Deep Gray Matter Volumes Research Articles

Magnetic Resonance Imaging Evaluation of Perivascular Space Abnormalities in Neuromyelitis Optica

ObjectiveAstrocytes outline the perivascular space (PVS) and regulate fluid exchange through the aquaporin‐4 water channel. As neuromyelitis optica is an autoimmune astrocytopathy targeting aquaporin‐4, we hypothesized that it could be associatied with PVS abnormalities.MethodsA total of 34 patients, and 46 age‐ and sex‐matched healthy controls from two independent cohorts (exploratory and validation dataset) underwent a standardized 3.0‐T magnetic resonance imaging protocol including conventional and diffusion tensor imaging. Susceptibility‐weighted imaging was also acquired in the exploratory dataset. We evaluated macroscopic and microstructural abnormalities of PVS in terms of enlargement and water diffusivity (DTI‐ALPS index). In the exploration dataset, a susceptibility‐weighted sequence was used to draw the regions of interest for the DTI‐ALPS index calculation in areas having veins perpendicular to lateral ventricles. Between‐group comparisons, correlations, and regression models were run to assess associations between PVS abnormalities, and clinical and magnetic resonance imaging variables.ResultsPatients had a higher frequency of severe PVS enlargement in the centrum semiovale (29.4% vs 8.7%), which correlated with brain atrophy, deep grey matter atrophy, and poorer cognitive performance (r‐values range: −0.44, −0.36; p values: 0.01–0.046).In both datasets, patients had reduced DTI‐ALPS index compared with controls (p values 0.004–0.038). Lower DTI‐ALPS index, deep gray matter volume, and cortical volume could discriminate between patients and controls (R 2 = 0.62), whereas lower DTI‐ALPS index, higher number of myelitis, and higher T2‐lesion volume were associated with worse disability (R 2 = 0.55).InterpretationPatients with neuromyelitis optica spectrum disorder are characterized by abnormal enlargement and impaired water diffusion along the PVS, whose clinical implications suggest a direct correlation with disease pathogenesis and severity. ANN NEUROL 2022;92:173–183

Association of Brain Atrophy With Disease Progression Independent of Relapse Activity in Patients With Relapsing Multiple Sclerosis

The mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood. To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss. In this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021. According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability. Mean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models. Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, -0.36; 95% CI, -0.60 to -0.12; P = .02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, -0.18; 95% CI, -0.34 to -0.02; P = .04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity. Our study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials.

The association between cognition and motor performance is beyond structural damage in relapsing–remitting multiple sclerosis

Previous studies demonstrated an association between motor and cognitive performance in multiple sclerosis (MS). However, disease-related brain damage might represent a common substrate to both phenomena, which was not considered before. Aim of this study is to investigate whether the association between cognition and motor function is beyond structural damage in patients with MS. Eighty-one healthy controls and 106 relapsing-remitting (RR) MS patients underwent a 3.0T MRI with quantification of T2-lesion volumes, T1-lesion volumes and normalized brain volumes. A functional examination [Nine-Hole Peg Test (9-HPT), Timed 25-Foot Walk test (T25FW) and Expanded Disability Status Scale] and a neuropsychological evaluation (Brief Repeatable Battery of Neuropsychological Tests) were also administered. Association between demographic, clinical, cognitive, MRI and functional measures were analysed with univariate analyses and hierarchical linear regression. In RRMS patients, Spatial Recall Test and Symbol Digit Modalities Test were positively correlated with 9-HPT (p < 0.001) and T25FW (p ≤ 0.035); Paced Auditory Serial Addition Test (PASAT) correlated with 9-HPT (p ≤ 0.009). 9-HPT and T25FW were significantly associated with normalized brain volumes (p ≤ 0.016), T2- and T1-lesion volumes (p ≤ 0.009). Hierarchical regression models selected age and normalized deep gray matter volume as predictors of T25FW (adjusted-R2 = 0.109). Younger age, female sex, higher normalized gray matter volume and higher PASAT 2″ scores predicted higher 9-HPT scores (adjusted-R2 = 0.337). In RRMS patients, deficit in information processing speed and executive function may contribute to hand motor dysfunction beyond the effect of structural disease-related burden, supporting the integration of motor and cognitive assessment in clinical settings.

