Open research questions in Cerebrovascular and Carotid Artery Diseases

What the literature leaves open

• SyNC remains an under-reported and under-recognized source of strokes, partly due to its current categorization within the TOAST classification system. The limited studies that have been reported on SyNC utilize varying definitions, which further complicates our under- standing of its prevalence, risk factors, and management.

  Non-stenotic Carotid Disease: Review of the Literature and Case Discussion of TCAR for Treatment · 2026 · DOI

• There were limitations of this study. Finally, this was a cross-sectional study that cannot reflect the continuous changes of plaque and hemodynam- ics and their interactions, which need to be investigated in longitudinal studies. Although previous studies have shown the prognostic value of CFD based on routine CTA/ MRA for stroke recurrence in sICAS [10, 22], wide clinical application remains limited by the computational demands and workflow complexity. Further longitudinal studies are warranted to verify the value of these geometric and hemodynamic features in predicting plaque progression, recurrent ischemic stroke, and treatment response. Therefore, larger-scale studies involving various ICAS locations are warranted to confirm these results.

  Atherosclerotic middle cerebral artery stenosis: adjacent arterial geometry, hemodynamics and plaque features · 2026 · DOI

• The underlying hemodynamic mechanisms through which MCA geometric configurations influence athero- sclerotic plaque development should be explored in future research. Future studies using quantitative WMH volumetry and territory-matched voxel-based mapping are warranted to confirm our findings.

  Association of middle cerebral artery atherosclerotic plaque with vessel tortuosity and white matter hyperintensity · 2026 · DOI

• Although the long-term efficacy of hybrid surgical revascularization (HSR) versus conservative medical therapy (CMT) remains controversial, preliminary studies suggest HSR may improve cognitive function.

  Mid- to long-term outcomes of different treatment strategies for chronic carotid artery occlusion: a single-center cohort study · 2026 · DOI

• Whether increasing ICAS severity confers incremental recurrence risk in medically treated elderly patients in routine clinical practice remains incompletely characterized.

  Association between intracranial arterial stenosis severity and recurrent stroke risk in elderly ischemic stroke patients · 2026 · DOI

• A major methodological innovation of the present meta‑ analysis is the deliberate restriction of eligible studies to randomized controlled trials and prospective observa‑ tional cohorts, with systematic exclusion of retrospective datasets commonly included in prior pooled analyses. This choice of study design is justified on multiple bases. Retrospective studies are inherently susceptible to selec‑ tion bias as operators performing TRA might select anatomically favourable patients with favourable vessel conditions, hence underestimating complications. More‑ over, retrospective studies are unable to control for tem‑ poral trends in operator experience, institution‑specific protocols, and the concomitant evolution of equipment, all of which confound outcome attribution. Furthermore, the inclusion of studies from multiple international cen‑ ters improves the external validity and generalizability of the pooled findings across diverse neurointerventional settings. Prospective studies ensure comparable baselines, specified outcome definitions, and standardized follow‑ up, thereby reducing the selection bias. The inclusion of RCTs and prospective observational studies allowed subgroup analysis to evaluate the source of heterogene‑ ity, which would have been obscured in a single‑design meta‑analysis. Lastly, the use of a random‑effects model throughout, validated sensitivity analyses, GRADE‑based certainty assessment, and Newcastle‑Ottawa Scale evalu‑ ation of cohort quality further strengthened confidence in the robustness of the pooled estimates. This design choice differentiates the present analysis from prior pooled studies and strengthens confidence in the comparative estimates. However, this study had multiple limitations. First, the total number of events recorded for outcomes such as neurological complications and access‑site complications was relatively low, reducing the statistical power and wid‑ ening the confidence intervals. Second, high heterogene‑ ity was observed for time to ambulation (I2 = 99%) and access‑site complications (I2 = 81%), reflecting variations in operator experience, learning curve phases, and insti‑ tutional protocols. Lastly, patient‑reported outcomes, including satisfaction, pain scores, and quality of life, were not uniformly reported and could not be analyzed despite their clinical importance. Publication bias could Khan et al. Egyptian Journal of Neurosurgery (2026) 41:99 not be formally assessed because only a few studies were available per outcome.

