Cingulate Sulcus Sign: A Descriptive Analysis in a Cerebral Small Vessel Disease Population

Cingulate Sulcus Sign: A Descriptive Analysis in a Cerebral Small Vessel Disease Population | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cingulate Sulcus Sign: A Descriptive Analysis in a Cerebral Small Vessel Disease Population Weishuai Li, Dongming Zheng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4247704/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The cingulate sulcus sign (CSS) has been observed in patients with idiopathic normal pressure hydrocephalus (iNPH), suggesting potential disruptions in cerebrospinal fluid circulation and compromised glymphatic system. Although there are similarities in the underlying mechanisms between cerebral small vessel disease (CSVD) and iNPH, the relationship between CSS and CSVD remains unclear. This study aimed to investigate the prevalence and potential mechanisms of CSS in patients with CSVD.Data from patients diagnosed with CSVD at Shengjing Hospital of China Medical University between January 2020 and October 2022 were retrospectively collected, including general information and four CSVD magnetic resonance imaging (MRI) markers(white matter hyperintensity (WMH), cerebral microbleeds (CMBs), lacunes, and enlarged perivascular spaces (EPVS), CSS and the Evan index (EI). A total of 308 patients were included, and CSS was detected in 80 patients (26%). Multivariable analysis showed an independent correlation between CSS and the presence of lacunes (odds ratio [OR] 0.347, 95% confidence interval [CI] 0.187–0.645, p = 0.001), the presence of lobar dominant CMBs (OR 2.741, 95%CI 1.416–5.308, p = 0.003), the periventricular WMH Fazekas score (OR 1.752, 95% CI 1.174–2.615, p = 0.006), and EI (0.25–0.3; OR 4.293, 95% CI 2.311–7.976, p < 0.001, reference group < 0.25).This preliminary study showed that CSS can be observed in some patients with CSVD. The presence of CSS may represent different mechanisms of CSVD pathogenesis and reflect differences in the degree of cerebrospinal fluid (CSF)/interstitial fluid (ISF) stasis. cingulate sulcus sign cerebral small vessel disease glymphatic system Evan index white matter hyperintensity Figures Figure 1 Figure 2 Figure 3 1.Introduction The cingulate sulcus is a prominent cerebral sulcus situated on the medial surface of the cerebral hemispheres. It originates in the medial portion of the frontal lobe and progresses posteriorly upward to the crest of the hemisphere’s medial surface, creating a boundary between the paracentral lobule and the precuneus[ 1 ]. Notably, the posterior segment of the cingulate sulcus exhibits greater variability than its anterior counterpart, owing to its later development during embryogenesis. Consequently, age-related dilation of the cingulate sulcus is predominantly observed within its posterior portion[ 2 ]. Researchers have surprisingly discerned a particular morphological variant termed the cingulate sulcus sign (CSS), characterized by an expanded anterior cingulate relative to the posterior cingulate, among some patients with idiopathic normal pressure hydrocephalus (iNPH) who are deemed suitable for ventriculoperitoneal shunt surgery[ 3 ]. Recent discoveries reveal the existence of a cerebrospinal fluid (CSF) / interstitial fluid (ISF) clearance mechanism known as the glymphatic system within the central nervous system[ 4 ]. This system is essential for the flow of CSF through brain tissue and the removal of solutes from the ISF, crucial for maintaining tissue homeostasis and metabolic equilibrium. Current understanding implicates a compromised glymphatic system in the pathophysiology of iNPH[ 5 , 6 ]. The detection of CSS could thus signify an altered CSF dynamic and perhaps indicate a malfunctioning glymphatic system in iNPH. Cerebral small vessel disease (CSVD) is a group of cerebrovascular diseases that primarily affect perforating arteries, capillaries or leptomeningeal vessels with various neuropathies[ 7 , 8 ], and cause a wide range of clinical manifestations, including stroke, cognitive impairment, and motor and gait impairment [ 9 ]. The clinical diagnosis of CSVD is primarily through magnetic resonance imaging (MRI) of parenchymal lesions corresponding to small cerebral arteries, which include recent small subcortical infarcts, lacunes of presumed vascular origin, white matter hyperintensities (WMH) of presumed vascular origin, enlarged perivascular spaces (EPVS), cerebral microbleeds (CMBs) and brain atrophy [ 10 ]. Indeed, more and more studies have revealed that damage of the glymphatic system played an important role in the initiation and progression of CSVD[ 11 , 12 ]. If there is an association between CSS and MRI markers of CSVD, the hypothesis that lymphatic system disorders are involved in the pathogenesis of CSVD will be strengthened. Therefore, this study aims to evaluate the relationship between CSS and CSVD and attempt to elucidate potential glymphatic system disorders associated with CSS by comparing the degree of CSF/ISF sludge. To the best of our knowledge, there have been no previous studies on this subject. 2.Methods 2.1 Study population and data collection. Patients who visited the clinic at the Neurology Department of Shengjing Hospital and met the following inclusion criteria were retrospectively enrolled in our study consecutively from January 2020 to October 2022. Subjects were enrolled if they met the following criteria: (1) Fazekas score 2–3 WMH and at least one of the following three markers: lacune, CMB, and EPVS; (2) CT or MRI excluding ICH ;(3) aged ≥ 55 years old. The following were the exclusion criteria: (1) cerebral infarction with an infarction core diameter greater than 2 cm; (2) stroke from any potential cardioembolic source; (3) cerebrovascular stenosis with > 50% luminal stenosis suggested by transcranial Doppler ultrasound, computed tomography angiography, or magnetic resonance angiography; (4) genetically confirmed hereditary CSVD or suspected hereditary CSVD based on family history and clinical features; (6) WMH that could be caused by something other than CSVD, such as multiple sclerosis; and (7) patients showed an EVAN index(EI) ≥ 0.3 or disproportionately enlarged subarachnoid-space hydrocephalus; Demographic and clinical information was obtained by a review of the medical records or interviews with the patients or their family members. The presence of hypertension, hyperlipidemia, diabetes and previous stroke was determined based on a prior medical diagnosis and treatment among all patients. Smoking or drinking was defined by a history of tobacco or alcohol use. The present study was performed in accordance with the ethical standards established in the 1964 Declaration of Helsinki and its subsequent amendments. Written informed consent from each subject and/or the subject’s relatives was obtained. The ethics committee of our institution approved the procedures of this study. 