Quantitative susceptibility mapping for differentiating multiple sclerosis from cerebral small vessel disease

Paramagnetic susceptibility versus QSM for estimating OEF: A comparative study in cerebral small vessel disease.

Background: Altered white matter brain networks have been extensively studied in cerebral small vessel disease (SVD). However, there exists currently a deficiency of comprehending the performance of changes within the structural networks of the brain in cases with cerebral SVD and depression symptoms. The main aim of the present research is to study the network topology behaviors and features of rich-club organization in SVD patients using graph theory and diffusion tensor imaging (DTI) to characterize changes in the microstructure of the brain. Methods: DTI datasets were acquired from 26 SVD patients with symptoms of depression (SVD + D) and 26 SVD patients without symptoms of depression (SVD − D), and a series of neuropsychological assessments were completed. A structural network was created using a deterministic fiber tracking method. The analysis of rich-club was performed in company with analysis of the global network features of the network to characterize the topological properties of all subjects. Results: DTI data were obtained from SVD patients who manifested symptoms of depression (SVD + D) and from control SVD patients (SVD − D). In comparison with SVD − D patients, SVD + D cases demonstrated a diminished coefficient of clustering along with lower global efficiencies and longer path length characteristics. Rich-club analysis showed SVD + D patients had decreased feeder connectivity and local connectivity strengths compared to SVD − D patients. Our data also showed that the feeder connections in the brain correlated significantly with the severity of depression in SVD + D patients. Conclusions: Our study revealed that SVD patients with depressive symptoms have disrupted white matter networks that characteristically have reduced network efficiency compared to the networks in other SVD patients. Disrupted information interactions among the regions of nonrich-club and rich-club in SVD cases are related to the severity of depression. Our data suggest that DTI may be utilized as an appropriate biomarker for the diagnosis of depression in comorbid SVD patients.

Background and PurposeCerebral small vessel disease (SVDs) are related with large artery atherosclerosis. However, the association between aortic atheroma (AA) and cerebral small vessel disease has rarely been reported. This study evaluated the relationship between presence and burden of AAs and those of SVDs in patients with acute ischemic stroke.MethodsWe included 737 consecutive patients who underwent transesophageal echocardiography (TEE) and brain magnetic resonance imaging (MRI) for evaluation of acute stroke. AA subtypes were classified as complex aortic plaque (CAP) and simple aortic plaque (SAP). Presence and burden of SVDs including cerebral microbleeds (CMBs), white matter hyperintensities (WMHs), perivascular spaces (PVSs), asymptomatic lacunar infarctions (ALIs), and total SVD score, were investigated.ResultsAA was found by TEE in 360 (48.8%) patients including 11.6% with CAP and 37.2% with SAP. One or more types of SVDs was found in 269 (36.4%) patients. In multivariable analysis, presence of CMBs (odds ratio [OR] 4.68), high-grade WMHs (OR 3.13), high-grade PVSs (OR 3.35), and ALIs (OR 4.24) were frequent in patients with AA than those without AA. Each 1-point increase in total SVD score increased the odds of presence of CAP (OR 1.94, 95% confidence interval (CI) 1.44-1.85) and SAP (OR 1.54, 95% CI 1.35-1.75).ConclusionsIn this study, patients with AA frequently had cerebral SVDs. Larger burden of AA was associated with advanced cerebral SVDs. Our findings give an additional information for positive relationship with systemic atherosclerosis and coexisting cerebral SVDs in acute ischemic stroke patients.

