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Estimates of the spectrum and frequency of pathogenic variants in Parkinsons disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinsons disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

Abstract There are 90 independent genome-wide significant genetic risk variants for Parkinson’s disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. We studied 6766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out genome-wide survival studies for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We also identified a locus within the TBXAS1 gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near MORN1, ASNS, PDE5A, and XPO1. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, these may represent new candidates for disease modification in PD.

Abstract Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson’s disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p

Abstract 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.

ObjectiveThe 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.MethodsWe 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.ResultsA 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.InterpretationThis 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.

BackgroundThe severity, progression, and outcomes of motor and non-motor symptoms in Parkinson’s disease (PD) are quite variable. Following PD cohorts holds promise for identifying predictors of disease severity and progression.MethodsPD patients (N = 871) were enrolled at five sites. Enrollment occurred within 5 years of initial motor symptom onset. Disease progression was assessed annually for 2-to-10 years after onset. Group-based trajectory modeling was used to identify groups differing in disease progression. Models were developed for UPDRS-III scores, UPDRS-III tremor and bradykinesia-rigidity subscores, Hoehn & Yahr (H&Y) stage, Mini-Mental Status Exam (MMSE) scores, and UPDRS-III, H&Y and MMSE scores considered together. Predictors of trajectory-group membership were modeled simultaneously with the trajectories. Kaplan–Meier survival analysis evaluated survival free of PD outcomes.ResultsThe best fitting models identified three groups. One showed a relatively benign, slowly progressing trajectory (Group 1), a second showed a moderate, intermediately progressing trajectory (Group 2), and a third showed a more severe, rapidly progressing trajectory (Group 3). Stable trajectory-group membership occurred relatively early in the disease course, 5 years after initial motor symptom. Predictors of intermediate and more severe trajectory-group membership varied across the single variable models and the multivariable model jointly considering UPDRS-III, H&Y and MMSE scores. In the multivariable model, membership in Group 2 (28.4% of patients), relative to Group 1 (50.5%), was associated with male sex, younger age-at-onset, fewer education-years, pesticide exposure, absence of reported head injury, and akinetic/rigid subtype at initial presentation. Membership in Group 3 (21.3%), relative to Group 1, was associated with older age-at-onset, fewer education-years, pesticide exposure, and the absence of a tremor-predominant subtype at initial presentation. Persistent freezing, persistent falls, and cognitive impairment occurred earliest and more frequently in Group 3, later and less frequently in Group 2, and latest and least frequently in Group 1. Furthermore, autonomic complications, dysphagia, and psychosis occurred more frequently in Groups 2 and 3 than in Group 1.ConclusionModeling disease course using multiple objective assessments over an extended follow-up duration identified groups that more accurately reflect differences in PD course, prognosis, and outcomes than assessing single parameters over shorter intervals.

BackgroundIncreased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls.MethodsCancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients.ResultsAlthough cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients.ConclusionsThe increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society.

Obtaining detailed and precise information from a classified refractory gold ore has been a long-standing challenge in mineral processing and process mineralogy. Although the concept of diagnostic leaching has been extensively addressed in the literature, very little information is available linking this approach with current advanced characterization techniques such as automated mineralogy. The present research study aims to characterize the flotation concentrate of refractory gold ore by combining diagnostic leaching and automated mineralogy to examine its processability. The diagnostic leaching process was applied stepwise at five stages, and the automated mineralogy was performed on different size fractions of the flotation concentrate. The chemical (X-ray fluorescence (XRF), atomic absorption spectroscopy (AAS), and inductively coupled plasma-optical emission spectroscopy (ICP-OES)) and mineralogical (X-ray diffraction (XRD)) analyses of the feed sample confirmed that the ore is a low-grade gold ore with 0.7 g/t Au. Initially, bottle roll tests were carried out to investigate leaching behavior, and the ore’s refractory nature, and gold recoveries of bottle roll tests in different sizes were below 40 wt%; it is classified as a high refractory gold ore as a result of direct cyanide leaching. Bulk sulfide flotation was applied to increase the gold content of the material. Automated mineralogy results demonstrated that most of the gold in the concentrate is present as an invisible gold form, and 63.7 wt% of gold was distributed in pyrite. Diagnostic leaching results showed 39.7 wt% of total gold was leachable using direct cyanide leaching, and around 33 wt% of undissolved gold was located in pyrite and arsenopyrite.

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.

