The Relationship between inflammation and atrophy in clinically isolated syndromes suggestive of multiple sclerosis

Abstract.Objective: To examine the relationship between inflammation and brain atrophy in patients with a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS).Methods: Monthly triple-dose gadolinium (Gd/DTPA)-enhanced MRI scans over 6 months were obtained in 62 consecutive CIS patients with an abnormal baseline MRI scan. Subsequently MRI was performed at months 12 and 18. Patients who developed a clinically definite MS (i. e., a second clinical episode) ended the study at the time of the relapse. For each scan, the number and volume of newly active lesions (Gd-enhancement/new or newly enlarging T2 lesion that did not enhance), and the number and volume of T2 hyperintense lesions (T2-LL) and T1-black holes (T1- LL) were calculated. The percentage of brain volume changes (PBVC) was assessed using a fully automated technique (SIENA; Structural Image Evaluation using Normalization of Atrophy).Results: Twenty-four (39%) developed clinically definite MS by month 18. Thirty-eight (61%) were relapsefree and completed the MRI follow-up. Relapse-free patients showed a progressive median increase between baseline and month 18 in T1-LL (25%, p < 0.001), but not in T2-LL (8.5%, p = ns). PBVC decreased by 1.1% (p < 0.001) in a time-dependent pattern (Kendall coefficient of concordance = 0.85). Exploratory subgroup analyses showed a trend towards progressive decreases in brain volume in active patients (i. e., those with at least one newly active lesion during monthly MRI scanning; Spearmans R = –0.61; p < 0.001), but not among inactive patients (Spearmans R = –0.10; p = 0.53). Significant differences in median brain volume changes between the active and inactive patient groups were found at months 12 and 18; the difference detected at month 6 was not significant. The cumulative number and volume of new Gd-enhancing lesions developed during the 6 months of frequent MRI scanning were highly correlated with PBVC over the 18-month period (Spearman R values were 0.73 and 0.85, respectively). The strongest predictor of PBVC at 18 months was the cumulative volume of newly active lesions during frequent MRI scanning [ß = –0. 83, standard error (SE) = 0.07, p < 0.001].Conclusions: This study shows that visible inflammation as detected by monthly, triple-dose Gd-enhanced MRI is an important factor in the pathogenesis of brain tissue loss in CIS patients. However, inflammation and brain atrophy do not proceed in parallel: atrophy appeared only after a delay of months following acute inflammation. Frequent MRI scanning allows for the detection of CIS patients who will develop brain atrophy in the short-term.     

Magnetic resonance imaging predictors of disability in primary progressive multiple sclerosis: a 5-year study

Magnetic resonance imaging (MRI) has become an accepted tool for monitoring therapeutic trials in relapsing-remitting and secondary progressive multiple sclerosis (MS); it is however unclear whether such MRI markers are equally applicable to primary progressive MS (PPMS). Forty-two patients with PPMS were reviewed five years after commencing a two-year MRI and clinical study. Clinical measures recorded at baseline and five years included both the Expanded Disability Status Scale and the MS functional composite. MRI data collected at baseline and two years included T1 and T2 lesion loads, the number of new brain and cord lesions, and measures of both brain and cord atrophy. The study demonstrated that both the number of new T2 lesions and rate of increase in ventricular volume over two years were modestly predictive of subsequent disease progression and therefore may be useful tools in the testing of new therapeutic agents in PPMS.     

Serum gelatinase B/MMP-9 in primary progressive multiple sclerosis patients treated with interferon-beta-1a