Association of Carotid Intima-Media Thickness with Brain MRI Markers in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS)

ObjectiveElevated carotid intima-media thickness (cIMT) and carotid plaque are markers of arterial injury and may be linked to structural brain injury. We hypothesized cIMT or presence of carotid plaque at midlife are associated with presence of infarcts and cerebral microbleeds, greater white matter hyperintensity (WMH) volume, and smaller regional brain volumes in late-life. MethodsWe included 1,795 Atherosclerosis Risk in Communities (ARIC) Study participants (aged 57±6 years, 57% female, 23% Black) with carotid ultrasounds in 1990-1992 and brain MRI scans in 2011-2013. Weighted linear regression was used for brain volume outcomes, while logistic regression was used for infarcts and cerebral microbleeds. ResultsAfter multivariable adjustments, the highest cIMT quintile was associated with smaller deep gray matter (β [95% CI]: -0.11 [-0.22, -0.01]) and cortical volume in a temporal-parietal meta region of interest (ROI) (β [95% CI]: -0.10 [-0.20, -0.01]) in late-life. Similarly, those with carotid plaque had smaller regional brain volumes than those without (βs [95% CIs]: -0.05 [-0.12, 0.03] and -0.06 [-0.13, 0.01] for deep gray matter and temporal-parietal meta ROI). No significant relations were observed with WMH volume, infarcts, or cerebral microbleeds. ConclusionOver a median follow-up of 21 years, greater midlife cIMT and presence of carotid plaque were associated with smaller deep gray matter volume and cortical volume in a meta ROI involving temporal and parietal lobe regions typically involved in neurodegeneration, including Alzheimer's disease, in later life. Contrary to our hypothesis, associations between measures of arterial injury and markers of vascular brain injury were null.

Relationship Between White Matter Lesions and Gray Matter Atrophy in Multiple Sclerosis: A Systematic Review.

Background and ObjectivesThere is currently no consensus about the extent of gray matter (GM) atrophy that can be attributed to secondary changes after white matter (WM) lesions or the temporal and spatial relationships between the 2 phenomena. Elucidating this interplay will broaden the understanding of the combined inflammatory and neurodegenerative pathophysiology of multiple sclerosis (MS), and separating atrophic changes due to primary and secondary neurodegenerative mechanisms will then be pivotal to properly evaluate treatment effects, especially if these treatments target the different processes individually. To untangle these complex pathologic mechanisms, this systematic review provides an essential first step: an objective and comprehensive overview of the existing in vivo knowledge of the relationship between brain WM lesions and GM atrophy in patients diagnosed with MS. The overall aim was to clarify the extent to which WM lesions are associated with both global and regional GM atrophy and how this may differ in the different disease subtypes.MethodsWe searched MEDLINE (through PubMed) and Embase for reports containing direct associations between brain GM and WM lesion measures obtained by conventional MRI sequences in patients with clinically isolated syndrome and MS. No restriction was applied for publication date. The quality and risk of bias in included studies were evaluated with the Quality Assessment Tool for observational cohort and cross-sectional studies (NIH, Bethesda, MA). Qualitative and descriptive analyses were performed.ResultsA total of 90 articles were included. WM lesion volumes were related mostly to global, cortical and deep GM volumes, and those significant associations were almost without exception negative, indicating that higher WM lesion volumes were associated with lower GM volumes or lower cortical thicknesses. The most consistent relationship between WM lesions and GM atrophy was seen in early (relapsing) disease and less so in progressive MS.DiscussionThe findings suggest that GM neurodegeneration is mostly secondary to damage in the WM during early disease stages while becoming more detached and dominated by other, possibly primary neurodegenerative disease mechanisms in progressive MS.

Serum NfL levels in the first five years predict 10-year thalamic fraction in patients with MS.

BackgroundSerum neurofilament light chain (sNfL) levels are associated with relapses, MRI lesions, and brain volume in multiple sclerosis (MS).ObjectiveTo explore the value of early serum neurofilament light (sNfL) measures in prognosticating 10-year regional brain volumes in MS.MethodsPatients with MS enrolled in the Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) study within five years of disease onset who had annual blood samples from years 1–10 (n = 91) were studied. sNfL was measured with a single molecule array (SIMOA) assay. We quantified global cortical thickness and normalized deep gray matter (DGM) volumes (fractions of the thalamus, caudate, putamen, and globus pallidus) from high-resolution 3 T MRI at 10 years. Correlations between yearly sNfL levels and 10-year MRI outcomes were assessed using linear regression models.ResultssNfL levels from years 1 and 2 were associated with 10-year thalamus fraction. Early sNfL levels were not associated with 10-year putamen, globus pallidus or caudate fractions. At 10 years, cortical thickness was not associated with early sNfL levels, but was weakly correlated with total DGM fraction.ConclusionsEarly sNfL levels correlate with 10-year thalamic volume, supporting its role as a prognostic biomarker in MS.

