INTRODUCTION: ND0612 is being investigated as a continuous, subcutaneous levodopa/carbidopa infusion, in combination with oral levodopa/carbidopa, for motor fluctuations in Parkinson's disease (PD). One-year data from the ongoing BeyoND study (NCT02726386) showed that the ND0612 regimen was safe and well tolerated and provided a sustained ≥2-h improvement in daily Good ON-time through 12 months of treatment. METHODS: We describe 3-year safety and efficacy outcomes for participants who completed 12 months of ND0612 treatment in the core study period and entered the extension phase. RESULTS: Of the 214 enrolled participants, 120 completed the core 1-year period, and 114 participants continued into the extension phase. Of these, 95/114 (83.3 %) completed 2 years and 77/114 (67.5 %) completed 3 years of study treatment. Key reasons for discontinuation were treatment-emergent adverse events (TEAEs) (n = 5 and n = 11 after 2 and 3 years, respectively) and withdrawal of consent (n = 9 and n = 5, respectively). TEAEs were reported by 105/114 (92.1 %) participants in Year 1, 77/114 (67.5 %) in Year 2, and 73/95 (76.8 %) in Year 3. While most participants experienced infusion site reactions, these led to discontinuation in only five participants during this extension. At Month 36, the mean reduction in OFF-time from baseline was 2.81 h and the increase in Good ON-time was 2.79 h. CONCLUSIONS: Three-year results from this open-label study support the long-term safety, tolerability, and efficacy of ND0612. For participants who entered the extension phase, the high rate of retention supports a favorable benefit-risk ratio of the ND0612 regimen for patients with PD experiencing motor fluctuations.

• Klíčová slova
• Infusion, Levodopa, Motor complications, ND0612, Parkinson's disease,
• MeSH
• antiparkinsonika * aplikace a dávkování   škodlivé účinky   MeSH
• fixní kombinace léků * MeSH
• karbidopa * aplikace a dávkování   MeSH
• levodopa * aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• Parkinsonova nemoc * farmakoterapie   MeSH
• senioři MeSH
• subkutánní infuze * MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Názvy látek
• antiparkinsonika * MeSH
• carbidopa, levodopa drug combination MeSH Prohlížeč
• fixní kombinace léků * MeSH
• karbidopa * MeSH
• levodopa * MeSH

Background and Objectives: The aim of this study was to determine the effect of immersive virtual reality used as a short-term multifaceted activity with a focus on motor and cognitive function in patients with Parkinson's Disease. The sub-objective focused on quality of life in the study group of patients. Materials and Methods: Nineteen patients (64.2 ± 12.8 years) were included in this study. Inclusion criteria for this study: adult patients in Hoehn and Yahr's stage 1-3, cooperative, with stable health status, independent and mobile. IVR therapy was performed twice a week for 20 min for one month. Input and output measurements were taken within 14 days of starting or ending therapy. The 10 Meter Walk test was used to examine and assess both comfortable and fast walking, and the Timed Up and Go (TUG) + s dual task was applied to quickly assess the highest possible level of functional mobility. The Berg Balance Scale test (BBS) was used to assess balance with a 14-item balance scale containing specific movement tasks. The standardized Parkinson's Disease Questionnaire (PDQ-39) was used to assess quality of life. Data were processed in the PAST program using a nonparametric paired Wilcoxon test. The significance level was set at α = 0.05. The value of the r score was used to evaluate the effect size. Results: A significant reduction in the time in the fast walk 10MWT (p = 0.006; r = 0.63) and TUG (p < 0.001; r = 0.80) parameter were found after therapy. Significant improvement in the BBS score was found after applied therapy (p = 0.016; r = 0.55). In the PDQ-39 questionnaire, significant improvements were found in the study group after therapy in the domains of mobility (p = 0.027; r = 0.51) and emotional well-being (p = 0.011; r = 0.58). Conclusions: The results of this study indicate a positive effect of virtual reality therapy on balance and gait, which is also good in terms of reducing the risk of falls in the study group. Therapy also promoted quality of life in the study group.

