Background: alpha-Synuclein (SNCA) gene hypomethylation was reported in idiopathic Parkinson's disease (iPD). Based on a high clinical resemblance between iPD and leucine-rich repeat kinase 2 (LRRK2)-driven Parkinson's disease (L2PD), we investigated the epigenetic status of SNCA in an extensive LRRK2 clinical cohort from Spain. Methods: We assessed the methylation levels of 23 CpG sites in the SNCA promoter region using peripheral blood DNA from L2PD patients (n = 151), LRRK2 nonmanifesting carriers (n = 55), iPD patients (n = 115), and healthy control subjects (n = 154) (total: N = 475). Results: Compared with control subjects, we found significant SNCA hypomethylation in 11 of 23 CpGs in L2PD (48%), whereas 22 CpGs (96%) were hypomethylated in iPD. In line with a healthy status, asymptomatic mutation carriers had similar SNCA methylation profiles to control subjects. Conclusions: This study shows for the first time that SNCA hypomethylation occurs in patients with L2PD. Further studies addressing SNCA methylation status in additional worldwide LRRK2 cohorts are warranted. (c) 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

We conducted the largest PSP GWAS of the Iberian population to date (522 cases from 22 Spanish and Portuguese institutions). We independently replicated seven known PSP risk variants, and unveiled a novel locus in NFASC/CNTN2 after meta-analysing our results with a newly available Dutch cohort and publicly available summary statistics. These findings highlight the importance of neuron-oligodendrocyte interactions in PSP etiopathology. ### Competing Interest Statement Vigil Neuroscience and Prevail therapeutics are in a public-private partnerschip research program of Sven J. van der Lee. All funding is paid to his institution. ### Funding Statement This work was funded by CIBERNED (Centro Investigacion Biomedica en Red Enfermedades Neurodegenerativas) 10th internal call for cooperative projects (Register number: 2019/09). Agustin Ruiz, Pascual Sanchez-Juan, Alberto Rabano, and Maria J. Bullido received funding from this convocatory. Pablo Garcia-Gonzalez received support by CIBERNED employment plan CNV-304-PRF-866. CIBERNED is integrated into ISCIII (Instituto de Salud Carlos III). Merce Boada, Marta Marquie and Agustin Ruiz are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240. PI19/01301, PI19/00335 and PI22/011403, and CIBERNED grant 2019/08. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Grifols SA, Fundacion bancaria La Caixa, Fundacio ACE, and CIBERNED. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII - Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER - Una manera de hacer Europa). Agustin Ruiz is supported by ISCIII national grant PMP22/00022, funded by the European Union (NextGenerationEU). The genotyping service to generate GR@ACE and PSP/DEGESCO GWAS data was carried out at CEGEN-PRB3-ISCIII; it is supported by grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDF. Itziar de Rojas received support by a national grant from ISCIII FI20/00215. Amanda Cano acknowledges the support of the Spanish Ministry of Science, Innovation and Universities under the grant Juan de la Cierva (FJC2018-036012-I), the support of ISCIII under the grant Sara Borrell (CD22/00125), Spanish Ministry of Science and Innovation, Proyectos de Generacion de Conocimiento grant PID2021-122473OA-I00, and Fundacion ADEY under the program Proyectos de Investigacion en Salud 2023. Fondo de Investigacion en Salud (Instituto Carlos III) (PI17/00096) in the frame of the European Regional Development Fund (ERDF) and to Fundacio ́ la Marato ́ de TV3 (PI043296 and 202009-10). This work was supported by the Spanish Ministry of Science and Innovation (RTC2019-007150-1), the Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union (PI14/01823, PI16/01575, PI18/01898, PI19/01576, PI21/01875), the Consejeria de Economia, Innovacion, Ciencia y Empleo de la Junta de Andalucia (CVI-02526, CTS-7685, PY20_00896), and the Consejeria de Salud y Bienestar Social de la Junta de Andalucia (PI-0471-2013, PE-0210-2018, PI-0459-2018, PE-0186-2019). Pilar Gomez-Garre was supported by the Nicolas Monardes program (C-0048-2017) from Andalusian Regional Ministry of Health. Laura Munoz-Delgado was supported by the Rio Hortega program [CM21/00051] from the Instituto de Salud Carlos III (ISCIII-FEDER). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sven J. van der Lee was funded for this study by NWO (#733050512, PROMO-GENODE: a PROspective study of MOnoGEnic causes Of Dementia) a substantial donation by Edwin Bouw Fonds and Dioraphte. SvdL further received funding for the GeneMINDS consortium, which is powered by Health-Holland, Top Sector Life Sciences & Health. Sven J. van der Lee is a recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD. ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. ABOARD also receives funding from de Hersenstichting, Edwin Bouw Fonds and Gieskes-Strijbisfonds. Array genotyping was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). This work has been supported by the Queen Sofia Foundation. Pascual Sanchez-Juan is supported by grants from ISCIII (PMP22/00022 and PI20/01011) and TED2021-131676B-100. Luis Miguel Real received support from The absence of seroconversion after exposition to hepatitis C virus is not related to KIR-HLA genotype combinations (GEHEP-012 study). Consejeria de Salud de la Junta de Andalucia (grant number PI-0001/2017) and CIBERINFEC -Consorcio Centro de Investigacion Biomedica en Red de Enfermedades Infecciosas- Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacion y Union Europea (Spain) (NextGeneration EU) (grant number CB21/13/00118). Jose Luis Royo received support from Project 23.04.2021 from Santangela Foundation (Sevilla, Spain). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: For the Iberian cohort, this study was approved by the competent research ethical committee (MED-FACE-2020-01, Universidad Internacional de Catalunya, Sant Cugat del Valles, Spain). For the Dutch cohorts, the local Medical Ethics Committees approved the protocols for the Amsterdam Dementia Cohort (ADC) and the other studies, and all participants of the ADC provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.

