Mirja Wallner-Blazek

Quantitative assessment of brain iron by R2* relaxometry in patients with clinically isolated syndrome and relapsing–remitting multiple sclerosis

Background Increased iron deposition has been implicated in the pathophysiology of multiple sclerosis (MS), based on visual analysis of signal reduction on T2-weighted images. R2* relaxometry allows to assess brain iron accumulation quantitatively. Objective To investigate regional brain iron deposition in patients with a clinically isolated syndrome (CIS) or relapsing–remitting MS (RRMS) and its associations with demographical, clinical, and conventional magnetic resonance imaging (MRI) parameters. Methods We studied 69 patients (CIS, n = 32; RRMS, n = 37) with 3T MRI and analyzed regional R2* relaxation rates and their correlations with age, disease duration, disability, T2 lesion load, and normalized brain volumes. Results Basal ganglia R2* relaxation rates increased in parallel with age (r = 0.3–0.6; P < 0.01) and were significantly higher in RRMS than in CIS (P < 0.05). Using multivariate linear regression analysis, the rate of putaminal iron deposition was independently predicted by the patients’ age, disease duration, and gray matter atrophy. Conclusions Quantitative assessment by R2* relaxometry suggests increased iron deposition in the basal ganglia of MS patients, which is associated with disease duration and brain atrophy. This technique together with long-term follow-up thus appears suited to clarify whether regional iron accumulation contributes to MS morbidity or merely reflects an epiphenomenon.

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.

Relationships of brain white matter microstructure with clinical and MR measures in relapsing-remitting multiple sclerosis

To assess the relationships of microstructural damage in the cerebral white matter (WM), as measured by diffusion tensor imaging (DTI), with clinical parameters and magnetic resonance imaging (MRI) measures of focal tissue damage in patients with multiple sclerosis (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.

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 3 T 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 (p < 0.001) followed by T2-lesion load (p < 0.05) in RRMS, whereas cortical MT ratio was the only MRI parameter associated with decreased mental processing speed in CIS (p < 0.005). 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.

Lesion probability mapping to explain clinical deficits and cognitive performance in multiple sclerosis

Background: Lesion dissemination in time and space represents a key feature and diagnostic marker of multiple sclerosis (MS). The correlation between magnetic resonance imaging (MRI) lesion load and disability is only modest, however. Strategic lesion location might at least partially account for this ‘clinico-radiologic paradox’. Objectives: Here we used a non-parametric permutation-based approach to map lesion location probability based on MS lesions identified on T2-weighted MRI. We studied 121 patients with clinically isolated syndrome, relapsing–remitting or secondary progressive MS and correlated these maps to assessments of neurologic and cognitive functions. Results: The Expanded Disability Status Scale correlated with bilateral periventricular lesion location (LL), and sensory and coordination functional system deficits correlated with lesion accumulation in distinct anatomically plausible regions, i.e. thalamus and middle cerebellar peduncule. Regarding cognitive performance, decreased verbal fluency correlated with left parietal LL comprising the putative superior longitudinal fascicle. Delayed spatial recall correlated with _amygdalar, _left frontal and parietal LL. Delayed selective reminding correlated with bilateral frontal and temporal LL. However, only part of the spectrum of cognitive and neurological problems encountered in our cohort could be explained by specific lesion location. Conclusions: Lesion probability mapping supports the association of specific lesion locations with symptom development in MS, but only to limited extent.

CSF neurofilament and N-acetylaspartate related brain changes in clinically isolated syndrome

Background: Axonal damage is considered a major cause of disability in multiple sclerosis (MS) and may start early in the disease. Specific biomarkers for this process are of great interest. Objective: To study if cerebrospinal fluid (CSF) biomarkers for axonal damage reflect and predict disease progression already in the earliest stages of the disease, that is, in clinically isolated syndrome (CIS). Methods: We assessed CSF levels of neurofilament heavy (NFH), neurofilament light (NFL) and N-acetylaspartate (NAA) in 67 patients with CIS and 18 controls with neuropsychiatric diseases of non-inflammatory aetiology (NC). Patients with CIS underwent baseline magnetic resonance imaging (MRI) at 3T, and a follow-up MRI after 1 year was obtained in 28 of them. Results: Compared with NC, patients with CIS had higher NFH (p=0.05) and NFL (p<0.001) levels. No significant group differences were found for NAA. Patients’ NFH levels correlated with physical disability (r=0.304, p<0.05) and with change in brain volume over 1 year of follow-up (r=-0.518, p<0.01) but not with change in T2 lesion load. Conclusion: Our results confirm increased neurofilament levels already in CIS being related to the level of physical disability. The association of NFH levels with brain volume but not lesion volume changes supports the association of these markers with axonal damage.

Cognitively preserved MS patients demonstrate functional differences in processing neutral and emotional faces.

The ability to recognize emotional facial expressions is crucial to adequate social behavior. Previous studies have suggested deficits in emotion recognition in multiple sclerosis (MS). These deficits were accompanied by several confounders including cognitive or visual impairments, disease duration, and depression. In our study we used functional MRI (fMRI) to test for potential early adaptive changes in only mildly disabled MS patients performing an emotion recognition task including the facial expressions of the emotions anger, fear and disgust. Fifteen relapsing-remitting MS patients with a median Expanded Disability Status Scale (EDSS) score of 2 (range: 0–3.5) and 15 healthy controls (HC) matched for age, gender, and education underwent behavioral (BERT: behavioral emotion recognition test; BRB-N: Brief Repeatable Battery for neuropsychological tests, WCST: Wisconsin Card Sorting Test) and clinical assessments (BDI: Beck Depression Inventory). Conventional MRI at 3.0T served to assess whole-brain volume, white matter, gray matter, cerebrospinal fluid, and T2-lesion load; during fMRI, participants were confronted with neutral, scrambled, angry, disgusted, and fearful faces, and houses. In the absence of differences in cognitive performance and in the ability to accurately recognize distinct emotional facial expressions, MS patients demonstrated excess fMRI activations during facial recognition compared to HC. These differences concerned the posterior cingulate cortex (PCC) and precuneus for anger and disgust contrasted to neutral faces, and the occipital fusiform gyri and the anterior CC for neutral faces versus houses. This study provides first evidence for excess activation during processing of higher order visual stimuli of emotional content in the absence of emotional, visual or cognitive behavior abnormalities already in earlier stages of MS.

Oxidative stress is associated with migraine and migraine-related metabolic risk in females.

Background and purpose:  Oxidative stress is discussed to be implicated in the pathophysiology of migraine. However, data are in part controversial and the possible underlying mechanisms remain elusive to date. The aim of this study was to investigate the oxidative stress status of female patients with migraine and its implications on migraine‐related metabolic alterations.

Increased nitric oxide stress is associated with migraine

Nitric oxide (NO) has been implicated in migraine attacks, but the role of NO in migraine remains unclear. We here hypothesize that increased NO in the headache-free period is associated with migraine. One hundred and thirty probands participated in this study. Various parameters of the NO pathway, such as nitrate, nitrite, arginine, citrulline, nitrosylated proteins, asymmetric dimethylarginine, symmetrical dimethylarginine, expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase and two polymorphisms of eNOS were investigated. We found significant increased nitrate and decreased nitrite levels in migraineurs in the headache-free period. Nitrate and nitrite levels showed a significant inverse correlation. Logistic regression revealed an odds ratio of 3.6 for migraine. Other parameters of the NO pathway were neither altered in migraineurs nor correlated with nitrate. We show here that migraine patients suffer under sustained increased nitrosative stress in the headache-free period, which is associated with a 3.6-fold higher risk for migraine.