White Matter T2 Hyperintensities Research Articles

Ultra-high-field 7-Tesla magnetic resonance imaging in fragile X tremor/ataxia syndrome (FXTAS).

Fragile X tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder characterized by premutation expansion of fragile X mental retardation 1 (FMR1) gene. It is a common single-gene cause of tremor, ataxia, and cognitive decline in adults. FXTAS affects the central, peripheral and autonomic nervous systems, leading to a range of neurological symptoms from dementia to dysautonomia. A characteristic imaging feature of FXTAS is symmetric T2 hyperintensity in the deep white matter of the cerebellar hemispheres and middle cerebral peduncle. However, recent studies have reported additional findings on diffusion weighted images (DWI), such as a symmetric high-intensity band-like signal at the cerebral corticomedullary junction. These findings, along with the characteristic cerebellar signal alterations, overlap with imaging findings seen in adult-onset neuronal intranuclear inclusion disease (NIID). Importantly, recent pathology studies have shown that both FXTAS and NIID can manifest intranuclear inclusion bodies, posing a diagnostic challenge and potential for misdiagnosis. We describe a 58-year-old man with FXTAS who received an erroneous diagnosis based on imaging and histopathology results. We emphasize the potential pitfalls in distinguishing NIID from FXTAS and stress the importance of genetic analysis in all cases with suspected NIID and FXTAS for confirmation. Additionally, we present the 7T MRI brain findings of FXTAS.

Relapsing White Matter Disease and Subclinical Optic Neuropathy: From the National Multiple Sclerosis Society Case Conference Proceedings

A 16-year-old adolescent boy presented with recurrent episodes of weakness and numbness. Brain MRI demonstrated subcortical, juxtacortical, and periventricular white matter T2 hyperintensities with gadolinium enhancement. CSF was positive for oligoclonal bands that were not present in serum. Despite treatment with steroids, IV immunoglobulins, plasmapheresis, and rituximab, he continued to have episodes of weakness and numbness and new areas of T2 hyperintensity on imaging. Neuro-ophthalmologic examination revealed a subclinical optic neuropathy with predominant involvement of the papillomacular bundle. Genetic evaluation and brain biopsy led to an unexpected diagnosis.

Chronic Active Lesions and Larger Choroid Plexus Explain Cognition and Fatigue in Multiple Sclerosis.

Chronic inflammation may contribute to cognitive dysfunction and fatigue in patients with multiple sclerosis (MS). Paramagnetic rim lesions (PRLs) and choroid plexus (CP) enlargement have been proposed as markers of chronic inflammation in MS being associated with a more severe disease course. However, their relation with cognitive impairment and fatigue has not been fully explored yet. Here, we investigated the contribution of PRL number and volume and CP enlargement to cognitive impairment and fatigue in patients with MS. Brain 3T MRI, neurologic evaluation, and neuropsychological assessment, including the Brief Repeatable Battery of Neuropsychological Tests and Modified Fatigue Impact Scale, were obtained from 129 patients with MS and 73 age-matched and sex-matched healthy controls (HC). PRLs were identified on phase images of susceptibility-weighted imaging, whereas CP volume was quantified using a fully automatic method on brain three-dimensional T1-weighted and fluid-attenuated inversion recovery MRI sequences. Predictors of cognitive impairment and fatigue were identified using random forest. Thirty-six (27.9%) patients with MS were cognitively impaired, and 31/113 (27.4%) patients had fatigue. Fifty-nine (45.7%) patients with MS had ≥1 PRLs (median = 0, interquartile range = 0;2). Compared with HC, patients with MS showed significantly higher T2-hyperintense white matter lesion (WM) volume; lower normalized brain, thalamic, hippocampal, caudate, cortical, and WM volumes; and higher normalized CP volume (p from <0.001 to 0.040). The predictors of cognitive impairment (relative importance) (out-of-bag area under the curve [OOB-AUC] = 0.707) were normalized brain volume (100%), normalized caudate volume (89.1%), normalized CP volume (80.3%), normalized cortical volume (70.3%), number (67.3%) and volume (66.7%) of PRLs, and T2-hyperintense WM lesion volume (64.0%). Normalized CP volume was the only predictor of the presence of fatigue (OOB-AUC = 0.563). Chronic inflammation, with higher number and volume of PRLs and enlarged CP, may contribute to cognitive impairment in MS in addition to gray matter atrophy. The contribution of enlarged CP in explaining fatigue supports the relevance of immune-related processes in determining this manifestation independently of disease severity. PRLs and CP enlargement may contribute to the pathophysiology of cognitive impairment and fatigue in MS, and they may represent clinically relevant therapeutic targets to limit the impact of these clinical manifestations in MS.