Background and Purpose:MRI studies have demonstrated magnetic susceptibility in multiple sclerosis (MS) lesions is dependent on lesion age. The objective of this study was to utilize quantitative susceptibility mapping (QSM) to determine whether lesions with hyperintense rim, indicative of iron-laden inflammatory cells (rim+), follow a unique time-dependent trajectory of susceptibility change compared to those without (rim−).Materials and Methods:MS patients with at least one new gadolinium (Gd)-enhancing lesion and at least three longitudinal QSM scans ranging between 1.1 to 6.1 years. Lesions were classified as rim+ if a hyperintense rim appeared on QSM at any time. A multilevel growth curve model compared longitudinal susceptibility among rim+ and rim− lesions.Results:Thirty-two new Gd-enhancing lesions from 19 MS patients were included and 16 lesions (50%) were identified as rim+. QSM rim+ lesions were larger than rim− lesions at Gd-enhancement (p<0.0001). Among all lesions, susceptibility increased sharply after enhancement to a peak between 1 to 2 years followed by a decrease. The overall susceptibility curve height for rim− lesions was 4.27 ppb lower than that for rim+ lesions (p=0.0097). Rim− lesions demonstrated higher linear slope relative to rim+ lesions (p=0.0232) but faster cubic decay relative to rim+ lesions (p=0.0053). Rim− lesions started decaying approximately 2 years earlier as compared to rim+ lesions.Conclusion:There was a marked difference in susceptibility temporal trajectory between rim+ and rim− lesions over the first six years of lesion formation. The majority of rim+ lesions retain iron for years after initial lesion appearance.

Introduction: There is evidence that circulating factors disrupt vessel function in the contralateral hemisphere after stroke. However, how different stroke subtypes, that have more severe vascular disruption, affect nonischemic vessels is unknown. Here, we compared circulating factors from human patients with distinct stroke subtypes of cardioembolic (CE), small vessel disease (SVD), and intracerebral hemorrhage (ICH). We hypothesized that serum from ICH patients would cause greater vascular dysfunction of nonischemic arteries than CE, and that serum from SVD patients would have an intermediate effect. Methods: Serum was obtained 24 hours poststroke from patients with SVD (n=3), ICH (n=4), and CE (n=7) and pooled. All patients had a medical history of hypertension. Only SVD and CE patients received tPA. Pooled serum 20% v/v was perfused into the lumen of 3 rd order posterior cerebral arteries (PCA, CE &amp; ICH n=5, SVD n=6) that were mounted on glass cannulas and pressurized in an arteriograph chamber. Blood brain barrier (BBB) permeability and vascular reactivity was studied to investigate effects on myogenic tone and endothelial function. Data are presented as mean±SEM. Results: All vessels reacted myogenically at pressures ≥40 mmHg. However, serum from ICH patients caused a significant increase in tone at 20 mmHg vs. CE and SVD groups: 37.5±1.6 vs. 9.0±1.9% and 13.0±4.8% p&lt;0.05. There was no difference in dilation to NS309; however, constriction to nitric oxide synthase (NOS) inhibition with L-NAME was impaired with SVD and ICH serum compared to CE: 14.0±2.3% vs. 4.6±0.8% (p&lt;0.05) and 5.8±2.1% (p=0.09). However, reactivity to sodium nitroprusside, an NO donor, was not different between groups. Serum caused an increase in BBB permeability over time that was not different with the different serums. Conclusions: Circulating factors from ICH, SVD and CE patients had differing vascular effects on nonischemic cerebral arteries. Serum from ICH patients was vasoconstrictive, potentially due to hemostatic factors, whereas serum from both SVD and ICH patients had impaired NO reactivity demonstrating endothelial dysfunction. These effects of ischemic stroke could affect the contralateral hemisphere and contribute to outcome and therapeutic responses.

Oligodendrocyte Progenitor Cell Susceptibility to Injury in Multiple Sclerosis

Susceptibility-sensitive magnetic resonance imaging (MRI) has gained importance in multiple sclerosis (MS) research because of its versatility, high resolution and excellent sensitivity to changes in tissue structure and composition. In particular, mapping of the resonance frequency of the MR signal and quantitative susceptibility mapping (QSM) have been explored for the description of MS lesions. Many current studies utilizing these techniques attribute increases in the MR frequency or QSM to elevated tissue iron content, in addition to myelin loss. However, this common interpretation is inconsistent with recent histopathological studies. Here, we investigate the nature of MR frequency shifts related to MS lesions by comparing post-mortem MRI data with histology, and contrast them with numerical simulations of the MR signal. We demonstrate that iron accumulation is not the driving source of the MR frequency or QSM image contrast in our sample; rather, most chronic MS lesions are characterized by advanced loss of both myelin and iron. Moreover, our results suggest that the appearance of MS lesions on MR frequency maps and QSM depends on changes in the non-lesional white matter surrounding the lesions. Understanding and accounting for these changes is essential for the quantitative interpretation of MR frequency or QSM data in white matter.

