Whole-brain diffusion tensor imaging predicts 6-month functional outcome in acute intracerebral haemorrhage.

INTRODUCTION: Small vessel disease (SVD) causes most spontaneous intracerebral haemorrhage (ICH) and is associated with widespread microstructural brain tissue disruption, which can be quantified via diffusion tensor imaging (DTI) metrics: mean diffusivity (MD) and fractional anisotropy (FA). Little is known about the impact of whole-brain microstructural alterations after SVD-related ICH. We aimed to investigate: (1) association between whole-brain DTI metrics and functional outcome after ICH; and (2) predictive ability of these metrics compared to the pre-existing ICH score. METHODS: Sixty-eight patients (38.2% lobar) were retrospectively included. We assessed whole-brain DTI metrics (obtained within 5 days after ICH) in cortical and deep grey matter and white matter. We used univariable logistic regression to assess the associations between DTI and clinical-radiological variables and poor outcome (modified Rankin Scale > 2). We determined the optimal predictive variables (via LASSO estimation) in: model 1 (DTI variables only), model 2 (DTI plus non-DTI variables), model 3 (DTI plus ICH score). Optimism-adjusted C-statistics were calculated for each model and compared (likelihood ratio test) against the ICH score. RESULTS: Deep grey matter MD (OR 1.04 [95% CI 1.01-1.07], p = 0.010) and white matter MD (OR 1.11 [95% CI 1.01-1.23], p = 0.044) were associated (univariate analysis) with poor outcome. Discrimination values for model 1 (0.67 [95% CI 0.52-0.83]), model 2 (0.71 [95% CI 0.57-0.85) and model 3 (0.66 [95% CI 0.52-0.82]) were all significantly higher than the ICH score (0.62 [95% CI 0.49-0.75]). CONCLUSION: Our exploratory study suggests that whole-brain microstructural disruption measured by DTI is associated with poor 6-month functional outcome after SVD-related ICH. Whole-brain DTI metrics performed better at predicting recovery than the existing ICH score.

Acute corticospinal tract diffusion tensor imaging predicts 6-month functional outcome after intracerebral haemorrhage.

INTRODUCTION: Diffusion tensor imaging (DTI) can assess the structural integrity of the corticospinal tract (CST) in vivo. We aimed to investigate whether CST DTI metrics after intracerebral haemorrhage (ICH) are associated with 6-month functional outcome and can improve the predictive performance of the existing ICH score. METHODS: We retrospectively included 42 patients with DTI performed within 5 days after deep supratentorial spontaneous ICH. Ipsilesional-to-contralesional ratios were calculated for fractional anisotropy (rFA) and mean diffusivity (rMD) in the pontine segment (PS) of the CST. We determined the most predictive variables for poor 6-month functional outcome [modified Rankin Scale (mRS) > 2] using the least absolute shrinkage and selection operator (LASSO) method. We calculated discrimination using optimism-adjusted estimation of the area under the curve (AUC). RESULTS: Patients with 6-month mRS > 2 had lower rFA (0.945 [± 0.139] vs 1.045 [± 0.130]; OR 0.004 [95% CI 0.00-0.77]; p = 0.04) and higher rMD (1.233 [± 0.418] vs 0.963 [± 0.211]; OR 22.5 [95% CI 1.46-519.68]; p = 0.02). Discrimination (AUC) values were: 0.76 (95% CI 0.61-0.91) for the ICH score, 0.71 (95% CI 0.54-0.89) for rFA, and 0.72 (95% CI 0.61-0.91) for rMD. Combined models with DTI and non-DTI variables offer an improvement in discrimination: for the best model, the AUC was 0.82 ([95% CI 0.68-0.95]; p = 0.15). CONCLUSION: In our exploratory study, PS-CST rFA and rMD had comparable predictive ability to the ICH score for 6-month functional outcome. Adding DTI metrics to clinical-radiological scores might improve discrimination, but this needs to be investigated in larger studies.

MRI-visible perivascular spaces as an imaging biomarker in Fabry disease.

