BACKGROUND: The initiation of early non-invasive ventilation (NIV) often involves a careful balance between tolerance and effectiveness. In amyotrophic lateral sclerosis (ALS) patients, the establishment of a strategy, including the decision to focus on adhering to a cut-off, setting specific targets, or correcting all events, is crucial.
OBJECTIVE: To identify factors at 1 month after early at-home NIV initiation that are associated with improved survival in ALS patients. We explored the impacts of adherence (ADH), quality of treatment, and NIV parameters at 1 month after early at-home NIV initiation on patient survival.
METHODS: We conducted a retrospective study of 184 ALS patients at the Bordeaux ALS Centre for whom NIV was initiated between September 2017 and June 2021, and we collected data for a minimum period of 2 years after the last patient included. The primary outcome was the risk of death according to baseline characteristics of our population and the NIV parameters and monitoring during the early NIV initiation period. The secondary outcomes were association with NIV ADH during the early NIV initiation period on prognosis, and NIV ADH cut-off for good versus poor prognosis.
RESULTS: Among the 178 ALS patients analysed, we found that quality of NIV treatment and device settings did not significantly influence prognosis. However, low ADH was significantly associated with a higher risk of death. The use of NIV for > 5 h/day during the early NIV initiation period was linked to a decreased risk of death [hazard ratio = 0.4; 95% confidence interval: 0.27-0.9].
CONCLUSIONS: The use of NIV for > 5 h/day during the early NIV initiation period was associated with increased survival.

BACKGROUND: Robust predictive models of clinical impairment and worsening in multiple sclerosis (MS) are needed to identify patients at risk and optimize treatment strategies.
OBJECTIVE: To evaluate whether machine learning (ML) methods can classify clinical impairment and predict worsening in people with MS (pwMS) and, if so, which combination of clinical and magnetic resonance imaging (MRI) features and ML algorithm is optimal.
METHODS: We used baseline clinical and structural MRI data from two MS cohorts (Berlin: n = 125, Amsterdam: n = 330) to evaluate the capability of five ML models in classifying clinical impairment at baseline and predicting future clinical worsening over a follow-up of 2 and 5 years. Clinical worsening was defined by increases in the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk Test (T25FW), 9-Hole Peg Test (9HPT), or Symbol Digit Modalities Test (SDMT). Different combinations of clinical and volumetric MRI measures were systematically assessed in predicting clinical outcomes. ML models were evaluated using Monte Carlo cross-validation, area under the curve (AUC), and permutation testing to assess significance.
RESULTS: The ML models significantly determined clinical impairment at baseline for the Amsterdam cohort, but did not reach significance for predicting clinical worsening over a follow-up of 2 and 5 years. High disability (EDSS ≥ 4) was best determined by a support vector machine (SVM) classifier using clinical and global MRI volumes (AUC = 0.83 ± 0.07, p = 0.015). Impaired cognition (SDMT Z-score ≤ -1.5) was best determined by a SVM using regional MRI volumes (thalamus, ventricles, lesions, and hippocampus), reaching an AUC of 0.73 ± 0.04 (p = 0.008).
CONCLUSIONS: ML models could aid in classifying pwMS with clinical impairment and identify relevant biomarkers, but prediction of clinical worsening is an unmet need.

Repetitive transcranial magnetic stimulation (rTMS) is a therapeutic strategy that shows promise in ameliorating the clinical sequelae following traumatic brain injury (TBI). These improvements are associated with neuroplastic changes in neurons and their synaptic connections. However, it has been hypothesized that rTMS may also modulate microglia and astrocytes, potentially potentiating their neuroprotective capabilities. This study aims to investigate the effects of high-frequency rTMS on microglia and astrocytes that may contribute to its neuroprotective effects. Feeney\'s weight-dropping method was used to establish rat models of moderate TBI. To evaluate the neuroprotective effect of high frequency rTMS on rats by observing the synaptic ultrastructure and the level of neuron apoptosis. The levels of several important inflammation-related proteins within microglia and astrocytes were assessed through immunofluorescence staining and western blot. Our findings demonstrate that injured neurons can be rescued through the modulation of microglia and astrocytes by rTMS. This modulation plays a key role in preserving the synaptic ultrastructure and inhibiting neuronal apoptosis. Among microglia, we observed that rTMS inhibited the levels of proinflammatory factors (CD16, IL-6 and TNF-α) and promoted the levels of anti-inflammatory factors (CD206, IL-10 and TNF-β). rTMS also reduced the levels of pyroptosis within microglia and pyroptosis-related proteins (NLRP3, Caspase-1, GSDMD, IL-1β and IL-18). Moreover, rTMS downregulated P75NTR expression and up-regulated IL33 expression in astrocytes. These findings suggest that regulation of microglia and astrocytes is the mechanism through which rTMS attenuates neuronal inflammatory damage after moderate TBI.

