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A team involving our Critical Care Research Group have discovered that patients with severe illnesses treated on intensive care units often have problems with their movement and mobility long after they are discharged from hospital.
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In Vivo Quantification of Creatine Kinase Kinetics in Mouse Brain Using 31P-MRS at 7 T
31P-MRS is a method of choice for studying neuroenergetics in vivo, but its application in the mouse brain has been limited, often restricted to ultrahigh field (> 7 T) MRI scanners. Establishing its feasibility on more readily available preclinical 7-T scanners would create new opportunities to study metabolism and physiology in murine models of brain disorders. Here, we demonstrate that the apparent forward rate constant (kf) of creatine kinase (CK) can be accurately quantified using a progressive saturation-transfer approach in the mouse brain at 7 T. We also find that a 20% reduction in respiration of anesthetized mice can lead to 36% increase in kf attributable to a drop in cellular pH and mitochondrial ATP production. To achieve this, we used a test–retest analysis to assess the reliability and repeatability of 31P-MRS acquisition, analysis, and experimental design protocols. We report that many 31P-containing metabolites can be reliably measured using a localized 3D-ISIS sequence, which showed highest SNR amplitude, SNR consistency, and minimal T2 relaxation signal loss. Our study identifies key physiological factors influencing mouse brain energy homeostasis in vivo and provides a methodological basis to guide future studies interested in implementing 31P-MRS on preclinical 7-T scanners.
Dopamine D2 receptor upregulation in dorsal striatum in the LRRK2-R1441C rat model of early Parkinson's disease revealed by in vivo PET imaging.
We conducted PET imaging with [18F]FDOPA and dopamine D2/3 receptor ligand [18F]fallypride in aged transgenic rats carrying human pathogenic LRRK2 R1441C or G2019S mutations. These rats have mild age-dependent deficits in dopamine release restricted to dorsal striatum despite no overt loss of dopamine neurons or dopamine content and demonstrate L-DOPA-responsive movement deficits.LRRK2 mutant rats displayed no deficit in [18F]FDOPA uptake, consistent with intact dopamine synthesis in striatal axons. However, LRRK2-R1441C rats demonstrated greater binding of [18F]fallypride than LRRK2-G2019S or non-transgenic controls, from a regionally selective increase in dorsal striatum. Immunocytochemical labelling post-mortem confirmed a greater density of D2 receptors in LRRK2-R1441C than other genotypes restricted to dorsal striatum, consistent with upregulation of D2-receptors as a compensatory response to the greater dopamine release deficit previously demonstrated in this genotype.These results show that [18F]fallypride PET imaging is sensitive to dysregulation of dopamine signalling in the LRRK2-R1441C rat, revealing upregulation of D2 receptors that parallels observations in human putamen in early sporadic PD. Future studies of candidate therapies could exploit this non-invasive approach to assess treatment efficacy.
EARLY NEUROLOGICAL DETERIORATION IN MINOR STROKE CAUSED BY SMALL ARTERY OCCLUSION: INCIDENCE, RISK FACTORS AND TREATMENT IMPACT.
INTRODUCTION: Early neurological deterioration (END) is a forecast factor in poor outcomes in minor strokes. END's prevalence and forecast factors in minor strokes caused by small artery occlusion (SAO) are still unclear. PATIENTS AND METHOD: We retrospectively analyzed 451 patients with minor stroke (NIHSS ≤ 5) caused by SAO hospitalized within an initial 24 hours at BachMai Hospital's stroke center. END was defined as conditions with an elevated two or more NIHSS points within an initial 72 hours. The primary outcome included the determination of the END incidence. The secondary outcome identified forecast factors for END through multivariate logistic regression analyses, and therapeutic impacts of antiplatelet and thrombolytic treatments. RESULTS: END occurred in 9.5% (43/451) of patients (62.7% male, mean age 63.8±11.8 years). Independent forecast included admission SBP ≥150mmHg (OR=1.99; 95%CI:1.01-3.94;p=0.048), diabetes history (OR=0.58; 95%CI:1.05-4.33;p=0.036), admission blood glucose ≥14mmol/L (OR=2.99; 95%CI:1.05-8.54;p=0.04), and internal capsule infarction (OR=2.23; 95%CI:1.01-4.92;p=0.048). The patients group admitted within 4.5 hours, DAPT has significantly lower END risk compared to SAPT (OR=0.079; 95%CI:0.007-0.939;p=0.04) and altepase (OR=0.013; 95%CI:0.01-0.12;p<0.01). END risk was similar between SAPT and altepase (p=0.074). DISCUSSION AND CONCLUSION: END is a 9.5% incidence in minor acute ischemic stroke due to SAO. Independent forecasts are admission SBP and blood glucose, diabetes history, and internal capsule infarction. The DAPT group has significantly lower END risk than the SAPT and alteplase groups.
