Brain Volume Loss Research Articles

Valproate associated brain volume-loss in pediatric epilepsy-A case series.

Brain atrophy associated with valproate therapy is known from single case reports and is frequently accompanied by cognitive deterioration. We present a case series of incidental findings of brain volume loss in children treated with valproate and employed automatic brain volumetry to assess the effect size of volume loss. 3D T1w datasets were automatically segmented into white matter, gray matter, and cerebrospinal fluid using the SPM-12 algorithm. Respective volumes of cerebrum and cerebellum were read out and normalized to the total intracranial volume. We identified six patients (median age 148.5 [85-178] months) who had received valproate for a median time of 5 (2-23) months prior to MRI in which a loss of brain volume was noted. None had reported the occurrence of new clinical symptoms. Volumetry showed a volume loss of up to 28% for cerebral GM, 25% for cerebellar GM, 10% for cerebral WM, and 20% for cerebellar WM. A volume loss of >5% in at least one of the subvolumes was found in all patients, with the more prominent volume loss in the cerebrum and in gray matter. In one patient, post-valproate MRI was available and showed normalization of brain volume. Our case series indicates that valproate therapy might be associated with an asymptomatic volume loss of brain parenchyma in children with epilepsy and that this volume loss is assessable with automatic volumetry.

TPL2 kinase activity regulates microglial inflammatory responses and promotes neurodegeneration in tauopathy mice.

Tumor progression locus 2 (TPL2) (MAP3K8) is a central signaling node in the inflammatory response of peripheral immune cells. We find that TPL2 kinase activity modulates microglial cytokine release and is required for microglia-mediated neuron death in vitro. In acute in vivo neuroinflammation settings, TPL2 kinase activity regulates microglia activation states and brain cytokine levels. In a tauopathy model of chronic neurodegeneration, loss of TPL2 kinase activity reduces neuroinflammation and rescues synapse loss, brain volume loss, and behavioral deficits. Single-cell RNA sequencing analysis indicates that protection in the tauopathy model was associated with reductions in activated microglia subpopulations as well as infiltrating peripheral immune cells. Overall, using various models, we find that TPL2 kinase activity can promote multiple harmful consequences of microglial activation in the brain including cytokine release, iNOS (inducible nitric oxide synthase) induction, astrocyte activation, and immune cell infiltration. Consequently, inhibiting TPL2 kinase activity could represent a potential therapeutic strategy in neurodegenerative conditions.

Dyke-Davidoff-Masson syndrome: an unusual cause of epilepsy

Background: Dyke-Davidoff-Masson syndrome (DDMS) is a rare neurological condition with unknown global prevalence and incidence. The characteristic clinical features include facial asymmetry, seizures, and contralateral hemiplegia. Signature neuroimaging findings include unilateral brain volume loss, ventriculomegaly, compensatory bone hypertrophy resulting in cerebral hemiatrophy, calvarial thickening and hyperpneumatization of paranasal and frontal sinuses neuroimaging. Case Presentation: 4-year-old girl patient presented seizures (diagnosed as epilepsy) and complained of left-sided hemiplegia since 1 year ago. Neurological examination revealed left-sided spastic hemiplegia with brisk tendon reflexes and extensor planter response on the left side, increased reflexes physiology in the left limb, and positive Babinski on the left leg. MRI showed right cerebral hemiatrophy with ex vacuo dilatation of the right lateral, III and IV ventricles, with hyper pneumatization of the right ethmoid sinus and right left mastoid Aircell and elevation of the right petrous ridge, and falcine displacement to the right as far as +/- 7mm and blurring right hippocampus, suspected atrophy. Therapy, she got multiple anti-epileptic drugs. Conclusion: Diagnosis of DDMS is made by a triad of hemiplegia, contralateral hemiatrophy, seizures, and classical radiological features. Imaging is important in diagnosing this rare entity and differentiating it from other causes of cerebral hemiatrophy. The long-term prognosis is good, provided the clinical entity is recognized early and managed appropriately.

Cognitive Impairment in Multiple Sclerosis.

