Deep White Matter Lesions Research Articles

Clinical and neuroradiological spectrum of biallelic variants in NOTCH3

NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised. In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants. Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches. We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD. The Wellcome Trust, the MRC.

A case of MERS presenting with acute motor aphasia and tetraparesis and literature review

BackgroundMild encephalopathy wıth reversible splenial lesions (MERS) are a clinical–radiological diagnosis that can be diagnosed with radiological imaging and can be accompanied by impaired consciousness, aphasia, headache, and paralysis. MERS can be divided into two different types based on radiological findings; Involvement of the splenium is seen in type 1, and involvement of the splenium and deep white matter is seen in type 2. MERS Type 2 is very rare in adults. Here, we describe a patient diagnosed with MERS Type 2 and our therapeutic intervention.Case presentationA 22-year-old woman presented with slurred speech, weakness in the extremities and headache that started 14 h ago. The patient had sore throat and fever of 37.6 °C for 2 days, and medical history or family history were unremarkable. Neurological examination revealed that she was conscious, cooperative, with no signs of meningeal irritation. Speech comprehension, naming, and repetition were preserved, motor examination revealed 5/5 left upper extremity strength, 4/5 right upper extremity strength, and 2/5 bilateral lower extremity strength. Diffusion-weighted magnetic resonance imaging (MRI-DWI) revealed bilateral deep white matter and splenium symmetrical diffusion restriction. Blood tests showed high C-reactive protein (CRP) and no leukocytosis. No cells were detected in the cerebrospinal fluid (CSF), protein was 151 mg/dl, glucose was within normal limits. The patient, who developed quadriparesis during follow-up, was started on pulse dose steroids. Neurological examination improved to patient’s baseline at the 12th hour of treatment. In the 72nd hour control MRI-DWI, it was seen that the lesions had regressed. Culture/Polymerase chain reaction (PCR) for bacterial/viral infection agents came back negative. After steroids were given for 5 days, patient was discharged at her baseline.ConclusionsMERS is a rare diagnosis in adults and can be radiologically confused with acute toxic leukoencephalopathy. It can be distinguished clinically by the absence of prior infection, fever, and toxic agent exposure. Although there is no consensus in the literature regarding the treatment, the clinical picture improved rapidly after steroid in our case. Despite being rare, it should be considered in the differential diagnosis of patients with deep white matter lesions in adults.

The association of structural versus load-dependent large artery stiffness mechanisms with cerebrovascular damage and cortical atrophy in humans.

Large central arterial stiffness is a risk factor for cerebrovascular damage and subsequent progression of neurodegenerative diseases, including Alzheimer's disease and dementia. However, arterial stiffness is determined by both the intrinsic components of the arterial wall (structural stiffness) and the load (i.e., arterial blood pressure) exerted upon it by the blood (load-dependent stiffness). This study aimed to determine the degree to which structural and/or load-dependent mechanisms of central arterial stiffness are associated with cerebrovascular damage. Among 128 healthy individuals (aged 63±6, age range: 50-80 years, 42% men), aortic and carotid artery stiffness was measured via carotid-femoral pulse wave velocity and B-mode ultrasonography, respectively. Using participant-specific exponential models, both aortic and carotid artery stiffness were standardized to a reference blood pressure to separate their structural and load-dependent stiffness mechanisms. Magnetic resonance imaging was used to derive total, periventricular, and deep cerebral white matter lesion volume (WMLV) and global cortical thickness. After adjusting for common cardiovascular disease risk factors, a 1 m/s increase in structural aortic stiffness was associated with 15% greater total WMLV (95% confidence interval [CI] = 0.01, 0.27, P = 0.036), 14% greater periventricular WMLV (95%CI = 0.004, 0.25, P = 0.044) and 0.011mm lower cortical thickness (95%CI = -0.022, -1.18, P = 0.028). No association was observed between structural carotid stiffness and WMLVs (total, periventricular, and deep), and neither aortic nor carotid load-dependent stiffness was associated with WMLVs or cortical thickness. Structural, not load-dependent, mechanisms of aortic stiffness are related to cerebrovascular-related white matter damage.

Leukoaraiosis: Epidemiology, Imaging, Risk Factors, and Management of Age-Related Cerebral White Matter Hyperintensities.