Background: Interferon- beta (IFN) acts by a variety of mechanisms in relapsing-remitting multiple sclerosis (MS). One of these is a cellular down-regulation of gelatinase B or matrix metalloproteinase-9 (MMP-9), which is known from biochemical, biological and immunohistochemical evidences to play a disease-promoting role in MS.Aims: a) To investigate the influence of IFN-1a (30 or 60 µg I. M./week) on serum MMP-9 levels in patients with primary progressive MS (PPMS). b) To correlate serum MMP-9 levels with clinical and magnetic resonance imaging (MRI) findings.Methods: Serial blood samples were collected every 3 months from 49 patients participating in a phase II trial of IFN-1a in PPMS. Serum MMP-9 was quantified by ELISA and correlations with clinical (EDSS) as well as MRI findings (brain and spinal cord atrophy, ventricular volume, T1 and T2 lesion load) were calculated.Results: No significant differences were found between serial serum MMP-9 levels in IFN-treated versus placebo-treated patients. MMP-9 levels did not differ between patients who progressed or did not progress during the study interval. Although mean absolute serum MMP-9 levels over the study period correlated with an increase in T2 lesion load (relative T2 change: r=0.51, p<0.001; absolute T2 change: r=0.30, p=0.038), absolute increase in brain ventricular volume (r=0.29, p=0.05) and increased brain atrophy (r=0.35, p=0.02), only the correlation with T2 lesion load was sustained throughout the study period. No correlations were found between MMP-9 levels and relative changes in ventricular volume or with relative/absolute changes in T1 lesion load and in spinal cord atrophy. None of the MRI measures correlated with MMP-9 changes between baseline levels and those on treatment.Conclusion: Although some evidence suggests a down-regulating effect of IFN on MMP-9, this was not confirmed for a once weekly intramuscular dose of IFN-1a in patients with PPMS. The sustained correlation between serum MMP-9 and changes in T2 volumes, and the lack of correlation with clinical or MRI measures of disease progression may suggest that MMP-9 is more directly related to non-specific central nervous system damage than to axonal loss.     

Magnetic resonance imaging measures of brain and spinal cord atrophy correlate with clinical impairment in secondary progressive multiple sclerosis

BackgroundNeuroaxonal loss is a pathological substrate of disability in progressive multiple sclerosis (MS) and can be estimated in vivo by measuring tissue atrophy on magnetic resonance imaging (MRI). While there is some evidence that brain atrophy correlates better with disability than T2 lesion load in secondary progressive MS, the clinical relevance of atrophy within specific regions of the central nervous system requires further evaluation.MethodsClinical and MRI examinations were performed in 117 subjects with secondary progressive MS. MRI analysis included measures of normalized brain volume (NBV), normalized grey matter (NGMV) and white matter volume (NWMV), central cerebral volume (CCV), spinal cord cross-sectional area (SCCA), and brain T2 and T1 lesion volume. Clinical assessments included the expanded disability status scale (EDSS) and MS functional composite (MSFC).ResultsAll MRI measures correlated significantly with the MSFC score, with the strongest correlation being for the NBV (r = 0.47; P < 0.001). NBV and SCCA were the only significant independent predictors of the MSFC score in a stepwise regression model containing all the MRI measures, and SCCA was the only MRI measure to show a significant association with the EDSS. While NGMV had stronger correlations with the clinical variables than NWMV, NBV was more correlated with clinical impairment than either measure.ConclusionsThis data suggests that measures of atrophy, particularly of the whole brain and spinal cord, are relevant and useful disease markers in secondary progressive MS.     

The normal appearing grey matter in primary progressive multiple sclerosis

Background: In 10–15 % of patients with multiple sclerosis (MS), the clinical course is characterized by slow progression in disability without relapses (primary progressive (PP) MS). The mechanism of disability in this form of MS is poorly understood. Using magnetization transfer ratio (MTR) imaging, we investigated normal appearing white matter (NAWM) and normal appearing grey matter (NAGM) in PPMS and explored the relationship of MTR measures with disability. Methods: Thirty patients with PPMS and 30 age matched controls had spin echo based MTR imaging to study lesions and normal appearing tissues. The brain was segmented into NAWM and NAGM using SPM99 with lesions segmented using a semiautomated local thresholding technique. A 75 % probability threshold for classification of NAWM and NAGM was used to diminish partial volume effects. From normalized histograms of MTR intensity values, six MTR parameters were measured. Mean lesion MTR and T2 lesion volume were also measured. Disability was assessed using Kurtzke's expanded disability status scale (EDSS). Results: Compared with controls, patients exhibited a significant reduction in mean NAWM (p = 0.001) and NAGM (p = 0.004) MTR. Spearman's rank correlation of EDSS with the six MTR parameters in NAWM and NAGM, mean lesion MTR, and T2 lesion volume, was only significant with mean NAGM MTR (r = −0.41, p = 0.02), the 25th percentile of NAGM MTR intensity (r = −0.37, p = 0.05), and T2 lesion volume (r = 0.39, p = 0.04). Multiple regression analysis of the relationship between EDSS and 4 MR parameters representing each tissue type (mean NAWM MTR, mean NAGM MTR, mean lesion MTR, T2 lesion volume) showed that the association of EDSS with mean NAGM MTR remained significant. Conclusions: There appear to be significant abnormalities in the NAGM in PP MS. Further investigation of the pathological basis and functional significance of grey matter abnormality in PPMS is warranted. Received: 7 September 2001, Received in revised form: 3 January 2002, Accepted: 16 January 2002 Correspondence to D. H. Miller     

