The ageing central nervous system in multiple sclerosis: the imaging perspective.

The interaction between ageing and multiple sclerosis is complex and carries significant implications for patient care. Managing multiple sclerosis effectively requires an understanding of how ageing and multiple sclerosis impact brain structure and function. Ageing inherently induces brain changes, including reduced plasticity, diminished grey matter volume, and ischaemic lesion accumulation. When combined with multiple sclerosis pathology, these age-related alterations may worsen clinical disability. Ageing may also influence the response of multiple sclerosis patients to therapies and/or their side-effects, highlighting the importance of adjusted treatment considerations. Magnetic resonance MRI is highly sensitive to age- and multiple sclerosis-related processes. Accordingly, MRI can provide insights into the relationship between ageing and multiple sclerosis, enabling a better understanding of their pathophysiological interplay and informing treatment selection. This review summarizes current knowledge on the immuno-pathological and MRI aspects of ageing in the central nervous system in the context of multiple sclerosis. Starting from immunosenescence, ageing-related pathological mechanisms, and specific features like enlarged Virchow-Robin spaces, this review then explores clinical aspects, including late-onset multiple sclerosis, the influence of age on diagnostic criteria, and comorbidity effects on imaging features. The role of MRI in understanding neurodegeneration, iron dynamics, and myelin changes influenced by ageing and how MRI can contribute to defining treatment effects in ageing multiple sclerosis patients, are also discussed.

Development of an initial training and evaluation programme for manual lower limb muscle MRI segmentation.

BACKGROUND: Magnetic resonance imaging (MRI) quantification of intramuscular fat accumulation is a responsive biomarker in neuromuscular diseases. Despite emergence of automated methods, manual muscle segmentation remains an essential foundation. We aimed to develop a training programme for new observers to demonstrate competence in lower limb muscle segmentation and establish reliability benchmarks for future human observers and machine learning segmentation packages. METHODS: The learning phase of the training programme comprised a training manual, direct instruction, and eight lower limb MRI scans with reference standard large and small regions of interest (ROIs). The assessment phase used test-retest scans from two patients and two healthy controls. Interscan and interobserver reliability metrics were calculated to identify underperforming outliers and to determine competency benchmarks. RESULTS: Three experienced observers undertook the assessment phase, whilst eight new observers completed the full training programme. Two of the new observers were identified as underperforming outliers, relating to variation in size or consistency of segmentations; six had interscan and interobserver reliability equivalent to those of experienced observers. The calculated benchmark for the Sørensen-Dice similarity coefficient between observers was greater than 0.87 and 0.92 for individual thigh and calf muscles, respectively. Interscan and interobserver reliability were significantly higher for large than small ROIs (all p < 0.001). CONCLUSIONS: We developed, implemented, and analysed the first formal training programme for manual lower limb muscle segmentation. Large ROI showed superior reliability to small ROI for fat fraction assessment. RELEVANCE STATEMENT: Observers competent in lower limb muscle segmentation are critical to application of quantitative muscle MRI biomarkers in neuromuscular diseases. This study has established competency benchmarks for future human observers or automated segmentation methods. KEY POINTS: • Observers competent in muscle segmentation are critical for quantitative muscle MRI biomarkers. • A training programme for muscle segmentation was undertaken by eight new observers. • We established competency benchmarks for future human observers or automated segmentation methods.

Lower limb muscle MRI fat fraction is a responsive outcome measure in CMT X1, 1B and 2A.

OBJECTIVE: With potential therapies for many forms of Charcot-Marie-Tooth disease (CMT), responsive outcome measures are urgently needed for clinical trials. Quantitative lower limb MRI demonstrated progressive calf intramuscular fat accumulation in the commonest form, CMT1A with large responsiveness. In this study, we evaluated the responsiveness and validity in the three other common forms, due to variants in GJB1 (CMTX1), MPZ (CMT1B) and MFN2 (CMT2A). METHODS: 22 CMTX1, 21 CMT1B and 21 CMT2A patients and matched controls were assessed at a 1-year interval. Intramuscular fat fraction (FF) was evaluated using three-point Dixon MRI at thigh and calf level along with clinical measures including CMT examination score, clinical strength assessment, CMT-HI and plasma neurofilament light chain. RESULTS: All patient groups had elevated muscle fat fraction at thigh and calf levels, with highest thigh FF and atrophy in CMT2A. There was moderate correlation between calf muscle FF and clinical measures (CMTESv2 rho = 0.405; p = 0.001, ankle MRC strength rho = -0.481; p < 0.001). Significant annualised progression in calf muscle FF was seen in all patient groups (CMTX1 2.0 ± 2.0%, p < 0.001, CMT1B 1.6 ± 2.1% p = 0.004 and CMT2A 1.6 ± 2.1% p = 0.002). Greatest increase was seen in patients with 10-70% FF at baseline (calf 2.7 ± 2.3%, p < 0.0001 and thigh 1.7 ± 2.1%, p = 0.01). INTERPRETATION: Our results confirm that calf muscle FF is highly responsive over 12 months in three additional common forms of CMT which together with CMT1A account for 90% of genetically confirmed cases. Calf muscle MRI FF should be a valuable outcome measure in upcoming CMT clinical trials.