Leukoaraiosis (LA) manifests as cerebral white matter hyperintensities on T2-weighted magnetic resonance imaging scans and corresponds to white matter lesions or abnormalities in brain tissue. Clinically, it is generally detected in the early 40s and is highly prevalent globally in individuals aged >60 years. From the imaging perspective, LA can present as several heterogeneous forms, including punctate and patchy lesions in deep or subcortical white matter; lesions with periventricular caps, a pencil-thin lining, and smooth halo; as well as irregular lesions, which are not always benign. Given its potential of having deleterious effects on normal brain function and the resulting increase in public health burden, considerable effort has been focused on investigating the associations between various risk factors and LA risk, and developing its associated clinical interventions. However, study results have been inconsistent, most likely due to potential differences in study designs, neuroimaging methods, and sample sizes as well as the inherent neuroimaging heterogeneity and multi-factorial nature of LA. In this article, we provided an overview of LA and summarized the current knowledge regarding its epidemiology, neuroimaging classification, pathological characteristics, risk factors, and potential intervention strategies.

Development and Validation of a Fusion Model Based on Carotid Plaques and White Matter Lesion Burden Imaging Characteristics to Evaluate Ischemic Stroke Severity in Symptomatic Patients.

The diagnostic value of carotid plaque characteristics based on higher-resolution vessel wall MRI (HRVW-MRI) combined with white matter lesion (WML) burden for the risk of ischemic stroke is unclear. To combine carotid plaque features and WML burden to construct a hybrid model for evaluating ischemic stroke severity and prognosis in patients with symptomatic carotid artery stenosis. Retrospective. One hundred and ninty-three patients with least one confirmed carotid atherosclerotic stenosis ≥30% and cerebrovascular symptoms within the last 2 weeks (136 in the training cohort and 57 in the test cohort). 3.0T, T2-weighted fluid attenuated inversion recovery (T2-FLAIR) and diffusion-weighted imaging (DWI); HRVW-MRI: 3D T1-weighted variable flip angle fast spin-echo sequences (VISTA), T2-weighted VISTA, simultaneous noncontrast angiography and intraplaque hemorrhage (SNAP), and contrast-enhanced T1-VISTA. The following features of the plaques or vessel wall were assessed by three MRI readers independently: calcification (CA), intraplaque hemorrhage (IPH), lipid-rich necrotic core (LRNC), ulceration, plaque enhancement (PE), maximum vessel diameter (Max VD), maximum wall thickness (Max WT), total vessel area (TVA), lumen area (LA), plaque volume, and lumen stenosis. WMLs were graded visually and categorized as absent-to-mild WMLs (Fazekas score 0-2) or moderate-severe WMLs (Fazekas score 3-6). WML volumes were quantified using a semiautomated volumetric analysis program. Modified Rankin scores (mRS) were assessed at 90 days, following an outpatient interview, or by telephone. LASSO-logistic regression analysis was performed to construct a model. The performance of the model was evaluated using receiver operating characteristic (ROC) curve analyses, calibration curves, decision curve analyses, and clinical imaging curves. Conditional logistic regression analysis was used to explore the associations between the hybrid model-derived score and the modified Rankin Scale (mRS) score at 90 days. The model was constructed using five selected features, including IPH, plaque enhancement, ulceration, NWI, and total Fazekas score in deep WMLs (DWMLs). The hybrid model yielded an area under the curve of 0.92 (95% confidence interval [CI] 0.87-0.97) in the training cohort and 0.88 (0.80-0.96) in the test cohort. Furthermore, the hybrid model-derived score (odds ratio = 1.28; 95% CI 1.06-1.53) was independently associated with the mRS score 90 days after stroke. The hybrid model constructed using MRI plaque characteristics and WML burden has potential to be an effective noninvasive method of assessing ischemic stroke severity. The model-derived score has promising utility in judging neurological function recovery. Stage 2.

The Microglial Transcriptome of Age-Associated Deep Subcortical White Matter Lesions Suggests a Neuroprotective Response to Blood-Brain Barrier Dysfunction.

