Aligning climate scenarios to emissions inventories shifts global benchmarks.

Taking stock of global progress towards achieving the Paris Agreement requires consistently measuring aggregate national actions and pledges against modelled mitigation pathways1. However, national greenhouse gas inventories (NGHGIs) and scientific assessments of anthropogenic emissions follow different accounting conventions for land-based carbon fluxes resulting in a large difference in the present emission estimates2,3, a gap that will evolve over time. Using state-of-the-art methodologies4 and a land carbon-cycle emulator5, we align the Intergovernmental Panel on Climate Change (IPCC)-assessed mitigation pathways with the NGHGIs to make a comparison. We find that the key global mitigation benchmarks become harder to achieve when calculated using the NGHGI conventions, requiring both earlier net-zero CO2 timing and lower cumulative emissions. Furthermore, weakening natural carbon removal processes such as carbon fertilization can mask anthropogenic land-based removal efforts, with the result that land-based carbon fluxes in NGHGIs may ultimately become sources of emissions by 2100. Our results are important for the Global Stocktake6, suggesting that nations will need to increase the collective ambition of their climate targets to remain consistent with the global temperature goals.

Delayed use of bioenergy crops might threaten climate and food security.

The potential of mitigation actions to limit global warming within 2 °C (ref. 1) might rely on the abundant supply of biomass for large-scale bioenergy with carbon capture and storage (BECCS) that is assumed to scale up markedly in the future2-5. However, the detrimental effects of climate change on crop yields may reduce the capacity of BECCS and threaten food security6-8, thus creating an unrecognized positive feedback loop on global warming. We quantified the strength of this feedback by implementing the responses of crop yields to increases in growing-season temperature, atmospheric CO2 concentration and intensity of nitrogen (N) fertilization in a compact Earth system model9. Exceeding a threshold of climate change would cause transformative changes in social-ecological systems by jeopardizing climate stability and threatening food security. If global mitigation alongside large-scale BECCS is delayed to 2060 when global warming exceeds about 2.5 °C, then the yields of agricultural residues for BECCS would be too low to meet the Paris goal of 2 °C by 2200. This risk of failure is amplified by the sustained demand for food, leading to an expansion of cropland or intensification of N fertilization to compensate for climate-induced yield losses. Our findings thereby reinforce the urgency of early mitigation, preferably by 2040, to avoid irreversible climate change and serious food crises unless other negative-emission technologies become available in the near future to compensate for the reduced capacity of BECCS.

Trial of Prasinezumab in Early-Stage Parkinson's Disease.

BACKGROUND: Aggregated α-synuclein plays an important role in the pathogenesis of Parkinson's disease. The monoclonal antibody prasinezumab, directed at aggregated α-synuclein, is being studied for its effect on Parkinson's disease. METHODS: In this phase 2 trial, we randomly assigned participants with early-stage Parkinson's disease in a 1:1:1 ratio to receive intravenous placebo or prasinezumab at a dose of 1500 mg or 4500 mg every 4 weeks for 52 weeks. The primary end point was the change from baseline to week 52 in the sum of scores on parts I, II, and III of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 236, with higher scores indicating greater impairment). Secondary end points included the dopamine transporter levels in the putamen of the hemisphere ipsilateral to the clinically more affected side of the body, as measured by 123I-ioflupane single-photon-emission computed tomography (SPECT). RESULTS: A total of 316 participants were enrolled; 105 were assigned to receive placebo, 105 to receive 1500 mg of prasinezumab, and 106 to receive 4500 mg of prasinezumab. The baseline mean MDS-UPDRS scores were 32.0 in the placebo group, 31.5 in the 1500-mg group, and 30.8 in the 4500-mg group, and mean (±SE) changes from baseline to 52 weeks were 9.4±1.2 in the placebo group, 7.4±1.2 in the 1500-mg group (difference vs. placebo, -2.0; 80% confidence interval [CI], -4.2 to 0.2; P = 0.24), and 8.8±1.2 in the 4500-mg group (difference vs. placebo, -0.6; 80% CI, -2.8 to 1.6; P = 0.72). There was no substantial difference between the active-treatment groups and the placebo group in dopamine transporter levels on SPECT. The results for most clinical secondary end points were similar in the active-treatment groups and the placebo group. Serious adverse events occurred in 6.7% of the participants in the 1500-mg group and in 7.5% of those in the 4500-mg group; infusion reactions occurred in 19.0% and 34.0%, respectively. CONCLUSIONS: Prasinezumab therapy had no meaningful effect on global or imaging measures of Parkinson's disease progression as compared with placebo and was associated with infusion reactions. (Funded by F. Hoffmann-La Roche and Prothena Biosciences; PASADENA ClinicalTrials.gov number, NCT03100149.).

