Blood-based CNS regionally and neuronally enriched extracellular vesicles carrying pTau217 for Alzheimer's disease diagnosis and differential diagnosis.

Accurate differential diagnosis among various dementias is crucial for effective treatment of Alzheimer's disease (AD). The study began with searching for novel blood-based neuronal extracellular vesicles (EVs) that are more enriched in the brain regions vulnerable to AD development and progression. With extensive proteomic profiling, GABRD and GPR162 were identified as novel brain regionally enriched plasma EVs markers. The performance of GABRD and GPR162, along with the AD molecule pTau217, was tested using the self-developed and optimized nanoflow cytometry-based technology, which not only detected the positive ratio of EVs but also concurrently presented the corresponding particle size of the EVs, in discovery (n = 310) and validation (n = 213) cohorts. Plasma GABRD+- or GPR162+-carrying pTau217-EVs were significantly reduced in AD compared with healthy control (HC). Additionally, the size distribution of GABRD+- and GPR162+-carrying pTau217-EVs were significantly different between AD and non-AD dementia (NAD). An integrative model, combining age, the number and corresponding size of the distribution of GABRD+- or GPR162+-carrying pTau217-EVs, accurately and sensitively discriminated AD from HC [discovery cohort, area under the curve (AUC) = 0.96; validation cohort, AUC = 0.93] and effectively differentiated AD from NAD (discovery cohort, AUC = 0.91; validation cohort, AUC = 0.90). This study showed that brain regionally enriched neuronal EVs carrying pTau217 in plasma may serve as a robust diagnostic and differential diagnostic tool in both clinical practice and trials for AD.

Cationic Hypervalent Chalcogen Bond Catalysis on the Povarov Reaction: Reactivity and Stereoselectivity.

Chalcogen bond catalysis, particularly cationic hypervalent chalcogen bond catalysis, is considered to be an effective strategy for organocatalysis. In this work, the cationic hypervalent chalcogen bond catalysis for the Povarov reaction between N-benzylideneaniline and ethyl vinyl ether was investigated by density functional theory (DFT). The catalytic reaction involves the cycloaddition process and the proton transfer process, and the rate-determining step is the cycloaddition process. Cationic hypervalent tellurium derivatives bearing CF3 and F groups exhibit superior catalytic activity. For the rate-determining step, the Gibbs free energy barrier decreases as the positive electrostatic potential of the chalcogen bond catalysts increases. More importantly, the Gibbs free energy barrier has a strong linear correlation with the electrostatic energy of the chalcogen bond in the catalyst-substrate complex. Furthermore, the catalytic reactions include the endo pathway and exo pathway. The C-H⋅⋅⋅π interaction between the substituent of the ethyl vinyl ether and the aryl ring of the N-benzylideneaniline contributes to the endo-selectivity of the reaction. This research contributes to a deeper understanding of chalcogen bond catalysis, providing insights for designing chalcogen bond catalysts with high performance.

Association between plasma CTRPs with cognitive impairment and neurodegeneration of Alzheimer's disease.

AIMS: Recent evidence indicated the biological basis of complement 1q (C1q)/tumor necrosis factor (TNF)-related protein (CTRP) 3, 4, and 14 for affecting brain structure and cognitive function. Thus, we aimed to investigate the association between plasma CTRPs with Alzheimer's disease (AD). METHODS: A multicenter, cross-sectional study recruited patients with AD (n = 137) and cognitively normal (CN) controls (n = 140). After the data collection of demographic characteristics, lifestyle risk factors, and medical history, plasma levels of tau phosphorylated at threonine 217 (pT217), pT181, neurofilament light (NfL), CTRP3, 4, and 14 were examined and compared. Multivariate logistic regression analysis was applied to determine associations of plasma CTPRs with the presence of AD. The correlation analysis was used to explore correlations between plasma CTPRs with scores of Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Activities of Daily Living (ADL) scale, and Clinical Dementia Rating Sum of Boxes (CDR-SB), and levels of plasma pT217, pT181, and NfL. Receiver-operating characteristic (ROC) analysis and Delong's test were used to determine the diagnostic power of plasma CTPRs. RESULTS: Plasma levels of CTRP3, 4, and 14 were higher in AD group than those in CN group. After adjusting for conventional risk factors, CTRP3, CTRP4, and CTRP14 were associated with the presence of AD. In AD patients, CTRP3 was negatively correlated with scores of MMSE and MoCA, while positively correlated with ADL score, CDR-SB score, pT217, and pT181; CTRP4 was positively correlated with CDR-SB score, pT181, and NfL; CTRP14 was negatively correlated with MMSE score, while positively correlated with CDR-SB score, pT217, and NfL. An independent addition of CTRP3 and 4 to the basic model combining age, sex, years of education, APOE4 status, BMI, TG, and HDL-C led to a significant improvement in diagnostic power for AD, respectively. CONCLUSIONS: All the findings preliminarily uncovered associations between plasma CTRPs and AD and suggested the potential of CTRPs as a blood-derived biomarker for AD.