2.2 Neuroimaging acquisition and analysis Conventional imaging was obtained with a 3.0T MR scanner including T2-weighted, T1-weighted and fluid attenuated inversion recovery (FLAIR). Susceptibility weighted imaging (SWI) acquisition was performed with a T2*-weighted gradient echo sequence with a flip angle of 15°, TR/TE = 30/20 ms, and slice thickness = 1.8 mm. SWI and minimum intensity projection images were acquired by in-line post processing of magnitude and phase images, and these post processed images were used for the evaluation of the imaging findings. EPVS, CMB, lacune and WMH were defined according to the STandards for ReportIng Vascular changes on Euroimaging [ 10 ]. Representative images of characteristic CSVD lesions are shown in Fig. 1 (a-f) .The number of EPVS was measured in the basal ganglia (BG) and centrum semiovale (CSO) and was dichotomized as either high degree (score > 20) or low degree (score < 20) according to a previously published protocol [ 13 ]. The number of CMBs was measured in lobar and/or deep and was categorized into the lobar dominant group and non-lobar dominant group according to the ratio of lobar to deep CMBs number .The WMH were scored on FLAIR images using the Fazekas score [ 14 ]. The EI was defined as the ratio between the maximal width of the frontal horns of the lateral ventricles and the maximal inner diameter of the skull on the same slice [ 15 ]. (Fig. 1 . g) . CSS were identified on paramedian-sagittal T1 weighted images according to a previously published protocol [ 3 ]. A normal finding was defined as the anterior part of the cingulate sulcus being the same width as the posterior part or the posterior part being wider than the anterior part (Fig. 2 . a). Positive CSS was narrowness of the posterior part of the cingulate sulcus with respect to the anterior part on a sagittal slice. (Fig. 2 . b) The above image features were identified and counted by two experienced researchers independently, and the researchers were blinded to the patients’ clinical data. In the event of any disagreement between the two raters, a consensus was reached with the help of a neuroradiologist (D.M.Z), 2.3 Statistics. Data normality was assessed using the Kolmogorov–Smirnov test. Continuous variables are represented as interquartile ranges (IQRs). Categorical variables were described using frequencies (N, %). Univariate analyses were performed to evaluate differences in demographic, clinical, and neuroimaging characteristics between the patients with and without CSS using χ2 and Fisher’s exact tests for categorical variables and Mann–Whitney U tests for continuous variables. To test for independent associations with the presence of CSS, all variables that showed a p value < 0.05 in the univariate analyses were entered in a multivariable logistic regression analysis. Logistic regression models were run with a stepwise forward elimination method to generate a minimal adjusted model. In this study, for purposes of statistical analyses, the EI was categorized into<0.25 and 0.25–0.3. All statistical analyses in this study were performed with SPSS 22.0 software (IBM SPSS Inc., Chicago, IL, United States), and statistical significance was set at p < 0.05. 3. Results A total of 308 patients with CSVD were included in the study. The average age of the patients was 66.0(61.0 -72.0) years. Approximately 55.2% of the patients were male. The presence of lacunes and CMBs, lobar dominant CMBs, high degree BG-PVS and high degree CSO-PVS, were observed in 187 (60.7%), 131 (42.5%), 82 (26.6%), 135 (43.8%), and 166 (53.9%) patients, respectively. The median scores for deep WMH and periventricular WMH, and EI were 2.0 (1.0 -3.0), 3.0 (2.0 -3.0) and 0.25 (0.23 - 0.27), respectively. 3.1 Univariable analysis of clinical and imaging characteristics of study population The basic characteristics of the CSS group and n-CSS group are listed in Table 1. Demographic and clinical information did not significantly difference between the two groups (all p>0.05). The presence of lacunes was significantly lower in the CSS group compared to the n-CSS group (p=0.023). Moreover, the CSS group displayed a higher EI (p<0.001), more severe deep WMH (P=0.001) and periventricular WMH (p<0.001), a higher prevalence of lobar dominant CMBs (P=0.02) and high degree CSO-PVS (P=0.01). However, no significant difference was observed in high degree BG-PVS and presence of CMBs between the two groups. 3.2 Multivariable analysis of neuroimaging markers associated with CSS The multivariable analysis of the association between imaging markers of CSVD and CSS is presented in Table 2. After adjustment for variables that were significant in the univariate analysis, CSS was independently correlated with presence of lacunes (odds ratio [OR] 0.347, 95% confidence interval [CI] 0.187-0.645, p=0.001)，presence of lobar dominant CMBs (OR 2.741, 95%CI 1.416-5.308, p=0.003), periventricular WMH Fazekas score (OR 1.752, 95% CI 1.174–2.615, p=0.006) and EI (0.25-0.3, OR 4.293, 95% CI 2.311–7.976, p＜0.001, reference group＜0.25) 4. Discussion In this paper, we demonstrate that approximately 26% of patients with cerebral small vessel disease (CSVD) exhibit the cingulate sulcus sign (CSS). Distinct from demographic and vascular risk factors, most CSVD imaging markers were noticeably differentiated between the two groups. Dominant lobar cerebral microbleeds (CMBs), periventricular white matter hyperintensities (WMH), and Evans Index (EI) were predictors of CSS, whereas lacunes were more frequently associated with the typical CSVD pattern of cingulate gyrus atrophy. The cingulate sulcus as an important brain anatomical structure, is widely used in the study of various neurological disorders, and the degree of its atrophy is related to the progression of the disease[ 16 , 17 ]. However, most of these studies employed computerized automated voxel morphometric analyses, which do not cater to individual assessment. Recently, a semi-quantitative visual method was utilized to demonstrate that CSS, which represents a narrowing of the posterior cingulate gyrus in the sagittal plane, could