Impulse control disorders and their consequences display variability among individuals, indicating potential involvement of environmental and genetic factors. In this retrospective study, we analyzed a cohort of Parkinson's disease patients treated with dopamine agonists and investigated the influence of the dopamine D4 receptor gene polymorphism, DRD4 7R+, which is linked to psychiatric disorders, impulsive traits, and addictive behaviors. We found that DRD4 7R+ is a significant genetic risk factor associated with the severity of ICD.

BACKGROUND:The pathological hallmarks of multiple system atrophy and Parkinson's disease are, respectively, misfolded-α-synuclein-laden glial cytoplasmic inclusions and Lewy bodies. CSF-soluble misfolded α-synuclein aggregates (seeds) are readily detected in people with Parkinson's disease by α-synuclein seed amplification assay (synSAA), but identification of seeds associated with multiple system atrophy for diagnostic purposes has proven elusive. We aimed to assess whether a novel synSAA could reliably distinguish seeds from Lewy bodies and glial cytoplasmic inclusions. METHODS:In this multicentre cohort study, a novel synSAA that multiplies and detects seeds by fluorescence was used to analyse masked CSF and brain samples from participants with either clinically diagnosed or pathology-confirmed multiple system atrophy, Parkinson's disease, dementia with Lewy bodies, isolated rapid eye movement sleep behaviour disorder (IRBD), disorders that were not synucleinopathies, or healthy controls. Participants were from eight available cohorts from seven medical centres in four countries: New York Brain Bank, New York, USA (NYBB); University of Pennsylvania, Philadelphia, PA, USA (UPENN); Paracelsus-Elena-Klinik, Kassel, Germany (DeNoPa and KAMSA); Hospital Clinic Barcelona, Spain (BARMSA); Universität Tübingen, Tübingen, Germany (EKUT); Göteborgs Universitet, Göteborgs, Sweden (UGOT); and Karolinska Institutet, Stockholm, Sweden (KIMSA). Clinical cohorts were classified for expected diagnostic accuracy as either research (longitudinal follow-up visits) or real-life (single visit). Sensitivity and specificity were estimated according to pathological (gold standard) and clinical (reference standard) diagnoses. FINDINGS:In 23 brain samples (from the NYBB cohort), those containing Lewy bodies were synSAA-positive and produced high fluorescence amplification patterns (defined as type 1); those containing glial cytoplasmic inclusions were synSAA-positive and produced intermediate fluorescence (defined as type 2); and those without α-synuclein pathology produced below-threshold fluorescence and were synSAA-negative. In 21 pathology-confirmed CSF samples (from the UPENN cohort), those with Lewy bodies were synSAA-positive type 1; those with glial cytoplasmic inclusions were synSAA-positive type 2; and those with four-repeat tauopathy were synSAA-negative. In the DeNoPa research cohort (which had no samples from people with multiple system atrophy), the novel synSAA had sensitivities of 95% (95% CI 88-99) for 80 participants with Parkinson's disease and 95% (76-100) for 21 participants with IRBD, and a specificity of 95% (86-99) for 60 healthy controls. Overall (combining BARMSA, EKUT, KAMSA, UGOT, and KIMSA cohorts that were enriched for cases of multiple system atrophy), the novel synSAA had 87% sensitivity for multiple system atrophy (95% CI 80-93) and specificity for type 2 seeds was 77% (67-85). For participants with multiple system atrophy just in research cohorts (BARMSA and EKUT), the novel synSAA had a sensitivity of 84% (95% CI 71-92) and a specificity for type 2 seeds of 87% (74-95), whereas cases from real-life cohorts (KAMSA, KIMSA, and UGOT) had a sensitivity of 91% (95% CI 80-97) but a decreased specificity for type 2 seeds of 68% (53-81). INTERPRETATION:The novel synSAA produced amplification patterns that enabled the identification of underlying α-synuclein pathology, showing two levels of fluorescence that corresponded with different pathological hallmarks of synucleinopathy. The synSAA might be useful for early diagnosis of synucleinopathies in clinical trials, and potentially for clinical use, but additional formal validation work is needed. FUNDING:Michael J Fox Foundation for Parkinson's Research, Amprion.

