Diffuse White Matter Research Articles

Clinical and MRI Evaluation of Children with Leukodystrophies

Introduction: Leukodystrophies are a diverse group of rare, inherited neurodegenerative disorders affecting the brain’s white matter, leading to progressive neurological impairment. Magnetic Resonance Imaging (MRI) plays a crucial role in diagnosing these conditions, offering detailed insight into white matter abnormalities and aiding in distinguishing various leukodystrophies. Objective: This study aims to evaluate children with leukodystrophies using MRI, establish accurate diagnoses, assess the severity and extent of white matter lesions, and demonstrate the different patterns of abnormal myelination. Methods: This prospective observational study was conducted in the Department of Radiodiagnosis and Imaging at Sher-I-Kashmir Institute of Medical Sciences, Srinagar, from June 2022 to June 2024. All children suspected of having white matter disorders based on clinical features and biochemical tests were included. MRI was performed to identify patterns of white matter involvement, and findings were correlated with clinical data. Results: A total of 29 children (age range: 2 months to 18 years) were evaluated. MRI findings revealed that demyelinating leukodystrophies were the most common, with symmetrical white matter involvement. Hypomyelinating disorders showed diffuse white matter changes with sparing of the U-fibers. Specific patterns, such as tigroid appearance in metachromatic leukodystrophy and posterior fossa involvement in Alexander disease, were identified. MRI was instrumental in narrowing down differential diagnoses and identifying characteristic patterns for various leukodystrophies. Conclusion: MRI is an invaluable tool in the diagnosis and management of leukodystrophies in children. It allows for early identification of disease patterns, which is critical for appropriate clinical management and potential therapeutic interventions. Further research is needed to explore the genetic basis of these disorders in the Kashmiri population.

Preventive treatment effects on brain structures and functions in patients with chronic migraine: A multimodel magnetic resonance imaging study.

Patients with chronic migraine (CM) often exhibit structural and functional alterations in pain-matrix regions, but it remains unclear how preventive treatment affects these changes. Therefore, this study aimed to investigate the structural and functional changes in pain-matrix regions in CM patients after 6-month treatment. A total of 24 patients with CM and 15 healthy controls were recruited for this study. Patients were divided into responder group (N = 9) and non-responder group (N = 15). After completing the Migraine Disability Assessment (MIDAS) questionnaire, all patients underwent whole-brain high-resolution T1-weighted images, diffusion-weighted imaging, and resting-state functional magnetic resonance imaging at baseline and 6-month follow-up. Whole brain gray matter volume and white matter diffusion indices were analyzed using voxel-based analysis. Structural and functional connectivity analyses were performed to understand brain changes in patients after 6-month preventive treatment. The responder group exhibited significantly higher MIDAS scores than the non-responder group at baseline, but no significant difference between the two groups at follow-up. No significant interval change was noted in gray matter volume, white matter diffusion indices, and structural connectivity in CM patients after 6-month treatment. Nonetheless, the functional connectivity was significantly increased between occipital, temporal lobes and cerebellum, and was significantly decreased between parietal and temporal lobes after 6-month preventive treatment. We concluded that resting-state functional connectivity was suitable for investigating the preventive treatment effect on CM patients.

Diffuse white matter pathology in multiple sclerosis during treatment with dimethyl fumarate-An observational study of changes in normal-appearing white matter using proton magnetic resonance spectroscopy.