INTRODUCTION: Fabry disease (FD) is an X-linked lysosomal storage disorder resulting in vascular glycosphingolipid accumulation and increased stroke risk. MRI findings associated with FD include white matter hyperintensities (WMH) and cerebral microbleeds (CMBs), suggesting the presence of cerebral small vessel disease. MRI-visible perivascular spaces (PVS) are another promising marker of small vessel disease associated with impaired interstitial fluid drainage. We investigated the association of PVS severity and anatomical distribution with FD. PATIENTS AND METHODS: We compared patients with genetically proven FD to healthy controls. PVS, WMH, lacunes and CMBs were rated on standardised sequences using validated criteria and scales, blinded to diagnosis. A trained observer (using a validated rating scale), quantified the total severity of PVS. We used logistic regression to investigate the association of severe PVS with FD. RESULTS: We included 33 FD patients (median age 44, 44.1% male) and 20 healthy controls (median age 33.5, 50% male). Adjusting for age and sex, FD was associated with more severe basal ganglia PVS (odds ratio (OR) 5.80, 95% CI 1.03-32.7) and higher total PVS score (OR 4.03, 95% CI 1.36-11.89). Compared with controls, participants with FD had: higher WMH volume (median 495.03 mm3 vs 0, p = 0.0008), more CMBs (21.21% vs none, p = 0.04), and a higher prevalence of lacunes (21.21% vs. 5%, p = 0.23). CONCLUSIONS: PVS scores are more severe in FD than control subjects. Our findings have potential relevance for FD diagnosis and suggest that impaired interstitial fluid drainage might be a mechanism of white matter injury in FD.

NAA is a Marker of Disability in Secondary-Progressive MS: A Proton MR Spectroscopic Imaging Study.

BACKGROUND AND PURPOSE: The secondary progressive phase of multiple sclerosis is characterised by disability progression due to processes that lead to neurodegeneration. Surrogate markers such as those derived from MRI are beneficial in understanding the pathophysiology that drives disease progression and its relationship to clinical disability. We undertook a 1H-MRS imaging study in a large secondary progressive MS (SPMS) cohort, to examine whether metabolic markers of brain injury are associated with measures of disability, both physical and cognitive. MATERIALS AND METHODS: A cross-sectional analysis of individuals with secondary-progressive MS was performed in 119 participants. They underwent 1H-MR spectroscopy to obtain estimated concentrations and ratios to total Cr for total NAA, mIns, Glx, and total Cho in normal-appearing WM and GM. Clinical outcome measures chosen were the following: Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Nine-Hole Peg Test, Timed 25-foot Walk Test, and the Expanded Disability Status Scale. The relationship between these neurometabolites and clinical disability measures was initially examined using Spearman rank correlations. Significant associations were then further analyzed in multiple regression models adjusting for age, sex, disease duration, T2 lesion load, normalized brain volume, and occurrence of relapses in 2 years preceding study entry. RESULTS: Significant associations, which were then confirmed by multiple linear regression, were found in normal-appearing WM for total NAA (tNAA)/total Cr (tCr) and the Nine-Hole Peg Test (ρ = 0.23; 95% CI, 0.06-0.40); tNAA and tNAA/tCr and the Paced Auditory Serial Addition Test (ρ = 0.21; 95% CI, 0.03-0.38) (ρ = 0.19; 95% CI, 0.01-0.36); mIns/tCr and the Paced Auditory Serial Addition Test, (ρ = -0.23; 95% CI, -0.39 to -0.05); and in GM for tCho and the Paced Auditory Serial Addition Test (ρ = -0.24; 95% CI, -0.40 to -0.06). No other GM or normal-appearing WM relationships were found with any metabolite, with associations found during initial correlation testing losing significance after multiple linear regression analysis. CONCLUSIONS: This study suggests that metabolic markers of neuroaxonal integrity and astrogliosis in normal-appearing WM and membrane turnover in GM may act as markers of disability in secondary-progressive MS.

Structural cortical network reorganization associated with early conversion to multiple sclerosis.

