Neuronally derived extracellular vesicle α-synuclein as a serum biomarker for individuals at risk of developing Parkinson disease

IMPORTANCE: Nonmotor symptoms of Parkinson disease (PD) often predate the movement disorder by decades. Currently, there is no blood biomarker to define this prodromal phase. OBJECTIVE: To investigate whether α-synuclein in neuronally derived serum-extracellular vesicles identifies individuals at risk of developing PD and related dementia. DESIGN, SETTING, and PARTICIPANTS: This retrospective, cross-sectional multicenter study of serum samples included the Oxford Discovery, Marburg, Cologne, and Parkinson’s Progression Markers Initiative cohorts. Participants were recruited from July 2013 through August 2023 and samples were analyzed from April 2022 through September 2023. The derivation group (n = 170) included participants with isolated rapid eye movement sleep behavior disorder (iRBD) and controls. Two validation groups were used: the first (n = 122) included participants with iRBD and controls and the second (n = 263) included nonmanifest GBA1N409S gene carriers, participants with iRBD or hyposmia, and available dopamine transporter single-photon emission computed tomography, healthy controls, and patients with sporadic PD. Overall the study included 199 participants with iRBD, 20 hyposmic participants with available dopamine transporter single-photon emission computed tomography, 146 nonmanifest GBA1N409S gene carriers, 21 GBA1N409S gene carrier patients with PD, 50 patients with sporadic PD, and 140 healthy controls. In the derivation group and validation group 1, participants with polysomnographically confirmed iRBD were included. In the validation group 2, at-risk participants with available Movement Disorder Society prodromal markers and serum samples were included. Among 580 potential participants, 4 were excluded due to alternative diagnoses. EXPOSURES: Clinical assessments, imaging, and serum collection. MAIN OUTCOME AND MEASURES: L1CAM-positive extracellular vesicles (L1EV) were immunocaptured from serum. α-Synuclein and syntenin-1 were measured by electrochemiluminescence. Area under the receiver operating characteristic (ROC) curve (AUC) with 95% CIs evaluated biomarker performance. Probable prodromal PD was determined using the updated Movement Disorder Society research criteria. Multiple linear regression models assessed the association between L1EV α-synuclein and prodromal markers. RESULTS: Among 576 participants included, the mean (SD) age was 64.30 (8.27) years, 394 were male (68.4%), and 182 were female (31.6%). A derived threshold of serum L1EV α-synuclein distinguished participants with iRBD from controls (AUC = 0.91; 95% CI, 0.86-0.96) and those with more than 80% probability of having prodromal PD from participants with less than 5% probability (AUC = 0.80; 95% CI, 0.71-0.89). Subgroup analyses revealed that specific combinations of prodromal markers were associated with increased L1EV α-synuclein levels. Across all cohorts, L1EV α-synuclein differentiated participants with more than 80% probability of having prodromal PD from current and historic healthy control populations (AUC = 0.90; 95% CI, 0.87-0.93), irrespective of initial diagnosis. L1EV α-synuclein was increased in at-risk participants with a positive cerebrospinal fluid seed amplification assay and was above the identified threshold in 80% of cases (n = 40) that phenoconverted to PD or related dementia. CONCLUSIONS AND RELEVANCE: L1EV α-synuclein in combination with prodromal markers should be considered in the stratification of those at high risk of developing PD and related Lewy body diseases

Funcionalidade de Indivíduos com Doença Oncológica Internados em Unidades de Terapia Intensiva

Introdução: Indivíduos com câncer representam cerca de 20% de todas as admissões em unidades de terapia intensiva. A redução da capacidade funcional é resultante do câncer e seus tratamentos e pode ser potencializada pela imobilização advinda neste setor. Objetivo: Analisar a funcionalidade de indivíduos com doença oncológica internados em unidades de terapia intensiva. Método: Estudo observacional de coorte prospectiva, no qual foram avaliados indivíduos com câncer, internados em unidades de terapia intensiva dentro de 24 horas da admissão e da alta quando esta ocorreu por meio da escala Perme. As condições sociodemográficas foram coletadas com a aplicação de um questionário e as informações clínicas obtidas do prontuário. Os dados foram analisados por estatística descritiva e inferencial. Foi aplicado o teste t para amostras pareadas e independentes. Para correlacionar as variáveis quantitativas, foi utilizado o teste de correlação de Pearson. Resultados: Foram incluídos 42 indivíduos com câncer em estado crítico, predominantemente homens e com média de idade de 62,86 anos. O principal tipo tumoral identificado foi no sistema gastrointestinal (40,5%). A ventilação mecânica foi indicativa de menor funcionalidade. Foram registradas associações significativas entre o tempo de internação e a funcionalidade na admissão e alta. O desfecho dos pacientes admitidos com menor funcionalidade foi o óbito. Ao comparar os resultados de admissão e alta, houve melhora significativa do estado funcional. Conclusão: Os indivíduos com câncer admitidos em unidades de terapia intensiva apresentaram melhora da funcionalidade durante a internação