Objective Few studies have followed Parkinson’s disease (PD) patients from the time of diagnosis to the date of death. This study compared mortality in the Trondheim PD cohort to the general population, investigated causes of death and analyzed the associations between mortality and age at disease onset (AAO) and cognitive decline defined as Montreal Cognitive Assessment (MoCA) score below 26. Methods The cohort was followed longitudinally from 1997. By the end of January 2020, 587 patients had died. Comparisons to the Norwegian population were performed by calculating standardized mortality ratios (SMRs). Survival curves were estimated using the standard Kaplan-Meier estimator, and multivariable Cox proportional hazard models were estimated to investigate associations. Results SMR was 2.28 [95% confidence interval (CI): 2.13–2.44] for the whole cohort. For participants with AAO 20–39 years, the SMR was 5.55 (95% CI: 3.38–8.61). Median survival was 15 years (95% CI: 14.2–15.5) for the whole cohort. Early-onset PD (EOPD) patients (AAO < 50 years) had the longest median survival time. For all groups, there was a significant shortening in median survival time and an almost 3-fold higher age- and sex-adjusted hazard ratio for death when the MoCA score decreased below 26. Conclusion PD patients with an AAO before 40 years had a more than fivefold higher mortality rate compared to a similar general population. EOPD patients had the longest median survival; however, their life expectancy was reduced to a greater degree than that of late-onset PD patients. Cognitive impairment was strongly associated with mortality in PD.

Abstract Background Asymptomatic carriers of leucine-rich repeat kinase 2 (LRRK2) gene mutations constitute an ideal population for discovering prodromal biomarkers of Parkinson’s disease (PD). In this study, we aim to identify CSF candidate risk biomarkers of PD in individuals with LRRK2 mutation carriers. Methods We measured the levels of CSF total- (t-), oligomeric (o-) and phosphorylated S129 (pS129-) α-syn, total-tau (tTau), phosphorylated threonine 181 tau (pTau), amyloid-beta 40 (Aβ-40), amyloid-beta-42 (Aβ-42) and 40 inflammatory chemokines in symptomatic (n = 23) and asymptomatic (n = 51) LRRK2 mutation carriers, subjects with a clinical diagnosis of PD (n = 60) and age-matched healthy controls (n = 34). General linear models corrected for age and gender were performed to assess differences in CSF biomarkers between the groups. Markers that varied significantly between the groups were then analyzed using backward-elimination logistic regression analysis to identify an ideal biomarkers panel of prodromal PD. Results Discriminant function analysis revealed low levels of CSF t-α-syn, high levels of CSF o-α-syn and TNF-α best discriminated asymptomatic LRRK2 mutation carriers from both symptomatic PD and healthy controls. Assessing the discriminative power using receiver operating curve analysis, an area under the curve > 0.80 was generated. Conclusions The current study suggests that CSF t-, o-α-syn and TNF-α are candidate risk biomarkers for the detection of PD at the prodromal stage. Our findings also highlight the dynamic interrelationships between CSF proteins and the importance of using a biomarkers’ panel approach for an accurate and timely diagnosis of PD.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects 1–2% of people by the age of 70 years. Age is the most important risk factor, and most cases are sporadic without any known environmental or genetic causes. Since the late 1990s, mutations in the genes SNCA, PRKN, LRRK2, PINK1, DJ-1, VPS35, and GBA have been shown to be important risk factors for PD. In addition, common variants with small effect sizes are now recognized to modulate the risk for PD. Most studies in genetic PD have focused on finding new genes, but few have studied the long-term outcome of patients with the specific genetic PD forms. Patients with known genetic PD have now been followed for more than 20 years, and we see that they may have distinct and different prognoses. New therapeutic possibilities are emerging based on the genetic cause underlying the disease. Future medication may be based on the pathophysiology individualized to the patient’s genetic background. The challenge is to find the biological consequences of different genetic variants. In this review, the clinical patterns and long-term prognoses of the most common genetic PD variants are presented.

Parkinson’s Disease is the most common neurodegenerative movement disorder globally, with prevalence increasing. There is an urgent need for new therapeutics which are disease-modifying rather than symptomatic. Mitochondrial dysfunction is a well-documented mechanism in both sporadic and familial Parkinson’s Disease. Furthermore, ursodeoxycholic acid (UDCA) has been identified as a bile acid which leads to increased mitochondrial function in multiple in vitro and in vivo models of Parkinson’s Disease. Here, we describe the synthesis of novel C-nor-D-homo bile acid derivatives and the 12-hydroxy-methylated derivative of lagocholic acid (7) and their biological evaluation in fibroblasts from patients with either sporadic or LRRK2 mutant Parkinson’s Disease. These compounds boost mitochondrial function to a similar level or above that of UDCA in many assays; notable, however, is their ability to boost mitochondrial function to a higher level and at lower concentrations than UDCA specifically in the fibroblasts from LRRK2 patients. Our study indicates that novel bile acid chemistry could lead to the development of more efficacious bile acids which increase mitochondrial function and ultimately cellular health at lower concentrations proving attractive potential novel therapeutics for Parkinson’s Disease.

