Alfa-sinukleina biomarkatzaile gisa Parkinson gaixotasunaren diagnostikoan

Parkinson disease (PD) is a common neurodegenerative disease, characterized pathologically by the presence of Lewy bodies and the progressive loss of dopaminergic neurons. Currently, the diagnosis of PD is based on clinical criteria; that is, it is diagnosed when motor symptoms appear such as limb tremor, slowness of movement or muscle stiffness. However, by the time motor symptoms appear, more than half of the dopaminergic neurons in the midbrain have been lost. Furthermore, as clinical diagnosis of PD is challenging, misdiagnosis is common. This highlights the need for disease-specific and early-stage biomarkers. Lewy bodies are rich in α-synuclein protein, who plays a fundamental role in the pathogenesis of PD. Therefore, α-synuclein may be useful as a PD biomarker. Therefore, the objective of this review is to summarize the efficacy of body fluid α-synuclein and its proteoforms measurements in the detection of PD. In fact, the identification of specific, sensitive, and non-invasive biomarkers is essential especially in regard to existing and future disease modifying treatments. Although the main candidate has been the measurement of α-synuclein in cerebrospinal fluid (CSF), CSF collection procedure is quite invasive and unsuitable in most clinical settings. Consequently, the presence of this protein and its proteoforms in biofluids such as blood plasma, saliva and tears has been investigated. Based on the results of these studies, phosphorylated and oligomeric α-synuclein are the best candidates for PD diagnosis. Until now, the measurement of α-synuclein has had multiple technical limitations, but the repeatability and reliability of immunoassays created in the last years has increased considerably. Therefore, it is expected that the potential of the main candidate biomarkers for PD diagnosis will be verified in the upcoming years.; Parkinson gaixotasuna ohiko gaixotasun neurodegeneratiboa da, patologikoki Lewy gorputzen presentziagatik eta neurona dopaminergikoen galera progresiboagatik bereizten dena. Gaur egun, Parkinson gaixotasunaren diagnostikoa irizpide klinikoetan oinarrituta dago; hau da, gorputz-adarren dardara, mugimenduen moteltasuna edo muskuluen gogortasuna bezalako sintoma motorrak agertzen direnean diagnostikatzen da. Hala ere, sintoma motorrak azaleratzen direnerako, mesentzefaloko neurona dopaminergikoen erdia baino gehiago galdu direla uste da. Gainera, Parkinsonaren diagnostiko klinikoa erronka bat denez, ohikoak dira diagnostiko okerrak. Horrek argi uzten du gaixotasunaren berariazko diagnostikorako biomarkatzaileak behar direla, batez ere fase goiztiarretan. Lewyren gorputzak aberatsak dira alfa-sinukleina (α-sinukleina) proteinatan, eta hauek funtsezko eginkizuna dute Parkinson gaixotasunaren patogenesian. Hori dela eta, α-sinukleina baliagarria izan daiteke Parkinsonaren biomarkatzaile gisa. Berrikuspen honen helburua, beraz, gorputzeko fluido desberdinetan α-sinukleinaren eta haren proteoformen neurketaren erabilgarritasun-diagnostikoari buruzko ebidentzia laburbiltzea da. Izan ere, espezifikoak, sentikorrak eta eskuragarriak diren biomarkatzaileak identifikatzea ezinbestekoa da Parkinson gaixotasuna aldatzeko dauden eta etorkizunean izango diren tratamenduei dagokienez. Nahiz eta hautagai nagusia α-sinukleina likido zefalorrakideoan (LZR) neurtzea izan den, LZR biltzeko prozedura nahiko inbaditzailea da, eta ez da egokia ingurune kliniko gehienetan. Ondorioz, odol-plasma, listua eta malkoa bezalako biofluidoetan ikertu da proteina honen eta haren proteoformen presentzia. Ikerketa hauen emaitzen arabera, α-sinukleina fosforilatua eta oligomerikoa izan daitezke hautagai egokienak Parkinson gaixotasunaren diagnostikorako. Orain arte α-sinukleinaren neurketak muga tekniko anitz izan dituen arren, azken urteetan sortutako tekniken bitartez entseguen errepikakortasuna eta fidagarritasuna nabarmen areagotu da. Beraz, hautagai nagusiek Parkinsonaren diagnostikorako biomarkatzailegisa izan dezaketen potentziala hurrengo urteetan egiaztatzea espero da