Glymphatic system impairment in multiple sclerosis: relation with brain damage and disability.

Recent evidence has shown the existence of a CNS 'waste clearance' system, defined as the glymphatic system. Glymphatic abnormalities have been described in several neurodegenerative conditions, including Alzheimer's and Parkinson's disease. Glymphatic function has not been thoroughly explored in multiple sclerosis, where neurodegenerative processes are intermingled with inflammatory processes. We aimed to investigate glymphatic system function in multiple sclerosis and to evaluate its association with clinical disability, disease course, demyelination and neurodegeneration, quantified using different MRI techniques. In this retrospective study, we enrolled 71 multiple sclerosis patients (49 relapsing-remitting and 22 progressive multiple sclerosis) and 32 age- and sex-matched healthy control subjects. All subjects underwent neurological and MRI assessment including high-resolution T1, T2 and double inversion recovery sequences, diffusion and susceptibility weighted imaging. We calculated the diffusion along perivascular space index, a proxy for glymphatic function, cortical and deep grey matter volume, white and cortical grey matter lesion volume and normal-appearing white matter microstructural damage. Multiple sclerosis patients showed an overall lower diffusion along perivascular space index versus healthy controls (estimated mean difference: -0.09, P = 0.01). Both relapsing-remitting and progressive multiple sclerosis patients had lower diffusion along perivascular space index versus healthy controls (estimated mean difference: -0.06, P = 0.04 for relapsing-remitting and -0.19, P = 0.001 for progressive multiple sclerosis patients). Progressive multiple sclerosis patients showed lower diffusion along perivascular space index versus relapsing-remitting multiple sclerosis patients (estimated mean difference: -0.09, P = 0.03). In multiple sclerosis patients, lower diffusion along perivascular space index was associated with more severe clinical disability (r = -0.45, P = 0.001) and longer disease duration (r = -0.37, P = 0.002). Interestingly, we detected a negative association between diffusion along perivascular space index and disease duration in the first 4.13 years of the disease course (r = -0.38, P = 0.04) without any association thereafter (up to 34 years of disease duration). Lower diffusion along perivascular space index was associated with higher white (r = -0.36, P = 0.003) and cortical (r = -0.41, P = 0.001) lesion volume, more severe cortical (r = 0.30, P = 0.007) and deep (r = 0.42, P = 0.001) grey matter atrophy, reduced fractional anisotropy (r = 0.42, P = 0.001) and increased mean diffusivity (r = -0.45, P = 0.001) in the normal-appearing white matter. Our results suggest that the glymphatic system is impaired in multiple sclerosis, especially in progressive stages. Impaired glymphatic function was associated with measures of both demyelination and neurodegeneration and reflects a more severe clinical disability. These findings suggest that glymphatic impairment may be a pathological mechanism underpinning multiple sclerosis. The dynamic interplay with other pathological substrates of the disease deserves further investigation.

Associations of Serum Magnesium with Brain Morphology and Subclinical Cerebrovascular Disease: The Atherosclerosis Risk in Communities-Neurocognitive Study.

Circulating magnesium has been associated with a lower risk of dementia, but the physiologic effects by which magnesium may prevent neurological insults remain unclear. We studied 1466 individuals (mean age 76.2 ± 5.3, 28.8% black, 60.1% female) free of prevalent stroke, with measured serum magnesium and with available MRI scans obtained in 2011–2013, participating in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Cross-sectional differences in frontal, temporal, parietal, and occipital lobe volume, along with deep grey matter, total brain, and white matter hyperintensity volume across serum magnesium (categorized into quintiles and per standard deviation increases) were assessed using multiple linear regression. We also examined associations of magnesium with the prevalence of cortical, subcortical, and lacunar infarcts using multiple logistic regression. After adjusting for demographics, biomarkers, medications, and cardiometabolic risk factors, higher circulating magnesium was associated with greater total brain volume and frontal, temporal, and parietal lobe volumes (volumes 0.14 to 0.19 standard deviations higher comparing Q5 to Q1). Elevated magnesium was also associated with lower odds of subcortical infarcts (OR (95%CI): 0.44 (0.25, 0.77) comparing Q5 to Q1) and lacunar infarcts (OR (95%CI): 0.40 (0.22, 0.71) comparing Q5 to Q1). Elevated serum magnesium was cross-sectionally associated with greater brain volumes and lower odds of subclinical cerebrovascular disease, suggesting beneficial effects on pathways related to neurodegeneration and cerebrovascular damage. Further exploration through prospective analyses is needed to assess increasing circulating magnesium as a potential neuroprotective intervention.