Low-frequency MR elastography reveals altered deep gray matter viscoelasticity in multiple sclerosis

IntroductionBrain viscoelasticity as assessed by magnetic resonance elastography (MRE) has been discussed as a promising surrogate of microstructural alterations due to neurodegenerative processes. Existing studies indicate that multiple sclerosis (MS) is associated with a global reduction in brain stiffness. However, no study to date systematically investigated the MS-related characteristics of brain viscoelasticity separately in normal-appearing white matter (NAWM), deep gray matter (DGM) and T2-hyperintense white matter (WM) lesions. Methods70 MS patients and 42 healthy volunteers underwent whole-cerebral MRE using a stimulated echo sequence (DENSE) with a low-frequency mechanical excitation at 20 Hertz. The magnitude |G∗| (Pa) and phase angle φ (rad) of the complex shear modulus G∗ were reconstructed by multifrequency dual elasto-visco (MDEV) inversion and related to structural imaging and clinical parameters. ResultsWe observed φ in the thalamus to be higher by 4.3 % in patients relative to healthy controls (1.11 ± 0.07 vs. 1.06 ± 0.07, p < 0.0001). Higher Expanded Disability Status Scale (EDSS) scores were negatively associated with φ in the basal ganglia (p = 0.01). We measured φ to be lower in MS lesions compared to surrounding NAWM (p = 0.001), which was most prominent for lesions in the temporal lobe (1.01 ± 0.22 vs. 1.06 ± 0.19, p = 0.003). Age was associated with lower values of |G∗| (p = 0.04) and φ (p = 0.004) in the thalamus of patients. No alteration in NAWM stiffness relative to WM in healthy controls was observed. ConclusionLow-frequency elastography in MS patients reveals age-independent alterations in the viscoelasticity of deep gray matter at early stages of disease.

Diagnostic Performance of Cortical Lesions and the Central Vein Sign in Multiple Sclerosis

Multiple sclerosis (MS) misdiagnosis remains an important issue in clinical practice. To quantify the performance of cortical lesions (CLs) and central vein sign (CVS) in distinguishing MS from other conditions showing brain lesions on magnetic resonance imaging (MRI). This was a retrospective, cross-sectional multicenter study, with clinical and MRI data acquired between January 2010 and May 2020. Centralized MRI analysis was conducted between July 2020 and December 2022 by 2 raters blinded to participants' diagnosis. Participants were recruited from 14 European centers and from a multicenter pan-European cohort. Eligible participants had a diagnosis of MS, clinically isolated syndrome (CIS), or non-MS conditions; availability of a brain 3-T MRI scan with at least 1 sequence suitable for CL and CVS assessment; presence of T2-hyperintense white matter lesions (WMLs). A total of 1051 individuals were included with either MS/CIS (n = 599; 386 [64.4%] female; mean [SD] age, 41.5 [12.3] years) or non-MS conditions (including other neuroinflammatory disorders, cerebrovascular disease, migraine, and incidental WMLs in healthy control individuals; n = 452; 302 [66.8%] female; mean [SD] age, 49.2 [14.5] years). Five individuals were excluded due to missing clinical or demographic information (n = 3) or unclear diagnosis (n = 2). MS/CIS vs non-MS conditions. Area under the receiver operating characteristic curves (AUCs) were used to explore the diagnostic performance of CLs and the CVS in isolation and in combination; sensitivity, specificity, and accuracy were calculated for various cutoffs. The diagnostic importance of CLs and CVS compared to conventional MRI features (ie, presence of infratentorial, periventricular, and juxtacortical WMLs) was ranked with a random forest model. The presence of CLs and the previously proposed 40% CVS rule had a sensitivity, specificity, and accuracy for MS of 59.0% (95% CI, 55.1-62.8), 93.6% (95% CI, 91.4-95.6), and 73.9% (95% CI, 71.6-76.3) and 78.7% (95% CI, 75.5-82.0), 86.0% (95% CI, 82.1-89.5), and 81.5% (95% CI, 78.9-83.7), respectively. The diagnostic performance of the CVS (AUC, 0.89 [95% CI, 0.86-0.91]) was superior to that of CLs (AUC, 0.77 [95% CI, 0.75-0.80]; P < .001), and was increased when combining the 2 imaging markers (AUC, 0.92 [95% CI, 0.90-0.94]; P = .04); in the random forest model, both CVS and CLs outperformed the presence of infratentorial, periventricular, and juxtacortical WMLs in supporting MS differential diagnosis. The findings in this study suggest that CVS and CLs may be valuable tools to increase the accuracy of MS diagnosis.

Choroid plexus and perivascular space enlargement in neuropsychiatric systemic lupus erythematosus.