Brain structural covariance networks (SCNs) based on pairwise statistical associations of cortical thickness data across brain areas reflect underlying physical and functional connections between them. SCNs capture the complexity of human brain cortex structure and are disrupted in neurodegenerative conditions. However, the longitudinal assessment of SCN dynamics has not yet been explored, despite its potential to unveil mechanisms underlying neurodegeneration. Here, we evaluated the changes of SCNs over 12 months in patients with a first inflammatory-demyelinating attack of the Central Nervous System and assessed their clinical relevance by comparing SCN dynamics of patients with and without conversion to multiple sclerosis (MS) over one year. All subjects underwent clinical and brain MRI assessments over one year. Brain cortical thicknesses for each subject and time point were used to obtain group-level between-area correlation matrices from which nodal connectivity metrics were obtained. Robust bootstrap-based statistical approaches (allowing sampling with replacement) assessed the significance of longitudinal changes. Patients who converted to MS exhibited significantly greater network connectivity at baseline than non-converters (p = 0.02) and a subsequent connectivity loss over time (p = 0.001-0.02), not observed in non-converters' network. These findings suggest SCN analysis is sensitive to brain tissue changes in early MS, reflecting clinically relevant aspects of the condition. However, this is preliminary work, indicated by the low sample sizes, and its results and conclusions should be treated with caution and confirmed with larger cohorts.

Spinal cord grey matter abnormalities are associated with secondary progression and physical disability in multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), pathological studies have identified substantial demyelination and neuronal loss in the spinal cord grey matter (GM). However, there has been limited in vivo investigation of cord GM abnormalities and their possible functional effects using MRI combined with clinical evaluation. METHODS: We recruited healthy controls (HC) and people with a clinically isolated syndrome (CIS), relapsing remitting (RR) and secondary progressive (SP) MS. All subjects had 3 T spinal cord MRI with measurement of cord cross-sectional area and diffusion tensor imaging metrics in the GM and posterior and lateral column white matter tracts using region of interest analysis. Physical disability was assessed using the expanded disability status scale (EDSS) and motor components of the MS functional composite scale. We calculated differences between MS and HC using a ANOVA and associations with disability using linear regression. RESULTS: 113 people were included in this study: 30 controls, 21 CIS, 33 RR and 29 SPMS. Spinal cord radial diffusivity (RD), fractional anisotropy and mean diffusivity in the GM and posterior columns were significantly more abnormal in SPMS than in RRMS. Spinal cord GM RD (ß=0.33, p<0.01) and cord area (ß=-0.45, p<0.01) were independently associated with EDSS (R(2)=0.77); spinal cord GM RD was also independently associated with a 9-hole peg test (ß=-0.33, p<0.01) and timed walk (ß=-0.20, p=0.04). CONCLUSIONS: The study findings suggest that pathological involvement of the spinal cord GM contributes significantly to physical disability in relapse-onset MS and SPMS in particular.

Accurate GM atrophy quantification in MS using lesion-filling with co-registered 2D lesion masks.

BACKGROUND: In multiple sclerosis (MS), brain atrophy quantification is affected by white matter lesions. LEAP and FSL-lesion_filling, replace lesion voxels with white matter intensities; however, they require precise lesion identification on 3DT1-images. AIM: To determine whether 2DT2 lesion masks co-registered to 3DT1 images, yield grey and white matter volumes comparable to precise lesion masks. METHODS: 2DT2 lesion masks were linearly co-registered to 20 3DT1-images of MS patients, with nearest-neighbor (NNI), and tri-linear interpolation. As gold-standard, lesion masks were manually outlined on 3DT1-images. LEAP and FSL-lesion_filling were applied with each lesion mask. Grey (GM) and white matter (WM) volumes were quantified with FSL-FAST, and deep gray matter (DGM) volumes using FSL-FIRST. Volumes were compared between lesion mask types using paired Wilcoxon tests. RESULTS: Lesion-filling with gold-standard lesion masks compared to native images reduced GM overestimation by 1.93 mL (p < .001) for LEAP, and 1.21 mL (p = .002) for FSL-lesion_filling. Similar effects were achieved with NNI lesion masks from 2DT2. Global WM underestimation was not significantly influenced. GM and WM volumes from NNI, did not differ significantly from gold-standard. GM segmentation differed between lesion masks in the lesion area, and also elsewhere. Using the gold-standard, FSL-FAST quantified as GM on average 0.4% of the lesion area with LEAP and 24.5% with FSL-lesion_filling. Lesion-filling did not influence DGM volumes from FSL-FIRST. DISCUSSION: These results demonstrate that for global GM volumetry, precise lesion masks on 3DT1 images can be replaced by co-registered 2DT2 lesion masks. This makes lesion-filling a feasible method for GM atrophy measurements in MS.

