Investigating Microstructural Changes in White Matter in Multiple Sclerosis:A Systematic Review and Meta-Analysis of Neurite Orientation Dispersion and Density Imaging

Multiple sclerosis (MS) is characterised by widespread damage of the central nervous system that includes alterations in normal-appearing white matter (NAWM) and demyelinating white matter (WM) lesions. Neurite orientation dispersion and density imaging (NODDI) has been proposed to provide a precise characterisation of WM microstructures. NODDI maps can be calculated for the Neurite Density Index (NDI) and Orientation Dispersion Index (ODI), which estimate orientation dispersion and neurite density. Although NODDI has not been widely applied in MS, this technique is promising in investigating the complexity of MS pathology, as it is more specific than diffusion tensor imaging (DTI) in capturing microstructural alterations. We conducted a meta-analysis of studies using NODDI metrics to assess brain microstructural changes and neuroaxonal pathology in WM lesions and NAWM in patients with MS. Three reviewers conducted a literature search of four electronic databases. We performed a random-effect meta-analysis and the extent of between-study heterogeneity was assessed with the I2 statistic. Funnel plots and Egger’s tests were used to assess publication bias. We identified seven studies analysing 374 participants (202 MS and 172 controls). The NDI in WM lesions and NAWM were significantly reduced compared to healthy WM and the standardised mean difference of each was −3.08 (95%CI −4.22 to (−1.95), p ≤ 0.00001, I2 = 88%) and −0.70 (95%CI −0.99 to (−0.40), p ≤ 0.00001, I2 = 35%), respectively. There was no statistically significant difference of the ODI in MS WM lesions and NAWM compared to healthy controls. This systematic review and meta-analysis confirmed that the NDI is significantly reduced in MS lesions and NAWM than in WM from healthy participants, corresponding to reduced intracellular signal fraction, which may reflect underlying damage or loss of neurites.</p

Investigating Microstructural Changes in White Matter in Multiple Sclerosis:A Systematic Review and Meta-Analysis of Neurite Orientation Dispersion and Density Imaging

Multiple sclerosis (MS) is characterised by widespread damage of the central nervous system that includes alterations in normal-appearing white matter (NAWM) and demyelinating white matter (WM) lesions. Neurite orientation dispersion and density imaging (NODDI) has been proposed to provide a precise characterisation of WM microstructures. NODDI maps can be calculated for the Neurite Density Index (NDI) and Orientation Dispersion Index (ODI), which estimate orientation dispersion and neurite density. Although NODDI has not been widely applied in MS, this technique is promising in investigating the complexity of MS pathology, as it is more specific than diffusion tensor imaging (DTI) in capturing microstructural alterations. We conducted a meta-analysis of studies using NODDI metrics to assess brain microstructural changes and neuroaxonal pathology in WM lesions and NAWM in patients with MS. Three reviewers conducted a literature search of four electronic databases. We performed a random-effect meta-analysis and the extent of between-study heterogeneity was assessed with the I2 statistic. Funnel plots and Egger’s tests were used to assess publication bias. We identified seven studies analysing 374 participants (202 MS and 172 controls). The NDI in WM lesions and NAWM were significantly reduced compared to healthy WM and the standardised mean difference of each was −3.08 (95%CI −4.22 to (−1.95), p ≤ 0.00001, I2 = 88%) and −0.70 (95%CI −0.99 to (−0.40), p ≤ 0.00001, I2 = 35%), respectively. There was no statistically significant difference of the ODI in MS WM lesions and NAWM compared to healthy controls. This systematic review and meta-analysis confirmed that the NDI is significantly reduced in MS lesions and NAWM than in WM from healthy participants, corresponding to reduced intracellular signal fraction, which may reflect underlying damage or loss of neurites.</p

Quantitative CT radiomics-based models for prediction of haematoma expansion and poor functional outcome in primary intracerebral haemorrhage