• Klíčová slova
• balance, clinical trials, mobility, neurodegenerative diseases, questionnaire, rehabilitation,
• MeSH
• kognice fyziologie   MeSH
• kvalita života * psychologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• Parkinsonova nemoc * psychologie   patofyziologie   terapie   komplikace   MeSH
• posturální rovnováha fyziologie   MeSH
• průzkumy a dotazníky MeSH
• senioři MeSH
• terapie pomocí virtuální reality metody   MeSH
• virtuální realita * MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Although neuromelanin-sensitive magnetic resonance imaging (NM-MRI) has been used to evaluate early neurodegeneration in Parkinson's disease, studies concentrating on the locus coeruleus (LC) in pre-dementia stages of dementia with Lewy bodies (DLB) are lacking. OBJECTIVES: The aims were to evaluate NM-MRI signal changes in the LC in patients with mild cognitive impairment with Lewy bodies (MCI-LB) compared to healthy controls (HC) and to identify the cognitive correlates of the changes. We also aimed to test the hypothesis of a caudal-rostral α-synuclein pathology spread using NM-MRI of the different LC subparts. METHODS: A total of 38 MCI-LB patients and 59 HCs underwent clinical and cognitive testing and NM-MRI of the LC. We calculated the contrast ratio of NM-MRI signal (LC-CR) in the whole LC as well as in its caudal, middle, and rostral MRI slices, and we compared the LC-CR values between the MCI-LB and HC groups. Linear regression analyses were performed to assess the relationship between the LC-CR and cognitive outcomes. RESULTS: The MCI-LB group exhibited a significant reduction in the right LC-CR compared to HCs (P = 0.021). The right LC-CR decrease was associated with impaired visuospatial memory in the MCI-LB group. Only the caudal part of the LC exhibited significant LC-CR decreases in MCI-LB patients compared to HCs on both sides (P < 0.0001). CONCLUSIONS: This is the first study that focuses on LC-CRs in MCI-LB patients and analyzes the LC subparts, offering new insights into the LC integrity alterations in the initial stages of DLB and their clinical correlates. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

• Klíčová slova
• locus coeruleus, mild cognitive impairment with Lewy bodies, neuromelanin‐sensitive magnetic resonance imaging,
• MeSH
• alfa-synuklein metabolismus   MeSH
• demence s Lewyho tělísky * diagnostické zobrazování   patologie   MeSH
• kognitivní dysfunkce * diagnostické zobrazování   patologie   patofyziologie   etiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• locus coeruleus * diagnostické zobrazování   patologie   MeSH
• magnetická rezonanční tomografie * MeSH
• neuropsychologické testy MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alfa-synuklein MeSH

DOPA Decarboxylase (DDC) has been proposed as a cerebrospinal fluid (CSF) biomarker with increased concentrations in Lewy body disorders (LBDs) and highest levels in patients receiving dopaminergic treatment. Here we evaluate plasma DDC, measured by proximity extension assay, and the effect of dopaminergic treatment in three independent LBD (with a focus on dementia with Lewy bodies (DLB) and Parkinson's disease (PD)) cohorts: an autopsy-confirmed cohort (n = 71), a large multicenter, cross-dementia cohort (n = 1498) and a longitudinal cohort with detailed treatment information (n = 66, median follow-up time[IQR] = 4[4, 4] years). Plasma DDC was not altered between different LBDs and other disease groups or controls in absence of treatment. DDC levels increased over time in PD, being significantly associated to higher dosages of dopaminergic treatment. This emphasizes the need to consider treatment effect when analyzing plasma DDC, and suggests that plasma DDC, in contrast to CSF DDC, is of limited use as a diagnostic biomarker for LBD, but could be valuable for treatment monitoring.