The current state-of-the-art of spinal cord imaging: methods.

A first-ever spinal cord imaging meeting was sponsored by the International Spinal Research Trust and the Wings for Life Foundation with the aim of identifying the current state-of-the-art of spinal cord imaging, the current greatest challenges, and greatest needs for future development. This meeting was attended by a small group of invited experts spanning all aspects of spinal cord imaging from basic research to clinical practice. The greatest current challenges for spinal cord imaging were identified as arising from the imaging environment itself; difficult imaging environment created by the bone surrounding the spinal canal, physiological motion of the cord and adjacent tissues, and small cross-sectional dimensions of the spinal cord, exacerbated by metallic implants often present in injured patients. Challenges were also identified as a result of a lack of "critical mass" of researchers taking on the development of spinal cord imaging, affecting both the rate of progress in the field, and the demand for equipment and software to manufacturers to produce the necessary tools. Here we define the current state-of-the-art of spinal cord imaging, discuss the underlying theory and challenges, and present the evidence for the current and potential power of these methods. In two review papers (part I and part II), we propose that the challenges can be overcome with advances in methods, improving availability and effectiveness of methods, and linking existing researchers to create the necessary scientific and clinical network to advance the rate of progress and impact of the research.

The current state-of-the-art of spinal cord imaging: applications.

A first-ever spinal cord imaging meeting was sponsored by the International Spinal Research Trust and the Wings for Life Foundation with the aim of identifying the current state-of-the-art of spinal cord imaging, the current greatest challenges, and greatest needs for future development. This meeting was attended by a small group of invited experts spanning all aspects of spinal cord imaging from basic research to clinical practice. The greatest current challenges for spinal cord imaging were identified as arising from the imaging environment itself; difficult imaging environment created by the bone surrounding the spinal canal, physiological motion of the cord and adjacent tissues, and small crosssectional dimensions of the spinal cord, exacerbated by metallic implants often present in injured patients. Challenges were also identified as a result of a lack of "critical mass" of researchers taking on the development of spinal cord imaging, affecting both the rate of progress in the field, and the demand for equipment and software to manufacturers to produce the necessary tools. Here we define the current state-of-the-art of spinal cord imaging, discuss the underlying theory and challenges, and present the evidence for the current and potential power of these methods. In two review papers (part I and part II), we propose that the challenges can be overcome with advances in methods, improving availability and effectiveness of methods, and linking existing researchers to create the necessary scientific and clinical network to advance the rate of progress and impact of the research.

Sample sizes for lesion magnetisation transfer ratio outcomes in remyelination trials for multiple sclerosis.

BACKGROUND: Enhancing remyelination in MS might improve function and protect axons from future damage. Lesion magnetisation transfer ratio (MTR) is sensitive to myelin content, and may be a useful measure for trials evaluating potential remyelinating agents. OBJECTIVE: Estimating sample sizes required for a parallel group, placebo-controlled trial in MS using change in mean MTR of all T2lesions as a primary outcome measure. METHODS: The primary sample size calculation was derived from data from a natural history study of relapsing remitting MS (n=18). The MTR values observed in demyelinated and remyelinated lesions in an ex vivo study were used to estimate the effect of remyelination on lesion MTR. The ex vivo data were also used to independently calculate sample sizes in order to inform the robustness of the in vivo estimates. RESULTS: Calculations suggest that 30% remyelination of T2 lesions could be detected with 80% power in 38 (95% confidence interval 12-96) patients per arm based on the in vivo data, and in 66 per arm based on the ex vivo data. CONCLUSION: The sample sizes derived are in a range that makes MTR a feasible outcome measure for proof-of-concept trials of putative therapies achieving remyelination in MS lesions.

Tissue- and column-specific measurements from multi-parameter mapping of the human cervical spinal cord at 3 T.