Dissecting genetic architecture of rare dystonia: genetic, molecular and clinical insights.

BACKGROUND: Dystonia is one of the most common movement disorders. To date, the genetic causes of dystonia in populations of European descent have been extensively studied. However, other populations, particularly those from the Middle East, have not been adequately studied. The purpose of this study is to discover the genetic basis of dystonia in a clinically and genetically well-characterised dystonia cohort from Turkey, which harbours poorly studied populations. METHODS: Exome sequencing analysis was performed in 42 Turkish dystonia families. Using co-expression network (CEN) analysis, identified candidate genes were interrogated for the networks including known dystonia-associated genes and genes further associated with the protein-protein interaction, animal model-based characteristics and clinical findings. RESULTS: We identified potentially disease-causing variants in the established dystonia genes (PRKRA, SGCE, KMT2B, SLC2A1, GCH1, THAP1, HPCA, TSPOAP1, AOPEP; n=11 families (26%)), in the uncommon forms of dystonia-associated genes (PCCB, CACNA1A, ALDH5A1, PRKN; n=4 families (10%)) and in the candidate genes prioritised based on the pathogenicity of the variants and CEN-based analyses (n=11 families (21%)). The diagnostic yield was found to be 36%. Several pathways and gene ontologies implicated in immune system, transcription, metabolic pathways, endosomal-lysosomal and neurodevelopmental mechanisms were over-represented in our CEN analysis. CONCLUSIONS: Here, using a structured approach, we have characterised a clinically and genetically well-defined dystonia cohort from Turkey, where dystonia has not been widely studied, and provided an uncovered genetic basis, which will facilitate diagnostic dystonia research.

Clonal hematopoiesis as a pitfall in germline variant interpretation in the context of Mendelian disorders.

Clonal hematopoiesis because of somatic mutations in hematopoietic stem/progenitor cells is an age-related phenomenon and commonly observed when sequencing blood DNA in elderly individuals. Several genes that are implicated in clonal hematopoiesis are also associated with Mendelian disorders when mutated in the germline, potentially leading to variant misinterpretation. We performed a literature search to identify genes associated with age-related clonal hematopoiesis followed by an OMIM query to identify the subset of genes in which germline variants are associated with Mendelian disorders. We retrospectively screened for diagnostic cases in which the presence of age-related clonal hematopoiesis confounded exome sequencing data interpretation. We found 58 genes in which somatic mutations are implicated in clonal hematopoiesis, while germline variants in the same genes are associated with Mendelian (mostly neurodevelopmental) disorders. Using five selected cases of individuals with suspected monogenic disorders, we illustrate how clonal hematopoiesis in either variant databases or exome sequencing datasets poses a pitfall, potentially leading to variant misclassification and erroneous conclusions regarding gene-disease associations.

Parkin mRNA Expression Levels in Peripheral Blood Mononuclear Cells in Parkin-Related Parkinson's Disease.