Intranasal oxytocin attenuates the effects of monetary feedback on procedural learning

Procedural learning is a vital brain function that allows us to acquire motor skills during development or re-learnthem after lesions affecting the motor system. Procedural learning can be improved by feedback of differentvalence, e.g., monetary or social, mediated by dopaminergic circuits. While processing motivationally relevantstimuli, dopamine interacts closely with oxytocin, whose effects on procedural learning, particularly feedbackbasedapproaches, remain poorly understood. In a randomized, double-blind, placebo-controlled trial, weinvestigated whether oxytocin modulates the differential effects of monetary and social feedback on procedurallearning. Sixty-one healthy male participants were randomized to receive a placebo or oxytocin intranasally. Theparticipants then performed a modified serial reaction time task. Oxytocin plasma concentrations were measuredbefore and after applying the placebo or verum. Groups did not differ regarding general reaction times ormeasures of procedural learning. For the placebo group, monetary feedback improved procedural learningcompared to a neutral control condition. In contrast, the oxytocin group did not show a differential effect ofmonetary or social feedback despite a significant increase in oxytocin plasma levels after intranasal application.The data suggest that oxytocin does not influence procedural learning per se. Instead, oxytocin seems toattenuate the effects of monetary feedback on procedural learning specifically

Quantification of the neurochemical profile of the human putamen using STEAM MRS in a cohort of elderly subjects at 3 T and 7 T: Ruminations on the correction strategy for the tissue voxel composition

The aim of this work is to quantify the metabolic profile of the human putamen in vivo in a cohort of elderly subjects using single-voxel proton magnetic resonance spectroscopy. To obtain metabolite concentrations specific to the putamen, we investigated a correction method previously proposed to account for the tissue composition of the volume of interest. We compared the method with the conventional approach, which a priori assumes equal metabolite concentrations in GM and WM. Finally, we compared the concentrations acquired at 3 Tesla (T) and 7 T MRI scanners. Spectra were acquired from 15 subjects (age: 67.7 ± 8.3 years) at 3 T and 7 T, using an ultra-short echo time, stimulated echo acquisition mode sequence. To robustly estimate the WM-to-GM metabolite concentration ratio, five additional subjects were measured for whom the MRS voxel was deliberately shifted from the putamen in order to increase the covered amount of surrounding WM. The concentration and WM-to-GM concentration ratio for 16 metabolites were reliably estimated. These ratios ranged from ~0.3 for γ-aminobutyric acid to ~4 for N-acetylaspartylglutamate. The investigated correction method led to significant changes in concentrations compared to the conventional method, provided that the ratio significantly differed from unity. Finally, we demonstrated that differences in tissue voxel composition cannot fully account for the observed concentration difference between field strengths. We provide not only a fully comprehensive quantification of the neurochemical profile of the putamen in elderly subjects, but also a quantification of the WM-to-GM concentration ratio. This knowledge may serve as a basis for future studies with varying tissue voxel composition, either due to tissue atrophy, inconsistent voxel positioning or simply when pooling data from different voxel locations

Compensatory articulatory mechanisms preserve intelligibility in prodromal Parkinson's disease

AbstractIntroduction: Dysarthria is highly prevalent in patients with Parkinson's disease (PD) and speech changes have already been detected in patients with prodromal PD on the acoustic level. However, the present study directly tracks underlying articulatory movements with electromagnetic articulography to investigate early speech alterations on the kinematic level in isolated REM sleep behavior disorder (iRBD) and compares them to PD and control speakers.Methods: Kinematic data of 23 control speakers, 22 speakers with iRBD, and 23 speakers with PD were collected. Amplitude, duration, and average speed of lower lip, tongue tip, and tongue body movements were analyzed. Naive listeners rated the intelligibility of all speakers.Results: Patients with iRBD produced tongue tip and tongue body movements that were larger in amplitude and longer in duration compared to control speakers, while remaining intelligible. Compared to patients with iRBD, patients with PD had smaller, longer and slower tongue tip and lower lip movements, accompanied by lower intelligibility. Thus, the data indicate that the lingual system is already affected in prodromal PD. Furthermore, lower lip and especially tongue tip movements slow down and speech intelligibility decreases if motor impairment is more pronounced.Conclusion: Patients with iRBD adjust articulatory patterns to counteract incipient motor detriment on speech to maintain their intelligibility level