Therapeutics for neurodegenerative diseases by targeting the gut microbiome: from bench to bedside.

The aetiologies and origins of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), are complex and multifaceted. A growing body of evidence suggests that the gut microbiome plays crucial roles in the development and progression of neurodegenerative diseases. Clinicians have come to realize that therapeutics targeting the gut microbiome have the potential to halt the progression of neurodegenerative diseases. This narrative review examines the alterations in the gut microbiome in AD, PD, ALS and HD, highlighting the close relationship between the gut microbiome and the brain in neurodegenerative diseases. Processes that mediate the gut microbiome-brain communication in neurodegenerative diseases, including the immunological, vagus nerve and circulatory pathways, are evaluated. Furthermore, we summarize potential therapeutics for neurodegenerative diseases that modify the gut microbiome and its metabolites, including diets, probiotics and prebiotics, microbial metabolites, antibacterials and faecal microbiome transplantation. Finally, current challenges and future directions are discussed.

Operative management of sacroiliac joint dislocation in children with unstable pelvic fractures - A STROBE-compliant investigation.

Objective: Injuries involving severe spinal axial loading may be accompanied by sacroiliac joint dislocations. In children, these injuries are relatively rare, and there is little information on their optimal management in young patients. We conducted a multicentre study to investigate the outcome of surgical treatment of unstable pelvic fracture with sacroiliac joint dislocation in children. Patients & methods: We assessed the quality of surgical reduction and functional outcome at follow-up in 7 patients (5 girls, 2 boys) with a median age of 6.4 years (range: 4.2-14.8 years). Patients with pelvic fractures and sacroiliac joint dislocations were treated at four international paediatric level 1 trauma centres between January 2008 and August 2023. We applied the Matta criteria to assess the quality of fracture reduction and graded the functional follow-up results using adjusted Majeed score. Results: At follow-up, 3 patients showed excellent fracture reduction, with 2 patients showing good reduction and 2 patients exhibiting fair fracture reduction according to the Matta criteria. At follow-up visits at a median of 12 months (range: 3-84 months) after the injury, patients achieved a median adjusted Majeed score of 76 (range: 63 to 76). Conclusions: Unstable pelvic injuries with sacroiliac joint dislocation without comminution can be stabilised with a single iliosacral screw in children. Comminuted pelvic fractures with unstable sacroiliac dislocation require stabilisation with lateral compression screws or plates. In case of residual pelvic instability after internal fixation, an additional external fixator or pelvic hammock should be applied to optimize the stability of fixation.

Spatial memory requires hypocretins to elevate medial entorhinal gamma oscillations.

The hypocretin (Hcrt) (also known as orexin) neuropeptidic wakefulness-promoting system is implicated in the regulation of spatial memory, but its specific role and mechanisms remain poorly understood. In this study, we revealed the innervation of the medial entorhinal cortex (MEC) by Hcrt neurons in mice. Using the genetically encoded G-protein-coupled receptor activation-based Hcrt sensor, we observed a significant increase in Hcrt levels in the MEC during novel object-place exploration. We identified the function of Hcrt at presynaptic glutamatergic terminals, where it recruits fast-spiking parvalbumin-positive neurons and promotes gamma oscillations. Bidirectional manipulations of Hcrt neurons' projections from the lateral hypothalamus (LHHcrt) to MEC revealed the essential role of this pathway in regulating object-place memory encoding, but not recall, through the modulation of gamma oscillations. Our findings highlight the significance of the LHHcrt-MEC circuitry in supporting spatial memory and reveal a unique neural basis for the hypothalamic regulation of spatial memory.

Difference of ventricular synchrony between LBBP, LBFP and LVSP: A speckle tracking echocardiographic study.