Associations of renal function with cerebral small vessel disease and functional outcome in acute intracerebral haemorrhage: A hospital-based prospective cohort study.

BACKGROUND: Intracerebral haemorrhage (ICH) is a severe clinical consequence of cerebral small vessel disease (SVD), but associations between renal impairment and SVD in patients with ICH have not been fully characterised. METHODS: Using data from the CROMIS-2 ICH observational study, we compared SVD neuroimaging markers and total burden (score 0-3) identified using CT brain imaging in patients with and without renal impairment (estimated glomerular filtration rate, eGFR<60). We assessed functional outcome at 6-month follow-up using the modified Rankin scale. RESULTS: 1027 participants were included (mean age 72.8, 57.1% male); 274 with and 753 without renal impairment. 18.7% of the eGFR<60 group had moderate-to-severe SVD burden (score 2-3), compared with 14.0% of those with eGFR>60 (p = 0.039). SVD burden was associated with renal impairment after adjusting for hypertension (OR 1.36, 95% CI 1.04-1.77, p = 0.023), but not after adjusting for age. Cerebral atrophy was more prevalent in patients with eGFR<60 (81.2% vs. 72.0%, p = 0.002), as were WMH (45.6% vs. 36.6%, p = 0.026). Neither was associated with renal function after adjusting for age and vascular risk factors. Renal impairment was associated with functional outcome (OR 0.65, 95% CI 0.47-0.89, p = 0.007), but not after adjusting for age, pre-morbid function and comorbidities (OR 0.95, 95% CI 0.65-1.38, p = 0.774). CONCLUSION: In acute ICH, renal impairment is associated with a higher cerebral SVD burden independent of hypertension, but not age. Reduced eGFR is associated with worse functional outcome, but not independent of age and comorbidities. Since CT has limited sensitivity to detect SVD severity and distribution, further studies including MRI are needed.

Evidence of nerve hypertrophy in patients with inclusion body myositis on lower limb MRI.

INTRODUCTION/AIMS: Inclusion body myositis (IBM) is a myopathic condition but in some patients has been associated with an axonal length-dependent polyneuropathy. In this study, we quantified the cross-sectional area of the sciatic and tibial nerves in patients with IBM comparing with Charcot-Marie-Tooth disease type 1A (CMT1A) and healthy controls using magnetic resonance neurography (MRN). METHODS: MRN of the sciatic and tibial nerves was performed at 3T using MPRAGE and Dixon acquisitions. Nerve cross-sectional area (CSA) was measured at the mid-thigh and upper third calf regions by an observer blinded to the diagnosis. Correlations were performed between these measurements and clinical data. RESULTS: A total of 20 patients with IBM, 20 CMT1A and 29 healthy controls (age- and sex-matched) were studied. Sciatic nerve CSA was significantly enlarged in patients with IBM and CMT1A compared to controls (sciatic nerve mean CSA 62.3 ± 22.9 mm2 (IBM) vs. 35.5 ± 9.9 mm2 (controls), p < 0.001; and 96.9 ± 35.5 mm2 (CMT1A) vs. 35.5 ± 9.9 mm2 (controls); p < 0.001). Tibial nerve CSA was also enlarged in IBM and CMT1 patients compared to controls. DISCUSSION: MRN reveals significant hypertrophy of the sciatic and tibial nerves in patients with IBM and CMT1A compared to controls. Further studies are needed to correlate with neurophysiological measures and assess whether this finding is useful diagnostically.

APOE and Cerebral Small Vessel Disease Markers in Patients With Intracerebral Hemorrhage.