Age-associated deep-subcortical white matter lesions (DSCLs) are an independent risk factor for dementia, displaying high levels of CD68+ microglia. This study aimed to characterize the transcriptomic profile of microglia in DSCLs and surrounding radiologically normal-appearing white matter (NAWM) compared to non-lesional control white matter. CD68+ microglia were isolated from white matter groups (n = 4 cases per group) from the Cognitive Function and Ageing Study neuropathology cohort using immuno-laser capture microdissection. Microarray gene expression profiling, but not RNA-sequencing, was found to be compatible with immuno-LCM-ed post-mortem material in the CFAS cohort and identified significantly differentially expressed genes (DEGs). Functional grouping and pathway analysis were assessed using the Database for Annotation Visualization and Integrated Discovery (DAVID) software, and immunohistochemistry was performed to validate gene expression changes at the protein level. Transcriptomic profiling of microglia in DSCLs compared to non-lesional control white matter identified 181 significant DEGs (93 upregulated and 88 downregulated). Functional clustering analysis in DAVID revealed dysregulation of haptoglobin-haemoglobin binding (Enrichment score 2.5, p = 0.017), confirmed using CD163 immunostaining, suggesting a neuroprotective microglial response to blood-brain barrier dysfunction in DSCLs. In NAWM versus control white matter, microglia exhibited 347 DEGs (209 upregulated, 138 downregulated), with significant dysregulation of protein de-ubiquitination (Enrichment score 5.14, p < 0.001), implying an inability to maintain protein homeostasis in NAWM that may contribute to lesion spread. These findings enhance understanding of microglial transcriptomic changes in ageing white matter pathology, highlighting a neuroprotective adaptation in DSCLs microglia and a potentially lesion-promoting phenotype in NAWM microglia.

Dual Inversion Recovery Magnetic Resonance Imaging's Diagnostic Value for Estimating the Overall Load of Multiple Sclerosis Lesions and its Anatomical Distribution

B Background: In young adults, multiple sclerosis is a prevalent chronic inflammatory demyelinating condition. It is characterized by white matter affection, but many individuals also have significant gray matter involvement. A double inversion recovery pulse pattern was recently proposed to improve the detectability of multiple sclerosis lesions. Objectives: To evaluate the diagnostic value of double inversion recovery sequence in the detection of cortical and white matter multiple sclerosis plaques in different brain anatomical locations. Subjects and methods: A total of 37 patients with an established diagnosis of multiple sclerosis were included in this cross-sectional study. Brain MRI was done using double inversion recovery, T2 and FLAIR sequences. The number of lesions was counted and compared in the three sequences. Results: Dual Inversion Recovery sequence was highly significant and superior to both T2 and FLAIR sequences (P &lt; 0.001) in depicting the lesions regardless of anatomical distribution. Dual Inversion Recovery was significantly superior to T2 (P =&lt;0.001) and FLAIR (P =&lt;0.001) in detecting lesions in cortical and juxtacortical. However, Dual Inversion Recovery shows less periventricular and deep white matter lesions in comparison to T2 and FLAIR sequences. Conclusion: The Dual Inversion Recovery sequence detected more multiple sclerosis lesions in cortical, subcortical and infratentorial than the traditional T2W and FLAIR sequences. It also demonstrated greater delineation between the white matter, grey matter, and multiple sclerosis lesions, which became more easily visualized.

Alteration of gut microbiota in post-stroke depression patients with Helicobacter pylori infection

Background: Several studies have identified an association between the gut microbiome and post-stroke depression(PSD), and Helicobacter pylori(H. pylori) infection cause significant alterations in the composition of the gastrointestinal microbiome. However, evidence regarding the role of the H. pylori infection in promoting PSD is still lacking. Here, we conducted a retrospective study to explore risk factors associated with PSD.Methods: Patients with cerebral infarction were consecutively enrolled from December 2021 to October 2022. The diagnosis of PSD is based on the DSM-V criteria, and the Hamilton Depression Rating Scale(HAMD) was used to identify patients with PSD. White matter lesions were evaluated using magnetic resonance imaging(MRI) and H. pylori infection was detected by 13C-urea breath test. Further, 16S rRNA gene sequencing was used to evaluate the changes in gut microbiota composition of fecal samples from PSD patients. The concentration of short-chain fatty acids(SCFAs) was determined by gas chromatography–mass spectrometry(GC–MS).Results: Multivariate regression analysis showed that deep white matter lesions(DWMLs) [odds ratio(OR) 3.382, 95% confidence interval(CI) 1.756–6.512; P = 0.001] and H. pylori infection(OR 2.186, 95% CI 1.149–4.159; P = 0.017) were the independent risk factors for PSD. Patients with H. pylori infection had more severe depressive symptoms than patients without infection. Intestinal microbiota was significantly different between H. pylori-positive PSD[H. pylori(+)] patients and H. pylori-negative PSD[H. pylori (−)] patients. Fecal SCFAs concentrations were significantly reduced in the H. pylori(+) group compared to the negative ones.Conclusion: DWMLs and H. pylori infection may play important roles in the development of PSD. H. pylori infection is likely to be involved in the pathogenesis of PSD by altering the intestinal flora.

