50 research outputs found
Nicht-motorische Symptome bei der hereditären spastischen Spinalparalyse Typ 4 (SPG4)
No full textDie hereditäre spastische Paraplegie ist eine neurodegenerative Erkrankung mit der we- sentlichen Eigenschaft einer spastischen Gangstörung. SPG4 macht etwa 25 % aller HSP Fälle aus und wird durch Mutationen im SPAST-Gen verursacht. Die motorischen Prob- leme dieser Erkrankung stehen insgesamt im Fokus und erzeugen die größte Krankheits- belastung. Bisher gibt es für die SPG4-Patienten keine kausale Therapie. Die nicht-mo- torischen Symptome, die in diesen Studien evaluiert wurden, sind häufige Begleiterkran- kungen bei chronischen Krankheiten und können die Lebensqualität deutlich beeinflus- sen. Im Hauptteil der Studie wurde bei 118 genetisch bestätigten SPG4-Fällen und alters- und geschlechtsgleichen Teilnehmern der Kontrollgruppe validierte Fragebögen verwen- det, um Müdigkeit, Depression, Schmerzen und das Restless-Legs-Syndrom zu bewerten. In der Substudie wurde Kognition mit Hilfe von CANTAB®-Tests und dem Montreal Cognitive Assessment bei 26 SPG4-Patienten untersucht. Es konnten keine signifikanten kognitiven Beeinträchtigungen bei SPG4-Patienten mit CANTAB® gegenüber der Kon- trollgruppe gemessen werden, auch wenn dies anamnestisch deutlich häufiger von selbst berichtet wurde und im familiären Umfeld auftrat. Die Lebensqualität war gegenüber der Kontrollgruppe reduziert und korrelierte mit allen anderen erhoben Symptomen. Fatigue, Schmerzen und Depressionen traten bei SPG4-Patienten ebenfalls häufiger auf. Das Rest- less-Legs-Syndrom war durch die Diagnosekriterien schwierig zu diagnostizieren. In Ab- hängigkeit von den Diagnosekriterien ergaben sich unterschiedlich hohe Fallzahlen. Bla- sen-, Sexual- und Defäkationsprobleme waren häufig und schienen in den aktuellen Be- handlungsstrategien unterschätzt zu werden. Polypharmazie war in beiden Studien häufig und bleibt ein bekanntes und unberücksichtigtes Problem
Cognitive impairment in Glucocerebrosidase (GBA)-associated PD: Not primarily associated with cerebrospinal fluid Abeta and Tau profiles
No full textA proportion of idiopathic Parkinson's disease patients (PDidiopathic ) with dementia show altered CSF profiles of amyloid β (Aβ) and Tau. PD patients with Glucocerebrosidase (GBA) mutations (PDGBA ) present with even more cognitive decline than seen in PDidiopathic
Test-Retest Reliability and Inter-Scanner Reproducibility of Improved Spinal Diffusion Tensor Imaging
No full textBackground/Objectives: Spinal diffusion tensor imaging (sDTI) remains a challenging method for the selective evaluation of key anatomical structures, like pyramidal tracts (PTs) and dorsal columns (DCs), and for reliably quantifying diffusion metrics such as fractional anisotropy (FA), radial diffusivity (RD), mean diffusivity (MD), and axial diffusivity (AD). This prospective, single-center study aimed to assess the reproducibility, robustness, and reliability of an optimized axial sDTI protocol, specifically intended for long fiber tracts. Methods: We developed an optimized Stejskal-Tanner sequence for high-resolution, axial sDTI of the cervical spinal cord at 3.0 T. Using advanced standardized evaluation and post-processing methods, we estimated DTI values for PTs, DCs, and AHs at the level of the second cervical vertebra. [...]. Results: The optimized sDTI protocol demonstrated high consistency for FA between test-retest sessions and across scanners. For the Skyra, the DC region showed the highest reliability (average ICC = 0.858) followed by the PT region (average ICC = 0.789). On the Prisma, the PT region reached an average ICC of 0.854, with the DC region at 0.758. Pooled inter-scanner data indicated good-to-excellent agreement, particularly in the PT region (average ICC = 0.860). FA CVs remained low (<10%) across all regions and scanners. RD showed good-to-excellent ICC values for PTs and DCs (average ICC for Skyra 0.642 and 0.769 and 0.926 and 0.830 for Prisma, respectively) but showed a higher CV between 14.6 and 19.4% for these two scanners. Conclusions: Improved sDTI offers highly reproducible FA measurements for all metrics with scanner independence, supporting its potential as a robust tool for detecting and monitoring spinal cord pathologies
Generation of induced pluripotent stem cells (iPSCs) from a hereditary spastic paraplegia patient carrying a homozygous Y275X mutation in CYP7B1 (SPG5)
No full textAbstractSkin fibroblasts were obtained from a 47-year-old hereditary spastic paraplegia patient carrying a homozygous mutation Y275X in CYP7B1 (Cytochrome P450, Family 7, Subfamily B, Polypeptide 1), responsible for causing hereditary spastic paraplegia type 5 (SPG5). Induced pluripotent stem cells (iPSCs) were generated by transfection with episomal plasmids carrying hOCT4, hSOX2, hKLF4, hL-MYC and hLIN28. The generated line iPS-SPG5-Y275X was transgene-free, retained the specific mutation with no additional genomic aberrations, expressed pluripotency markers and was able to differentiate into cells of all germ layers in vitro. The generated iPS-SPG5-Y275X line may be a useful resource for disease modelling of SPG5