INTRODUCTION: Pathogenic variants in parkin (PRKN gene) are the second most prevalent known monogenic cause of Parkinson's disease (PD). How monoallelic or biallelic pathogenic variants in the PRKN gene may affect its transcription in patient-derived biological material has not been systematically studied. METHODS: PRKN mRNA expression levels were measured with real-time polymerase chain reaction (RT-PCR) in peripheral blood mononuclear cells (PBMCs). PBMCs were derived from PRKN-mutated PD patients (PRKN-PD) (n = 12), sporadic PD (sPD) (n = 21) and healthy controls (n = 21). Six of the PRKN-PD patients were heterozygous, four were compound heterozygous, and two were homozygous for PRKN variants. RESULTS: A statistically significant decrease in PRKN expression levels was present, compared to healthy controls and sPD, in heterozygous (P = 0.019 and 0.031 respectively) and biallelic (P < 0.001 for both) PRKN-PD. PRKN expression levels in biallelic PD patients were uniformly very low and were reduced, albeit not significantly, compared to heterozygotes. Based on receiver operating characteristic analysis, low PRKN expression levels were a sensitive and extremely specific indicator for the presence of PRKN pathogenic variants. CONCLUSIONS: Assessment of PRKN mRNA levels in PBMCs may be a useful way to screen for biallelic pathogenic variants in the PRKN gene. Suspicion for certain variants in a heterozygous state may also be raised based on low PRKN mRNA levels. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Novel PINK1 p.F385S Loss-of-Function Mutation in an Indian Family with Parkinson's Disease.

BACKGROUND: Most Parkinson's disease (PD) loci have shown low prevalence in the Indian population, highlighting the need for further research. OBJECTIVE: The aim of this study was to characterize a novel phosphatase tensin homolog-induced serine/threonine kinase 1 (PINK1) mutation causing PD in an Indian family. METHODS: Exome sequencing of a well-characterized Indian family with PD. A novel PINK1 mutation was studied by in silico modeling using AlphaFold2, expression of mutant PINK1 in human cells depleted of functional endogenous PINK1, followed by quantitative image analysis and biochemical assessment. RESULTS: We identified a homozygous chr1:20648535-20648535 T>C on GRCh38 (p.F385S) mutation in exon 6 of PINK1, which was absent in 1029 genomes from India and in other known databases. PINK1 F385S lies within the highly conserved Deutsche Forschungsgemeinschaft (DFG) motif, destabilizes its active state, and impairs phosphorylation of ubiquitin at serine 65 and proper engagement of parkin upon mitochondrial depolarization. CONCLUSIONS: We characterized a novel nonconservative mutation in the DFG motif of PINK1, which causes loss of its ubiquitin kinase activity and inhibition of mitophagy. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Association of elevated cerebrospinal fluid levels of the longevity protein α-Klotho with a delayed onset of cognitive impairment in Parkinson's disease patients.

BACKGROUND AND PURPOSE: Parkinson's disease (PD) is an age-related condition characterized by substantial phenotypic variability. Consequently, pathways and proteins involved in biological aging, such as the central aging pathway comprising insulin-like growth factor 1-α-Klotho-sirtuin 1-forkhead box O3-peroxisome proliferator-activated receptor γ, may potentially influence disease progression. METHODS: Cerebrospinal fluid (CSF) levels of α-Klotho in 471 PD patients were examined. Of the 471 patients, 96 carried a GBA1 variant (PD GBA1), whilst the 375 non-carriers were classified as PD wild-type (PD WT). Each patient was stratified into a CSF α-Klotho tertile group based on the individual level. Kaplan-Meier survival curves and Cox regression analysis stratified by tertile groups were conducted. These longitudinal data were available for 255 patients. Follow-up times reached from 8.4 to 12.4 years. The stratification into PD WT and PD GBA1 was undertaken to evaluate potential continuum patterns, particularly in relation to CSF levels. RESULTS: Higher CSF levels of α-Klotho were associated with a significant later onset of cognitive impairment. Elevated levels of α-Klotho in CSF were linked to higher Montreal Cognitive Assessment scores in male PD patients with GBA1 mutations. CONCLUSIONS: Our results indicate that higher CSF levels of α-Klotho are associated with a delayed cognitive decline in PD. Notably, this correlation is more prominently observed in PD patients with GBA1 mutations, potentially reflecting the accelerated biological aging profile characteristic of individuals harboring GBA1 variants.

The contributions of individual countries and regions to the global radiative forcing.