Multiple sclerosis (MS) is an inflammatory demyelinating disease with neurodegenerative features causing risk for neurologic irreversible disability over time. Examination of normal-appearing white matter (NAWM) changes in MS by proton magnetic resonance spectroscopy (1H-MRS), may detect diffuse white matter pathology that is associated with neurodegeneration. In this observational study of in total twenty-six patients with MS, starting treatment with dimethyl fumarate (DMF), we measured the absolute concentration of metabolites in periventricular NAWM using 1H-MRS at baseline and after one and three years of treatment. Metabolite concentrations were analyzed both cross-sectionally, in relation to 10 controls and longitudinally in relation to disease activity. Patients with MS had higher concentrations of myo-inositol (mIns) in NAWM at baseline compared with controls (mean 5.98 ± 1.37 (SD) and 4.32 ± 1.16 (SD), p<0.01, independent samples t-test). The disease duration was inversely correlated with concentrations of total N-acetylaspartate and N-acetylaspartylglutamate (tNA) (r = -0.62, p<0.01) in NAWM as well as positively to the ratio of mIns and tNA (r = 0.51, p = 0.03). Metabolite concentrations during one-year (n = 19) and three-years (n = 11) follow-up were generally stable. The dropouts were caused by treatment switch after one year, mainly due to new MRI activity. Cross-sectional analyses showed that there was an inverse correlation between concentrations of tNA and mIns at both baseline and at 1 and 3-years follow-up (r = -0.44 to -0.65, p = 0.04 to 0.004). Metabolite concentrations were stable during 1-year follow-up independently of disease activity. Higher concentrations of the astrogliosis marker mIns in MS compared to controls, the inverse relation between MS disease duration and the neuroaxonal integrity marker tNA, as well as the consistent inverse relation between these two metabolites during follow-up, showed that non-lesional white matter pathology is present in this cohort of MS patients in early disease stages. However, metabolite concentrations during follow-up were generally stable and did not reflect differences in disease activity among patients.

Choroid Plexus Volume in Rural Chinese Older Adults: Distribution and Association With Cardiovascular Risk Factors and Cerebral Small Vessel Disease.

The choroid plexus (CP) is involved in neurodegenerative diseases. However, the association of CP with cardiovascular risk factors and cerebral small vessel disease in older adults remains unclear. This population-based study included 1263 participants (60 years and older) from the MIND-China (Multimodal Interventions to Delay Dementia and Disability in Rural China) substudy (2018-2020), of which 111 individuals completed diffusion tensor imaging examination. CP volume was automatically segmented. White matter hyperintensities (WMHs), enlarged perivascular spaces (EPVS), cerebral microbleeds, and lacunes were assessed following the Standards for Reporting Vascular Changes on Neuroimaging 1. Peak width of skeletonized mean diffusivity and free water were derived from diffusion tensor imaging images. We used linear regression models to evaluate the association between CP volume and cardiovascular risk factors, WMH volumes, and diffusion tensor imaging metrics, and logistic regression models to examine the association between CP volume and EPVS, cerebral microbleeds, and lacunes. The CP volume increased with age (P<0.001). Men (β coefficient=0.47 [95% CI, 0.29-0.64]) and participants with diabetes (β coefficient=0.16 [95% CI, 0.01-0.31]) had larger CP volumes than women and individuals without diabetes, respectively (P<0.05). Greater CP volume was significantly associated with larger total and periventricular WMH volumes and moderate to severe EPVS in basal ganglia (P<0.05) but not with deep WMHs, EPVS in centrum semiovale, lacunes, or cerebral microbleeds. In the diffusion tensor imaging subsample, enlarged CP was significantly associated with higher peak width of skeletonized mean diffusivity and free water of periventricular and deep white matter (P<0.05). An enlarged CP is associated with larger global and periventricular WMH volume and higher likelihoods of EPVS in basal ganglia and impaired white matter integrity, suggesting that an enlarged CP may represent a precursor of cerebral small vessel disease.

A Chinese CADASIL family with a rare heterozygous mutation in exon 2 of NOTCH3: A case report.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease caused by the neurogenic locus notch homolog protein 3 (NOTCH3) gene mutation. In recent years, most of the newly reported mutations of CADASIL patients mainly occur in exon 3 to 24, while the cases related to exon 2 mutation are rare, and clinical research data are relatively insufficient. In this study, we have reported a case of a rare heterozygous mutation c.128G>A (p.Cys43Tyr) in exon 2 of NOTCH3 in a 41-year-old Chinese man in the light of relevant literatures. A 41-year-old man who suffered slurred speech for 5 days and right lower limb weakness for 4 days was admitted to our hospital. Magnetic resonance imaging of the head revealed diffuse white matter lesions involving the outer capsular area and bilateral temporal poles. The rare heterozygous mutation c.128G>A (p.Cys43Tyr) in exon 2 of NOTCH3 was identified through molecular genetic testing. The proband was diagnosed as having CADASIL. Meanwhile, the same mutation was detected in 2 other family members III5 and IV9. Atorvastatin calcium tablet (20 mg qd) and aspirin enteric-coated tablet (100 mg qd). The patient was hospitalized for 3 weeks and discharged after his symptoms improved. The heterozygous Cys43Tyr mutation in exon 2 of NOTCH3 is rare. Thus, our case report complements the rare mutation of exon 2 and offers additional clinical data for CADASIL patients.