The aim of this study was to quantify a range of MR parameters [apparent proton density, longitudinal relaxation time T1, magnetisation transfer (MT) ratio, MT saturation (which represents the additional percentage MT saturation of the longitudinal magnetisation caused by a single MT pulse) and apparent transverse relaxation rate R2*] in the white matter columns and grey matter of the healthy cervical spinal cord. The cervical cords of 13 healthy volunteers were scanned at 3 T using a protocol optimised for multi-parameter mapping. Intra-subject co-registration was performed using linear registration, and tissue- and column-specific parameter values were calculated. Cervical cord parameter values measured from levels C1-C5 in 13 subjects are: apparent proton density, 4822 ± 718 a.u.; MT ratio, 40.4 ± 1.53 p.u.; MT saturation, 1.40 ± 0.12 p.u.; T1 = 1848 ± 143 ms; R2* = 22.6 ± 1.53 s(-1). Inter-subject coefficients of variation were low in both the cervical cord and tissue- and column-specific measurements, illustrating the potential of this method for the investigation of changes in these parameters caused by pathology. In summary, an optimised cervical cord multi-parameter mapping protocol was developed, enabling tissue- and column-specific measurements to be made. This technique has the potential to provide insight into the pathological processes occurring in the cervical cord affected by neurological disorders.

Sulcal and gyral crown cortical grey matter involvement in multiple sclerosis: A magnetisation transfer ratio study.

BACKGROUND: Histopathology has demonstrated extensive cortical grey matter (GM) demyelination in multiple sclerosis (MS), and suggests that sulcal folds may be preferentially affected, particularly in progressive MS. This has not been confirmed in vivo, and it is not known if it is relevant to clinical status. OBJECTIVES: To determine sulcal and gyral crown magnetisation transfer ratio (MTR) in MS cortical GM, and the MTR associations with clinical status. METHODS: We measured sulcal and gyral crown cortical GM MTR values in 61 MS patients and 32 healthy controls. Disability was measured using Expanded Disability Status Scale and Multiple Sclerosis Functional Composite scores. RESULTS: MTR values were reduced in sulcal and gyral crown regions in all MS subtypes, more so in secondary progressive (SP) MS than relapsing remitting (RR) MS, and similarly in primary progressive (PP) MS and RRMS. Sulcal MTR was lower than gyral crown MTR in controls, PPMS and RRMS patients, but not in SPMS. MTR correlated with clinical status in RRMS and SPMS, but not PPMS. CONCLUSIONS: Cortical pathology, as reflected by MTR, is present in all MS subtypes and most pronounced in SPMS. A preferential disease effect on sulcal cortical regions was not observed. Cortical MTR abnormalities appear to be more clinically relevant in relapse-onset rather than progressive-onset MS.

Feasibility of grey matter and white matter segmentation of the upper cervical cord in vivo: a pilot study with application to magnetisation transfer measurements.

Spinal cord pathology can be functionally very important in neurological disease. Pathological studies have demonstrated the involvement of spinal cord grey matter (GM) and white matter (WM) in several diseases, although the clinical relevance of abnormalities detected histopathologically is difficult to assess without a reliable way to assess cord GM and WM in vivo. In this study, the feasibility of GM and WM segmentation was investigated in the upper cervical spinal cord of 10 healthy subjects, using high-resolution images acquired with a commercially available 3D gradient-echo pulse sequence at 3T. For each healthy subject, tissue-specific (i.e. WM and GM) cross-sectional areas were segmented and total volumes calculated from a 15 mm section acquired at the level of C2-3 intervertebral disc and magnetisation transfer ratio (MTR) values within the extracted volumes were also determined, as an example of GM and WM quantitative measurements in the cervical cord. Mean (± SD) total cord cross-sectional area (TCA) and total cord volume (TCV) of the section studied across 10 healthy subjects were 86.9 (± 7.7) mm(2) and 1302.8 (± 115) mm(3), respectively; mean (±SD) total GM cross-sectional area (TGMA) and total GM volume (TGMV) were 14.6 (± 1.1) mm(2) and 218.3 (± 16.8) mm(3), respectively; mean (± SD) GM volume fraction (GMVF) was 0.17 (± 0.01); mean (± SD) MTR of the total WM volume (WM-MTR) was 51.4 (± 1.5) and mean (± SD) MTR of the total GM volume (GM-MTR) was 49.7 (± 1.6). The mean scan-rescan, intra- and inter-observer % coefficient of variation for measuring the TCA were 0.7%, 0.5% and 0.5% and for measuring the TGMA were 6.5%, 5.4% and 12.7%. The difference between WM-MTR and GM-MTR was found to be statistically significant (p=0.00006). This study has shown that GM and WM segmentation in the cervical cord is possible and the MR imaging protocol and analysis method presented here in healthy controls can be potentially extended to study the cervical cord in disease states, with the option to explore further quantitative measurements alongside MTR.

