Number Of White Matter Lesions Research Articles

Association of Levels of CSF Osteopontin With Cortical Atrophy and Disability in Early Multiple Sclerosis.

To evaluate CSF inflammatory markers with accumulation of cortical damage as well as disease activity in patients with early relapsing-remitting MS (RRMS). CSF levels of osteopontin (OPN) and 66 inflammatory markers were assessed using an immune-assay multiplex technique in 107 patients with RRMS (82 F/25 M, mean age 35.7 ± 11.8 years). All patients underwent regular clinical assessment and yearly 3T MRI scans for 2 years while 39 patients had a 4-year follow-up. White matter lesion number and volume, cortical lesions (CLs) and volume, and global cortical thickness (CTh) were evaluated together with the 'no evidence of disease activity' (NEDA-3) status, defined by no relapses, no disability worsening, and no MRI activity, including CLs. The random forest algorithm selected OPN, CXCL13, TWEAK, TNF, IL19, sCD30, sTNFR1, IL35, IL16, and sCD163 as significantly associated with changes in global CTh. OPN and CXCL13 were most related to accumulation of atrophy after 2 and 4 years. In a multivariate linear regression model on CSF markers, OPN (p < 0.001), CXCL13 (p = 0.001), and sTNFR1 (p = 0.024) were increased in those patients with accumulating atrophy (adjusted R-squared 0.615). The 10 markers were added in a model that included all clinical, demographic, and MRI variables: OPN (p = 0.002) and IL19 (p = 0.022) levels were confirmed to be significantly increased in patients developing more CTh change over the follow-up (adjusted R-squared 0.619). CXCL13 and OPN also revealed the best association with NEDA-3 after 2 years, with OPN significantly linked to disability accumulation (OR 2.468 [1.46-5.034], p = 0.004) at the multivariate logistic regression model. These data confirm and expand our knowledge on the prognostic role of the CSF inflammatory profile in predicting changes in cortical pathology and disease activity in early MS. The data emphasize a crucial role of OPN.

Cortical Lesions as an Early Hallmark of Multiple Sclerosis: Visualization by 7 T MRI.

Compelling evidence indicates a significant involvement of cortical lesions in the progressive phase of multiple sclerosis (MS), significantly contributing to late-stage disability. Despite the promise of ultra-high-field magnetic resonance imaging (MRI) in detecting cortical lesions, current evidence falls short in providing insights into the existence of such lesions during the early stages of MS or their underlying cause. This study delineated, at the early stage of MS, (1) the prevalence and spatial distribution of cortical lesions identified by 7 T MRI, (2) their relationship with white matter lesions, and (3) their clinical implications. Twenty individuals with early-stage relapsing-remitting MS (disease duration <1 year) underwent a 7 T MRI session involving T1-weighted MP2RAGE, T2*-weighted multiGRE, and T2-weighted FLAIR sequences for cortical and white matter segmentation. Disability assessments included the Expanded Disability Status Scale, the Multiple Sclerosis Functional Composite, and an extensive evaluation of cognitive function. Cortical lesions were detected in 15 of 20 patients (75%). MP2RAGE revealed a total of 190 intracortical lesions (median, 4 lesions/case [range, 0-44]) and 216 leukocortical lesions (median, 2 lesions/case [range, 0-75]). Although the number of white matter lesions correlated with the total number of leukocortical lesions ( r = 0.91, P < 0.001), no correlation was observed between the number of white matter or leukocortical lesions and the number of intracortical lesions. Furthermore, the number of leukocortical lesions but not intracortical or white-matter lesions was significantly correlated with cognitive impairment ( r = 0.63, P = 0.04, corrected for multiple comparisons). This study highlights the notable prevalence of cortical lesions at the early stage of MS identified by 7 T MRI. There may be a potential divergence in the underlying pathophysiological mechanisms driving distinct lesion types, notably between intracortical lesions and white matter/leukocortical lesions. Moreover, during the early disease phase, leukocortical lesions more effectively accounted for cognitive deficits.

CSF levels of Chitinase3like1 correlate with early response to cladribine in multiple sclerosis.

Cladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug initiation. Biomarkers that can predict early disease activity are needed. To estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine. Forty-two RRMS patients (30F/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The 'no evidence of disease activity' (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs. Three patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91). CSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug's effect on chronic macrophage and microglia activation deserves further evaluation.

Structural neuroimaging changes associated with subjective cognitive decline from a clinical sample

BackgroundAlzheimer’s disease (AD) is characterized by progressive deterioration of cognitive functions. Some individuals with subjective cognitive decline (SCD) are in the early phase of the disease and subsequently progress through the AD continuum. Although neuroimaging biomarkers could be used for the accurate and early diagnosis of preclinical AD, the findings in SCD samples have been heterogeneous. This study established the morphological differences in brain magnetic resonance imaging (MRI) findings between individuals with SCD and those without cognitive impairment based on a clinical sample of patients defined according to SCD-Initiative recommendations. Moreover, we investigated baseline structural changes in the brains of participants who remained stable or progressed to mild cognitive impairment or dementia. MethodsThis study included 309 participants with SCD and 43 healthy controls (HCs) with high-quality brain MRI at baseline. Among the 99 subjects in the SCD group who were followed clinically, 32 progressed (SCDp) and 67 remained stable (SCDnp). A voxel-wise statistical comparison of gray and white matter (WM) volume was performed between the HC and SCD groups and between the HC, SCDp, and SCDnp groups. XTRACT ATLAS was used to define the anatomical location of WM tract damage. Region-of-interest (ROI) analyses were performed to determine brain volumetric differences. White matter lesion (WML) burden was established in each group. ResultsVoxel-based morphometry (VBM) analysis revealed that the SCD group exhibited gray matter atrophy in the middle frontal gyri, superior orbital gyri, superior frontal gyri, right rectal gyrus, whole occipital lobule, and both thalami and precunei. Meanwhile, ROI analysis revealed decreased volume in the left rectal gyrus, bilateral medial orbital gyri, middle frontal gyri, superior frontal gyri, calcarine fissure, and left thalamus. The SCDp group exhibited greater hippocampal atrophy (p < 0.001) than the SCDnp and HC groups on ROI analyses. On VBM analysis, however, the SCDp group exhibited increased hippocampal atrophy only when compared to the SCDnp group (p < 0.001). The SCD group demonstrated lower WM volume in the uncinate fasciculus, cingulum, inferior fronto-occipital fasciculus, anterior thalamic radiation, and callosum forceps than the HC group. However, no significant differences in WML number (p = 0.345) or volume (p = 0.156) were observed between the SCD and HC groups. ConclusionsThe SCD group showed brain atrophy mainly in the frontal and occipital lobes. However, only the SCDp group demonstrated atrophy in the medial temporal lobe at baseline. Structural damage in the brain regions was anatomically connected, which may contribute to early memory decline.

28 Neurocognitive profile of pediatric acquired demyelinating syndrome with and without myelin oligodendrocyte glycoprotein antibody disease (MOGAD)

Objective:Pediatric acquired demyelinating syndromes (PADS) include a heterogeneous group of diagnoses, including acute disseminated encephalomyelitis (ADEM), neuromyelitis optica spectrum disorders (NMOSD), optic neuritis (ON) and transverse myelitis (TM). Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is often associated with demyelinating conditions, but may also present with encephalopathy without demyelinating lesions. Approximately 30% of patients diagnosed with MOGAD experience a relapse. Neurocognitive outcomes in PADS have reduced performance on tasks related to attention, processing speed, visual motor, and fine motor functioning. Psychosocial problems include anxiety, depression, and fatigue. Neurocognitive and psychosocial impacts of MOGAD events for the pediatric population are sparse. The current study sought to characterize neurocognitive sequelae from MOGAD (MAGAD+) compared to patients diagnosed with PADS without MOGAD (MOGAD-).Participants and Methods:Twenty children and adolescents (6–18 years) diagnosed with PADS were recruited using a clinic convenience sample of patients. Study participants completed a neurocognitive battery and parents completed questionnaires of behavioral and emotional functioning. Demographic and medical variables were collected via retrospective chart review. Chi square and t-test analyses were used to compare MOGAD+ and MOGAD- groups. Performance on neuropsychological and behavioral questionnaires were compared to established sex and age norms to assess the degree to which group means deviate from normative expectations.Results:MOGAD+ and MOGAD- groups did not significantly differ based on demographic, neurocognitive, or parent reported social and behavioral functioning. Neurocognitive testing documented mean scores that were in the average range between groups. Notable variability in performance was observed within both MOGAD+ and MOGAD- groups. Bilateral fine motor deficits, visual motor, visual perception attention, and executive functioning deficits were notable for the combined PADS group, with 30-50% performing &gt;1.5 SD below the mean. The number of white matter lesions or hospital duration were not significantly associated with performance on neurocognitive measures. However, older age of onset of PADS was significantly correlated with lower performance on visual motor integration and visual perception tasks (r(18) = -.50 p = .026; r(18) = -.53 p = .016). Findings also revealed associations of shorter hospitalization stays with higher behavioral symptoms on a parent measure of social/behavioral functioning (r(18) = -.47 p = .037).Conclusions:Consistent with the PADS literature, relative to control norms, lower performance on tasks related to attention, executive functioning, visual motor, and fine motor skills, irrespective of MOGAD status, are observed in the current study. The variability of functioning and heterogeneity observed across PADS diagnoses warrants further study to better understand the impact of clinical course, treatment outcomes, and neuropsychological sequelae over time in this population. Higher behavioral distress with shorter hospital stays may indicate a potential opportunity for patient and family education preparing for return to home/community. The current study was limited by small sample size, variable time since hospitalization, and heterogeneous diagnoses within PADS that make it difficult to generalize findings. Future studies could prospectively follow patients over time to better understand the trajectory of recovery, identify predictors for relapse, and those at greatest risk of neurocognitive and behavioral deficits.

Dots and spots: A retrospective review of T2-hyperintense white matter lesions in pediatric patients with and without headache.

We aimed to determine if T2-weighted hyperintense white matter lesions (WMLs) on brain magnetic resonance imaging (MRI) occur more frequently in pediatric patients with migraine and other primary headache disorders compared to the general pediatric population. Small foci of T2 hyperintensity in the white matter are frequently identified on brain MRI during the workup of pediatric headache. Such lesions have been reported to be more common among adults with migraine versus adults without migraine; however, this association has not been well established in the pediatric population. We performed a retrospective cross-sectional single-center study of electronic medical records and radiologic studies, examining pediatric patients from 3 to 18 years old who underwent brain MRI between 2016 and 2021. Patients with existing intracranial disease or abnormalities were excluded. Patients with reports of headache were categorized. Imaging was reviewed to determine the number and location of WMLs. Headache-associated disability scores (Pediatric Migraine Disability Assessment) were noted, when available. Brain MRI of 248 patients with a diagnosis of headache (144 with migraine, 42 with non-migraine primary headache, and 62 with headache that could not be further classified) and 490 controls were reviewed. WMLs were encountered commonly among all study participants, with a prevalence of 40.5% (17/42) to 54.1% (265/490). There was no statistically significant difference comparing the number of lesions between each of the headache groups and the control group: migraine group versus control group median [interquartile range (IQR)], 0 [0-3] versus 1 [0-4], incidence rate ratio [95% confidence interval (CI)], 0.99 [0.69-1.44], p = 0.989, non-migraine headache group versus control group median [IQR], 0 [0-3] versus 1 [0-4], 0.71 [0.46-1.31], p = 0.156, headache not otherwise specified group versus control group median [IQR], 0 [0-4] versus 1 [0-4], 0.77 [0.45-1.31], p = 0.291. There was no significant correlation between headache-associated disability and the number of WMLs (0.07 [-0.30 to 0.17], rho [95% CI]). T2 hyperintense WMLs are common within the pediatric population and are not encountered more frequently in pediatric patients with migraine or other primary headache disorders. Thus, such lesions are presumably incidental and unlikely related to headache history.

Cortical lesions at diagnosis predict long-term cognitive impairment in multiple sclerosis: A 20-year study.

Although cognitive impairment (CI) is frequent in multiple sclerosis (MS) patients, few studies (and with conflicting results) have evaluated early predictors of CI in the long term. We aimed at determining associations between early clinical/neuroradiological variables with reference to CI after 20 years of MS. We investigated in 170 MS patients the relationship between clinical/magnetic resonance imaging (MRI) data at diagnosis and cognitive status almost 20 years after MS onset. Among others, number and volume of both white matter lesions (WMLs) and cortical lesions (CLs) were evaluated at diagnosis and after 2 years. All MS patients were followed over time and underwent a comprehensive neuropsychological assessment at the end of study. Advanced statistical methods (unsupervised cluster analysis and random forest model) were conducted. CI patients showed higher focal cortical pathology at diagnosis compared to cognitively normal subjects (p< 0.001). Volumes of both WMLs and CLs emerged as the MRI metrics most associated with long-term CI. Moreover, number of CLs (especially ≥3) was also strongly associated with long-term CI (≥3 CLs: odds ratio [OR]=3.7, 95% confidence interval=1.8-7.5, p< 0.001), more than number of WMLs; the optimal cutoff of three CLs (area under the curve=0.67, specificity=75%, sensitivity=55%) was estimated according to the risk of developing CI. These results highlight the impact of considering both white and gray matter focal damage from early MS stages. Given the low predictive value of WML number and the poor clinical applicability of lesion volume estimation in the daily clinical context, the evaluation of number of CLs could represent a reliable prognostic marker of CI.

White-matter hyperintensities in patients with carotid artery stenosis: An exploratory connectometry study.

White-matter lesions (WMLs) are frequently found in magnetic resonance imaging (MRi), and the WML load tends to be higher in patients affected by cervical internal carotid artery (cICA) stenosis. This study aimed to investigate whether and how WMLs influence cerebral networking in patients with asymptomatic cICA stenosis eligible for carotid endarterectomy (CEA) by exploiting the connectometry technique. The study was designed as a cross-sectional exploratory investigation, and 28 patients with cICA stenosis eligible for CEA were enrolled. All patients received an MRI scan, including a T1-weighted, a FLAIR and a diffusion-weighted (DW) sequence. The T1 and FLAIR sequences were analysed for quantification of WML burden (WMLB) and total number of WMLs (TNWMLs). The DW data were reconstructed in the MNI space using q-space diffeomorphic reconstruction, and were grouped to create a connectometry database. The connectometry analysis evaluated the influence of both the WMLB and TNWMLs to local connectivity in a multiple regression model that included age, WMLB and TNWMLs, adopting three different T-score thresholds (1, 2 and 3). A p-value corrected for false discovery rate of <0.05 was adopted as a threshold to identify statistically significant results. The connectometry analysis identified several white-matter bundles negatively correlated with WMLB; no statistically significant correlation was found for TNWMLs. Results of our study suggest that WMLs influence brain connectivity measured by the connectometry technique in patients with cICA stenosis eligible for CEA. Further studies are warranted to understand the role of WMLs better as a marker of disease in patients with cICA stenosis.

Semi-automatic detection of increased susceptibility in multiple sclerosis white matter lesions imaged with 1.5T MRI

ObjectiveThe identification of regions of increased susceptibility (RoIS) in multiple sclerosis (MS) white matter lesions (WML) is currently performed by the radiologist’s visual inspection of magnetic resonance imaging (MRI) data acquired with high-field MRI scanners. The aims of this study were: 1) to define and validate a semi-automatic method for detecting RoIS in WML from quantitative susceptibility maps (QSM) and susceptibility-weighted imaging (SWI) acquired with a 1.5 T MRI scanner; 2) to assess the prevalence of WML with RoIS and the susceptibility in those areas; and 3) to test the association between RoIS in WML and clinical outcomes. MethodsThirty-eight MS patients were scanned on a 1.5 T MRI scanner. T2-hyperintense WML were segmented and superimposed on SWI and QSM images. Two intensity thresholds were defined and consecutively applied for identifying RoIS within WML (thrhyper_QSM to identify QSM hyperintensity within WML and thrhypoSWI to identify SWI hypointensity within WML). The sensitivity and specificity were assessed on a subgroup of subjects. The numbers of WML with RoIS and RoIS volume were determined. Differences between phenotypes and correlations with clinical outcome were tested. ResultsThe method showed good sensitivity (95.6%) and specificity (92.1%). On average, 44.7% of the WML showed RoIS, occupying 11.0% of the total lesion volume, with an average susceptibility of 39.4 ± 12.2 ppb. The number of WML with RoIS was negatively correlated with disease duration (r = −0.342, p = 0.035). ConclusionThe proposed semi-automatic method proved to be suitable for the detection of RoIS in WML at 1.5 T. This approach may be useful in longitudinal studies aiming to monitor susceptibility in WML.

Sequelae of Premature Birth in Young Adults

Background and PurposeQualitative studies about the abnormalities appreciated on routine magnetic resonance imaging (MRI) sequences in prematurely born adults are lacking. This article aimed at filling this knowledge gap by (1) qualitatively describing routine imaging findings in prematurely born adults, (2) evaluating measures for routine image interpretation and (3) investigating the impact of perinatal variables related to premature birth.MethodsIn this study two board-certified radiologists assessed T1-weighted and FLAIR-weighted images of 100 prematurely born adults born very preterm (VP <32 weeks) and/or at very low birth weight (VLBW <1500 g) and 106 controls born at full term (FT) (mean age 26.8 ± 0.7 years). The number of white matter lesions (WML) was counted according to localization. Lateral ventricle volume (LVV) was evaluated subjectively and by measurements of Evans’ index (EI) and frontal-occipital-horn ratio (FOHR). Freesurfer-based volumetry served as reference standard. Miscellaneous incidental findings were noted as free text.ResultsThe LVV was increased in 24.7% of VP/VLBW individuals and significantly larger than in FT controls. This was best identified by measurement of FOHR (AUC = 0.928). Ventricular enlargement was predicted by low gestational age (odds ratio: 0.71, 95% CI 0.51–0.98) and presence of neonatal intracranial hemorrhage (odds ratio: 0.26, 95% CI 0.07–0.92). The numbers of deep and periventricular WML were increased while subcortical WMLs were not.ConclusionEnlargement of the LVV and deep and periventricular WMLs are typical sequelae of premature birth that can be appreciated on routine brain MRI. To increase sensitivity of abnormal LVV detection, measurement of FOHR seems feasible in clinical practice.

Neuroimaging consequences of cerebral small vessel disease in patients with obstructive sleep apnea–hypopnea syndrome

ObjectiveThis study aimed to investigate the association between severity of obstructive sleep apnea–hypopnea syndrome (OSAHS) and the neuroimaging consequences of cerebral small vessel disease (SVD).MethodsPatients with OSAHS and age‐ and gender‐matched healthy control subjects completed the mini‐mental state examination and underwent an evoked‐related potential study and overnight polysomnographic monitoring. Magnetic resonance imaging (MRI) was performed to detect markers of silent cerebral SVD, including Virchow–Robin spaces (VRS) rated on a five‐point scale, white matter lesions, lacunar infarcts, and deep microbleeds. Multinomial logistic regression models were used to examine the associations of the apnea–hypopnea index (AHI) and arousal index (AI) values, mean oxyhemoglobin saturation, the duration of snoring history, and MRI markers of small vessel disease with the incidence of enlarged VRS.ResultsThe study included 72 patients with severe OSAHS and 53 volunteers without OSAHS. The duration of snoring history ranged from 5 to 22 years in the OSAHS group. Smaller P3 amplitudes at Cz were found in OSAHS patients than control subjects (p < .05), which is associated with neurocognitive impairment. Enlarged VRS were more prevalent in the basal ganglia and centrum semiovale of patients with OSAHS than in the control group. No significant between‐group differences were observed in the number of white matter lesions, lacunar infarcts, and deep microbleeds. Enlarged VRS were positively correlated with AHI and AI values in the OSAHS group (r = .63, p < .001; r = .55, p < .001, respectively).ConclusionsSilent cerebral SVD was more prevalent in patients with OSAHS than in the controls. Enlarged VRS observed in the basal ganglia and centrum semiovale were positively correlated with severity of OSAHS, which may contribute to cognitive impairment.

Evidence for a white matter lesion size threshold to support the diagnosis of relapsing remitting multiple sclerosis

BackgroundThe number of white matter lesions (WML) in brain MRI is the most established paraclinical tool to support the diagnosis of multiple sclerosis (MS) and to monitor its course. Diagnostic criteria have stipulated a minimum detectable diameter of 3 mm per WML, although this threshold is not evidence-based. We aimed to provide a rationale for a WML size threshold for three-dimensional MRI sequences at 3 T by comparing patients with relapsing-remitting MS (RRMS) to control subjects (CS). MethodsWe analyzed MR images from two cohorts, obtained at scanners from two different vendors, each comprising patients with RRMS and CS. Both cohorts were examined with FLAIR and T1w sequences. In total, 232 patients with RRMS (Expanded Disability Status Scale: mean = 1.6 ± 1.2; age: mean = 36 ± 10) as well as 116 age- and sex-matched CS were studied. We calculated odds ratios across WML volumes. The WML size threshold, which discriminated best between patients and CS, was estimated with receiver operating characteristic curve analysis. ResultsIn both cohorts, odds ratios increased continuously with increasing WML volumes, and discriminative power was highest at a WML size threshold corresponding to a diameter of about 3 mm. ConclusionThe stipulated WML size threshold of 3 mm in diameter for the diagnostic criteria of MS seems a reasonable choice for three-dimensional MRI sequences at 3 T.

Study on the relationship between H type hypertension as well as the changes of serum lipid and white matter lesions

Objective To investigate the relationship between H type hypertension as well as the changes of serum lipid and white matter lesions(WML). Methods From January 2015 to October 2017, the clinical characteristics of 507 WML patients who admitted to the Affiliated Hospital of Chengde Medical College were analyzed retrospectively.The patients were divided into simple hypertension group(A group, hypertension accompanied by Hcy 10μmol/L, 132cases) and H type hypertension group(C group, hypertension accompanied by homocysteine >10μmol/L, 264cases) according to homocysteine concentration and hypertension.The patients' clinical data, including imaging information such as MRI, diffusion weighted imaging(DWI), and levels of homocysteine (Hcy), serum lipid were collected.The patients were divided into three subgroups based on the severity of WML, including the mild, moderate, severe.The differences of TG, TC, HDL-C, LDL-C, Apo-A1, Apo-B in each group were compared. Results The levels of TC in A, B and C group were (4.14±1.16)mmol/L, (4.39±1.39)mmol/L, (3.67±1.29)mmol/L, respectively.The levels of LDL-C in the three groups were (2.24±0.88)mmol/L, (2.38±0.91)mmol/L and (1.99±0.89)mmol/L, respectively.Compared with A group and B group, the levels of TC and LDL-C in C group were lower(F=15.411, 9.271, all P<0.05). In A group, the number of mild WML, moderate and severe WML accounted for 51.4%, 32.4% and 16.2%, which in B group accounted for 50.0%, 33.3% and 16.7%, which in C group accounted for 32.6%, 33.3% and 34.1%.The number of WML patients had statistically significant differences between A group and C group(χ2=16.407, P<0.05), and B group and C group(χ2=15.912, P<0.05). In A group, the TC levels in the moderate group [(4.45±1.07)mmol/L] and severe group[(5.04±0.99)mmol/L] were significantly higher than that in the mild group[(3.68±1.03)mmol/L], the difference was statistically significant(F=22.391, P<0.05); the LDL-C level in the severe group[(2.88±0.65)mmol/L] was significantly higher than (1.98±0.84)mmol/L in the mild group and (2.33±0.89)mmol/L in the moderate group(F=14.764, P<0.05). In B group, the TC levels in the moderate group [(4.79±1.38)mmol/L] and the severe group[(5.20±1.43)mmol/L] were significantly higher than (3.85±1.16)mmol/L in the mild group, the difference was statistically significant(F=20.515, P<0.05). Compared with the mild group[(2.13±0.83)mmol/L], the LDL-C level was higher in the severe group[(2.81±1.01)mmol/L], the difference was statistically significant(F=9.235, P<0.05). In C group, the levels of TC and LDL-C in the moderate group were (3.94±1.22)mmol/L and (2.02±0.74)mmol/L, respectively, which in the severe group were (3.93±1.16)mmol/L and (2.30±0.85)mmol/L, respectively, which were significantly higher than those in the mild group[(3.12±1.34)mmol/L, (1.62±0.88)mmol/L], the differences were statistically significant(F=27.141, 27.078, all P<0.05). Spearman correlation analysis showed that there was a positive correlation between hypertension, TC, LDL-C and the severity of WML(H type hypertension: r=0.211, P<0.05; TC: r=0.266, P<0.05; LDL-C: r=0.258, P<0.05). Conclusion H type hypertension and high levels of TC, LDL-C can increase the number and severity of WML. Key words: Hypertension; Leukoencephalopathy, progressive multifocal; Hyperhomocysteinemia; Cholesterol, LDL; Cholesterol, HDL

Diagnosis of gray matter lesions in multiple sclerosis using variant sequences of magnetic resonance imaging (T2, fluid-attenuated inversion recovery, and double inversion recovery)

Background and aim Gray matter atrophy is significantly correlated with both physical and cognitive disability in patients with multiple sclerosis (MS). Patients and methods The study was conducted on 40 patients with definite relapsing-remitting MS according to McDonald criteria. All patients were subjected to conventional MRI [T2 and fluid-attenuated inversion recovery (FLAIR) sequences] and double inversion recovery (DIR) sequence to assess their sensitivity for detecting gray matter lesions in patients with MS. Results Comparative studies between serial MRI sequences revealed highly significant increase in detected number of white matter lesions in FLAIR and DIR-MRI sequences (P=0.0007). Comparative studies also revealed a nonsignificant difference in detection rate in all 3 MRI sequences (P>0.05). Moreover, there were significant increases in detected number of gray matter lesions in DIR-MRI sequences (P=0.021) and a highly significant increase in detection rate in DIR-MRI sequences compared with T2 and FLAIR-MRI sequences (P Conclusion DIR is a valuable MRI sequence in imaging of MS because of the following: (a) it showed better delineation between the white matter, the gray matter, and the MS lesions owing to its high image contrast measurements; (b) it detected more MS lesions compared with T2WI and FLAIR sequences in all anatomic locations; (c) it revealed more periventricular and juxta-cortical MS lesions, which are characteristic of MS; and (d) it detected more intracortical lesions as well, which should be considered in all patients with MS.

Imaging markers of multiple sclerosis prognosis.

Studies of large longitudinal cohorts of patients with multiple sclerosis (MS) have emphasized the prognostic value of conventional MRI markers, at least during early stages. Advanced imaging metrics derived from quantitative MRI and PET provide relevant information about microstructural damage within and outside visible lesions that may be more sensitive to predict long-term disability. Here, we summarize the most recent findings regarding the prognostic value of imaging markers throughout MS stages. In clinically isolated syndrome, the presence of at least one brain or spinal cord T2 lesion strongly increases the risk of conversion to clinically definite MS (hazard ratio ranging from 5 to 11). Similarly, the occurrence of new white matter lesions is strongly predictive of subsequent relapse rate and response to current disease modifying therapies. Beyond white matter lesions, volumetric changes in the grey matter and normal-appearing tissue damage are more sensitive prognostic markers for physical and cognitive disability, especially in progressive MS. Although white matter lesion number and volume still remains the imaging metric used in daily clinical practice, further development of advanced imaging predictors of long-term disability should allow a better stratification of patients in future clinical trials aimed at promoting repair or neuroprotection.

Reducing Timp3 or vitronectin ameliorates disease manifestations in CADASIL mice

CADASIL is a genetic paradigm of cerebral small vessel disease caused by NOTCH3 mutations that stereotypically lead to the extracellular deposition of NOTCH3 ectodomain (Notch3(ECD) ) on the vessels. TIMP3 and vitronectin are 2 extracellular matrix proteins that abnormally accumulate in Notch3(ECD) -containing deposits on brain vessels of mice and patients with CADASIL. Herein, we investigated whether increased levels of TIMP3 and vitronectin are responsible for aspects of CADASIL disease phenotypes. Timp3 and vitronectin expression were genetically reduced in TgNotch3(R169C) mice, a well-established preclinical model of CADASIL. A mouse overexpressing human TIMP3 (TgBAC-TIMP3) was developed. Disease-related phenotypes, including cerebral blood flow (CBF) deficits, white matter lesions, and Notch3(ECD) deposition, were evaluated between 6 and 20 months of age. CBF responses to neural activity (functional hyperemia), topical application of vasodilators, and decreases in blood pressure (CBF autoregulation) were similarly reduced in TgNotch3(R169C) and TgBAC-TIMP3 mice, and myogenic responses of brain arteries were likewise attenuated. These defects were rescued in TgNotch3(R169C) mice by haploinsufficiency of Timp3, although the number of white matter lesions was unaffected. In contrast, haploinsufficiency or loss of vitronectin in TgNotch3(R169C) mice ameliorated white matter lesions, although CBF responses were unchanged. Amelioration of cerebrovascular reactivity or white matter lesions in these mice was not associated with reduced Notch3(ECD) deposition in brain vessels. Elevated levels of TIMP3 and vitronectin, acting downstream of Notch3(ECD) deposition, play a role in CADASIL, producing divergent influences on early CBF deficits and later white matter lesions.

Cerebral white matter lesions in patients with cirrhosis - causative for hepatic encephalopathy or bystanders?

Focal white matter lesions mimicking microvascular lesions were connected to the development of hepatic encephalopathy (HE) in patients with cirrhosis. This study aims to assess the relationship between cerebrovascular risk factors and the prevalence and extent of these lesions in patients with cirrhosis, as well as their impact upon cognitive function. 55 cirrhotic patients underwent neurological examination, psychometric testing and magnetic resonance imaging. T2-weighted images were reviewed for white matter lesions by a neuroradiologist and a neurologist, independently. Patients were allocated into three groups: (i) no or <5, (ii) 6-15 and (iii) more than 15 lesions. Allocation was confirmed by a senior neuroradiologist blinded for the clinical data. The patient groups were compared concerning age, underlying liver disease, mortality, MELD Score, history of HE, treatment for HE, cerebrovascular risk factors and psychometric test results. Regression analysis was performed to identify risk factors for the presence and extent of white matter lesions. Patient groups 2 and 3 were older and showed worse results in the psychometric tests than group 1 (P < 0.05). Correlation analyses showed a significant relationship between the number of white matter lesions and the grade of HE (P < 0.001) and cognitive function (P < 0.05), but no interrelationship between the lesions and cerebrovascular risk factors or other factors tested. Focal white matter lesions in patients with cirrhosis do not represent cerebrovascular small-vessel disease but are related to the pathology of HE. Further studies are needed to clarify the mechanisms behind in detail.

Increased number of white matter lesions in patients with familial cerebral cavernous malformations.

Familial cerebral cavernous malformations, an autosomal dominant disorder, result in excess morbidity and mortality in affected patients. The disorder is most prevalent in the Southwest United States, where the affected families are most often carriers of the CCM1-KRIT1 Common Hispanic Mutation. The brain and spinal cord parenchyma in these individuals is usually affected by multiple cavernous malformations. Previous studies have shown abnormalities of endothelial cell junctions and the blood-brain barrier in cerebral cavernous malformations. Endothelial cell abnormalities have also been described in pathologic studies of white matter hyperintensities. We compared the prevalence of white matter hyperintensities in a population with known familial cerebral cavernous malformations. We examined 191 subjects with familial cerebral cavernous malformations who were enrolled into an institutional review board-approved study. All carry the same Common Hispanic Mutation in the CCM1 gene. Each subject underwent 3T MR imaging, including gradient recalled-echo, SWI, and FLAIR sequences. The number of cavernous malformations and the number of nonhemorrhagic white matter hyperintensities were counted. Subjects older than 60 years of age were excluded due to the high prevalence of white matter lesions in this population, and children younger than 6 were excluded due to potential sedation requirements. Logistic regression analysis was performed to determine the prevalence of abnormal white matter hyperintensities in those with familial cerebral cavernous malformations compared with healthy controls or those with sporadic cerebral cavernous malformation within the familial cerebral cavernous malformations group; it was also performed to evaluate the associations between abnormal white matter hyperintensities and age, sex, headaches, thyroid disease, diabetes, hypertension, hyperlipidemia, seizure history, or modified Rankin Scale score. Familial CCM1 carriers have a higher prevalence of abnormal white matter hyperintensities (15.4%) compared with both control populations (2.1% and 2.5%, respectively) (P < .05). Logistic regression showed no statistical association with sex, headaches, hyperlipidemia, hypertension, thyroid disease, seizure history, number of cerebral cavernous malformations, or modified Rankin Scale score among those with familial cerebral cavernous malformation. An expected correlation with age was shown. Familial CCM1 carriers have not only an increased number of cerebral cavernous malformations but also an increased number of white matter T2 hyperintensities, spatially distinct from cerebral cavernous malformations, which exceeded that of a healthy population. Clinical findings did not explain the association with abnormal white matter hyperintensities in the familial cerebral cavernous malformation population. To our knowledge, these relationships have not been previously reported. This finding suggests an additional manifestation of endothelial abnormalities in this population.

Enzyme Replacement Therapy Stabilized White Matter Lesion Progression in Fabry Disease

Background: The central nervous system manifestations in Fabry disease (FD) include progressive white matter lesions (WMLs) and stroke. Due to progressive microvascular involvement, men and women with FD over 35 years of age develop WMLs. Moreover, the prevalence of stroke has been estimated to be 12 times higher in FD compared with the general population. Enzyme replacement therapy (ERT) is available and has shown beneficial effects on renal, cardiac, and peripheral nerve function in FD, but the ERT effect on the progression of WMLs, or the reduction in cerebrovascular events, remains unknown. Methods: The WML burden and the effect of agalsidase beta 1 mg/kg biweekly on WML progression were assessed longitudinally in a Phase 4 agalsidase-beta placebo-controlled analysis of untreated and treated FD patients with mild-to-moderate renal involvement (serum creatinine measurements of ≥1.2 mg/dl and <3.0 mg/dl). The primary end point was the difference in the number of patients with increased WML burden between the agalsidase beta and placebo groups at the end of treatment. The diameters of the WMLs were determined manually using axial flow-attenuated-inversion-recovery-weighted magnetic resonance imaging (MRI) scans taken at baseline and follow-up. Results: MRI scans from 41 FD patients (mean age 43.9, age range 20-68, 3 females; n = 25 on ERT, n = 16 on placebo) were analyzed. WML burden was present in 63% of patients at baseline, increased over a mean of 27 months (range 12-33 months) follow-up, and correlated with left ventricular hypertrophy (LVPW). Patients with previous or recent strokes (n = 11, 39-68 years) showed an increase in the number of WMLs (p = 0.005). A greater proportion of younger patients (≤50 years) on ERT (n = 18) had stable WML burden compared with younger patients in the placebo group (n = 13): 44% (8 of 18) versus 31% (4 of 13), p = 0.014. The number needed to treat was 8. Conclusions: This FD patient cohort, with mild-to-moderate renal involvement, had a significant WML burden and high inter-individual variability associated with the degree of LVPW but not the degree of kidney dysfunction. These advanced patients with increased LVPW and stroke evidence may have had a higher cerebrovascular risk. The WML burden in patients on ERT was more likely to remain stable, compared with patients on placebo. Thus, ERT may reduce the progression of vascular disease, even in advanced FD patients, suggesting that early treatment may stabilize WML progression and stroke risk.

Macrostructural Brain Changes in Patients with Longstanding Type 1 Diabetes Mellitus - a Cortical Thickness Analysis Study

Longstanding diabetes mellitus (DM) is associated with the risk of complications affecting the central nervous system. The aims were to study brain volume and cortical thickness in regional brain areas in DM patients and to correlate the findings with relevant clinical data.15 patients with longstanding (average 24.6 years) type 1 DM and 20 healthy controls were studied in a 3T magnetic resonance scanner. Using an automated surface based cortical segmentation method, cortical thickness was assessed in anatomical regions including total and lobe-wise grey and white matter volumes. Also morphological changes were evaluated.No differences between patients and controls were found in regard to number of white matter lesions (P=0.50), grey and white matter volumes (P=0.25) and overall cortical thickness (P=0.64). Subanalysis revealed exclusively reduced cortical thickness of the postcentral (P=0.03) and superior parietal gyrus (P=0.008) in patients. The cortical thickness of these regions was not associated with diabetes duration, age at diabetes onset or to HbA1c (all P>0.08). Patients with peripheral neuropathy showed reduced right postcentral gyrus cortical thickness compared to patients without peripheral neuropathy (P=0.02).Patients with longstanding type 1 diabetes showed cortical thinning involving sensory related areas, even though no overall macrostructural brain alterations were detected. This could possibly have underlying functional significance since cortical thinning was associated to presence of peripheral neuropathy. The absence of universal macrostructural changes might illustrate that more pronounced brain pathology is likely to be preceded by more subtle microstructural changes as reported in other studies.