Microangiopathy in temporal lobe epilepsy with diffusion MRI alterations and cognitive decline

White matter microvascular alterations in temporal lobe epilepsy (TLE) may be relevant to acquired neurodegenerative processes and cognitive impairments associated with this condition. We quantified microvascular changes, myelin, axonal, glial and extracellular-matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in vivo pre-operative MRI diffusion measurements in co-registered regions and neuropsychological measures of cognitive impairment and decline. In resections, increased arteriolosclerosis was observed in TLE compared to non-epilepsy controls (greater sclerotic index, p < 0.001), independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (quantified with collagen-4, p < 0.05–0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (quantified with platelet-derived growth factor receptorβ and smooth muscle actin, p < 0.01) which was more marked the longer the duration of epilepsy (p < 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlation with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with white matter abnormality quantified using fixel-based analysis. Increased perivascular space was associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (p < 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features correlate with white matter diffusion MRI alterations and might explain cognitive decline in TLE.

Early Postnatal Neuroinflammation Produces Key Features of Diffuse Brain White Matter Injury in Rats.

Perinatal infection is a major risk factor for diffuse white matter injury (dWMI), which remains the most common form of neurological disability among very preterm infants. The disease primarily targets oligodendrocytes (OL) lineage cells in the white matter but also involves injury and/or dysmaturation of neurons of the gray matter. This study aimed to investigate whether neuroinflammation preferentially affects the cellular compositions of the white matter or gray matter. Neuroinflammation was initiated by intracerebral administration of lipopolysaccharide (LPS) to rat pups at postnatal (P) day 5, and neurobiological and behavioral outcomes were assessed between P6 and P21. LPS challenge rapidly activates microglia and astrocytes, which is associated with the inhibition of OL and neuron differentiation leading to myelination deficits. Specifically, neuroinflammation reduces the immature OLs but not progenitors and causes acute axonal injury (β-amyloid precursor protein immunopositivity) and impaired dendritic maturation (reduced MAP2+ neural fiber density) in the cortical area at P7. Neuroinflammation also reduces the expression of doublecortin in the hippocampus, suggesting compromise in neurogenesis. Utilizing a battery of behavioral assessments, we found that LPS-exposed animals exhibited deficits in sensorimotor, neuromuscular, and cognitive domains. Our overall results indicate that neuroinflammation alone in the early postnatal period can produce cardinal neuropathological features of dWMI.

Differences in brain structure and cognitive performance between patients with long-COVID and those with normal recovery

BackgroundThe pathophysiology of protracted symptoms after COVID-19 is unclear. This study aimed to determine if long-COVID is associated with differences in baseline characteristics, markers of white matter diffusivity in the brain, and lower scores on objective cognitive testing. MethodsIndividuals who experienced COVID-19 symptoms for more than 60 days post-infection (long-COVID) (n = 56) were compared to individuals who recovered from COVID-19 within 60 days of infection (normal recovery) (n = 35). Information regarding physical and mental health, and COVID-19 illness was collected. The National Institute of Health Toolbox Cognition Battery was administered. Participants underwent magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI). Tract-based spatial statistics were used to perform a whole-brain voxel-wise analysis on standard DTI metrics (fractional anisotropy, axial diffusivity, mean diffusivity, radial diffusivity), controlling for age and sex. NIH Toolbox Age-Adjusted Fluid Cognition Scores were used to compare long-COVID and normal recovery groups, covarying for Age-Adjusted Crystallized Cognition Scores and years of education. False discovery rate correction was applied for multiple comparisons. ResultsThere were no significant differences in age, sex, or history of neurovascular risk factors between the groups. The long-COVID group had significantly (p < 0.05) lower mean diffusivity than the normal recovery group across multiple white matter regions, including the internal capsule, anterior and superior corona radiata, corpus callosum, superior fronto-occiptal fasciculus, and posterior thalamic radiation. However, the effect sizes of these differences were small (all β<|0.3|) and no significant differences were found for the other DTI metrics. Fluid cognition composite scores did not differ significantly between the long-COVID and normal recovery groups (p > 0.05). ConclusionsDifferences in diffusivity between long-COVID and normal recovery groups were found on only one DTI metric. This could represent subtle areas of pathology such as gliosis or edema, but the small effect sizes and non-specific nature of the diffusion indices make pathological inference difficult. Although long-COVID patients reported many neuropsychiatric symptoms, significant differences in objective cognitive performance were not found.