UNASSIGNED: Migraine is a prevalent headache disorder with a significant impact on the quality of life. This study aims to investigate the effectiveness and safety of erenumab, mAb targeting the CGRP receptor, in treating chronic (CM) and episodic (EM) migraine in clinical practice Kuwait, providing region-specific insights to treatment options.
UNASSIGNED: This was a prospective observational cohort study of patients diagnosed with EM or CM treated with erenumab. The primary outcome of the study was to assess the proportion of patients achieving ≥ 50% reduction in monthly mean migraine days, and several changes including the mean number of monthly migraine days, the frequency of analgesic use, attack severity, AEs, and QoL.
UNASSIGNED: The study included 151 patients with a mean age of 44.0±11.4 years, and 81.9% female. The primary outcome was achieved in 74.2% of patients, with a significant (p < 0.001) reduction in headache frequency, pain severity, analgesic use, and improvement in QoL. Age and duration of migraine were significant predictors of achieving a ≥ 50% reduction in headache frequency after therapy (OR = 0.955; p = 0.009) and (OR = 0.965; p = 0.025), respectively. Treatment compliance was observed in 76.2% of patients, and 24.5% discontinued treatment. Constipation was the most commonly reported AEs (6.0%), and conservative management was the most common approach to managing AEs.
UNASSIGNED: Erenumab was effective in reducing the frequency and severity of migraine attacks and improving QoL, and safe with manageable AEs in a real-world setting in Kuwait. Further research is needed to better understand erenumab\'s effectiveness and safety in different populations and settings, as well as to compare it with other migraine prophylactic treatments.

BACKGROUND Papillary fibroelastoma is the most common type of benign primary cardiac tumor and is usually asymptomatic. However, tumor fragments or surface thrombus can embolize and cause transient ischemic attacks, strokes, or myocardial infarction. This report describes a 76-year-old woman who presented with dysarthria and right-sided weakness due to a stroke associated with a left atrial papillary fibroelastoma. CASE REPORT A 76-year-old woman visited the Emergency Department because she had right-sided weakness and dysarthria from 12 h ago. Brain magnetic resonance image was done at the Emergency Department, showing multiple small embolic, acute infarction in left basal ganglia and fronto-temporo-parietal lobes. Transthoracic and transesophageal echocardiogram showed a hypermobile echogenic mass (0.8×1.5 cm) with villous surface on the orifice of left atrial appendage. Twenty-four-hour Holter monitoring was performed to evaluate the cause of cerebral infarction, and there was no paroxysmal atrial fibrillation. Thoracic computed tomography angiography also showed a sea anemone-shaped mass around the left atrial appendage. Cardiac tumor excision was done via a lower partial sternotomy. Histopathologic analysis showed multiple delicate fronds, and the avascular fibroelastic cores were lined by a single layer of CD31-positive endothelial cells. Histopathologic findings were consistent with papillary fibroelastoma. The patient was discharged without any other complications on day 30 of hospitalization. CONCLUSIONS This case highlights the importance of cardiac imaging in patients with acute stroke, including transthoracic and transesophageal echocardiography, which can show the typical imaging features of papillary fibroelastoma and other intracardiac sources of embolus.

BACKGROUND: Aim of this study was to detect predictors of better adherence to the AgeWell.de-intervention, a two-year randomized multi-domain lifestyle intervention against cognitive decline.
METHODS: Data of 317 intervention group-participants comprising a risk group for dementia (Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) score of  ≥ 9; mean age 68.9 years, 49.5% women) from the AgeWell.de intervention study were analysed. Regression models with four blocks of predictors (sociodemographic, cognitive and psychosocial, lifestyle factors and chronic conditions) were run on adherence to the components of nutrition, enhancement of social and physical activity and cognitive training. Adherence to each component was operationalised by assessing the degree of goal achievement per component at up to seven time points during the intervention period, measured using a 5-point Likert scale (mean score of goal achievement).
RESULTS: Increasing age was negatively associated with adherence, while higher education positively predicted adherence. Participants with better mental state (Montreal Cognitive Assessment (MoCA)-score > 25) at baseline and higher self-efficacy adhered better. Diabetes and cardiovascular conditions were not associated with adherence, whereas smoking negatively affected adherence. Highest education and quitting smoking in the past were the only predictors associated with all four intervention components.
CONCLUSIONS: Results identified predictors for better and worse adherence. Particularly self-efficacy seems to be of considerable influence on adherence. This should be considered when designing future intervention trials.
BACKGROUND: German Clinical Trials Register (ref. number: DRKS00013555).