Cognitive function in primary and secondary progressive multiple sclerosis: A multiparametric magnetic resonance imaging study

Background and purpose

The differences in cognitive function between primary progressive and secondary progressive multiple sclerosis (MS) remain unclear. We compared cognitive performance between primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS), and explored the structural and functional magnetic resonance imaging (MRI) correlates of their cognitive functions.

Methods

Seventy-five healthy controls and 183 MS patients (60 PPMS and 123 SPMS) underwent 3.0-T MRI. MS patients were administered the Brief Repeatable Battery of Neuropsychological Tests; cognitive domain z-scores were calculated and then averaged to obtain a measure of global cognition. Using hierarchical linear regression analysis, the contribution of lesion volumes, normalized brain volumes, white matter (WM) fractional anisotropy (FA) and mean diffusivity abnormalities, and resting state (RS) functional connectivity (FC) alterations to global cognition in PPMS and SPMS was investigated.

Results

PPMS and SPMS had similar z-scores in all investigated cognitive domains. Poor global cognitive function was associated with decreased FA of the medial lemniscus (ΔR ² = 0.11, p = 0.011) and lower normalized gray matter volume (ΔR ² = 0.29, p < 0.001) in PPMS, and with decreased FA of the fornix (ΔR ² = 0.35, p < 0.001) and lower normalized WM volume (ΔR ² = 0.05; p = 0.034) in SPMS.

Conclusions

PPMS and SPMS had similar neuropsychological performance. Cognitive dysfunction in PPMS and SPMS was related to distinct patterns of structural MRI abnormalities and involvement of different WM tracts, whereas RS FC alterations did not contribute to explaining their global cognitive functioning.     

T1 lesion load and cerebral atrophy as a marker for clinical progression in patients with multiple sclerosis. A prospective 18 months follow-up study

We investigated the relationship between local tissue destruction, diffuse cerebral atrophy and clinical progression in patients with established multiple sclerosis (MS). Twenty-nine patients with MS (13 patients with relapsing--remitting and 16 with secondary progressive disease) were included in a prospective serial study. Cerebral volumes, T1 hypointense lesion volumes, T2 hyperintense lesion volumes at baseline and at 18 months follow-up, and the volume of monthly enhancing lesions from month 0 to month 9 were assessed on magnetic resonance imaging (MRI) brain scans using highly reproducible semi-automated quantitative techniques. The main outcome measures were the MRI parameters and disability on Kurtzkes' Expanded Disability Status Scale. There was a significant correlation between the change (increase) in T1 lesion volume and progressive cerebral atrophy, whereas no correlation between the T2 lesion volume and atrophy was seen over the same follow-up period. The change in T1 lesion volume correlated more strongly than did T2 lesion volume change with the change in disability. We conclude that hypointense abnormalities detected in T1-weighted brain scans and cerebral atrophy may be directly linked. Although one should bear in mind some potential for reversibility due to inflammatory, oedematous lesions, these MR measures are a useful marker of progressive tissue damage and clinical progression in established MS.     

Automated structural imaging analysis detects premanifest Huntington's disease neurodegeneration within 1 year