Instant tissue field and magnetic susceptibility mapping from MRI raw phase using Laplacian enhanced deep neural networks

Multiple sclerosis (MS) misdiagnosis remains an important issue in clinical practice. To quantify the performance of cortical lesions (CLs) and central vein sign (CVS) in distinguishing MS from other conditions showing brain lesions on magnetic resonance imaging (MRI). This was a retrospective, cross-sectional multicenter study, with clinical and MRI data acquired between January 2010 and May 2020. Centralized MRI analysis was conducted between July 2020 and December 2022 by 2 raters blinded to participants' diagnosis. Participants were recruited from 14 European centers and from a multicenter pan-European cohort. Eligible participants had a diagnosis of MS, clinically isolated syndrome (CIS), or non-MS conditions; availability of a brain 3-T MRI scan with at least 1 sequence suitable for CL and CVS assessment; presence of T2-hyperintense white matter lesions (WMLs). A total of 1051 individuals were included with either MS/CIS (n = 599; 386 [64.4%] female; mean [SD] age, 41.5 [12.3] years) or non-MS conditions (including other neuroinflammatory disorders, cerebrovascular disease, migraine, and incidental WMLs in healthy control individuals; n = 452; 302 [66.8%] female; mean [SD] age, 49.2 [14.5] years). Five individuals were excluded due to missing clinical or demographic information (n = 3) or unclear diagnosis (n = 2). MS/CIS vs non-MS conditions. Area under the receiver operating characteristic curves (AUCs) were used to explore the diagnostic performance of CLs and the CVS in isolation and in combination; sensitivity, specificity, and accuracy were calculated for various cutoffs. The diagnostic importance of CLs and CVS compared to conventional MRI features (ie, presence of infratentorial, periventricular, and juxtacortical WMLs) was ranked with a random forest model. The presence of CLs and the previously proposed 40% CVS rule had a sensitivity, specificity, and accuracy for MS of 59.0% (95% CI, 55.1-62.8), 93.6% (95% CI, 91.4-95.6), and 73.9% (95% CI, 71.6-76.3) and 78.7% (95% CI, 75.5-82.0), 86.0% (95% CI, 82.1-89.5), and 81.5% (95% CI, 78.9-83.7), respectively. The diagnostic performance of the CVS (AUC, 0.89 [95% CI, 0.86-0.91]) was superior to that of CLs (AUC, 0.77 [95% CI, 0.75-0.80]; P < .001), and was increased when combining the 2 imaging markers (AUC, 0.92 [95% CI, 0.90-0.94]; P = .04); in the random forest model, both CVS and CLs outperformed the presence of infratentorial, periventricular, and juxtacortical WMLs in supporting MS differential diagnosis. The findings in this study suggest that CVS and CLs may be valuable tools to increase the accuracy of MS diagnosis.

Central vein sign: A diagnostic biomarker in multiple sclerosis (CAVS-MS) study protocol for a prospective multicenter trial