Almost three million individuals suffer from multiple sclerosis (MS) throughout the world, a demyelinating disease in the nervous system with increased prevalence over the last five decades, and is now being recognized as one significant etiology of cognitive loss and dementia. Presently, disease modifying therapies can limit the rate of relapse and potentially reduce brain volume loss in patients with MS, but unfortunately cannot prevent disease progression or the onset of cognitive disability. Innovative strategies are therefore required to address areas of inflammation, immune cell activation, and cell survival that involve novel pathways of programmed cell death, mammalian forkhead transcription factors (FoxOs), the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), and associated pathways with the apolipoprotein E (APOE-ε4) gene and severe acute respiratory syndrome coronavirus (SARS-CoV-2). These pathways are intertwined at multiple levels and can involve metabolic oversight with cellular metabolism dependent upon nicotinamide adenine dinucleotide (NAD+). Insight into the mechanisms of these pathways can provide new avenues of discovery for the therapeutic treatment of dementia and loss in cognition that occurs during MS.

FDG-PET versus Amyloid-PET Imaging for Diagnosis and Response Evaluation in Alzheimer's Disease: Benefits and Pitfalls.

In June 2021, the US Federal Drug and Food Administration (FDA) granted accelerated approval for the antibody aducanumab and, in January 2023, also for the antibody lecanemab, based on a perceived drug-induced removal of cerebral amyloid-beta as assessed by amyloid-PET and, in the case of lecanemab, also a presumption of limited clinical efficacy. Approval of the antibody donanemab is awaiting further data. However, published trial data indicate few, small and uncertain clinical benefits, below what is considered "clinically meaningful" and similar to the effect of conventional medication. Furthermore, a therapy-related decrease in the amyloid-PET signal may also reflect increased cell damage rather than simply "amyloid removal". This interpretation is more consistent with increased rates of amyloid-related imaging abnormalities and brain volume loss in treated patients, relative to placebo. We also challenge the current diagnostic criteria for AD based on amyloid-PET imaging biomarkers and recommend that future anti-AD therapy trials apply: (1) diagnosis of AD based on the co-occurrence of cognitive decline and decreased cerebral metabolism assessed by FDA-approved FDG-PET, (2) therapy efficacy determined by favorable effect on cognitive ability, cerebral metabolism by FDG-PET, and brain volumes by MRI, and (3) neuropathologic examination of all deaths occurring in these trials.

Deviation From Normative Whole Brain and Deep Gray Matter Growth in Children With MOGAD, MS, and Monophasic Seronegative Demyelination.

Pediatric-acquired demyelination of the CNS associated with antibodies directed against myelin oligodendrocyte glycoprotein (MOG; MOG antibody-associated disease [MOGAD]) occurs as a monophasic or relapsing disease and with variable but often extensive T2 lesions in the brain. The impact of MOGAD on brain growth during maturation is unknown. We quantified the effect of pediatric MOGAD on brain growth trajectories and compared this with the growth trajectories of age-matched and sex-matched healthy children and children with multiple sclerosis (MS, a chronic relapsing disease known to lead to failure of normal brain growth and to loss of brain volume) and monophasic seronegative demyelination. We included children enrolled at incident attack in the prospective longitudinal Canadian Pediatric Demyelinating Disease Study who were recruited at the 3 largest enrollment sites, underwent research brain MRI scans, and were tested for serum MOG-IgG. Children seropositive for MOG-IgG were diagnosed with MOGAD. MS was diagnosed per the 2017 McDonald criteria. Monophasic seronegative demyelination was confirmed in children with no clinical or MRI evidence of recurrent demyelination and negative results for MOG-IgG and aquaporin-4-IgG. Whole and regional brain volumes were computed through symmetric nonlinear registration to templates. We computed age-normalized and sex-normalized z scores for brain volume using a normative dataset of 813 brain MRI scans obtained from typically developing children and used mixed-effect models to assess potential deviation from brain growth trajectories. We assessed brain volumes of 46 children with MOGAD, 26 with MS, and 51 with monophasic seronegative demyelinating syndrome. Children with MOGAD exhibited delayed (p < 0.001) age-expected and sex-expected growth of thalamus, caudate, and globus pallidus, normalized for the whole brain volume. Divergence from expected growth was particularly pronounced in the first year postonset and was detected even in children with monophasic MOGAD. Thalamic volume abnormalities were less pronounced in children with MOGAD compared with those in children with MS. The onset of MOGAD during childhood adversely affects the expected trajectory of growth of deep gray matter structures, with accelerated changes in the months after an acute attack. Further studies are required to better determine the relative impact of monophasic vs relapsing MOGAD and whether relapsing MOGAD with attacks isolated to the optic nerves or spinal cord affects brain volume over time.

Central Versus Peripheral Drug Exposure Ratio, a Key Differentiator for Siponimod Over Fingolimod?