Brain MRI signatures of atrophy in genetic frontotemporal lobar degeneration

AbstractBackgroundGenetic heterogeneity underlying different clinical presentations of the frontotemporal lobar degeneration (FTLD) spectrum hampers the identification of useful biomarkers that may be able to monitor disease progression and/or facilitate the enrolment in clinical trials. The aim of this study was to assess cortical, subcortical and cerebellar grey matter (GM) atrophy using magnetic resonance imaging (MRI) in patients affected by disorders of the FTLD spectrum with known genetic mutations.MethodSixty‐six patients carrying FTLD‐related mutations were enrolled, including 44 with pure motor neuron disease (MND) and 22 with frontotemporal dementia (FTD). Sixty‐one patients with sporadic FTLD (sFTLD) matched for age, sex and disease severity with genetic FTLD (gFTLD) were also included, as well as 52 healthy controls (HC). A whole‐brain voxel‐based morphometry (VBM) analysis was performed. GM volumes of subcortical and cerebellar structures were also obtained.ResultCompared with HC, GM volume loss on VBM was generally greater and more diffuse in genetic FTD (gFTD) cases, followed by sporadic FTD (sFTD) cases and genetic MND (gMND) cases, whereas sporadic MND (sMND) showed very focal atrophy of the motor cortex. Patients carrying GRN and C9ORF72 mutations showed the most widespread cortical volume loss, whereas SOD1 and TARDBP patients were the least atrophic. Greater atrophy of the parietal cortices and thalami was found, globally, in genetic FTLD patients compared with sporadic FTLD and, particularly, in C9‐MND patients compared with sMND. When assessing deep GM volumes, genetic FTLD patients showed significant volume loss compared with sporadic FTLD in the caudate nuclei and thalami. In particular, greater atrophy of the left caudate and right thalamus was found in C9MND compared with sMND. At the cerebellar level, greater atrophy of the right lobule VIIb could discriminate genetic FTLD from sporadic FTLD patients.ConclusionOur data suggest that measures of deep GM and cerebellar involvement might be useful markers of genetic FTLD, particularly C9ORF72‐related disorders, regardless of the clinical presentation within the FTLD spectrum.Supported by: Italian Ministry of Health (RF‐2011‐02351193; GR‐2011‐02351217) and European Research Council (StG‐2016_714388_NeuroTRACK).

Differentiation of multiple system atrophy subtypes by gray matter atrophy.

Multiple system atrophy(MSA) is a rare adult-onset synucleinopathy that can be divided in two subtypes depending on whether the prevalence of its symptoms is more parkinsonian or cerebellar (MSA-P and MSA-C, respectively). The aim of this work is to investigate the structural MRI changes able to discriminate MSA phenotypes. The sample includes 31 MSA patients (15 MSA-C and 16 MSA-P) and 39 healthy controls. Participants underwent a comprehensive motor and neuropsychological battery. MRI data wereacquired with a 3T scanner (MAGNETOM Trio, Siemens, Germany). FreeSurfer was used to obtain volumetric and cortical thickness measures. A Support Vector Machine (SVM) algorithm was used to assess the classification between patients' group using cortical and subcortical structural data. After correction for multiple comparisons, MSA-C patients had greater atrophy than MSA-P in the left cerebellum, whereas MSA-P showed reduced volume bilaterally in the pallidum and putamen. Using deep gray matter volume ratios and mean cortical thickness as features, the SVM algorithm provided a consistent classification between MSA-C and MSA-P patients (balanced accuracy 74.2%, specificity 75.0%, and sensitivity 73.3%). The cerebellum, putamen, thalamus, ventral diencephalon, pallidum, and caudate were the most contributing features to the classification decision (z>3.28; p<.05 [false discovery rate]). MSA-C and MSA-P with similar disease severity and duration have a differential distribution of gray matter atrophy. Although cerebellar atrophy is a clear differentiator between groups, thalamic and basal ganglia structures are also relevant contributors to distinguishing MSA subtypes.