Sexu-desberdintasunak Parkinson gaixotasunean

Increasing evidence indicates that biological sex is an important factor in the development and phe-notypic expression of Parkinson’s disease. The prevalence of Parkinson’s disease affects men twice more often than women. However, women experience a more rapid progression of the disease. In addition, it is increasingly ac-knowledged that the frequency and/or severity of motor and non-motor symptoms are different in female and male patients with Parkinson’s disease. It is also considered that their response to pharmacological and surgical treat-ments differs significantly. Although the precise underlying mechanisms supporting sex differences are still to be elucidated, the pathophysiological underpinnings are presumably different in women and men with Parkinson’s dis-ease. This review aims to gather the current evidence regarding sex differences in clinical features, risk factors, pathophysiological mechanisms and response to treatments (pharmacological and surgical). Clarifying how the dis-ease affects each sex can improve patient care by tailoring the therapeutic management of men and women and by developing innovative programmes to respond to unmet needs.; Gero eta ebidentzia gehiagok adierazten du sexu biologikoa faktore garrantzitsua dela Parkinson gaixotasunaren garapenean eta adierazpen fenotipikoan. Jakina da Parkinson gaixotasunaren prebalentzia ia bi aldiz altuagoa dela gizonezkoetan emakumezkoetan baino. Hala ere, emakumezkoek gaixotasunaren progresio azkarragoa izaten dute. Gainera, azken urteotan egindako ikerketek agerian utzi dute Parkinson gaixotasunaren ondorioz agertzen diren sintoma motorrak eta ez-motorrak maiztasun edota larritasun desberdina dutela sexuaren arabera. Halaber, emakumeek eta gizonezkoek tratamendu farmakologikoen eta kirurgikoen aurrean duten erantzuna ere desberdina dela uste da. Sexu-desberdintasun hauen oinarriak zehatz-mehatz ezagutzen ez badira ere, mekanismo fisiopatologikoak desberdinak direla iradoki da. Berrikuspen honetan Parkinsona duten emakumezkoen eta gizonezkoen artean dauden desberdintasunak laburbiltzen dira, besteak beste, ezaugarri klinikoetan, arrisku-faktoreetan, gaixotasunaren fisiopatologian eta tratamenduen erantzunean. Patologiak sexu bakoitzari nola eragiten dion argitzeak pazienteen arreta hobetzea ahalbidetu dezake gizonen eta emakumeen maneiu terapeutikoa neurrira diseinatuz eta bakoitzaren beharrei erantzuteko programa berritzaileak garatuz

Automated procedure to detect subtle motor alterations in the balance beam test in a mouse model of early Parkinson’s disease

Parkinson’s disease (PD) is the most common motor neurodegenerative disorder, characterised by aggregated α-synuclein (α-syn) constituting Lewy bodies. We aimed to investigate temporal changes in motor impairments in a PD mouse model induced by overexpression of α-syn with the conventional manual analysis of the balance beam test and a novel approach using machine learning algorithms to automate behavioural analysis. We combined automated animal tracking using markerless pose estimation in DeepLabCut, with automated behavioural classification in Simple Behavior Analysis. Our automated procedure was able to detect subtle motor deficits in mouse performances in the balance beam test that the manual analysis approach could not assess. The automated model revealed time-course significant differences for the “walking” behaviour in the mean interval between each behavioural bout, the median event bout duration and the classifier probability of occurrence in male PD mice, even though no statistically significant loss of tyrosine hydroxylase in the nigrostriatal system was found in either sex. These findings are valuable for early detection of motor impairment in early PD animal models. We provide a user-friendly, step-by-step guide for automated assessment of mouse performances in the balance beam test, which aims to be replicable without any significant computational and programming knowledge.The authors would like to thank Dr. Benjamin Dehay (Univ. Bordeaux, CNRS, IMN, UMR 5293, F-33000, Bordeaux, France) for providing the viruses used in this work. This study was funded by Grants from the Basque Government (IT1706-22) and the Spanish Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033; PID2 021-126434OB-I00). This research was conducted in the scope of the Transborder Joint Laboratory (LTC) “non-motor Comorbidities in Parkinson’s Disease (CoMorPD)”. M.Z has a fellowship from the University of the Basque Country

Plasma and serum alpha-synuclein as a biomarker in Parkinson's disease: A meta-analysis

Background Reliable biomarkers for Parkinson's disease (PD) diagnosis are urgently needed. Alpha-synuclein (α-syn) and its proteoforms play a key role in PD pathology but in vivo measurements have raised conflicting results, and whether α-syn in blood could distinguish PD patients from healthy controls is still controversial. Methods A systematic literature search yielded 35 eligible studies for meta-analysis reporting the concentration of total, oligomeric or phosphorylated α-syn in plasma and/or serum of PD patients and healthy controls. Standardized mean differences (SMD) were pooled using multivariate/multilevel linear mixed-effects models. Meta-regression analyses were conducted to investigate possible modifiers. Results A meta-analysis of 32 articles involving 2683 PD patients and 1838 controls showed a significant overall effect of PD on total α-syn levels (SMD = 0.85, p = 0.004). Meta-regression showed that increased SMD of total α-syn in PD was significantly associated with lower age, shorter disease duration, mild motor impairment, and Immunomagnetic Reduction assay for protein quantification. In contrast, no significant differences were observed for oligomeric or phosphorylated α-syn between PD and controls but increased oligomeric α-syn was significantly associated with shorter disease duration. The heterogeneity among studies was high (>98%). Conclusions These findings suggest that increased total plasma/serum α-syn levels in PD primarily occur in early phases of the disease. The evidence obtained from a small number of studies measuring plasma/serum concentrations of oligomeric and phosphorylated species of α-syn shows no difference. The clinical applicability of measuring plasma or serum α-syn species for differentiating PD from healthy control warrants further studies with better clinical profiling of PD patients.This study was partially co-funded by the Basque Government [project PIBA 2019–38] and University of the Basque Country (UPV/EHU) [project GIU19/092]