Intense efforts are underway to evaluate neuroimaging measures as biomarkers for neurodegeneration in premanifest Huntington's disease (preHD). We used a completely automated longitudinal analysis method to compare structural scans in preHD individuals and controls. Using a 1‐year longitudinal design, we analyzed T₁‐weighted structural scans in 35 preHD individuals and 22 age‐matched controls. We used the SIENA (Structural Image Evaluation, using Normalization, of Atrophy) software tool to yield overall percentage brain volume change (PBVC) and voxel‐level changes in atrophy. We calculated sample sizes for a hypothetical disease‐modifying (neuroprotection) study. We found significantly greater yearly atrophy in preHD individuals versus controls (mean PBVC controls, ?0.149%; preHD, ?0.388%; P = .031, Cohen's d = .617). For a preHD subgroup closest to disease onset, yearly atrophy was more than 3 times that of controls (mean PBVC close‐to‐onset preHD, ?0.510%; P = .019, Cohen's d = .920). This atrophy was evident at the voxel level in periventricular regions, consistent with well‐established preHD basal ganglia atrophy. We estimated that a neuroprotection study using SIENA would only need 74 close‐to‐onset individuals in each arm (treatment vs placebo) to detect a 50% slowing in yearly atrophy with 80% power. Automated whole‐brain analysis of structural MRI can reliably detect preHD disease progression in 1 year. These results were attained with a readily available imaging analysis tool, SIENA, which is observer independent, automated, and robust with respect to image quality, slice thickness, and different pulse sequences. This MRI biomarker approach could be used to evaluate neuroprotection in preHD. © 2011 Movement Disorder Society     

White matter T(1) relaxation time histograms and cerebral atrophy in multiple sclerosis

T(1) relaxation time (T(1)) provides a quantitative magnetic resonance imaging (MRI) parameter for evaluating tissue damage in the brain. We aimed to measure T(1) in the white matter of patients with multiple sclerosis (MS) and study relationships with cerebral atrophy, T(2) lesion load and clinical parameters. Twenty-six patients with relapsing-remitting MS and sixteen healthy controls were scanned with dual-echo T(2)-weighted, 3-dimensional (3-D) magnetization-prepared rapid acquisition gradient echo and whole brain, multi-slice inversion recovery (IR) sequences. White matter masks were defined on axial T(1) map slices using semi-automated seed growing and normalized 'total white matter' T(1) histograms generated. Atrophy data was obtained using the Cavalieri method of modern design stereology. T(2) lesion volume was also determined using seed growing.T(1) histogram-derived measures (median, peak height, peak position and standard deviation) in MS patients were significantly different (p < 0.0001) from controls. Median T(1) correlated significantly with supratentorial (r = 0.42, p = 0.036), lateral ventricle (r = 0.55, p = 0.004), and T(2) lesion volumes (r = 0.84, p < 0.0001), but not with clinical parameters.Total white matter T(1) provides a robust, quantitative measure of global disease burden in MS, and also correlates significantly with cerebral atrophy. Serial studies are required to determine its potential role as a surrogate marker of disease progression.     

MR correlates of cerebral atrophy in patients with multiple sclerosis

Objective To investigate the in-vivo correlates of brain atrophy in patients with multiple sclerosis (MS) by assessing the relationship between normalized measures of brain volume (NBV) and other magnetic resonance (MR) measures of tissue damage. Background Brain atrophy diffusely occurs and progressively increases in patients with MS. Nevertheless, the mechanisms leading to brain atrophy in this disease are not fully understood. Methods MR examinations were performed in 20 patients with relapsing-remitting MS. Conventional MRI was used to assess NBV and total brain T2-hyperintense and T1-hypointense lesion volumes. Proton MR spectroscopic imaging and diffusion tensor MR imaging were also performed for large portions of brain containing mainly normal-appearing tissue to provide indices of tissue damage, including N-acetylaspartate to creatine ratio (NAA/Cr) and mean diffusivity (). Results Values of NBV correlated significantly with those of average brain (r = -0.58, p = 0.007) and NAA/Cr (r = 0.67, p < 0.001). The relationship of these markers of tissue damage to NBV was also found when NAA/Cr and were computed together in a composite MR score (r = 0.70, p < 0.001). In contrast, NBV values did not correlate with measurements of average lesion , T₂ and T₁ weighted total brain MRI lesion volumes. Conclusions This study suggests that brain atrophy in MS is not simply due to axonal loss, but rather reflects a more generalized process that involves various brain tissue components. Damage to the normal-appearing tissue rather than the extent and intrinsic pathology of macroscopic lesions seems to be important in the destructive process leading to MS-related irreversible cerebral atrophy. Received: 13 September 2001 Received in revised form: 18 January 2002 Accepted: 4 March 2002     

Two-year follow-up study of primary and transitional progressive multiple sclerosis