Value of magnetic resonance imaging in multiple sclerosis patients

Background: Magnetic Resonance Imaging (MRI) has many advantages in the investigation of Multiple Sclerosis (MS). It delivers precise measurements of disorder activity, simplifies accurate diagnosing, and help in the evaluation of novel treatments. The present work aim is to recognize the roles of MRI in in the characterizations of MS-connected brain and spinal cord involvement. Methods: 30-cases relapsing-remitting MS (RRMS) cases were involved. The number, volume, and distribution of brain MRI lesions have been assessed via T2-weighted (T2W) image. Cross-sectional full normalized brain volume (NBV), normalized deep gray matter volume (NDGMV), normalized white matter volume (NWMV), normalized cortical gray matter volume (NCGMV), and normalized thalamic volume (NTV) have been calculated. Results: MRI findings revealed that the mainstream of case’s lesions were detected via T2W-imaging with a mean value of Number of lesions measured of 4.43±3.329, MRI accuracy to detect MS was 86.67% with sensitivity and specificity 88.9 and 66.7 correspondingly, Conclusion: MRI suggestion have a supporting function in what is eventually a clinical MS diagnosing, in the suitable medical condition, and at all times at the exclusion of substitute diagnosing. MRI has improved into the most significant tool for diagnosing and screening of MS. Its elevated sensitivity for the assessment of inflammation and neuro-degenerative procedures in the brain and spinal cord has made it the commonest employed way for the valuation of MS-cases, Key words: Magnetic resonance imaging, multiple sclerosis

Serum docosahexaenoic acid levels are associated with brain volumes in extremely preterm born infants.

Docosahexaenoic acid (DHA) and arachidonic acid (AA) are important for fetal brain growth and development. Our aim was to evaluate the association between serum DHA and AA levels and brain volumes in extremely preterm infants. Infants born at <28 weeks gestational age in 2013-2015, a cohort derived from a randomized controlled trial comparing two types of parenteral lipid emulsions, were included (n = 90). Serum DHA and AA levels were measured at postnatal days 1, 7, 14, and 28, and the area under the curve was calculated. Magnetic resonance (MR) imaging was performed at term-equivalent age (n = 66), and volumes of six brain regions were automatically generated. After MR image quality assessment and area under the curve calculation, 48 infants were included (gestational age mean [SD] 25.5 [1.4] weeks). DHA levels were positively associated with total brain (B = 7.966, p = 0.012), cortical gray matter (B = 3.653, p = 0.036), deep gray matter (B = 0.439, p = 0.014), cerebellar (B = 0.932, p = 0.003), and white matter volume (B = 3.373, p = 0.022). AA levels showed no association with brain volumes. Serum DHA levels during the first 28 postnatal days were positively associated with volumes of several brain structures in extremely preterm infants at term-equivalent age. Higher serum levels of DHA in the first 28 postnatal days are positively associated with brain volumes at term-equivalent age in extremely preterm born infants. Especially the most immature infants suffer from low DHA levels in the first 28 postnatal days, with little increase over time. Future research is needed to explore whether postnatal fatty acid supplementation can improve brain development and may serve as a nutritional preventive and therapeutic treatment option in extremely preterm infants.

Right entorhinal cortical thickness is associated with Mini-Mental State Examination scores from multi-country datasets using MRI.

To discover common biomarkers correlating with the Mini-Mental State Examination (MMSE) scores from multi-country MRI datasets. The first dataset comprised 112 subjects (49 men, 63 women; range, 46-94 years) at the National Hospital Organization Kyushu Medical Center. A second dataset comprised 300 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (177 men, 123 women; range, 57-91 years). Three-dimensional T1-weighted MR images were collected from both datasets. In total, 14 deep gray matter volumes and 70 cortical thicknesses were obtained from MR images using FreeSurfer software. Total hippocampal volume and the ratio of hippocampus to cerebral volume were also calculated. Correlations between each variable and MMSE scores were assessed using Pearson's correlation coefficient. Parameters with moderate correlation coefficients (r > 0.3) from each dataset were determined as independent variables and evaluated using general linear model (GLM) analyses. In Pearson's correlation coefficient, total and bilateral hippocampal volumes, right amygdala volume, and right entorhinal cortex (ERC) thickness showed moderate correlation coefficients (r > 0.3) with MMSE scores from the first dataset. The ADNI dataset showed moderate correlations with MMSE scores in more variables, including bilateral ERC thickness and hippocampal volume. GLM analysis revealed that right ERC thickness correlated significantly with MMSE score in both datasets. Cortical thicknesses of the left parahippocampal gyrus, left inferior parietal lobe, and right fusiform gyrus also significantly correlated with MMSE score in the ADNI dataset (p < 0.05). A positive correlation between right ERC thickness and MMSE score was identified from multi-country datasets.