The Taiwan-Associated Genetic and Non-genetic Small Vessel Disease (TAG-SVD) cohort prospectively enrolls patients with cerebral small vessel disease (SVD). The aim of this study was to determine the prevalence and characteristics of monogenic SVD in patients within the TAG-SVD cohort. All patients in the TAG-SVD cohort underwent initial screening for NOTCH3 p.R544C variant, which is the hotspot disease-causing variant in Taiwan. Those who tested negative for NOTCH3 p.R544C variant underwent next-generation sequencing targeting 5 candidate SVD genes: NOTCH3, HTRA1, GLA, TREX1, and COL4A1. Clinical and neuroimaging features were compared between the genetic and nongenetic groups, as well as between specific pathogenic variants in NOTCH3 and HTRA1. A total of 1,086 patients (mean age 62.9 ± 12.4 years, 61% male) were enrolled. Disease-causing variants in the candidate genes were identified in 284 patients (26.2%), including 244 with the NOTCH3 p.R544C variants, 12 with NOTCH3 variants in EGFr 7-34 outside the p.R544C hotspot, 11 with NOTCH3 variants in EGFr 1-6, 9 with HTRA1, 5 with TREX1, 2 with COL4A1, and 1 with a GLA pathogenic variant. Compared with those with nongenetic SVD, individuals with monogenic SVD were more likely to be female, exhibited a higher familial stroke history, had lower rates of hypertension and diabetes, and experienced fewer previous strokes. They also displayed more severe white matter hyperintensity (WMH) and a higher prevalence of anterior temporal and external capsule WMH involvement on MRI. Patients with HTRA1 pathogenic variants had similar ages at genetic diagnosis, ages at stroke, and WMH severity compared with those with NOTCH3 pathogenic variants in EGFr 7-34. However, they had a later age at onset and milder severity compared with those with NOTCH3 pathogenic variants in EGFr 1-6. Anterior temporal WMH involvement was most pronounced in patients with NOTCH3 EGFr 1-6 (82%), less in NOTCH3 EGFr 7-34 (33%), and absent in those with HTRA1 pathogenic variants. Monogenic disease-causing variants are relatively common in Taiwanese patients with SVD, particularly the NOTCH3 p.R544C variants. HTRA1 variants exhibited similar clinical and imaging features to NOTCH3 EGFr 7-34 variants, but without anterior temporal WMH involvement. These findings underscore the importance of genetic screening to understand SVD heterogeneity and guide personalized management.

Multiple sclerosis: Classification revisited reveals homogeneity and recapitulation

Primary lateral sclerosis (PLS) is a neurodegenerative disorder that primarily affects the central motor system. In rare cases, clinical features of PLS may overlap with those of progressive supranuclear palsy (PSP). We investigate neuroimaging features that can help distinguish PLS with overlapping features of PSP (PLS-PSP) from PSP. Six patients with PLS-PSP were enrolled between 2019 and 2023. We compared their clinical and neuroimaging characteristics with 18 PSP-Richardson syndrome (PSP-RS) patients and 20 healthy controls. Magnetic resonance imaging, 18F-flortaucipir positron emission tomography (PET), quantitative susceptibility mapping, and diffusion tensor imaging tractography (DTI) were performed to evaluate eight brain regions of interest. Area under the receiver operating characteristic curve (AUROC) was calculated. Five of the six PLS-PSP patients (83.3%) were male. Median age at symptom onset was 61.5 (52.5-63) years, and all had mixed features of PLS and PSP. Volumes of the pallidum, caudate, midbrain, and cerebellar dentate were smaller in PSP-RS than PLS-PSP, providing good discrimination (AUROC = 0.75 for all). The susceptibilities in pallidum, midbrain, and cerebellar dentate were greater in PSP-RS compared to PLS-PSP, providing excellent discrimination (AUROC ≥ 0.90 for all). On DTI, fractional anisotropy (FA) in the posterior limb of the internal capsule from the corticospinal tract was lower in PLS-PSP compared to PSP-RS (AUROC = 0.86), but FA in the superior cerebellar peduncle was lower in PSP-RS (AUROC = 0.95). Pallidum flortaucipir PET uptake was greater in PSP-RS compared to PLS-PSP (AUROC = 0.74). Regional brain volume, tractography, and magnetic susceptibility, but not tau-PET, are useful in distinguishing PLS-PSP from PSP.