This study documents changes in clinical and magnetic resonance imaging (MRI) characteristics in a large cohort of patients with primary and transitional progressive multiple sclerosis (PP and TPMS) over 2 years. Patients with PPMS and TPMS were recruited from six European centres and underwent clinical and MRI examination at three time points: baseline, year one and year two. Of the 190 patients recruited clinical data were available on 125 patients (66%, five centres) and MRI data were available on 113 patients (59%, four centres) at 2 years. Significant increases were seen in T2 load and T1 hypointensity, while brain and cord volume decreased. In PPMS significantly higher lesion loads were found in those who presented with non-cord syndromes when compared to cord presentation and there was a trend to greater brain atrophy in those who deteriorated clinically over the course of the study compared to those who remained stable. Significant cord atrophy was only seen in those with a cord presentation. Measurable changes in MRI parameters can be detected in PPMS patients over a relatively short period of time. MRI quantification is likely to be useful in elucidating disease mechanisms in PPMS and in the execution of clinical trials.     

Serial MRI in multiple sclerosis: a prospective pilot study of lesion load, whole brain volume and thalamic atrophy.

Using serial magnetic resonance imaging (MRI), we investigated the relationship between diffuse cerebral atrophy, T1 and T2 lesion volumes, mean thalamic volumes and clinical progression in patients with established multiple sclerosis (MS). Eleven patients were included in this prospective serial study. Cerebral volumes, T1 hypointense lesion volumes, and T2 hyperintense lesion volumes at baseline and at up to 3 years follow-up were assessed on MRI brain scans. As a putative measure of cerebral atrophy mean thalamic volumes were also obtained. The outcome measures were the MRI parameters and disability on Kurtzke's expanded disability status scale (EDSS). Of the 11 patients 6 worsened clinically as measured by an increase of 0.5 or more on the EDSS. Cerebral atrophy occurred in 91% of patients and was independent of changes in lesion volumes and was not associated with disease progression as determined by the EDSS.     

Volumetric quantitation by MRI in primary progressive multiple sclerosis: volumes of plaques and atrophy correlated with neurological disability

In primary progressive multiple sclerosis (PPMS) abnormalities in brain magnetic resonance imaging (MRI) differ from abnormalities in other subtypes of multiple sclerosis (MS). It was investigated whether the extent of brain and spinal cord MRI abnormalities is reflected in the neurological disability in PPMS. Focal and diffuse changes and atrophy in central nervous system (CNS) in patients with PPMS (n = 28) and healthy controls (n = 20) were assessed by semi-automatic MRI segmentation and volumetric analysis. The measurements were related to neurological disability as expressed by the expanded disability status scale (EDSS), the regional functional scoring system (RFSS), the arm index and the ambulation index. Plaques in T1- and/or T2-weighted images were seen in all brains, while spinal plaques were detected in 23 of 28 patients (82%). The total volumes of brain and spinal cord were significantly smaller in patients than in controls (P = 0.001 and 0.000, respectively). The volumes of T1 or T2 lesions in the brain correlated to the ambulation index (r = 0.51, P = 0.005 and r = 0.53, P = 0.004, respectively). No correlations were detected between MRI measurements and total EDSS score, but relative brain atrophy correlated inversely with the total RFSS scores, poor arm index and higher cerebral disturbances (r = -0.53, P = 0.004; r = -0.53, P = 0.004; and r = -0.52, P = 0.005, respectively). Although the number of spinal T2 lesions correlated with sensory disturbances (r = 0.60, P = 0.001), no correlations were found between EDSS subscores and spinal cord atrophy. These findings show that marked atrophy of brain and spinal cord detected by volumetric quantitation correlates with neurological disability. This observation indicates the importance of neurodegenerative events in PPMS.     