Association of Disease Severity and Socioeconomic Status in Black and White Americans With Multiple Sclerosis

To compare clinical and imaging features of multiple sclerosis (MS) severity between Black Americans (BAs) and White Americans (WAs) and to evaluate the role of socioeconomic status. We compared BA and WA participants in the Multiple Sclerosis Partners Advancing Technology Health Solutions (MS PATHS) cohort with respect to MS characteristics, including self-reported disability, objective neurologic function assessments, and quantitative brain MRI measurements, after covariate adjustment (including education level, employment, or insurance as socioeconomic indicators). In a subgroup, we evaluated within-race, neighborhood-level indicators of socioeconomic status (SES) using 9-digit zip codes. Of 1,214 BAs and 7,530 WAs with MS, BAs were younger, had lower education level, and were more likely to have Medicaid insurance or to be disabled or unemployed than WAs. BAs had worse self-reported disability (1.47-fold greater odds of severe vs mild disability, 95% confidence interval [CI] 1.18, 1.86) and worse performances on tests of cognitive processing speed (-5.06 fewer correct, 95% CI -5.72, -4.41), walking (0.66 seconds slower, 95% CI 0.36, 0.96), and manual dexterity (2.11 seconds slower, 95% CI 1.69, 2.54). BAs had more brain MRI lesions and lower overall and gray matter brain volumes, including reduced thalamic (-0.77 mL, 95% CI -0.91, -0.64), cortical (-30.63 mL, 95% CI -35.93, -25.33), and deep (-1.58 mL, 95% CI -1.92, -1.23) gray matter volumes. While lower SES correlated with worse neuroperformance scores in WAs, this association was less clear in BAs. We observed a greater burden of disease in BAs with MS relative to WAs with MS, despite adjustment for SES indicators. Beyond SES, future longitudinal studies should also consider roles of other societal constructs (e.g., systemic racism). Such studies will be important for identifying prognostic factors; developing optimal treatment strategies among BAs with MS is warranted.

Assessment of the genetic contribution to brain magnetic resonance imaging lesion load and atrophy measures in multiple sclerosis patients.

Multiple sclerosis (MS) susceptibility is influenced by genetics; however, little is known about genetic determinants of disease expression. We aimed at assessing genetic factors influencing quantitative neuroimaging measures in two cohorts of progressive MS (PMS) and relapsing-remitting MS (RRMS) patients. Ninety-nine PMS and 214 RRMS patients underwent a 3-T brain magnetic resonance imaging (MRI) scan, with the measurement of five MRI metrics including T2 lesion volumes and measures of white matter, grey matter, deep grey matter, and hippocampal volumes. A candidate pathway strategy was adopted; gene set analysis was carried out to estimate cumulative contribution of genes to MRI phenotypes, adjusting for relevant confounders, followed by single nucleotide polymorphism (SNP) regression analysis. Seventeen Kyoto Encyclopedia of Genes and Genomes pathways and 42 Gene Ontology (GO) terms were tested. We additionally included in the analysis genes with enriched expression in brain cells. Gene set analysis revealed a differential pattern of association across the two cohorts, with processes related to sodium homeostasis being associated with grey matter volume in PMS (p=0.002), whereas inflammatory-related GO terms such as adaptive immune response and regulation of inflammatory response appeared to be associated with T2 lesion volume in RRMS (p=0.004 and p=0.008, respectively). As for SNPs, the rs7104613T mapping to SPON1 gene was associated with reduced deep grey matter volume (β=-0.731, p=3.2*10-7 ) in PMS, whereas we found evidence of association between white matter volume and rs740948A mapping to SEMA3A gene (β=22.04, p=5.5*10-6 ) in RRMS. Our data suggest a different pattern of associations between MRI metrics and functional processes across MS disease courses, suggesting different phenomena implicated in MS.