BACKGROUND AND OBJECTIVE: We investigated the associations between the APOE genotype, intracerebral hemorrhage (ICH), and neuroimaging markers of cerebral amyloid angiopathy (CAA). METHODS: We included patients from a prospective, multicenter UK observational cohort study of patients with ICH and representative UK population controls. First, we assessed the association of the APOE genotype with ICH (compared with controls without ICH). Second, among patients with ICH, we assessed the association of APOE status with the hematoma location (lobar or deep) and brain CT markers of CAA (finger-like projections [FLP] and subarachnoid extension [SAE]). RESULTS: We included 907 patients with ICH and 2,636 controls. The mean age was 73.2 (12.4 SD) years for ICH cases vs 69.6 (0.2 SD) for population controls; 50.3% of cases and 42.1% of controls were female. Compared with controls, any APOE ε2 allele was associated with all ICH (lobar and nonlobar) and lobar ICH on its own in the dominant model (OR 1.38, 95% CI 1.13-1.7, p = 0.002 and OR 1.50, 95% CI 1.1-2.04, p = 0.01, respectively) but not deep ICH in an age-adjusted analyses (OR 1.26, 95% CI 0.97-1.63, p = 0.08). In the cases-only analysis, the APOE ε4 allele was associated with lobar compared with deep ICH in an age-adjusted analyses (OR 1.56, 95% CI 1.1-2.2, p = 0.01). When assessing CAA markers, APOE alleles were independently associated with FLP (ε4: OR 1.74, 95% CI 1.04-2.93, p = 0.04 and ε2/ε4: 2.56, 95% CI 0.99-6.61, p = 0.05). We did not find an association between APOE alleles and SAE. DISCUSSION: We confirmed associations between APOE alleles and ICH including lobar ICH. Our analysis shows selective associations between APOE ε2 and ε4 alleles with FLP, a CT marker of CAA. Our findings suggest that different APOE alleles might have diverging influences on individual neuroimaging biomarkers of CAA-associated ICH.

Longitudinal Changes in MRI Muscle Morphometry and Composition in People With Inclusion Body Myositis.

BACKGROUND AND OBJECTIVES: Limited data suggest that quantitative MRI (qMRI) measures have potential to be used as trial outcome measures in sporadic inclusion body myositis (sIBM) and as a noninvasive assessment tool to study sIBM muscle pathologic processes. Our aim was to evaluate changes in muscle structure and composition using a comprehensive multiparameter set of qMRI measures and to assess construct validity and responsiveness of qMRI measures in people with sIBM. METHODS: This was a prospective observational cohort study with assessments at baseline (n = 30) and 1 year (n = 26). qMRI assessments include thigh muscle volume (TMV), inter/intramuscular adipose tissue (IMAT), muscle fat fraction (FF), muscle inflammation (T2 relaxation time), IMAT from T2* relaxation (T2*-IMAT), intermuscular connective tissue from T2* relaxation (T2*-IMCT), and muscle macromolecular structure from the magnetization transfer ratio (MTR). Physical performance assessments include sIBM Physical Functioning Assessment (sIFA), 6-minute walk distance, and quantitative muscle testing of the quadriceps. Correlations were assessed using the Spearman correlation coefficient. Responsiveness was assessed using the standardized response mean (SRM). RESULTS: After 1 year, we observed a reduction in TMV (6.8%, p < 0.001) and muscle T2 (6.7%, p = 0.035), an increase in IMAT (9.7%, p < 0.001), FF (11.2%, p = 0.030), connective tissue (22%, p = 0.995), and T2*-IMAT (24%, p < 0.001), and alteration in muscle macromolecular structure (ΔMTR = -26%, p = 0.002). A decrease in muscle T2 correlated with an increase in T2*-IMAT (r = -0.47, p = 0.008). Deposition of connective tissue and IMAT correlated with deterioration in sIFA (r = 0.38, p = 0.032; r = 0.34, p = 0.048; respectively), whereas a decrease in TMV correlated with a decrease in quantitative muscle testing (r = 0.36, p = 0.035). The most responsive qMRI measures were T2*-IMAT (SRM = 1.50), TMV (SRM = -1.23), IMAT (SRM = 1.20), MTR (SRM = -0.83), and T2 relaxation time (SRM = -0.65). DISCUSSION: Progressive deterioration in muscle quality measured by qMRI is associated with a decline in physical performance. Inflammation may play a role in triggering fat infiltration into muscle. qMRI provides valid and responsive measures that might prove valuable in sIBM experimental trials and assessment of muscle pathologic processes. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that qMRI outcome measures are associated with physical performance measures in patients with sIBM.

The Effect of Right Temporal Lobe Gliomas on Left and Right Hemisphere Neural Processing During Speech Perception and Production Tasks.

