GBA fibroblasts were added to recombinant α-synuclein solutions. The kinetics of α-synuclein aggregation were significantly accelerated after addition of PD-GBA extracts as compared to control samples. Amyloid fibrils collected at the end of these incubations contained lipids, indicating α-synuclein-lipid co-assembly. Lipids extracted from α-synuclein fibrils were also analysed by shotgun lipidomics. Data revealed that the lipid content of these fibrils was significantly enriched by shorter-chain sphingolipids. In a final set of experiments, control and PD-GBA fibroblasts were incubated in the presence of the small molecule chaperone ambroxol. This treatment restored glucocerebrosidase activity and sphingolipid levels and composition of PD-GBA cells. It also reversed the pro-aggregation effect that lipid extracts from PD-GBA fibroblasts had on α-synuclein. Taken together, the findings of this study indicate that the L444P GBA mutation and consequent enzymatic loss are associated with a distinctly altered membrane lipid profile that provides a biological fingerprint of this mutation in Parkinson fibroblasts. This altered lipid profile could also be an indicator of increased risk for α-synuclein aggregate pathology., (© The Author(s) (2022). Published by Oxford University Press on behalf of the Guarantors of Brain.)

A growing amount of evidence has indicated contributions of variants in causative genes of Parkinson's disease (PD) to the development of sleep disturbance in PD and prodromal PD stages. In this article, we aimed to investigate the role of genetics in sleep disorders in PD patients and asymptomatic carriers at prodromal stage of PD. A systematic review and meta-analysis of observational studies was conducted based on the MEDLINE, EMBASE and PsychINFO databases. A pooled effect size was calculated by odds ratio (OR) and standard mean difference (SMD). Forty studies were selected for quantitative analysis, including 17 studies on glucocerebrosidase (GBA), 25 studies on Leucine-rich repeat kinase 2 (LRRK2) and 7 on parkin (PRKN) genes, and 3 studies on alpha-synuclein gene (SNCA) were used for qualitative analysis. Patients with PD carrying GBA variants had a significantly higher risk for rapid-eye-movement behavior disorders (RBD) (OR, 1.82) and higher RBD Screening Questionnaire scores (SMD, 0.33). Asymptomatic carriers of GBA variants had higher severity of RBD during follow-up. Patients with PD carrying the LRRK2 G2019S variant had lower risk and severity of RBD compared with those without LRRK2 G2019S. Variants of GBA, LRRK2 and PRKN did not increase or decrease the risk and severity of excessive daytime sleepiness and restless legs syndrome in PD. Our findings suggest that the genetic heterogeneity plays a role in the development of sleep disorders, mainly RBD, in PD and the prodromal stage of PD., (© 2022. The Author(s).)

The GBA gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis. Approximately 5-15% of PD patients have mutations in the GBA gene, making it numerically the most important genetic risk factor for Parkinson disease (PD). Clinically, GBA -associated PD is identical to sporadic PD, aside from the earlier age at onset (AAO), more frequent cognitive impairment and more rapid progression. Mutations in GBA can be associated with loss- and gain-of-function mechanisms. A key hallmark of PD is the presence of intraneuronal proteinaceous inclusions named Lewy bodies, which are made up primarily of alpha-synuclein. Mutations in the GBA gene may lead to loss of GCase activity and lysosomal dysfunction, which may impair alpha-synuclein metabolism. Models of GCase deficiency demonstrate dysfunction of the autophagic-lysosomal pathway and subsequent accumulation of alpha-synuclein. This dysfunction can also lead to aberrant lipid metabolism, including the accumulation of glycosphingolipids, glucosylceramide and glucosylsphingosine. Certain mutations cause GCase to be misfolded and retained in the endoplasmic reticulum (ER), activating stress responses including the unfolded protein response (UPR), which may contribute to neurodegeneration. In addition to these mechanisms, a GCase deficiency has also been associated with mitochondrial dysfunction and neuroinflammation, which have been implicated in the pathogenesis of PD. This review discusses the pathways associated with GBA -PD and highlights potential treatments which may act to target GCase and prevent neurodegeneration.