Contrasting the brain imaging features of MOG-antibody disease, with AQP4-antibody NMOSD and multiple sclerosis

Background: Identifying magnetic resonance imaging (MRI) markers in myelin-oligodendrocytes-glycoprotein antibody-associated disease (MOGAD), neuromyelitis optica spectrum disorder-aquaporin-4 positive (NMOSD-AQP4) and multiple sclerosis (MS) is essential for establishing objective outcome measures. Objectives: To quantify imaging patterns of central nervous system (CNS) damage in MOGAD during the remission stage, and to compare it with NMOSD-AQP4 and MS. Methods: 20 MOGAD, 19 NMOSD-AQP4, 18 MS in remission with brain or spinal cord involvement and 18 healthy controls (HC) were recruited. Volumetrics, lesions and cortical lesions, diffusion-imaging measures, were analysed. Results: Deep grey matter volumes were lower in MOGAD (p = 0.02) and MS (p = 0.0001), compared to HC and were strongly correlated with current lesion volume (MOGAD R = −0.93, p < 0.001, MS R = −0.65, p = 0.0034). Cortical/juxtacortical lesions were seen in a minority of MOGAD, in a majority of MS and in none of NMOSD-AQP4. Non-lesional tissue fractional anisotropy (FA) was only reduced in MS (p = 0.01), although focal reductions were noted in NMOSD-AQP4, reflecting mainly optic nerve and corticospinal tract pathways. Conclusion: MOGAD patients are left with grey matter damage, and this may be related to persistent white matter lesions. NMOSD-AQP4 patients showed a relative sparing of deep grey matter volumes, but reduced non-lesional tissue FA. Observations from our study can be used to identify new markers of damage for future multicentre studies.

Abstract MP24: Sedentary Behavior (SB) In Mid-life And Structural Brain Magnetic Resonance Imaging (MRI) Markers Of Cerebrovascular Disease And Neurodegeneration In Late-life: The Atherosclerosis Risk In Communities Neurocognitive Study (ARIC-NCS)

Introduction: Few prospective studies have examined the associations of SB on brain MRI markers. We tested the hypotheses that higher levels of, and persistence of mid-life television viewing, a cognitively passive SB, are associated with structural brain MRI markers in late-life, and that these associations are independent from physical activity (PA). Methods: ARIC participants (n=1,601, mean age: 76.2 years, 60.5% female, 27.2% Black) with reported television viewing at visits 1 (1987-89) and 3 (1993-95), and brain MRI in 2011-13 were included. Participants were categorized as low [never/seldom], medium [sometimes], or high [often/very often] television viewing. Persistent pattern of television viewing was quantified as the same frequency of reported television viewing at visits 1 and 3 (n=971). Imaging using 3T brain MRI quantified the presence of cerebrovascular lesions, white matter microstructural integrity and disease, and grey matter volumes using a standardized protocol. Models were adjusted for age, race-center, sex, education, APOE-ε4, smoking status, and total intracranial volume in volumetric analysis. Sampling weights were included to generalize MRI sample to the visit 5 cohort. Interactions by meeting (or not) 2018 PA guidelines were tested. Results: Compared to low television viewing, medium and high television viewing in midlife was significantly associated with smaller deep grey matter volumes in late-life after multivariable adjustment; associations were stronger for persistent television viewing ( Table ). All other associations of midlife, or persistent midlife, television viewing with structural brain MRI markers were statistically null. Interactions with meeting PA guidelines were also non-significant. Conclusions: Findings suggest an inverse association of mid-life television viewing with later-life deep grey matter volumes. Studies examining the associations of daily accumulated SB, and differences by SB type (active versus passive), with brain MRI markers are needed.

Abstract P120: Association Of Carotid Intima-Media Thickness With Brain MRI Markers In The Atherosclerosis Risk In Communities Neurocognitive Study (ARIC-NCS)

