Search results
Found 22737 matches for
Neuroimaging-based Spatial and Circuit-level Optimization for Psychiatric Endophenotyping: NeuroSCOPE lab uses high-resolution 7T imaging to characterize motivation in depression
Alzheimer's disease patient-derived high-molecular-weight tau impairs bursting in hippocampal neurons.
Tau accumulation is closely related to cognitive symptoms in Alzheimer's disease (AD). However, the cellular drivers of tau-dependent decline of memory-based cognition remain elusive. Here, we employed in vivo Neuropixels and patch-clamp recordings in mouse models and demonstrate that tau, independent of β-amyloid, selectively debilitates complex-spike burst firing of CA1 hippocampal neurons, a fundamental cellular mechanism underpinning learning and memory. Impaired bursting was associated with altered hippocampal network activities that are coupled to burst firing patterns (i.e., theta rhythms and high-frequency ripples) and was concurrent with reduced neuronal expression of CaV2.3 calcium channels, which are essential for burst firing in vivo. We subsequently identify soluble high molecular weight (HMW) tau, isolated from human AD brain, as the tau species responsible for suppression of burst firing. These data provide a cellular mechanism for tau-dependent cognitive decline in AD and implicate a rare species of intracellular HMW tau as a therapeutic target.
Progression and life expectancy in primary lateral sclerosis
Objectives To characterise the clinical characteristics and longitudinal outcomes in primary lateral sclerosis (PLS), including median survival from symptom onset and age at death. Methods The authors retrospectively reviewed electronic health records of patients diagnosed with PLS referred to a specialised motor neuron disorders clinic from 2002 to 2024, analysed longitudinal Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) assessments using joint models and used Kaplan-Meier methods and life tables to calculate median survival and age at death compared with population-based values. Results Of 52 patients, 34 (65%) were male, 41 (79%) first noted symptoms in the lower limbs and 10 (19%) in corticobulbar function. Median age of symptom onset was 53 years. The mean annual rate of functional decline was -1.92 ALSFRS-R points (95% CI -3.03 to -0.78), with equal highest rates of decline in fine and gross motor subscores. Five patients (10%) received gastrostomy and three (6%) non-invasive ventilation. Median survival from symptom onset was 23.1 years (22.7 to not reached), and median age at death was 79.5 years (77.8 to not reached) compared with a population-based reference mean of 81.9 years (81.1 to 82.8). Discussion PLS may be commensurate with near-normal life expectancy. Significant disability arises from limb motor dysfunction, with a minority of patients requiring nutritional or respiratory support. This has important implications for counselling and trial design.
Ultra‐high temporal resolution 4D angiography using arterial spin labeling with subspace reconstruction
AbstractPurposeTo achieve ultra‐high temporal resolution non‐contrast 4D angiography with improved spatiotemporal fidelity.MethodsContinuous data acquisition using 3D golden‐angle sampling following an arterial spin labeling preparation allows for flexibly reconstructing 4D dynamic angiograms at arbitrary temporal resolutions. However, k‐space data is often temporally “binned” before image reconstruction, negatively affecting spatiotemporal fidelity and limiting temporal resolution. In this work, a subspace was extracted by linearly compressing a dictionary constructed from simulated curves of an angiographic kinetic model. The subspace was used to represent and reconstruct the voxelwise signal timecourse at the same temporal resolution as the data acquisition without temporal binning. Physiological parameters were estimated from the resulting images using a Bayesian fitting approach. A group of eight healthy subjects were scanned and the in vivo results reconstructed by different methods were compared. Because of the difficulty of obtaining ground truth 4D angiograms with ultra‐high temporal resolution, the in vivo results were cross‐validated with numerical simulations.ResultsThe proposed method enables 4D time‐resolved angiography with much higher temporal resolution (14.7 ms) than previously reported (˜50 ms) while maintaining high spatial resolution (1.1 mm isotropic). Blood flow dynamics were depicted in greater detail, thin vessel visibility was improved, and the estimated physiological parameters also exhibited more realistic spatial patterns with the proposed method.ConclusionIncorporating a subspace compressed kinetic model into the reconstruction of 4D ASL angiograms notably improved the temporal resolution and spatiotemporal fidelity, which was subsequently beneficial for accurate physiological modeling.