Clinical subtypes in patients with isolated REM sleep behaviour disorder

Patients with Parkinson's disease (PD) show a broad heterogeneity in dinical presentation, and subtypes may already arise inprodromal disease stages. lsolated REM sleep behaviour disorder (iRBD) is the most specific marker of prodromal PD, but data ondinical subtyping of patients with iRBD remain scarce. Therefore, this study aimed to identify iRBD subtypes. We conductedcomprehensive dinical assessments in 66 patients with polysomnography-proven iRBD, induding motor and non-motorevaluations, and applied a two-step duster analysis. Besides, we compared iRBD dusters to matched healthy controls and relatedthe resulting duster solution to cortical and subcortical grey matter volumes by voxel-based morphometry analysis. We identifiedtwo distinct subtypes of patients based on olfactory function, dominant electroencephalography frequency, amount of REM sleepwithout atonia, depressive symptoms, disease duration, and motor functions. One iRBD duster (Cluster 1, late onset-aggressive)was characterised by higher non-motor symptom burden despite shorter disease duration than the more benign subtype (Cluster II,early onset-benign). Motor functions were comparable between the dusters. Patients from Cluster I were significantly older atiRBD onset and exhibited a widespread reduction of cortical grey matter volume compared to patients from Cluster II. In condusion,our findings suggest the existence of dinical subtypes already in the prodromal stage of PD. Future longitudinal studies arewarranted that replicate these findings and investigate the risk of the more aggressive phenotype for earlier phenoconversion anddementia development

Short Pulse and Conventional Deep Brain Stimulation Equally Improve the Parkinsonian Gait Disorder

Background: Gait disturbances and balance remain challenging issues in Parkinsonian patients (PD) with deep brain stimulation (DBS). Short pulse deep brain stimulation (spDBS) increases the therapeutic window in PD patients, yet the effect on gait and postural symptoms remains unknown. Objective: We assessed the efficacy of spDBS compared to conventional DBS (cDBS) within the subthalamic nucleus (STN) on Parkinsonian gait. Methods: The study was a single-centre, randomized, double-blind, clinical short-term trial. 20 PD patients were studied postoperatively in three different conditions (DBS stimulation switched off (off DBS), spDBS with 40 mu s pulse width, cDBS with 60 mu s pulse width) on regular medication. The primary endpoint was the relative difference of gait velocity at selfpaced speed during quantitative gait analysis between stimulation conditions. Secondary endpoints were changes of further measures of quantitative gait analysis, Ziegler course, Berg balance scale, FOG questionnaire, MDS-UPDRS, PDQ-39, and HADS. Mixed-model analysis and post-hoc t-tests were performed. Results: Both spDBS and cDBS improved gait velocity at self-paced speed compared to off DBS, however, there was no significant difference between both stimulation modes. Still, 40% of the patients preferred spDBS over cDBS subjectively. Both stimulation modes were equally effective in improving secondary endpoints of gait, balance, motor and non-motor performances. Conclusion: The use of spDBS and cDBS is equally effective in improving gait and balance in PD and might be beneficial in specified cohorts of PD patients

Visuo‐spatial processing is linked to cortical glutamate dynamics in Parkinson's disease – a 7 Tesla functional MRS study

Background and purpose: Cognitive decline is a frequent and debilitating non-motor symptom for patients with Parkinson's disease (PD). Metabolic alterations in the occipital cortex during visual processing may serve as a biomarker for cognitive decline in patients with PD.Methods: Sixteen patients with PD (Unified Parkinson's Disease Rating Scale Part 3, OFF, 38.69 ± 17.25) and 10 age- and sex-matched healthy controls (HC) underwent 7-T functional magnetic resonance spectroscopy (MRS) utilizing a visual checkerboard stimulation. Glutamate metabolite levels during rest versus stimulation were compared. Furthermore, correlates of the functional MRS response with performance in visuo-cognitive tests were investigated.Results: No differences in static MRS between patients with PD and HC were detected, but a dynamic glutamate response was observed in functional MRS in HC upon visual stimulation, which was blunted in patients with PD (F1,22 = 7.13, p = 0.014; η2p= 0.245). A diminished glutamate response correlated with poorer performance in the Benton Judgment of Line Orientation test in PD (r = -0.57, p = 0.020).Conclusions: Our results indicate that functional MRS captures even subtle differences in neural processing linked to the behavioral performance, which would have been missed by conventional, static MRS. Functional MRS thus represents a promising tool for studying molecular alterations at high sensitivity. Its prognostic potential should be evaluated in longitudinal studies, prospectively contributing to earlier diagnosis and individual treatment decisions.Keywords: biomarker; cognitive decline; functional magnetic resonance spectroscopy; visuo-cognition