effectively identify patients with idiopathic normal pressure hydrocephalus (iNPH) suitable for shunt surgery [ 3 ]. This finding raises the speculation that CSS may potentially represent a glymphatic system dysfunction. In our current exploration, we observed the presence of CSS in some CSVD patients. The observations are consistent with earlier study findings which suggest that atherosclerosis and small vessel stiffness lead to reduced vascular pulsation and subsequently result in weakening cerebrospinal fluid (CSF) / interstitial fluid (ISF) exchange [ 18 – 20 ]. Even though a healthy control group was not considered in this study, the similarity in age and vascular risk factors between the two groups suggest that the emergence of CSS is not merely a result of aging or atherosclerosis, but may be linked to different pathogenic mechanisms of CSVD, such as cerebral amyloid angiopathy (CAA),which is typically characterized by the accumulation of amyloid β in the walls of leptomeningeal vessels and cortical capillaries in the brain [ 21 ]. EI is frequently used as a quick and easy way to evaluate ventriculomegaly [ 15 ], which can either be secondary to brain atrophy or represent an impairment of CSF circulation. A automated surface-based study on the morphology of the cingulate sulcus found that patients with vascular cognitive disorders, exhibiting widened cingulate sulcus and accompanying ventriculomegaly, differed from both iNPH patients and healthy controls [ 22 ]. However, our study revealed a strong association between the presence of CSS and a larger EI. To minimize the interference of iNPH, we specifically selected patients with an EI of less than 0.3 for this study, which might have reduced the power to detect associations. Nevertheless, we were still able to find significant associations between CSS and EI. One possible explanation for the contradictory results is that CSS is different from the mechanism underlying computer-automated morphological changes in the cingulate sulcus. Unlike the latter, CSS represents impaired CSF circulation rather than being solely secondary to cerebral atrophy. Furthermore, our research has uncovered a greater prevalence of lacunar within the non-CSS group. This can be attributed to the relationship between lacunar infarcts and brain atrophy. Previous studies have demonstrated that lacunar infarcts are associated with a greater progression of brain atrophy and cortical thickness in patient of CSVD [ 23 ]. Notably, these pathological atrophies are particularly pronounced in the posterior region [ 2 , 16 ]. This form of atrophy is consistent with the morphological characteristics of the non-CSS group in this study. CMBs are small, round collections of hemosiderin-laden macrophages in the brain that represent areas of previous microhemorrhages [ 24 ], They are now considered an imaging marker for CSVD [ 7 ]. In the present study, we found that CSS was mostly present in CSVD patients with predominantly lobar CMBs. Previous studies have reported that different topographic distributions of CMBs indicate different pathological mechanisms. For instance, CMBs in deep brain regions are radiological biomarkers of hypertensive arterial pathology [ 25 ], whereas CMBs in superficial or predominantly lobar regions are strongly associated with CAA pathology [ 26 , 27 ]. Our results suggest that the emergence of CSS may be related to CAA. Additionally, the imaging characteristics of CSS mentioned in this study are similar to those observed by Wang et al.[ 28 ] and Beaman et al.[ 29 ] who found that the presence of superficial CMBs can lead to an increase in white matter volume, especially in the parietal and occipital regions, due to impaired glymphatic system function.(Fig .3) WMH of presumed vascular origin are frequent in cerebral MRI of older people [ 14 , 30 ].They are promoted by vascular risk factors, especially hypertension and usually reflect axonal loss and demyelination following chronic ischemia [ 19 ].Our data suggest that despite increased WMH scores in the CSS group, there was no difference in vascular risk factors, including hypertension, which suggests that the mechanism underlying WMH may be multifactorial. This finding is supported by previous research, that WMHs are also a consequence of failure to eliminate interstitial fluid (ISF) from the white matter [ 12 , 31 ].In contrary to deep WMH, which may be impacted by both ischemia-hypoperfusion and malfunction of the glymphatic route, periventricular WMH is primarily linked to glymphatic pathway dysfunction [ 32 ]. Based on the aforementioned studies, the independent association between periventricular WMH and CSS in our study strengthens the notion that disturbances of the glymphatic system may be linked to CSS. Although there is an overlap of risk factors for centrum semiovale enlarged perivascular spaces (CSO-EPVS) and basal ganglia perivascular spaces (BG-EPVS), as MRI biomarkers for CSVD, different topographic distributions of EPVS indicate different pathological mechanisms of CSVD[ 33 ]. CSO-EPVS suggests CAA whereas BG-EPVS is associated with hypertensive vasculopathy [ 13 ]. In the present study, the CSS group had a higher occurrence of CSO-EPVS, which is in line with our hypothesis that CSS may represent an imaging change associated with CAA. Recent studies on CSF circulation disorders have linked EPVS in CSVD to the glymphatic system [ 34 ]. However, there are conflicting reports regarding the association of the topographic distribution of EPVS and the glymphatic system, One study on the pathology of CAA showed that CSO-EPVS were associated with glymphatic failure [ 35 ], and two clinical studies found glymphatic failure were associated with BG-EPVS evaluated by diffusion tensor image analysis along the perivascular space [ 36 , 37 ]. In our study, we could not replicate these findings. This discrepancy may be related to the study population, but it also raises the possibility that CSS, as a semi-quantitative visual imaging marker, may not be sensitive enough to indicate impaired glymphatic system function. In the future, automated computerized measurements may be used to further clarify the connection between the glymphatic system and the cingulate sulcus 5. Limitations There are also a few limitations to consider. Firstly, our study had a retrospective design and a relatively small sample size, which limits the ability to establish a causal relationship between CSS and imaging markers. To validate this relationship, future research