Knowing the historical relative contribution of greenhouse gases (GHGs) and short-lived climate forcers (SLCFs) to global radiative forcing (RF) at the regional level can help understand how future GHGs emission reductions and associated or independent reductions in SLCFs will affect the ultimate purpose of the Paris Agreement. In this study, we use a compact Earth system model to quantify the global RF and attribute global RF to individual countries and regions. As our evaluation, the United States, the first 15 European Union members, and China are the top three contributors, accounting for 21.9 ± 3.1%, 13.7 ± 1.6%, and 8.6 ± 7.0% of global RF in 2014, respectively. We also find a contrast between developed countries where GHGs dominate the RF and developing countries where SLCFs including aerosols and ozone are more dominant. In developing countries, negative RF caused by aerosols largely masks the positive RF from GHGs. As developing countries take measures to improve the air quality, their negative contributions from aerosols will likely be reduced in the future, which will in turn enhance global warming. This underlines the importance of reducing GHG emissions in parallel to avoid any detrimental consequences from air quality policies.

Polygenic Resilience Modulates the Penetrance of Parkinson Disease Genetic Risk Factors.

OBJECTIVE: The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual-level genetic data available. METHODS: We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership-Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome-wide association study meta-analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene-based analyses and functional enrichment analyses. RESULTS: A higher polygenic resilience score was associated with a lower risk for PD (ß = -0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome-wide significance, MAGMA gene-based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow-sense heritability associated with resilience to PD (h2  = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci. INTERPRETATION: The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high-risk genetic burden from developing PD. ANN NEUROL 2022;92:270-278.

Genetic testing for Parkinson's disease in clinical practice.

The identification of disease-causing mutations or strong risk factors for Parkinson's disease in genes encoding proteins such as α-synuclein (SNCA), leucine-rich repeat kinase-2 (LRRK2), or glucocerebrosidase (GBA1) has led to a better understanding of the different components of disease pathogenesis. Many gene and mutation-specific targeted disease-modifying treatments are under development and several studies are under way. It is, therefore, important to raise awareness among patients and their families and to offer genetic testing, at least to those patients who are considering to participate in innovative trials.

The heterogeneity of Parkinson's disease.

The heterogeneity of Parkinson's disease (PD), i.e. the various clinical phenotypes, pathological findings, genetic predispositions and probably also the various implicated pathophysiological pathways pose a major challenge for future research projects and therapeutic trail design. We outline several pathophysiological concepts, pathways and mechanisms, including the presumed roles of α-synuclein misfolding and aggregation, Lewy bodies, oxidative stress, iron and melanin, deficient autophagy processes, insulin and incretin signaling, T-cell autoimmunity, the gut-brain axis and the evidence that microbial (viral) agents may induce molecular hallmarks of neurodegeneration. The hypothesis is discussed, whether PD might indeed be triggered by exogenous (infectious) agents in susceptible individuals upon entry via the olfactory bulb (brain first) or the gut (body-first), which would support the idea that disease mechanisms may change over time. The unresolved heterogeneity of PD may have contributed to the failure of past clinical trials, which attempted to slow the course of PD. We thus conclude that PD patients need personalized therapeutic approaches tailored to specific phenomenological and etiologic subtypes of disease.

Minimal invasiveness in soft tissue augmentation at dental implants: A systematic review and meta-analysis of patient-reported outcome measures.