Advanced MR imaging techniques and characterization of residual anatomy.

Advances in technology in recent decades have contributed to rapid developments in non-invasive methods for imaging human anatomy, and advanced imaging methods are now one of the primary tools for clinical diagnosis after neurological trauma or disease. Here we review the current and upcoming capabilities of one of the most rapidly developing methods, magnetic resonance imaging (MRI). The underlying theory is introduced so that the reasons for the strengths, weaknesses, and future expectations of this method, can be explained. Current techniques for imaging anatomical changes, inflammation, and changes in white matter, axonal integrity, blood flow and function, are reviewed. Applications for specific purposes of assessing traumatic injury in the brain or spinal cord, and for multiple-sclerosis are also presented, and are used as examples of how the advanced techniques are being used in practice.

Linking white matter tracts to associated cortical grey matter: a tract extension methodology.

Quantitative diffusion analysis of white matter (WM) tracts has been utilised in many diseases for determining damage to, and changes in, WM tracts throughout the brain. However, there are limited studies investigating associations between quantitative measures in WM tracts and anatomically linked grey matter (GM), due to the difficulty in determining GM regions connected with a given WM tract. This work describes a straightforward method for extending a WM tract through GM based on geometry. The tract is extended by following a straight line from each point on the tract boundary to the outer boundary of the cortex. A comparison between a multiplanar 2D approach and a 3D method was made. This study also tested an analysis pipeline from tracking WM tracts to quantifying magnetisation transfer ratios (MTR) in the associated cortical GM, and assessed the applicability of the method to healthy control subjects. Tract and associated cortical volumes and MTR values for the cortico-spinal tracts, genu and body of the corpus callosum were extracted; the between-subjects standard deviation was calculated. It was found that a multiplanar 2D approach produced a more anatomically plausible volume of GM than a 3D approach, at the expense of possible overestimation of the GM volume. The between-subjects standard deviation of the tract specific quantitative measurements (from both the WM and GM masks) ranged between 1.2 and 7.3% for the MTR measures, and between 10 and 45% for the absolute volume measures. The results show that the method can be used to produce anatomically plausible extensions of the WM tracts through the GM, and regions defined in this way yield reliable estimates of the MTR from the regions.

A comprehensive assessment of cerebellar damage in multiple sclerosis using diffusion tractography and volumetric analysis.

BACKGROUND: White matter (WM) and grey matter (GM) brain damage in multiple sclerosis (MS) is widespread, but the extent of cerebellar involvement and impact on disability needs to be clarified. OBJECTIVE: This study aimed to assess cerebellar WM and GM atrophy and the degree of fibre coherence in the main cerebellar connections, and their contribution to disability in relapsing-remitting MS (RRMS) and primary progressive MS (PPMS). METHODS: Fourteen patients with RRMS, 12 patients with PPMS and 16 healthy controls were recruited. Cerebellar WM and GM volumes and tractography-derived measures from the middle and superior cerebellar peduncles, including fractional anisotropy (FA), mean diffusivity (MD), and directional diffusivities, were quantified from magnetic resonance imaging (MRI). Patients were assessed on clinical scores, including the MS Functional Composite score subtests. Linear regression models were used to compare imaging measures between 12 RRMS, 11 PPMS and 16 controls, and investigate their association with clinical scores. RESULTS: Patients with PPMS showed reduced FA and increased radial diffusivity in the middle cerebellar peduncle compared with controls and patients with RRMS. In PPMS, lower cerebellar WM volume was associated with worse performance on the upper limb test. In the same patient group, we found significant relationships between superior cerebellar peduncle FA and upper limb function, and between superior cerebellar peduncle FA, MD and radial diffusivity and speed of walking. CONCLUSION: These findings indicate reduced fibre coherence in the main cerebellar connections, and link damage in the whole cerebellar WM, and, in particular, in the superior cerebellar peduncle, to motor deficit in PPMS.

Early pericalcarine atrophy in acute optic neuritis is associated with conversion to multiple sclerosis.