Siponimod, a potent and selective sphingosine-1-phosphate (S1P1,5) agonist, is the only therapeutic agent that has shown efficacy against disability progression, decline in cognitive processing speed, total brain volume loss, gray matter atrophy and signs of demyelination in patients with secondary progressive multiple sclerosis (SPMS). Although the pathophysiology of progression in SPMS and primary progressive MS (PPMS) is thought to be similar, fingolimod, the prototype S1P1,3,45 agonist, failed to show efficacy against disability progression in PPMS. Differentiating siponimod from fingolimod at the level of their central effects is believed to be the key to a better understanding of the underlying characteristics that could make siponimod uniquely efficacious in progressive MS (PMS). Here, we compared the central vs. peripheral dose-dependent drug exposures for siponimod and fingolimod in healthy mice and mice with experimental autoimmune encephalomyelitis (EAE). Siponimod treatment achieved dose-dependent efficacy and dose-proportional increases in steady-state drug blood levels, with a central nervous system (CNS)/blood drug-exposure ratio (CNS/bloodDER) of ~ 6 in both healthy and EAE mice. In contrast, fingolimod treatments achieved dose-proportional increases in fingolimod and fingolimod-phosphate blood levels, with respective CNS/bloodDER that were markedly increased (≥ threefold) in EAE vs. healthy mice. If proven to have translational value, these observations would suggest that CNS/bloodDER may be a key differentiator for siponimod over fingolimod for clinical efficacy in PMS.

Brain Volume Changes after COVID-19 Compared to Healthy Controls by Artificial Intelligence-Based MRI Volumetry.

Cohort studies that quantify volumetric brain data among individuals with different levels of COVID-19 severity are presently limited. It is still uncertain whether there exists a potential correlation between disease severity and the effects of COVID-19 on brain integrity. Our objective was to assess the potential impact of COVID-19 on measured brain volume in patients with asymptomatic/mild and severe disease after recovery from infection, compared with healthy controls, using artificial intelligence (AI)-based MRI volumetry. A total of 155 participants were prospectively enrolled in this IRB-approved analysis of three cohorts with a mild course of COVID-19 (n = 51, MILD), a severe hospitalised course (n = 48, SEV), and healthy controls (n = 56, CTL) all undergoing a standardised MRI protocol of the brain. Automated AI-based determination of various brain volumes in mL and calculation of normalised percentiles of brain volume was performed with mdbrain software, using a 3D T1-weighted magnetisation-prepared rapid gradient echo (MPRAGE) sequence. The automatically measured brain volumes and percentiles were analysed for differences between groups. The estimated influence of COVID-19 and demographic/clinical variables on brain volume was determined using multivariate analysis. There were statistically significant differences in measured brain volumes and percentiles of various brain regions among groups, even after the exclusion of patients undergoing intensive care, with significant volume reductions in COVID-19 patients, which increased with disease severity (SEV > MILD > CTL) and mainly affected the supratentorial grey matter, frontal and parietal lobes, and right thalamus. Severe COVID-19 infection, in addition to established demographic parameters such as age and sex, was a significant predictor of brain volume loss upon multivariate analysis. In conclusion, neocortical brain degeneration was detected in patients who had recovered from SARS-CoV-2 infection compared to healthy controls, worsening with greater initial COVID-19 severity and mainly affecting the fronto-parietal brain and right thalamus, regardless of ICU treatment. This suggests a direct link between COVID-19 infection and subsequent brain atrophy, which may have major implications for clinical management and future cognitive rehabilitation strategies.

Brain volume loss in multiple sclerosis is independent of disease activity and might be prevented by early disease-modifying therapy.

Neurodegeneration is likely to be present from the earliest stages of multiple sclerosis (MS). MS responds poorly to disease-modifying treatments (DMTs) and leads to irreversible brain volume loss (BVL), which is a reliable predictor of future physical and cognitive disability. Our study aimed to discover the relationship between BVL, disease activity, and DMTs in a cohort of patients with MS. A total of 147 patients fulfilled our inclusion criteria. Relevant demographic and clinical data (age, gender, time of MS onset, time of treatment initiation, DMT characteristics, Expanded Disability Status Scale (EDSS), number of relapses in the last two years prior to MRI examination) were correlated with MRI findings. Patients with progressive MS had significantly lower total brain and grey matter volumes (p = 0.003; p < 0.001), and higher EDSS scores (p < 0.001), compared to relapsing-remitting patients matched by disease duration and age. There was no association between MRI atrophy and MRI activity (c2 = 0.013, p = 0.910). Total EDSS negatively correlated with the whole brain (rs = -0.368, p < 0.001) and grey matter volumes (rs = -0.308, p < 0.001), but was not associated with the number of relapses in the last two years (p = 0.278). Delay in DMT negatively correlated with whole brain (rs = -0.387, p < 0.001) and grey matter volumes (rs = -0.377, p < 0.001). Treatment delay was connected with a higher risk for lower brain volume (b = -3.973, p < 0.001), and also predicted a higher EDSS score (b = 0.067, p < 0.001). Brain volume loss is a major contributor to disability progression, independent of disease activity. Delay in DMT leads to higher BVL and increased disability. Brain atrophy assessment should be translated into daily clinical practice to monitor disease course and response to DMTs. The assessment of BVL itself should be considered a suitable marker for treatment escalation.