The B-MaP-C study:Breast cancer Management Pathways during the COVID-19 pandemic. Study protocol
No full textIntroduction Approximately 55000 women in the United Kingdom are diagnosed with new breast cancer annually. Since emerging in December 2019, SARS-CoV-2 (coronavirus disease 2019, COVID-19) has be-come a global pandemic, affecting healthcare delivery worldwide. In response to the pandemic, mul-tiple guidelines were issued to assist with rationalising breast cancer care. The primary aim of the B-MaP-C study is to audit and describe breast cancer management of patients newly diagnosed with breast cancer during the COVID-19 pandemic against pre-COVID-19 management practice in the UK. The implications of changes to management will be determined and the impact of a COVID-19 diagnosis on the patient’s breast cancer management will be determined.Methods and analysis This is a multi-centre collaborative audit of consecutive breast cancer patients undergoing treatment decisions during the acute and recovery phases of the COVID-19 pandemic. All patients with newly diagnosed primary breast cancer, whose treatment was decided in a multidisciplinary meeting from the 16th March 2020, are eligible for inclusion. Ethics and disseminationAs this is an audit ethical approval is not required. Each participating centre is required to register the study locally and obtain local governance approvals prior to commencement of data collection. Local audit data will be available to individual participating units for governance purposes. The results of the data analysis will be submitted for publication, as well as disseminated via the ABS newsletter and a webinar. All data will be presented at national and international conferences, circumstances permitting.Registration detailsEach participating centre received local governance audit registration. <br/
Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study
No full textBackgroundThe B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions.MethodsThis was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting.FindingsOf 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey.ConclusionsThe majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown
Cerebrospinal fluid findings in patients with psychotic symptoms-a retrospective analysis
No full textHereditary spastic paraplegia type 5: Natural history, biomarkers and a randomized controlled trial
No full textAbstract: SPG5 is a rare subtype of Hereditary Spastic Paraplegia caused by mutations in the oxysterol-7 alpha-hydroxylase gene CYP7B1. Schols et al. study properties of lipid biomarkers in SPG5 and evaluate a treatment strategy targeting oxysterol accumulation in a randomized controlled trial (STOP-SPG5).Spastic paraplegia type 5 (SPG5) is a rare subtype of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative disorders defined by progressive neurodegeneration of the corticospinal tract motor neurons. SPG5 is caused by recessive mutations in the gene CYP7B1 encoding oxysterol-7 alpha-hydroxylase. This enzyme is involved in the degradation of cholesterol into primary bile acids. CYP7B1 deficiency has been shown to lead to accumulation of neurotoxic oxysterols. In this multicentre study, we have performed detailed clinical and biochemical analysis in 34 genetically confirmed SPG5 cases from 28 families, studied dose-dependent neurotoxicity of oxysterols in human cortical neurons and performed a randomized placebo-controlled double blind interventional trial targeting oxysterol accumulation in serum of SPG5 patients. Clinically, SPG5 manifested in childhood or adolescence (median 13 years). Gait ataxia was a common feature. SPG5 patients lost the ability to walk independently after a median disease duration of 23 years and became wheelchair dependent after a median 33 years. The overall cross-sectional progression rate of 0.56 points on the Spastic Paraplegia Rating Scale per year was slightly lower than the longitudinal progression rate of 0.80 points per year. Biochemically, marked accumulation of CYP7B1 substrates including 27-hydroxycholesterol was confirmed in serum (n = 19) and cerebrospinal fluid (n = 17) of SPG5 patients. Moreover, 27-hydroxycholesterol levels in serum correlated with disease severity and disease duration. Oxysterols were found to impair metabolic activity and viability of human cortical neurons at concentrations found in SPG5 patients, indicating that elevated levels of oxysterols might be key pathogenic factors in SPG5. We thus performed a randomized placebo-controlled trial (EudraCT 2015-000978-35) with atorvastatin 40 mg/day for 9 weeks in 14 SPG5 patients with 27-hydroxycholesterol levels