C. Enzinger

Visual Rating of Age-Related White Matter Changes on Magnetic Resonance Imaging Scale Comparison, Interrater Agreement, and Correlations With Quantitative Measurements

Background and Purpose— To provide further insight into the MRI assessment of age-related white matter changes (ARWMCs) with visual rating scales, 3 raters with different levels of experience tested the interrater agreement and comparability of 3 widely used rating scales in a cross-sectional and follow-up setting. Furthermore, the correlation between visual ratings and quantitative volumetric measurement was assessed. Methods— Three raters from different sites using 3 established rating scales (Manolio, Fazekas and Schmidt, Scheltens) evaluated 74 baseline and follow-up scans from 5 European centers. One investigator also rated baseline scans in a set of 255 participants of the Austrian Stroke Prevention Study (ASPS) and measured the volume of ARWMCs. Results— The interrater agreement for the baseline investigation was fair to good for all scales (&kgr; values, 0.59 to 0.78). On the follow-up scans, all 3 raters depicted significant ARWMC progression; however, the direct interrater agreement for this task was poor (&kgr;, 0.19 to 0.39). Comparison of the interrater reliability between the 3 scales revealed a statistical significant difference between the scale of Manolio and that of Fazekas and Schmidt for the baseline investigation (z value, −2.9676;P =0.003), demonstrating better interrater agreement for the Fazekas and Schmidt scale. The rating results obtained with all 3 scales were highly correlated with each other (Spearman rank correlation, 0.712 to 0.806;P ≤0.01), and there was significant agreement between all 3 visual rating scales and the quantitative volumetric measurement of ARWMC (Kendall W, 0.37, 0.48, and 0.57;P <0.001). Conclusions— Our data demonstrate that the 3 rating scales studied reflect the actual volume of ARWMCs well. The 2 scales that provide more detailed information on ARWMCs seemed preferential compared with the 1 that yields more global information. The visual assessment of ARWMC progression remains problematic and may require modifications or extensions of existing rating scales.

Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes

Objective: To assess the time course of brain atrophy and the difference across clinical subtypes in multiple sclerosis (MS). Methods: The percent brain volume change (PBVC) was computed on existing longitudinal (2 time points) T1-weighted MRI from untreated (trial and nontrial) patients with MS. Patients (n = 963) were classified as clinically isolated syndromes suggestive of MS (CIS, 16%), relapsing-remitting (RR, 60%), secondary progressive (SP, 15%), and primary progressive (9%) MS. The median length of follow-up was 14 months (range 12–68). Results: There was marked heterogeneity of the annualized PBVC (PBVC/y) across MS subtypes (p = 0.003), with higher PBVC/y in SP than in CIS (p = 0.003). However, this heterogeneity disappeared when data were corrected for the baseline normalized brain volume. When the MS population was divided into trial and nontrial subjects, the heterogeneity of PBVC/y across MS subtypes was present only in the second group, due to the higher PBVC/y values found in trial data in CIS (p = 0.01) and RR (p < 0.001). The estimation of the sample sizes required for demonstrating a reduction of brain atrophy in patients in a placebo-controlled trial showed that this was larger in patients with early MS than in those with the progressive forms of the disease. Conclusions: This first large study in untreated patients with multiple sclerosis (MS) with different disease subtypes shows that brain atrophy proceeds relentlessly throughout the course of MS, with a rate that seems largely independent of the MS subtype, when adjusting for baseline brain volume.