Choroid plexus (CP) enlargement is proposed as a marker of neuroinflammation in immune-mediated conditions. CP involvement has also been hypothesized in the immunopathology of systemic lupus erythematosus (SLE). We investigated whether CP enlargement occurs in SLE patients and its association with neuropsychiatric involvement. Additionally, we explored abnormalities along the glymphatic system in SLE patients through enlarged perivascular space (PVS) quantification. Clinical assessment and 3 Tesla brain dual-echo and T1-weighted MRI scans were obtained from 32 SLE patients and 32 sex and age-matched healthy controls (HC). CPs were manually segmented on 3D T1-weighted sequence and enlarged PVS (ePVS) were assessed through Potter's score. Compared to HC, SLE patients showed higher normalized CP volume (nCPV) (p = 0.023), with higher CP enlargement in neuropsychiatric SLE (NPSLE) (n = 12) vs. non-NPSLE (p = 0.027) patients. SLE patients with antiphospholipid antibodies (APA) positivity (n = 18) had higher nCPV compared to HC (p = 0.012), while APA negative ones did not. SLE patients also had higher Potter's score than HC (p < 0.001), with a tendency towards a higher number of basal ganglia ePVS in NPSLE vs. non-NPSLE patients. Using a random forest analysis, nCPV emerged as a significant predictor of NPSLE, together with T2-hyperintense white matter (WM) lesion volume (LV) and APA positivity (out-of-bag AUC 0.81). Our findings support the hypothesis of a role exerted by the CP in SLE physiopathology, especially in patients with neuropsychiatric involvement. The higher prevalence of ePVS in SLE patients, compared to HC, suggests the presence of glymphatic system impairment in this population.

Influence of cardiorespiratory fitness and MRI measures of neuroinflammation on hippocampal volume in multiple sclerosis

BackgroundThe hippocampus is a clinically relevant region where neurogenesis and neuroplasticity occur throughout the whole lifespan. Neuroinflammation and cardiorespiratory fitness (CRF) may influence hippocampal integrity by modulating the processes promoting...

Toll-like receptor 4-mediated microglial inflammation exacerbates early white matter injury following experimental subarachnoid hemorrhage.

Neuroinflammation has been reported to be associated with white matter injury (WMI) after subarachnoid hemorrhage (SAH). As the main resident immune cells of the brain, microglia can be activated into proinflammatory and anti-inflammatory phenotypes. Toll-like receptor 4 (TLR4), expressed on the surface of the microglia, plays a key role in microglial inflammation. However, the relationship between TLR4, microglial polarization, and WMI following SAH remains unclear. In this study, a total of 121 male adult C57BL/6 wild-type (WT) mice, 20 WT mice at postnatal day 1 (P1), and 41 male adult TLR4 gene knockout (TLR4-/-) mice were used to investigate the potential role of TLR4-induced microglial polarization in early WMI after SAH by radiological, histological, microstructural, transcriptional, and cytological evidence. The results indicated that microglial inflammation was associated with myelin loss and axon damage, shown as a decrease in myelin basic protein (MBP), as well as increase in degraded myelin basic protein (dMBP) and amyloid precursor protein (APP). Gene knockout of TLR4 revised microglial polarization toward the anti-inflammatory phenotype and protected the white matter at an early phase after SAH (24 h), as shown through reduction of toxic metabolites, preservation of myelin, reductions in APP accumulation, reductions in white matter T2 hyperintensity, and increases in FA values. Cocultures of microglia and oligodendrocytes, the cells responsible for myelin production and maintenance, were established to further elucidate the relationship between microglial polarization and WMI. In vitro, TLR4 inhibition decreased the expression of microglial MyD88 and phosphorylated NF-κB, thereby inhibiting M1 polarization and mitigating inflammation. Decrease in TLR4 in the microglia increased preservation of neighboring oligodendrocytes. In conclusion, microglial inflammation has dual effects on early WMI after experimental SAH. Future explorations on more clinically relevant methods for modulating neuroinflammation are warranted to combat stroke with both WMI and gray matter destruction.

Functional and structural brain MRI changes associated with cognitive worsening in multiple sclerosis: a 3-year longitudinal study.