The aim of this study was to compare patient-reported outcome measures (PROMs) of soft tissue substitutes versus autogenous grafts for soft tissue augmentation procedures at implant sites. Comprehensive and systematic literature searches were performed until December 2021. A focused question was formulated based on the Population, Intervention, Comparison and Outcome criteria (PICO): In patients with dental implants undergoing soft tissue augmentation (P), do soft tissue substitutes (I) compared to autogenous soft tissue graft (SCTG [subepithelial connective tissue graft]) (C) limit the post-operative morbidity and other patient reported-outcomes measures (O). Randomized controlled clinical trials, prospective-, retrospective- and case-series studies were included. Meta-analyses were performed whenever possible and the results were expressed as weighted mean differences (WMD). A total of 29 clinical studies were included. For mucosal thickness gain, soft tissue substitutes significantly reduced the pain perception compared to SCTG (n = 4; WMD = 14.91 Visual Analog Scale [VAS] units; 95% confidence interval [CI] 6.42-23.40; P < .0006) based on a 0-100 VAS scale. Based on a 0-10 VAS scale, a borderline significance of pain reduction was found when soft tissue substitutes were applied (n = 4; WMD = 1.62 VAS units; 95% CI 0.01-3.23; P = .05). For keratinized tissue gain, soft tissue substitutes significantly reduced the pain perception after keratinized tissue augmentation compared to SCTG based on a 0-100 VAS scale (n = 2; WMD = 21.43 VAS units; 95% CI 12.58-30.28; P < .0001). Based on the 0-10 VAS scale, soft tissue substitutes significantly reduced the pain as compared to SCTG (n = 4; WMD = 1.65 VAS units; 95% CI 0.66-2.64; P = .001). Regarding pain medication, soft tissue substitutes required less painkillers (n = 6; WMD = 1.56 tablets; 95% CI 1.22-1.91; P < .00001) after soft tissue augmentation. The surgery time was significantly reduced when soft tissue substitutes were used (n = 5; WMD = 10.9 minutes; 95% CI 4.60-17.19; P < .00001). There were no significant differences in satisfaction, aesthetics, and quality of life (OHIP-14) between soft tissue substitutes and autogenous grafts following soft tissue augmentation at implants sites. Soft tissue substitutes, compared to autogenous grafts, significantly improve PROMs following soft tissue augmentation at implant sites. Soft tissue substitutes can reduce pain perception, amounts of painkillers and surgery time while achieving similar levels of patient´s satisfaction as autogenous grafts without impairing the clinical outcomes. The current evidence indicates that they constitute a valid and reliable alternative to minimize the invasiveness in soft tissue augmentation procedures at implant sites.

Temperature Changes Induced by Biogeochemical and Biophysical Effects of Bioenergy Crop Cultivation.

The production of bioenergy with carbon capture and storage (BECCS) is a pivotal negative emission technology. The cultivation of dedicated crops for BECCS impacts the temperature through two processes: net CO2 removal (CDR) from the atmosphere (biogeochemical cooling) and changes in the local energy balance (biophysical warming or cooling). Here, we compare the magnitude of these two processes for key grass and tree species envisioned for large-scale bioenergy crop cultivation, following economically plausible scenarios using Earth System Models. By the end of this century, the cumulative CDR from the cultivation of eucalypt (72-112 Pg C) is larger than that of switchgrass (34-83 Pg C) because of contrasting contributions of land use change carbon emissions. The combined biogeochemical and biophysical effects are cooling (-0.26 to -0.04 °C) at the global scale, but 13-28% of land areas still have net warming signals, mainly due to the spatial heterogeneity of the biophysical effects. Our study shows that the deployment of bioenergy crop cultivation should not only be guided by the principles of maximizing yield and CDR but should also take an integrated perspective that includes all relevant Earth system feedbacks.

Mitochondrial and autophagy-lysosomal pathway polygenic risk scores predict Parkinson's disease.

Polygenic Risk Scores (PRS), which allow assessing an individuals' genetic risk for a complex disease, are calculated as the weighted number of genetic risk alleles in an individual's genome, with the risk alleles and their weights typically derived from the results of genome-wide association studies (GWAS). Among a wide range of applications, PRS can be used to identify at-risk individuals and select them for further clinical follow-up. Pathway PRS are genetic scores based on single nucleotide polymorphisms (SNPs) assigned to genes involved in major disease pathways. The aim of this study is to assess the predictive utility of PRS models constructed based on SNPs corresponding to two cardinal pathways in Parkinson's disease (PD) including mitochondrial PRS (Mito PRS) and autophagy-lysosomal PRS (ALP PRS). PRS models were constructed using the clumping-and-thresholding method in a German population as prediction dataset that included 371 cases and 249 controls, using SNPs discovered by the most recent PD-GWAS. We showed that these pathway PRS significantly predict the PD status. Furthermore, we demonstrated that Mito PRS are significantly associated with later age of onset in PD patients. Our results may add to the accumulating evidence for the contribution of mitochondrial and autophagy-lysosomal pathways to PD risk and facilitate biologically relevant risk stratification of PD patients.

[Introduction to Gene Therapy]. / Einführung in die Gentherapie.