Objectives: To test radiomics-based features extracted from noncontrast CT of patients with spontaneous intracerebral haemorrhage for prediction of haematoma expansion and poor functional outcome and compare them with radiological signs and clinical factors.Materials and methods: Seven hundred fifty-four radiomics-based features were extracted from 1732 scans derived from the TICH-2 multicentre clinical trial. Features were harmonised and a correlation-based feature selection was applied. Different elastic-net parameterisations were tested to assess the predictive performance of the selected radiomics-based features using grid optimisation. For comparison, the same procedure was run using radiological signs and clinical factors separately. Models trained with radiomics-based features combined with radiological signs or clinical factors were tested. Predictive performance was evaluated using the area under the receiver operating characteristic curve (AUC) score.Results: The optimal radiomics-based model showed an AUC of 0.693 for haematoma expansion and an AUC of 0.783 for poor functional outcome. Models with radiological signs alone yielded substantial reductions in sensitivity. Combining radiomics-based features and radiological signs did not provide any improvement over radiomics-based features alone. Models with clinical factors had similar performance compared to using radiomics-based features, albeit with low sensitivity for haematoma expansion. Performance of radiomics-based features was boosted by incorporating clinical factors, with time from onset to scan and age being the most important contributors for haematoma expansion and poor functional outcome prediction, respectively.Conclusion: Radiomics-based features perform better than radiological signs and similarly to clinical factors on the prediction of haematoma expansion and poor functional outcome. Moreover, combining radiomics-based features with clinical factors improves their performance.Key points: Linear models based on CT radiomics-based features perform better than radiological signs on the prediction of haematoma expansion and poor functional outcome in the context of intracerebral haemorrhage. Linear models based on CT radiomics-based features perform similarly to clinical factors known to be good predictors. However, combining these clinical factors with radiomics-based features increases their predictive performance

Measures of intracranial compartments in acute intracerebral haemorrhage: data from the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke-2 Trial (RIGHT-2)

Background and purpose: Intracerebral haemorrhage volume (ICHV) is prognostically important but does not account for intracranial volume (ICV) and cerebral parenchymal volume (CPV). We assessed measures of intracranial compartments in acute ICH using computerised tomography scans and whether ICHV/ICV and ICHV/CPV predict functional outcomes. We also assessed if cistern effacement, midline shift, old infarcts, leukoaraiosis and brain atrophy were associated with outcomes. Methods: Data from 133 participants from the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke-2 Trial trial were analysed. Measures included ICHV (using ABC/2) and ICV (XYZ/2) (by independent observers); ICHV, ICV and CPV (semiautomated segmentation, SAS); atrophy (intercaudate distance, ICD, Sylvian fissure ratio, SFR); midline shift; leukoaraiosis and cistern effacement (visual assessment). The effects of these measures on death at day 4 and poor functional outcome at day 90 (modified Rankin scale, mRS of >3) was assessed. Results: ICV was significantly different between XYZ and SAS: mean (SD) of 1357 (219) vs 1420 (196), mean difference (MD) 62 mL (p<0.001). There was no significant difference in ICHV between ABC/2 and SAS. There was very good agreement for ICV measured by SAS, CPV, ICD, SFR, leukoaraiosis and cistern score (all interclass correlations, n=10: interobserver 0.72-0.99, intraobserver 0.73-1.00). ICHV/ICV and ICHV/CPV were significantly associated with mRS at day 90, death at day 4 and acute neurological deterioration (all p<0.05), similar to ICHV. Midline shift and cistern effacement at baseline were associated with poor functional outcome but old infarcts, leukoaraiosis and brain atrophy were not. Conclusions: Intracranial compartment measures and visual estimates are reproducible. ICHV adjusted for ICH and CPV could be useful to prognosticate in acute stroke. The presence of midline shift and cistern effacement may predict outcome but the mechanisms need validation in larger studies

Automated segmentation of haematoma and perihaematomal oedema in MRI of acute spontaneous intracerebral haemorrhage

BackgroundSpontaneous intracerebral haemorrhage (SICH) is a common condition with high morbidity and mortality. Segmentation of haematoma and perihaematoma oedema on medical images provides quantitative outcome measures for clinical trials and may provide important markers of prognosis in people with SICH.MethodsWe take advantage of improved contrast seen on magnetic resonance (MR) images of patients with acute and early subacute SICH and introduce an automated algorithm for haematoma and oedema segmentation from these images. To our knowledge, there is no previously proposed segmentation technique for SICH that utilises MR images directly. The method is based on shape and intensity analysis for haematoma segmentation and voxel-wise dynamic thresholding of hyper-intensities for oedema segmentation.ResultsUsing Dice scores to measure segmentation overlaps between labellings yielded by the proposed algorithm and five different expert raters on 18 patients, we observe that our technique achieves overlap scores that are very similar to those obtained by pairwise expert rater comparison. A further comparison between the proposed method and a state-of-the-art Deep Learning segmentation on a separate set of 32 manually annotated subjects confirms the proposed method can achieve comparable results with very mild computational burden and in a completely training-free and unsupervised way.ConclusionOur technique can be a computationally light and effective way to automatically delineate haematoma and oedema extent directly from MR images. Thus, with increasing use of MR images clinically after intracerebral haemorrhage this technique has the potential to inform clinical practice in the future

