Paramagnetic rims are a promising diagnostic imaging biomarker in multiple sclerosis

MRI; Multiple sclerosis; BiomarkersRessonància magnètica; Esclerosi múltiple; BiomarcadorsResonancia magnética; Esclerosis múltiple; BiomarcadoresBackground: White matter lesions (WMLs) on brain magnetic resonance imaging (MRI) in multiple sclerosis (MS) may contribute to misdiagnosis. In chronic active lesions, peripheral iron-laden macrophages appear as paramagnetic rim lesions (PRLs). Objective: To evaluate the sensitivity and specificity of PRLs in differentiating MS from mimics using clinical 3T MRI scanners. Method: This retrospective international study reviewed MRI scans of patients with MS (n = 254), MS mimics (n = 91) and older healthy controls (n = 217). WMLs, detected using fluid-attenuated inversion recovery MRI, were analysed with phase-sensitive imaging. Sensitivity and specificity were assessed for PRLs. Results: At least one PRL was found in 22.9% of MS and 26.1% of clinically isolated syndrome (CIS) patients. Only one PRL was found elsewhere. The identification of ⩾1 PRL was the optimal cut-off and had high specificity (99.7%, confidence interval (CI) = 98.20%–99.99%) when distinguishing MS and CIS from mimics and healthy controls, but lower sensitivity (24.0%, CI = 18.9%–36.6%). All patients with a PRL showing a central vein sign (CVS) in the same lesion (n = 54) had MS or CIS, giving a specificity of 100% (CI = 98.8%–100.0%) but equally low sensitivity (21.3%, CI = 16.4%–26.81%) Conclusion: PRLs may reduce diagnostic uncertainty in MS by being a highly specific imaging diagnostic biomarker, especially when used in conjunction with the CVS

Widespread inflammation in CLIPPERS syndrome indicated by autopsy and ultra-high-field 7T MRI

OBJECTIVE: To examine if there is widespread inflammation in the brain of patients with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) syndrome by using histology and ultra-high-field MRI at 7.0T. METHODS: We performed a detailed neuropathologic examination in 4 cases, including 1 autopsy case, and studied 2 additional patients by MRI at 7.0T to examine (1) extension of inflammation to areas appearing normal on 3.0T MRI, (2) potential advantages of 7.0T MRI compared to 3.0T MRI in reflecting widespread inflammation, perivascular pathology, and axonal damage, and (3) the possibility of lymphoma. RESULTS: In the autopsy case, perivascular inflammation dominated by CD4+ T cells was not only detected in the brainstem and cerebellum but also in brain areas with normal appearance on 3.0T MRI, including supratentorial regions and cranial nerve roots. There was no evidence of lymphoma in any of the 4 patients. The 7.0T MRI in clinical remission also revealed supratentorial lesions and perivascular pathology in vivo with contrast-enhancing lesions centered around a small venous vessel. Ultra-high-field MRI at 7.0T disclosed prominent T1 hypointensities in the brainstem, which were not seen on 3.0T MRI. This corresponded to neuropathologic detection of axonal injury in the autopsy case. CONCLUSION: Our findings suggest more widespread perivascular inflammation and postinflammatory axonal injury in patients with CLIPPERS

Evaluation of the ‘ring sign’ and the ‘core sign’ as a magnetic resonance imaging marker of disease activity and progression in clinically isolated syndrome and early multiple sclerosis