should include a larger cohort of CSVD patients and employ a longitudinal study design. Secondly, the participants in our study were symptomatic CSVD patients who sought medical care, potentially leading to a selection bias. Thirdly, due to the lack of pathological evidence, we were unable to solely rely on clinical and imaging manifestations to differentiate CSVD from conditions like iNPH or other dementing diseases. This may have exaggerated the relationship between CSS and CSVD 6. Conclusion In this study, we examined the relationship between CSS and CSVD for the first time. The findings presented here suggest that CSS may represent a different etiology of CSVD and indicate some degree of glymphatic system disorder. Future longitudinal studies using high-field brain MRI and Glymphatic MRI will provide further insights into the relationship between CSS and the glymphatic system in CSVD, enhancing our understanding of the etiology and clinical relevance of this marker. Declarations Acknowledgments We thank all of the subjects and medical staff for their assistance with this study. Author Contributions Conceptualization, W.S.L and D.M.Z; Data collection，analysis and investigation, W.S.L; Writing (Original Draft Preparation), W.S.L and D.M.Z; Writing (Review and Editing), D.M.Z. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work. Ethics approval and consent to participate This study was approved by the Ethics Committee of Affiliated Shengjing Hospital of China Medical University. Funding Data collection, analysis, and interpretation of the study was supported by grants from 345 Project of Shengjing Hospital. Competing interests The authors declare that they have no competing interests. References Allison T, McCarthy G, Luby M, et al. Localization of functional regions of human mesial cortex by somatosensory evoked potential recording and by cortical stimulation. Electroencephalogr Clin Neurophysiol . 1996 ;100(2):126-40 . Naidich TP, Grant J, Altman N, et al .The developing cerebral surface. Preliminary report on the patterns of sulcal and gyral maturation--anatomy, ultrasound, and magnetic resonance imaging. Neuroimaging Clin N Am . 1994;4(2):201-40. 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Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4247704","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":290387411,"identity":"c23d9e97-d8ff-4bec-8448-b1b8c95e5d4d","order_by":0,"name":"Weishuai Li","email":"","orcid":"","institution":"Shengjing Hospital of China Medical University","correspondingAuthor":false,"prefix":"","firstName":"Weishuai","middleName":"","lastName":"Li","suffix":""},{"id":290387415,"identity":"9c527972-4f3c-4160-bec8-e3915b4cf0f4","order_by":1,"name":"Dongming Zheng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsElEQVRIiWNgGAWjYFCCBCDmseHh528gTUuajOSMAyRpYThsY9CQQKQG+fbsBMYfMud5DBgOMH74mEOEFsaetxuYeXhu85gzNzBLztxGhBZmidwNzAxALZYNB9iYeYnRwgbUwviD5xyPwYEEIrXwALUw8PAcIEGLBA/YL8k8kjMONhPnF/l2oMN+9tjZ8/M3H/zwkRgtQMD+g7EHRDM2EKceAn6QongUjIJRMApGHAAAnoowZ6ZRBscAAAAASUVORK5CYII=","orcid":"","institution":"Shengjing Hospital of China Medical University","correspondingAuthor":true,"prefix":"","firstName":"Dongming","middleName":"","lastName":"Zheng","suffix":""}],"badges":[],"createdAt":"2024-04-10 13:42:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4247704/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4247704/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":54931744,"identity":"ef62dd1e-b285-4c7a-a09e-7c550553694d","added_by":"auto","created_at":"2024-04-18 18:49:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1119278,"visible":true,"origin":"","legend":"\u003cp\u003eCases of MRI findings for lesions related to small vessel disease and Evan index；a: Axial T2-weighted MRI showing punctuate and linear hyperintensities characteristic of enlarged perivascular spaces (EPVS) in the centrum semiovale. b: punctuate hyperintensities characteristic of EPVS in the basal ganglia. c: Deep white matter hyperintensity (WMH ) graded as 3(red arrowheads) in a patient who also has periventricularWMH (graded as 2, red arrows). d-e: different topographic distributions cerebral microbleeds (lobar/ deep). f: lacunes of presumed vascular origin. g: Evan index= x/y.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4247704/v1/c0ce7280a508c874fa5f0d7a.png"},{"id":54931745,"identity":"cc4d0f84-5f30-410b-9cae-0338efb663e2","added_by":"auto","created_at":"2024-04-18 18:49:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":225340,"visible":true,"origin":"","legend":"\u003cp\u003eParamedian sagittal T1-weighted image of MRI; \u003cstrong\u003ea\u003c/strong\u003e: a 64-year-old man (negative), the posterior part (arrowheads) of the cingulate sulcus is slightly wider than the anterior part (arrows). \u003cstrong\u003eb\u003c/strong\u003e : cingulate sulcus sign (CSS): a 67-year-old man, the anterior part of the cingulate sulcus are wide (arrows), whereas the posterior part is tight (arrowheads)\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4247704/v1/d1327b89ece26b364f4de196.png"},{"id":54931748,"identity":"9c74dd6d-ffff-4b5f-a3be-6face7d491ca","added_by":"auto","created_at":"2024-04-18 18:49:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":305119,"visible":true,"origin":"","legend":"\u003cp\u003eElucidation of possible mechanisms of cingulate signatures (CSS); Arteriosclerosis and vascular Aβdeposition decrease vascular pulsation, leading to cerebrospinal fluid (CSF) stagnation, resulting in lateral ventricle enlargement and an increased Evan index (EI). Concurrently, impaired paravascular lymphatic drainage disrupts the exchange of CSF and interstitial fluid (ISF), leading to CSF/ISF accumulation and the appearance of white matter hyperintensities (WMH). Additionally, arteriosclerosis and vascular Aβdeposition increase the occurrence of cerebral microbleeds (CMBs), and the presence of lobar CMBs contributes to an increase in the volume of the posterior white matter, ultimately resulting in the formation of the cingulate sulcus sign (CSS).\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-4247704/v1/9ad7d1494de2591ca5e321d5.png"},{"id":56752661,"identity":"14a17688-dff1-475f-b74b-29624dd92037","added_by":"auto","created_at":"2024-05-20 04:09:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2772170,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4247704/v1/4b0cac79-0e59-4659-a714-c613ceaf525c.pdf"},{"id":54931746,"identity":"2a4bd38f-1eae-4ecd-b040-48e7e8874671","added_by":"auto","created_at":"2024-04-18 18:49:32","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":284641,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Table.docx","url":"https://assets-eu.researchsquare.com/files/rs-4247704/v1/e7b5a35525380b28a0eaa765.