  Transradial versus transfemoral access for diagnostic cerebral angiography: a systematic review and meta-analysis of randomized and prospective studies with grade assessment · 2026 · DOI

• Available literature on cognitive outcomes after carotid revascularization was highly heterogeneous with substantial variability in patient selection, design, periprocedural management, and cognitive assessment strategies between studies. Additionally, our analysis had no true control to compare outcomes due to limited reporting of controls in individual studies, making a comparison to best medical treatment nonsensical. medRxiv preprint The copyright holder has placed this preprint (which was not certified by peer review) in the Public Domain. It is no longer restricted by copyright. Anyone can legally share, reuse, remix, or adapt this material for any purpose without crediting the original authors. https://doi.org/10.64898/2026.05.04.26351899 this version posted May 10, 2026. doi: ; Inconsistent test selection, follow-up timing, and reporting of changes in scores meant meta analysis was restricted to the most commonly reported global screening instruments (MoCA and MMSE). This approach excludes other studies assessing global cognition with other individual tests (Mini-Cog, ACE-III, GPCOG, etc.), limiting our study selection. Additionally, domain specific outcomes were summarized qualitatively using direction of change categories without meaningful interpretation. This allowed for synthesis across instruments and should be interpreted as descriptive only. The inclusion of both symptomatic and asymptomatic carotid stenosis populations represents an additional limitation. Baseline cognitive status, cerebrovascular reserve, and vulnerability to peri-procedural injury are likely to differ between these groups, yet these factors were inconsistently reported and adjusted for across studies. Most included studies were observational, introducing potential confounding related to vascular comorbidities, educational attainment, baseline cognition, and treatment selection. Practice effects and regression to the mean may also have influenced observed improvements, particularly in studies lacking appropriate control groups or repeated baseline testing. As noted earlier, follow-up timing was inconsistent across studies and cognitive trajectories after carotid revascularization may vary over time. To enable quantitative synthesis, follow-up intervals were divided into early and late time points. While this approach allows for cross-study comparison and prevents double counting, it sacrifices temporal granularity and can obscure short-term fluctuations. This study was not registered to PROSPERO, an additional limitation to our study.

  Cognitive Outcomes After Stenting vs. Endarterectomy: A Systematic Review with Meta-Analysis · 2026 · DOI

• More head-to-head studies comparing stenting to endarterectomy should be done before meaningful results can be drawn. Single and double-armed analysis should also incorporate standardized, longitudinal cognitive testing protocols with follow up intervals reflecting the immediate post-operative, short-term, and long-term cognitive effects of each intervention. Future studies should also outline true, standardized, non-surgical controls to prevent confounding in medical management. While some single arm studies included the use of best medical treatment, most commonly statins + P2Y12 inhibitor, many did not have a true control to compare outcomes. These changes can provide the adjustment needed for future studies investigating stenting, endarterectomy, and other techniques such as trans-carotid artery revascularization (TCAR) or investigational procedures like intravascular lithotripsy with angioplasty and stenting.

  Cognitive Outcomes After Stenting vs. Endarterectomy: A Systematic Review with Meta-Analysis · 2026 · DOI

• This study has several limitations. CT is less sensitive in detecting small recent or chronic infarcts, which may result in underestimation of infarct burden. Only the presence and type of infarcts were evalu- ated; infarct volume was not assessed, and volume- based analyses stratified by symptomatic status were not performed. Plaque thickness was used instead of volumetric plaque assessment, and qualitative plaque characterization was applied rather than automated segmentation, which may underestimate vulnerable plaque components due to overlapping attenuation values. Photon counting CT technology could have improved plaque component differentiation. As a retrospective cohort study, our analysis is subject to potential treatment indication bias and variability in imaging timing relative to symptom onset; however, adjustment for symptomatic status likely mitigates these effects. Cause-specific mortality data were unavailable, necessitating reliance on overall mor- tality. These limitations reflect real-world clinical constraints but do not diminish the robustness of the observed associations.

  Carotid plaque vulnerability and circle of Willis anatomy predict ipsilateral brain infarcts and long-term mortality in carotid endarterectomy patients · 2026 · DOI

