Journal of Investigative Medicine最新文献

Aim: To develop and validate retinal vascular biomarkers for detecting mild cognitive impairment (MCI) in cerebral small vessel disease (CSVD) using swept-source optical coherence tomography angiography (SS-OCTA).

Methods: Participants with MCI and normal cognition were prospectively enrolled from two ongoing cohorts (Dream-10 and FRESH-CSVD; NCT06164262 and NCT06431711). All participants underwent SS-OCTA and structural MRI (S-MRI). Individuals with Alzheimer's disease were excluded based on plasma biomarkers. Participants were split into development (January-August 2024) and temporal validation (September 2024-January 2025) cohorts. Feature selection was conducted using least absolute shrinkage and selection operator regression, followed by receiver operating characteristic analyses.

Results: A total of 209 participants were included, with 48.8% (102/209) diagnosed with MCI. In the development cohort (n=136), the 3-6 mm macular choriocapillaris perfusion area (CCPA) of the left eye (oculus sinister, OS) showed superior diagnostic accuracy for MCI (AUC=0.906), outperforming S-MRI markers (all p<0.05). Temporal validation confirmed diagnostic accuracy (AUC 0.902; sensitivity 88.6%, specificity 81.3%) with minimal performance drift (ΔAUC 0.002). Adding S-MRI markers did not significantly enhance diagnostic performance (p>0.05). Both 0-3 and 3-6 mm OS macular CCPA were significantly associated with cognitive decline (Mini-Mental State Examination, Montreal Cognitive Assessment and Clinical Dementia Rating Sum of Boxes; all p<0.01), and mediation analyses suggested partial effects through white matter hyperintensity volume and right choroid plexus volume ratio.

Conclusion: SS-OCTA-derived macular CCPA, especially in the 3-6 mm OS region, may serve as a promising and non-invasive biomarker for CSVD-related MCI. Further multicentre studies are needed to establish its clinical applicability.

Introduction: Tenecteplase (TNK) offers logistical advantages in stroke thrombolytic therapy with its single bolus administration compared with alteplase. Moreover, its high specificity for fibrin may contribute to a reduction in haemorrhage complications. However, the safety, tolerability and efficacy of TNK, combined with neuronavigation-assisted stereotactic minimally invasive puncture, in patients with acute spontaneous deep cerebral haemorrhage remain unknown.

Methods: We conducted a prospective, open-label phase I trial in a 3+3 dose escalation design to evaluate the safety and tolerability, and maximum tolerated dose (MTD) of TNK in patients with acute spontaneous basal ganglia or thalamic haemorrhage, with haematoma volumes ranging from 20 to 50 mL, combined with neuronavigation-assisted stereotactic minimally invasive puncture surgery (MIPS). During the dose-escalation phases of the trial, patients received intra-haematoma injection of TNK via a haematoma evacuation catheter every 24 hours after surgery until three doses were administered or any termination criteria were met (residual haematoma ≤10 mL or rebleeding event), with doses ranging from 0.001 to 0.003 and 0.009 mg per mL of haematoma volume. The primary safety endpoint was drug-related rebleeding during the dose escalation phases, while the primary efficacy endpoint was the mean drug-related haematoma clearance per dose.

Results: In total, 12 patients were recruited. No drug-related rebleeding events at any dose escalation phase occurred. By the 24 hours after the last dose, the residual haematoma volume for each patient across all groups was reduced to less than 10 mL. The 0.009 mg TNK dose group achieved the highest mean haematoma clearance of 17.49 mL per dosing. The MTD was 0.009 mg/mL of haematoma volume in the dose escalation phase.

Discussion and conclusion: TNK is well tolerated with encouraging signs of dissolving blood clots. Further exploration of TNK combined with neuronavigation-assisted stereotactic MIPS in patients with acute spontaneous deep cerebral haemorrhage is warranted.

Trial registration number: NCT06668441.

Background: Although previous evidence generally agreed on the short-term dual antiplatelet therapy (DAPT) for mild stroke or transient ischaemic attack (TIA), there is no consensus on the optimal threshold for stroke severity and initiation timing of DAPT. We conducted an updated meta-analysis of randomised controlled trials to evaluate early DAPT versus single therapy in mild stroke or TIA.