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cingulate Sulcus Sign: A Descriptive Analysis in a Cerebral Small Vessel Disease Population","fulltext":[{"header":"1.Introduction","content":"\u003cp\u003eThe cingulate sulcus is a prominent cerebral sulcus situated on the medial surface of the cerebral hemispheres. It originates in the medial portion of the frontal lobe and progresses posteriorly upward to the crest of the hemisphere\u0026rsquo;s medial surface, creating a boundary between the paracentral lobule and the precuneus[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Notably, the posterior segment of the cingulate sulcus exhibits greater variability than its anterior counterpart, owing to its later development during embryogenesis. Consequently, age-related dilation of the cingulate sulcus is predominantly observed within its posterior portion[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Researchers have surprisingly discerned a particular morphological variant termed the cingulate sulcus sign (CSS), characterized by an expanded anterior cingulate relative to the posterior cingulate, among some patients with idiopathic normal pressure hydrocephalus (iNPH) who are deemed suitable for ventriculoperitoneal shunt surgery[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Recent discoveries reveal the existence of a cerebrospinal fluid (CSF) / interstitial fluid (ISF) clearance mechanism known as the glymphatic system within the central nervous system[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This system is essential for the flow of CSF through brain tissue and the removal of solutes from the ISF, crucial for maintaining tissue homeostasis and metabolic equilibrium. Current understanding implicates a compromised glymphatic system in the pathophysiology of iNPH[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The detection of CSS could thus signify an altered CSF dynamic and perhaps indicate a malfunctioning glymphatic system in iNPH.\u003c/p\u003e \u003cp\u003eCerebral small vessel disease (CSVD) is a group of cerebrovascular diseases that primarily affect perforating arteries, capillaries or leptomeningeal vessels with various neuropathies[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], and cause a wide range of clinical manifestations, including stroke, cognitive impairment, and motor and gait impairment [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The clinical diagnosis of CSVD is primarily through magnetic resonance imaging (MRI) of parenchymal lesions corresponding to small cerebral arteries, which include recent small subcortical infarcts, lacunes of presumed vascular origin, white matter hyperintensities (WMH) of presumed vascular origin, enlarged perivascular spaces (EPVS), cerebral microbleeds (CMBs) and brain atrophy [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Indeed, more and more studies have revealed that damage of the glymphatic system played an important role in the initiation and progression of CSVD[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. If there is an association between CSS and MRI markers of CSVD, the hypothesis that lymphatic system disorders are involved in the pathogenesis of CSVD will be strengthened. Therefore, this study aims to evaluate the relationship between CSS and CSVD and attempt to elucidate potential glymphatic system disorders associated with CSS by comparing the degree of CSF/ISF sludge. To the best of our knowledge, there have been no previous studies on this subject.\u003c/p\u003e"},{"header":"2.Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study population and data collection.\u003c/h2\u003e \u003cp\u003ePatients who visited the clinic at the Neurology Department of Shengjing Hospital and met the following inclusion criteria were retrospectively enrolled in our study consecutively from January 2020 to October 2022. Subjects were enrolled if they met the following criteria: (1) Fazekas score 2\u0026ndash;3 WMH and at least one of the following three markers: lacune, CMB, and EPVS; (2) CT or MRI excluding ICH ;(3) aged\u0026thinsp;\u0026ge;\u0026thinsp;55 years old. The following were the exclusion criteria: (1) cerebral infarction with an infarction core diameter greater than 2 cm; (2) stroke from any potential cardioembolic source; (3) cerebrovascular stenosis with \u0026gt;\u0026thinsp;50% luminal stenosis suggested by transcranial Doppler ultrasound, computed tomography angiography, or magnetic resonance angiography; (4) genetically confirmed hereditary CSVD or suspected hereditary CSVD based on family history and clinical features; (6) WMH that could be caused by something other than CSVD, such as multiple sclerosis; and (7) patients showed an EVAN index(EI)\u0026thinsp;\u0026ge;\u0026thinsp;0.3 or disproportionately enlarged subarachnoid-space hydrocephalus;\u003c/p\u003e \u003cp\u003eDemographic and clinical information was obtained by a review of the medical records or interviews with the patients or their family members. The presence of hypertension, hyperlipidemia, diabetes and previous stroke was determined based on a prior medical diagnosis and treatment among all patients. Smoking or drinking was defined by a history of tobacco or alcohol use. The present study was performed in accordance with the ethical standards established in the 1964 Declaration of Helsinki and its subsequent amendments. Written informed consent from each subject and/or the subject\u0026rsquo;s relatives was obtained. The ethics committee of our institution approved the procedures of this study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Neuroimaging acquisition and analysis\u003c/h2\u003e \u003cp\u003eConventional imaging was obtained with a 3.0T MR scanner including T2-weighted, T1-weighted and fluid attenuated inversion recovery (FLAIR). Susceptibility weighted imaging (SWI) acquisition was performed with a T2*-weighted gradient echo sequence with a flip angle of 15\u0026deg;, TR/TE\u0026thinsp;=\u0026thinsp;30/20 ms, and slice thickness\u0026thinsp;=\u0026thinsp;1.8 mm. SWI and minimum intensity projection images were acquired by in-line post processing of magnitude and phase images, and these post processed images were used for the evaluation of the imaging findings. EPVS, CMB, lacune