Feedback-loop between psychotic symptoms and brain volume: A cross-lagged panel model study

Brain structural changes are known to be associated with psychotic symptoms, with worse symptoms consistently associated with brain volume loss in some areas. It is not clear whether volume and symptoms interfere with each other over the course of psychosis. In this paper, we analyse the temporal relationships between psychosis symptom severity and total gray matter volume. We applied a cross-lagged panel model to a public dataset from the NUSDAST cohorts. The subjects were assessed at three-time points: baseline, 24 months, and 48 months. Psychosis symptoms were measured by SANS and SAPS scores. The cohort contained 673 subjects with schizophrenia, healthy subjects and their siblings. There were significant effects of symptom severity on total gray matter volume and vice-versa. The worse the psychotic symptoms, the smaller the total gray volume, and the smaller the volume, the worse the symptomatology. There is a bidirectional temporal relationship between symptoms of psychosis and brain volume.

Association of Daily Physical Activity with Cervical Spinal Cord Areas in Multiple Sclerosis

Background and purpose Remote activity monitoring has the potential to evaluate real-world motor function and disability outside of the clinic. The relationships of daily physical activity with spinal cord white matter and grey matter areas, MS disability, and leg function are unknown. Our purpose was to evaluate the association of remotely captured ambulatory activity with structural central nervous system pathology via quantitative magnetic imaging, in people with multiple sclerosis (MS). Methods Fifty adults with progressive or relapsing MS with motor disability who could walk at least 2 minutes, were assessed using clinical, patient-reported, and quantitative brain and spinal cord MRI measures. Fitbit Flex2, worn on the non-dominant wrist, remotely assessed activity over 30 consecutive days. Univariate and multivariate analyses were performed to assess correlations between remote physical activity and other disability metrics. Results The mean age of the cohort was 53.3 years and the median EDSS was 4.0. Average daily step counts (STEPS) were highly correlated with EDSS and walking measures (i.e., Timed 25-foot Walk, Timed up and Go tests, and subjective 12- item MS Walking Scale). Greater STEPS correlated with greater C2-C3 spinal cord grey matter areas (rho=0.39, p=0.04), total cord area (rho=0.35, p=0.04), and brain volume (rho=0.32, p=0.04). Discussion These results provide preliminary evidence that spinal cord grey matter area is a neuroanatomical substrate associated with STEPS. STEPS could serve as a proxy to alert clinicians and researchers to possible changes in structural nervous system pathology. Longitudinal observations are needed to determine directionality and value of STEPS as a proxy for generalized brain and cord volume loss. These results have potential implications for structural and functional modification of disease progression via therapeutic interventions aimed at altering STEPS. Remote activity monitoring has the potential to evaluate real-world motor function and disability outside of the clinic. The relationships of daily physical activity with spinal cord white matter and grey matter areas, MS disability, and leg function are unknown. Our purpose was to evaluate the association of remotely captured ambulatory activity with structural central nervous system pathology via quantitative magnetic imaging, in people with multiple sclerosis (MS). Fifty adults with progressive or relapsing MS with motor disability who could walk at least 2 minutes, were assessed using clinical, patient-reported, and quantitative brain and spinal cord MRI measures. Fitbit Flex2, worn on the non-dominant wrist, remotely assessed activity over 30 consecutive days. Univariate and multivariate analyses were performed to assess correlations between remote physical activity and other disability metrics. The mean age of the cohort was 53.3 years and the median EDSS was 4.0. Average daily step counts (STEPS) were highly correlated with EDSS and walking measures (i.e., Timed 25-foot Walk, Timed up and Go tests, and subjective 12- item MS Walking Scale). Greater STEPS correlated with greater C2-C3 spinal cord grey matter areas (rho=0.39, p=0.04), total cord area (rho=0.35, p=0.04), and brain volume (rho=0.32, p=0.04). These results provide preliminary evidence that spinal cord grey matter area is a neuroanatomical substrate associated with STEPS. STEPS could serve as a proxy to alert clinicians and researchers to possible changes in structural nervous system pathology. Longitudinal observations are needed to determine directionality and value of STEPS as a proxy for generalized brain and cord volume loss. These results have potential implications for structural and functional modification of disease progression via therapeutic interventions aimed at altering STEPS.