Dorsomedial and ventromedial prefrontal cortex lesions differentially impact social influence and temporal discounting.
The medial prefrontal cortex (mPFC) has long been associated with economic and social decision-making in neuroimaging studies. Several debates question whether different ventral mPFC (vmPFC) and dorsal mPFC (dmPFC) regions have specific functions or whether there is a gradient supporting social and nonsocial cognition. Here, we tested an unusually large sample of rare participants with focal damage to the mPFC (N = 33), individuals with lesions elsewhere (N = 17), and healthy controls (N = 71) (total N = 121). Participants completed a temporal discounting task to estimate their baseline discounting preferences before learning the preferences of two other people, one who was more temporally impulsive and one more patient. We used Bayesian computational models to estimate baseline discounting and susceptibility to social influence after learning others' economic preferences. mPFC damage increased susceptibility to impulsive social influence compared to healthy controls and increased overall susceptibility to social influence compared to those with lesions elsewhere. Importantly, voxel-based lesion-symptom mapping (VLSM) of computational parameters showed that this heightened susceptibility to social influence was attributed specifically to damage to the dmPFC (area 9; permutation-based threshold-free cluster enhancement (TFCE) p < 0.025). In contrast, lesions in the vmPFC (areas 13 and 25) and ventral striatum were associated with a preference for seeking more immediate rewards (permutation-based TFCE p < 0.05). We show that the dmPFC is causally implicated in susceptibility to social influence, with distinct ventral portions of mPFC involved in temporal discounting. These findings provide causal evidence for sub-regions of the mPFC underpinning fundamental social and cognitive processes.
Sleep-related hypermotor epilepsy in a patient with myelin-oligodendrocyte-glycoprotein antibody disease.
Unusual seizure phenotypes in myelin-oligodendrocyte-glycoprotein (MOG) seropositive patients have previously been reported, although so far, no cases of sleep-related hypermotor epilepsy (SHE). In our case, a patient with a diagnosis of MOG antibody-associated disease (MOGAD) began reporting unusual sleep disturbances; video-audio documentation was in keeping with the clinical diagnosis of SHE. MRI brain was normal at the time of the assessment for seizures. Symptoms responded to antiepileptic drugs (AEDs). These unusual seizure events were thought to be indicative of the underlying autoimmune condition, suggesting that the clinical spectrum of MOGAD is wider than previously thought.
Evaluation of an adaptation to the Oxford Cognitive Screen for reduced visual acuity: a cohort study.
BACKGROUND: The Oxford Cognitive Screen (OCS) was specifically designed for acute stroke survivors and to be inclusive of aphasia, neglect, motor impairments. However, reduced visual acuity (VA), including lack of access to required reading glasses, can impact completion rates and performance. The aim of the study was to evaluate contrast enhanced OCS-tasks for completion rates and equivalence to the original version. METHODS: Adult stroke survivors were asked to complete two versions (standard and adapted) of two tasks (broken hearts cancellation and trails) in a randomized order, to determine relative completion rates and equivalency. A bedside vision assessment, completed by an orthoptist was collected, including near and distance VA with required refractive correction if available. Two groups were created based on near VA; normal near VA (≥0.2LogMAR) and reduced near VA (<0.2LogMAR). RESULTS: Five hundred participants were recruited, 56.8% male, mean age 70.62 years. Mean near VA was 0.278 (SD0.277) LogMAR. The broken hearts and trails tasks were completed by 2.2% (p=0.041) and 0.4% (p=0.791) more participants respectively with the adapted version. Participants completing both versions with good near VA were used to analyze equivalence. All the lower and upper bounds of the two one-sided test of equivalence fell within the range of 0.5SD for all scores, indicating that the means are equivalent. Analysis of impairment detection revealed fair to good agreement. CONCLUSION: The adapted version is suitable for stroke survivors with reduced near VA to complete the assessment. In the presence of good VA, the tasks were deemed to be equivalent.
Service evaluation of having an additional CT scan for motor neurone disease patients undergoing a gastrostomy.