BACKGROUND: Lipid droplet (LD)-laden microglia is a key pathological hallmark of multiple sclerosis. The recent discovery of this novel microglial subtype, lipid-droplet-accumulating microglia (LDAM), is notable for increased inflammatory factor secretion and diminished phagocytic capability. Lipophagy, the autophagy-mediated selective degradation of LDs, plays a critical role in this context. This study investigated the involvement of microRNAs (miRNAs) in lipophagy during demyelinating diseases, assessed their capacity to modulate LDAM subtypes, and elucidated the potential underlying mechanisms involved.
METHODS: C57BL/6 mice were used for in vivo experiments. Two weeks post demyelination induction at cervical level 4 (C4), histological assessments and confocal imaging were performed to examine LD accumulation in microglia within the lesion site. Autophagic changes were observed using transmission electron microscopy. miRNA and mRNA multi-omics analyses identified differentially expressed miRNAs and mRNAs under demyelinating conditions and the related autophagy target genes. The role of miR-223 in lipophagy under these conditions was specifically explored. In vitro studies, including miR-223 upregulation in BV2 cells via lentiviral infection, validated the bioinformatics findings. Immunofluorescence staining was used to measure LD accumulation, autophagy levels, target gene expression, and inflammatory mediator levels to elucidate the mechanisms of action of miR-223 in LDAM.
RESULTS: Oil Red O staining and confocal imaging revealed substantial LD accumulation in the demyelinated spinal cord. Transmission electron microscopy revealed increased numbers of autophagic vacuoles at the injury site. Multi-omics analysis revealed miR-223 as a crucial regulatory gene in lipophagy during demyelination. It was identified that cathepsin B (CTSB) targets miR-223 in autophagy to integrate miRNA, mRNA, and autophagy gene databases. In vitro, miR-223 upregulation suppressed CTSB expression in BV2 cells, augmented autophagy, alleviated LD accumulation, and decreased the expression of the inflammatory mediator IL-1β.
CONCLUSIONS: These findings indicate that miR-223 plays a pivotal role in lipophagy under demyelinating conditions. By inhibiting CTSB, miR-223 promotes selective LD degradation, thereby reducing the lipid burden and inflammatory phenotype in LDAM. This study broadens the understanding of the molecular mechanisms of lipophagy and proposes lipophagy induction as a potential therapeutic approach to mitigate inflammatory responses in demyelinating diseases.

BACKGROUND: Aging and sex are major risk factors for developing late-onset Alzheimer\'s disease. Compared to men, women experience worse neuropathological burden and cognitive decline despite living longer with the disease. Similarly, male 3xTg-AD mice, developed to model Alzheimer\'s disease, no longer consistently exhibit standard Alzheimer\'s neuropathology yet experience higher rates of mortality - providing a unique opportunity to further elucidate this dichotomy. We hypothesized that sex differences in the biological aging process yield distinct pathological and molecular Alzheimer\'s disease signatures in males and females, which could be harnessed for therapeutic and biomarker development.
METHODS: We aged male and female, 3xTg-AD and B6129 control mice across their respective lifespans (n = 3-8 mice per sex, strain, and age group) and longitudinally assessed neuropathological hallmarks of Alzheimer\'s disease, markers of hepatic inflammation, splenic mass and morphology, as well as plasma cytokine levels. We conducted RNA sequencing analysis on bulk brain tissue and examined differentially expressed genes (DEGs) between 3xTg-AD and B6129 samples and across ages in each sex. We also examined DEGs between clinical Alzheimer\'s and control parahippocampal gyrus brain tissue samples from the Mount Sinai Brain Bank study in each sex.
RESULTS: 3xTg-AD females significantly outlived 3xTg-AD males and exhibited progressive Alzheimer\'s neuropathology, while 3xTg-AD males demonstrated progressive hepatic inflammation, splenomegaly, circulating inflammatory proteins, and minimal Alzheimer\'s neuropathological hallmarks. Instead, 3xTg-AD males experienced an accelerated upregulation of immune-related gene expression in the brain relative to females. Our clinical investigations revealed that individuals with Alzheimer\'s disease develop similar sex-specific alterations in neuronal and immune function. In diseased males of both species, we observed greater upregulation of complement-related gene expression, and lipopolysaccharide was predicted as the top upstream regulator of DEGs.
CONCLUSIONS: Our data demonstrate that chronic inflammation and complement activation are associated with increased mortality, indicating that age-related changes in immune response contribute to sex differences in Alzheimer\'s disease trajectories. We provide evidence that aging and transgene-driven disease progression trigger a widespread inflammatory response in 3xTg-AD males, which mimics the impact of lipopolysaccharide stimulation despite the absence of infection.