Parkinson’s disease (PD) patients may have a specific personality profile, which includes being introvert, cautious and devoted to hard work. The evaluation of psychological characteristics must be evaluated according to methods for assessments of personality disorders. Such evaluations are often time-consuming and available only in research settings. The “parkinsonian trait” may be established early in life but may change with disease progression. To overcome this long interval before onset of PD questions on literary activities were included in the medical record. Three percent of PD patients could be defined as writers, significantly higher than observed in the general population. PD writers published their first books long before onset of disease. Being a writer is an extrovert trait meaning that the patient is prepared for criticism and publicity. We suggest that questions regarding personal activities prior to disease onset add valuable information on personality which differs significantly from traits observed later in the disease period.

ImportancePatients with Parkinson disease (PD) who harbor LRRK2 G2019S mutations may have increased risks of nonskin cancers. However, the results have been inconsistent across studies.ObjectivesTo analyze pooled data from 5 centers to further examine the association between LRRK2 G2019S mutation and cancer among patients with PD and to explore factors that could explain discrepancies.Design, setting, and participantsClinical, demographic, and genotyping data as well as cancer outcomes were pooled from 1549 patients with PD recruited across 5 movement disorders clinics located in Europe, Israel, and the United States. Associations between LRRK2 G2019S mutation and the outcomes were examined using mixed-effects logistic regression models to estimate odds ratios (ORs) and 95% CIs. Models were adjusted for age and ethnicity (Ashkenazi Jewish vs others) as fixed effects and study center as a random effect.Main outcomes and measuresAll cancers combined, nonskin cancers, smoking-related cancers, hormone-related cancers, and other types of cancer.ResultsThe overall prevalence of the LRRK2 G2019S mutation was 11.4% among all patients with PD. Mutation carriers were younger at PD diagnosis and more likely to be women (53.1%) and of Ashkenazi Jewish descent (76.8%) in comparison with individuals who were not mutation carriers. The LRRK2 G2019S mutation carriers had statistically significant increased risks for nonskin cancers (OR, 1.62; 95% CI, 1.04-2.52), hormone-related cancers (OR, 1.87; 95% CI, 1.07-3.26) and breast cancer (OR, 2.34; 95% CI, 1.05-5.22) in comparison with noncarriers. There were no associations with other cancers. There were no major statistically significant differences in the results when the data were stratified by Ashkenazi Jewish ethnicity; however, there was some evidence of heterogeneity across centers.Conclusions and relevanceThis multinational study from 5 centers demonstrates that LRRK2 G2019S mutation carriers have an overall increased risk of cancer, especially for hormone-related cancer and breast cancer in women. Larger prospective cohorts or family-based studies investigating associations between LRRK2 mutations and cancer among patients with PD are warranted to better understand the underlying genetic susceptibility between PD and hormone-related cancers.

Recently, α-synuclein (α-syn) and DJ-1, 2 proteins critically involved in Parkinson's disease (PD), have been shown to be present in saliva, suggesting their potential utility as biomarkers of PD. However, the origin and influence of demographic characteristics (e.g., age or sex) on these proteins are unknown. We identified cheek epithelium, which forms the majority of the cellular component of saliva and is readily accessible clinically, as 1 of several potential sources of salivary α-syn and DJ-1. However, no PD-related trend in the cellular component was present. In the supernatant collected from 198 healthy subjects, no correlation was seen between salivary DJ-1 or α-syn with age. When male and female subjects were analyzed separately, a weak age-dependent increase in DJ-1 level was present in male subjects, along with slightly increased α-syn in female subjects. These results, albeit largely negative, provide critical information for understanding the salivary gland pathology and saliva as a PD biomarker source, and must be considered in future investigations of salivary changes in PD.