Determinants of brain iron in multiple sclerosis A quantitative 3T MRI study

Objectives: Abnormal high cerebral iron deposition may be implicated in chronic neurologic disorders, including multiple sclerosis (MS). R2* relaxometry has been recently validated in a postmortem study to indicate brain iron accumulation in a quantitative manner. We used this technique to assess brain iron levels in different stages of MS and healthy controls (HC) and determined their relation with demographic, clinical, neuropsychological, and other imaging variables. Methods: We studied 113 consecutive patients (35 clinically isolated syndrome [CIS], 78 MS) and 35 HC with 3 T MRI and clinical and neuropsychological examination. Iron deposition in subcortical gray matter structures was assessed by automated, regional calculation of R2* rates. Results: Basal ganglia (BG) R2* levels were significantly increased in MS compared to CIS (p < 0.001) and HC (p < 0.005). They were correlated with age (r = 0.5, p < 0.001), disease duration (r = 0.5, p < 0.001), Expanded Disability Status Scale (r = 0.3, p < 0.005), and the z values of mental processing speed (r = −0.3, p < 0.01). Stepwise linear regression analysis revealed gray matter atrophy as the strongest independent predictor of BG R2* levels (p < 0.001), followed by age (p < 0.001) and T2 lesion load (p < 0.005). Conclusion: BG iron accumulation in MS occurs with advancing disease and is related to the extent of morphologic brain damage, which argues for iron deposition as an epiphenomenon. The absence of increased iron levels in patients with CIS indicates that iron accumulation does not precede the development of MS.

Reorganization in cognitive networks with progression of multiple sclerosis Insights from fMRI

Objectives: Cognitive dysfunction (CD) is frequent in multiple sclerosis (MS) and can occur at early stages. Whereas functional reorganization with disease progression has been described for the motor system in MS using fMRI, no such studies exist for cognition. We attempted to assess the concept of functional reorganization concerning cognition using a simple “Go/No-go” fMRI paradigm. Methods: Patients with a clinically isolated syndrome (CIS, n = 10), relapsing-remitting MS (RRMS) (n = 10), or secondary progressive MS (SPMS) (n = 10), and 28 healthy controls (HC), underwent a comprehensive neuropsychological test battery, clinical examination, structural imaging, and an fMRI Go/No-go discrimination task at 3 T. Results: Patients performed worse than HC regarding memory, sustained attention and concentration, and information processing. These differences were driven by patients with SPMS. The fMRI task elicited activation in a widespread network including bilateral mesial and dorsolateral frontal, parietal, insular, basal ganglia, and cerebellar regions. Task performance was similar between phenotypes, but deviation from the activation pattern observed in HC and patients with CIS increased with disease progression. Patients with RRMS showed increased brain activation in the precuneus, both superior parietal lobes, and the right fusiform gyrus, and recruited the hippocampus with increasing demands. Patients with SPMS demonstrated the most abnormal network function, including recruitment of pre-SMA, bilateral superior and inferior parietal, dorsolateral prefrontal, right precentral, bilateral postcentral, and right temporal brain areas. Conclusion: Using a cognitive fMRI paradigm, we were able to confirm adaptive changes of neuronal activation with progressing MS and to provide strong evidence for their compensatory nature, at least partially.

Quantitative magnetization transfer imaging of pre-lesional white-matter changes in multiple sclerosis

Objective: Previous magnetization transfer (MT) studies in multiple sclerosis (MS) suggest a reduction of the MT ratio (MTR) precedes new lesion development. To gain further insight into pre-lesional tissue abnormalities, we investigated the time course of additional quantitative MT parameters. Methods: Serial magnetic resonance imaging (MRI), including a gadolinium-enhanced T1 scan and MT imaging by means of a FastPACE sequence, was performed on 12 patients (4 males, 8 females) with relapsing-remitting MS. Quantitative MT values including the magnetization exchange rate (kfor) and the native relaxation time (T1free) were analysed in the six months prior to the appearance of 44 enhancing lesions and in 88 control regions of persistently normal-appearing white matter (NAWM). Results: Appearance of new active lesions was preceded by a significant decrease of the MTR (F7,166=91.5; p <0.0001) and of kfor (F7,166=105.2; p <0.0001), and by an increase of T1free (F7,166=57.3; p <0.0001). The drop of kfor was the most pronounced pre-lesional change and together with the MTR was statistically significant already four months before the appearance of new lesion. The observed increase of T1free was relatively small. MT variables of reactivated lesions were always different from NAWM but showed no characteristic time course. Conclusions: Multiparametric MT measurements suggest both a reduction of macromolecular material and a focal increase of free water to occur several months before the appearance of an active lesion. Reduction of the magnetization exchange rate, which may result from primary damage to myelin, appears to be the leading event.