Using fMRI, we investigated how right temporal lobe gliomas affecting the posterior superior temporal sulcus alter neural processing observed during speech perception and production tasks. Behavioural language testing showed that three pre-operative neurosurgical patients with grade 2, grade 3 or grade 4 tumours had the same pattern of mild language impairment in the domains of object naming and written word comprehension. When matching heard words for semantic relatedness (a speech perception task), these patients showed under-activation in the tumour infiltrated right superior temporal lobe compared to 61 neurotypical participants and 16 patients with tumours that preserved the right postero-superior temporal lobe, with enhanced activation within the (tumour-free) contralateral left superior temporal lobe. In contrast, when correctly naming objects (a speech production task), the patients with right postero-superior temporal lobe tumours showed higher activation than both control groups in the same right postero-superior temporal lobe region that was under-activated during auditory semantic matching. The task dependent pattern of under-activation during the auditory speech task and over-activation during object naming was also observed in eight stroke patients with right hemisphere infarcts that affected the right postero-superior temporal lobe compared to eight stroke patients with right hemisphere infarcts that spared it. These task-specific and site-specific cross-pathology effects highlight the importance of the right temporal lobe for language processing and motivate further study of how right temporal lobe tumours affect language performance and neural reorganisation. These findings may have important implications for surgical management of these patients, as knowledge of the regions showing functional reorganisation may help to avoid their inadvertent damage during neurosurgery.

Effects of Dimethyl Fumarate on Brain Atrophy in Relapsing-Remitting Multiple Sclerosis: Pooled Analysis Phase 3 DEFINE and CONFIRM Studies.

Objective: In the pivotal DEFINE and CONFIRM trials for dimethyl fumarate (DMF), patterns of brain volume changes were different, potentially due to low sample sizes and because MRIs were analyzed at two different reading centers. We evaluated effects of DMF on brain volume change in patients with multiple sclerosis (MS) through reanalysis of pooled images from DEFINE/CONFIRM trials in one reading center. Methods: MRIs from DEFINE/CONFIRM at weeks 0, 24, 48, and 96 from patients randomized to twice-daily DMF or placebo (PBO) were reanalyzed at the Cleveland Clinic to measure brain parenchymal fraction (BPF). To account for pseudoatrophy, brain volume estimates were re-baselined to calculate changes for weeks 48-96. Results: Across studies, 301 and 314 patients receiving DMF and PBO, respectively, had analyzable MRIs. In weeks 0-48, mean ± SE percentage change in BPF was -0.44 ± 0.04 vs. -0.34 ± 0.04% in DMF vs. PBO, respectively, whereas in weeks 48-96, mean ± SE percentage change in BPF was -0.27 ± 0.03 vs. -0.41 ± 0.04% in DMF vs. PBO, respectively. The mixed-effect model for repeated measures showed similar results: in weeks 48-96, estimated change (95% confidence interval) in BPF was -0.0021 (-0.0027, -0.0016) for DMF vs. -0.0033 (-0.0039, -0.0028) for PBO (35.9% reduction; p = 0.0025). Conclusions: The lower rate of whole brain volume loss with DMF in this pooled BPF analysis in the second year vs. PBO is consistent with its effects on relapses, disability, and MRI lesions. Brain volume changes in the first year may be explained by pseudoatrophy effects also described in other MS clinical trials.

Muscle "islands": An MRI signature distinguishing neurogenic from myopathic causes of early onset distal weakness.

Muscle MRI has an increasing role in diagnosis of inherited neuromuscular diseases, but no features are known which reliably differentiate myopathic and neurogenic conditions. Using patients presenting with early onset distal weakness, we aimed to identify an MRI signature to distinguish myopathic and neurogenic conditions. We identified lower limb MRI scans from patients with either genetically (n = 24) or clinically (n = 13) confirmed diagnoses of childhood onset distal myopathy or distal spinal muscular atrophy. An initial exploratory phase reviewed 11 scans from genetically confirmed patients identifying a single potential discriminatory marker concerning the pattern of fat replacement within muscle, coined "islands". This pattern comprised small areas of muscle tissue with normal signal intensity completely surrounded by areas with similar intensity to subcutaneous fat. In the subsequent validation phase, islands correctly classified scans from all 12 remaining genetically confirmed patients, and 12/13 clinically classified patients. In the genetically confirmed patients MRI classification of neurogenic/myopathic aetiology had 100% accuracy (24/24) compared with 65% accuracy (15/23) for EMG, and 79% accuracy (15/19) for muscle biopsy. Future studies are needed in other clinical contexts, however the presence of islands appears to highly suggestive of a neurogenic aetiology in patients presenting with early onset distal motor weakness.

Small vessel disease burden and intracerebral haemorrhage in patients taking oral anticoagulants.