Ocrelizumab-treated patients with relapsing multiple sclerosis show volume loss rates similar to healthy aging

Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by two major and interconnected hallmarks: inflammation and progressive neurodegeneration. Objective: The aim of this work was to compare neurodegenerative processes, in the form of global and regional brain volume loss rates, in healthy controls (HCs) and in patients with relapsing MS (RMS) treated with ocrelizumab, which suppresses acute inflammation. Methods: Whole brain, white matter, cortical gray matter, thalamic, and cerebellar volume loss rates were assessed in 44 HCs that were part of a substudy in the OPERA II randomized controlled trial (NCT01412333) and 59 patients with RMS enrolled in the same substudy as well as age- and sex-matched patients in OPERA I (NCT01247324) and II. Volume loss rates were computed using random coefficients models over a period of 2 years. Results: Ocrelizumab-treated patients showed global and regional brain volume loss rates that were approaching that of HCs. Conclusion: These findings are consistent with an important role of inflammation on overall tissue loss and the role of ocrelizumab in reducing this phenomenon.

Annual Plasma Neurofilament Dynamics Is a Sensitive Biomarker of Disease Activity in Patients with Multiple Sclerosis.

Background and Objectives: Neurofilament light chain (NfL) is a sensitive biomarker of neuroaxonal damage. This study aimed to assess the relationship between the annual change in plasma NfL (pNfL) and disease activity in the past year, as defined by the concept no evidence of disease activity (NEDA) in a cohort of multiple sclerosis (MS) patients. Materials and Methods: Levels of pNfL (SIMOA) were examined in 141 MS patients and analyzed in relationship to the NEDA-3 status (absence of relapse, disability worsening, and MRI activity) and NEDA-4 (NEDA-3 extended by brain volume loss ≤ 0.4%) during the last 12 months. Patients were divided into two groups: annual pNfL change with an increase of less than 10% (group 1), and pNfL increases of more than 10% (group 2). Results: The mean age of the study participants (n = 141, 61% females) was 42.33 years (SD, 10.17), and the median disability score was 4.0 (3.5-5.0). The ROC analysis showed that a pNfL annual change ≥ 10% correlates with the absence of the NEDA-3 status (p < 0.001; AUC: 0.92), and the absence of the NEDA-4 status (p < 0.001; AUC: 0.839). Conclusions: Annual plasma NfL increases of more than 10% appear to be a useful tool for assessing disease activity in treated MS patients.

Smoking History and Increasing Pack Years Predict Brain Volume Loss in 8831 Healthy Participants (P6-12.003)

<h3>Objective:</h3> To determine the relationship between smoking history and pack years on brain volume loss. <h3>Background:</h3> Smoking is a risk factor for both Alzheimer and vascular dementia. Understanding this risk requires an investigation of relationship between smoking and brain volume loss on MRI, a biomarker for neurodegeneration. <h3>Design/Methods:</h3> In total, 8831 healthy participants from 4 sites were scanned on 1.5T MR with a short whole-body MR imaging protocol. Sequences included whole body coronal T1, STIR from vertex to feet, whole-body axial DWI from vertex to proximal-thighs and axial T2 TSE without fat suppression from skull base to pelvis. Brain sequences were T1 MPRAGE and 2D FLAIR. Deep learning volumetric software, FastSurfer, trained over 134 participants aged 27–66, segmented 96 brain volumes. Smokers versus non-smokers were compared by gray and white matter volumes normalized to total intracranial volume using a two tailed t-test. Partial correlation analysis was done between pack years and brain volumes, controlling of age, sex, and total intracranial volume. The Benjamini Hochberg False Discovery Rate of 5% accounted for multiple comparisons. <h3>Results:</h3> This cohort averaged 52.90 ± 13.06 years, between 23 to 84, with 52.5% men and 47.5% women. Overall, 2860 individuals (32.3%) self-reported a history of smoking. Participants who smoked were older than non-smokers (p = .024). Smokers had lower normalized gray and white matter volumes compared to non-smokers (t = 8.95, p = 4.39e-19). Adjusting for co-variates and multiple comparisons, smoking predicted brain volume loss in: gray and white matter volumes (Partial R =−.08, p = 6.84e-12), hippocampus (Partial R = −.06, p = 3.16e-7), frontal cortex (Partial R = −.08, p = 7.91e-13), temporal lobes (Partial R = −.07, 2.12e-9), left posterior cingulate gyrus (Partial R = −.06, p = 1.99e-8). <h3>Conclusions:</h3> Both smoking history and pack years predict both lower whole brain and regional volumes. <b>Disclosure:</b> Dr. Meysami has nothing to disclose. Prof. Raji has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Brainreader ApS. Prof. Raji has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Apollo Health . Prof. Raji has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Neurevolution Medicine. Mr. Hashemi has received personal compensation for serving as an employee of Prenuvo. Mr. Garg has received personal compensation for serving as an employee of Prenuvo. Dr. Nguyen has nothing to disclose. Dr. Chodakiewitz has received personal compensation for serving as an employee of Prenuvo . Dr. Chodakiewitz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Aidoc. Ms. Akbari has nothing to disclose. Mr. Gouda has received personal compensation for serving as an employee of Prenuvo. Dr. Attariwala has received personal compensation in the range of $100,000-$499,999 for serving as a Radiologist reading cases and helping build in house software tools with Prenuvo.