A longitudinal study of MRI-detected atrophy in secondary progressive multiple sclerosis

MRI measures of tissue atrophy within the central nervous system may reflect the neurodegenerative process which underpins the progressive phase of multiple sclerosis (MS). There has been limited longitudinal investigation of MRI-detected atrophy in secondary progressive MS. This study includes 56 subjects with secondary progressive MS. Subjects were followed up for 2 years and MRI analysis was conducted at 12 month intervals using the following measures: (1) whole brain (WB) volume change; (2) grey and white matter (WM) volumes; (3) central brain volume; (4) upper cervical spinal cord (SC) area; (5) T2 lesion volumes. Clinical measures included the Expanded Disability Status Scale and the MS Functional Composite. All volumetric MRI measures were assessed for sensitivity, responsiveness, reliability and correlation with disability. The mean annual atrophy rate of WB was 0.59% per year and this was the most responsive atrophy measure assessed. Grey matter (GM) atrophy (−1.18% per year) was greater and more responsive than WM atrophy (0.12% per year). The SC demonstrated the highest atrophy rate at 1.63% per year. WB, GM and SC atrophy all correlated with change in the Multiple Sclerosis Functional Composite z score (r = 0.35, 0.42, 0.34), and GM atrophy was the only correlate of change in the 9 Hole Peg Test and Paced Auditory Serial Addition Test performance. None of the MRI measures correlated with Expanded Disability Status Score progression. Measures of WB, GM and SC atrophy all have attributes for use as surrogate markers in secondary progressive MS trials and improvement in the reliability of the GM and SC volume measurements may enhance these further.     

A longitudinal uncontrolled study of cerebral gray matter volume in patients receiving natalizumab for multiple sclerosis

Objective: Brain atrophy in multiple sclerosis (MS) selectively affects gray matter (GM), which is highly relevant to disability and cognitive impairment. We assessed cerebral GM volume (GMV) during one year of natalizumab therapy. Design/methods: Patients with relapsing–remitting (n = 18) or progressive (n = 2) MS had MRI ～1 year apart during natalizumab treatment. At baseline, patients were on natalizumab for (mean ± SD) 16.6 ± 10.9 months with age 38.5 ± 7.4 and disease duration 9.7 ± 4.3 years. Results: At baseline, GMV was 664.0 ± 56.4 ml, Expanded Disability Status Scale (EDSS) score was 2.3 ± 2.0, timed 25-foot walk (T25FW) was 6.1±3.4 s; two patients (10%) had gadolinium (Gd)-enhancing lesions. At follow-up, GMV was 663.9 ± 60.2 mL; EDSS was 2.6 ± 2.1 and T25FW was 5.9 ± 2.9 s. One patient had a mild clinical relapse during the observation period (0.052 annualized relapse rate for the entire cohort). No patients had Gd-enhancing lesions at follow-up. Linear mixed-effect models showed no significant change in annualized GMV [estimated mean change per year 0.338 mL, 95% confidence interval ?9.66, 10.34, p = 0.94)], GM fraction (p = 0.92), whole brain parenchymal fraction (p = 0.64), T2 lesion load (p = 0.64), EDSS (p = 0.26) or T25FW (p = 0.79). Conclusions: This pilot study shows no GM atrophy during one year of natalizumab MS therapy. We also did not detect any loss of whole brain volume or progression of cerebral T2 hyperintense lesion volume during the observation period. These MRI results paralleled the lack of clinical worsening.     

Cord atrophy separates early primary progressive and relapsing remitting multiple sclerosis

Background and objective

The onset of multiple sclerosis is relapsing remitting or primary progressive. An improved understanding of the causes of early progressive disability in primary progressive multiple sclerosis (PPMS) could provide mechanistic targets for therapeutic intervention.

Methods

Five magnetic resonance imaging (MRI) parameters that could potentially cause progressive disability were investigated in 43 patients with early PPMS and in 37 patients with early relapsing remitting multiple sclerosis (RRMS): atrophy in brain, both grey matter and white matter; intrinsic abnormality in brain, both grey matter and white matter (measured by the magnetisation transfer ratio (MTR)); and atrophy of the upper cervical spinal cord. Both groups were also compared with controls.

Results

Patients with PPMS were older and more likely to be men. Both patient groups had atrophy of brain grey matter and white matter, and intrinsic abnormality in MTR of normal‐appearing grey matter and white matter. Cord atrophy was present only in the PPMS (mean cord area: PPMS, 67.8 mm²; RRMS, 72.7 mm²; controls, 73.4 mm²; p = 0.007). This was confirmed by multivariate analysis of all five MRI parameters, age and sex.