Heterogeneous processes may contribute to cognitive impairment in multiple sclerosis (MS). To apply a longitudinal multiparametric MRI approach to identify mechanisms associated with cognitive worsening in MS patients. 3T brain functional and structural MRI scans were acquired at baseline and after a median follow-up of 3.4years in 35 MS patients and 22 healthy controls (HC). Associations between cognitive worsening (reliable change index score < -1.25 at the Rao's battery) and longitudinal changes in regional T2-hyperintense white matter (WM) lesions, diffusion tensor microstructural WM damage, gray matter (GM) atrophy and resting state (RS) functional connectivity (FC) were explored. At follow-up, HC showed no clusters of significant microstructural WM damage progression, GM atrophy or changes in RS FC. At follow-up, 10 MS patients (29%) showed cognitive worsening. Compared to cognitively stable, cognitively worsened MS patients showed more severe GM atrophy of the right anterior cingulate cortex and bilateral supplementary motor area (p < 0.001). Cognitively worsened vs cognitively stable MS patients showed also decreased RS FC in the right hippocampus of the right working memory network and in the right insula of the default mode network. Increased RS FC in the left insula of the executive control network was found in the opposite comparison (p < 0.001). No significant regional accumulation of focal WM lesions nor microstructural WM abnormalities occurred in both patients' groups. GM atrophy progression in cognitively relevant brain regions combined with functional impoverishment in networks involved in cognitive functions may represent the substrates underlying cognitive worsening in MS.

Prevalence of White Matter Hyperintensities in Young Adults With and Without Mild Traumatic Brain Injury (S28.004)

<h3>Objective:</h3> To determine the prevalence and severity of white matter T2 hyperintensities (WMHs) in young healthy adults and those with recent mild traumatic brain injury (mTBI). <h3>Background:</h3> WMHs on T2-weighted (T2W) MRI are common. Normative data on their prevalence in young healthy adults and in the setting of mTBI is not well characterized, and dependent upon classification system, MRI field strength, scan resolution and imaging parameters. <h3>Design/Methods:</h3> High-resolution 3-Tesla 3D T2W FLAIR and SWI images were retrospectively reviewed from 602 mTBI and control patients who participated in a larger multicenter study of advanced neuroimaging biomarkers. All scans were independently reviewed by 2 board-certified blinded neuroradiologists. All patients with WMHs were identified; patients with excessive WMHs were also identified if ≥5 objective, punctate, white matter foci were present or lesions were &gt;3 mm or atypical in location. <h3>Results:</h3> 413 patients with documented mTBI and 189 controls were analyzed. 32% (134/413) of the mTBI patients and 40% (76/189) of the control patients demonstrated at least 1 WMH on high-resolution T2W-FLAIR imaging. Of these patients, 34% (45/134) of the mTBI group and 34% (26/76) of the control group demonstrated ≥5 lesions, one &gt;3 mm lesion, or lesions in atypical locations. There was no significant difference in number of patients with at least 1 WMH (p=0.064) or excessive WMHs (p=0.313) between mTBI and control groups. <h3>Conclusions:</h3> This represents the largest study cohort of mTBI patients and healthy controls assessing the prevalence of WMHs on high-resolution 3-Telsa 3D T2W-FLAIR. Prevalence of WMHs did not differ between groups and were observed at higher rates than reported in the current literature. These results reflect an evidence-based need to reassess our understanding and clinical interpretation of WMHs in normal healthy adults and patients with mTBI. <b>Disclosure:</b> Dr. Shetty has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Biohaven Pharmaeucticals. Dr. Shetty has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for mTBI, Inc. The institution of Dr. Shetty has received research support from Marker AG. The institution of Dr. Shetty has received research support from Teva Pharmaceuticals Industry. The institution of Dr. Shetty has received research support from GE-NFL. Mr. Westafer has nothing to disclose. Joseph T Nguyen has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for The American Journal of Sports Medicine. Joseph T Nguyen has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for The Women’s Journal of Sports Medicine. Miss Coffey has nothing to disclose.

Spatial Association Between Gene Expression and Brain Damage in Neuromyelitis Optica Spectrum Disorders (S50.004)

