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Estimates of the spectrum and frequency of pathogenic variants in Parkinson's 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 Parkinson's 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 (â¼0.2%). 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 â¼15% 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.
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Testes Genéticos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson , Humanos , Doença de Parkinson/genética , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Testes Genéticos/métodos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Glucosilceramidase/genética , alfa-Sinucleína/genética , Predisposição Genética para Doença , Ubiquitina-Proteína Ligases/genética , Estudos de Coortes , Proteínas Quinases/genética , Mutação , AdultoRESUMO
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.
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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 < 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials.
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Background: The 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. Methods: PD 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. Results: The 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. Conclusion: Modeling 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.
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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.
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Nanoporos , Doença de Parkinson , Piper nigrum , Humanos , Doença de Parkinson/genética , Virulência , Sequenciamento de Nucleotídeos em Larga EscalaRESUMO
BACKGROUND AND OBJECTIVES: Robust biomarkers that can mirror Parkinson disease (PD) are of great significance. In this study, we present a novel approach to investigate disease-associated α-synuclein (αSyn) aggregates as biomarkers of PD clinical stage. METHODS: We combined both seed amplification assay (SAA) and ELISA to provide a quantitative test readout that reflects the clinical severity of patients with PD. To attain this goal, we initially explored the potential of our test using 2 sets of human brain homogenates (pilot and validation sets) and then verified it with 2 independent human CSF cohorts; discovery (62 patients with PD and 34 controls) and validation (49 patients with PD and 48 controls) cohorts. RESULTS: We showed that oligomers-specific ELISA robustly quantified SAA end product from patients with PD or dementia with Lewy bodies with high sensitivity and specificity scores (100%). Analysis also demonstrated that seeding activity could be detected earlier with oligomeric ELISA as the test readout rather than SAA alone. Of more importance, multiplexing the assays provided robust information about the patients' clinical disease stage. In the discovery cohort, levels of CSF-seeded αSyn oligomers correlated with the severity of the clinical symptoms of PD as measured by the Unified Parkinson Disease Rating Scale (UPDRS) motor (r = 0.58, p < 0.001) and Hoehn and Yahr (H&Y) scores (r = 0.43, p < 0.01). Similar correlations were observed in the validation cohort between the concentrations of CSF-seeded αSyn oligomers and both UPDRS motor (r = 0.50, p < 0.01) and H&Y scores (r = 0.49, p < 0.01). At 20 hours, receiver operating characteristic curves analysis yielded a sensitivity of 91.9% (95% CI 82.4%-96.5%) and a specificity of 85.3% (95% CI 69.8%-93.5%), with an area under the curve of 0.969 for CSF-seeded αSyn oligomers differentiating those with PD from controls in the discovery CSF cohort, whereas, a sensitivity of 80.7% (95% CI 69.1%-88.5%), a specificity of 76.5% (95% CI 60.0%-87.5%), and area under the curve of 0.860 were generated with thioflavin T maximum intensity of fluorescence at the same time point. DISCUSSION: We showed that combining SAA and ELISA assays is a more promising diagnostic tool than SAA alone, providing information about the disease stage by correlating with clinical measures of disease severity. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CSF-seeded αSyn oligomers can accurately discriminate patients with PD and normal controls and CSF-seeded αSyn oligomers levels correlate with PD severity.
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Doença de Parkinson , alfa-Sinucleína , Humanos , alfa-Sinucleína/análise , Doença de Parkinson/diagnóstico , Biomarcadores , Curva ROC , EncéfaloRESUMO
The presence of autonomic symptoms are a common part of the symptomatology of Parkinsons disease (PD), with the potential to impact the quality of life of patients. The aim of this study was to assess the frequency of autonomic symptoms among Faroese PD patients compared to a control group, using the Scales for Outcome in Parkinson's Disease - Autonomic (SCOPA-AUT), and to determine the relationship between autonomic and motor symptoms in PD patients using the Unified Parkinsons Disease Rating Scale - Part III (UPDRS) and Hoehn and Yahr Scale (H&Y). The study included 54 PD patients and 190 control individuals which were unaffected relatives. The mean SCOPA-AUT scores were significantly higher for PD patients in gastrointestinal (OR = 1.62), urinary (OR = 1.38), cardiovascular (OR = 1.65), thermoregulatory (OR = 1.54) and sexual dysfunction (OR = 1.71) scores, as well as the total score (OR = 1.26). UPDRS scores were significant correlated with SCOPA-AUT scores (p = 0.015), while H&Y scores were not (p = 0.103). In conclusion, PD patients experience an increased frequency of autonomic symptoms compared with controls and the frequency is associated with the motor symptoms assessed with UPDRS. Our findings are consistent with similar studies and our current understanding of PD pathology.