Conclusion

Grey matter and white matter of the brain are abnormal in both early RRMS and PPMS, but cord atrophy is present only in PPMS. This is concordant with myelopathy being the usual clinical presentation of PPMS. Measurement of cord atrophy seems to be clinically relevant in PPMS treatment trials.About 15% of patients with multiple sclerosis present with a steadily accumulating neurological deficit—usually a spastic paraplegia that indicates spinal cord dysfunction—known as primary progressive multiple sclerosis (PPMS). These patients are older at onset (mean age 40 v 30 years) and the proportion of male patients is higher than in those with an onset of relapsing remitting multiple sclerosis (RRMS).¹ The mechanisms of disability in patients with PPMS are not well understood. Patients with PPMS become disabled at an earlier stage despite having no greater load of lesions visible on magnetic resonance imaging (MRI) of the brain,² nor have differences been noted between patients with RRMS and those with PPMS in terms of the number of focal spinal cord lesions that are visible on T2‐weighted MRI scans.^3,4 One study reported a higher frequency of diffuse hyperintensity on proton‐density‐weighted scans of the spinal cord in patients with PPMS.⁵In recent years, we have recruited two cohorts of patients in the early stages of RRMS and PPMS to investigate—using serial multimodal MRI and clinical follow‐up—potential prognostic markers and pathogenic mechanisms in the two types of multiple sclerosis. The present study directly compares quantitative MRI measures in these patients with early RRMS, those with early PPMS, and controls using identical analysis methods applied to anonymised scans by a blinded investigator (MB) to identify imaging features that might associate with the more disabling clinical course seen in PPMS. Five MRI parameters were pre‐selected for investigation because each could—if more severely abnormal—help explain disability in PPMS: (a) brain grey matter volume; (b) brain white matter volume; (c) normal‐appearing brain grey matter magnetisation transfer ratio (MTR); (d) normal‐appearing brain white matter MTR; and (e) upper cervical cord cross‐sectional area. We hypothesised that patients with early PPMS have a more disabling course of their multiple sclerosis, because one or more of the five MRI parameters is abnormal when compared with patients with early RRMS.     

N-acetylaspartic acid in cerebrospinal fluid of multiple sclerosis patients determined by gas-chromatography-mass spectrometry

Abstract Background Axonal degeneration is considered to play a major role in the development of clinical disability in multiple sclerosis (MS). N-AcetylAspartic Acid (NAA) is a neuron-specific marker constantly identified in MR-spectroscopy studies of the normal and MS brain. To our knowledge there are no studies available that evaluated NAA in cerebrospinal fluid (CSF) as a possible marker for disease severity. Objective To evaluate CSF concentrations of NAA in MS in relation to disease phenotype, clinical measures of disability and MRI markers of disease burden. Methods NAA concentrations were determined in CSF of 46 patients with MS (26 relapsing remitting (RRMS), 12 secondary progressive (SPMS) and 8 primary progressive (PPMS)). Prior to lumbar puncture, MS-patients underwent MRI and clinical examination, including the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC). Additionally, CSF concentrations of NAA were determined in 12 patients with other neurological diseases (OND). Results Median CSF NAA concentration was 0.74 (IQR: 0.59–0.94) in RRMS , 0.54 (IQR: 0.35–0.73) in SPMS and 0.83 μmol/l (IQR: 0.56–1.03) in PPMS patients. SPMS patients had a significantly lower NAA concentration than RRMS patients. NAA concentrations correlated with EDSS (r = )0.37, p = 0.016), MSFC (r = 0.41, p = 0.010), normalised brain volume (r = 0.49, p = 0.001), T2 lesion load (r = )0.35, p = 0.021) and black hole lesion load (r = )0.47, p = 0.002). No differences were observed between OND (median: 0.57 IQR: 0.28–0.73) and MS patients. Conclusion CSF NAA concentration in MS patients is related to clinical performance and MRI measures of disease burden and may therefore be an important neuron specific marker of disease severity and possibly progression.     