PURPOSE: Left bundle branch area pacing (LBBAP) has emerged as a physiological and stable form of pacing. We aim to compare the mechanical ventricular synchrony of LBBP, LBFP, and LVSP. METHODS: Proximal Left bundle branch pacing (LBBP), left bundle fascicular pacing (LBFP) and left ventricular septal pacing (LVSP) were identified in patients with bradycardia who successfully underwent LBBAP. Patients with left ventricular ejection fraction (LVEF) < 50% or QRS duration (QRSd) ≥ 120 ms were excluded. By using electrocardiograms, the left ventricular activation time (LVAT) and QRS duration (QRSd) were measured to examine electrophysiological synchrony. As indications of mechanical synchrony, global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), and peak strain dispersion (PSD) were evaluated by using 2-dimensional speckle tracking echocardiography (2D-STE). RESULTS: In 56 patients, data were collected during LBBP (n = 18), LBFP (n = 16), and LVSP (n = 22). LVSP resulted in a longer LVAT (91.3 ± 14.9 ms) than LBBP (77.1 ± 10.8 ms, P < 0.05) and LBFP (72.1 ± 9.6 ms, P < 0.05), but all three groups had similar QRSd. There were no differences in GLS, GCS, GRS, or PSD between LBBP, LBFP, and LVSP. CONCLUSIONS: In patients with normal cardiac function and narrow QRS, though LBBAP with LBB capture resulted in better electrophysiological synchrony than without, the mechanical synchrony of the three groups was comparable.

Intermittent Theta Burst Stimulation Attenuates Cognitive Deficits and Alzheimer's Disease-Type Pathologies via ISCA1-Mediated Mitochondrial Modulation in APP/PS1 Mice.

Intermittent theta burst stimulation (iTBS), a time-saving and cost-effective repetitive transcranial magnetic stimulation regime, has been shown to improve cognition in patients with Alzheimer's disease (AD). However, the specific mechanism underlying iTBS-induced cognitive enhancement remains unknown. Previous studies suggested that mitochondrial functions are modulated by magnetic stimulation. Here, we showed that iTBS upregulates the expression of iron-sulfur cluster assembly 1 (ISCA1, an essential regulatory factor for mitochondrial respiration) in the brain of APP/PS1 mice. In vivo and in vitro studies revealed that iTBS modulates mitochondrial iron-sulfur cluster assembly to facilitate mitochondrial respiration and function, which is required for ISCA1. Moreover, iTBS rescues cognitive decline and attenuates AD-type pathologies in APP/PS1 mice. The present study uncovers a novel mechanism by which iTBS modulates mitochondrial respiration and function via ISCA1-mediated iron-sulfur cluster assembly to alleviate cognitive impairments and pathologies in AD. We provide the mechanistic target of iTBS that warrants its therapeutic potential for AD patients.

Disease trajectories in older adults with non-AD pathologic change and comparison with Alzheimer's disease pathophysiology: A longitudinal study.

Based on the 'AT(N)' system, individuals with normal amyloid biomarkers but abnormal tauopathy or neurodegeneration biomarkers are classified as non-Alzheimer's disease (AD) pathologic change. This study aimed to assess the long-term clinical and cognitive trajectories of individuals with non-AD pathologic change among older adults without dementia, comparing them to those with normal AD biomarkers and AD pathophysiology. Analyzing Alzheimer's Disease Neuroimaging Initiative data, we evaluated clinical outcomes and conversion risk longitudinally using mixed effects models and multivariate Cox proportional hazard models. We found that compared to individuals with A-T-N-, those with abnormal tauopathy or neurodegeneration biomarkers (A-T + N-, A-T-N + , and A-T + N + ) had a faster rate of cognitive decline and disease progression. Individuals with A-T + N + had a faster rate of decline than those with A-T + N-. Additionally, in individuals with the same baseline tauopathy and neurodegeneration biomarker status, the presence of baseline amyloid could accelerate cognitive decline and clinical progression. These findings provide a foundation for future studies on non-AD pathologic change and its comparison with AD pathophysiology.

Case of Autosomal Dominant Alzheimer Disease With Negative Findings From PiB-PET Examination.

Background and Objectives: This study reports an uncommon case of autosomal dominant Alzheimer disease (AD) with negative PiB-PET findings. Methods: A 55-year-old woman was admitted to the hospital due to a progressive cognitive decline for over 9 years, along with a possible dementia family history. The patient underwent routine laboratory tests, neuropsychological assessments, and neuroimaging examinations. Additionally, the cerebrospinal fluid sample was analyzed for AD biomarkers using the Single Molecular Array (Simoa) technique. A targeted Next-Generation-Sequencing (NGS) panel screening was also conducted. Results: Routine blood and CSF laboratory tests, as well as CSF tap test, yielded negative results. Cranial MRI showed atrophy of the whole brain. PiB-PET scanning indicated that PiB was merely retained in her brain with an overall standard uptake value ratio (SUVR) <1.0. Simoa analysis showed an increase in the level of CSF t-tau and a decrease in that of CSF Aß42. NGS panel screening detected a c.G2032A (p.D678N) heterozygous mutation in APP. Consequently, the patient was diagnosed with autosomal dominant AD. Discussion: We have reported an uncommon case of autosomal dominant AD carrying p.D678N variant in APP with negative PiB-PET results. The diagnosis of AD should not be directly excluded solely based on the negative PiB-PET results.