Methods: We systematically reviewed double-blind and randomised controlled trials up to October 2024 evaluating DAPT versus monotherapy for acute mild, non-cardioembolic ischaemic stroke (National Institute of Health Stroke Scale; NIHSS≤5) or TIA within 72 hours of ictus. Random effects models generated risk ratio (RR) with 95% CIs for outcomes including stroke, composite vascular events, ischaemic stroke, major bleeding, haemorrhagic stroke and all-cause mortality.

Results: Pooled data from five trials (n=27 559) demonstrated that DAPT versus monotherapy lowered the risk of stroke recurrence (RR, 0.77; 95% CI 0.70 to 0.83), composite vascular events (RR, 0.75; 95% CI 0.68 to 0.83) and ischaemic stroke (RR, 0.74; 95% CI 0.68 to 0.81). However, DAPT increased the risk of major bleeding (RR, 2.19; 95% CI 1.38 to 3.49) and haemorrhagic stroke (RR, 2.08; 95% CI 1.13 to 3.82), with no significant increase in the risk of all-cause mortality (RR, 1.28; 95% CI 0.95 to 1.71).

Conclusions: For acute mild stroke (NIHSS ≤5) or patients with TIA within 72 hours of ictus, early DAPT initiation demonstrates net clinical benefit through reducing ischaemic events, despite an increase in bleeding complications, without affecting mortality.

Background and aims: Covert MRI markers of cerebral small vessel disease (CSVD) can coexist with large artery atherosclerosis. We aimed to explore whether the spatial distributions of these markers were diverse in people with or without intracranial artery stenosis (ICAS).

Methods: This cross-sectional analysis included 1206 stroke-free participants (aged 55.69±9.27, 62.94% female) with brain MRI and MR angiography from community-based Shunyi cohort. We analysed the relationships between ICAS and CSVD markers. We also compared the probability maps of lacunes, cerebral microbleeds (CMB), white matter hyperintensities (WMH) and cortex morphology at a voxel/vertex-wise level in groups with and without ICAS.

Results: ICAS increased the risk of lacunes by 2.99-fold (95% CI 1.99 to 4.50, p<0.001), lacunes ≥3 by 5.32 times (95% CI 2.76 to 10.28, p<0.001), correlated with WMH volume (β=0.332, SE=0.059, p<0.001), WMH Fazekas scores ≥5 (OR 4.50, 95% CI 2.44 to 8.29, p<0.001) and brain parenchymal fraction (β=-0.012, SE=0.002, p<0.001), but not with CMB. ICAS is associated with lacunes in the corresponding blood supply area. Lacunes that coexist with ICAS were prone in basal ganglia, while the lacunes without ICAS appeared in centrum semiovale more often. WMH with ICAS was prone to present in deep white matter involving the bilateral pyramidal tracts and superior thalamic radiation. People with ICAS were susceptible to worse cortical atrophy of right superior frontal and left rostral anterior cingulate. No obvious distributional differences were found for CMB between the two groups.

Conclusions: Since ICAS may be involved in the upstream pathogenesis of lacunes, white matter lesions and cortical atrophy, the impact of ICAS should not be ignored when evaluating MRI markers of CSVD.

Background: Subarachnoid haemorrhage (SAH) is primarily caused by ruptured aneurysms with high mortality worldwide. Cuproptosis is a copper-induced cell death that regulates lipoylated tricarboxylic acid cycle proteins. The link between cuproptosis and SAH is unclear. To inhibit cuproptosis for SAH treatment, we designed brain-targeted delivery of siRNA to inhibit cuproptosis.

Methods: Transcriptome data of SAH related to cuprotosis were extracted from the Gene Expression Omnibus and defined using quantitative reverse transcription-PCR. We injected RVG-RBCEVs/siRNA (rabies virus glycoprotein-red blood cell extracellular vesicles/siRNA) peripherally to deliver LIAS (lipoyl synthase) siRNA to the brain tissues of SAH mice. The influences of RVG-RBCEVs/siRNA on copper levels, enrichment of cuproptosis functional proteins, glutathione and malondialdehyde content, mitochondrial respiration and membrane potential, transmission electron microscope, a neurological score, brain water content, blood-brain barrier injury and Fluoro-Jade C staining were examined.