Background and Purpose: Variants in the glucocerebrosidase (GBA) gene are recognized as a common and important genetic risk factor for Parkinson disease (PD). However, the impact of variant severity on the clinical phenotype of PD in the Chinese population remains unclear. Thus, the present study aimed to determine the frequency of GBA-related PD (GBA-PD) and the relationship of GBA variant severity with clinical characteristics in a large Chinese cohort., Methods: Long-range polymerase chain reaction and next generation sequencing were performed for the entire GBA gene. GBA variant severity was classified into five classes: mild, severe, risk, complex, and unknown., Results: Among the total 737 PD patients, 47 GBA variants were detected in 79 (10.72%) patients, and the most common GBA variants were R163Q, L444P, and R120W. Complete demographic and clinical data were obtained for 673 patients, which revealed that 18.50% of early onset PD patients had GBA variants. Compared with patients without GBA variants, GBA-PD patients experienced PD onset an average of 4 years earlier and had more severe motor and nonmotor symptoms. Patients carrying severe and complex variants had a higher burden of nonmotor symptoms, especially depression, and more mood/cognitive and gastrointestinal symptoms than patients carrying mild variants., Conclusions: GBA-PD is highly prevalent in the Chinese population. The severity of GBA variants underlies distinct phenotypic spectrums, with PD patients carrying severe and complex variants seeming to have similar phenotypes. PD patient stratification by GBA variant severity should become a prerequisite for selecting specific treatments., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: To study the longitudinal disease course of Parkinson's disease (PD) patients with glucocerebrosidase (GBA) mutation (GBA-positive) compared to PD non-carriers (GBA-negative) along a 5-year follow-up, evaluating changes in clinical and cognitive outcomes, cortical thickness, and gray-matter (GM) volumes., Methods: Ten GBA-positive and 20 GBA-negative PD patients underwent clinical, neuropsychological, and MRI assessments (cortical thickness and subcortical, hippocampal, and amygdala volumes) at study entry and once a year for 5 years. At baseline and at the last visit, each group of patients was compared with 22 age-matched healthy controls. Clinical, cognitive, and MRI features were compared between groups at baseline and over time., Results: At baseline, GBA-positive and GBA-negative PD patients had similar clinical and cognitive profiles. Compared to GBA-negative and controls, GBA-positive patients showed cortical thinning of left temporal, parietal, and occipital gyri. Over time, compared to GBA-negative, GBA-positive PD patients progressed significantly in motor and cognitive symptoms, and showed a greater pattern of cortical thinning of posterior regions, and frontal and orbito-frontal cortices. After 5 years, compared to controls, GBA-negative PD patients showed a pattern of cortical thinning similar to that showed by GBA-positive cases at baseline. The two groups of patients showed similar patterns of subcortical, hippocampal, and amygdala volume loss over time., Conclusions: Compared to GBA-negative PD, GBA-positive patients experienced a more rapid motor and cognitive decline together with a greater, earlier and faster cortical thinning. Cortical thickness measures may be a useful tool for monitoring and predicting PD progression in accordance with the genetic background., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

It is well established that lysosomal glucocerebrosidase gene (GBA) variants are a risk factor for Parkinson's disease (PD), with increasing evidence suggesting a loss of function mechanism. One question raised by this genetic association is whether variants of genes involved in other aspects of sphingolipid metabolism are also associated with PD. Recent studies in sporadic PD have identified variants in multiple genes linked to diseases of glycosphingolipid (GSL) metabolism to be associated with PD. GSL biosynthesis is a complex pathway involving the coordinated action of multiple enzymes in the Golgi apparatus. GSL catabolism takes place in the lysosome and is dependent on the action of multiple acid hydrolases specific for certain substrates and glycan linkages. The finding that variants in multiple GSL catabolic genes are over-represented in PD in a heterozygous state highlights the importance of GSLs in the healthy brain and how lipid imbalances and lysosomal dysfunction are associated with normal ageing and neurodegenerative diseases. In this article we will explore the link between lysosomal storage disorders and PD, the GSL changes seen in both normal ageing, lysosomal storage disorders (LSDs) and PD and the mechanisms by which these changes can affect neurodegeneration., (© 2021. The Author(s).)

Mutations in leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA) represent two most common genetic causes of Parkinson's disease (PD). Both genes are important in the autophagic-lysosomal pathway (ALP), defects of which are associated with α-synuclein (α-syn) accumulation. LRRK2 regulates macroautophagy via activation of the mitogen activated protein kinase/extracellular signal regulated protein kinase (MAPK/ERK) kinase (MEK) and the calcium-dependent adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathways. Phosphorylation of Rab GTPases by LRRK2 regulates lysosomal homeostasis and endosomal trafficking. Mutant LRRK2 impairs chaperone-mediated autophagy, resulting in α-syn binding and oligomerization on lysosomal membranes. Mutations in GBA reduce glucocerebrosidase (GCase) activity, leading to glucosylceramide accumulation, α-syn aggregation and broad autophagic abnormalities. LRRK2 and GBA influence each other: GCase activity is reduced in LRRK2 mutant cells, and LRRK2 kinase inhibition can alter GCase activity in GBA mutant cells. Clinically, LRRK2 G2019S mutation seems to modify the effects of GBA mutation, resulting in milder symptoms than those resulting from GBA mutation alone. However, dual mutation carriers have an increased risk of PD and earlier age of onset compared with single mutation carriers, suggesting an additive deleterious effect on the initiation of PD pathogenic processes. Crosstalk between LRRK2 and GBA in PD exists, but its exact mechanism is unclear. Drugs that inhibit LRRK2 kinase or activate GCase are showing efficacy in pre-clinical models. Since LRRK2 kinase and GCase activities are also altered in idiopathic PD (iPD), it remains to be seen if these drugs will be useful in disease modification of iPD., (© 2022. The Author(s).)