Multiparametric cerebellar imaging and clinical phenotype in childhood ataxia telangiectasia

BackgroundAtaxia Telangiectasia (A-T) is an inherited multisystem disorder with cerebellar neurodegeneration. The relationships between imaging metrics of cerebellar health and neurological function across childhood in A-T are unknown, but may be important for determining timing and impact of therapeutic interventions.PurposeTo test the hypothesis that abnormalities of cerebellar structure, physiology and cellular health occur in childhood A-T and correlate with neurological disability, we performed multiparametric cerebellar MRI and establish associations with disease status in childhood A-T.MethodsProspective cross-sectional observational study. 22 young people (9 females / 13 males, age 6.6-17.8 years) with A-T and 24 matched healthy controls underwent 3-Tesla MRI with volumetric, diffusion and proton spectroscopic acquisitions. Participants with A-T underwent structured neurological assessment, and expression / activity of ataxia-telangiectasia mutated (ATM) kinase were recorded.ResultsAtaxia-telangiectasia participants had cerebellar volume loss (fractional total cerebellar volume: 5.3% vs 8.7%, P less than 0.0005, fractional 4th ventricular volumes: 0.19% vs 0.13%, P less than 0.0005), that progressed with age (fractional cerebellar volumes, r=-0.66, P=0.001), different from the control group (t=-4.88, P less than 0.0005). The relationship between cerebellar volume and age was similar for A-T participants with absent ATM kinase production and those producing non-functioning ATM kinase. Markers of cerebellar white matter injury were elevated in ataxia-telangiectasia vs controls (apparent diffusion coefficient: 0.89×10−3mm2s−1 vs 0.69×10−3mm2s−1, p less than 0.0005) and correlated (age-corrected) with neurometabolite ratios indicating impaired neuronal viability (N-acetylaspartate:creatine r=-0.70, P less than 0.001); gliosis (inositol:creatine r=0.50, P=0.018; combined glutamine/glutamate:creatine r=-0.55, P=0.008) and increased myelin turnover (choline:creatine r=0.68, P less than 0.001). Fractional 4th ventricular volume was the only variable retained in the regression model predicting neurological function (adjusted r2=0.29, P=0.015).ConclusionsQuantitative MRI demonstrates cerebellar abnormalities in children with A-T, providing non-invasive measures of progressive cerebellar injury and markers reflecting neurological status. These MRI metrics may be of value in determining timing and impact of interventions aimed at altering the natural history of A-T

White Matter Microstructural Alteration in Type 2 Diabetes: A Combined UK Biobank Study of Diffusion Tensor Imaging and Neurite Orientation Dispersion and Density Imaging

Background: Type 2 diabetes mellitus impacts the brain microstructural environment. Diffusion tensor imaging (DTI) has been widely used to characterize white matter microstructural abnormalities in type 2 diabetes but fails to fully characterise disease effects on complex white matter tracts. Neurite orientation dispersion and density imaging (NODDI) has been proposed as an alternative to DTI with higher specificity to characterize white matter microstructures. Although NODDI has not been widely applied in diabetes, this biophysical model has the potential to investigate microstructural changes in white matter pathology.Aims and objectives: (1) To investigate brain white matter alterations in people with type 2 diabetes using DTI and NODDI; (2) To assess the association between white matter changes in type 2 diabetes with disease duration and diabetes control as reflected by glycated haemoglobin (HbA1c) levels.Methods: We examined white matter microstructure in 48 white matter tracts using data from the UK Biobank in 3,338 participants with type 2 diabetes (36% women, mean age 66 years) and 30,329 participants without type 2 diabetes (53% women, mean age 64 years). The participants had undergone 3.0T multiparametric brain imaging, including T1 weighted imaging and diffusion imaging for DTI and NODDI. Region of interest analysis of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), orientation dispersion index (ODI), intracellular volume fraction (ICVF), and isotropic water fraction (IsoVF) were conducted to assess white matter abnormalities. A general linear model was applied to evaluate intergroup white matter differences and their association with the metabolic profile.Result: Reduced FA and ICVF and increased MD, AD, RD, ODI, and IsoVF values were observed in participants with type 2 diabetes compared to non-type 2 diabetes participants (P<0.05). Reduced FA and ICVF in most white matter tracts were associated with longer disease duration and higher levels of HbA1c (0< r ≤0.2, P<0.05). Increased MD, AD, RD, ODI and IsoVF also correlated with longer disease duration and higher HbA1c (0< r ≤0.2, P<0.05).Discussion: NODDI detected microstructural changes in brain white matter in participants with type 2 diabetes. The revealed abnormalities are proxies for lower neurite density and loss of fibre orientation coherence, which correlated with longer disease duration and an index of poorly controlled blood sugar. NODDI contributed to DTI in capturing white matter differences in participants with type 2 diabetes, suggesting the feasibility of NODDI in detecting white matter alterations in type 2 diabetes.Conclusion: Type 2 diabetes can cause white matter microstructural abnormalities that have associations with glucose control. The NODDI diffusion model allows the characterisation of white matter neuroaxonal pathology in type 2 diabetes, giving biophysical information for understanding the impact of type 2 diabetes on brain microstructure