BACKGROUND:Evidence regarding cortical atrophy patterns in Parkinson's disease (PD) with probable rapid eye movement sleep behavior disorder (RBD) (PD-pRBD) remains scarce. Cortical mean diffusivity (cMD), as a novel imaging biomarker highly sensitive to detecting cortical microstructural changes in different neurodegenerative diseases, has not been investigated in PD-pRBD yet. OBJECTIVES:The aim was to investigate cMD as a sensitive measure to identify subtle cortical microstructural changes in PD-pRBD and its relationship with cortical thickness (CTh). METHODS:Twenty-two PD-pRBD, 31 PD without probable RBD (PD-nonpRBD), and 28 healthy controls (HC) were assessed using 3D T1-weighted and diffusion-weighted magnetic resonance imaging on a 3-T scanner and neuropsychological testing. Measures of cortical brain changes were obtained through cMD and CTh. Two-class group comparisons of a general linear model were performed (P < 0.05). Cohen's d effect size for both approaches was computed. RESULTS:PD-pRBD patients showed higher cMD than PD-nonpRBD patients in the left superior temporal, superior frontal, and precentral gyri, precuneus cortex, as well as in the right middle frontal and postcentral gyri and paracentral lobule (d > 0.8), whereas CTh did not detect significant differences. PD-pRBD patients also showed increased bilateral posterior cMD in comparison with HCs (d > 0.8). These results partially overlapped with CTh results (0.5 < d < 0.8). PD-nonpRBD patients showed no differences in cMD when compared with HCs but showed cortical thinning in the left fusiform gyrus and lateral occipital cortex bilaterally (d > 0.5). CONCLUSIONS:cMD may be more sensitive than CTh displaying significant cortico-structural differences between PD subgroups, indicating this imaging biomarker's utility in studying early cortical changes in PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Elevated urine bis(monoacylglycerol)phosphate (BMP) levels have been found in gain-of-kinase function LRRK2 G2019S mutation carriers. Here, we have expanded urine BMP analysis to other Parkinson’s disease (PD) associated mutations and found them to be consistently elevated in carriers of LRRK2 G2019S and R1441G/C as well as VPS35 D620N mutations. Urine BMP levels are promising biomarkers for patient stratification and potentially target engagement in clinical trials of emerging targeted PD therapies.

Neuromelanin (NM) loss in substantia nigra pars compacta (SNc) and locus coeruleus (LC) reflects neuronal death in Parkinson's disease (PD). Since genetically-determined PD shows varied clinical expressivity, we wanted to accurately quantify and locate brainstem NM and iron, to discover whether specific MRI patterns are linked to Leucine-rich repeat kinase 2 G2019S PD (LRRK2-PD) or idiopathic Parkinson's disease (iPD). A 3D automated MRI atlas-based segmentation pipeline (3D-ABSP) for NM/iron-sensitive MRI images topographically characterized the SNc, LC, and red nucleus (RN) neuronal loss and calculated NM/iron contrast ratio (CR) and normalized volume (nVol). Left-side NM nVol was larger in all groups. PD had lower NM CR and nVol in ventral-caudal SNc, whereas iron increased in lateral, medial-rostral, and caudal SNc. The SNc NM CR reduction was associated with psychiatric symptoms. LC CR and nVol discriminated better among subgroups: LRRK2-PD had similar LC NM CR and nVol as that of controls, and larger LC NM nVol and RN iron CR than iPD. PD showed higher iron SNc nVol than controls, especially among LRRK2-PD. ROC analyses showed an AUC > 0.92 for most pairwise subgroup comparisons, with SNc NM being the best discriminator between HC and PD. NM measures maintained their discriminator power considering the subgroup of PD patients with less than 5 years of disease duration. The SNc iron CR and nVol increase was associated with longer disease duration in PD patients. The 3D-ABSP sensitively identified NM and iron MRI patterns strongly correlated with phenotypic PD features.