Longitudinal Brain Volume Findings in an Outpatient Practice of Young People with MS (P11-3.001)

<h3>Objective:</h3> To assess in an outpatient setting the application of volumetrics with brain MRI among young people with multiple sclerosis (MS). <h3>Background:</h3> Research on brain atrophy in MS has illuminated how inflammation and neurodegenerative processes lead to cognitive and neurologic declines. However, brain volume assessment is rarely used in routine practice. Here, we examined predominantly pediatric onset MS and some younger adult-onset MS patients who underwent routine brain MRI including volumetrics. Our goal was to assess the impact of brain volume change on clinical outcomes including SDMT in this relatively young and stable MS subset. <h3>Design/Methods:</h3> 77 patients with pediatric or adult onset RRMS or CIS, 31 years of age or younger, were evaluated with at least two MRI studies. Volume data was computed on MRI images with icobrain ms software, compared to age- and sex-related norms and adjusted for differences across the various Siemens 3T scanners. Changes in volumes of whole brain (WB), white matter (WM), grey matter (GM), lateral ventricles (LV), and thalamus were calculated as an average annualized percent brain volume change per year. <h3>Results:</h3> The mean patient age was 21.6 years (range 12–31); 70% were female. The annual mean decrease of WB volume: −0.473%, WM: −0.390%, GM: −0.517%, thalamus: −0.552%, and annual LV volume increase: 1.78%. A total of 32.5% of patients had an annual decrease in GM volume &gt;0.8% (the 90% threshold for measurement error). 29.9% of patients had LV volumes increase &gt;3.5%. Whole brain volume loss and lateral ventricle increase was significantly correlated, r=−0.34 (p=0.002). Clinical and demographic features between those whose brain volume declined and those whose brain volumes remained stable will be presented. <h3>Conclusions:</h3> Quantitative MRI is a useful technique which has only begun to be incorporated into clinical practice. A proportion of young otherwise stable patients with RRMS show brain volume loss under computer-assisted analyses. <b>Disclosure:</b> Dr. O’Neill has nothing to disclose. Dr. Couvreur has received personal compensation in the range of $10,000-$49,999 for serving as a Intern Clinical application specialist at icometrix with The Prince Albert Fund. Dr. Hu has nothing to disclose. Mr. Zhang has nothing to disclose. Ms. Pehel has nothing to disclose. Ms. Sosa has nothing to disclose. Ms. Fade has nothing to disclose. Elayne Feld has nothing to disclose. Dr. Chen has received personal compensation for serving as an employee of icometrix. Dr. De Barros has received personal compensation for serving as an employee of Icometrix. Thibo Billiet has received personal compensation for serving as an employee of icometrix. Annemie Ribbens, 9599 has received personal compensation for serving as an employee of icometrix. Annemie Ribbens, 9599 has stock in icometrix. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gerson Lerhman. Dr. Krupp has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for medscape. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NeuroLive. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Krupp has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for Cleveland Clinic. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for MCIC. The institution of Dr. Krupp has received research support from Biogen. The institution of Dr. Krupp has received research support from National Multiple Sclerosis Society. Dr. Krupp has received intellectual property interests from a discovery or technology relating to health care.