• MeSH
• biologické markery * krev   mozkomíšní mok   MeSH
• demence s Lewyho tělísky * farmakoterapie   krev   mozkomíšní mok   MeSH
• DOPA-dekarboxylasa * metabolismus   MeSH
• dopaminové látky terapeutické užití   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• longitudinální studie MeSH
• Parkinsonova nemoc * farmakoterapie   krev   mozkomíšní mok   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Názvy látek
• biologické markery * MeSH
• DOPA-dekarboxylasa * MeSH
• dopaminové látky MeSH

BACKGROUND AND OBJECTIVES: Patients with synucleinopathies such as multiple system atrophy (MSA) and Parkinson's disease (PD) frequently display speech and language abnormalities. We explore the diagnostic potential of automated linguistic analysis of natural spontaneous speech to differentiate MSA and PD. METHODS: Spontaneous speech of 39 participants with MSA compared to 39 drug-naive PD and 39 healthy controls matched for age and sex was transcribed and linguistically annotated using automatic speech recognition and natural language processing. A quantitative analysis was performed using 6 lexical and syntactic and 2 acoustic features. Results were compared with human-controlled analysis to assess the robustness of the approach. Diagnostic accuracy was evaluated using sensitivity analysis. RESULTS: Despite similar disease duration, linguistic abnormalities were generally more severe in MSA than in PD, leading to high diagnostic accuracy with an area under the curve of 0.81. Compared to controls, MSA showed decreased grammatical component usage, more repetitive phrases, shorter sentences, reduced sentence development, slower articulation rate, and increased duration of pauses, whereas PD had only shorter sentences, reduced sentence development, and longer pauses. Only slower articulation rate was distinctive for MSA while unchanged for PD relative to controls. The highest correlation was found between bulbar/pseudobulbar clinical score and sentence length (r = -0.49, p = 0.002). Despite the relatively high severity of dysarthria in MSA, a strong agreement between manually and automatically computed results was achieved. DISCUSSION: Automated linguistic analysis may offer an objective, cost-effective, and widely applicable biomarker to differentiate synucleinopathies with similar clinical manifestations.

• Klíčová slova
• Automated linguistic analysis, Language, Multiple system atrophy, Natural language processing, Spontaneous discourse,
• MeSH
• diferenciální diagnóza MeSH
• lidé středního věku MeSH
• lidé MeSH
• multisystémová atrofie * diagnóza   patofyziologie   komplikace   MeSH
• Parkinsonova nemoc * diagnóza   komplikace   patofyziologie   MeSH
• řeč fyziologie   MeSH
• senioři MeSH
• zpracování přirozeného jazyka MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Rare diseases may affect the quality of life of patients and be life-threatening. Therapeutic opportunities are often limited, in part because of the lack of understanding of the molecular mechanisms underlying these diseases. This can be ascribed to the low prevalence of rare diseases and therefore the lower sample sizes available for research. A way to overcome this is to integrate experimental rare disease data with prior knowledge using network-based methods. Taking this one step further, we hypothesized that combining and analyzing the results from multiple network-based methods could provide data-driven hypotheses of pathogenic mechanisms from multiple perspectives.We analyzed a Huntington's disease transcriptomics dataset using six network-based methods in a collaborative way. These methods either inherently reported enriched annotation terms or their results were fed into enrichment analyses. The resulting significantly enriched Reactome pathways were then summarized using the ontological hierarchy which allowed the integration and interpretation of outputs from multiple methods. Among the resulting enriched pathways, there are pathways that have been shown previously to be involved in Huntington's disease and pathways whose direct contribution to disease pathogenesis remains unclear and requires further investigation.In summary, our study shows that collaborative network analysis approaches are well-suited to study rare diseases, as they provide hypotheses for pathogenic mechanisms from multiple perspectives. Applying different methods to the same case study can uncover different disease mechanisms that would not be apparent with the application of a single method.