Deep learning-based white matter lesion volume on CT is associated with outcome after acute ischemic stroke.

Intravenous thrombolysis (IVT) before endovascular treatment (EVT) for acute ischemic stroke might induce intracerebral hemorrhages which could negatively affect patient outcomes. Measuring white matter lesions size using deep learning (DL-WML) might help safely guide IVT administration. We aimed to develop, validate, and evaluate a DL-WML volume on CT compared to the Fazekas scale (WML-Faz) as a risk factor and IVT effect modifier in patients receiving EVT directly after IVT. We developed a deep-learning model for WML segmentation on CT and validated with internal and external test sets. In a post hoc analysis of the MR CLEAN No-IV trial, we associated DL-WML volume and WML-Faz with symptomatic-intracerebral hemorrhage (sICH) and 90-day functional outcome according to the modified Rankin Scale (mRS). We used multiplicative interaction terms between WML measures and IVT administration to evaluate IVT treatment effect modification. Regression models were used to report unadjusted and adjusted common odds ratios (cOR/acOR). In total, 516 patients from the MR CLEAN No-IV trial (male/female, 291/225; age median, 71 [IQR, 62-79]) were analyzed. Both DL-WML volume and WML-Faz are associated with sICH (DL-WML volume acOR, 1.78 [95%CI, 1.17; 2.70]; WML-Faz acOR, 1.53 95%CI [1.02; 2.31]) and mRS (DL-WML volume acOR, 0.70 [95%CI, 0.55; 0.87], WML-Faz acOR, 0.73 [95%CI 0.60; 0.88]). Only in the unadjusted IVT effect modification analysis WML-Faz was associated with more sICH if IVT was given (p= 0.046). Neither WML measure was associated with worse mRS if IVT was given. DL-WML volume and WML-Faz had a similar relationship with functional outcome and sICH. Although more sICH might occur in patients with more severe WML-Faz receiving IVT, no worse functional outcome was observed. White matter lesion severity on baseline CT in acute ischemic stroke patients has a similar predictive value if measured with deep learning or the Fazekas scale. Safe administration of intravenous thrombolysis using white matter lesion severity should be further studied. White matter damage is a predisposing risk factor for intracranial hemorrhage in patients with acute ischemic stroke but remains difficult to measure on CT. White matter lesion volume on CT measured with deep learning had a similar association with symptomatic intracerebral hemorrhages and worse functional outcome as the Fazekas scale. A patient-level meta-analysis is required to study the benefit of white matter lesion severity-based selection for intravenous thrombolysis before endovascular treatment.

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.

Genotypic and phenotypic heterogeneity among Chinese pediatric genetic white matter disorders

BackgroundThe pediatric genetic white matter disorders are characterized by a broad disease spectrum. Genetic testing is valuable in the diagnosis. However, there are few studies on the clinical and genetic spectrum of Chinese pediatric genetic white matter disorders.MethodsThe participants were enrolled from the cohort of Peking Union Medical College Hospital. They all received history collection, brain MRI and gene sequencing. Their neurologic complaints which were related to white matter disorders occurred before 18. Brain MRI indicated periventricular and/or deep white matter lesions, fazekas grade 2–3.ResultsAmong the 13 subjects, there were 11 males and two females. The average age of onset was 10.0 ± 5.5 years old. The potential genetic variants were found in 84.6% (11/13) subjects. The ABCD1 showed the greatest mutation frequency (30.8%, 4/13). The EIF2B3 A151fs, EIF2B4 c.885 + 2T > G, EIF2B5 R129X and MPV17 Q142X were novel pathogenic/likely pathogenic variants. 100% (4/4) ABCD1 carriers were accompanied by visual impairment, whereas 100% (3/3) EIF2B carriers developed dysuria. 100% (4/4) ABCD1 carriers exhibited diffuse white matter hyperintensities mainly in the posterior cortical regions, while the EIF2B4 and EIF2B5 carriers were accompanied by cystic degeneration.ConclusionThere is genotypic and phenotypic heterogeneity among Chinese subjects with pediatric genetic white matter disorders. The knowledge of these clinical and genetic characteristics facilitates an accurate diagnosis of these diseases.

Higher High-Mobility Group Box-1 Levels are Associated with White Matter Lesions in Ischemic Stroke Patients.