Early neurological deterioration in patients with minor stroke: A single-center study conducted in Vietnam
A minor ischemic stroke is associated with a higher likelihood of poor clinical outcomes at 90 days when there is early neurological deterioration (END). The objective of this case-control study conducted in a comprehensive stroke facility in Vietnam is to examine the frequency, forecast, and outcomes of patients with END in minor strokes. The study employs a descriptive observational design, longitudinally tracking patients with minor strokes admitted to Bach Mai Hospital’s Stroke Center between December 1, 2023, and August 31, 2024. Hospitalized within 24 hours of symptom onset, minor stroke patients with National Institutes of Health Stroke Scale (NIHSS) scores ≤ 5 and items 1a, 1b, and 1c on the NIHSS scale, each equal to 0, were included in the study. The primary measure of interest is the END rate, defined as a rise of 2 or more points in the NIHSS score during the first 72 hours after admission. We conduct a logistic regression analysis to identify forecasting factors for END. Out of 839 patients, 88 (10.5%) had END. In the END group, we found that most patients had complications within the first 24 hours of stroke, accounting for 43.2%; the 24 – 48-hour window accounted for 35.2%, and the 48 – 72-hour window accounted for 21.6%. END was associated with a higher likelihood of poor outcomes (mRS 2 – 6) at discharge (OR = 22.76; 95% CI 11.22 – 46.20; p < 0.01), 30 days post-stroke(OR = 24.38; 95% CI 14.40 – 41.29; p < 0.01), and 90 days post-stroke (OR = 21.74; 95% CI 12.63 – 37.43; p < 0.01). Some of the prognostic factors for END were admission NIHSS score (OR = 1.24; 95% CI 1.03 – 1.49; p = 0.02), admission systolic blood pressure greater than 150mmHg (OR = 1.70; 95% CI 1.03 – 2.81; p = 0.04), admission blood glucose (OR = 1.07; 95% CI 1.01 – 1.14; p = 0.02), reperfusion therapy (OR = 3.35; 95% CI 1.50 – 7.49; p < 0.01), use of antiplatelet monotherapy (OR = 3.69; 95% CI 2.24 – 6.08; p < 0.01), internal capsule infarction (OR = 2.54; 95% CI 1.37 – 4.71; p < 0.01), hemorrhagic transformation (OR = 5.72; 95% CI 1.07 – 30.45; p = 0.04), corresponding extracranial carotid artery occlusion (OR = 4.84; 95% CI 1.26 – 18.65; p = 0.02), and middle cerebral artery occlusion OR = 3.06; 95% CI 1.29 – 7.30; p = 0.01). END in minor stroke patients accounts for 10.5% and is a risk factor for poor neurological outcomes. Admission NIHSS score, higher systolic blood pressure, admission blood glucose, reperfusion therapy, use of antiplatelet monotherapy, internal capsule infarction, hemorrhagic transformation, corresponding extracranial carotid artery occlusion, and middle cerebral artery occlusion were some of the prognostic factors for END in our observational study.
Mapping of validated apathy scales onto the apathy diagnostic criteria for neurocognitive disorders.
BACKGROUND: Diagnostic criteria for apathy in neurocognitive disorders (DCA-NCD) have recently been updated. OBJECTIVES: We investigated whether validated scales measuring apathy severity capture the three dimensions of the DCA-NCD (diminished initiative, diminished interest, diminished emotional expression). MEASUREMENTS: Degree of mapping ("not at all", "weakly", or "strongly") between items on two commonly used apathy scales, the Neuropsychiatric Inventory-Clinician (NPI-C) apathy and Apathy Evaluation Scale (AES), with the DCA-NCD overall and its 3 dimensions was evaluated by survey. DESIGN: Survey participants, either experts (n = 12, DCA-NCD authors) or scientific community members (n = 19), rated mapping for each item and mean scores were calculated. Interrater reliability between expert and scientific community members was assessed using Cohen's kappa. RESULTS: According to experts, 9 of 11 (81.8%) NPI-C apathy items and 6 of 18 (33.3%) AES items mapped strongly onto the DCA-NCD overall. For the scientific community group, 10 of 11 (90.9%) NPI-C apathy items and 7 of 18 (38.8%) AES items mapped strongly onto the DCA-NCD overall. The overall mean mapping scores were higher for the NPI-C apathy compared to the AES for both expert (t (11) = 3.13, p = .01) and scientific community (t (17) = 3.77, p = .002) groups. There was moderate agreement between the two groups on overall mapping for the NPI-C apathy (kappa= 0.74 (0.57, 1.00)) and AES (kappa= 0.63 (0.35, 1.00)). CONCLUSIONS: More NPI-C apathy than AES items mapped strongly and uniquely onto the DCA-NCD and its dimensions. The NPI-C apathy may better capture the DCA-NCD and its dimensions compared with the AES.