Results: Our findings revealed that three cuproptosis-related genes (CRGs) were differentially expressed. The RVG peptides were conjugated to the red blood cell extracellular vesicle surface by bio-orthogonal click chemistry reactions, and then the loading of siRNA was conducted. RVG-RBCEVs/siRNA was selectively taken up by neurons but not glial cells; it facilitated the downregulation of LIAS of CRGs, reduced the accumulation of reactive oxygen species, inhibited neuronal cuprotosis and exerted neuroprotective effects in vivo.

Conclusions: These findings suggest that cuprotosis is critical for inducing neural injury after SAH. Neuron-targeted RVG-RBCEVs/siRNA treatment attenuated oxidative stress by inhibiting cuproptosis via suppressed LIAS expression. This innovative approach alleviates neurobehavioural impairments and represents a neuroprotective strategy following SAH.

Rationale: Radial artery spasm (RAS) is a common complication during transradial cerebral angiography (TRA), but currently, the optimal prevention strategy is not well established. Papaverine has anti-vasospasm, sedative and analgesic effects. However, the efficacy of papaverine in preventing RAS during TRA remains unknown.

Aims: To assess the efficacy of papaverine in preventing RAS during TRA.

Sample size estimates: 240 participants will provide 80% power at a two-tailed significance level of 0.05 to test the superiority hypothesis with the assumption that the incidence of RAS is 4% and 14.62% in the intervention and control groups, respectively, allowing for a 5% drop-out rate.

Methods and design: The Efficacy of Papaverine to Prevent Radial Artery Spasm During Transradial Cerebral Angiography is a multicentre, randomised, placebo-controlled, double-blind trial. Eligible participants scheduled for TRA are 1:1 randomised to the intervention group and the control group. The intervention group will be slowly injected with 10 mL of papaverine hydrochloride solution through the successfully implanted radial artery sheath and continuously dripped papaverine hydrochloride solution through the artery sheath during the procedure, and the control group will be given normal saline in the same manner.

Study outcome: The primary outcome is the incidence of RAS during the procedure. The operator assessed RAS based on a questionnaire addressing the following five signs: persistent forearm pain, pain response on catheter manipulation, pain response to introducer withdrawal and difficult catheter manipulation after being 'trapped' by the radial artery with considerable resistance on withdrawal of the introducer. RAS was indicated by the presence of at least two of these five signs or by the presence of just one when the operator considered it necessary to administer other spasmolytic agents.

Trial registration number: NCT05861765.

Objective: The study aimed to assess the incidence and impact of brain lesions and cognitive impairment after coronary artery bypass grafting (CABG) in patients with moderate-to-severe cerebral artery stenosis using low-field MRI.

Methods: 110 patients with moderate-to-severe cerebral artery stenosis who underwent CABG between November 2023 and May 2024 were enrolled. Postoperative brain lesions were evaluated using low-field MRI. Cognitive decline was defined as a reduction of ≥3 points in the Montreal Cognitive Assessment score from baseline. Risk factors associated with postoperative brain lesions and cognitive impairment were identified in univariate and multivariate logistic regression analyses.

Results: A total of 110 patients were enrolled, with a mean age of 65±7 years and 22 (20.0%) were female. New brain lesions were identified in 24 patients (21.8%). Logistic regression analysis identified operation time (OR 1.014, 95% CI 1.003 to 1.025, p=0.013) to be independently associated with brain lesions. 22.2% of the patients (20/90) experienced postoperative cognitive decline. New brain lesions were independently associated with cognitive decline (OR 4.651, 95% CI 1.158 to 18.676, p=0.030), particularly the new brain lesions impairing orientation ability (OR 4.534, 95% CI 1.438 to 14.289, p=0.010).

Conclusions: Low-field MRI has proven effective in detecting new brain lesions after CABG. Both postoperative new brain lesions and CABG operation were significant contributors to cognitive decline.

Background: Tongxinluo capsule has demonstrated multiple beneficial effects on microcirculation, endothelial cells and inflammation. However, evidence supporting their efficacy in improving vascular cognitive decline is limited. This trial aims to investigate the potential benefits of Tongxinluo capsules in Chinese patients with cerebral small vessel disease (CSVD) who have been diagnosed with mild cognitive impairment.