B - 109 Long-Term Cognitive Effects of Combined Opioid/Non-Opioid Use

Abstract Objective Chronic pain is estimated to afflict 25–50% of community-dwelling older adults (Cravello et al., 2019). Despite the growing epidemic, opioids remain commonly prescribed analgesics, and approximately 10% of older adults with intermittent opioid use become chronic users (Ramachandran et al., 2021). This is concerning given an observed association between cognitive decline and prescription opioid use within this population (Warner et al., 2022). In efforts to reduce opioid consumption, opioid/non-opioid combinations have been used (Pergolizzi et al., 2023); however, the long-term cognitive impact of such alternatives has not been investigated. Thus, the current case report investigates the neurocognitive outcome following longtime opioid/non-opioid combination cessation in the context of chronic pain. Method A 69-year-old Black woman with approximate 30-year history of chronic pain underwent neuropsychological re-evaluation 2 years post-initial assessment and 1.5 years after stopping combined hydromorphone/clonidine use via intrathecal pump. Baseline MRI brain revealed mild diffuse atrophy and punctate nonspecific T2 white matter hyperintensities. CT head approximately 1 year later was unremarkable. Results Neuropsychological re-assessment approximately 2 years post-baseline evaluation revealed significantly declined performances on speed-mediated tasks (e.g., oral numeric sequencing, fluency) amid an otherwise grossly stable, albeit globally impaired, cognitive profile. Conclusions This study elucidates the impact of a 1.5-year period of abstinence from 13 years of combined intrathecal opioid/non-opioid use. Overall, results suggest that cognitive performance, even following this abstinence period, is not improved. Thus, while opioid/non-opioid therapies may reduce opioid exposure, deleterious cognitive effects persist. This study highlights the importance of non-opioid analgesics in efforts to attenuate cognitive impairment risk.

Brain white matter pathways of resilience to chronic back pain: a multisite validation.

Chronic back pain (CBP) is a global health concern with significant societal and economic burden. While various predictors of back pain chronicity have been proposed, including demographic and psychosocial factors, neuroimaging studies have pointed to brain characteristics as predictors of CBP. However, large-scale, multisite validation of these predictors is currently lacking. In two independent longitudinal studies, we examined white matter diffusion imaging data and pain characteristics in patients with subacute back pain (SBP) over six- and 12-month periods. Diffusion data from individuals with CBP and healthy controls (HC) were analyzed for comparison. Whole-brain tract-based spatial statistics analyses revealed that a cluster in the right superior longitudinal fasciculus (SLF) tract had larger fractional anisotropy (FA) values in patients who recovered (SBPr) compared to those with persistent pain (SBPp), and predicted changes in pain severity. The SLF FA values accurately classified patients at baseline and follow-up in a third publicly available dataset (Area under the Receiver Operating Curve ∼ 0.70). Notably, patients who recovered had FA values larger than those of HC suggesting a potential role of SLF integrity in resilience to CBP. Structural connectivity-based models also classified SBPp and SBPr patients from the three data sets (validation accuracy 67%). Our results validate the right SLF as a robust predictor of CBP development, with potential for clinical translation. Cognitive and behavioral processes dependent on the right SLF, such as proprioception and visuospatial attention, should be analyzed in subacute stages as they could prove important for back pain chronicity.