Implementation of pay for performance in primary care: a qualitative study 8 years after introduction.
BACKGROUND: Pay for performance is now a widely adopted quality improvement initiative in health care. One of the largest schemes in primary care internationally is the English Quality and Outcomes Framework (QOF). AIM: To obtain a longer term perspective on the implementation of the QOF. DESIGN AND SETTING: Qualitative study with 47 health professionals in 23 practices across England. Method Semi-structured interviews. RESULTS: Pay for performance is accepted as a routine part of primary care in England, with previous more individualistic and less structured ways of working seen as poor practice. The size of the QOF and the evidence-based nature of the indicators are regarded as key to its success. However, pay for performance may have had a negative impact on some aspects of medical professionalism, such as clinical autonomy, and led a significant minority of GPs to prioritise their own pay rather than patients' best interests. A small minority of GPs tried to increase their clinical autonomy with further unintended consequences. CONCLUSION: Pay for performance indicators are now welcomed by primary healthcare teams and GPs across generations. Almost all interviewees wanted to see a greater emphasis on involving front line practice teams in developing indicators. However, almost all GPs and practice managers described a sense of decreased clinical autonomy and loss of professionalism. Calibrating the appropriate level of clinical autonomy is critical if pay for performance schemes are to have maximal impact on patient care.
Quantifying axonal features of human superficial white matter from three-dimensional multibeam serial electron microscopy data assisted by deep learning.
Short-range association fibers located in the superficial white matter play an important role in mediating higher-order cognitive function in humans. Detailed morphological characterization of short-range association fibers at the microscopic level promises to yield important insights into the axonal features driving cortico-cortical connectivity in the human brain yet has been difficult to achieve to date due to the challenges of imaging at nanometer-scale resolution over large tissue volumes. This work presents results from multi-beam scanning electron microscopy (EM) data acquired at 4 × 4 × 33 nm3 resolution in a volume of human superficial white matter measuring 200 × 200 × 112 μm (Braitenberg and Schüz, 2013), leveraging automated analysis methods. Myelin and myelinated axons were automatically segmented using deep convolutional neural networks (CNNs), assisted by transfer learning and dropout regularization techniques. A total of 128,285 myelinated axons were segmented, of which 70,321 and 2,102 were longer than 10 and 100 μm, respectively. Marked local variations in diameter (i.e., beading) and direction (i.e., undulation) were observed along the length of individual axons. Myelinated axons longer than 10 μm had inner diameters around 0.5 µm, outer diameters around 1 µm, and g-ratios around 0.5. This work fills a gap in knowledge of axonal morphometry in the superficial white matter and provides a large 3D human EM dataset and accurate segmentation results for a variety of future studies in different fields.
The profile of gastrointestinal dysfunction in prodromal to late-stage Parkinson's disease.