• Klíčová slova
• Collaborative analysis, Huntington’s disease, Network analysis, Rare disease,
• MeSH
• genové regulační sítě MeSH
• Huntingtonova nemoc * genetika   MeSH
• lidé MeSH
• stanovení celkové genové exprese * metody   MeSH
• transkriptom * MeSH
• výpočetní biologie metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Wilson disease (WD) primarily presents with hepatic and neurological symptoms. While hepatic symptoms typically precede the neurological manifestations, copper accumulates in the brain already in this patient group and leads to subclinical brain MRI abnormalities including T2 hyperintensities and atrophy. This study aimed to assess brain morphological changes in mild hepatic WD. WD patients without a history of neurologic symptoms and decompensated cirrhosis and control participants underwent brain MRI at 3T scanner including high-resolution T1-weighted images. A volumetric evaluation was conducted on the following brain regions: nucleus accumbens, caudate, pallidum, putamen, thalamus, amygdala, hippocampus, midbrain, pons, cerebellar gray matter, white matter (WM), and superior peduncle, using Freesurfer v7 software. Whole-brain analyses using voxel- and surface-based morphometry were performed using SPM12. Statistical comparisons utilized a general linear model adjusted for total intracranial volume, age, and sex. Twenty-six WD patients with mild hepatic form (30 ± 9 years [mean age ± SD]); 11 women; mean treatment duration 13 ± 12 (range 0-42) years and 28 healthy controls (33 ± 9 years; 15 women) were evaluated. Volumetric analysis revealed a significantly smaller pons volume and a trend for smaller midbrain and cerebellar WM in WD patients compared to controls. Whole-brain analysis revealed regions of reduced volume in the pons, cerebellar, and lobar WM in the WD group. No significant differences in gray matter density or cortical thickness were found. Myelin or WM in general seems vulnerable to low-level copper toxicity, with WM volume loss showing promise as a marker for assessing brain involvement in early WD stages.

• Klíčová slova
• MRI, Wilson disease, brain atrophy, brainstem, hepatic, morphometry, white matter,
• MeSH
• bílá hmota patologie   diagnostické zobrazování   MeSH
• dospělí MeSH
• hepatolentikulární degenerace * patologie   diagnostické zobrazování   MeSH
• játra patologie   diagnostické zobrazování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie * MeSH
• mladý dospělý MeSH
• mozek * patologie   diagnostické zobrazování   MeSH
• šedá hmota patologie   diagnostické zobrazování   MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Huntington's disease (HD) is a debilitating neurodegenerative disorder characterized by severe motor deficits, cognitive decline and psychiatric disturbances. An early and significant morphological hallmark of HD is the activation of astrocytes triggered by mutant huntingtin, leading to the release of inflammatory mediators. Fingolimod (FTY), an FDA-approved sphingosine-1-phosphate (S1P) receptor agonist is used to treat multiple sclerosis (MS), a neuroinflammatory disease, and has shown therapeutic promise in other neurological conditions. Our study aimed to investigate the therapeutic potential of FTY for treating HD by utilizing a well-characterized mouse model of HD (zQ175dn) and wild-type littermates. The study design included a crossover, long-term oral treatment with 1 mg/kg to 2 mg/kg FTY from the age of 15-46 weeks (n = 128). Different motor behavior and physiological parameters were assessed throughout the study. The findings revealed that FTY rescued disease-related body weight loss in a sex-dependent manner, indicating its potential to regulate metabolic disturbances and to counteract neurodegenerative processes in HD. FTY intervention also rescued testicular atrophy, restored testis tissue structure in male mice suggesting a broader impact on peripheral tissues affected by huntingtin pathology. Histological analyses of the brain revealed delayed accumulation of activated astrocytes contributing to the preservation of the neural microenvironment by reducing neuroinflammation. The extent of FTY-related disease improvement was sex-dependent. Motor functions and body weight improved mostly in female mice with sustained estrogen levels, whereas males had to compensate for the ongoing, disease-related testis atrophy and the loss of androgen production. Our study underscores the beneficial therapeutic effects of FTY on HD involving endogenous steroid hormones and their important anabolic effects. It positions FTY as a promising candidate for therapeutic interventions targeting various aspects of HD pathology. Further studies are needed to fully evaluate its therapeutic potential in patients.