The first families with LRRK2 related Parkinson’s disease (PD) were presented around 15 years ago and numerous papers have described the characteristics of the LRRK2 phenotype. The prevalence of autosomal dominant PD varies around the world mainly depending on local founder effects. The highest prevalence of LRRK2 G2019S PD in Norway is located to the central part of the country and most families could be traced back to common ancestors. The typical Norwegian LRRK2 phenotype is not different from classical PD and similar to that seen in most other LRRK2 families. The discovery of LRRK2 PD has allowed us to follow-up multi-incident families and to study their phenotype longitudinally. In the Norwegian LRRK2 families there has been a significantly higher incidence of inflammatory diseases like multiple sclerosis and rheumatoid arthritis that seen in other PD populations. Recent studies in LRRK2 mechanisms have indicated that this protein may be crucial in initiating disease processes. In this short survey of 100 Norwegian mutation carriers followed through more than 15 years are presented. The prevalence of inflammatory diseases among these cases is highlighted. The role of LRRK2 in the conversion process from carrier status to PD phenotype is still unknown and disease generating mechanisms important for initiating LRRK2 PD are still to be identified.

Several mutations in leucine-rich repeat kinase-2 (LRRK2) have been associated with Parkinson's disease (PD). The most common substitution, G2019S, interferes with LRRK2 kinase activity, which is regulated by autophosphorylation. Yet, the penetrance of this gain-of-function mutation is incomplete, and thus far, few factors have been correlated with disease status in carriers. This includes (i) LRRK2 autophosphorylation in urinary exosomes, (ii) serum levels of the antioxidant urate, and (iii) abundance of mitochondrial DNA (mtDNA) transcription-associated 7S DNA. In light of a mechanistic link between LRRK2 kinase activity and mtDNA lesion formation, we previously investigated mtDNA integrity in fibroblasts from manifesting (LRRK2+/PD+) and non-manifesting carriers (LRRK2+/PD−) of the G2019S mutation as well as from aged-matched controls. In our published study, mtDNA major arc deletions correlated with PD status, with manifesting carriers presenting the highest levels. In keeping with these findings, we now further explored mitochondrial features in fibroblasts derived from LRRK2+/PD+ (n = 10), LRRK2+/PD− (n = 21), and control (n = 10) individuals. In agreement with an accumulation of mtDNA major arc deletions, we also detected reduced NADH dehydrogenase activity in the LRRK2+/PD+ group. Moreover, in affected G2019S carriers, we observed elevated mitochondrial mass and mtDNA copy numbers as well as increased expression of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates antioxidant signaling. Taken together, these results implicate mtDNA dyshomeostasis—possibly as a consequence of impaired mitophagy—in the penetrance of LRRK2-associated PD. Our findings are a step forward in the pursuit of unveiling markers that will allow monitoring of disease progression of LRRK2 mutation carriers.

Background: Different factors influence severity, progression, and outcomes in Parkinson's disease (PD). Lack of standardized clinical assessment limits comparison of outcomes and availability of well-characterized cohorts for collaborative studies.Methods: Structured clinical documentation support (SCDS) was developed within the DNA Predictions to Improve Neurological Health (DodoNA) project to standardize clinical assessment and identify molecular predictors of disease progression. The Longitudinal Clinical and Genetic Study of Parkinson's Disease (LONG-PD) was launched within the Genetic Epidemiology of Parkinson's disease (GEoPD) consortium using a Research Electronic Data Capture (REDCap) format mirroring the DodoNA SCDS. Demographics, education, exposures, age at onset (AAO), Unified Parkinson's Disease Rating Scale (UPDRS) parts I-VI or Movement Disorders Society (MDS)–UPDRS, Montreal Cognitive Assessment (MoCA)/Short Test of Mental Status (STMS)/Mini Mental State Examination (MMSE), Geriatric Depression Scale (GDS), Epworth Sleepiness Scale (ESS), dopaminergic therapy, family history, nursing home placement, death and blood samples were collected. DodoNA participants (396) with 6 years of follow-up and 346 LONG-PD participants with up to 3 years of follow-up were analyzed using group-based trajectory modeling (GBTM) focused on: AAO, education, family history, MMSE/MoCA/STMS, UPDRS II-II, UPDRS-III tremor and bradykinesia sub-scores, Hoehn and Yahr staging (H&Y) stage, disease subtype, dopaminergic therapy, and presence of autonomic symptoms. The analysis was performed with either cohort as the training/test set.Results: Patients are classified into slowly and rapidly progressing courses by AAO, MMSE score, H &Y stage, UPDRS-III tremor and bradykinesia sub-scores relatively early in the disease course. Late AAO and male sex assigned patients to the rapidly progressing group, whereas tremor to the slower progressing group. Classification is independent of which cohort serves as the training set. Frequencies of disease-causing variants in LRRK2 and GBA were 1.89 and 2.96%, respectively.Conclusions: Standardized clinical assessment provides accurate phenotypic characterization in pragmatic clinical settings. Trajectory analysis identified two different trajectories of disease progression and determinants of classification. Accurate phenotypic characterization is essential in interpreting genomic information that is generated within consortia, such as the GEoPD, formed to understand the genetic epidemiology of PD. Furthermore, the LONGPD study protocol has served as the prototype for collecting standardized phenotypic information at GEoPD sites. With genomic analysis, this will elucidate disease etiology and lead to targeted therapies that can improve disease outcomes.