Gastrointestinal dysfunction (GID) may play a key role in Parkinson's disease (PD) but its relationship with disease progression remains unclear. We recruited 404 PD cases, 37 iRBD (isolated REM Sleep Behaviour Disorder) and 105 controls. Participants completed the Gastrointestinal Dysfunction Scale for PD (GIDS-PD) and standardised disease severity assessments. Whole gut transit time (WGTT) was measured by ingestion of blue dye and recorded time to blue stools appearance ('Blue Poop Challenge') in a subset of PD cases. Gastrointestinal symptoms were more common and prevalent in iRBD and PD versus controls, and WGTT was significantly higher in PD versus controls. After adjustment for confounding factors, disease stage was not a significant predictor of GIDS-PD Constipation or Bowel Irritability scores. Longitudinal assessment of GIDS-PD scores and WGTT confirmed stability over a 4 year period. Bowel dysfunction may be a phenotypic feature in a subset of Parkinson's with implications for patient stratification and management.
Advancing atmospheric solids analysis probe mass spectrometry applications: a multifaceted approach to optimising clinical data set generation.
The use of rapid mass spectrometry techniques, such as atmospheric-solids-analysis-probe mass spectrometry (ASAP-MS), in the analysis of metabolite patterns in clinical samples holds significant promise for developing new diagnostic tools and enabling rapid disease screening. The rapid measurement times, ease of use, and relatively low cost of ASAP-MS makes it an appealing option for use in clinical settings. However, despite the potential of such approaches, a number of important experimental considerations are often overlooked. As well as instrument-specific choices and settings, these include the treatment of background noise and/or contaminant peaks in the mass spectra, and the influence of consumables, different users, and batch effects more generally. The present study assesses the impact of these various factors on measurement accuracy and reproducibility, using human brain and cerebrospinal fluid samples as examples. Based on our results, we make a series of recommendations relating to optimisation of measurement and cleaning protocols, consumable selection, and batch effect detection and correction, in order to optimise the reliability and reproducibility of ASAP-MS measurements in clinical settings.
ZFP36-family RNA-binding proteins in regulatory T cells reinforce immune homeostasis
RNA binding proteins (RBP) of the ZFP36 family limit the differentiation and effector functions of CD4 and CD8 T cells, but little is known of their expression or function in regulatory T (Treg) cells. By using Treg cell-restricted deletion of Zfp36 family members we identify the role of Zfp36l1 and Zfp36l2 in Treg cells to maintain immune homeostasis. Mice with Treg cells deficient in these RBP display an inflammatory phenotype with an expansion in the numbers of type-2 conventional dendritic cells, T effector cells, T follicular helper and germinal center B cells and elevated serum cytokines and immunoglobulins. In the absence of Zfp36l1 and Zfp36l2, the pool of cycling CTLA-4 in naïve Treg cells is reduced, Treg cells are less sensitive to IL-2 and IL-7 but are more sensitive to IFNγ. In mice lacking both RBP in Treg cells, the deletion of a single allele of Ifng is sufficient to ameliorate the pathology. Our results indicate that ZFP36L1 and ZFP36L2 regulate the availability of IFNγ and are required for the maintenance of Treg cell stability. Thus, ZFP36L1 and ZFP36L2 regulate multiple pathways that enable Treg cells to enforce immune homeostasis.
Case report on severe myelin oligodendrocyte glycoprotein antibody-associated disease relapse after ectopic pregnancy and laparoscopic medical abortion: relevance of peripheral inflammation for demyelinating disease activity.
BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare neurological condition. Tubal ectopic pregnancy is an important cause of maternal morbidity and mortality worldwide. Regular pregnancy has a disease-modifying effect on MOGAD, with an increased relapse rate postpartum. Still, there are neither case reports nor cohort studies on abortions and ectopic pregnancy as a disease-modifying event for MOGAD. MATERIALS AND METHODS: This is a case report on a severe MOGAD relapse after ectopic pregnancy and laparoscopic abortion. DISCUSSION: For the first time we described that elevated interleukin-1 (IL-1), which was found in cerebrospinal fluid in the current case may be pathogenetically related to ectopic pregnancy. Rituximab (anti-CD20 treatment), downregulated IL-1 and TNF-alfa inflammatory pathways thus is an appropriate drug of choice to treat relapse. Cytokines secreted during ectopic pregnancy could play a disease-modifying role in multiple sclerosis and Guillian-Barré syndrome. CONCLUSION: The first case report of a MOGAD severe relapse after ectopic pregnancy and laparoscopic abortion which resolved with rituximab treatment.