Associations between white and grey matter damage and gait impairment in cerebral amyloid angiopathy

BackgroundCerebral amyloid angiopathy (CAA) is associated with white matter damage and neurodegeneration. Gait is impaired in CAA; however, the neural basis of this impairment is unclear. Research questionAre gait impairments in patients with CAA associated with altered cerebral white matter diffusivity and/or atrophy of cortical and subcortical grey matter. MethodsParticipants with CAA (n=29), Alzheimer’s disease (AD; n=16), and normal controls (n=47) were included. Gait was assessed using a 6 m walkway with parameters categorized into rhythm, pace, postural control, and variability domains. The dual-task cost (DTC) of gait speed was calculated for counting backwards, animal fluency, and serial sevens tasks. Whole-brain white matter disruption was quantified using the peak width of skeletonized mean diffusivity (PSMD), and thickness and volume of select cortical, subcortical, and cerebellar regions were quantified using FreeSurfer. ResultsIn CAA participants, associations were found between PSMD and pace (standardized parameter estimate (β), 95 % confidence interval (CI): 0.17, 0.03–0.32), and medial orbital frontal cortical thickness and counting backwards DTC (parameter estimate (PE), 95 % CI: −5.7 %/SD, −0.24 to −11.23). Across all groups, including CAA, associations were found between PSMD and pace, variability, counting backwards DTC, and animal fluency DTC; between frontal cortical thickness and pace, counting backwards DTC, and animal fluency DTC; between cortical regions affected by AD (inferior parietal cortex, inferior and middle temporal gyrus) and counting backwards DTC; and between thalamus volume and postural control. SignificanceReduced white matter structural integrity and grey matter loss is associated with poor overall gait performance in CAA, AD, and normal controls.

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.

Antiphospholipid Antibodies in Mental Disorders.

Thrombotic events striking the central nervous system are clinical criteria for the antiphospholipid syndrome (APS). Besides these, neuropsychiatric non-APS criteria manifestations are increasingly described in patients with persistently positive antiphospholipid antibodies (aPL). Among these are psychiatric manifestations. Animal models mainly describe hyperactive behavior and anxiety associated with hippocampal abnormalities. Cases of associations with psychosis, mood disorders, bipolarity, anxiety, obsessive-compulsive behavior, and depression have been reported but are still rare. Systematic human clinical association studies are concordant with a risk of psychosis, depression (simple to major), and anxiety disorders, but these are limited and of inconstant methodological quality. Brain imaging in patients, also insufficiently investigated, shows early signs of hypoperfusion and of subtle diffuse white matter changes compatible with an alteration of the axonal structure and changes in the myelin sheath. Direct interactions of aPL with the brain cells, both on cell lines and on animal and human brain biopsies, targeting both glial cells, astrocytes, and neurons, can be demonstrated. These clusters of arguments make the association between psychiatric diseases and aPL increasingly plausible. However, a considerable amount of clinical research must still be performed in accordance with the highest standards of methodological quality. The therapeutic management of this association, in terms of both prevention and cure, currently remains unresolved.

High cognitive reserve attenuates the risk of dementia associated with cardiometabolic diseases

BackgroundCardiometabolic diseases (CMDs) including type 2 diabetes, heart disease, and stroke have been linked to a higher risk of dementia. We examined whether high levels of cognitive reserve (CR) can attenuate the increased dementia risk and brain pathologies associated with CMDs.MethodsWithin the UK Biobank, 216,178 dementia-free participants aged ≥ 60 were followed for up to 15 years. Baseline CMDs and incident dementia were ascertained from medical records, medication use, and medical history. Latent class analysis was used to generate an indicator of CR (low, moderate, and high) based on education, occupational attainment, confiding in others, social contact, leisure activities, and television watching time. A subsample (n = 13,663) underwent brain MRI scans during follow-up. Volumes of total gray matter (GMV), hippocampus (HV), and white matter hyperintensities (WMHV) were ascertained, as well as mean diffusivity (MD) and fractional anisotropy (FA) in white matter tracts.ResultsAt baseline, 43,402 (20.1%) participants had at least one CMD. Over a mean follow-up of 11.7 years, 6,600 (3.1%) developed dementia. The presence of CMDs was associated with 57% increased risk of dementia (HR 1.57 [95% CI 1.48, 1.67]). In joint effect analysis, the HRs of dementia for people with CMDs and moderate-to-high CR and low CR were 1.78 [1.66, 1.91] and 2.13 [1.97, 2.30]), respectively (reference: CMD-free, moderate-to-high CR). Dementia risk was 17% lower (HR 0.83 [0.77, 0.91], p < 0.001) among people with CMDs and moderate-to-high compared to low CR. On brain MRI, CMDs were associated with smaller GMV (β -0.18 [-0.22, -0.13]) and HV (β -0.13 [-0.18, -0.08]) as well as significantly larger WMHV (β 0.06 [0.02, 0.11]) and MD (β 0.08 [0.02, 0.13]). People with CMDs and moderate-to-high compared to low CR had significantly larger GMV and HV, but no differences in WMHV, MD, or FA.ConclusionsAmong people with CMDs, having a higher level of CR was associated with lower dementia risk and larger gray matter and hippocampal volumes. The results highlight a mentally and socially active life as a modifiable factor that may support cognitive and brain health among people with CMDs.