• Shi-Chao Zhu 1†, Jia-Xin Dong 2†, Yu-Dan Wu 2†, Yue Gao 1, Rui Gao 1, Yong-Hui Yuan 3,4*, Shuang Wang 1* and Guang-Wei Zhang 1,5,6* 1Department of General Practice, The First Hospital of China Medical University, Shenyang, China, 2School of Nursing, Fudan University, Shanghai, China, 3Cancer Hospital of Dalian University of Technology, Shenyang, China, 4Liaoning Cancer Hospital & Institute, Clinical Research Center for Malignant Tumor of Liaoning Province, Cancer Hospital of China Medical University, Shenyang, China, 5Department of Smart Hospital Management, The First Hospital of China Medical University, Shenyang, China, 6The Internet Hospital Branch of the Chinese Research Hospital Association, Beijing, China Background: Artificial intelligence (AI) technology advancements have revolutionized carotid artery research, driving innovations in diagnostics and treatment. The exponential growth of studies underscores the critical need for systematic analysis to ensure clinical relevance and algorithmic robustness. Objective: To systematically evaluate the status of AI applications in carotid artery research, identify emerging themes and track development trends, and establish a guiding framework for future research. Methods: A retrospective bibliometric analysis of Web of Science Core Collection data, Scopus, and PubMed databases from 2000 to 2025 was performed, focusing on title/abstract/keyword queries related to AI-driven carotid artery research. Network visualizations and structural analyses generated by CiteSpace reveal evolving thematic clusters and emerging frontiers in this interdisciplinary field. Results: A total of 1,220 relevant publications were identified in this study, with an overall increasing trend in publication volume. China and the United States emerged as the primary contributing countries. Research mainly focuses on early, accurate diagnosis, monitoring, individualized intervention of carotid artery disease, imaging omics analysis, and advanced physiological and pathological analysis. Recent progress is characterized by big data, multi-omics, multi-modality, and multi-scale integration, emphasizing precision medicine and full-process evaluation of disease management, marking a major shift in carotid research toward a data-driven approach. Conclusion: This bibliometric study employs visualization techniques to delineate AI’s transformative role in carotid artery research, demonstrating its potential to redefine research paradigms and drive sustained advancements through advanced data analytics.

  Artificial intelligence in carotid research: a 25-year bibliometric analysis of global trends and future directions · 2026 · DOI

• The sample size is limited, and it is necessary to expand the pro- spective cohort and conduct in-depth exploration under standardized protocols. And external validation across multiple centers and devices is not carried out, which further limits the generalization of the research conclusions. Based on this, in the future, we will integrate clinical data to construct a hybrid model to improve the clinical appli- cability of the model and its efficacy in predicting stroke risk. learning approaches in automated stroke risk stratification using carotid plaque ultrasound imaging (AUC improvement: 9.7%; p < 0.05). Crucially, the absence of statistically significant perfor- mance differences among five state-of-the-art CNN architectures (ResNet-50 vs. SE-ResNet-50/SE-ResNeXt-50/DenseNet-121/ InceptionResNet-V2; p > 0.05) indicates architectural conver- gence under current data constraints, revealing a practical per- formance plateau rather than a bottleneck. This convergence underscores that clinical translation efforts should prioritize operational efficiency over marginal AUC gains. Consequently, ResNet-50 emerges as the optimal balance of predictive accuracy and deployability for real-time, resource-conscious clinical deployment—a critical advancement toward accessible stroke prevention in diverse healthcare settings.

  A clinically deployable deep learning model for automated stroke risk stratification in carotid atherosclerotic plaque · 2026 · DOI

• The Carotid Plaque-RADS classification system is introduced as a novel stroke risk framework, but long-term prospective validation and clinical implementation across different healthcare systems requires further work.

  Bibliometric Analysis and Visualization of Vulnerable Carotid Plaque Research (2010-2025): From Morphological Imaging to Artificial Intelligence and Digital Twins · 2026 · DOI

• Multiple imaging modalities (contrast-enhanced ultrasound, 18F-NaF PET/MRI, conventional MRI) are available for plaque assessment, but standardized comparative protocols and inter-modality validation frameworks are lacking.

  Bibliometric Analysis and Visualization of Vulnerable Carotid Plaque Research (2010-2025): From Morphological Imaging to Artificial Intelligence and Digital Twins · 2026 · DOI

• While recent works on radiomics for plaque vulnerability prediction are cited, systematic validation of these AI-based diagnostic approaches across diverse patient populations remains incomplete.

  Bibliometric Analysis and Visualization of Vulnerable Carotid Plaque Research (2010-2025): From Morphological Imaging to Artificial Intelligence and Digital Twins · 2026 · DOI

• OBJECTIVE: Peripheral metabo-inflammatory disturbances and ferropathological processes are closely linked to steno-occlusive pathologies in Parkinson's disease (PD), though their roles remain to be fully elucidated.