Background: Brain lesions with a hypointense ring or core were described in multiple sclerosis on susceptibility weighted imaging. Objective: The purpose of this study was to study the evolution and prognostic relevance of susceptibility weighted imaging hypointense lesions in clinically isolated syndrome and early multiple sclerosis. Methods: Sixty-six early multiple sclerosis and clinically isolated syndrome patients were followed over a median period of 2.9 years (range 1.6-4.6 years) and underwent 3T magnetic resonance imaging including 3D susceptibility weighted imaging and T2-weighted fluid-attenuated inversion recovery. We assessed the presence of susceptibility weighted imaging hypointense core or ring lesions, and Expanded Disability Status Scale at baseline and follow-up. Results: Of 611 lesions at baseline, 64 (10.5%) had a susceptibility weighted imaging hypointense core, and 28 (4.6%) had a susceptibility weighted imaging hypointense ring. Hypointense ring lesions were larger (p < 0.001) and more T1w hypointense (p = 0.002) than others. During follow-up, hypointense core lesions became susceptibility weighted imaging isointense (52 lesions, 81%); few developed into hypointense ring lesions (two lesions, 3%). Hypointense ring lesions did not shrink on T2-weighted fluid-attenuated inversion recovery images (p = 0.077, trend towards more enlargement compared to others), while hypointense core lesions more often shrunk in comparison to lesions without a hypointense core (p = 0.002). The number of susceptibility weighted imaging hypointense ring lesions at baseline correlated with Expanded Disability Status Scale progression at follow-up (p = 0.021, R = 0.289). Conclusion: In our cohort of patients with clinically isolated syndrome or early multiple sclerosis, susceptibility weighted imaging hypointense ring lesions were only rarely detectable, but did not shrink and were associated with future disability progression

7 Tesla MRI of Balo's concentric sclerosis versus multiple sclerosis lesions

Background: Baló’s concentric sclerosis (BCS) is a rare condition characterized by concentrically layered white matter lesions. While its pathogenesis is unknown, hypoxia-induced tissue injury and chemotactic stimuli have been proposed as potential causes of BCS lesion formation. BCS has been suggested to be a variant of multiple sclerosis (MS). Here, we aimed to elucidate similarities and differences between BCS and MS by describing lesion morphology and localization in high-resolution 7 Tesla (7 T) magnetic resonance imaging (MRI) scans. Methods: Ten patients with Baló-type lesions underwent 7 T MRI, and 10 relapsing remitting MS patients served as controls. The 7 T MR imaging protocol included 3D T1-weighted (T1w) magnetization-prepared rapid gradient echo, 2D high spatial resolution T2*-weighted (T2*w) fast low-angle shot and susceptibility-weighted imaging. Results: Intralesional veins were visible in the center of all but one Baló-type lesion. Four Baló-type lesions displayed inhomogeneous intralesional T2*w signal intensities, which are suggestive of microhemorrhages or small ectatic venules. Eight of 10 BCS patients presented with 97 additional lesions, 36 of which (37%) had a central vein. Lesions involving the cortical gray matter and the U-fibers were not detected in BCS patients. Conclusion: Our findings support the hypothesis that BCS and MS share common pathogenetic mechanisms but patients present with different lesion phenotypes

Sex differences of vascular brain lesions in patients with atrial fibrillation.

OBJECTIVE To examine sex differences in prevalence, volume and distribution of vascular brain lesions on MRI among patients with atrial fibrillation (AF). METHODS In this cross-sectional analysis, we included 1743 patients with AF (27% women) from the multicentre Swiss Atrial Fibrillation study (SWISS-AF) with available baseline brain MRI. We compared presence and total volume of large non-cortical or cortical infarcts (LNCCIs), small non-cortical infarcts, microbleeds (MB) and white matter hyperintensities (WMH, Fazekas score ≥2 for moderate or severe degree) between men and women with multivariable logistic regression. We generated voxel-based probability maps to assess the anatomical distribution of lesions. RESULTS We found no strong evidence for an association of female sex with the prevalence of all ischaemic infarcts (LNCCI and SNCI combined; adjusted OR 0.86, 95% CI 0.67 to 1.09, p=0.22), MB (adjusted OR 0.91, 95% CI 0.68 to 1.21, p=0.52) and moderate or severe WMH (adjusted OR 1.15, 95% CI 0.90 to 1.48, p=0.27). However, total WMH volume was 17% larger among women than men (multivariable adjusted multiplicative effect 1.17, 95% CI 1.01 to 1.35; p=0.04). Lesion probability maps showed a right hemispheric preponderance of ischaemic infarcts in both men and women, while WMH were distributed symmetrically. CONCLUSION Women had higher white matter disease burden than men, while volume and prevalence of other lesions did not differ. Our findings highlight the importance of controlling risk factors for cerebral small vessel disease in patients with AF, especially among women

Biomarker, Imaging, and Clinical Factors Associated With Overt and Covert Stroke in Patients With Atrial Fibrillation.