Early Childhood Onset Vanishing White Matter Disease with Multiple Cranial Nerve Enhancement: A New Consensus Criteria?

Vanishing White Matter Disease (VWM), also known as Childhood Ataxia with Central Nervous System Hypomyelination (CACH), although a rare neurological condition, is a prevalent hereditary leukoencephalopathy with a characteristic phenotype of gradual neurologic deterioration with ataxia being a prominent feature. It is characterized by a wide range of onset, from antenatal and infantile periods to early childhood and later adulthood periods. The early childhood form is considered the prevailing form, characterized by a preceding phase of normal development until the second or 3rd year of life, followed by progressive neurologic deterioration, accentuated by certain stressors, such as infections or minor trauma. Diagnosis is achieved based on the clinical pretext combined with distinctive MRI brain features, confirmed by DNA analysis detection of elf2B mutation. Our case is a healthy 18-month-old male who after a preceding upper respiratory tract infection, developed an ataxic gait, encephalopathy, and recurrent generalized seizures. Physical assessment revealed signs of generalized spasticity and hyperreflexia. Neuroimaging revealed diffuse symmetric supratentorial and infratentorial diffuse white matter hypomyelination. Interestingly, there was notable enhancement of the 3rd and 5th cranial nerves. Differential diagnosis included acute demyelinating leukoencephalopathies; and neuromatobolic disorders with acute presentations (including leukodystrophies, hypomyelinating disorders, and mitochondrial encephalopathies). In the early course of his management, he received immunomodulatory therapy in the form of pulse steroids, intravenous immunoglobulins, and oral tapering course of steroids. He had limited response to these interventions. Whole exome sequencing yielded a homozygous mutation in EIF2B3, confirming the diagnosis of VWMD/CACH. The presence of enhancing cranial neuropathies represent an atypical phenotype reported in other case reports and should alert the physician to avoid unnecessary intervention with immunosuppressive therapies.

Mitochondrial neurogastrointestinal encephalopathy: a case report

BackgroundMitochondrial neurogastrointestinal encephalopathy (MNGIE) is an autosomal recessive disease associated with alterations in mitochondrial DNA (mtDNA). The typical age of onset of MNGIE is between the first and second decade of life. Diagnosis requires the presence of several key clinical features: sensorimotor neuropathy, external ophthalmoplegia, ocular ptosis, leukoencephalopathy, and gastrointestinal (GI) dysmotility. Unfortunately, MNGIE diagnosis is very challenging, and patients often undergo multiple diagnostic and surgical operations that are unnecessary.Case presentationThis case is of a 51-year-old male presenting with a 2-year history of limb weakness, GI problems and cachexia. There was also a 1-year history of progressive ptosis and ophthalmoplegia. The patient’s uncle and brother had both died from GI-related issues prior to the age of 40. On physical examination, ocular motility was impaired in all directions and there was atrophy and reduction in power in both lower and upper extremities. FLAIR and T2-weighted sequences of brain MRI demonstrated diffuse cerebral white matter hyperintensity (leukoencephalopathy). On discharge, the patient was referred for genetic consultation for bone marrow transplantation and had regular follow-up with a gastroenterology specialist.ConclusionIn patients presenting with chronic progressive ophthalmoplegia, severe gastrointestinal complications, sensorimotor neuropathy and white matter lesions on MRI, it is important to consider investigating for MNGIE.