Oxygen metabolism abnormality and Alzheimer's disease: An update.

Oxygen metabolism abnormality plays a crucial role in the pathogenesis of Alzheimer's disease (AD) via several mechanisms, including hypoxia, oxidative stress, and mitochondrial dysfunction. Hypoxia condition usually results from living in a high-altitude habitat, cardiovascular and cerebrovascular diseases, and chronic obstructive sleep apnea. Chronic hypoxia has been identified as a significant risk factor for AD, showing an aggravation of various pathological components of AD, such as amyloid ß-protein (Aß) metabolism, tau phosphorylation, mitochondrial dysfunction, and neuroinflammation. It is known that hypoxia and excessive hyperoxia can both result in oxidative stress and mitochondrial dysfunction. Oxidative stress and mitochondrial dysfunction can increase Aß and tau phosphorylation, and Aß and tau proteins can lead to redox imbalance, thus forming a vicious cycle and exacerbating AD pathology. Hyperbaric oxygen therapy (HBOT) is a non-invasive intervention known for its capacity to significantly enhance cerebral oxygenation levels, which can significantly attenuate Aß aggregation, tau phosphorylation, and neuroinflammation. However, further investigation is imperative to determine the optimal oxygen pressure, duration of exposure, and frequency of HBOT sessions. In this review, we explore the prospects of oxygen metabolism in AD, with the aim of enhancing our understanding of the underlying molecular mechanisms in AD. Current research aimed at attenuating abnormalities in oxygen metabolism holds promise for providing novel therapeutic approaches for AD.

Clarity on the blazing trail: clearing the way for amyloid-removing therapies for Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a complex pathogenesis. Senile plaques composed of the amyloid-ß (Aß) peptide in the brain are the core hallmarks of AD and a promising target for the development of disease-modifying therapies. However, over the past 20 years, the failures of clinical trials directed at Aß clearance have fueled a debate as to whether Aß is the principal pathogenic factor in AD and a valid therapeutic target. The success of the recent phase 3 trials of lecanemab (Clarity AD) and donanemab (Trailblazer Alz2), and lessons from previous Aß clearance trials provide critical evidence to support the role of Aß in AD pathogenesis and suggest that targeting Aß clearance is heading in the right direction for AD treatment. Here, we analyze key questions relating to the efficacy of Aß targeting therapies, and provide perspectives on early intervention, adequate Aß removal, sufficient treatment period, and combinatory therapeutics, which may be required to achieve the best cognitive benefits in future trials in the real world.

CHIT1-positive microglia drive motor neuron ageing in the primate spinal cord.

Ageing is a critical factor in spinal-cord-associated disorders1, yet the ageing-specific mechanisms underlying this relationship remain poorly understood. Here, to address this knowledge gap, we combined single-nucleus RNA-sequencing analysis with behavioural and neurophysiological analysis in non-human primates (NHPs). We identified motor neuron senescence and neuroinflammation with microglial hyperactivation as intertwined hallmarks of spinal cord ageing. As an underlying mechanism, we identified a neurotoxic microglial state demarcated by elevated expression of CHIT1 (a secreted mammalian chitinase) specific to the aged spinal cords in NHP and human biopsies. In the aged spinal cord, CHIT1-positive microglia preferentially localize around motor neurons, and they have the ability to trigger senescence, partly by activating SMAD signalling. We further validated the driving role of secreted CHIT1 on MN senescence using multimodal experiments both in vivo, using the NHP spinal cord as a model, and in vitro, using a sophisticated system modelling the human motor-neuron-microenvironment interplay. Moreover, we demonstrated that ascorbic acid, a geroprotective compound, counteracted the pro-senescent effect of CHIT1 and mitigated motor neuron senescence in aged monkeys. Our findings provide the single-cell resolution cellular and molecular landscape of the aged primate spinal cord and identify a new biomarker and intervention target for spinal cord degeneration.

Association of Adipokines with Alzheimer's Disease in a Chinese Cohort.