<h3>Objective:</h3> To investigate the spatial association between brain damage and gene expression in NMOSD. <h3>Background:</h3> A former study suggested that typical brain lesions in aquaporin-4 positive Neuromyelitis Optica Spectrum Disorders (AQP4+NMOSD) occur at areas with high AQP4 expression. However, this represents a partial view of both brain damage and NMOSD pathogenesis, since the former also includes atrophy and microstructural abnormalities, and the latter involves other elements of the immune system such as complement and granulocytes. <h3>Design/Methods:</h3> 3.0 and 1.5 T brain MRI scans were acquired from 80 AQP4+NMOSD and 94 controls at two European centers. In patients, brain damage was assessed through (i) T2-hyperintense lesion probability map, (ii) white (WM) and grey matter (GM) atrophy at voxel-based morphometry on 3D T1-weighted sequences, (iii) WM microstructural abnormalities at tract-based spatial statistics on diffusion-tensor imaging. The spatial association between maps and expression of 313 genes according to the Allen Human Brain Atlas was obtained with the MENGA platform. Functional-enrichment analysis investigated the overrepresented biological processes involving the genes significantly associated with the different types of brain damage. <h3>Results:</h3> T2-hyperintense lesions were mainly located in the periventricular WM; GM atrophy was observed in the visual, prefrontal cortex, and insula, WM atrophy selectively involved the optic tracts; patients also had a widespread increase of WM mean diffusivity and no fractional anisotropy abnormalities. The expression of AQP4 and C5 were associated with all types of brain damage, IL6 family signal transducer was associated with brain atrophy only, and CD59 was protective. Interferon-gamma, interleukin-4/-13 signalling and activation of C3/C5 were associated with both lesions and microstructural abnormalities. Pathways sometimes not specific for NMOSD pathogenesis were associated with brain atrophy. <h3>Conclusions:</h3> Brain lesions and WM microstructural abnormalities are associated with biological processes specific of AQP4+NMOSD, including complement activation and eosinophils/neutrophils recruitment. More complex mechanisms contribute to atrophy. <b>Disclosure:</b> Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BMS Celgene. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BIOMEDIA. Loredana Storelli has nothing to disclose. Elisabetta Pagani has nothing to disclose. Dr. Martinelli has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis, Biogen, Sanofi Genzyme, TEVA and Merck. Dr. Martinelli has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck . Dr. Moiola has nothing to disclose. 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 Case of CNS Lymphoma Imitating Post-Vaccination ADEM (P14-13.003)

<h3>Objective:</h3> NA <h3>Background:</h3> A previously healthy 42-year-old male presented acutely with slurred speech, confusion and urinary incontinence several weeks after receiving a COVID booster and Tdap vaccination. <h3>Design/Methods:</h3> NA <h3>Results:</h3> Initial workup revealed multifocal enhancing T2 white matter hyperintensities in the bilateral frontal/parietal lobes, corpus callosum and bilateral midbrain, sparing the cerebellum and spinal cord. Contrast enhanced CT of the chest, abdomen and pelvis showed no masses or lymphadenopathy. Cerebrospinal fluid analysis showed a mild lymphocytic pleocytosis (12) with normal RBC, protein, glucose, negative meningitis/encephalitis PCR, cytology and autoimmune encephalitis antibodies. Serum testing was negative for HIV, RPR, NMO, MOG and antinuclear antibodies. Working diagnosis of acute disseminated encephalomyelitis was made and he was started on IV methylprednisolone 1g daily for 5 days followed by an oral steroid taper with a weekslong improvement in symptoms to his neurologic baseline followed by relapse. We repeated MRI brain which demonstrated mixed response to treatment and two repeat CSF analyses showed 2 WBC with negative cytology. Given symptom recurrence, 1g daily IV methylprednisolone was re-administered for 5 days with another brief improvement, followed by IVIG 2g/kg over 5 days. Despite aggressive immunotherapy, his symptoms continued to worsen, and he was referred for brain biopsy confirming the diagnosis of primary diffuse large B-cell lymphoma of the CNS. At the direction of neuro-oncology, the patient underwent 6 cycles of systemic high-dose methotrexate and rituximab and 2 cycles of temozolomide with PET/MRI evidence of complete response (no lesion enhancement). His performance status improved significantly, and he underwent autologous hematopoietic stem cell transplant for consolidative therapy. <h3>Conclusions:</h3> CNS lymphoma should be considered in the differential for contrast-enhancing FLAIR hyperintensities and can be steroid responsive. Brain biopsy should not be delayed in cases where CNS lymphoma is a leading differential as it can guide early disease management and help improve patient outcomes. <b>Disclosure:</b> Dr. Frank has nothing to disclose. Dr. Alalami has nothing to disclose. An immediate family member of Dr. Livingston has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. An immediate family member of Dr. Livingston has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. The institution of an immediate family member of Dr. Livingston has received research support from Vertex. The institution of an immediate family member of Dr. Livingston has received research support from Roche. The institution of an immediate family member of Dr. Livingston has received research support from AstraZeneca. The institution of an immediate family member of Dr. Livingston has received research support from Enanta. Dr. Hu has nothing to disclose. Dr. Shadbehr has nothing to disclose.