OBJECTIVE: We investigated the contribution of small vessel disease (SVD) to anticoagulant-associated intracerebral haemorrhage (ICH). METHODS: Clinical Relevance of Microbleeds in Stroke-2 comprised two independent multicentre observation studies: first, a cross-sectional study of patients with ICH; and second, a prospective study of patients taking anticoagulants for atrial fibrillation (AF) after cerebral ischaemia. In patients with ICH, we compared SVD markers on CT and MRI according to prior anticoagulant therapy. In patients with AF and cerebral ischaemia treated with anticoagulants, we compared the rates of ICH and ischaemic stroke according to SVD burden score during 2 years follow-up. RESULTS: We included 1030 patients with ICH (421 on anticoagulants), and 1447 patients with AF and cerebral ischaemia. Medium-to-high severity SVD was more prevalent in patients with anticoagulant-associated ICH (CT 56.1%, MRI 78.7%) than in those without prior anticoagulant therapy (CT 43.5%, p<0.001; MRI 64.5%, p=0.072). Leukoaraiosis and atrophy were more frequent and severe in ICH associated with prior anticoagulation. In the cerebral ischaemia cohort (779 with SVD), during 3366 patient-years of follow-up the rate of ICH was 0.56%/year (IQR 0.27-1.03) in patients with SVD, and 0.06%/year (IQR 0.00-0.35) in those without (p=0.001); ICH was independently associated with severity of SVD (HR 5.0, 95% CI 1.9 to 12.2,p=0.001), and was predicted by models including SVD (c-index 0.75, 95% CI 0.63 to 0.85). CONCLUSIONS: Medium-to-high severity SVD is associated with ICH occurring on anticoagulants, and independently predicts ICH in patients with AF taking anticoagulants; its absence identifies patients at low risk of ICH. Findings from these two complementary studies suggest that SVD is a contributory factor in ICH in patients taking anticoagulants and suggest that anticoagulation alone should no longer be regarded as a sufficient 'cause' of ICH. TRIAL REGISTRATION: NCT02513316.

Cerebral Small Vessel Disease and Functional Outcome Prediction After Intracerebral Hemorrhage.

OBJECTIVE: To determine whether CT-based cerebral small vessel disease (SVD) biomarkers are associated with 6-month functional outcome after intracerebral hemorrhage (ICH) and whether these biomarkers improve the performance of the preexisting ICH prediction score. METHODS: We included 864 patients with acute ICH from a multicenter, hospital-based prospective cohort study. We evaluated CT-based SVD biomarkers (white matter hypodensities [WMH], lacunes, brain atrophy, and a composite SVD burden score) and their associations with poor 6-month functional outcome (modified Rankin Scale score >2). The area under the receiver operating characteristic curve (AUROC) and Hosmer-Lemeshow test were used to assess discrimination and calibration of the ICH score with and without SVD biomarkers. RESULTS: In multivariable models (adjusted for ICH score components), WMH presence (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.12-2.06), cortical atrophy presence (OR 1.80, 95% CI 1.19-2.73), deep atrophy presence (OR 1.66, 95% CI 1.17-2.34), and severe atrophy (either deep or cortical) (OR 1.94, 95% CI 1.36-2.74) were independently associated with poor functional outcome. For the revised ICH score, the AUROC was 0.71 (95% CI 0.68-0.74). Adding SVD markers did not significantly improve ICH score discrimination; for the best model (adding severe atrophy), the AUROC was 0.73 (95% CI 0.69-0.76). These results were confirmed when lobar and nonlobar ICH were considered separately. CONCLUSIONS: The ICH score has acceptable discrimination for predicting 6-month functional outcome after ICH. CT biomarkers of SVD are associated with functional outcome, but adding them does not significantly improve ICH score discrimination. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02513316.

Automated quantitative MRI volumetry reports support diagnostic interpretation in dementia: a multi-rater, clinical accuracy study.