High-mobility group box-1 (HMGB1) is a useful biomarker for disease severity stratification and prognosis prediction. We aim to explore whether the circulating HMGB1 concentrations are associated with the white matter lesions (WMLs) burden in stroke patients. Between 2022 June and December 2022, patients with acute ischemic stroke were prospectively enrolled. HMGB1 levels were measured by an enzyme-linked immunosorbent assay after admission for all patients. The WMLs severity was assessed by the Fazekas scale. We dichotomized patients into those with moderate-severe WMLs (Fazekas score 3-6) versus those with none-mild WMLs (Fazekas score 0-2). Furthermore, based on the severity of periventricular WMLs (PWMLs) and deep WMLs (DWMLs), patients were categorized as none-mild (Fazekas score 0-1) or moderate-severe (Fazekas score 2-3). A total of 287 participants (mean age: 64.9 years; 157 male) were analyzed. The median serum HMGB1 levels were 7.3 ng/mL (interquartile, 4.3 ng/mL-12.3 ng/mL). After adjustment for potential confounders, elevated HMGB1 levels were associated with the presence of moderate-severe WMLs (first quartile vs fourth quartile, odds ratio [OR], 4.101; 95% confidence interval [CI], 1.948-8.633; P = 0.001) and moderate-severe PWMLs (first quartile vs fourth quartile, OR, 9.181; 95% CI, 4.078-20.671; P = 0.001). Similar results were found when the HMGB1 levels were analyzed as a continuous variable. This study demonstrated that increased HMGB1 levels were associated with the severity of WMLs, mainly in the periventricular region.

Childhood-onset epilepsy in patients with dyskinetic cerebral palsy caused by basal ganglia and thalamic lesions

ObjectiveTo elucidate the incidence and outcomes of childhood-onset epilepsy and associated factors in term-born patients with basal ganglia and thalamic lesion (BGTL)-induced dyskinetic cerebral palsy (DCP) caused by perinatal hypoxic-ischemic encephalopathy (HIE). MethodsWe studied 104 term-born patients with BGTL-induced DCP (63 males and 41 females, aged 2–22 years) to investigate the incidence of epilepsy and the factors related to its development. We used multivariate analysis to assess perinatal factors, gross motor function, and the extent of brain lesions. We also investigated the seizure onset, clinical course, and electroencephalography (EEG) characteristics. ResultsThe cumulative epilepsy incidence was 36%. Multiple logistic regression analysis revealed that deep white matter lesions were the only independent risk factor for epilepsy. The confirmed seizure types included epileptic spasms (ES, n = 13), myoclonic seizures (MS, n = 6), and focal-onset seizures (FS, n = 24). Only patients with deep white matter lesions exhibited ES or MS. The symptoms of FS resembled those of self-limited epilepsy with centrotemporal spikes; however, only half of the patients reached remission by the time of investigation, and four patients had more than one seizure per month despite appropriate drug therapy. Focal spikes in the peri-rolandic area were detected not only in patients with FS but also in half of the patients without epilepsy. ConclusionsOne-third of term-born patients with BGTL-induced DCP caused by perinatal HIE develop epilepsy, and deep white matter lesions increase the likelihood of epilepsy. Preparation for early-onset ES, MS, and subsequent FS is beneficial.

Abstract P230: Central Artery Pulsatile Hemodynamics Are Associated With Cerebral Total, Periventricular, And Deep White Matter Lesions: Role Of Reservoir-excess Pressure Components.