and WMH were defined according to the STandards for ReportIng Vascular changes on Euroimaging [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Representative images of characteristic CSVD lesions are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e(a-f) .The number of EPVS was measured in the basal ganglia (BG) and centrum semiovale (CSO) and was dichotomized as either high degree (score\u0026thinsp;\u0026gt;\u0026thinsp;20) or low degree (score\u0026thinsp;\u0026lt;\u0026thinsp;20) according to a previously published protocol [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The number of CMBs was measured in lobar and/or deep and was categorized into the lobar dominant group and non-lobar dominant group according to the ratio of lobar to deep CMBs number .The WMH were scored on FLAIR images using the Fazekas score [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe EI was defined as the ratio between the maximal width of the frontal horns of the lateral ventricles and the maximal inner diameter of the skull on the same slice [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. g) .\u003c/p\u003e \u003cp\u003eCSS were identified on paramedian-sagittal T1 weighted images according to a previously published protocol [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. A normal finding was defined as the anterior part of the cingulate sulcus being the same width as the posterior part or the posterior part being wider than the anterior part (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. a). Positive CSS was narrowness of the posterior part of the cingulate sulcus with respect to the anterior part on a sagittal slice. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. b)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe above image features were identified and counted by two experienced researchers independently, and the researchers were blinded to the patients\u0026rsquo; clinical data. In the event of any disagreement between the two raters, a consensus was reached with the help of a neuroradiologist (D.M.Z),\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistics.\u003c/h2\u003e \u003cp\u003eData normality was assessed using the Kolmogorov\u0026ndash;Smirnov test. Continuous variables are represented as interquartile ranges (IQRs). Categorical variables were described using frequencies (N, %). Univariate analyses were performed to evaluate differences in demographic, clinical, and neuroimaging characteristics between the patients with and without CSS using χ2 and Fisher\u0026rsquo;s exact tests for categorical variables and Mann\u0026ndash;Whitney U tests for continuous variables. To test for independent associations with the presence of CSS, all variables that showed a p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 in the univariate analyses were entered in a multivariable logistic regression analysis. Logistic regression models were run with a stepwise forward elimination method to generate a minimal adjusted model. In this study, for purposes of statistical analyses, the EI was categorized into\u0026lt;0.25 and 0.25\u0026ndash;0.3. All statistical analyses in this study were performed with SPSS 22.0 software (IBM SPSS Inc., Chicago, IL, United States), and statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eA total of 308 patients with CSVD were included in the study. The average age of the patients was 66.0(61.0 -72.0) years. Approximately 55.2% of the patients were male. The presence of lacunes and CMBs, lobar dominant CMBs, high degree BG-PVS and high degree CSO-PVS, were observed in 187 (60.7%), 131 (42.5%), 82 (26.6%), 135 (43.8%), and 166 (53.9%) patients, respectively. The median scores for deep WMH and periventricular WMH, and EI were 2.0 (1.0 -3.0), 3.0 (2.0 -3.0) and 0.25 (0.23 - 0.27), respectively.\u003c/p\u003e\n\u003cp\u003e3.1 Univariable analysis of clinical and imaging characteristics of study population\u003c/p\u003e\n\u003cp\u003eThe basic characteristics of the CSS group and n-CSS group are listed in Table 1. Demographic and clinical information did not significantly difference between the two groups (all p\u0026gt;0.05). The presence of lacunes was significantly lower in the CSS group compared to the n-CSS group (p=0.023). Moreover, the CSS group displayed a higher EI (p\u0026lt;0.001), more severe deep WMH (P=0.001) and periventricular WMH (p\u0026lt;0.001), a higher prevalence of lobar dominant CMBs (P=0.02) and high degree CSO-PVS (P=0.01). However, no significant difference was observed in high degree BG-PVS and presence of CMBs between the two groups.\u003c/p\u003e\n\u003cp\u003e3.2 Multivariable analysis of neuroimaging markers associated with CSS\u003c/p\u003e\n\u003cp\u003eThe multivariable analysis of the association between imaging markers of CSVD and CSS is presented in Table 2. After adjustment for variables that were significant in the univariate analysis, CSS was independently correlated with presence of lacunes (odds ratio [OR] 0.347, 95% confidence interval [CI] 0.187-0.645, p=0.001)，presence of lobar dominant CMBs (OR 2.741, 95%CI 1.416-5.308, p=0.003), periventricular WMH Fazekas score (OR 1.752, 95% CI 1.174\u0026ndash;2.615, p=0.006) and EI (0.25-0.3, OR 4.293, 95% CI 2.311\u0026ndash;7.976, p＜0.001, reference group＜0.25)\u0026nbsp;\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this paper, we demonstrate that approximately 26% of patients with cerebral small vessel disease (CSVD) exhibit the cingulate sulcus sign (CSS). Distinct from demographic and vascular risk factors, most CSVD imaging markers were noticeably differentiated between the two groups. Dominant lobar cerebral microbleeds (CMBs), periventricular white matter hyperintensities (WMH), and Evans Index (EI) were predictors of CSS, whereas lacunes were more frequently associated with the typical CSVD pattern of cingulate gyrus atrophy.