in serum as the primary outcome measure. Atorvastatin, but not placebo, reduced serum 27-hydroxycholesterol from 853 ng/ml [interquartile range (IQR) 683-1113] to 641 (IQR 507-694) (-31.5%, P = 0.001, Mann-Whitney U-test). Similarly, 25-hydroxycholesterol levels in serum were reduced. In cerebrospinal fluid 27-hydroxycholesterol was reduced by 8.4% but this did not significantly differ from placebo. As expected, no effects were seen on clinical outcome parameters in this short-term trial. In this study, we define the mutational and phenotypic spectrum of SPG5, examine the correlation of disease severity and progression with oxysterol concentrations, and demonstrate in a randomized controlled trial that atorvastatin treatment can effectively lower 27-hydroxycholesterol levels in serum of SPG5 patients. We thus demonstrate the first causal treatment strategy in hereditary spastic paraplegia
Uniparental disomy determined by whole-exome sequencing in a spectrum of rare motoneuron diseases and ataxias
No full textAbstract: Background The genetic causes of many rare inherited motoneuron diseases and ataxias (MND and ATX) remain largely unresolved, especially for sporadic patients, despite tremendous advances in gene discovery. Whole exome data is often available for patients, but it is rarely evaluated for unusual inheritance patterns, such as uniparental disomy (UPD). UPD is the inheritance of two copies of a chromosomal region from one parent, which may generate homozygosity for a deleterious recessive variant from only one carrier-parent. Detection of UPD-caused homozygous disease-causing variants is detrimental to accurate genetic counseling. Whole-exome sequencing can allow for the detection of such events. Methods We systematically studied the exomes of a phenotypically heterogeneous cohort of unresolved cases (n = 96 families) to reveal UPD events hindering a diagnosis and to evaluate the prevalence of UPD in recessive MND and ATX. Results One hereditary spastic paraplegia case harbored homozygous regions spanning 80% of chromosome 16. A homozygous disease-causing mutation in the SPG35 disease gene was then identified within this region. Conclusion This study demonstrates the ability to detect UPD in exome data of index patients. Our results suggest that UPD is a rare mechanism for recessive MND and ATX
Amantadine for NeuroenhaNcement in acutE patients Study - a protocol for a prospective pilot proof of concept phase IIb study in intensive and intermediate care unit patients (ANNES)
No full textAbstract Background Persisting coma is a common complication in (neuro)intensive care in neurological disease such as acute ischemic stroke, intracerebral hemorrhage or subarachnoid hemorrhage. Amantadine acts as a nicotinic receptor antagonist, dopamine receptor agonist and non-competitive N-Methyl-D-aspartate receptor antagonist. Amantadine is a long-known drug, originally approved for treatment of influenza A and Parkinson`s Disease. It has been proven effective in improving vigilance after traumatic brain injury. The underlying mechanisms remain largely unknown, albeit anti-glutamatergic and dopaminergic effects might be most relevant. With limited evidence of amantadine efficacy in non-traumatic pathologies, the aim of our study is to assess the effects of amantadine for neuroenhancement in non-traumatic neurointensive patients with persisting coma. Methods An investigator-initiated, monocenter, phase IIb proof of concept open-label pilot study will be carried out. Based on the Simon design, 43 adult (neuro)intensive care patients who meet the clinical criteria of persisting coma not otherwise explained and < 8 points on the Glasgow Coma Scale (GCS) will be recruited. Amantadine will be administered intravenously for five days at a dosage of 100 mg bid. The primary endpoint is an improvement of at least 3 points on the GCS. If participants present as non-responders (increase < 3 points or decrease on the GCS) within the first 48 h, the dosage will be doubled from day three to five. Secondary objectives aim to demonstrate that amantadine improves vigilance via alternative scales. Furthermore, the incidence of adverse events will be investigated and electroencephalography (EEG) will be recorded at baseline and end of treatment. Discussion The results of our study will help to systematically assess the clinical utility of amantadine for treatment of persisting coma in non-traumatic brain injury. We expect that, in the face of only moderate treatment risk, a relevant number of patients will benefit from amantadine medication by improved vigilance (GCS increase of at least 3 points) finally leading to a better rehabilitation potential and improved functional neurological outcome. Further, the EEG data will allow evaluation of brain network states in relation to vigilance and potentially outcome prediction in this study cohort. Trial Registration NCT05479032