OBJECTIVES: We examined whether providing a quantitative report (QReport) of regional brain volumes improves radiologists' accuracy and confidence in detecting volume loss, and in differentiating Alzheimer's disease (AD) and frontotemporal dementia (FTD), compared with visual assessment alone. METHODS: Our forced-choice multi-rater clinical accuracy study used MRI from 16 AD patients, 14 FTD patients, and 15 healthy controls; age range 52-81. Our QReport was presented to raters with regional grey matter volumes plotted as percentiles against data from a normative population (n = 461). Nine raters with varying radiological experience (3 each: consultants, registrars, 'non-clinical image analysts') assessed each case twice (with and without the QReport). Raters were blinded to clinical and demographic information; they classified scans as 'normal' or 'abnormal' and if 'abnormal' as 'AD' or 'FTD'. RESULTS: The QReport improved sensitivity for detecting volume loss and AD across all raters combined (p = 0.015* and p = 0.002*, respectively). Only the consultant group's accuracy increased significantly when using the QReport (p = 0.02*). Overall, raters' agreement (Cohen's κ) with the 'gold standard' was not significantly affected by the QReport; only the consultant group improved significantly (κs 0.41➔0.55, p = 0.04*). Cronbach's alpha for interrater agreement improved from 0.886 to 0.925, corresponding to an improvement from 'good' to 'excellent'. CONCLUSION: Our QReport referencing single-subject results to normative data alongside visual assessment improved sensitivity, accuracy, and interrater agreement for detecting volume loss. The QReport was most effective in the consultants, suggesting that experience is needed to fully benefit from the additional information provided by quantitative analyses. KEY POINTS: • The use of quantitative report alongside routine visual MRI assessment improves sensitivity and accuracy for detecting volume loss and AD vs visual assessment alone. • Consultant neuroradiologists' assessment accuracy and agreement (kappa scores) significantly improved with the use of quantitative atrophy reports. • First multi-rater radiological clinical evaluation of visual quantitative MRI atrophy report for use as a diagnostic aid in dementia.

Clinical evaluation of automated quantitative MRI reports for assessment of hippocampal sclerosis.

OBJECTIVES: Hippocampal sclerosis (HS) is a common cause of temporal lobe epilepsy. Neuroradiological practice relies on visual assessment, but quantification of HS imaging biomarkers-hippocampal volume loss and T2 elevation-could improve detection. We tested whether quantitative measures, contextualised with normative data, improve rater accuracy and confidence. METHODS: Quantitative reports (QReports) were generated for 43 individuals with epilepsy (mean age ± SD 40.0 ± 14.8 years, 22 men; 15 histologically unilateral HS; 5 bilateral; 23 MR-negative). Normative data was generated from 111 healthy individuals (age 40.0 ± 12.8 years, 52 men). Nine raters with different experience (neuroradiologists, trainees, and image analysts) assessed subjects' imaging with and without QReports. Raters assigned imaging normal, right, left, or bilateral HS. Confidence was rated on a 5-point scale. RESULTS: Correct designation (normal/abnormal) was high and showed further trend-level improvement with QReports, from 87.5 to 92.5% (p = 0.07, effect size d = 0.69). Largest magnitude improvement (84.5 to 93.8%) was for image analysts (d = 0.87). For bilateral HS, QReports significantly improved overall accuracy, from 74.4 to 91.1% (p = 0.042, d = 0.7). Agreement with the correct diagnosis (kappa) tended to increase from 0.74 ('fair') to 0.86 ('excellent') with the report (p = 0.06, d = 0.81). Confidence increased when correctly assessing scans with the QReport (p < 0.001, η2p = 0.945). CONCLUSIONS: QReports of HS imaging biomarkers can improve rater accuracy and confidence, particularly in challenging bilateral cases. Improvements were seen across all raters, with large effect sizes, greatest for image analysts. These findings may have positive implications for clinical radiology services and justify further validation in larger groups. KEY POINTS: • Quantification of imaging biomarkers for hippocampal sclerosis-volume loss and raised T2 signal-could improve clinical radiological detection in challenging cases. • Quantitative reports for individual patients, contextualised with normative reference data, improved diagnostic accuracy and confidence in a group of nine raters, in particular for bilateral HS cases. • We present a pre-use clinical validation of an automated imaging assessment tool to assist clinical radiology reporting of hippocampal sclerosis, which improves detection accuracy.

Association of enlarged perivascular spaces and anticoagulant-related intracranial hemorrhage.