  The Role of Metabo-Inflammatory Syndrome and Ferropathological Processes in Atherosclerotic Plaque Formation in Parkinson’s Disease: Insights from High-Resolution Carotid Duplex Analysis · 2025 · DOI

• Our investigation is subject to a few constraints that warrant recognition. The backward-looking methodology and sparse clinical information limit the applicability of our results, as the sample group may not adequately reflect the variability of atherosclerotic conditions across broader demographic groups. Furthermore, while the HSS performed robustly in postmortem examinations, its applicability to living patients remains untested. Translating the score to clinical settings will require validation in prospective studies with larger, more diverse cohorts, coupled with correlations to clinical outcomes such as myocardial infarction or stroke. Such studies could also refine the score by identifying additional histological or molecular markers that enhance its predictive value. Another avenue for future research is integrating the HSS with advanced imaging techniques, such as IVUS and OCT. These techniques could provide a non-invasive complement to histological assessment, potentially allowing the HSS to be adapted for real-time evaluation of plaque stability in vivo. This integration could bridge the gap between postmortem pathology and clinical management, offering a pathway to identify and treat high-risk patients before adverse events occur. Additionally, exploring the molecular underpinnings of the histological features captured by the HSS, such as the role of specific inflammatory cytokines or angiogenic factors, could further refine its diagnostic and prognostic capabilities.  Conclusions This study provides a detailed profile of CV pathology in SCD patients, highlighting gender disparities, key macroscopic and histological features, and a predominance of unstable atherosclerotic plaques. Notably, 75.4% of cases were male, reflecting a significant predominance consistent with the global literature, which indicates higher male risks due to biological and behavioral factors, thus underscoring the need for targeted prevention. Macroscopically, diffuse cardiosclerosis was highly prevalent (94.9%), exceeding typical rates in ischemic cohorts, with healed and acute myocardial infarcts in 26.4% and 13.6% of cases, respectively – patterns aligning with SCD autopsies where ischemic lesions trigger fatal events. Lower rates of myocardial hypertrophy (7.8%) and lipomatosis (2.5%) emphasize fibrotic over hypertrophic changes, consistent with broader series. Histologically, vulnerable plaque features included elevated intraplaque hemorrhage (76.0%), necrotic cores (92.6%), cholesterol crystals (61.7%), inflammation (39.2%), erosion (42.7%), and rupture (15.3%). Notably, 98.5% of plaques were unstable. These surpass prevalences in other studies, signaling advanced disease and SCD risk via thrombosis and ischemia. The median FCT of 150 μm suggests partial stability; however, coexisting risks indicate a mixed vulnerability, with weak correlations to plaque severity. A key innovation is the HSS, a reproducible metric that integrates thin caps, lipid cores, macrophages, and hemorrhage, thereby enhancing forensic and research applications beyond qualitative assessments. These findings 498 Daniela Cristina Pavel Mironescu et al. support intensified screening, risk modification (e.g., statins, anti-inflammatory agents), and antithrombotic therapy, particularly for high-risk males, while underscoring the cohort-specific burdens that necessitate tailored healthcare.

  Development and assessment of a histopathological stability score for atheroma plaques · 2025 · DOI

• Introduction: Temporal changes of intracranial arterial disease (ICAD) in patients with ischemic stroke in high-resolution vessel wall imaging (HR-VWI) have not been elucidated.

  Abstract 38: Temporal Changes in Intracranial Arterial Diseases: A Longitudinal High-Resolution Vessel Wall Imaging Analysis · 2024 · DOI

• However, some of them obtained conflicting data confirming both the advantage of carotid stenting (SAPPHIRE) and carotid endarterectomy (EVA-3S), as well as the equivalence of the two treatments (CAVATAS, SPACE, CREST).

  Comparative analysis of the effectiveness of carotid endarterectomy operations with stenting of the carotid arteries: a systematic review · 2023 · DOI

• For patients with stage III CA and T2DM, age and sex differences in the parameters of cerebral circulation both in the vessels of the carotid and in the vessels of the vertebro-basilar basins have not been established.

  Age and Sex Differences in Cerebral Circulation in Patients with Cerebral Atherosclerosis and Diabetes mellitus · 2020 · DOI

• Despite considerable progress in methods of diagnosis and increasing number of operations etiology, pathogenesis and morphogenesis of PT ICA remain unclear.

  Pathological tortuosity of the internal carotid artery: morphological characteristics · 2014 · DOI

• Further investigation is needed to compare the amount of lipid among lesions with similar plaque burden between transplant and traditional atherosclerotic patients in a larger population. Also, the early-stage lipid deposition of CAV detected by NIRS-IVUS should be validated by histopatho- logical analysis. atherosclerosis by NIRS-IVUS Page 7 of 7 relatively low LCBI by NIRS as well as the feasibility for assessment of very distal coronary arteries—especially among transplant recipients with CAV—has not been fully investigated.