The diagnosis of Parkinson's disease (PD) relies on the clinical effects of dopamine deficiency, including bradykinesia, rigidity and tremor, usually manifesting asymmetrically. Misdiagnosis is common, due to overlap of symptoms with other neurodegenerative disorders such as multiple system atrophy and progressive supranuclear palsy, and only autopsy can definitively confirm the disease. Motor deficits generally appear when 50–60% of dopaminergic neurons in the substantia nigra are already lost, limiting the effectiveness of potential neuroprotective therapies. Today, we consider PD to be not just a movement disorder, but rather a complex syndrome non-motor symptoms (NMS) including disorders of sleep-wake cycle regulation, cognitive impairment, disorders of mood and affect, autonomic dysfunction, sensory symptoms and pain. Symptomatic LRRK2 mutation carriers share non-motor features with individuals with sporadic PD, including hyposmia, constipation, impaired color discrimination, depression, and sleep disturbance. Following the assumption that the pre-symptomatic gene mutation carriers will eventually exhibit clinical symptoms, their neuroimaging results can be extended to the pre-symptomatic stage of PD. The long latent phase of PD, termed prodromal-PD, represents an opportunity for early recognition of incipient PD. Early recognition could allow initiation of possible neuroprotective therapies at a stage when therapies might be most effective. The number of markers with the sufficient level of evidence to be included in the MDS research criteria for prodromal PD have increased during the last 10 years. Here, we review the approach to prodromal PD, with an emphasis on clinical and imaging markers and report results from our neuroimaging study, a retrospective evaluation of a cohort of 39 participants who underwent DAT-SPECT scan as part of their follow up. The study was carried out to see if it was possible to detect subclinical signs in the preclinical (neurodegenerative processes have commenced, but there are no evident symptoms or signs) and prodromal (symptoms and signs are present, but are yet insufficient to define disease) stages of PD.

Polymetallic manganese nodules (PMN), cobalt-rich manganese crusts (CRC) and seafloor massive sulfides (SMS) have been identified as important resources of economically valuable metals and critical raw materials. The currently proposed mineral processing operations are based on metallurgical approaches applied for land resources. Thus far, significant endeavors have been carried out to describe the extraction of metals from PMN; however, to the best of the authors’ knowledge, it lacks a thorough review on recent developments in processing of CRC and SMS. This paper begins with an overview of each marine mineral. It is followed by a systematic review of common methods used for extraction of metals from marine mineral deposits. In this review, we update the information published so far in peer-reviewed and technical literature, and briefly provide the future perspectives for processing of marine mineral deposits.

Abstract Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene can cause late-onset Parkinson disease (PD). LRRK2 mutations increase LRRK2 kinase activities that may increase levels of LRRK2 autophosphorylation at serine 1292 (pS1292) and neurotoxicity in model systems. pS1292-LRRK2 protein can be packaged into exosomes and measured in biobanked urine. Herein we provide evidence that pS1292-LRRK2 protein is robustly expressed in cerebral spinal fluid (CSF) exosomes. In a novel cohort of Norwegian subjects with and without the G2019S-LRRK2 mutation, with and without PD, we quantified levels of pS1292-LRRK2, total LRRK2, and other exosome proteins in urine from 132 subjects and in CSF from 82 subjects. CSF and urine were collected from the same morning clinic visit in 55 of the participants. We found that total LRRK2 protein concentration was similar in exosomes purified from either CSF or urine but the levels did not correlate. pS1292-LRRK2 levels were higher in urinary exosomes from male and female subjects with a LRRK2 mutation. Male LRRK2 mutation carriers without PD had intermediate pS1292-LRRK2 levels compared to male carriers with PD and controls. However, female LRRK2 mutation carriers without PD had the same pS1292-LRRK2 levels compared to female carriers with PD. pS1292-LRRK2 levels in CSF exosomes were near saturated in most subjects, ten-fold higher on average than pS1292-LRRK2 levels in urinary exosomes, irrespective of LRRK2 mutation status or PD diagnosis. These results provide insights into the effects of LRRK2 mutations in both the periphery and brain in a well-characterized clinical population and show that LRRK2 protein in brain exosomes may be much more active than in the periphery in most subjects.