Lesion probability maps of white matter hyperintensities in elderly individuals: results of the Austrian stroke prevention study.

ObjectiveWhite matter hyperintensities (WMH) are common on brain MRI of the elderly. Their size ranges from punctate to early confluent to confluent lesions. While this increase in extension is frequently seen as evidence for a continuum of changes, histological data and clinical follow-up suggest differences in underlying pathology and their progression.MethodsWe tested this hypothesis by exploring the distributions of punctuate and confluent lesions using lesion probability maps (LPM) generated from MRI scans of 189 participants (mean age 60.8+/−6.2xa0years) in the Austrian Stroke Prevention Study. We dichotomised WMH according to the classification by Fazekas et al. [punctate (n=143) vs. early confluent and confluent (n=33)] to run voxel-based t-tests using permutation-based nonparametric inference. To test alternative hypotheses, we created similar LPM for age and arterial hypertension.ResultsWe observed significant differences in the spatial distribution of lesions for the two WMH groups (p<0.01). Punctate lesions were more diffusely distributed throughout the cerebral white matter (peak probability ∼5%) relative to confluent lesions (peak probability 45%). Confluent lesions had greatest likelihood of being found in perfusion “watershed” regions. These differences in distribution could not be explained by differences in age or hypertension only, as both greater age and the diagnosis of hypertension were associated with WMH abutting the occipital horns.ConclusionsPunctate and early confluent to confluent WMH show distinguishable differences in their spatial distribution within a normal elderly population. The pattern of punctate WMH is probably a consequence of mixed etiologies. Preferential localization of the more confluent WMH with arterial watershed areas implies a stronger ischemic component in their development.

Cognitive impairment in relation to MRI metrics in patients with clinically isolated syndrome

Background: Cognitive deficits are frequent in multiple sclerosis (MS) and have been associated with morphologic brain changes. Less information exists on their extent and relation to MRI findings in clinically isolated syndrome (CIS). It is also unclear if structural changes as detected by magnetization transfer (MT) imaging may provide an additional explanation for cognitive dysfunction. Objective: To analyse the extent of cognitive deficits and their relation to MRI metrics including MT imaging in CIS compared to relapsing-remitting MS (RRMS). Methods: Forty-four CIS and 80 RRMS patients underwent the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) and a 3u2009T MRI scan. Results: BRB-N subtests revealed similar results in CIS and RRMS. Impaired mental processing speed was most prevalent in both groups (CIS 13.6%; RRMS 16.3%) and thus served for correlation with MRI metrics. Using stepwise linear regression analyses, the strongest predictor for decreased mental processing speed was normalized cortex volume (pu2009<u20090.001) followed by T2-lesion load (pu2009<u20090.05) in RRMS, whereas cortical MT ratio was the only MRI parameter associated with decreased mental processing speed in CIS (pu2009<u20090.005). Conclusion: Cognitive dysfunction occurs in CIS in a pattern similar to RRMS, with impaired mental processing speed being most prevalent. Cortical MT-ratio changes may be an early sign for tissue changes related to impaired mental processing speed in CIS while this association shifts to increased signs of cortical atrophy and lesion load in RRMS.

Acute small subcortical infarctions on diffusion weighted MRI: clinical presentation and aetiology