Serial magnetic resonance imaging in experimental primate stroke: Validation of MRI for pre-clinical cerebroprotective trials

Abstract

Precise assessment of stroke outcome is critical for pre-clinical testing of cerebroprotective strategies. Differences in stroke volume measured by various magnetic resonance imaging (MRI) techniques are documented in humans, but not well described in experimental primate stroke. This study characterizes changes in stroke volume using serial MRI scans in a baboon model of reperfused cerebral ischemia. The location/area of hyperintensity on MRI corresponded with the TTC-stained infarct region. T2-weighted fast spin echo (T2W FSE), fluid attenuated inversion recovery (FLAIR), and diffusion weighted imaging (DWI) showed a decrease in infarct volume between 72 h and nine days post-ischemia (p = ns, p = 0.029, and p = 0.006). T2W FSE and FLAIR demonstrated an increase in infarct volume from 24 h to nine days postischemia, while DWI displayed a decrease over the same period. While early T2W FSE, FLAIR, and DWI all correlated with late infarct volume (p < 0.001), 72 h T2W FSE was the best direct measure (2.39% ± 1.40% unity deviation). Serial MRI in a nonhuman primate model of focal cerebral ischemia recapitulates findings in clinical stroke. MRI at 72 h accurately predicts late infarct volume.     

Proton MR spectroscopy of lesion evolution in multiple sclerosis: Steady‐state metabolism and its relationship to conventional imaging

Although MRI assessment of white matter lesions is essential for the clinical management of multiple sclerosis, the processes leading to the formation of lesions and underlying their subsequent MRI appearance are incompletely understood. We used proton MR spectroscopy to study the evolution of N‐acetyl‐aspartate (NAA), creatine (Cr), choline (Cho), and myo‐inositol (mI) in pre‐lesional tissue, persistent and transient new lesions, as well as in chronic lesions, and related the results to quantitative MRI measures of T1‐hypointensity and T2‐volume. Within 10 patients with relapsing‐remitting course, there were 180 regions‐of‐interest consisting of up to seven semi‐annual follow‐ups of normal‐appearing white matter (NAWM, n = 10), pre‐lesional tissue giving rise to acute lesions which resolved (n = 3) or persisted (n = 3), and of moderately (n = 9) and severely hypointense (n = 6) chronic lesions. Compared with NAWM, pre‐lesional tissue had higher Cr and Cho, while compared with lesions, pre‐lesional tissue had higher NAA. Resolving acute lesions showed similar NAA levels pre‐ and post‐formation, suggesting no long‐term axonal damage. In chronic lesions, there was an increase in mI, suggesting accumulating astrogliosis. Lesion volume was a better predictor of axonal health than T1‐hypointensity, with lesions larger than 1.5 cm³ uniformly exhibiting very low (<4.5 millimolar) NAA concentrations. A positive correlation between longitudinal changes in Cho and in lesion volume in moderately hypointense lesions implied that lesion size is mediated by chronic inflammation. These and other results are integrated in a discussion on the steady‐state metabolism of lesion evolution in multiple sclerosis, viewed in the context of conventional MRI measures. Hum Brain Mapp 38:4047–4063, 2017. © 2017 Wiley Periodicals, Inc.     

Motor evoked potential: A reliable and objective measure to document the functional consequences of multiple sclerosis? Relation to disability and MRI

OBJECTIVE: In an attempt to analyze whether MEP can serve as a valid measure for evaluating neurological dysfunction in multiple sclerosis (MS), we related MEP to clinical and MRI measures. METHODS: Transcranial magnetic stimulation was applied in 52 MS patients to determine the central motor conduction time (CMCT) to the extremities. We calculated Z-scores for each CMCT (Zcmct) corrected for height. All patients underwent two clinical measurements and a MRI scan, of which T1 and T2 brain lesion volumes, brain volume, spinal cord volume and the number of T2 spinal cord lesions were derived. RESULTS: The clinical measurements correlated significantly with various Zcmct (Spearman correlation coefficients ranged from 0.29 to 0.53; p<0.05). The number of spinal cord lesions, brain T1 and T2 lesion volume and spinal cord volume correlated with various Zcmct (r=0.31-0.53; p<0.05). Linear regression analysis revealed that the clinical measurements were explained by Zcmct left leg and T1 lesion volume (adjusted R(2)=0.38). For one clinical measurement the number of spinal cord lesions was also included (adjusted R(2)=0.43). CONCLUSION: We found a relation between MEP, brain and spinal cord MRI measures, and two clinical measures. Moreover, a model for explaining disability in MS revealed that MEP measures provide information in addition to MRI measures. SIGNIFICANCE: This study suggests that MEP is a measure that might adequately reflect pathology and neurological dysfunction in MS.