After many years of research and numerous setbacks, there are now undeniable success stories of gene therapies, namely the direct modification of genetic information on the DNA or RNA level. Both "ex vivo" strategies, i. e. the genetic manipulation of patient cells in a dish, as well as "in vivo" approaches are being used successfully. In addition to the supplementation of defective genes, the use of the CRISPR-Cas9 system to alter nuclear DNA sequences and the sequence-specific interference with the transcriptional process on the RNA level can be designated as gene therapies in a broad sense.

Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease.

OBJECTIVE: Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average ~ 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide association studies (GWAS) have identified numerous genetic risk factors for PD, however, it is unclear whether genetics contribute to disease etiology in a sex-specific manner. METHODS: In an effort to study sex-specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson's Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases. RESULTS: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (~ 20%). INTERPRETATION: We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients. ANN NEUROL 2021;90:41-48.

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.

OBJECTIVE: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. METHODS: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. RESULTS: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. INTERPRETATION: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.

PIAS2-mediated blockade of IFN-ß signaling: a basis for sporadic Parkinson disease dementia.

Familial Parkinson disease (PD) is associated with rare genetic mutations, but the etiology in most patients with sporadic (s)PD is largely unknown, and the basis for its progression to dementia (sPDD) is poorly characterized. We have identified that loss of IFNß or IFNAR1, the receptor for IFNα/ß, causes pathological and behavioral changes resembling PDD, prompting us to hypothesize that dysregulated genes in IFNß-IFNAR signaling pathway predispose one to sPD. By transcriptomic analysis, we found defective neuronal IFNß-IFNAR signaling, including particularly elevated PIAS2 associated with sPDD. With meta-analysis of GWASs, we identified sequence variants in IFNß-IFNAR-related genes in sPD patients. Furthermore, sPDD patients expressed higher levels of PIAS2 mRNA and protein in neurons. To determine its function in brain, we overexpressed PIAS2 under a neuronal promoter, alone or with human α-synuclein, in the brains of mice, which caused motor and cognitive impairments and correlated with intraneuronal phosphorylated (p)α-synuclein accumulation and dopaminergic neuron loss. Ectopic expression of neuronal PIAS2 blocked mitophagy, increased the accumulation of senescent mitochondrial and oxidative stress, as evidenced by excessive oxDJ1 and 8OHdG, by inactivating ERK1/2-P53 signaling. Conversely, PIAS2 knockdown rescued the clinicopathological manifestations of PDD in Ifnb-/- mice on restoring mitochondrial homeostasis, oxidative stress, and pERK1/2-pP53 signaling. The regulation of JAK-STAT2-PIAS2 signaling was crucial for neurite outgrowth and neuronal survival and excitability and thus might prevent cognitive impairments. Our findings provide insights into the progression of sPD and dementia and have implications for new therapeutic approaches.

Evaluation of the Dementia Apraxia Test in Parkinson's Disease Patients.

INTRODUCTION: Ideomotor apraxia, a disorder of skilled movements affecting limbs and/or face, can be seen in patients with Parkinson's disease (PD), yet tests of apraxia in PD are rare. The aim of this project was to evaluate the psychometric properties and validity of the Dementia Apraxia Test (DATE) in a PD sample. METHODS: 118 PD patients were included. Besides DATE performance, motor and non-motor burden, cognition, and activity of daily living (ADL) function were assessed. Patients were classified as cognitively impaired (n = 41) or non-cognitively impaired (n = 77). RESULTS: Interrater reliability of the DATE (sub-)scores between video ratings and on-site ratings by the investigator was good (0.81 ≤ rk ≤ 0.87). Items were mostly easy to perform, especially the buccofacial apraxia items, which had also low discriminatory power. DATE scores were associated with cognition and ADL function. DATE performance was confounded by motor impairment and patients' age; however, when analysed for both cognitive groups separately, the correlation between DATE and motor performance was not significant. DISCUSSION/CONCLUSION: The DATE seems to be an objective and predominantly valid apraxia screening tool for PD patients, with a few items needing revision. Due to the potential effect of motor impairment and age, standardized scores adjusting for these confounders are needed.