Objective: To determine the clinical presentation and aetiology of small subcortical infarctions as found on diffusion weighted magnetic resonance imaging (DWI). DWI is both sensitive and specific in the early detection of acute ischaemic brain lesions irrespective of pre-existing vascular damage. Methods: Ninety three patients were identified showing subcortical or brainstem DWI lesions <1.5 cm in diameter within a maximum of 7 days from the onset of stroke symptoms. The patients’ clinical status on admission was reviewed according to the Oxfordshire Community Stroke Project (OCSP). The results of procedures searching for cerebrovascular risk factors, large artery disease, and potential sources of cardiac embolism were included to determine stroke aetiology. Magnetic resonance imaging scans were also reviewed for concomitant changes that could support the aetiologic classification. Results: Only 41 (44.1%) patients presented clinically with a lacunar syndrome according to OCSP criteria. The nine (9.7%) patients who showed two or more DWI lesions in different vascular territories were also significantly more likely to have potential sources of cardiac embolism (5/9, 55.6% v 20/84, 23.8%). Hypertension was significantly more prevalent in the group of patients who showed a microangiopathy related imaging pattern, but this pattern did not exclude the presence of large artery disease or a possible cardioembolic source of stroke. Conclusion: Identification of small subcortical infarctions as the cause of stroke appears quite uncertain based on clinical characteristics only. DWI adds significant aetiologic information but does not obviate the search for other potentially causative mechanisms.

Clinically benign multiple sclerosis despite large T2 lesion load: Can we explain this paradox?

Magnetic resonance imaging (MRI) techniques such as magnetization transfer imaging and magnetic resonance spectroscopy (MRS) may reveal otherwise undetectable tissue damage in multiple sclerosis (MS) and can serve to explain more severe disability than expected from conventional MRI. That an inverse situation may exist where non-conventional quantitative MRI and MRS metrics would indicate less abnormality than expected from T2 lesion load to explain preserved clinical functioning was hypothesized. Quantitative MRI and MRS were obtained in 13 consecutive patients with clinically benign MS (BMS; mean age 44 ± 9 years) despite large T 2 lesion load and in 15 patients with secondary progressive MS (SPMS; mean age 47 ± 6 years) matched for disease duration. The magnetization transfer ratio (MTR), magnetization transfer rate (k for), brain parenchymal fraction (BPF) and brain metabolite concentrations from proton MRS were determined. BMS patients were significantly less disabled than their SPMS counterparts (mean expanded disability status score: 2.1 ± 1.1 versus 6.2 ± 1.1; P < 0.001) and had an even somewhat higher mean T2 lesion load (41.2 ± 27.1 versus 27.9 ± 24.8 cm3; P = 0.19). Normal appearing brain tissue histogram metrics for MTR and k for, mean MTR and k for of MS lesions and mean BPF were similar in BMS and SPMS patients. Levels of N-acetyl-aspartate, choline and myoinositol were comparable between groups. This study thus failed to explain the preservation of function in our BMS patients with large T2 lesion load by a higher morphologic or metabolic integrity of the brain parenchyma. Functional compensation must come from other mechanisms such as brain plasticity. Multiple Sclerosis 2008; 14: 205—211. http://msj.sagepub.com

The impact of sex and vascular risk factors on brain tissue changes with aging: magnetization transfer imaging results of the Austrian stroke prevention study.

BACKGROUND AND PURPOSE: Quantitative MR imaging techniques allow detection of subtle tissue changes that occur with brain aging beyond the accumulation of WMH and brain atrophy. To what extent sex and cerebrovascular risk factors impact these changes is largely unknown. We attempted to study these risk factors in the context of the community-based ASPS. MATERIAL AND METHODS: We performed MTI in 328 neurologically asymptomatic ASPS participants (age range, 52–87 years). FLAIR was used to delineate WMH and to define NABT. The MTR was measured globally in NABT by using a histogram analysis technique and focally in WMH. Associations of MTR metrics with sex and a large battery of different cerebrovascular risk factors (age, arterial hypertension, diabetes mellitus, smoking, body mass index, cholesterol and triglyceride levels, glycated hemoglobin, and the presence of cardiac disease) were assessed with univariate and multiple regression analysis. RESULTS: Age was seen to affect all MTR histogram metrics of NABT, and a faster decrease of the MTR peak height occurred in men. Independent associations with MTR metrics were found for arterial hypertension and diabetes mellitus. Besides lesion grade, arterial hypertension was also significantly associated with a lower MTR in WMH. CONCLUSIONS: Microstructural tissue changes of NABT increase with aging and may be more extensive in men. Diabetes mellitus and hypertension appear to add to tissue destruction. The exact mechanisms involved await further clarification.