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Doenças do Sistema Nervoso Autônomo , Doença de Parkinson , Sistema Nervoso Autônomo , Doenças do Sistema Nervoso Autônomo/complicações , Doenças do Sistema Nervoso Autônomo/etiologia , Humanos , Qualidade de Vida , Índice de Gravidade de DoençaRESUMO
A patient with Parkinson's disease (PD) who was examined as a candidate for DBS was initially rejected due to extensive brain calcifications. Upon second opinion and planning of trajectories she underwent successful surgery. Genetic analyses identified a mutation in SLC20A2, a gene known to cause brain calcifications, but no mutation known to cause PD was found.
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Calcinose , Estimulação Encefálica Profunda , Doença de Parkinson , Calcinose/genética , Feminino , Testes Genéticos , Humanos , Mutação/genética , Doença de Parkinson/genética , Doença de Parkinson/terapia , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genéticaRESUMO
OBJECTIVE: This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease. METHODS: Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS-), and noncarriers with or without DBS (GBA-DBS+, GBA-DBS-). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. RESULTS: Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS-, 98 GBA-DBS+, and 128 GBA-DBS- subjects), who were longitudinally followed (range = 36-60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA-DBS- subjects (95% confidence interval [CI] = -2.35 to -1.69), 1.71 points/yr more than GBA+DBS- subjects (95% CI = -2.14 to -1.28), and 1.49 points/yr more than GBA-DBS+ subjects (95% CI = -1.80 to -1.18). INTERPRETATION: Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN-DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision-making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN-DBS so that alternative options may be considered. ANN NEUROL 2022;91:424-435.
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Cognição/fisiologia , Estimulação Encefálica Profunda/métodos , Glucosilceramidase/genética , Heterozigoto , Doença de Parkinson/terapia , Núcleo Subtalâmico/fisiopatologia , Idoso , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Testes Neuropsicológicos , Doença de Parkinson/genética , Doença de Parkinson/fisiopatologia , Doença de Parkinson/psicologiaRESUMO
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.
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Doença de Parkinson , Humanos , Ácidos e Sais Biliares , Doença de Parkinson/tratamento farmacológico , Ácido Ursodesoxicólico/farmacologia , Colanos/químicaRESUMO
INTRODUCTION: Accumulation of polyglutamine (polyQ) ataxin-3 (ATXN3) contributes to the pathobiology of spinocerebellar ataxia type 3 (SCA3). Recently, we showed that polyQ ATXN3 is elevated in the plasma and cerebrospinal fluid (CSF) of SCA3 patients, and has the potential to serve as a biological marker for this disease [1]. Based on these findings, we investigated whether polyQ ATXN3 can also be detected in urine samples from SCA3 patients. METHODS: We analyzed urine samples from 30 SCA3 subjects (including one pre-symptomatic subject), 35 subjects with other forms of ataxia, and 37 healthy controls. To quantify polyQ ATXN3 protein levels, we used our previously developed immunoassay. RESULTS: PolyQ ATXN3 can be detected in the urine of SCA3 patients, but not in urine samples from healthy controls or other forms of ataxia. There was a significant statistical association between polyQ ATXN3 levels in urine samples and those in plasma. Further, the levels of polyQ ATXN3 urine associated with an earlier age of SCA3 disease onset. CONCLUSION: As clinical trials for SCA3 advance, urine polyQ ATXN3 protein has potential to be a useful, non-invasive and inexpensive biomarker for SCA3.
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Ataxina-3/urina , Doença de Machado-Joseph/urina , Peptídeos/urina , Proteínas Repressoras/urina , Adulto , Estudos de Casos e Controles , Feminino , Humanos , MasculinoRESUMO
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.