Background: There is a need for identifying risk factors for hospitalization in Parkinson’s disease (PD) and also interventions to reduce acute hospital admission. Objective: To analyze the frequency, causes, and predictors of acute hospitalization (AH) in PD patients from a Spanish cohort. Methods: PD patients recruited from 35 centers of Spain from the COPPADIS-2015 (COhort of Patients with PArkinson’s DIsease in Spain, 2015) cohort from January 2016 to November 2017, were included in the study. In order to identify predictors of AH, Kaplan-Meier estimates of factors considered as potential predictors were obtained and Cox regression performed on time to hospital encounter 1-year after the baseline visit. Results: Thirty-five out of 605 (5.8%) PD patients (62.5±8.9 years old; 59.8% males) presented an AH during the 1-year follow-up after the baseline visit. Traumatic falls represented the most frequent cause of admission, being 23.7% of all acute hospitalizations. To suffer from motor fluctuations (HR [hazard ratio] 2.461; 95% CI, 1.065–5.678; p = 0.035), a very severe non-motor symptoms burden (HR [hazard ratio] 2.828; 95% CI, 1.319–6.063; p = 0.008), falls (HR 3.966; 95% CI 1.757–8.470; p = 0.001), and dysphagia (HR 2.356; 95% CI 1.124–4.941; p = 0.023) was associated with AH after adjustment to age, gender, disease duration, levodopa equivalent daily dose, total number of non-antiparkinsonian drugs, and UPDRS-IIIOFF. Of the previous variables, only falls (HR 2.998; 95% CI 1.080–8.322; p = 0.035) was an independent predictor of AH. Conclusion: Falls is an independent predictor of AH in PD patients.

To evaluate the management of rare movement disorders (RMD) at the international level and identify care needs to be addressed, the Rare Movement Disorders Study Group of the International Parkinson and Movement Disorders Society (MDS) has conducted an exploratory survey. We sent an online survey to experts in Africa, Asia, Oceania and American continents following the classification of the MDS Regional Sections: Africa, Asia and Oceania (A&O), and Pan-America. We did not include Europe as the European Reference Network for Rare Neurological Diseases recently performed a similar care needs survey across European countries. We obtained responses from experts from 20 African, 26 A&O and 19 Pan-American countries. According to the respondents, only 55% of African countries had movement disorders experts, while these were present in 96% of A&O and 91% of Pan-American. Access to care for patients with RMD was stated difficult in 70% of African, 54% of A&O, and 65% of Pan-American countries. Africa was the region with greatest difficulties in accessing diagnostic tests. However, in Pan-America and A&O, large inequalities were observed between countries with quite variable access to therapeutic options such as deep brain stimulation. The survey results reflect wide variability in the management of RMD and provide evidence that a worldwide care-focused network is highly warranted. Scientific and medical organisations should raise awareness of deficits in managing RMD and care disparities among regions. The goals should be to facilitate the training of professionals, establish improvement strategies, and increase support and budgeting for these diseases.

Background: The neuropathology of Parkinson's disease (PD) associated with leucine-rich repeat kinase 2 (LRRK2) mutations (LRRK2-PD) is heterogeneous and varies with the type of mutation. There are only a few studies evaluating seeding aggregation assays to detect alpha-synuclein (alpha-syn) in patients with LRRK2-PD. Objective: We aimed to investigate whether alpha-syn real-time quaking induced conversion (RT-QuIC) is a sensitive biomarker of synucleinopathy in LRRK2-PD.MethodsWe studied alpha-syn RT-QuIC in brain tissue and postmortem ventricular cerebrospinal fluid (CSF) of LRRK2-PD cases with and without Lewy-type pathology. Results: The accuracy of alpha-syn RT-QuIC in substantia nigra and CSF samples of patients with LRRK2-PD was 100%. The test also obtained 100% sensitivity to detect misfolded alpha-syn in substantia nigra of cases with idiopathic PD and was negative in the substantia nigra of all the control brains without Lewy-type pathology. Conclusions: Substantia nigra and ventricular CSF RT-QuIC discriminates with high sensitivity and specificity LRRK2 cases with Lewy-type pathology from those without it. RT-QuIC assay could be of particular interest in the selection of cases for clinical trials in this genetic form of PD. (C) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.