To evaluate prospectively whether an intravenous gadolinium injection could improve the detection of the central vein sign on susceptibility-weighted imaging sequences obtained with a 1.5 T magnetic resonance scanner in patients with multiple sclerosis compared to unenhanced susceptibility-weighted images. This prospective, institution review board-approved study included 19 patients affected by multiple sclerosis (six men; 13 women; mean age 40.8 years, range 20-74 years). Patients had the relapsing-remitting clinical subtype in 95% of cases, and only one (5%) patient had the primary progressive clinical subtype of multiple sclerosis. T2-weighted images, fluid-attenuated inversion recovery images, unenhanced and contrast-enhanced susceptibility-weighted images were evaluated in consensus by two neuroradiologists for the presence of the central vein sign. The readers were blinded to magnetic resonance imaging reports, clinical information, the presence and the localisation of focal hyperintense white matter lesions. Any discordance between readers was resolved through a joint review of the recorded images with an additional neuroradiologist. A total of 317 multiple sclerosis lesions were analysed. The central vein sign had a higher prevalence detection rate on gadolinium-enhanced susceptibility-weighted images (272 of 317 lesions, 86%) compared to unenhanced susceptibility-weighted images (172 of 317 lesions, 54%). Gadolinium-enhanced susceptibility-weighted imaging improves the detection rate of the central vein sign in multiple sclerosis lesions.

Objectives To investigate the changes of intracranial hemodynamics of symptomatic and asymptomatic in patients with the small vessel disease (SVD), to find the cut off value for the diagnosis of SVD by TCD. Methods Form June 2013 to December 2014, a total of 279 SVD patients were recruited confirmed by magnetic resonance imaging (MRI) in the Second Clinical Hospital of Guangzhou University of Traditional Chinese Medicine. All patients underwent magnetic resonance angiography (MRA), color Doppler ultrasound and TCD examination. The white matter lesions, number of infarcts and hemodynamic parameters were recorded. The cerebral vascular risk factors, stroke number, degree of cerebral white matter lesions and hemodynamic parameters were compared between symptomatic and asymptomatic in patients with SVD. The sensitivity and specificity of pulsatility index (PI) in the diagnosis of SVD were calculated, and the receiver operating characteristic (ROC) curve was plotted. Results There was statistically difference in degree of white matter lesion between the asymptomatic and symptomatic group (P<0.05). The degree of leukoaraiosis in asymptomatic SVD group was mainly grade 0~1 accounting for 34.6% (28/81) and 35.8% (29/81) respectively, and grade 3~4 accounting for 14.8% (12/81). In symptomatic SVD group, grade 0 accounted for 15.7% (31/198), grade 1~3 for 29.8% (59/198), 29.3% (58/198) and 25.3% (50/198), respectively. The proportion of leukoaraiosis with grade 0 in asymptomatic SVD was higher than in symptomatic group, while the grade 2~3 was lower than that in symptomatic SVD, and the difference was statistically significant (χ2=13.574, P=0.001; χ2=6.423, P=0.040; χ2=8.265; P=0.005). The mean flow velocity of vertebral artery (VA) and basilar artery (BA) in the symptomatic group was lower than that in asymptomatic group [(23.6±7.3) cm/s vs (27.8±7.0) cm/s, (31.9±10.3) cm/s vs (35.3±9.3) cm/s], and the difference was statistically significant (t=4.269, P<0.001; t=2.500, P=0.013). There was no significant difference in mean velocity of anterior cerebral artery (ACA), middle cerebral artery (MCA) and posterior cerebral artery (PCA) between the two groups. PI were higher in patients with symptom group than asymptomatic group (P<0.05). The mean flow velocity of vertebral and basilar artery of symptom group were lower than those in the asymptomatic group (P<0.05). The optimum cut-off values of PI in diagnosing symptomatic SVD were 1.05 and 1.10, and their sensitivity, specificity and area under the ROC curve was 37.9%, 78.7%, 0.590 and 22.6%, 82.5%, 0.534 respectively. Conclusion It may be lack of sensitivity to screen SVD by TCD, although the PI were higher in patients with the symptomatic SVD than the asymptomatic SVD. Key words: Ultrasonography, Doppler, transcranial; Small vessel disease; Hemodynamic