\u003c/p\u003e \u003cp\u003eThe cingulate sulcus as an important brain anatomical structure, is widely used in the study of various neurological disorders, and the degree of its atrophy is related to the progression of the disease[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, most of these studies employed computerized automated voxel morphometric analyses, which do not cater to individual assessment. Recently, a semi-quantitative visual method was utilized to demonstrate that CSS, which represents a narrowing of the posterior cingulate gyrus in the sagittal plane, could effectively identify patients with idiopathic normal pressure hydrocephalus (iNPH) suitable for shunt surgery [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This finding raises the speculation that CSS may potentially represent a glymphatic system dysfunction. In our current exploration, we observed the presence of CSS in some CSVD patients. The observations are consistent with earlier study findings which suggest that atherosclerosis and small vessel stiffness lead to reduced vascular pulsation and subsequently result in weakening cerebrospinal fluid (CSF) / interstitial fluid (ISF) exchange [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Even though a healthy control group was not considered in this study, the similarity in age and vascular risk factors between the two groups suggest that the emergence of CSS is not merely a result of aging or atherosclerosis, but may be linked to different pathogenic mechanisms of CSVD, such as cerebral amyloid angiopathy (CAA),which is typically characterized by the accumulation of amyloid β in the walls of leptomeningeal vessels and cortical capillaries in the brain [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEI is frequently used as a quick and easy way to evaluate ventriculomegaly [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], which can either be secondary to brain atrophy or represent an impairment of CSF circulation. A automated surface-based study on the morphology of the cingulate sulcus found that patients with vascular cognitive disorders, exhibiting widened cingulate sulcus and accompanying ventriculomegaly, differed from both iNPH patients and healthy controls [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, our study revealed a strong association between the presence of CSS and a larger EI. To minimize the interference of iNPH, we specifically selected patients with an EI of less than 0.3 for this study, which might have reduced the power to detect associations. Nevertheless, we were still able to find significant associations between CSS and EI. One possible explanation for the contradictory results is that CSS is different from the mechanism underlying computer-automated morphological changes in the cingulate sulcus. Unlike the latter, CSS represents impaired CSF circulation rather than being solely secondary to cerebral atrophy. Furthermore, our research has uncovered a greater prevalence of lacunar within the non-CSS group. This can be attributed to the relationship between lacunar infarcts and brain atrophy. Previous studies have demonstrated that lacunar infarcts are associated with a greater progression of brain atrophy and cortical thickness in patient of CSVD [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Notably, these pathological atrophies are particularly pronounced in the posterior region [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This form of atrophy is consistent with the morphological characteristics of the non-CSS group in this study.\u003c/p\u003e \u003cp\u003eCMBs are small, round collections of hemosiderin-laden macrophages in the brain that represent areas of previous microhemorrhages [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], They are now considered an imaging marker for CSVD [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In the present study, we found that CSS was mostly present in CSVD patients with predominantly lobar CMBs. Previous studies have reported that different topographic distributions of CMBs indicate different pathological mechanisms. For instance, CMBs in deep brain regions are radiological biomarkers of hypertensive arterial pathology [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], whereas CMBs in superficial or predominantly lobar regions are strongly associated with CAA pathology [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Our results suggest that the emergence of CSS may be related to CAA. Additionally, the imaging characteristics of CSS mentioned in this study are similar to those observed by Wang et al.[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] and Beaman et al.[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] who found that the presence of superficial CMBs can lead to an increase in white matter volume, especially in the parietal and occipital regions, due to impaired glymphatic system function.(Fig .3)\u003c/p\u003e \u003cp\u003eWMH of presumed vascular origin are frequent in cerebral MRI of older people [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].They are promoted by vascular risk factors, especially hypertension and usually reflect axonal loss and demyelination following chronic ischemia [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].Our data suggest that despite increased WMH scores in the CSS group, there was no difference in vascular risk factors, including hypertension, which suggests that the mechanism underlying WMH may be multifactorial. This finding is supported by previous research, that WMHs are also a consequence of failure to eliminate interstitial fluid (ISF) from the white matter [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].In contrary to deep WMH, which may be impacted by both ischemia-hypoperfusion and malfunction of the glymphatic route, periventricular WMH is primarily linked to glymphatic pathway dysfunction [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Based on the aforementioned studies, the independent association between periventricular WMH and CSS in our study strengthens the notion that disturbances of the glymphatic system may be linked to CSS.\u003c/p\u003e \u003cp\u003eAlthough there is an overlap of risk factors for centrum semiovale enlarged perivascular spaces (CSO-EPVS) and basal ganglia perivascular spaces (BG-EPVS), as MRI biomarkers for CSVD, different topographic distributions of EPVS indicate different pathological mechanisms of CSVD[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. CSO-EPVS suggests CAA whereas BG-EPVS is associated with hypertensive vasculopathy [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In the present study, the CSS group had a higher occurrence of CSO-EPVS, which is in line with our hypothesis that CSS may represent an imaging change associated with CAA. Recent studies on CSF circulation disorders have linked EPVS in CSVD to the glymphatic system [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. However, there are conflicting reports regarding the association of the topographic distribution of EPVS and the glymphatic system, One study on the pathology of CAA showed