Introduction: Accumulating evidence suggests that increased central, rather than peripheral, blood pressure (BP) may be a better predictor of cardiovascular risk. The shape of the central BP waveform is determined by ventricular-arterial interactions that can be quantified via novel hemodynamic analyses, from which some parameters have been implicated in the development of cardiac, vascular, and renal dysfunction. Comparatively, the potential effect of central pulsatile hemodynamics on brain structure has been understudied. Thus, we sought to determine the association of novel central hemodynamic parameters with cerebral white matter lesions. Methods: Central BP waveforms were measured in 130 healthy adults (age 63±6y; 58% female) via non-invasive carotid tonometry and modeled using reservoir-excess pressure analysis to separate the central BP waveform into a reservoir (Rp TI ) and excess (Ep TI ) pressure component. Systolic (Sk) and diastolic (Dk) rate constants were estimated from the rate of increase and decrease of the Rp TI component, respectively. Total, periventricular, and deep cerebral white matter lesion volumes (WMLV) were estimated from T2 weighted and FLAIR MRI and adjusted for total intracranial volume. Results: Both Sk and Ep TI were correlated with total (Sk: r = -0.19, p = 0.033; Ep TI : r = 0.21, p = 0.016), periventricular (Sk: r = -0.18, p = 0.037; Ep TI : r = 0.23, p = 0.009), and deep (Sk: r = -0.28, p = 0.002; Ep TI : r = 0.20, p = 0.027) WMLV. The association of Sk with total ( B = -0.032; 95% confidence interval [CI] = -0.054, -0.010; p = 0.0056), periventricular ( B = -0.030; 95%CI = -0.051, -0.009; p = 0.0063), and deep ( B = -0.064; 95%CI = -0.101, -0.028; p &lt;0.001) WMLV remained significant in multivariable analyses adjusting for age, sex, BMI, peripheral pulse pressure, carotid-femoral pulse wave velocity, heart rate, and non-HDL cholesterol. Additionally, the association between Ep TI and deep WMLV persisted in multivariable analysis ( B = 0.158; 95%CI = 0.045, 0.271; p = 0.007). Conclusion: Pulsatile components of central artery hemodynamics are associated with cerebral WMLV independent of traditional cardiovascular risk factors. In particular, Sk may represent a novel biomarker of early central BP-related cerebral white matter damage.

Changes in leukoencephalopathy and serum neurofilament after (neo)adjuvant chemotherapy for breast cancer

BackgroundPrevious case studies have provided evidence for chemotherapy-induced leukoencephalopathy in patients with breast cancer. However, prospective research is lacking. Hence, we investigated leukoencephalopathy before and after chemotherapy and its association with a serum neuroaxonal damage marker. MethodsThis prospective cohort study included 40 patients receiving chemotherapy for breast cancer, and two age- and education-matched control groups, recruited between 2018 and 2021 (31–64 years of age). The latter control groups consisted of 39 chemotherapy-naïve patients and 40 healthy women. Fluid-attenuated inversion-recovery magnetic resonance imaging was used for lesion volumetry (total, juxtacortical, periventricular, infratentorial, and deep white matter) and blood serum to measure neurofilament light chain (NfL) levels. Acquisition took place pre-chemotherapy and three months and one-year post-chemotherapy, or at corresponding intervals. Within/between group differences were compared using robust mixed-effects modeling, and associations between total lesion volume and serum-NfL with linear regression. ResultsStronger increases in deep white matter lesion volumes were observed shortly post-chemotherapy, compared with healthy women (ßstandardized=0.09, pFDR<0.001). Increases in total lesion volume could mainly be attributed to enlargement of existing lesions (mean±SD, 0.12±0.16 mL), rather than development of new lesions (0.02±0.02 mL). A stronger increase in serum-NfL concentration was observed shortly post-chemotherapy compared with both control groups (ß>0.70, p<0.004), neither of which showed any changes over time, whereas a decrease was observed compared with healthy women one-year post-chemotherapy (ß=-0.54, p = 0.002). Serum-NfL concentrations were associated with lesion volume one-year post-chemotherapy (or at matched timepoint; ß=0.36, p = 0.010), whereas baseline or short-term post-therapy levels or changes were not. ConclusionThese results underscore the possibility of chemotherapy-induced leukoencephalopathy months post-treatment, as well as the added value of serum-NfL as a prognostic marker for peripheral/central neurotoxicity. Translational relevancePrevious case studies have provided evidence of chemotherapy-induced leukoencephalopathy in patients with breast cancer. However, prospective studies to estimate longitudinal changes are currently missing. In this study, we used longitudinal fluid-attenuated inversion-recovery magnetic resonance imaging to assess white matter lesion volumes in patients treated for non-metastatic breast cancer and healthy women. Our findings demonstrate that chemotherapy-treated patients exhibit stronger increases in lesion volumes compared with healthy women, specifically in deep white matter, at three months post-chemotherapy. Increases could mainly be attributed to enlargement of existing lesions, rather than development of new lesions. Last, serum concentrations of neurofilament light chain, a neuroaxonal damage marker, increased shortly after chemotherapy and long-term post-chemotherapy levels were associated with lesion volumes. These findings highlight the potential of this non-invasive serum marker as a prognostic marker for peripheral and/or central neurotoxicity. Implementation in clinical practice could aid in therapeutic decisions, assessing disease activity, or monitoring treatment response.