Serum Glial Fibrillary Acidic Protein compared with Neurofilament Light Chain as Biomarker for Multiple Sclerosis Disease Progression (P5-3.016)

Serum Glial Fibrillary Acidic Protein compared with Neurofilament Light Chain as Biomarker for Multiple Sclerosis Disease Progression (P5-3.016)

AARS2-related Leukodystrophy Without Ovarian Failure Mimicking Multiple Sclerosis in a Female: A Case Report With a Novel Pathogenic Variant (P4-12.010)

<h3>Objective:</h3> N/A <h3>Background:</h3> <i>AARS2</i> mutations affect mitochondrial alanyl-transfer RNA (tRNA) synthetase. This enzyme is responsible of charging alanine to its cognate tRNA for protein translation within mitochondria. Individuals with <i>AARS2</i> mutations were reported to present either severe infantile cardiomyopathy or progressive leukoencephalopathy as the main clinical presentation. <i>AARS2</i>-related leukoencephalopathy is an ultra-rare white matter disorder, characterized by spasticity, ataxia, and impaired cognition. Further disease progression manifests as psychiatric illness and executive dysfunction. Ovarian failure is reported in almost all females with <i>AARS2</i>-related leukoencephalopathy. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> A 32-year-old female was referred to the clinic due to the development of progressive neurological symptoms since 2011. Ascending numbness of the lower limbs was the first clinical symptom that further extended to her abdomen. Patient, then, developed visual impairment in both eyes. Other symptoms included cognitive decline and language impairment that began abruptly with fast progression. She has one child and her menstrual cycles have been always regular. Multiple sclerosis was initially diagnosed and she was treated with corticosteroid, natalizumab, and rituximab without achieving improvements. The brain magnetic resonance imaging (MRI) of a patient performed in our institute showed multiple focal and confluent areas of diffusion restriction in bilateral periventricular and deep white matter, involving bilateral centrum semiovale/ corona radiate. Diffuse brain volume loss and bilateral thinning of optic nerves were observed. The MRI of thoracic spinal cord showed non-enhancing short segment T2 hyperintense lesions within the right ventral cord at T8-T9 and T12-L1. Molecular study reported a novel homozygous variant of c.929G&gt;T (p.Gly310Val) in <i>AARS2</i>. <h3>Conclusions:</h3> <i>AARS2</i>-related leukoencephalopathy in females can present without ovarian failure. The overlapping clinical and imaging features of white matter disorders may lead to misdiagnosis of the disease. Detailed review of clinical characteristics, MRI patterns, and molecular study can be helpful to reach to an accurate diagnosis. <b>Disclosure:</b> Mr. Amanat has nothing to disclose. Julie Cohen, 377 has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PTC Therapeutics. Julie Cohen, 377 has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Illumina. The institution of Julie Cohen, 377 has received research support from A Cure for Ellie. Dr. Fatemi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bluebirdbio. Dr. Fatemi has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for RCO law. The institution of Dr. Fatemi has received research support from Minoryx. The institution of Dr. Fatemi has received research support from Viking Therapeutics. The institution of Dr. Fatemi has received research support from Swanbio Therapeutics . The institution of Dr. Fatemi has received research support from Autobahn Therapeutics. The institution of Dr. Fatemi has received research support from Nuvelution. The institution of Dr. Fatemi has received research support from NIH. The institution of Dr. Fatemi has received research support from A Cure for Ellie Foundation. The institution of Dr. Fatemi has received research support from Brian’s Hope Foundation . Dr. Fatemi has received intellectual property interests from a discovery or technology relating to health care. Dr. Fatemi has a non-compensated relationship as a Director (Board member) with ALDConnect that is relevant to AAN interests or activities. The institution of Dr. Fine has received research support from NIH.

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)

Association of protein-based indices with brain volume and cognition in the Baltimore Longitudinal Study of Aging (BLSA) (P12-6.007)