that CSO-EPVS were associated with glymphatic failure [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], and two clinical studies found glymphatic failure were associated with BG-EPVS evaluated by diffusion tensor image analysis along the perivascular space [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. In our study, we could not replicate these findings. This discrepancy may be related to the study population, but it also raises the possibility that CSS, as a semi-quantitative visual imaging marker, may not be sensitive enough to indicate impaired glymphatic system function. In the future, automated computerized measurements may be used to further clarify the connection between the glymphatic system and the cingulate sulcus\u003c/p\u003e"},{"header":"5. Limitations","content":"\u003cp\u003eThere are also a few limitations to consider. Firstly, our study had a retrospective design and a relatively small sample size, which limits the ability to establish a causal relationship between CSS and imaging markers. To validate this relationship, future research should include a larger cohort of CSVD patients and employ a longitudinal study design. Secondly, the participants in our study were symptomatic CSVD patients who sought medical care, potentially leading to a selection bias. Thirdly, due to the lack of pathological evidence, we were unable to solely rely on clinical and imaging manifestations to differentiate CSVD from conditions like iNPH or other dementing diseases. This may have exaggerated the relationship between CSS and CSVD\u003c/p\u003e"},{"header":"6. Conclusion","content":"\u003cp\u003eIn this study, we examined the relationship between CSS and CSVD for the first time. The findings presented here suggest that CSS may represent a different etiology of CSVD and indicate some degree of glymphatic system disorder. Future longitudinal studies using high-field brain MRI and Glymphatic MRI will provide further insights into the relationship between CSS and the glymphatic system in CSVD, enhancing our understanding of the etiology and clinical relevance of this marker.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all of the subjects and medical staff for their assistance with this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization, W.S.L and D.M.Z; Data collection，analysis and investigation, W.S.L; Writing (Original Draft Preparation), W.S.L and D.M.Z; Writing (Review and Editing), D.M.Z. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Affiliated Shengjing Hospital of China Medical University.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData collection, analysis, and interpretation of the study was supported by grants from 345 Project of Shengjing Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAllison T, McCarthy G, Luby M, et al. 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Caruso P.Small Vessel Disease-Related Dementia: An Invalid Neurovascular Coupling? \u003cem\u003eInt J Mol Sci\u003c/em\u003e.2020; 21:1095. \u003c/li\u003e\n\u003cli\u003eVan Veluw SJ, Biessels GJ, Bouvy WH, et al.Cerebral amyloid angiopathy severity is linked to dilation of juxtacortical perivascular spaces.\u003cem\u003e J Cereb Blood Flow Metab\u003c/em\u003e.2016; 36(3):576-80. \u003c/li\u003e\n\u003cli\u003eZhang W, Zhou Y, Wang J, et al. Glymphatic clearance function in patients with cerebral small vessel disease. \u003cem\u003eNeuroimage\u003c/em\u003e.2021; 238:118257. \u003c/li\u003e\n\u003cli\u003eXu J, Su Y, Fu J, et al .Glymphatic dysfunction correlates with severity of small vessel disease and cognitive impairment in cerebral amyloid angiopathy. \u003cem\u003eEur J Neurol\u003c/em\u003e.2022; 29(10):2895-2904.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"cingulate sulcus sign, cerebral small vessel disease, glymphatic system; Evan index, white matter hyperintensity","lastPublishedDoi":"10.21203/rs.3.rs-4247704/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4247704/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe cingulate sulcus sign (CSS) has been observed in patients with idiopathic normal pressure hydrocephalus (iNPH), suggesting potential disruptions in cerebrospinal fluid circulation and compromised glymphatic system. Although there are similarities in the underlying mechanisms between cerebral small vessel disease (CSVD) and iNPH, the relationship between CSS and CSVD remains unclear. This study aimed to investigate the prevalence and potential mechanisms of CSS in patients with CSVD.Data from patients diagnosed with CSVD at Shengjing Hospital of China Medical University between January 2020 and October 2022 were retrospectively collected, including general information and four CSVD magnetic resonance imaging (MRI) markers(white matter hyperintensity (WMH), cerebral microbleeds (CMBs), lacunes, and enlarged perivascular spaces (EPVS), CSS and the Evan index (EI). A total of 308 patients were included, and CSS was detected in 80 patients (26%). Multivariable analysis showed an independent correlation between CSS and the presence of lacunes (odds ratio [OR] 0.347, 95% confidence interval [CI] 0.187\u0026ndash;0.645, p\u0026thinsp;=\u0026thinsp;0.001), the presence of lobar dominant CMBs (OR 2.741, 95%CI 1.416\u0026ndash;5.308, p\u0026thinsp;=\u0026thinsp;0.003), the periventricular WMH Fazekas score (OR 1.752, 95% CI 1.174\u0026ndash;2.615, p\u0026thinsp;=\u0026thinsp;0.006), and EI (0.25\u0026ndash;0.3; OR 4.293, 95% CI 2.311\u0026ndash;7.976, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, reference group\u0026thinsp;\u0026lt;\u0026thinsp;0.25).This preliminary study showed that CSS can be observed in some patients with CSVD. The presence of CSS may represent different mechanisms of CSVD pathogenesis and reflect differences in the degree of cerebrospinal fluid (CSF)/interstitial fluid (ISF) stasis.\u003c/p\u003e","manuscriptTitle":"Cingulate Sulcus Sign: A Descriptive Analysis in a Cerebral Small Vessel Disease Population","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-18 18:49:27","doi":"10.21203/rs.3.rs-4247704/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"07fd85f1-a344-4f01-bd40-097859b7738a","owner":[],"postedDate":"April 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-20T04:08:47+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-18 18:49:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4247704","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4247704","identity":"rs-4247704","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}