OBJECTIVE: To investigate whether enlarged perivascular spaces (PVS) within the basal ganglia or deep cerebral white matter are risk factors for intracranial hemorrhage in patients taking oral anticoagulants (OACs), independent of established clinical and radiologic risk factors, we conducted a post hoc analysis of Clinical Relevance of Microbleeds in Stroke (CROMIS-2) (atrial fibrillation [AF]), a prospective inception cohort study. METHODS: Patients with atrial fibrillation and recent TIA or ischemic stroke underwent standardized MRI prior to starting OAC. We rated basal ganglia PVS (BGPVS) and centrum semiovale PVS (CSOPVS), cerebral microbleeds (CMBs), white matter hyperintensities, and lacunes. We dichotomized the PVS rating using a threshold of >10 PVS in the relevant region of either cerebral hemisphere. The primary outcome was symptomatic intracranial hemorrhage (sICH). We identified risk factors for sICH using Cox regression. RESULTS: A total of 1,386 participants with available clinical and imaging variables were followed up for a mean of 2.34 years; 14 sICH occurred (11 intracerebral). In univariable analysis, diabetes, CMB presence, lacune presence, and >10 BGPVS, but not CSOPVS, were associated with sICH. In a multivariable model incorporating all variables with significant associations in univariable analysis, >10 BGPVS (hazard ratio [HR] 8.96, 95% [CI] 2.41-33.4, p = 0.001) and diabetes (HR 3.91, 95% CI 1.34-11.4) remained significant risk factors for sICH. CONCLUSION: Enlarged BGPVS might be a novel risk factor for OAC-related ICH. The strength of this association and potential use in predicting ICH in clinical practice should be investigated in larger cohorts.

MRI quantifies lumbosacral nerve root and sciatic nerve hypertrophy in chronic inflammatory demyelinating polyradiculoneuropathy.

PURPOSE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a treatable, immune-mediated condition characterised by progressive or relapsing motor and sensory neurological deficits. The diagnosis is based on a combination of clinical, neurophysiological and supportive criteria, but can be challenging. In this study, we quantified the diameter and cross-sectional area of the lumbosacral nerve roots, and explored the imaging characteristics of the sciatic nerves, in patients with CIDP versus healthy controls using MRI. METHODS: MRI of the lumbosacral plexus and both thighs was performed at 3 T. Orthogonal diameter and cross-sectional area of the lumbosacral nerve roots were measured, along with sciatic nerve cross-sectional area at the mid-thigh level. The MRI appearance of the sciatic nerves was also evaluated qualitatively. All measurements were performed by an observer blinded to the diagnosis. RESULTS: 10 patients with CIDP and 10 healthy controls (age and sex-matched) were studied. Lumbosacral nerve root diameter and cross-sectional area were significantly increased in patients with CIDP compared to controls (mean diameter 6.0 ±â€¯1.1 mm vs 4.8 ±â€¯0.3 mm; p = 0.006), with a high sensitivity (89 %) and specificity (90 %) on ROC analysis. Sciatic nerve cross sectional area was also significantly increased in the CIDP group, and was accompanied by qualitative MRI changes. CONCLUSIONS: Quantitative MRI reveals significant hypertrophy of the lumbosacral nerve roots and sciatic nerves in patients with CIDP compared to controls. This study provides further evidence for the inclusion of lumbosacral nerve root and sciatic nerve hypertrophy on MRI as a supportive feature in the diagnostic criteria for CIDP.

MAGNIMS consensus recommendations on the use of brain and spinal cord atrophy measures in clinical practice.

Early evaluation of treatment response and prediction of disease evolution are key issues in the management of people with multiple sclerosis (MS). In the past 20 years, MRI has become the most useful paraclinical tool in both situations and is used clinically to assess the inflammatory component of the disease, particularly the presence and evolution of focal lesions - the pathological hallmark of MS. However, diffuse neurodegenerative processes that are at least partly independent of inflammatory mechanisms can develop early in people with MS and are closely related to disability. The effects of these neurodegenerative processes at a macroscopic level can be quantified by estimation of brain and spinal cord atrophy with MRI. MRI measurements of atrophy in MS have also been proposed as a complementary approach to lesion assessment to facilitate the prediction of clinical outcomes and to assess treatment responses. In this Consensus statement, the Magnetic Resonance Imaging in MS (MAGNIMS) study group critically review the application of brain and spinal cord atrophy in clinical practice in the management of MS, considering the role of atrophy measures in prognosis and treatment monitoring and the barriers to clinical use of these measures. On the basis of this review, the group makes consensus statements and recommendations for future research.

Haptoglobin genotype and outcome after spontaneous intracerebral haemorrhage.