Design: Thistrail is a randomised, double-blind, placebo-controlled, multicentre study involving 1052 individuals aged 50-80 years with MRI-confirmed CSVD and a diagnosis of mild cognitive impairment. Participants were randomly assigned in a 1:1 ratio to receive either Tongxinluo capsules or placebo. The treatment period spans 12 months, with follow-up assessments conducted every 3 months to collect cognitive scale results and other relevant data.

Study outcome: The primary outcome of this clinical trial is the change in the Vascular Dementia Assessment Scale-cognitive subscale from baseline to 12 months. The primary safety outcome focuses on the incidence of adverse vital signs, including abnormalities in body temperature, heart rate, respiration and blood pressure.

Discussion: This trial has the potential to offer novel insights into the management of cognitive decline associated with CSVD through the application of traditional Chinese medicine.

Trial registration number: NCT06061692.

Background and aims: Preclinical and clinical studies found that head-down position (HDP) during ischaemic phase improved neurological function of acute ischaemic stroke, but the effect of HDP after reperfusion has never been investigated. This study aimed to investigate whether HDP after reperfusion can ameliorate cerebral ischaemic injury in rats.

Methods: The middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in rats, and different HDP interventions were performed. Survival rate, haemorrhage transformation rate, neurological deficit scores, infarct volume, weight loss and brain oedema were measured at 24 hours after surgery to explore the cerebroprotective effect of HDP. Immunohistochemistry, ELISA and western blot were used to determine the possible mechanisms.

Results: Compared with MCAO/R group, HDP -20° immediately after reperfusion with 1 hour duration exerted a significant cerebroprotective effect including reducing brain infarction and oedema, and improving neurological impairment, with a favourable safety profile such as less haemorrhagic transformation and death. These protective effects were not observed under other HDP intervention conditions. Mechanistically, this HDP procedure may exert its effects by regulating microglial polarisation, inhibiting microglial activation and neuroinflammation, reducing brain oedema and blood-brain barrier (BBB) disruption, suppressing apoptosis and improving neurological function.

Conclusion: This is the first study to demonstrate the cerebroprotective effect of HDP -20° with 1 hour duration immediately after reperfusion in MCAO/R model rats, which involved inhibition of neuroinflammation and apoptosis as well as protection of BBB.

Rationale: Cerebral small vessel disease (CSVD) is responsible for 25% of ischaemic strokes and 45% of dementia cases. Currently, therapies targeting individual mechanisms have not shown significant efficacy. As CSVD involves multiple pathophysiological mechanisms, Cerebralcare pills, a traditional Chinese medicine with multiple pharmacological mechanisms, may be effective in treating cognitive dysfunction in CSVD.

Aims: The objective of this study was to assess the efficacy of Cerebralcare pills in improving cognitive dysfunction (measured by Montreal Cognitive Assessment (MoCA)) in patients with CSVD.

Sample size estimates: A sample size of 114 patients with CSVD (57 in each group) will allow 2.74 points (with an SE of 0.56 points) difference between two groups on the MoCA score with 5% significance, 80% power and assuming a 10% dropout rate.

Methods and design: This is a randomised double-blind, multicentre, placebo-controlled trial involving individuals with mild cognitive impairment (MoCA score ranging from 16 to 24) associated with CSVD. CSVD was defined by the presence of white matter hyperintensities consistent with lacunar infarcts or the presence of more than two vascular risk factors. Participants were randomised 1:1 to orally take 5 g of Cerebralcare pills or placebo twice a day for 6 months.

Study outcomes: The primary outcome measure is the change in MoCA score at 6 months. Secondary outcome measures include the assessment of clinical manifestations, cognitive performance, conventional MRI markers, blood-brain barrier permeability and proteomics over a follow-up period of 6 months and 12 months.

Discussion: The objective of this trial is to evaluate the efficacy of Cerebralcare pills in improving cognitive dysfunction associated with CSVD. Additionally, the trial aims to provide insights into the pathological processes involved in this condition.

Trial registration number: NCT05578521.