Parkinson's disease (PD) is defined as a complex disorder with multifactorial pathogenesis, yet a more accurate definition could be that PD is not a single entity, but rather a mixture of different diseases with similar phenotypes. Attempts to classify subtypes of PD have been made based on clinical phenotypes or biomarkers. However, the most practical approach, at least for a portion of the patients, could be to classify patients based on genes involved in PD. GBA and LRRK2 mutations are the most common genetic causes or risk factors of PD, and PRKN is the most common cause of autosomal recessive form of PD. Patients carrying variants in GBA, LRRK2 or PRKN differ in some of their clinical characteristics, pathology and biochemical parameters. Thus, these three PD-associated genes are of special interest for drug development. Existing therapeutic approaches in PD are strictly symptomatic, as numerous clinical trials aimed at modifying PD progression or providing neuroprotection have failed over the last few decades. The lack of precision medicine approach in most of these trials could be one of the reasons why they were not successful. In the current review we discuss novel therapeutic approaches targeting GBA, LRRK2 and PRKN and discuss different aspects related to these genes and clinical trials., (Copyright © 2021. Published by Elsevier Ltd.)

Background: PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy., Objective: To examine the role of PSAP mutations in iRBD., Methods: We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected p = 0.018)., Results: Two variants were stop mutations, p.Gln260Ter and p.Glu166Ter, and one was an in-frame deletion, p.332&#95;333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332&#95;333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria, was 98% or more., Conclusion: These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.

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.

Background: Mutations in the GBA gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are risk factors for Parkinson's disease (PD)., Objective: To explore the association between GCase activity, PD phenotype, and probability for prodromal PD among carriers of mutations in the GBA and LRRK2 genes., Methods: Participants were genotyped for the G2019S-LRRK2 and nine GBA mutations common in Ashkenazi Jews. Performance-based measures enabling the calculation of the Movement Disorder Society (MDS) prodromal probability score were collected., Results: One hundred and seventy PD patients (102 GBA-PD, 38 LRRK2-PD, and 30 idiopathic PD) and 221 non-manifesting carriers (NMC) (129 GBA-NMC, 45 LRRK2-NMC, 15 GBA-LRRK2-NMC, and 32 healthy controls) participated in this study. GCase activity was lower among GBA-PD (3.15 ± 0.85 μmol/L/h), GBA-NMC (3.23 ± 0.91 μmol/L/h), and GBA-LRRK2-NMC (3.20 ± 0.93 μmol/L/h) compared to the other groups of participants, with no correlation to clinical phenotype., Conclusions: Low GCase activity does not explain the clinical phenotype or risk for prodromal PD in this cohort. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

GBA variants are associated with increased risk and earlier onset of Parkinson's disease (PD), and more rapid disease progression especially with "severe" variants typified by p.L483P. GBA mutation screening studies from South-East Asia, with > 650 million inhabitants of diverse ancestries, are very limited. We investigated the spectrum of GBA variants, and associated clinico-demographic features, in a multi-ethnic PD cohort in Malaysia. Patients (n = 496) were recruited from seven centres, primarily of Chinese (45%), Malay (37%), and Indian (13%) ethnicities. All GBA coding exons were screened using a next-generation sequencing-based PD gene panel and verified with Sanger sequencing. We identified 14 heterozygous GBA alleles consisting of altogether 17 missense variants (8 classified as pathogenic or likely pathogenic for PD) in 25 (5.0%) patients, with a substantially higher yield among early (< 50 years) vs. late-onset patients across all three ethnicities (9.1-13.2% vs. 1.0-3.2%). The most common variant was p.L483P (including RecNciI, n = 11, 2.2%), detected in all three ethnicities. Three novel variants/recombinant alleles of uncertain significance were found; p.P71L, p.L411P, and p.L15S(;)S16G(;)I20V. The common European risk variants, p.E365K, p.T408M, and p.N409S, were not detected. A severe disease course was noted in the majority of GBA-variant carriers, across a range of detected variants. We report a potentially novel observation of spine posture abnormalities in GBA-variant carriers. This represents the largest study on GBA variation from South-East Asia, and highlights that these populations, especially those with EOPD, would be relevant for studies including clinical trials targeting GBA pathways., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Mutations in GBA which are causative of Gaucher disease in their biallelic form, are the most common genetic risk factor for Parkinson's disease (PD). The diagnosis of PD relies upon clinically defined motor features which appear after irreversible neurodegeneration. Prodromal symptoms of PD may provide a means to predict latent pathology, years before the onset of motor features. Previous work has reported prodromal features of PD in GBA mutation carriers, however this has been insufficiently sensitive to identify those that will develop PD. The Remote Assessment of Parkinsonism Supporting Ongoing Development of Interventions in Gaucher Disease (RAPSODI GD) study assesses a large cohort of GBA mutation carriers, to aid development of procedures for earlier diagnosis of PD.