Tranexamic Acid for Prevention of Hematoma Expansion in Intracerebral Hemorrhage Patients With or Without Spot Sign

Background and Purpose:The computed tomography angiography or contrast-enhanced computed tomography based spot sign has been proposed as a biomarker for identifying on-going hematoma expansion in patients with acute intracerebral hemorrhage. We investigated, if spot-sign positive participants benefit more from tranexamic acid versus placebo as compared to spot-sign negative participants.Methods:TICH-2 trial (Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage) was a randomized, placebo-controlled clinical trial recruiting acutely hospitalized participants with intracerebral hemorrhage within 8 hours after symptom onset. Local investigators randomized participants to 2 grams of intravenous tranexamic acid or matching placebo (1:1). All participants underwent computed tomography scan on admission and on day 2 (24±12 hours) after randomization. In this sub group analysis, we included all participants from the main trial population with imaging allowing adjudication of spot sign status.Results:Of the 2325 TICH-2 participants, 254 (10.9%) had imaging allowing for spot-sign adjudication. Of these participants, 64 (25.2%) were spot-sign positive. Median (interquartile range) time from symptom onset to administration of the intervention was 225.0 (169.0 to 310.0) minutes. The adjusted percent difference in absolute day-2 hematoma volume between participants allocated to tranexamic versus placebo was 3.7% (95% CI, −12.8% to 23.4%) for spot-sign positive and 1.7% (95% CI, −8.4% to 12.8%) for spot-sign negative participants (Pheterogenity=0.85). No difference was observed in significant hematoma progression (dichotomous composite outcome) between participants allocated to tranexamic versus placebo among spot-sign positive (odds ratio, 0.85 [95% CI, 0.29 to 2.46]) and negative (odds ratio, 0.77 [95% CI, 0.41 to 1.45]) participants (Pheterogenity=0.88).Conclusions:Data from the TICH-2 trial do not support that admission spot sign status modifies the treatment effect of tranexamic acid versus placebo in patients with acute intracerebral hemorrhage. The results might have been affected by low statistical power as well as treatment delay.REGISTRATION:URL: http://www.controlled-trials.com; Unique identifier: ISRCTN93732214

Congenital monocular elevation deficiency associated with a novel TUBB3 gene variant

Background The genetic basis of monocular elevation deficiency (MED) is unclear. It has previously been considered to arise due to a supranuclear abnormality.Methods Two brothers with MED were referred to Leicester Royal Infirmary, UK from the local opticians. Their father had bilateral ptosis and was unable to elevate both eyes, consistent with the diagnosis of congenital fibrosis of extraocular muscles (CFEOM). Candidate sequencing was performed in all family members.Results Both affected siblings (aged 7 and 12 years) were unable to elevate the right eye. Their father had bilateral ptosis, left esotropia and bilateral limitation of elevation. Chin up head posture was present in the older sibling and the father. Bell’s phenomenon and vertical rotational vestibulo-ocular reflex were absent in the right eye for both children. Mild bilateral facial nerve palsy was present in the older sibling and the father. Both siblings had slight difficulty with tandem gait. MRI revealed hypoplastic oculomotor nerve. Left anterior insular focal cortical dysplasia was seen in the older sibling. Sequencing of TUBB3 revealed a novel heterozygous variant (c.1263G>C, p.E421D) segregating with the phenotype. This residue is in the C-terminal H12 α-helix of β-tubulin and is one of three putative kinesin binding sites.Conclusion We show that familial MED can arise from a TUBB3 variant and could be considered a limited form of CFEOM. Neurological features such as mild facial palsy and cortical malformations can be present in patients with MED. Thus, in individuals with congenital MED, consideration may be made for TUBB3 mutation screening