BACKGROUND Atrial fibrillation is a major risk factor for stroke and silent brain infarcts. We studied whether a multimodal approach offers additional insights to the CHA2DS2-VASc score in predicting stroke or new brain infarcts on magnetic resonance imaging (MRI) over a 2-year follow-up. METHODS Swiss-AF is a prospective, multicenter cohort study of patients with known atrial fibrillation. We included patients with available brain MRI both at enrollment and 2 years later. The dates of the baseline and follow-up visits ranged from March 2014 to November 2020. The primary outcome was assessed 2 years after baseline and was defined as a composite of clinically identified stroke or any new brain infarct on the 2-year MRI. We compared a multivariable logistic regression model including prespecified clinical, biomarker, and baseline MRI variables to the CHA2DS2-VASc score. RESULTS We included 1232 patients, 89.8% of them taking oral anticoagulants. The primary outcome occurred in 78 patients (6.3%). The following baseline variables were included in the final multivariate model and were significantly associated with the primary outcome: white matter lesion volume in milliliters (adjusted odds ratio [aOR], 1.91 [95% CI, 1.45-2.56]), NT-proBNP (N-terminal pro-B-type natriuretic peptide; aOR, 1.75 [95% CI, 1.20-2.63]), GDF-15 (growth differentiation factor-15; aOR, 1.68 [95% CI, 1.11-2.53]), serum creatinine (aOR, 1.50 [95% CI, 1.02-2.22]), IL (interleukin)-6 (aOR, 1.37 [95% CI, 1.00-1.86]), and hFABP (heart-type fatty acid-binding protein; aOR, 0.48 [95% CI, 0.31-0.73]). Overall performance and discrimination of the new model was superior to that of the CHA2DS2-VASc score (C statistic, 0.82 [95% CI, 0.77-0.87] versus 0.64 [95% CI, 0.58-0.70]). CONCLUSIONS In patients with atrial fibrillation, a model incorporating white matter lesion volume on baseline MRI and selected blood markers yielded new insights on residual stroke risk despite a high proportion of patients on oral anticoagulants. This may be relevant to develop further preventive measures

Association of Heart Rate Variability With Silent Brain Infarcts in Patients With Atrial Fibrillation

Purpose: Silent brain infarcts (SBI) are frequently detected in patients with atrial fibrillation (AF), but it is unknown whether SBI are linked to autonomic dysfunction. We aimed to explore the association of autonomic dysfunction with SBI in AF patients. Methods: 1,358 AF patients without prior stroke or TIA underwent brain MRI and 5-min resting ECG. We divided our cohort into AF patients who presented in sinus rhythm (SR-group, n = 816) or AF (AF-group, n = 542). HRV triangular index (HRVI), standard deviation of normal-to-normal intervals, mean heart rate, root mean square root of successive differences of normal-to-normal intervals, 5-min total power and power in the low frequency, high frequency and very low frequency range were calculated. Primary outcome was presence of SBI in the SR group, defined as large non-cortical or cortical infarcts. Secondary outcomes were SBI volumes and topography. Results: Mean age was 72 ± 9 years, 27% were female. SBI were detected in 10.5% of the SR group and in 19.9% of the AF group (p < 0.001). HRVI <15 was the only HRV parameter associated with the presence of SBI after adjustment for clinical covariates in the SR group [odds ratio (OR) 1.67; 95% confidence interval (CI): 1.03–2.70; p = 0.037]. HRVI <15 was associated with larger brain infarct volumes [β (95% CI) −0.47 (−0.84; −0.09), p = 0.016] in the SR group and was more frequently observed in patients with right- than left-hemispheric SBI (p = 0.017). Conclusion: Impaired HRVI is associated with SBI in AF patients. AF patients with autonomic dysfunction might undergo systematic brain MRI screening to initiate intensified medical treatment