UNLABELLED: This article presents the findings of a 6-month service evaluation following the addition of a computed tomography (CT) abdomen scan to the gastrostomy placement pathway for patients with motor neurone disease (MND). BACKGROUND: several patients had failed percutaneous endoscopic gastrostomy (PEG) placements. A CT scan was introduced to identify if it would be possible to place a PEG or another gastrostomy such as a radiologically inserted gastrostomy (RIG). AIMS: To assess cost-effectiveness of adding a CT scan to the pathway and evaluate if it was improving patient experience. METHOD: Data from 1 February 2024 to 1 August 2024 indicated when the PEG was planned, CT outcomes and whether the gastrostomy was successful. RESULTS: Results from patients (n=19) showed changes from the CT scan for 4 patients; 18 patients had a successful gastrostomy. There were cost savings from the implementation of the CT scan. There were minimal differences reported by patients in post-procedural complications. CONCLUSION: Incorporating a CT scan before gastrostomy procedures for patients with MND can enhance planning, reduce failures, and improve patient outcomes. Cost savings were evident.
Phase-dependent closed-loop deep brain stimulation of the fornix provides bidirectional manipulation of hippocampal theta oscillations.
INTRODUCTION: Alzheimer's disease (AD) has very limited treatment options and therapies to prevent or reverse neurodegeneration remain elusive. Deep brain stimulation (DBS), whereby high-frequency pulses of electricity are delivered continuously to a specific part of the brain, has been trialled as an experimental treatment for AD. In AD patients, continuous, high frequency DBS targeted to the fornix (fx-DBS) has been shown to be safe, but not reliably effective across patients. In movement disorders, high-frequency DBS is thought to act as a virtual lesion, disrupting pathophysiological activity. In AD, it may be more advantageous to use stimulation to reinforce or rebuild oscillatory activities that are disrupted by the disease process. A primary candidate for such a target is the hippocampal theta oscillation, which provides a temporal framework for mnemonic processing and is altered in rodent models of AD. MATERIAL AND METHODS: We applied closed-loop electrical stimulation to the fornix of rats traversing a linear track, triggered by different phases of the ongoing theta oscillation in the hippocampal local field potential (LFP) using the OscillTrack algorithm. RESULTS: Stimulation at different target phases could robustly suppress or amplify the theta oscillation, and these effects were significantly larger than those caused by open-loop replay of the same stimulation pattern. Amplification of the theta oscillation could be achieved irrespective of the locomotor speed of the animal, showing that it did not result from a secondary effect of behavioural change. CONCLUSIONS: Our findings demonstrate that closed-loop fx-DBS is a viable method of modulating the amplitude of hippocampal theta oscillations that could be applied in human devices to provide a constructive intervention with the potential to boost memory circuit function in AD.
Nature documentaries vs. quiet rest: no evidence for an impact on event-related desynchronization during motor imagery and neurofeedback
Motor imagery (MI) in combination with neurofeedback (NF) has emerged as a promising approach in motor neurorehabilitation, facilitating brain activity modulation and promoting motor learning. Although MI-NF has been demonstrated to enhance motor performance and cortical plasticity, its efficacy varies considerably across individuals. Various context factors have been identified as influencing neurophysiological outcomes in motor execution and MI, however, their specific impact on event-related desynchronization (ERD), a key neurophysiological marker in NF, remains insufficiently understood. Previous research suggested that declarative interference following MI-NF may serve as a context factor hindering the progression of ERD. Yet, no significant changes in ERD within the mu and beta (8–30 Hz) frequency bands were observed across blocks in either a declarative interference or a control condition. This raises the question of whether the absence of ERD modulation could be attributed to the break task that was common to both declarative interference and control condition: watching nature documentaries immediately after MI blocks. To investigate this, we conducted a follow-up study replicating the original methodology while collecting new data. We compared NF-MI-ERD between groups with and without nature documentaries as a post-MI condition. Participants completed three sessions of kinesthetic MI-NF training involving a finger-tapping task over two consecutive days, with quiet rest as the post-MI condition (group quiet rest). 64-channel EEG data were analyzed from 17 healthy participants (8 females, 18–35 years, M and SD: 25.2 ± 4.2 years). Data were compared to a previously recorded dataset (group documentaries), in which 17 participants (10 females, 23–32 years, M and SD: 25.8 ± 2.5 years) watched nature documentaries after MI blocks. The results showed no significant main effects for blocks or group, though a session-by-group interaction was observed. Post-hoc tests, however, did not reveal significant differences in ERD development between the groups across individual blocks. These findings do not provide evidence that nature documentaries used as a post-MI condition negatively affect across-block development of NF-MI-ERD. This study highlights the importance of exploring additional context factors in MI-NF training to better understand their influence on ERD development.