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Factitious disorders (FDs) are well known to a majority of physicians; however, the corresponding ICD-10 diagnosis F68.1 remains severely under assigned and often misdiagnosed. Based on a previously conducted nationwide survey in Germany, we extended the analyzed variables to further understand FD characteristics.The assignments regarding the following variables in the German diagnosis-related group statistics were analyzed: residence of the patient and location of the diagnosing institution, primary referral to the diagnosing institution, reason for admission and discharge, specialty department, total length of stay, length of stay in the longest treating department, surgery performed, case mix revenue, regional type of the treating institution, and patients' region of origin.A very distinct difference was observed in the assignment rates based on the homeland of the diagnosed patient and diagnosing institution. The assignment rate showed no significant difference across German regions. Based on our findings, a patient with FD in Germany might exhibit the following "typical" traits: A woman in her late thirties from a rural area is referred by a physician or another hospital wherein she was previously treated for more than a day to an institution for fully inpatient hospital treatment wherein she completes her treatment regularly. Dermatology, neurology, emergency, and internal medicine departments tend to be confronted with patients with FDs more often than other departments; however, surgery is performed in every fifth case. Patients are primarily treated in only one department for ~ 25 days. The case mix revenue will most probably not exceed 5000.
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Transtornos Autoinduzidos , Transtornos Autoinduzidos/diagnóstico , Feminino , Alemanha , Hospitalização , Humanos , Inquéritos e QuestionáriosRESUMO
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.
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Doença de Parkinson , Progressão da Doença , Humanos , Estudos Longitudinais , Personalidade , Transtornos da PersonalidadeRESUMO
OBJECTIVE: To develop a reliable and fast assay to quantify the α-synuclein (α-syn)-containing extracellular vesicles (EVs) in CSF and to assess their diagnostic potential for Parkinson disease (PD). METHODS: A cross-sectional, multicenter study was designed, including 170 patients with PD and 131 healthy controls (HCs) with a similar distribution of age and sex recruited from existing center studies at the University of Washington and Oregon Health and Science University. CSF EVs carrying α-syn or aggregated α-syn were quantified using antibodies against total or aggregated α-syn, respectively, and highly specific, sensitive, and rapid assays based on the novel Apogee nanoscale flow cytometry technology. RESULTS: No significant differences in the number and size distribution of total EVs between patients with PD and HCs in CSF were observed. When examining the total α-syn-positive and aggregated α-syn-positive EV subpopulations, the proportions of both among all detected CSF EVs were significantly lower in patients with PD compared to HCs (p < 0.0001). While each EV subpopulation showed better diagnostic sensitivity and specificity than total CSF α-syn measured directly with an immunoassay, a combination of the 2 EV subpopulations demonstrated a diagnostic accuracy that attained clinical relevance (area under curve 0.819, sensitivity 80%, specificity 71%). CONCLUSION: Using newly established, sensitive nanoscale flow cytometry assays, we have demonstrated that total α-syn-positive and aggregated α-syn-positive EVs in CSF may serve as a helpful tool in PD diagnosis. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that total and aggregated α-syn-positive EVs in CSF identify patients with PD.
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Vesículas Extracelulares/metabolismo , Citometria de Fluxo/métodos , Nanotecnologia/métodos , Doença de Parkinson/diagnóstico , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Idoso , Animais , Estudos Transversais , Vesículas Extracelulares/química , Feminino , Humanos , Imunoensaio/métodos , Masculino , Camundongos da Linhagem 129 , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , alfa-Sinucleína/análiseRESUMO
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.
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Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Doença de Parkinson/genética , Idoso , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , PenetrânciaRESUMO
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.
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CSF from unique groups of Parkinson's disease (PD) patients was biochemically profiled to identify previously unreported metabolic pathways linked to PD pathogenesis, and novel biochemical biomarkers of the disease were characterized. Utilizing both 1H NMR and DI-LC-MS/MS we quantitatively profiled CSF from patients with sporadic PD (n = 20) and those who are genetically predisposed (LRRK2) to the disease (n = 20), and compared those results with age and gender-matched controls (n = 20). Further, we systematically evaluated the utility of several machine learning techniques for the diagnosis of PD. 1H NMR and mass spectrometry-based metabolomics, in combination with bioinformatic analyses, provided useful information highlighting previously unreported biochemical pathways and CSF-based biomarkers associated with both sporadic PD (sPD) and LRRK2 PD. Results of this metabolomics study further support our group's previous findings identifying bile acid metabolism as one of the major aberrant biochemical pathways in PD patients. This study demonstrates that a combination of two complimentary techniques can provide a much more holistic view of the CSF metabolome, and by association, the brain metabolome. Future studies for the prediction of those at risk of developing PD should investigate the clinical utility of these CSF-based biomarkers in more accessible biomatrices. Further, it is essential that we determine whether the biochemical pathways highlighted here are recapitulated in the brains of PD patients with the aim of identifying potential therapeutic targets.