Timed fetal inflammation and postnatal hypoxia cause cortical white matter injury, interneuron imbalances, and behavioral deficits in a double-hit rat model of encephalopathy of prematurity

Extreme preterm birth-associated adversities are a major risk factor for aberrant brain development, known as encephalopathy of prematurity (EoP), which can lead to long-term neurodevelopmental impairments. Although progress in clinical care for preterm infants has markedly improved perinatal outcomes, there are currently no curative treatment options available to combat EoP. EoP has a multifactorial etiology, including but not limited to pre- or postnatal immune activation and oxygen fluctuations. Elucidating the underlying mechanisms of EoP and determining the efficacy of potential therapies relies on valid, clinically translatable experimental models that reflect the neurodevelopmental and pathophysiological hallmarks of EoP. Here, we expand on our double-hit rat model that can be used to study EoP disease mechanisms and therapeutic options in a preclinical setting. Pregnant Wistar dams were intraperitoneally injected with 10 μg/kg LPS on embryonic day (E)20 and offspring was subjected to hypoxia (140 min, 8% O2) at postnatal day 4. Rats exposed to fetal inflammation and postnatal hypoxia (FIPH) showed neurodevelopmental impairments, such as reduced nest-seeking ability, ultrasonic vocalizations, social engagement, and working memory, and increased anxiety and sensitivity. Impairments in myelination, oligodendrocyte maturation and interneuron development were examined as hallmarks for EoP, in different layers and coordinates of the cortex using histological and molecular techniques. Myelin density and complexity was decreased in the cortex, which partially coincided with a decrease in mature oligodendrocytes. Furthermore, interneuron populations (GAD67+ and PVALB+) were affected. To determine if the timing of inducing fetal inflammation affected the severity of EoP hallmarks in the cortex, multiple timepoints of fetal inflammation were compared. Inflammation at E20 combined with postnatal hypoxia gave the most severe EoP phenotype in the cortex. In conclusion, we present a double-hit rat model which displays various behavioral, anatomical and molecular hallmarks of EoP, including diffuse white matter injury. This double-hit model can be used to investigate pathophysiological mechanisms and potential therapies for EoP.

Brain white matter microstructural alterations in Behcet's syndrome correlate with cognitive impairment and disease severity: A diffusion tensor imaging study

ObjectivesTo evaluate the microstructural integrity of brain white matter tracts in patients with Neuro-Behcet's syndrome (NBS) and Behcet's syndrome (BS) without neurological manifestations using diffusion tensor imaging (DTI) and to investigate potential utility of DTI as a surrogate biomarker of neurocognitive functioning and disease severity. MethodsThis cross-sectional study comprised 34 NBS patients and 32 BS patients without neurological involvement, identified based on the International Study Group of the Behcet's disease (ISGBD) and the International Consensus Recommendation (ICR) criteria, as well as 33 healthy controls. Cognitive functions, including attention, memory, language, abstraction, executive control, visuospatial skills, and sensorimotor performance were assessed using standardized questionnaires. DTI data were analyzed using tract-based spatial statistics (TBSS) and automated probabilistic tractography to investigate inter-group differences. Subsequently, correlations between tensor-derived parameters of white matter tracts, neurocognitive test scores, and disease severity measures were examined. ResultsDTI revealed decreased fractional anisotropy and increased radial diffusivity, mean diffusivity, and axial diffusivity in both supratentorial and infratentorial white matter in NBS patients, indicating widespread loss of microstructural integrity. Moreover, this loss of integrity was also observed in BS patients without neurological manifestations, albeit to a lesser extent. In NBS patients, certain white matter tracts, including cingulum bundle, were associated with poor cognitive performance across multiple domains and disease severity. DiscussionDTI findings might potentially serve as a neuroimaging marker to predict the extent of neurocognitive impairment and disease severity associated with central nervous system involvement in BS.