High-throughput screen of 100 000 small molecules in C9ORF72 ALS neurons identifies spliceosome modulators that mobilize G4C2 repeat RNA into nuclear export and repeat associated non-canonical translation.
An intronic G4C2 repeat expansion in the C9ORF72 gene is the major known cause for Amyotrophic Lateral Sclerosis (ALS), with current evidence for both, loss of function and pathological gain of function disease mechanisms. We screened 96 200 small molecules in C9ORF72 patient iPS neurons for modulation of nuclear G4C2 RNA foci and identified 82 validated hits, including the Brd4 inhibitor JQ1 as well as novel analogs of Spliceostatin-A, a known modulator of SF3B1, the branch point binding protein of the U2-snRNP. Spliceosome modulation by these SF3B1 targeted compounds recruits SRSF1 to nuclear G4C2 RNA, mobilizing it from RNA foci into nucleocytoplasmic export. This leads to increased repeat-associated non-canonical (RAN) translation and ultimately, enhanced cell toxicity. Our data (i) provide a new pharmacological entry point with novel as well as known, publicly available tool compounds for dissection of C9ORF72 pathobiology in C9ORF72 ALS models, (ii) allowing to differentially modulate RNA foci versus RAN translation, and (iii) suggest that therapeutic RNA foci elimination strategies warrant caution due to a potential storage function, counteracting translation into toxic dipeptide repeat polyproteins. Instead, our data support modulation of nuclear export via SRSF1 or SR protein kinases as possible targets for future pharmacological drug discovery.
Neuroimaging-based data-driven subtypes of spatiotemporal atrophy due to Parkinson's disease.
Parkinson's disease is the second most common neurodegenerative disease. Despite this, there are no robust biomarkers to predict progression, and understanding of disease mechanisms is limited. We used the Subtype and Stage Inference algorithm to characterize Parkinson's disease heterogeneity in terms of spatiotemporal subtypes of macroscopic atrophy detectable on T1-weighted MRI-a successful approach used in other neurodegenerative diseases. We trained the model on covariate-adjusted cortical thicknesses and subcortical volumes from the largest known T1-weighted MRI dataset in Parkinson's disease, Enhancing Neuroimaging through Meta-Analysis consortium Parkinson's Disease dataset (n = 1100 cases). We tested the model by analyzing clinical progression over up to 9 years in openly-available data from people with Parkinson's disease from the Parkinson's Progression Markers Initiative (n = 584 cases). Under cross-validation, our analysis supported three spatiotemporal atrophy subtypes, named for the location of the earliest affected regions as: 'Subcortical' (n = 359, 33%), 'Limbic' (n = 237, 22%) and 'Cortical' (n = 187, 17%). A fourth subgroup having sub-threshold/no atrophy was named 'Sub-threshold atrophy' (n = 317, 29%). Statistical differences in clinical scores existed between the no-atrophy subgroup and the atrophy subtypes, but not among the atrophy subtypes. This suggests that the prime T1-weighted MRI delineator of clinical differences in Parkinson's disease is atrophy severity, rather than atrophy location. Future work on unravelling the biological and clinical heterogeneity of Parkinson's disease should leverage more sensitive neuroimaging modalities and multimodal data.
Collaborative care for pregnant women with eye conditions.
The management of ophthalmic conditions in pregnancy presents unique challenges that demand a nuanced approach. Significant knowledge gaps and practice variations persist, likely as a result of the infrequent nature of these issues in pregnancy, as well as the lack of crossover in the specialty training curriculum for both specialties. This commentary explores how multidisciplinary team (MDT) working can address these uncertainties to support shared decision-making and potentially improve outcomes in this vulnerable patient population. We highlight the need to involve ophthalmologists in obstetric MDTs, where appropriate, and the importance of establishing clear communication channels and referral pathways between both specialties and across hospitals in the region. We also share our experience of establishing these pathways locally, the feedback we have received from interdisciplinary educational initiatives to improve knowledge sharing, and possible future directions for this collaborative approach to help fill the evidence gap.