Influence of Cardiorespiratory Fitness and MRI Measures of Neuroinflammation on Hippocampal Volume in Multiple Sclerosis Patients (S27.007)

<h3>Objective:</h3> To investigate whether higher cardiorespiratory fitness (CRF) may limit the detrimental effects of neuroinflammation on hippocampal volume in the main multiple sclerosis (MS) clinical phenotypes. <h3>Background:</h3> The hippocampus is a clinically-relevant brain region that is characterized by neuroplasticity and neurogenesis also in adults. Neuroinflammation and CRF may specifically influence hippocampal integrity, thus modulating the processes promoting neurogenesis and neuroprotection that contribute to the preservation of functions. <h3>Design/Methods:</h3> Brain structural MRI scans and maximum oxygen consumption (VO₂max), a proxy of CRF, were acquired from 81 MS patients (27 relapsing-remitting [RR] and 54 progressive [P]), and 47 age- and sex-matched healthy controls (HC). White matter T2-hyperintense lesion volume (T2-LV) and choroid plexus volume (CPV) were quantified as neuroinflammatory measures. Associations of T2-LV, CPV and CRF with normalized brain (NBV), gray matter (NGMV), thalamic (NTV) and hippocampal volumes were assessed using linear regression analysis. Stepwise hierarchical regression models were used to evaluate the independent contribution of demographic, clinical, T2-LV, CPV and VO₂max in explaining the aforementioned volumes. <h3>Results:</h3> In MS, higher T2-LV was significantly associated with lower global and regional brain volumes (standardized-β from −0.706 to −0.356, p≤0.009), except for NGMV (p=0.105). Higher CPV was significantly associated only with lower NBV and NTV in both RRMS and PMS patients (standardized-β from −0.545 to −0.290, p≤0.045). Higher VO₂max was significantly associated only with higher normalized hippocampal volume only in RRMS patients (standardized-β=0.448, p=0.013). Using stepwise hierarchical regression models, T2-LV in both RRMS (ΔR²=0.124, p=0.043) and PMS patients (ΔR²=0.095, p=0.028) and VO₂max only in RRMS patients (ΔR²=0.153, p=0.014) were found to explain a significant portion of hippocampal volume variance. <h3>Conclusions:</h3> By exerting beneficial neurotrophic effects, a higher CRF may have a specific neuroprotective role for the hippocampus, mainly in the early phases of MS. <b>Disclosure:</b> Mr. Morozumi 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. Albergoni has nothing to disclose. Monica Margoni has received research support from MAGNIMS. Elisabetta Pagani has nothing to disclose. Alessandro Meani has nothing to disclose. 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.

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.

Recurrence of methotrexate-induced leukoencephalopathy after methotrexate rechallenge: A case report and literature review

Methotrexate (MTX) is potent chemotherapeutic agent, often administered intrathecally to treat or prevent central nervous system involvement in lymphomas and leukemias, particularly T-cell lymphoblastic leukemia (T-LBL). MTX has been linked to adverse neurologic effects that mimic acute stroke, including facial drooping, hemiplegia, impaired consciousness, and seizures, as well as changes on imaging-known as MTX-induced leukoencephalopathy (LE). We report a case of a 17-year-old male diagnosed with T-LBL, who had been receiving MTX chemotherapy for 4 months. After receiving his fourth dose of MTX, he presented to the emergency department with fever, facial drooping, and acute left-sided weakness. Brain magnetic resonance imaging (MRI) revealed bilateral deep white matter T2 hyperintense foci, increased on the right, with associated diffusion restriction in the right centrum semiovale-consistent with MTX-induced LE. After his symptoms resolved, he was discharged on leucovorin. Six months afterward, he was rechallenged with MTX and developed recurrence of symptoms. Repeat MRI showed well-defined T2/FLAIR hyperintensities in the right centrum semiovale without corresponding diffusion restriction. The left centrum semiovale hyperintensity became less conspicuous in comparison to the previous MRI study. We report a rare case of recurrence of LE after MTX rechallenge and discuss mechanisms, best imaging modalities, and possible treatment options for MTX-induced LE. Given the ominous presentation of MTX-induced LE, we urge clinicians to maintain a high index of suspicion for this condition. Further research is necessary to understand why only certain patients develop recurrence of LE after subsequent doses of MTX.

Abstract TP118: Brain Iron Quantification By MRI In Normal Human Subjects And Contra-lesional Hemisphere Of Intraparenchymal Hemorrhage (IPH) Patients