<h3>Objective:</h3> Determine whether proteomic indicators of peripheral (non-neurologic) health are associated with change in cognition and brain volume. <h3>Background:</h3> Numerous peripheral diseases have been associated with brain health. Changes in the plasma proteome related to physical health and disease status likely contribute to cognitive and structural brain changes. Plasma proteomic changes may therefore be leveraged to study the link between peripheral health and brain health. <h3>Design/Methods:</h3> We used plasma samples from participants of the Baltimore Longitudinal Study of Aging (BLSA) to assess 7000+ proteins using SomaScan assay. Brain health was assessed using in BLSA participants with concurrent 3T brain MR imaging to assess total brain volume (TBV). Using SomaLogic’s SomaSignal Test (SST) algorithm, we generated protein-based measures of cardiovascular risk, kidney disease, resting energy rate, body composition, and other health indicators. Linear mixed effects models were used to examine the relationship between SST protein-based health indicators and longitudinal change in TBV and memory. <h3>Results:</h3> The analysis included 1220 participants (mean age: 68.1 [14.3 SD]; 99% cognitively normal). We evaluated 14 unique protein-based health indices (SSTs). None were associated with longitudinal brain volume loss. At baseline, the protein-based indicator of liver fat was associated with better memory. Protein-based indicators of lower V02 max and kidney disease risk were associated with longitudinal declines in memory. <h3>Conclusions:</h3> Protein-based health indicators can be used to understand how facets of peripheral health and disease risk influence brain health in cognitively healthy older adults. Our findings implicate cardiovascular, pulmonary, and kidney health in brain structure or function. <b>Disclosure:</b> Ms. Daya has nothing to disclose. Dr. Dark has nothing to disclose. Dr. Duggan has nothing to disclose. Dr. Peng has nothing to disclose. An immediate family member of Dr. Moore has received personal compensation for serving as an employee of Gilead. Dr. Tanaka has nothing to disclose. Dr. Candia has nothing to disclose. The institution of Keenan Walker has received research support from NIH.

Exploring New Imaging Biomarkers: 3D Conformational Analysis Of The Medulla And Upper Cervical Spinal Cord In People With Relapsing Multiple Sclerosis (P11-3.015)

<h3>Objective:</h3> Explore three-dimensional (3D) medulla-upper cervical spinal cord (MUCSC) conformational imaging metrics as biomarkers in multiple sclerosis (MS). <h3>Background:</h3> Measures of spinal cord atrophy are associated with MS disease progression but have yet to emerge as reliable biomarkers of treatment efficacy. 3D MUCSC conformational analysis is a new technique that may provide additional information about neurodegenerative changes in MS beyond conventional magnetic resonance imaging metrics. In the placebo-controlled Phase 3 TEMSO trial (NCT00134563), teriflunomide 14 mg/day lowered the risk of disability worsening and reduced brain volume loss in participants with relapsing MS. 3D MUCSC conformational analysis of the TEMSO dataset has not been explored. <h3>Design/Methods:</h3> TEMSO baseline and 2-year end of study follow-up 3D T1-Magnetization Prepared Rapid Gradient Echo (MP-RAGE) images acquired primarily at 1.5T were assessed for quality, then segmented and analyzed using in-house proprietary software. Change from baseline in MUCSC volume, local curvature and surface texture were summarized with descriptive statistics. <h3>Results:</h3> Quality assessments led to the exclusion of 481 of the 799 TEMSO participants, comprising 64.0%, 62.1%, and 54.5% of participants in the placebo, 7 mg/day, and 14 mg/day arms, respectively. Mean age and disease duration were lower for placebo participants versus teriflunomide arms. No between-group differences were apparent for mean (SD) change from baseline in MUCSC volume (−86±236, −85±218, and −75±218 mm³ for placebo, 7 mg/day, and 14 mg/day arms, respectively), mean curvature (0.01±0.06, 0.02±0.07, and 0.02±0.07 mm), or surface texture (−15.6±28.0, −21.3±26.6, and −19.0±24.2 triangle count). <h3>Conclusions:</h3> 3D conformational analysis of MP-RAGE images from the TEMSO trial showed no discernable between-group differences for MUCSC surface features or volume; however, imbalanced exclusion of participants during quality assessment likely introduced attrition bias. Further development of 3D conformational metrics as MS biomarkers may better illuminate mechanisms related to neurodegenerative changes and treatment efficacy. <b>Disclosure:</b> Miss Moog has nothing to disclose. Janneke Van Wingerden has received personal compensation for serving as an employee of Sanofi Genzyme. Dr. Sanofi has received personal compensation for serving as an employee of Sanofi. Dr. Sanofi has received personal compensation for serving as an employee of Sanofi. Dr. Sanofi has stock in Sanofi. Dr. Sanofi has stock in Sanofi. Dr. Geertsen has received personal compensation for serving as an employee of Sanofi. Dr. Rawlings has received personal compensation for serving as an employee of Sanofi. Dr. Rawlings has stock in Sanofi. Dr. Okuda has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Okuda has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Okuda has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Celgene. Dr. Okuda has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genzyme. Dr. Okuda has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Dr. Okuda has received personal compensation in the range of $500-$4,999 for serving as a Consultant for TG Therapeutics. Dr. Okuda has received personal compensation in the range of $500-$4,999 for serving as a Consultant for VielaBio.