#3517 BRAIN MAGNETIC RESONANCE IMAGING AND COGNITIVE FUNCTION IN PATIENTS RECEIVING HEMODIALYSIS

Abstract Background and Aims Chronic kidney disease is high risk to adverse events including stroke, cardiovascular diseases and cognitive decline. Cognitive function was known to be linked to chronic kidney disease. The Fazefa's scale, which was used for assessing white matter hyperdensities(WMH), has been reported to associate with poor cognitive performance. We aim to investigate the associations between mini-mental status examination (MMSE), Montreal cognitive assessment (MoCA), cognitive abilities screening instrument (CASI) and Fazefa's scale in patients under hemodialysis (HD). Method The periventricular (PV) and deep white matter (DWM) lesions in brain MR images of 59 patients under dialysis for at least 90 days were graded by Fazefa's scale. Cognition function tests including MMSE, MoCA, and CASI were performed. Multivariable ordinal regression and logistic regression were used for identifying the associations between cognitive performance and Fazekas scale. Results Inverse associations were found between three cognitive function tests across the Fazekas scale of PV lesions (p = 0.037, 0.006 and 0.008 for MMSE, MoCA, and CASI, respectively), and higher scales were associated with lower cognitive function scores in trend; however, the association attenuated in the DWM group. In subdomains of CASI, significant differences were identified in five subdomains, including short-term memory, mental manipulation, abstract thinking, spatial construction, and name fluency; nevertheless, in DWM hyperdensities, only abstract thinking and short-term memory showed obvious correspondence. Conclusion Inverse correlation between the Fazefa's scale, predominantly in PV lesions, and cognition was detected in HD patients. The Fazefa's scale of PV lesions were associated with cognitive performance assessed by MMSE, MoCA and CASI, as well as with subdomains of CASI such as memory, language, and name fluency in HD patients.

White matter lesions predominantly located in deep white matter represent embolic etiology rather than small vessel disease

AbstractBackgroundIndividuals with cerebral small vessel disease (CSVD) usually have both periventricular and deep white matter hyperintensities (dpWMH). However, we often encounter individuals whose WMH lesions are mainly located in the corticomedullary or deep white matter with minimal periventricular WMHs (dWMH). We aimed to determine if the dWMH pattern could be attributed to embolic etiologies.MethodsWe retrospectively recruited participants who had undergone comprehensive dementia evaluation, agitated saline contrast echocardiography, and brain MRI. The participants were classified into two groups according to WMH distributions, the dWMH (WMHs in deep and corticomedullary area, with minimal periventricular WMHs) and the dpWMH (mainly periventricular WMHs with or without deep WMHs) groups. We hypothesized that dWMH is more likely associated with embolism, whereas dpWMH with CSVD. We compared the clinical characteristics, WMH distributions, and the positive rate of agitated saline study between the two groups.ResultsOf the 90 participants, 27 fulfilled the dWMH criteria and 12 met the dpWMH criteria. The dWMH group was younger (62.2±7.5 vs 78.9±7.3, p&lt;0.001), and had a lower prevalence of hypertension (29.6% vs. 75%, p = 0.008), DM (3.7% vs. 25%, p = 0.043), and hyperlipidemia (33.3% vs. 83.3%, p = 0.043) than the dpWMH group. Regarding deep white matter lesions, the number of small lesions (&lt;3 mm) was higher in the dWMH (10.9±9.7) than the dpWMH (3.1±6.4) group (p = 0.008), and WMHs were predominantly distributed in border‐zones of major cerebral arteries and corticomedullary areas.Most importantly, the positive rate of agitated saline was higher in the dWMH than the dpWMH group (81.5% vs. 33.3%, p = 0.003).ConclusionsThe dWMH group with younger age, fewer cardiovascular risk factors showed more border‐zone distributions, and higher positivity of agitated saline test than dpWMH group, indicating that WMH distributions mainly in the corticomedullary or deep area with minimal periventricular WMH lesions suggest embolic etiologies.

Distinct Etiologies of RANBP2-negative Acute Necrotizing Encephalopathy of Childhood (P10-9.008)