Introduction: Human cadaveric studies have correlated higher transverse relaxation rate (R2*) to higher tissue Fe concentrations. These methods enable non-invasive brain tissue Fe quantification after IPH. This study tested these methods on live human IPH patients vs. normal subjects to assess using the contra-lesional cerebral hemisphere as an internal control for future longitudinal tissue Fe quantification studies. Methods: Normal and IPH subjects underwent MRI on a 3T clinical scanner with a 32-channel head coil. Scans included anatomic T1- and T2-weighted images and a 3D gradient 8-echo sequence. Seven regions on the contra-lesional hemisphere were segmented using registered T1 and gradient-echo images. R2* maps were generated and the mean values per region were compared to identical regions in normal subjects using a T-test with Bonferroni correction (corrected p = p * 7). Results: 14 IPH patients, aged 18-85, and 10 control subjects, aged 35-73, underwent MRI scanning. Mean R2* varied from 17.8-40.8 Hz in IPH subjects and 19.5-38.4 Hz in normal subjects. There was a significant difference in the mean R2* values in the centrum semiovale (p=2.9e-5). The other regions demonstrate no significant differences in mean R2* values, as shown in the figure. Conclusion: In the contra-lesional centrum semiovale, the average R2* values of IPH patients correlate to lower Fe concentrations compared to controls. Upon further review of anatomic T1- and T2- weighted images, we found that the IPH patients had more white matter T2-hyperintense foci likely accounted for by underlying small vessel disease. In the other brain regions, the contralateral cerebral hemisphere of IPH subjects had R2* values not significantly different from controls. This suggests the Fe released from a hematoma does not cross into the contra-lesional hemisphere, which may be used as an internal control in future longitudinal IPH studies.

Abruptly Stopping an Adamantane Management for Fatigue in an Elderly Multiple Sclerosis Patient Provoked Acute Withdrawal Symptoms (AWS); A Case Report

Introduction: Health care workers are continuously being burdened with acute conditions especially with the current pandemic of Covid-19. Staying home and feeling trapped can be particularly detrimental to patients with history of depression or psychotic as well as multiple sclerosis. We present a case of a 63-year-old patient with Multiple Sclerosis whose condition is being managed with mainly dopamine agonists. Withdrawal symptoms arose acutely after abrupt cessation of Amantadine; a dopamine agonist. Amantadine is thought to work by raising the amount of dopamine available to brain cells. The purpose of this research is to report a case of a 63-yearold Multiple Sclerosis patient who presented with Acute Withdrawal Syndrome (AWS) after being managed with Amantadine for two years and abruptly stopping the medication. Case Presentation: A 63-year-old woman with past medical history of stroke and multiple sclerosis reported symptoms of AWS after abruptly stopping amantadine use for multiple sclerosis. The patient was on cyclobenzaprine for spasticity, gabapentin and lamotrigine for neuropathic pain and seizure disorder respectively. She also had a history of hypertension and hyperlipidemia and presented with 1-week history of nausea and vomiting followed by visual hallucination, tremor, slurred speech and lethargy. On presentation, the patient was afebrile and hemodynamically stable. This patient denies blurred vision and severe fatigue with bathing or exercise. Upon further evaluation, patient did not report electrical sensation down her limbs or back especially with neck flexion. The initial labs were remarkable for hemoglobin of 8.5mg/dL and hypokalemia of 3.2mmol/L. We suspected vasculitis of CNS. One of the proposed pathophysiology for this is the extensive inflammatory damage to the blood brain barrier, allowing inflammatory cell recruitment into the CNS. The patient was admitted for acute altered mental status with waxing and wanning symptoms. Her acute delirium symptoms lead to the withdrawal of amantadine and cyclobenzaprine. Within about 48-70 hours later, patient developed severe agitation requiring emergent intubation. EEG showed generalized medium voltage delta, theta, and fast activity throughout indicative of diffuse cerebral dysfunction, but no lateralized or epileptic activity was seen. CT brain was negative for acute stroke or bleed. The patient underwent lumbar puncture, and was started on empiric coverage with IV acyclovir, vancomycin, and ceftriaxone for possible meningoencephalitis along with methylprednisolone for possible multiple sclerosis flare vs autoimmune encephalitis. MRI showed stable extensive white matter T2 hyperintense lesions. CSF was negative for infectious processes, and vancomycin, ceftriaxone, and acyclovir were discontinued. The patient continued to require sedation for severe agitation. The severe agitation was suspected to be due to discontinuation of her home medications, one of which was amantadine. The amantadine was resumed with improvement of her mental status within 24 hours. Patient was extubated within 48 hours of initiation of amantadine and was transferred to the floor for continuity of care and eventually discharged home after 15 days of hospitalization. Conclusion: Acute Withdrawal Syndrome (AWS) symptoms are often as a result of abrupt cessation of a medication(s) particularly central acting agents like clonidine, beta adrenergic antagonists as well as diuretics but Amantadine is starting to be a strong culprit since it is also thought to act centrally as a dopamine agonist. Clinicians should always be mindful of AWS especially from patients on long term central acting medications that have been abruptly stopped.