Examining the neurostructural architecture of intelligence: The Lothian Birth Cohort 1936 study

Examining underlying neurostructural correlates of specific cognitive abilities is practically and theoretically complicated by the existence of the positive manifold (all cognitive tests positively correlate): if a brain structure is associated with a cognitive task, how much of this is uniquely related to the cognitive domain, and how much is due to covariance with all other tests across domains (captured by general cognitive functioning, also known as general intelligence, or ‘g’)? We quantitatively address this question by examining associations between brain structural and diffusion MRI measures (global tissue volumes, white matter hyperintensities, global white matter diffusion fractional anisotropy and mean diffusivity, and FreeSurfer processed vertex-wise cortical volumes, smoothed at 20mm fwhm) with g and cognitive domains (processing speed, crystallised ability, memory, visuospatial ability). The cognitive domains were modelled using confirmatory factor analysis to derive both hierarchical and bifactor solutions using 13 cognitive tests in 697 participants from the Lothian Birth Cohort 1936 study (mean age 72.5 years; SD = .7). Associations between the extracted cognitive factor scores for each domain and g were computed for each brain measure covarying for age, sex and intracranial volume, and corrected for false discovery rate.There were a range of significant associations between cognitive domains and global MRI brain structural measures (r range .008 to .269, p < .05). Regions implicated by vertex-wise regional cortical volume included a widespread number of medial and lateral areas of the frontal, temporal and parietal lobes. However, at both global and regional level, much of the domain-MRI associations were shared (statistically accounted for by g). Removing g-related variance from cognitive domains attenuated association magnitudes with global brain MRI measures by 27.9–59.7% (M = 46.2%), with only processing speed retaining all significant associations. At the regional cortical level, g appeared to account for the majority (range 22.1–88.4%; M = 52.8% across cognitive domains) of regional domain-specific associations. Crystallised and memory domains had almost no unique cortical correlates, whereas processing speed and visuospatial ability retained limited cortical volumetric associations. The greatest spatial overlaps across cognitive domains (as denoted by g) were present in the medial and lateral temporal, lateral parietal and lateral frontal areas.

IMG-20. IDENTIFICATION OF PRE-OPERATIVE IMAGING FEATURES ASSOCIATED WITH COGNITIVE IMPAIRMENT IN CHILDREN WITH BRAIN TUMOURS USING A LANGUAGE MODELLING SYSTEM COMBINED WITH MACHINE LEARNING ANALYSIS

Abstract BACKGROUND Cognitive impairments caused by paediatric brain tumours negatively impact future quality-of-life. Impairments of processing speed and working memory are important contributors to challenges these children encounter in education. Inconsistent image acquisition and poor imaging quality can restrict advanced radiomic analysis in historical datasets. We developed and refined a language modelling human image-analysis support system, passing data to specific machine learning techniques that can utilise datasets with many data points in a limited population. METHODS Medical records of children treated for brain tumours with surgery and radiotherapy in Manchester between 2000-2020 were reviewed with imaging accessible from 2006-2020. Pre-operative MRI scans were reviewed for 52 patients along with their most recent processing speed and/or working memory test scores. 274 radiological variables analysing tumour features and damage to brain structures were reported per patient using a standardised reporting tool. Univariate analysis was performed using Linear Regression with time-to-test analysed as a covariate. Multivariate analysis used Elastic Net Regression. RESULTS Univariate analysis revealed risk factors for slower processing speed included midline shift, tumour in the corpus callosum, right temporal periventricular white matter oedema, diffusion changes in the left frontal lobe or amygdala and FLAIR changes in the left caudate nucleus (p&amp;lt;0.005). Risk factors for impaired working memory included midline shift, cortical tumour location, left periventricular white matter oedema and diffusion or FLAIR changes in the left frontal lobe (p&amp;lt;0.005). Despite the limited population size and review of only pre-operative features, multivariate analysis produced multiple predictive models able to outperform chance when predicting processing speed and working memory outcomes. CONCLUSIONS This study provides evidence that a radiological language modelling approach can be utilised for outcome prediction. It identified imaging features predictive of cognitive impairments prior to surgery and radiotherapy. Further work is needed to assess inter-observer variability and validate these findings.