  Vocational Agriculture and the Future Farmers of Japan. · 1972 · DOI

• Optical coherence tomography (OCT) provides superior resolution, yet standardised protocols for carotid artery imaging are lacking.

  Optical coherence tomography for carotid artery plaque: a standardised imaging and analysis methodology · 2026 · DOI

• Further prospective and mul- ticenter studies are warranted to validate our results, define standardized platelet function testing protocols, and assess the long-term cognitive and neurological outcomes associated with guided antiplatelet therapy in carotid stenting.

  Cerebral DWI lesion burden following carotid artery stenting with guided antiplatelet therapy: a retrospective comparative study · 2026 · DOI

• Future validation in vascular surgery populations is warranted to determine whether routinely available carotid duplex parameters can contribute to targeted cardiovascular risk recognition before major vascular procedures.

  Carotid Duplex-Derived Markers Across Angiographic Coronary Artery Disease Burden: A Pandemic-Era Real-World Cohort Study · 2026 · DOI

• There is scarce data in the contemporary literature regarding the correlation of the microanatomy of the perforating arteries, their atherosclerosis, and the ischemia in their territory.

  Clinical Significance of the Cerebral Perforating Arteries · 2017 · DOI

Most-cited papers in Cerebrovascular and Carotid Artery Diseases

• Carotid Wall Thickness is Predictive of Incident Clinical Stroke: The Atherosclerosis Risk in Communities (ARIC) Study · American Journal of Epidemiology · 2000 · 573 citations
• Sprawozdanie z VI Międzynarodowego Sympozjum Naukowego Polskiego Towarzystwa Psychologii Behawioralnej · Psychologia Rozwojowa · 2011 · 139 citations
• Management of Carotid Artery Trauma · Craniomaxillofacial Trauma & Reconstruction · 2014 · 89 citations
• Balloon Angioplasty vs Medical Management for Intracranial Artery Stenosis · JAMA · 2024 · 86 citations
• Diagnosis, Treatment and Follow-up in Extracranial Carotid Stenosis · Deutsches Ärzteblatt international · 2020 · 27 citations
• Carotid calcification in panoramic radiographs: radiographic appearance and the degree of carotid stenosis · Dentomaxillofacial Radiology · 2016 · 26 citations
• A new approach of statin therapy in carotid atherosclerosis: Targeting indices of plaque vulnerability on the top of lipid-lowering. A narrative review · Kardiologia Polska · 2022 · 19 citations
• Association between apical periodontitis and secondary outcomes of atherosclerotic cardiovascular disease: A case–control study · International Endodontic Journal · 2024 · 17 citations
• Evaluation of the relationship between plaque formation leading to symptomatic carotid artery stenosis and cytomegalovirus by investigating the virus DNA · Archives of Medical Science - Atherosclerotic Diseases · 2019 · 15 citations
• Diagonal ear lobe crease and atherosclerosis: A review of the medical literature and dental implications · Medicina oral, patología oral y cirugía bucal · 2012 · 13 citations

Most recent work

• Distinct Perforator Hemodynamic Phenotypes Differentiate Mechanisms of Single Subcortical Infarction: In Vivo Evidence from 7T Phase-Contrast MRI · International Journal of Stroke · 2026
• Bibliometric Analysis and Visualization of Vulnerable Carotid Plaque Research (2010-2025): From Morphological Imaging to Artificial Intelligence and Digital Twins · Research in Health Science · 2026
• Intravascular position-sensitive positron-counting catheter for atherosclerotic plaques · EJNMMI Physics · 2026
• Plaque-level machine-learning prediction of carotid plaque vulnerability on computed tomography angiography · Neuroradiology · 2026
• Deep learning for carotid Doppler spectra classification · Medical & Biological Engineering & Computing · 2026
• Inflammation in Carotid Stenosis: Scoping Review with ☸SAIMSARA · SAIMSARA Journal · 2026
• A clinically deployable deep learning model for automated stroke risk stratification in carotid atherosclerotic plaque · Frontiers in Medicine · 2026
• Deep learning-based early prediction of carotid plaque response to lipid-lowering therapy using longitudinal multimodal ultrasound imaging · Insights into Imaging · 2026
• Asymptomatic Carotid Stenosis: Scoping Review with ☸SAIMSARA · SAIMSARA Journal · 2026
• Correlation between TLR2 expression and common carotid artery bifurcation angle in carotid atherosclerotic plaque: a cross-sectional study · Postgraduate Medicine · 2026

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