BACKGROUND: Migraine has been associated with mental disorders, however whether parental migraine is associated with an increased risk of major mental disorders (MMDs) in offspring has not been investigated. We aimed to examine the risk of the development of MMDs in the offspring of parents with migraine compared with those of parents without migraine.
METHODS: This study used data derived from the Taiwan National Health Insurance Research Database. Offspring of parents with migraine and a control group consisting of offspring of parents without migraine matched for demographic and parental mental disorders were included. Cox regression was used to estimate the risk of MMDs, including schizophrenia, depressive disorder, bipolar disorder, autistic spectrum disorder (ASD), and attention deficit/hyperactivity disorder (ADHD). Sub-analyses stratified by the fathers and mothers were further performed to separately clarify the risks of MMDs among the offspring.
RESULTS: We included 22,747 offspring of parents with migraine and 227,470 offspring of parents without migraine as the controls. Parental migraine was significantly associated with an increased risk of ADHD (reported as hazard ratios with 95% confidence intervals: 1.37, 1.25-1.50), bipolar disorder (1.35, 1.06-1.71), and depressive disorder (1.33, 1.21-1.47) compared to the offspring of parents without migraine. Importantly, sub-analyses showed that only maternal migraine was significantly associated with these risks.
CONCLUSIONS: Due to the heavy burden of MMDs, healthcare workers should be aware of the risk of MMDs in the offspring of parents with migraine, particular in mothers.

BACKGROUND: Studies suggest that cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)42 and Aβ40 present a circadian rhythm. However sustained sampling of large volumes of CSF with indwelling intrathecal catheters used in most of these studies might have affected CSF dynamics and thereby confounded the observed fluctuations in the biomarker levels.
METHODS: We included 38 individuals with either normal (N = 20) or abnormal (N = 18) CSF Aβ42/Aβ40 levels at baseline. CSF and plasma were collected at two visits separated by an average of 53 days with lumbar punctures and venipunctures performed either in the morning or evening. At the first visit, sample collection was performed in the morning for 17 participants and the order was reversed for the remaining 21 participants. CSF and plasma samples were analyzed for Alzheimer\' disease (AD) biomarkers, including Aβ42, Aβ40, GFAP, NfL p-tau181, p-tau217, p-tau231 and t-tau. CSF samples were also tested using mass spectrometry for 22 synaptic and endo-lysosomal proteins.
RESULTS: CSF Aβ42 (mean difference [MD], 0.21 ng/mL; p = 0.038), CSF Aβ40 (MD, 1.85 ng/mL; p < 0.001), plasma Aβ42 (MD, 1.65 pg/mL; p = 0.002) and plasma Aβ40 (MD, 0.01 ng/mL, p = 0.002) were increased by 4.2-17.0% in evening compared with morning samples. Further, CSF levels of 14 synaptic and endo-lysosomal proteins, including neurogranin and neuronal pentraxin-1, were increased by 4.5-13.3% in the evening samples (MDrange, 0.02-0.56 fmol/µl; p < 0.042). However, no significant differences were found between morning and evening levels for the Aβ42/Aβ40 ratio, different p-tau variants, GFAP and NfL. There were no significant interaction between sampling time and Aβ status for any of the biomarkers, except that CSF t-tau was increased (by 5.74%) in the evening samples compared to the morning samples in Aβ-positive (MD, 16.46 ng/ml; p = 0.009) but not Aβ-negative participants (MD, 1.89 ng/ml; p = 0.47). There were no significant interactions between sampling time and order in which samples were obtained.
CONCLUSIONS: Our findings provide evidence for diurnal fluctuations in Aβ peptide levels, both in CSF and plasma, while CSF and plasma p-tau, GFAP and NfL were unaffected. Importantly, Aβ42/Aβ40 ratio remained unaltered, suggesting that it is more suitable for implementation in clinical workup than individual Aβ peptides. Additionally, we show that CSF levels of many synaptic and endo-lysosomal proteins presented a diurnal rhythm, implying a build-up of neuronal activity markers during the day. These results will guide the development of unified sample collection procedures to avoid effects of diurnal variation for future implementation of AD biomarkers in clinical practice and drug trials.