BACKGROUND: The correlation between plasma adipose factor levels and Alzheimer's patients is not entirely clear. OBJECTIVE: We aimed to investigate associations between AD and plasma levels of three adipokines including plasma adiponectin, leptin, and resistin. METHODS: A single-center, cross-sectional study recruited AD patients (n = 148) and cognitively normal (CN) controls (n = 110). The multivariate logistic regression analysis was applied to determine associations of adiponectin, leptin, and resistin with the presence of AD. The receiver operating characteristic (ROC) analysis was employed to determine the diagnostic power of adiponectin, leptin and resistin for AD. RESULTS: After adjusted for the conventional risk factors, plasma levels of leptin (OR = 0.417, 95% CI: 0.272-0.638, p < 0.0001) and adiponectin (OR = 1.249, 95% CI: 1.151-1.354, p < 0.0001) were associated with the presence of AD. In total participants, the plasma adiponectin level was negatively correlated with MMSE scores (p < 0.0001) and was positively with CDR scores (p < 0.0001) and age (p < 0.0001). The plasma level of leptin was negatively correlated with CDR scores (p < 0.0001) and positively correlated with MMSE scores (p < 0.0001). Both adiponectin (p < 0. 0001) and leptin (p < 0. 0001) featured higher AUC than the random chance. CONCLUSIONS: Plasma adiponectin and leptin were associated with the presence, symptomatic severity, and diagnostic power of AD, suggesting a potential role of adipokines in the pathogenesis of AD.

Chalcogen Bond Catalysis with Telluronium Cations for Bromination Reaction: Importance of Electrostatic and Polarization Effects.

Recently, chalcogen bond catalysts with telluronium cations have garnered considerable attention in organic reactions. In this work, chalcogen bond catalysis on the bromination reaction of anisole with N-bromosuccinimide (NBS) with the telluronium cationic catalysts has been explored with density functional theory (DFT). The catalytic reaction is divided into two stages: the bromine transfer step and the proton transfer step. Based on the computational results, one can find the rate-determining step is the bromine transfer step. Moreover, the present study elucidates that a stronger chalcogen bond between catalysts and NBS will give better catalytic performance. Additionally, this work also clarified the importance of the electrostatic and polarization effects in the chalcogen bond between the oxygen atom of NBS and the Te atom of the catalyst in this bromination reaction. The electrostatic and polarization effects are significantly influenced by the electron-withdrawing ability of the substitution groups on the catalysts. Moreover, the structure-property relationship between the strength of chalcogen bond, electrostatic effect, polarization effect and catalytic performance are established for the design of more efficient chalcogen bond catalysts.

Fibroblast activation protein imaging in atrial fibrillation: a proof-of-concept study.

BACKGROUND: To evaluate the feasibility of using radiolabeled fibroblast activation protein inhibitor (FAPI) PET/CT imaging to assess activated fibroblasts in the atria of individuals with AF and to identify factors contributing to enhanced atrial activity. METHODS: We constructed left atrial appendage (LAA) pacing beagle dog AF models (n = 5) and conducted 18F-FAPI PET/CT imaging at baseline and eight weeks after pacing. Right atrial (RA) specimens were collected from these models. Additionally, 28 AF patients and ten age- and sex-matched healthy volunteers underwent 18F-FAPI PET/CT imaging. RESULTS: RA of AF beagles showed increased 18F-FAPI uptake. Among AF patients, 18 out of 28 (64.3%) exhibited enhanced atrial FAPI activity. No atrial 18F-FAPI uptake was observed in the sham beagle and healthy volunteers. In animal RA specimens, 18F-FAPI activity correlated positively with FAP mRNA (r = .98, P = .002) and protein (r = .82, P = .03) levels, as well as collagen I mRNA expression (r = .85, P = .02). B-type natriuretic peptide levels were associated with atrial 18F-FAPI activity (OR = 3.01, P = .046). CONCLUSION: This proof-of-concept study suggests that 18F-FAPI PET/CT imaging may be a feasible method for evaluating activated fibroblasts in the atria of AF patients.

Pulsed field ablation of superior vena cava in paroxysmal atrial fibrillation: a case report.

Paroxysmal atrial fibrillation originates most commonly in the pulmonary veins. However, the superior vena cava has proved to be arrhythmogenic in some cases. Pulsed field ablation, an emerging ablation technology, selectively affects myocardial tissue. Herein, we present a case of paroxysmal atrial fibrillation in a 64-year-old man who was admitted to our hospital for pulsed field ablation. The tachycardia was recurrent despite four successful pulmonary vein isolations. The superior vena cava was determined to be involved in arrhythmogenesis. The atrial fibrillation terminated immediately after the pulsed field ablation discharge at the superior vena cava.