Background: Elevated carotid intima-media thickness (cIMT) and presence of carotid plaque are markers of atherosclerosis, which may be linked to structural brain injury. Using data from the ARIC-NCS cohort, we tested the hypotheses that greater cIMT and presence of carotid plaque at late midlife were each associated with presence of infarcts (lacunar and cortical) and cerebral microbleeds (lobar and subcortical), greater white matter hyperintensity (WMH) volume, and smaller regional brain volumes in late life. Methods: We included 1,795 ARIC participants who had carotid ultrasounds in 1990-92 and brain MRI scans in 2011-13. Weighted linear regression was used for continuous (brain volume) outcomes, and weighted logistic regression for dichotomous outcomes (infarcts and cerebral microbleeds). Results: Participants were aged 57±6 years at baseline, 57% were female, and 23% were Black. Mean ± SD follow-up was 21±1 years. After multivariable adjustments, the highest quintile of cIMT in late midlife was associated with smaller deep grey matter volume (β [95% CI]: -0.11 [-0.22, -0.01]) and cortical volume in a temporal-parietal meta region of interest (ROI) (β [95% CI]: -0.10 [-0.20, -0.01]) in late life (Table). At baseline, 473 (26%) participants had carotid plaque present on their carotid ultrasound. Similar to cIMT, those with carotid plaque had smaller regional brain volumes than those without carotid plaque present (βs [95% CIs]: -0.05 [-0.12, 0.03] and -0.06 [-0.13, 0.01] for deep grey matter and temporal-parietal meta ROI volumes, respectively). No significant relations were observed with WMH volume, or the presence of any infarcts or cerebral microbleeds. Conclusion: Greater midlife cIMT and presence of carotid plaque were associated with smaller deep grey matter volume and cortical volume in a temporal-parietal meta ROI in later life. Contrary to our hypothesis, associations between midlife subclinical atherosclerosis and markers of vascular brain injury in later life were null.

Abstract P485: Predictors and Clinical Impact of Deep Grey Matter Infarction After Endovascular Treatment for Large Vessel Occlusion Stroke: Results From the Escape-NA1 Trial

Purpose: In this post-hoc analysis of the ESCAPE-NA1 trial, we investigated the prevalence of deep grey matter infarcts and their influence on clinical outcome. Methods: Infarcts on 24 hour follow up imaging (non contrast head CT or diffusion-weighted MRI) were categorized as predominantly deep grey matter infarcts (caudate and/or lentiform nucleus infarcts with sparing of the superficial grey matter and white matter) vs. other infarcts. Total infarct volume was manually segmented in all patients. When MRI follow-up was available, deep grey matter and grey matter infarct volumes were segmented separately. Multivariable logistic regression with adjustment for key minimization variables and by infarct volume was used to assess the association of predominantly deep grey matter infarcts and good outcome. Results: Of the 1026 included patients, 316 (30.8%) had predominantly deep grey matter infarcts. Cumulative proportions of good outcome for overall, grey matter, deep grey matter, and superficial grey matter infarct volumes are shown in the figure. Good outcomes were more frequently achieved in patients with predominantly deep grey matter infarcts (239/316 [75.6%] vs. 374/704 [53.1%]). Deep infarcts were tightly correlated with infarct volume (Pearson rho -0.35) and in multivariable analysis deep grey matter infarcts were predictive of outcome overall; when examined in volume percentiles, there was no effect of deep infarct location. Conclusion: Predominantly deep grey matter infarcts are associated with good outcomes. Deep grey matter infarct location favorable prognosis is associated with small overall infarct size.

Vascular comorbidity is associated with lower brain volumes and lower neuroperformance in a large multiple sclerosis cohort

Objective: The objective of this study is to assess the association between vascular comorbidity burden with clinical and imaging features of disease burden in a large population of people with multiple sclerosis (MS). Methods: We included participants from the MS Partners Advancing Technology Health Solutions (MS PATHS) cohort. We evaluated if vascular comorbidities (diabetes, hypertension, and dyslipidemia) or a composite sum of comorbidities was associated with MS characteristics, including objective neurologic function assessments and quantitative brain magnetic resonance imaging (MRI) measurements in propensity score–weighted models. Results: In total, 11,506 participants (6409 (55%) with brain MRI) were included. Individuals with 2+ vascular comorbidities had slower walking speed (standard deviation (SD) = −0.49; 95% confidence interval (CI) = −0.78, −0.19; p = 0.001), slower manual dexterity (SD = −0.41; 95% CI = −0.57, −0.26; p < 0.0001), and fewer correct scores on cognitive processing speed (SD = −0.11; 95% CI = −0.20, −0.02; p = 0.02) versus those with no comorbidities. Those with 2+ had lower brain parenchymal (−0.41%, 95% CI = −0.64, −0.17) and gray matter fractions (−0.30%, 95% CI = −0.49, −0.10), including reduced cortical (−10.10 mL, 95% CI = −15.42, −4.78) and deep (−0.44 mL, 95% CI = −0.84, −0.04) gray matter volumes versus those with no comorbidity. Conclusion: Increased vascular comorbidity burden was associated with clinical and imaging markers of neurologic dysfunction and neurodegeneration in MS. Strategies to optimize comorbidity management in people with MS are warranted.