Serum neurofilament light in atrial fibrillation: clinical, neuroimaging and cognitive correlates

Emerging evidence suggests that atrial fibrillation is associated with cognitive dysfunction independently of stroke, but the underlying mechanisms remain unclear. In this cross-sectional analysis from the Swiss-atrial fibrillation Study (NCT02105844), we investigated the association of serum neurofilament light protein, a neuronal injury biomarker, with (i) the CHA; 2; DS; 2; -VASc score (congestive heart failure, hypertension, age 65-74 or >75 years, diabetes mellitus, stroke or transient ischaemic attack, vascular disease, sex), clinical and neuroimaging parameters and (ii) cognitive measures in atrial fibrillation patients. We measured neurofilament light in serum using an ultrasensitive single-molecule array assay in a sample of 1379 atrial fibrillation patients (mean age, 72 years; female, 27%). Ischaemic infarcts, small vessel disease markers and normalized brain volume were assessed on brain MRI. Cognitive testing included the Montreal cognitive assessment, trail-making test, semantic verbal fluency and digit symbol substitution test, which were summarized using principal component analysis. Results were analysed using univariable and multivariable linear regression. Neurofilament light was associated with the CHA; 2; DS; 2; -VASc score, with an average 19.2% [95% confidence interval (17.2%, 21.3%)] higher neurofilament per unit CHA; 2; DS; 2; -VASc increase. This association persisted after adjustment for age and MRI characteristics. In multivariable analyses, clinical parameters associated with neurofilament light were higher age [32.5% (27.2%, 38%) neurofilament increase per 10 years], diabetes mellitus, heart failure and peripheral artery disease [26.8% (16.8%, 37.6%), 15.7% (8.1%, 23.9%) and 19.5% (6.8%, 33.7%) higher neurofilament, respectively]. Mean arterial pressure showed a curvilinear association with neurofilament, with evidence for both an inverse linear and a U-shaped association. MRI characteristics associated with neurofilament were white matter lesion volume and volume of large non-cortical or cortical infarcts [4.3% (1.8%, 6.8%) and 5.5% (2.5%, 8.7%) neurofilament increase per unit increase in log-volume of the respective lesion], as well as normalized brain volume [4.9% (1.7%, 8.1%) higher neurofilament per 100 cm; 3; smaller brain volume]. Neurofilament light was inversely associated with all cognitive measures in univariable analyses. The effect sizes diminished after adjusting for clinical and MRI variables, but the association with the first principal component was still evident. Our results suggest that in atrial fibrillation patients, neuronal loss measured by serum neurofilament light is associated with age, diabetes mellitus, heart failure, blood pressure and vascular brain lesions, and inversely correlates with normalized brain volume and cognitive function

Association of Statin Use and Lipid Levels with Cerebral Microbleeds and Intracranial Hemorrhage in Patients with Atrial Fibrillation: a Prospective Cohort Study.