OBJECTIVE: Haptoglobin is a haemoglobin-scavenging protein that binds and neutralises free haemoglobin and modulates inflammation and endothelial progenitor cell function. A HP gene copy number variation (CNV) generates HP1 and HP2 alleles, while the single-nucleotide polymorphism rs2000999 influences their levels. The HP1 allele is hypothesised to improve outcome after spontaneous (non-traumatic) intracerebral haemorrhage (ICH). We investigated the associations of the HP CNV genotype and rs2000999 with haematoma volume, perihaematomal oedema (PHO) volume, functional outcome and mortality after ICH. METHODS: We included patients with neuroimaging-proven ICH, available DNA and 6-month follow-up in an observational cohort study (CROMIS-2). We classified patients into three groups according to the HP CNV: 1-1, 2-1 or 2-2 and also dichotomised HP into HP1-containing genotypes (HP1-1 and HP2-1) and HP2-2 to evaluate the HP1 allele. We measured ICH and PHO volume on CT; PHO was measured by oedema extension distance. Functional outcome was assessed by modified Rankin score (unfavourable outcome defined as mRS 3-6). RESULTS: We included 731 patients (mean age 73.4, 43.5% female). Distribution of HP CNV genotype was: HP1-1 n=132 (18.1%); HP2-1 n=342 (46.8%); and HP2-2 n=257 (35.2%). In the multivariable model mortality comparisons between HP groups, HP2-2 as reference, were as follows: OR HP1-1 0.73, 95% CI 0.34 to 1.56 (p value=0.41) and OR HP2-1 0.5, 95% CI 0.28 to 0.89 (p value=0.02) (overall p value=0.06). We found no evidence of association of HP CNV or rs200999 with functional outcome, ICH volume or PHO volume. CONCLUSION: The HP2-1 genotype might be associated with lower 6-month mortality after ICH; this finding merits further study.

A special role for the right posterior superior temporal sulcus during speech production.

This fMRI study of 24 healthy human participants investigated whether any part of the auditory cortex was more responsive to self-generated speech sounds compared to hearing another person speak. The results demonstrate a double dissociation in two different parts of the auditory cortex. In the right posterior superior temporal sulcus (RpSTS), activation was higher during speech production than listening to auditory stimuli, whereas in bilateral superior temporal gyri (STG), activation was higher for listening to auditory stimuli than during speech production. In the second part of the study, we investigated the function of the identified regions, by examining how activation changed across a range of listening and speech production tasks that systematically varied the demands on acoustic, semantic, phonological and orthographic processing. In RpSTS, activation during auditory conditions was higher in the absence of semantic cues, plausibly indicating increased attention to the spectral-temporal features of auditory inputs. In addition, RpSTS responded in the absence of any auditory inputs when participants were making one-back matching decisions on visually presented pseudowords. After analysing the influence of visual, phonological, semantic and orthographic processing, we propose that RpSTS (i) contributes to short term memory of speech sounds as well as (ii) spectral-temporal processing of auditory input and (iii) may play a role in integrating auditory expectations with auditory input. In contrast, activation in bilateral STG was sensitive to acoustic input and did not respond in the absence of auditory input. The special role of RpSTS during speech production therefore merits further investigation if we are to fully understand the neural mechanisms supporting speech production during speech acquisition, adult life, hearing loss and after brain injury.

Somatotopic organization of corticospinal/corticobulbar motor tracts in controls and patients with tumours: A combined fMRI-DTI study.

OBJECTIVES: To investigate the relative somatotopic organization of the motor corticospinal/corticobulbar foot, hand, lip and tongue fascicles by combining fMRI with DTI and to examine the influence of subjacent intrinsic tumours on these fascicles. METHODS: The study was approved by the local ethics committee. Seven male and three female volunteers (median age: 35 years) and one female and eight male patients with brain tumours (median age: 37 years) were scanned on a 1.5-T MRI scanner. fMRI data, analysed using SPM5, identified the motor task-driven fMRI grey matter activations of the hand, foot, lips and tongue as seed regions for probabilistic tractography. The relationship between the components of the CST was assessed and the distances between them were measured. A statistical comparison was performed comparing these distances in the group of healthy hemispheres with those of the group of non-affected hemispheres and healthy hemispheres. RESULTS: Hand fascicles were identified in all subjects (38/38, 100%), followed by foot (32/38, 84%), lip (31/38, 81%) and tongue fascicles (28/38, 74%). At superior levels, the hand fascicles were anterolateral to the foot fascicles in 77-93% of healthy hemispheres (HH), in 50-71% of non-affected patients' hemispheres (pH) and in 67-89% of affected PH. At inferior levels, the hand fascicles were either anteromedial in 46-45% of HH or anterior in 75% of non-affected PH and in 67-83% of affected PH. Tongue and lip fascicles overlapped in 25-45% of HH, in 10-20% of non-affected PH and in 15-25% of affected PH. No significant difference was found between the group of affected hemispheres and that of healthy and non-affected hemispheres. CONCLUSION: The somatotopy of the hand fascicles in relation to the foot fascicles was anterolateral in patients and volunteers at superior levels but anteromedial in volunteers and mostly anterior in patients at inferior levels. The lip and tongue fascicles generally overlapped. Intracranial tumours displaced the motor fascicles without affecting their relative somatotopy.