<h3>Objective:</h3> We sought to determine the etiology of <i>RANBP2</i>-negative pediatric patients presenting with acute necrotizing encephalopathy of childhood (ANEC). <h3>Background:</h3> ANEC is a rare childhood syndrome associated with fulminant encephalopathy and characteristic neuroimaging typically precipitated by acute infection and often associated with heterozygous mutation in <i>RANBP2</i>. Additional genes implicated in ANEC include <i>CPT2, MC1DN1</i> and <i>ILAE4</i>, yet many patients who meet clinical criteria for ANEC do not have mutations in any known genes and the cause of these cases has remained cryptic. <h3>Design/Methods:</h3> We performed a multicenter trio-based whole exome analysis of 12 <i>RANBP2</i>-negative pediatric patients diagnosed with ANEC using our established pipeline and filtering criteria. Whole exome sequencing was performed using a TruSeq exome capture kit and run on an Illumina NovaSeq 6000. Fastq files were analyzed using our established GATK-based pipeline and filtered for rare variants using our published approach. We prioritized rare candidate genes to determine plausible candidates based on the existing literature. <h3>Results:</h3> 32 candidate genes survived filtering and were considered in our analysis. We identified three high-confidence candidate genes. The first was <i>SCN1A</i>, segregating a heterozygous <i>de novo</i> (p.F1765Cfs*28). SCN1A encodes a voltage-gated sodium channel subunit. Mutations in SCN1A are well-known causes of Dravet Syndrome and other forms of epilepsy, but have also been associated with a fulminant encephalopathy phenotype independent of seizure burden. The second was <i>TNFAIP3</i> (heterozygous <i>de novo</i> p.R728C), previously shown to lead to an autoinflammatory Behcet-like syndrome. The third was <i>PRF1</i> (homozygous p.R225W), associated with a hemophagocytic lymphocystiocytosis-like phenotype with encephalopathy, ataxia, deep white matter lesions, and increased intracranial pressure. <h3>Conclusions:</h3> Our study indicates that ANEC is genetically heterogeneous and highlights three additional genes that should be considered in individuals presenting with ANEC. Our results also showcase how monogenic conditions can impact immune system regulation and lead to neuroimmunologic disorders. <b>Disclosure:</b> Dr. Vaidyanathan has nothing to disclose. Somayeh Bakhtiari has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Xilis Inc. Somayeh Bakhtiari has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant (Bioinformatics) with Phoenix Childrens Hospital. Dr. Appavu has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Natus. The institution of Dr. Appavu has received research support from American Heart Association. The institution of Dr. Appavu has received research support from United States Department of Defense. Derek Neilson has nothing to disclose. The institution of Dr. Kruer has received research support from NIH NINDs. Dr. Kruer has received research support from Cure CP. Dr. Kruer has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant with NHRSA.

Development of a stroke risk score with MRI asymptomatic brain lesions attributes to evaluate prognostic vascular events

BackgroundThe use of a combination of stroke predictors, such as clinical factors and asymptomatic lesions on brain magnetic resonance imaging (MRI), may improve the accuracy of stroke risk prediction. Therefore, we attempted to develop a stroke risk score for healthy individuals. MethodsWe investigated the presence of cerebral stroke in 2365 healthy individuals who underwent brain dock screening at the Health Science Center in Shimane. We examined the factors that contributed to stroke and attempted to determine the risk of stroke by comparing background factors and MRI findings. ResultsThe following items were found to be significant risk factors for stroke: age (≥60 years), hypertension, subclinical cerebral infarction, deep white matter lesion, and microbleeds. Each item was scored with 1 point, and the hazard ratios for the risk of developing stroke based on the group with 0 points were 17.2 (95% confidence interval [CI] 2.31–128) for 3 points, 18.1 (95% CI 2.03–162) for 4 points, and 102 (95% CI 12.6–836) for 5 points. ConclusionsA precise stroke prediction score biomarker can be obtained by combining MRI findings and clinical factors.

Sentinel seizure heralding Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease

BackgroundIsolated seizure as a manifestation of myelin oligodendrocyte antibody-associated disease (MOGAD) has rarely been reported previously.Case presentationA 16-year-old-male presented with single episode of left focal onset motor seizure with secondary generalization and impaired awareness, without any other focal neurological deficits. There was a history of right focal onset motor seizure with secondary generalized tonic–clonic seizure and impaired awareness 4 years ago. Neurological examination showed bilateral gaze evoked nystagmus. Brain imaging revealed bilateral superficial and deep white matter lesions including the corpus callosum. Anti-MOG antibody was positive. The patient received steroids and Rituximab therapy without any further recurrence of seizure or any neuro-deficits and gradual improvement in lesion burden in brain imaging.ConclusionsThis case of an adolescent boy with sole manifestation of episodes of focal seizures 4 years apart, finally diagnosed to be a case of MOGAD, not only boosts the evidence of establishing the possibility of MOG antibody-associated autoimmune epilepsy but also reinforces the importance of unexplained seizure as a clinical phenotype in MOGAD.