BACKGROUND An increased risk of intracranial hemorrhage (ICH) associated with statins has been reported; but data on the relationship between statin-use and cerebral microbleeds (CMBs) in patients with atrial fibrillation (AF), a population at high bleeding and cardiovascular risk are lacking. AIMS To explore the association between statin-use and blood lipid-levels with the prevalence and progression of CMBs in patients with atrial fibrillation with particular focus on anticoagulated patients. METHODS Data of Swiss-AF, a prospective cohort of patients with established AF were analyzed. Statin-use was assessed during baseline and throughout follow-up. Lipid values were measured at baseline. CMBs were assessed using magnetic resonance imagining (MRI) at baseline and at 2-years follow-up. Imaging data were centrally assessed by blinded investigators. Associations of statin-use and low-density lipoprotein (LDL) levels with CMB prevalence at baseline or CMB progression (at least one additional or new CMB on follow-up MRI at 2-years compared to baseline) were assessed using logistic regression models; the association with ICH was assessed using flexible parametric survival models. Models were adjusted for hypertension, smoking, body mass index, diabetes, stroke/transient ischemic attack, coronary heart disease, antiplatelet use, anticoagulant use and education. RESULTS Of the 1693 patients with CMB data at baseline MRI (mean±SD age 72.5±8.4y, 27.6% women, 90.1% on oral anticoagulants), 802 patients (47.4%) were statin users. The multivariable adjusted odds ratio (adjOR) for CMBs prevalence at baseline for statin users was 1.10 (95% CI, 0.83-1.45). AdjOR for 1 unit increase in LDL-levels was 0.95 (95% CI, 0.82-1.10). At 2-years, 1188 patients had follow-up MRI. CMBs progression was observed in 44 (8.0%) statin users and 47 (7.4%) non-statin users. Of these patients 64 (70.3%) developed a single new CMB, 14 (15.4%) developed 2 CMBs and 13 developed more than 3 CMBs. The multivariable adjOR for statin users was 1.09 (95% CI, 0.66-1.80). There was no association between LDL-levels and CMBs progression (adjOR 1.02, 95% CI, 0.79-1.32). At follow-up 14 (1.2%) statin users had ICH vs 16 (1.3%) non-users. The age and sex adjusted Hazard Ratio (adjHR) was 0.75 (95% CI, 0.36-1.55). Results remained robust in sensitivity analyses excluding participants without anticoagulants. CONCLUSIONS In this prospective cohort of patients with AF, a population at increased hemorrhagic risk due to anticoagulation, the use of statins was not associated with an increased risk of CMBs

Silent brain infarcts impact on cognitive function in atrial fibrillation

Aims: We aimed to investigate the association of clinically overt and silent brain lesions with cognitive function in atrial fibrillation (AF) patients. Methods and results: We enrolled 1227 AF patients in a prospective, multicentre cohort study (Swiss-AF). Patients underwent standardized brain magnetic resonance imaging (MRI) at baseline and after 2 years. We quantified new small non-cortical infarcts (SNCIs) and large non-cortical or cortical infarcts (LNCCIs), white matter lesions (WML), and microbleeds (Mb). Clinically, silent infarcts were defined as new SNCI/LNCCI on follow-up MRI in patients without a clinical stroke or transient ischaemic attack (TIA) during follow-up. Cognition was assessed using validated tests. The mean age was 71 years, 26.1% were females, and 89.9% were anticoagulated. Twenty-eight patients (2.3%) experienced a stroke/TIA during 2 years of follow-up. Of the 68 (5.5%) patients with ≥1 SNCI/LNCCI, 60 (88.2%) were anticoagulated at baseline and 58 (85.3%) had a silent infarct. Patients with brain infarcts had a larger decline in cognition [median (interquartile range)] changes in Cognitive Construct score [-0.12 (-0.22; -0.07)] than patients without new brain infarcts [0.07 (-0.09; 0.25)]. New WML or Mb were not associated with cognitive decline. Conclusion: In a contemporary cohort of AF patients, 5.5% had a new brain infarct on MRI after 2 years. The majority of these infarcts was clinically silent and occurred in anticoagulated patients. Clinically, overt and silent brain infarcts had a similar impact on cognitive decline. Clinical trial registration: ClinicalTrials.gov Identifier: NCT02105844, https://clinicaltrials.gov/ct2/show/NCT02105844. Keywords: Atrial fibrillation; Brain infarction; Cognitive function; Magnetic resonance imaging; Oral anticoagulation