BACKGROUND: Previous work showed that pericalcarine cortical volume loss is evident early after presentation with acute clinically isolated optic neuritis (ON). The aims of this study were: (1) to determine whether pericalcarine atrophy in patients with ON is associated with conversion to multiple sclerosis (MS); (2) to investigate whether regional atrophy preferentially affects pericalcarine cortex; and (3) to investigate potential causes of early pericalcarine atrophy using MRI. METHODS: 28 patients with acute ON and 10 controls underwent structural MRI (brain and optic nerves) and were followed-up over 12 months. Associations between the development of MS, optic nerve, optic radiation and pericalcarine cortical damage measures were investigated using multiple linear regression models. Regional cortical volumetric differences between patients and controls were calculated using t tests. RESULTS: The development of MS at 12 months was associated with greater whole brain and optic radiation lesion loads, shorter acute optic nerve lesions and smaller pericalcarine cortical volume at baseline. Regional atrophy was not evident in other sampled cortical regions. Pericalcarine atrophy was not directly associated with whole brain lesion load, optic radiation measures or optic nerve lesion length. However, the association between pericalcarine atrophy and MS was not independent of these parameters. CONCLUSIONS: Reduced pericalcarine cortical volumes in patients with early clinically isolated ON were associated with the development of MS but volumes of other cortical regions were not. Hence pericalcarine cortical regions appear particularly susceptible to early damage. These findings could be explained by a combination of pathological effects to visual grey and white matter in patients with ON.

Spinal cord repair in MS: does mitochondrial metabolism play a role?

OBJECTIVE: To investigate the mechanisms of spinal cord repair and their relative contribution to clinical recovery in patients with multiple sclerosis (MS) after a cervical cord relapse, using spinal cord (1)H-magnetic resonance spectroscopy (MRS) and volumetric imaging. METHODS: Fourteen patients with MS and 13 controls underwent spinal cord imaging at baseline and at 1, 3, and 6 months. N-acetyl-aspartate (NAA) concentration, which reflects axonal count and metabolism in mitochondria, and the cord cross-sectional area, which indicates axonal count, were measured in the affected cervical region. Mixed effect linear regression models investigated the temporal evolution of these measures and their association with clinical changes. Ordinal logistic regressions identified predictors of recovery. RESULTS: Patients who recovered showed a sustained increase in NAA after 1 month. In the whole patient group, a greater increase of NAA after 1 month was associated with greater recovery. Patients showed a significant decline in cord area during follow-up, which did not correlate with clinical changes. A worse recovery was predicted by a longer disease duration at study entry. CONCLUSIONS: The partial recovery of N-acetyl-aspartate levels after the acute event, which is concurrent with a decline in cord cross-sectional area, may be driven by increased axonal mitochondrial metabolism. This possible repair mechanism is associated with clinical recovery, and is less efficient in patients with longer disease duration. These insights into the mechanisms of spinal cord repair highlight the need to extend spinal cord magnetic resonance spectroscopy to other spinal cord disorders, and explore therapies that enhance recovery by modulating mitochondrial activity.

Tractography of the parahippocampal gyrus and material specific memory impairment in unilateral temporal lobe epilepsy.

INTRODUCTION: Temporal lobe epilepsy (TLE) is associated with disrupted memory function. The structural changes underlying this memory impairment have not been demonstrated previously with tractography. METHODS: We performed a tractography analysis of diffusion magnetic resonance imaging scans in 18 patients with unilateral TLE undergoing presurgical evaluation, and in 10 healthy controls. A seed region in the anterior parahippocampal gyrus was selected from which to trace the white matter connections of the medial temporal lobe. A correlation analysis was carried out between volume and mean fractional anisotropy (FA) of the connections, and pre-operative material specific memory performance. RESULTS: There was no significant difference between the left and right sided connections in controls. In the left TLE patients, the connected regions ipsilateral to the epileptogenic region were found to be significantly reduced in volume and mean FA compared with the contralateral region, and left-sided connections in control subjects. Significant correlations were found in left TLE patients between left and right FA, and verbal and non-verbal memory respectively. CONCLUSION: Tractography demonstrated the alteration of white matter pathways that may underlie impaired memory function in TLE. A detailed knowledge of the integrity of these connections may be useful in predicting memory decline in chronic temporal lobe epilepsy.