• Klíčová slova
• Anabolic, Astrocytes, FTY720, Fingolimod, Huntington’s disease, Microglia, Motor function, Neurodegeneration, Neuroinflammation, S1PR1, Sphingosin-1-phosphate, Steroid hormones, ZQ175dn,
• MeSH
• fingolimod hydrochlorid * terapeutické užití   farmakologie   MeSH
• Huntingtonova nemoc * farmakoterapie   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• modulátory receptorů sfingosin-1-fosfátu * farmakologie   terapeutické užití   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• pohybová aktivita účinky léků   MeSH
• receptory sfingosin-1-fosfátu agonisté   metabolismus   MeSH
• testis účinky léků   patologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fingolimod hydrochlorid * MeSH
• modulátory receptorů sfingosin-1-fosfátu * MeSH
• receptory sfingosin-1-fosfátu MeSH

The aim of this work was to study the effect of deep brain stimulation of the subthalamic nucleus (STN-DBS) on the subnetwork of subcortical and cortical motor regions and on the whole brain connectivity using the functional connectivity analysis in Parkinson's disease (PD). The high-density source space EEG was acquired and analyzed in 43 PD subjects in DBS on and DBS off stimulation states (off medication) during a cognitive-motor task. Increased high gamma band (50-100 Hz) connectivity within subcortical regions and between subcortical and cortical motor regions was significantly associated with the Movement Disorders Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III improvement after DBS. Whole brain neural correlates of cognitive performance were also detected in the high gamma (50-100 Hz) band. A whole brain multifrequency connectivity profile was found to classify optimal and suboptimal responders to DBS with a positive predictive value of 0.77, negative predictive value of 0.55, specificity of 0.73, and sensitivity of 0.60. Specific connectivity patterns related to PD, motor symptoms improvement after DBS, and therapy responsiveness predictive connectivity profiles were uncovered.

• Klíčová slova
• Connectivity patterns, Deep brain stimulation, EEG, Functional connectivity, Parkinson’s disease, Subthalamic nucleus,
• MeSH
• elektroencefalografie metody   MeSH
• hluboká mozková stimulace * metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mozek patofyziologie   diagnostické zobrazování   MeSH
• nucleus subthalamicus * patofyziologie   MeSH
• Parkinsonova nemoc * terapie   patofyziologie   MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

In Parkinson's disease (PD), impaired gait and cognition affect daily activities, particularly in the more advanced stages of the disease. This study investigated the relationship between gait parameters, cognitive performance, and brain morphology in patients with early untreated PD. 64 drug-naive PD patients and 47 healthy controls (HC) participated in the study. Single- and dual-task gait (counting task) were examined using an expanded Timed Up & Go Test measured on a GaitRite walkway. Measurements included gait speed, stride length, and cadence. A brain morphometry analysis was performed on T1-weighted magnetic resonance (MR) images. In PD patients compared to HC, gait analysis revealed reduced speed (p < 0.001) and stride length (p < 0.001) in single-task gait, as well as greater dual-task cost (DTC) for speed (p = 0.007), stride length (p = 0.014) and cadence (p = 0.029). Based on the DTC measures in HC, PD patients were further divided into two subgroups with normal DTC (PD-nDTC) and abnormally increased DTC (PD-iDTC). For PD-nDTC, voxel-based morphometric correlation analysis revealed a positive correlation between a cluster in the left primary motor cortex and stride-length DTC (r = 0.57, p = 0.027). For PD-iDTC, a negative correlation was found between a cluster in the right lingual gyrus and the DTC for gait cadence (r=-0.35, pFWE = 0.018). No significant correlations were found in HC. The associations found between brain morphometry and gait performance with a concurrent cognitive task may represent the substrate for gait and cognitive impairment occurring since the early stages of PD.

• Klíčová slova
• Dual-task cost, Gait speed, Morphometric correlation analysis, Stepping cadence, Stride length, Timed up and go test,
• MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie * MeSH
• mozek * diagnostické zobrazování   patologie   patofyziologie   MeSH
• neurologické poruchy chůze * etiologie   patofyziologie   diagnostické zobrazování   patologie   MeSH
• neuropsychologické testy MeSH
• Parkinsonova nemoc * diagnostické zobrazování   patofyziologie   patologie   komplikace   MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH