White Matter Lesion Volume Research Articles

EDSS and infratentorial white matter lesion volume are considered predictors of fatigue severity in RRMS

Fatigue is a common disabling symptom of relapsing remitting multiple sclerosis (RRMS). Many studies have linked grey matter atrophy to fatigue, but white matter lesion load (WM-LL) has received less attention. Here we assess the relation between fatigue and regional WM-LL volumetric measures. 63 patients with RRMS participated in this study; mean age was 31.9 ± 8.1 years. Each patient provided demographic details and was scored on the expanded disability status scale (EDSS) and fatigue severity scale (FSS). VolBrain, a fully automated, operator-independent tool was used to assess WM-LL and whole brain volume. The patients were classified into three groups: no fatigue (FSS < 4), low to moderate fatigue (FSS ≥ 4 ≤ 5) and high fatigue (FSS > 5). 33.3% of patients had no significant fatigue, 25.4% had mild-to-moderate fatigue, and 41.3% had significant fatigue. Age, disease duration, relapses, and EDSS were positively correlated to fatigue severity (P = 0.034, 0.002, 0.009 and 0.001 respectively). Whole brain volume, total and regional WM-LL (juxtacortical, periventricular, infratentorial) were also correlated with fatigue severity. Ordinal regression analysis for fatigue severity showed EDSS and infratentorial lesion volume were the best predictors. In conclusion, EDSS and infratentorial lesion volume (cerebellar and brainstem) are the best predictors of fatigue severity.

Association Between Frequency of Social Contact and Brain Atrophy in Community-Dwelling Older People Without Dementia: The JPSC-AD Study.

Epidemiologic evidence has shown that social isolation, a low frequency of social contact with others, is associated with the risk of dementia and late-life depressive symptoms. Therefore, we hypothesized that low frequency of social contact may be involved in brain atrophy, and depressive symptoms may play some role in this relationship. We aimed to evaluate the association between low frequency of social contact and the volumes of various brain regions and to assess the extent to which depressive symptoms mediate these relationships from a large population-based multisite cohort study. Dementia-free community-dwelling Japanese aged 65 years or older underwent brain MRI scans and a comprehensive health examination. Frequency of contact with noncohabiting relatives and friends was determined by asking a single question with 4 categories: everyday, several times a week, several times a month, and seldom. Total and regional brain volumes, intracranial volume (ICV), and white matter lesion volume were estimated using FreeSurfer software. The associations between frequency of social contact and brain volumes per ICV were examined using analyses of covariance. Mediation analyses were conducted to calculate the proportion of the associations explained by depressive symptoms. We included 8,896 participants. The multivariable-adjusted mean of the total brain volume in the group with the lowest frequency of social contact was significantly lower compared with that in the group with the highest frequency of social contact (67.3% vs 67.8%), with a significant increasing trend across the groups (p value for trend <0.001). The white matter lesion volume increased significantly with lower frequency of social contact (0.30% in the lowest frequency group vs 0.26% in the highest frequency group, p value for trend <0.001). Lower frequency of social contact was associated with smaller volumes in the temporal lobe, occipital lobe, cingulum, hippocampus, and amygdala (all q values of false discovery rate correction <0.05). The relationships seemed to be partly mediated by depressive symptoms, which accounted for 15%-29% of the observed associations. Lower frequency of social contact was associated with decreased total and cognitive function-related regional brain volumes. In addition, depressive symptoms partially explained the association in community-dwelling older people without dementia in Japan.

Enlarged choroid plexus related to iron rim lesions and deep gray matter atrophy in relapsing-remitting multiple sclerosis.

Choroid plexus (CP) is considered to be linked to inflammation of multiple sclerosis (MS), but its connection with markers of inflammation in vivo in MS is unclear, the markers such as lesions load and brain atrophy, particularly the white matter lesions (WMLs) edge surrounded by an iron rim, termed as iron rim lesions (IRLs). To investigate the association between CP volume and brain lesions load, especially IRLs load and atrophy in MS, and its relationship with clinical characteristics. 3.0 T brain MRI images were acquired from 99 relapsing-remitting MS (RRMS) and 60 healthy controls (HCs) to obtain the volumes of CP, whole brain and lesions. Volumes were expressed as a ratio of intracranial volume. Expanded Disability Status Scale (EDSS), Montreal Cognitive Assessment (MoCA) and Symbol Digit Modalities Test (SDMT) were used to assess the severity of disability and cognitive function. Student's t-test and Multivariable regression analyses were performed to evaluate the difference of CP volumes between RRMS and HC and the association between CP volume and lesions load, brain volumes and clinical scale scores in RRMS. CP volume was 30% larger in patients with RRMS than HCs (p < 0.001) and was 20% larger in patients with IRLs than those without IRLs (p=0.007). Moreover, the larger CP volume was related to greater WMLs volume in the whole RRMS (r=0.46, p < 0.001). Further analysis in patients with IRLs showed a positive correlation between CP volume and WMLs volume (r=0.45, p=0.003), and IRLs volume (r=0.51, p < 0.001). Meanwhile, enlarged CP was related to lower volumes in the whole brain (r=-0.30, p=0.006), deep gray matter (r=-0.51, p < 0.001) and most regional deep gray matter nuclei (except amygdala), but no correlation with cortical lesions or cortex volume (both p > 0.05). In addition, CP volume was significantly higher in patients with cognitive impairment than those with cognitive preservation by MoCA scores (p=0.011); the larger CP volume was associated with higher EDSS scores (r=0.25, p=0.014) and lower SDMT Z scores in RRMS (r=-0.26, p=0.014). The enlargement of CP in RRMS had close correlations with inflammatory lesions, especially IRLs and deep gray matter atrophy, but not the cortex. Meanwhile, the larger CP volume was associated with higher disability and lower cognitive scores. CP volume may be a surrogate imaging marker for MS disease activity.

Epileptogenicity of white matter lesions in cerebral small vessel disease: a systematic review and meta-analysis.

The epileptogenic properties of white matter lesions (WML) in cerebral small vessel disease (CSVD) are not yet understood. The aim of our systematic review and meta-analysis was to estimate the association between the extent of WML in CSVD and epilepsy, analyze whether these WML are associated with an increased risk of seizure recurrence, and evaluate if treatment with anti-seizure medication (ASM) is justified in first-seizure patients with WML and no cortical lesions. Following a pre-registered study protocol (PROSPERO-ID CRD42023390665), we systematically searched Pubmed and Embase for relevant literature comparing WML load between patients with epilepsy and controls as well as studies on seizure recurrence risk and ASM therapy in the presence vs. absence of WML. We calculated pooled estimates using a random effects model. Eleven studies comprising 2983 patients were included in our study. Presence of WML (OR 2.14, 95% CI 1.38-3.33) and presence of relevant WML as assessed by visual rating scales (OR 3.96, 95% CI 2.55-6.16) but not WML volume (OR 1.30, 95% CI 0.91-1.85) were significantly associated with seizures. These results stayed robust in sensitivity analyses restricted to studies on patients with late-onset seizures/epilepsy. Only two studies assessed the association between WML and risk of seizure recurrence with conflicting results. Currently, there are no studies on the efficacy of ASM therapy in the presence of WML in CSVD. This meta-analysis suggests an association between presence of WML in CSVD and seizures. More research is needed addressing the association between WML and risk of seizure recurrence and ASM therapy focusing on a population of patients with a first unprovoked seizure.

Serum neurofilament light and white matter characteristics in the general population: a longitudinal analysis

Neurofilament light polypeptide (NfL) is a component of the neuronal cytoskeleton and particularly abundant in large-caliber axons. When axonal injury occurs, NfL is released and reaches the cerebrospinal fluid and the blood. Associations between NfL and white matter alterations have previously been observed in studies based on patients with neurological diseases. The current study aimed to explore the relationship between serum NfL (sNfL) and white matter characteristics in a population-based sample. The cross-sectional associations between sNfL as dependent variable, fractional anisotropy (FA), and white matter lesion (WML) volume were analyzed with linear regression models in 307 community-dwelling adults aged between 35 and 65 years. These analyses were repeated with additional adjustment for the potential confounders age, sex, and body mass index (BMI). Longitudinal associations over a mean follow-up of 5.39 years were analyzed with linear mixed models. The unadjusted cross-sectional models yielded significant associations between sNfL, WML volume, and FA, respectively. However, after the adjustment for confounders, these associations did not reach significance. In the longitudinal analyses, the findings corroborated the baseline findings showing no significant associations between sNfL and white matter macrostructure and microstructure beyond the effects of age. In synopsis with previous studies in patients with acute neurological diseases showing a significant association of sNfL with white matter changes beyond the effects of age, the present results based on a sample from the general population suggest the perspective that changes in sNfL reflect age-related effects that also manifest in altered white matter macrostructure and microstructure.

Vascular disease risk factors in multiple sclerosis: Effect on metabolism and brain volumes.

Vascular disease risk factors (VDRF) such as hypertension, hyperlipidemia, obesity, diabetes and heart disease likely play a role in disease progression in people with multiple sclerosis (PwMS) (Marrie, Rudick etal. 2010). Studies exploring the mechanistic connection between vascular disease and MS disease progression are scant. We hypothesized that phosphate energy metabolism impairment in PwMS with VDRFs (VDRF+) will be greater compared to PwMS without VDRFs (VDRF-) and is related to increased brain atrophy in VDRF+. To test this hypothesis, we planned to study the differences in the high energy phosphate (HEP) metabolites in cerebral gray matter as assessed by 31P magnetic resonance spectroscopic imaging (MRSI) and MRI brain volumetric in the VDRF+ and VDRF- PwMS at four different timepoints over a 3 yearlong period using a 7T MR system. We present here the results from the cross-sectional evaluation of HEP metabolites and brain volumes. We also evaluated the differences in clinical impairment, blood metabolic biomarkers and quality of life in VDRF+ and VDRF- PwMS in this cohort. Group differences in high energy phosphate metabolites were assessed from a volume of interest in the occipital region using linear mixed models. Brain parenchymal and white matter lesion volumes were determined from MR anatomic images. We present here the cross-sectional analysis of the baseline data collected as part of a longitudinal 3 yearlong study where we obtained baseline and subsequent 6-monthly clinical and laboratory data and annual 7T MRI volumetric and 31P MR spectroscopic imaging (MRSI) data on 52 PwMS with and without VDRF. Key clinical and laboratory outcomes included: body mass index (BMI), waist and thigh circumferences and disability [Expanded Disability Status Scale (EDSS)], safety (complete blood count with differential, complete metabolic), lipid panel including total cholesterol and HbA1C. We analyzed clinical and laboratory data for the group differences using student's t or χ2 test. We investigated relationship between phosphate metabolites and VDRF using mixed effect linear regression. Complete MRI data were available for 29 VDRF+, age 56.3 (6.8) years [mean (SD)] (83% female), and 23 VDRF-, age 52.5 (7.5) years (57% female) individuals with MS. The mean value of normalized adenosine triphosphate (ATP) (calculated as the ratio of ATP to total phosphate signal in a voxel) was decreased by 4.5% (p < .05) in VDRF+ compared to VDRF- MS group. White matter lesion (WML) volume fraction in VDRF+ individuals {0.007 (0.007)} was more than doubled compared to VDRF- participants {0.003 (0.006), p= .02}. We found significantly lower brain ATP and higher inorganic phosphate (Pi) in those PwMS with VDRFs compared to those without. ATP depletion may reflect mitochondrial dysfunction. Ongoing longitudinal data analysis from this study, not presented here, will evaluate the relationship of phosphate metabolites, brain atrophy and disease progression in PwMS with and without vascular disease.

Association between 10‐year cardiovascular mortality‐risk and neuroimaging biomarkers in the FINGER trial

AbstractBackgroundCardiovascular risk factors are associated with cognitive decline and dementia. Timely estimation and targeting of cardiovascular risk burden may contribute towards the prevention of cognitive decline. The cardiovascular risk scores of the European Society of Cardiology’s, SCORE (for adults up to 64 years) and SCORE‐OP (for older adults aged 65 years or more), are commonly used tool for estimation of 10‐year CVD mortality and may reflect the impact of cardiovascular risk burden on brain pathology if validated against neuroimaging biomarkers.MethodThis study investigated associations between (i) baseline SCORE/SCORE‐OP and baseline neuroimaging biomarkers (brain magnetic resonance imaging [MRI] and Pittsburgh Compound B‐positron emission tomography [PiB‐PET] measures) (ii) change in SCORE/SCORE‐OP and change in neuroimaging measures during the 2‐year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). FINGER targeted at‐risk older adults, aged 60‐77 years, from the general population. Participants were randomized to either multidomain intervention (diet, exercise, cognitive training, and vascular risk management) or control group (general health advice). Neuroimaging (MRI and PiB‐PET) data from baseline and 2‐year visits were used. A total of 112 participants had repeated brain MRI measures (hippocampus, total grey matter, and white matter lesion volumes, and Alzheimer’s disease signature cortical thickness). Repeated PiB‐PET scans were available for 39 participants.ResultPreliminary results suggest that at baseline higher SCORE/SCORE‐OP, indicating increased risk of CVD mortality was significantly associated with lower hippocampus volume (estimate = ‐0.010; p = 0.004), lower total grey matter volume (estimate = ‐0.016; p = 0.007), higher white matter lesion volume (estimate = 0.048; p = 0.015), and lower AD signature cortical thickness (‐0.004; p = 0.048) but not with PiB‐PET. No significant associations were found for change in neuroimaging measures and baseline SCORE/SCORE‐OP or change in SCORE/SCORE‐OP during the 2‐year follow‐up.ConclusionCardiovascular risk scores need to be validated against different brain pathology markers in diverse populations. This will enable more precise identification and estimation of dementia risk profiles, guiding at‐risk persons to precise intervention strategies, good for both, heart, and brain.

FLAIR MRI biomarkers of the Normal‐Appearing Brain Matter (NABM) are related to APOE‐4 status and CSF markers Aβ42 and Tau

AbstractBackgroundReduced amyloid‐beta‐42 (Aβ42) and elevated total tau (t‐tau) protein concentrations in the CSF are characteristic of Alzheimer’s disease (AD) pathology [1]. Aβ42 contributes to extracellular plaque formation between neurons [2]. The total level of tau, a microtubule‐stabilizer in neuron axons [3], is associated with neuronal death [1]. Additionally, presence of ApoE4 (ε4) alleles is an established identifier for increased risk of AD [4]. Non‐invasive imaging‐based correlates of the CSF markers are lacking. This study examines correlations of novel FLAIR texture, intensity, and volume biomarkers, along with white matter lesion (WML) burden, with Aβ42, t‐tau, and ε4 status.MethodFLAIR volumes (n = 4044) from the ADNI database were used for analysis with CSF biomarkers. A subset (n = 921) was used for ε4 analysis based on available data. Normal‐appearing brain matter (NABM) was obtained by removing CSF and WML. Macrostructural damage (MAD), microstructural damage (MID), and integrity (MII) texture biomarkers [5] were extracted from each NABM volume (Fig. 1), along with median intensity, NABM/ICV ratio, and normalized WML volume [5]. Relationships between FLAIR biomarkers and AD markers were described using parametric statistical analyses. Statistical significance was set at p&lt;0.05.ResultAll FLAIR biomarkers were statistically significantly correlated with CSF Aβ42 levels. All features except MID and WML burden were significantly correlated with CSF t‐tau levels (Table 1). MAD, MID, and WML burden showed negative correlations with Aβ42, while MAD showed a positive correlation with t‐tau. Opposite trends were seen with MII, intensity, and NABM/ICV (Fig. 2). Significant differences between groups without and with one ε4 allele were found in all FLAIR biomarkers except WML burden. Significant differences in MAD, MII and NABM/ICV were found between groups with one and two ε4 alleles (Table 2).ConclusionFLAIR biomarkers were inversely associated with CSF Aβ42 concentrations, suggesting they may be surrogate markers of Aβ plaque formation. They were associated with CSF t‐tau concentrations, suggesting they could also be indicators of GM degeneration and neuronal death. They could also be indicators for patients at increased risk of AD, as they demonstrated significant differences with the presence of ε4. Further longitudinal studies are required to establish the exact mechanism of neurodegeneration.

An Investigation of the Relationship Between Carotid Artery Stenosis and White Matter Hyperintensities.

Introduction White matter hyperintensities (WMHs) are frequently detected on magnetic resonance imaging (MRI) with age. Although the etiology of WMH has not been fully explained, it was reported to be associated with internal carotid artery (ICA) stenosis as well as small vessel diseases. The number and volume of these lesions might increase in cases of internal carotid artery (ICA) stenosis. The present study aimed to calculate the localization and volumes of white matter lesions in the VolBrain Program and investigate the relationship between age and sex in patients with symptomatic and asymptomatic internal carotid artery stenosis. Methods MRI scans of patients with carotid stenosis with T1-weighted and fluid-attenuated inversion recovery (FLAIR) sequences were performed retrospectively for the present study, which had a retrospective design. The patients were divided into two groups (<70% and ≥70%) because endovascular intervention was considered in patients with asymptomatic stenosis over 70%. Digital subtraction angiography was used to detect carotid artery stenosis. They were also divided into four groups.According to laterality and degree of stenosis, ICA stenosis was separated as those with <70% stenosis on both sides (group 1), right side ICA <70%, left side ≥70% stenosis (group 2), right side ICA ≥70%, left side <70% stenosis (group 3), and ≥70% stenosis on both sides (group 4). A total of 102 patient images were selected that met the inclusion criteria. The measurements of white matter lesion volumes were made using the LesionBrain application in the VolBrain Program. Results The MRI of 82 patients (mean age: 65.55 ± 9.28 years), 28 females and 54 males, were used in the present study. According to LesionBrain Analysis, the total WMH volume was seen in the first and third groups at most. When analyzed in regional terms, stenosis was mostly detected in the first and third groups in the periventricular region. WMH volume was less in all areas in group 4. When examined according to the number of lesions, the most lesions were detected in the third group in the juxtacortical region. When the difference between the groups was examined, a significant difference was detected only in the volume change in the deep white region (p=0.011). No significant differences were found between WMH volumes and age and gender (p>0.05). Conclusion Stenosis of the external internal carotid artery might cause hypoperfusion and silent embolization in the brain. As a result, as well as pathological conditions in cortical areas, ischemic areas in the white matter might also cause cognitive disorders.

Association of Chronic Kidney Disease With Plasma NfL and Other Biomarkers of Neurodegeneration: The H70 Birth Cohort Study in Gothenburg.

Studies associate chronic kidney disease (CKD) with neurodegeneration. This study investigated the relationship between kidney function, blood, CSF, and structural brain MRI markers of neurodegeneration in a sample including individuals with and without CKD. Participants from the Gothenburg H70 Birth Cohort Study, with data on plasma neurofilament light (P-NfL), estimated glomerular filtration rate (eGFR), and structural brain MRI were included. Participants were invited to also have the CSF collected. The primary endpoint of this study was to determine any association between CKD and P-NfL. Secondary endpoints included cross-sectional associations between CKD, eGFR, and CSF-derived and MRI-derived markers of neurodegeneration and Alzheimer disease (AD) pathology (MRI: cortical thickness, hippocampal volume, lateral ventricle volume, and white matter lesion volume; CSF: β-amyloid (Aβ) 42, Aβ42/40, Aβ42/p-tau, t-tau, p-tau, and NfL). Participants with P-NfL and eGFR at baseline were re-examined on eGFR, 5.5 (5.3-6.1) years (median; IQR) after the first visit, and the predictive value of P-NfL levels on incident CKD was estimated longitudinally, using a Cox proportional hazards model. We included 744 participants, 668 without CKD (age 71 [70-71] years, 50% males) and 76 with CKD (age 71 [70-71] years, 39% males). Biomarkers from the CSF were analyzed in 313 participants. A total of 558 individuals returned for a re-examination of eGFR (75% response rate, age 76 [76; 77] years, 48% males, 76 new cases of CKD). Participants with CKD had higher P-NfL levels than those with normal kidney function (median; 18.8 vs 14.1 pg/mL, p < 0.001), while MRI and CSF markers were similar between the groups. P-NfL was independently associated with CKD after adjustment for confounding variables, including hypertension and diabetes (OR; 3.231, p < 0.001), in a logistic regression model. eGFR and CSF Aβ 42/40: R = 0.23, p = 0.004 correlated in participants with Aβ42 pathology. P-NfL levels in the highest quartile were associated with incident CKD at follow-up (HR; 2.39 [1.21: 4.72]). In a community-based cohort of 70-year olds, P-NfL was associated with both prevalent and incident CKD, while CSF and/or imaging measures did not differ by CKD status. Participants with CKD and dementia presented similar levels of P-NfL.

Multiparametric quantitative MRI reveals progressive cortical damage over time in clinically stable relapsing-remitting MS

BackgroundIn relapsing-remitting multiple sclerosis (RRMS), cortical grey matter pathology relevantly contributes to long-term disability. Still, diffuse cortical inflammation cannot be detected with conventional MRI.ObjectiveWe aimed to assess microstructural damage of...

Choroid Plexus Enlargement In Systemic Lupus Erythematosus: Relationship With Auto-Antibody Status And Neuropsychiatric Involvement (P10-3.016)

<h3>Objective:</h3> To evaluate whether choroid plexus (CP) enlargement occurs in patients with systemic lupus erythematosus (SLE) compared to healthy controls (HC) and is associated with auto-antibody status, neuropsychiatric involvement (NP-SLE) and structural brain damage. <h3>Background:</h3> CP enlargement has been suggested as a marker of neuroinflammation in multiple sclerosis, being associated with disease activity and clinical disability. CP involvement in SLE immunopathology has been recently hypothesized, however, the associations between CP enlargement, auto-antibody status, clinical manifestations and brain structural damage have not been fully explored yet. <h3>Design/Methods:</h3> Brain 3T dual-echo and 3D T1-weighted sequences were acquired from 32 SLE patients and 32 age- and sex-matched HC. CP volume was manually obtained from 3D T1-weighted scans and normalized by head size. CP volumes were compared between HC and SLE patients stratified according to auto-antibody status (anti-antiphospholipid [APA] and anti-double-stranded DNA [ADNA] antibodies) and NP involvement using linear models. Associations between CP volume and clinical and structural MRI variables were explored using linear regression analyses. <h3>Results:</h3> Compared to HC, only SLE patients with positive autoantibody status (APA [n=18] or ADNA [n=24) showed significantly higher white matter (WM) lesion volume (LV) (p=0.020 and 0.033), whereas only SLE patients with APA antibodies had a significant CP enlargement (p=0.013). Compared to HC, both non-NP-SLE (n=20) and NP-SLE patients (n=12) showed significantly higher CP volume (p=0.002 and &lt;0.001), whereas WM LV was significantly higher only in NP-SLE (p=0.001). Compared to non-NP-SLE, NPSLE patients had significantly higher CP volume (p=0.024) and WM LV (p=0.015). No between-group volumetric brain differences were found. No significant associations of CP volume with disease duration and activity, WM LV and normalized brain volume were found. <h3>Conclusions:</h3> CP enlargement occurs in SLE patients, especially in those with APA and NP involvement, suggesting its potential role in the pathophysiology of SLE related brain involvement. <b>Disclosure:</b> Dr. Gueye has nothing to disclose. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Giuseppe A. Ramirez has nothing to disclose. Enrica Bozzolo has nothing to disclose. Valentina Canti has nothing to disclose. Monica Margoni has received research support from MAGNIMS. Alessandro Meani has nothing to disclose. Patrizia Rovere-Querini has nothing to disclose. Angelo Manfredi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Clinical &amp; Experimental Immunology. Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Radiological features of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and its longitudinal progression (P8-4.003)

Radiological features of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and its longitudinal progression (P8-4.003)

Choroid Plexus Enlargement in Pediatric Multiple Sclerosis: Clinical Relevance and Effect of Sex (P10-3.009)

<h3>Objective:</h3> We investigated choroid plexus (CP) volume in pediatric multiple sclerosis (MS) patients compared to matched healthy controls (HC), possible sex-related effect, and the associations with clinical and structural MRI variables. <h3>Background:</h3> CP enlargement has been suggested as a reliable marker of neuroinflammation in adult MS patients, correlating with measures of brain structural damage and clinical disability. The presence and clinical relevance of CP enlargement in pediatric MS patients has not been evaluated yet. <h3>Design/Methods:</h3> Brain 3.0 T dual-echo and 3D T1-weighted sequences were identified retrospectively from 69 pediatric MS patients and 23 age- and sex-matched HC. CP volume was manually obtained from 3D T1-weighted scans by two expert raters. <h3>Results:</h3> CP segmentation was highly reproducible (intra-observer agreement: rater I=0.963, rater II=0.958; inter-observer agreement=0.968). Compared to HC, pediatric MS patients showed higher normalized CP volume (p&lt;0.001). When looking at sex-specific effect, both female and male pediatric MS patients showed higher normalized CP volume compared to sex-matched HC (females: p&lt;0.001; males: p=0.021), with a significant disease (MS vs HC) ‘ sex (females vs males) interaction (p=0.040). In MS patients, a higher normalized CP volume was significantly associated with higher brain T2-hyperintense white matter (WM) lesion volume (β=0.252, p=0.017), larger lateral ventricle volume (β=0.470, FDR p&lt;0.001), lower normalized brain volume (β=−0.413, FDR p=0.002) and lower normalized thalamic volume (β=0.291, FDR p=0.046). No associations with disease duration, EDSS score, normalized cortical and WM volumes were found (FDR p≥0.172). A significant effect of the disease in the negative association between normalized volumes of CP and thalami was found (FDR p=0.046). <h3>Conclusions:</h3> CP enlargement occurs in pediatric MS patients, suggesting its early involvement in the pathophysiology of the disease. The higher CP volume, that is found especially in female patients, supports the hypothesis of sex-related differences in the neuroinflammatory processes occurring already in pediatric MS patients. <b>Disclosure:</b> Monica Margoni has received research support from MAGNIMS. Dr. Gueye has nothing to disclose. Alessandro Meani has nothing to disclose. Elisabetta Pagani has nothing to disclose. Dr. Moiola has nothing to disclose. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla.

A Prospective Natural History Study of Patients with Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (S49.008)

A Prospective Natural History Study of Patients with Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (S49.008)

Shared imaging markers of fatigue across multiple sclerosis, aquaporin-4 antibody neuromyelitis optica spectrum disorder and MOG antibody disease.

Fatigue is frequently reported by patients with multiple sclerosis, aquaporin-4-antibody neuromyelitis optica spectrum disorder and myelin-oligodendrocyte-glycoprotein antibody disease; thus they could share a similar pathophysiological mechanism. In this cross-sectional cohort study, we assessed the association of fatigue with resting-state functional MRI, diffusion and structural imaging measures across these three disorders. Sixteen patients with multiple sclerosis, 17 with aquaporin-4-antibody neuromyelitis optica spectrum disorder and 17 with myelin-oligodendrocyte-glycoprotein antibody disease assessed, outside of relapses, at the Oxford Neuromyelitis Optica Service underwent Modified Fatigue Impact Scale, Hospital Anxiety and Depression Scale and Expanded Disability Status Scale scoring. A 3T brain and spinal cord MRI was used to derive cortical, deep grey and white matter volumetrics, lesions volume, fractional anisotropy, brain functional connectivity metrics, cervical spinal cord cross-sectional area, spinal cord magnetic transfer ratio and average functional connectivity between the ventral and the dorsal horns of the cervical cord. Linear relationships between MRI measures and total-, cognitive- and physical-fatigue scores were assessed. All analyses were adjusted for correlated clinical regressors. No significant differences in baseline clinical characteristics, fatigue, depression and anxiety questionnaires and disability measures were seen across the three diseases, except for older age in patients with aquaporin-4-antibody neuromyelitis optica spectrum disorder (P = 0.0005). In the total cohort, median total-fatigue score was 35.5 (range 3-72), and 42% of patients were clinically fatigued. A positive correlation existed between the total-fatigue score and functional connectivity of the executive/fronto-temporal network in the in left middle temporal gyrus (P = 0.033) and between the physical-fatigue score and functional connectivity of the sensory-motor network (P = 0.032) in both pre- and post-central gyri. A negative relationship was found between the total-fatigue score and functional connectivity of the salience network (P = 0.023) and of the left fronto-parietal network (P = 0.026) in the right supramarginal gyrus and left superior parietal lobe. No clear relationship between fatigue subscores and the average functional connectivity of the spinal cord was found. Cognitive-fatigue scores were positively associated with white matter lesion volume (P = 0.018) and negatively associated with white matter fractional anisotropy (P = 0.032). Structural, diffusion and functional connectivity alterations were not influenced by the disease group. Functional and structural imaging metrics associated with fatigue relate to brain rather than spinal cord abnormalities. Salience and sensory-motor networks alterations in relation to fatigue might indicate a disconnection between the perception of the interior body state and activity and the actual behavioural responses and performances (reversible or irreversible). Future research should focus on functional rehabilitative strategies.

Morphofunctional Changes in the Spinal Cord of Rats after Contusion Injury with Local Delivery of Methylprednisolone in Combination with a Copolymer.

We studied the neuroprotective effect of local application of methylprednisolone in combination with a block copolymer after contusion spinal cord injury in rats. Histological analysis of the spinal cord showed that delivery of a complex of methylprednisolone with a block copolymer reduced the volume of white and gray matter lesions. An increase in the amplitude of the evoked response of the gastrocnemius muscle was observed during epidural stimulation of the spinal cord 6 h after the injury. The maximum amplitude of the muscle response was greater in the group with local delivery of the methylprednisolone complex with the polymer 72 h after the injury. The obtained results demonstrate the neuroprotective effect of the local administration of the complex and allow to make positive prognosis for the recovery of the sensorimotor functions in rats.

The non-linear correlation between the volume of cerebral white matter lesions and incidence of bipolar disorder: A secondary analysis of data from a cross-sectional study.

A non-linear relationship between the volume of cerebral white matter lesions (WML) and bipolar disorder (BD) incidence is shown. The cerebral WML volume is positively and non-linearly correlated to the BD risk. The correlation is stronger when the cerebral WML volume was <6,200 mm3.Graphical AbstractA non-linear relationship between the volume of cerebral white matter lesions and bipolar disorder incidence is shown after adjusting for age; sex; lithium, atypical antipsychotic, antiepileptic, and antidepressant drug use; BMI; migraine; smoking; hypertension; diabetes mellitus; substance and alcohol dependency; and anxiety disorder.

Association of volumetric MRI measures and disability in MS patients of the same age: Descriptions from a birth year cohort.

Although MRI-based markers of neuroinflammation have proven crucial for the diagnosis of multiple sclerosis (MS), predicting clinical progression with inflammation remains difficult. Neurodegenerative markers such as brain volume loss show stronger clinical (predictive) correlations, but also harbor age-related variation that must be disentangled from disease duration. In this study we investigated how clinical disability is related to volumetric MRI measures in a cohort of MS patients and healthy controls (HC) of the same age: Project Y. This study included 234 MS patients born in 1966 and 112 HC born between 1965 and 1967 in the Netherlands. Disability was quantified using the expanded disability status scale (EDSS), nine hole peg test (9HPT), and timed 25 foot walking test (T25FWT). Volumes were quantified on 3T MRI as normalized whole brain (NBV) and regional gray matter (GM) volumes using the same scanner and MRI protocol: cortical (normalized cortical gray matter volume; NCGMV), deep (NDGMV), thalamic (NThalV), and cerebellar (NCbV) GM volumes. In addition, mean upper cervical cord area (MUCCA), white matter lesion volume (LV), and spinal cord lesions were assessed. These measures were compared between patients and HC, and related to disability measures using linear regression. Mean age of people with MS (PwMS) was 52.8 years (SD 0.9) and median disease duration 15.8 years (IQR 8.7-24.8). All global and regional brain measures were lower in MS patients compared to HC. Univariate regression models showed that NDGMV (β=-0.20) and MUCCA (β=-0.38) were most strongly related to the EDSS in all PwMS. After subtype stratification, MUCCA was most strongly related to the EDSS (β=-0.60) and 9HPT (β=-0.55) in secondary progressive PwMS. Multivariate regression models demonstrated that in all PwMS, the EDSS was best explained by lower MUCCA, longer disease durations and a progressive disease course (adjusted-R (Sastre-Garrigaetal., 2017)=0.26, p < 0.001). MUCCA was a consistent correlate in separate models of the EDSS for all PwMS, relapsing and progressive onset PwMS. The 9HPT (adjusted-R (Sastre-Garrigaetal., 2017)=0.20, p < 0.001) was best explained by lower MUCCA, higher LV and pack years, while lower limb disability (adjusted-R (Sastre-Garrigaetal., 2017)=0.11, p < 0.001) was best explained by lower MUCCA, progressive onset MS and female sex. Our results indicate that in a cohort unbiased by age differences, spinal cord and deep gray matter volumes best related to physical disability. Our results support the use of these measures in clinical practice and trials.

Association of Intensive vs Standard Blood Pressure Control With Regional Changes in Cerebral Small Vessel Disease Biomarkers

Little is known about the associations of strict blood pressure (BP) control with microstructural changes in small vessel disease markers. To investigate the regional associations of intensive vs standard BP control with small vessel disease biomarkers, such as white matter lesions (WMLs), fractional anisotropy (FA), mean diffusivity (MD), and cerebral blood flow (CBF). The Systolic Blood Pressure Intervention Trial (SPRINT) is a multicenter randomized clinical trial that compared intensive systolic BP (SBP) control (SBP target <120 mm Hg) vs standard control (SBP target <140 mm Hg) among participants aged 50 years or older with hypertension and without diabetes or a history of stroke. The study began randomization on November 8, 2010, and stopped July 1, 2016, with a follow-up duration of approximately 4 years. A total of 670 and 458 participants completed brain magnetic resonance imaging at baseline and follow-up, respectively, and comprise the cohort for this post hoc analysis. Statistical analyses for this post hoc analysis were performed between August 2020 and October 2022. At baseline, 355 participants received intensive SBP treatment and 315 participants received standard SBP treatment. The main outcomes were regional changes in WMLs, FA, MD (in white matter regions of interest), and CBF (in gray matter regions of interest). At baseline, 355 participants (mean [SD] age, 67.7 [8.0] years; 200 men [56.3%]) received intensive BP treatment and 315 participants (mean [SD] age, 67.0 [8.4] years; 199 men [63.2%]) received standard BP treatment. Intensive treatment was associated with smaller mean increases in WML volume compared with standard treatment (644.5 mm3 vs 1258.1 mm3). The smaller mean increases were observed specifically in the deep white matter regions of the left anterior corona radiata (intensive treatment, 30.3 mm3 [95% CI, 16.0-44.5 mm3]; standard treatment, 80.5 mm3 [95% CI, 53.8-107.2 mm3]), left tapetum (intensive treatment, 11.8 mm3 [95% CI, 4.4-19.2 mm3]; standard treatment, 27.2 mm3 [95% CI, 19.4-35.0 mm3]), left superior fronto-occipital fasciculus (intensive treatment, 3.2 mm3 [95% CI, 0.7-5.8 mm3]; standard treatment, 9.4 mm3 [95% CI, 5.5-13.4 mm3]), left posterior corona radiata (intensive treatment, 26.0 mm3 [95% CI, 12.9-39.1 mm3]; standard treatment, 52.3 mm3 [95% CI, 34.8-69.8 mm3]), left splenium of the corpus callosum (intensive treatment, 45.4 mm3 [95% CI, 25.1-65.7 mm3]; standard treatment, 83.0 mm3 [95% CI, 58.7-107.2 mm3]), left posterior thalamic radiation (intensive treatment, 53.0 mm3 [95% CI, 29.8-76.2 mm3]; standard treatment, 106.9 mm3 [95% CI, 73.4-140.3 mm3]), and right posterior thalamic radiation (intensive treatment, 49.5 mm3 [95% CI, 24.3-74.7 mm3]; standard treatment, 102.6 mm3 [95% CI, 71.0-134.2 mm3]). This study suggests that intensive BP treatment, compared with standard treatment, was associated with a slower increase of WMLs, improved diffusion tensor imaging, and FA and CBF changes in several brain regions that represent vulnerable areas that may benefit from more strict BP control. ClinicalTrials.gov Identifier: NCT01206062.