Spectrum of Neurodegeneration with Brain Iron Accumulation with PLA2G6 Variation: A Report of Three Cases from Two Families

AbstractNeurodegeneration with brain iron accumulation consists of disorders characterized by progressive neuronal degeneration, cognitive decline, brain iron accumulation in extrapyramidal system, dentate nucleus, and gray and white matters boundary. We present a case series of PLA2G6-associated neurodegeneration (PLAN), with definite PLA2G6 gene mutations in two cases and suspected in one case. Diagnosis was based on clinical presentations, brain magnetic resonance imaging (MRI) findings, and detection of PLA2G6 mutations. Case 1: An 8-year-old boy presented with weakness of lower limbs, subnormal intelligence, scanning speech, spasticity, dysdiadochokinesia, pendular knee jerk, and extensor plantar reflex. MRI of the brain showed diffuse cerebellar atrophy and white matter T2 hyperintensity with iron deposition in bilateral globus pallidi. Case 2: Elder sister of Case 1, who developed ataxia at the age of 6 years and became bedridden at 14 years. She had nocturnal enuresis, seizures, cervical dystonia, dysphagia, and died at 23 years of age. MRI showed cerebral and cerebellar atrophies and iron deposition in basal ganglia and substantia nigra. Case 3 had infantile onset with quadriparesis, optic atrophy, developmental delay, cerebral and cerebellar atrophies, and brain iron accumulation in basal ganglia. Case 1 revealed two heterozygous mutations of PLA2G6 gene in exons 16 (c.2264G &gt; A, p. Arg755Gln) and 12 (c.1637G &gt; A, p. Arg546Gln), classified as likely pathogenic. Elder sister (Case 2) could not be tested for this mutation. Case 3 showed homozygous silent splice site point variation in exon 7 (c.1077 G &gt; A; p. Ser 359 Ser) of PLA2G6 gene. Thus, in patients presenting with neurodegeneration and imaging findings of brain iron accumulation, diagnosis can be established by PLA2G6 gene mutation analysis.

Magnetic Resonance Imaging Evaluation of Suspected High-Altitude Cerebral Edema in Patients from High Altitude.

Trekkers in high altitude of Himalayas could lead to Acute Mountain Sickness and High Altitude Cerebral Edema. This study was conducted to evaluate magnetic resonance imaging findings among the clinically suspected High Altitude Cerebral Edema patients rescued from high altitudes in Nepal Himalayas. 49 patients with clinically suspected High Altitude Cerebral Edema were retrospectively evaluated in this cross-sectional study who were sent for a brain magnetic resonance imaging. They were categorized in 3 groups according to the magnetic resonance imaging features in this study. There was a slight male preponderance. 6 patients (12.25%) had magnetic resonance imaging findings highly suggestive of High Altitude Cerebral Edema. 5 patients had T2 high signal intensity and restricted diffusion in the splenium of corpus callosum of which 3 had features of microhemorrhage. One patient with normal brain morphology and intensity in T1, T2, and FLAIR images showed innumerable variable-sized microhemorrhages in Susceptibility Weighted Imaging. 14 of patients showed various T2 and FLAIR white matter high signal intensity without restricted diffusion. And one patient had features of subacute lacunar infarcts. 28 patients (57.14 %) showed no abnormal signal changes in the magnetic resonance imaging scan. Typical magnetic resonance imaging features of cytotoxic edema in corpus callosum and microhemorrhage in the patients with High Altitude Cerebral Edema further support the findings in other similar studies. T2 white matter hyperintensities in deep, subcortical or periventricular location and lacunar infarcts could be seen in High Altitude Cerebral Edema. Normal magnetic resonance imaging of the brain is not infrequent.

White matter hyperintensities and brain microbleeds in ataxia-telangiectasia: the Cambridge cohort

BackgroundIsolated reports indicate the presence of MRI T2 white matter hyperintensities (WMH) and brain microbleeds (BMB) in ataxia telangiectasia (AT), but this has not previously been assessed in a sys- tematic way. We report the MRI brain findings of a large cohort of adults with variant and classical AT.MethodsTwo investigators independently assessed T2-FLAIR, SWI, GRE sequences of 38 AT patients, for WMH using the Fazekas and modified-Scheltens scales, and for probable BMB using the BOMBs scale.ResultsWMH were observed more frequently in variant AT (81.8% vs 58.3% classic), in the periventricular and deep white matter. Modified-Scheltens score was mean 2.29 (range 0- 11, SD 2.46), without signifi- cant differences between classic and variants (p=0.51); our cohort scored between mean 0.32 (range 0–1, SD 0.47) using Fazekas scale (p=0.25).BMB were seen more frequently in classic AT (57.1% versus 4.6% variant, p&lt;0.01, SD 33.80) in cortical and subcortical regions. Three classic AT patients had extensive (&gt;100) BMBs.ConclusionsMild WMH is a common finding in AT, of which the significance is unknown. The presence of BMBs in a large proportion of patients supports the presence of neurovascular abnormalities in AT, which could contribute to the neurodegenerative process or predispose to cerebral haemorrhage.myt29@cam.ac.uk