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.

Reduced urinary glutamate levels are associated with the frequency of migraine attacks in females.

BACKGROUND AND PURPOSE: Recent evidences indicate that glutamatergic homeostasis disorders are implicated in the pathogenesis of migraine. In particular, plasma and cerebrospinal fluid glutamate levels seem to be altered in migraine patients. However, the impacts of glutamate on migraine and especially on aura symptoms, alterations in the frequency of migraine attacks as well as investigations on glutamate on migraine-related metabolic dysfunctions, like hyperinsulinaemia, and an atherogenic lipid profile remain elusive to date. The aim of the present study was to investigate the impact of glutamate on migraine and related metabolic dysfunctions. METHODS: We investigated the urinary glutamate levels of female migraineurs (n = 48) in the interictal phase and healthy controls (n = 48). Parameters of the insulin- and lipid metabolism, inflammatory parameters and anthropometric parameters were additionally determined. RESULTS: Urinary glutamate levels of female migraineurs were significantly decreased with respect to the control group. Logistic regression revealed an odds ratio of 4.04 for migraine. We found a significant correlation with the time-period of patients' last attack and a significant inverse correlation with the annual frequency of migraine attacks. Other parameters of the insulin- and lipid metabolism, anthropometric and inflammatory parameters showed no significant correlation with glutamate levels. CONCLUSION: We show here that female migraineurs exhibit decreased urinary glutamate levels which are associated with a 4.04-fold higher risk for migraine and correlated with patients' frequency of migraine attacks.

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.

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. METHODS: Oxidative stress markers malondialdehyde (MDA), 4-hydroxy-2-nonenal (HNE), carbonylated proteins, parameters of associated nitric oxide stress, inflammation, lipid- and glucose-metabolism were determined in the interictal phase in female patients with migraine and controls. RESULTS: We found significantly increased HNE levels in female migraineurs compared with controls. Logistic regression analyses of HNE revealed an odds ratio for migraine of 4.55. HNE showed significant correlations with the nitric oxide pathway, the insulin- and the lipid-metabolism. CONCLUSIONS: We show here that increased oxidative stress is associated with migraine and contributes to migraine-related metabolic risk like nitrosative stress, an atherogenic lipid profile and hyperinsulinemia. Our data suggest that oxidative stress may represent a key event in the pathophysiology of migraine and a suitable therapeutic target.

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.

Predicting the severity of relapsing-remitting MS: the contribution of cross-sectional and short-term follow-up MRI data.

BACKGROUND AND OBJECTIVE: Predicting the long-term clinical course of multiple sclerosis (MS) is difficult on clinical grounds. Recent studies have suggested magnetic resonance imaging (MRI) metrics to be helpful. We wanted to confirm this. METHODS: Contactable individuals (N=84) from an initial 99 patients with relapsing-remitting MS (RRMS) who had undergone careful baseline and 2-year follow-up examinations including MRI were reassessed after a mean of 10.8±2.7 years. We investigated using multivariate linear regression analyses if clinical and MRI data obtained at the prior time-points and the rates of change in morphologic variables over a mean observational period of 2.5 years could have served to predict a patient's MS severity score (MSSS) 11 years later. Conversion to secondary progressive MS (SPMS) was a further outcome variable. RESULTS: In univariate analyses, the 'black hole ratio' (BHR) at baseline (p=0.017, beta=0.148) and at first follow-up (p=0.007, beta= -0.154) was the only MRI parameter showing a significant correlation with the MSSS. In a multiple regression model, the independent predictive value of imaging variables became statistically non-significant and the latest MSSS was predicted primarily by the baseline EDSS (r (2)=0.28; p<0.001). The BHR at baseline explained 9.4% of variance of conversion to SPMS (p=0.033). Over the observational period the MSSS remained stable in patients remaining RRMS, but increased in converters to SPMS from 4.0 to 6.4. CONCLUSIONS: We failed to confirm a clear independent contribution of cross-sectional and short-term follow-up MRI data for the prediction of the long-term clinical course of MS. The MSSS is not a stable indicator of disease severity but may increase in converters to SPMS.

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.

Increased matrix metalloproteinase activity is associated with migraine and migraine-related metabolic dysfunctions.

OBJECTIVE: Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are discussed to be involved in the pathophysiology of migraine. Moreover, MMPs may also be involved in migraine-related metabolic alterations like an atherogenic lipid profile and hyperinsulinemia. The aim of this study was to investigate the impact of MMPs and TIMPs on migraine with and without aura and related metabolic dysfunctions. METHODS: MMP activity, six MMPs and three TIMPs, parameters of the insulin and lipid metabolism as well as anthropometric parameters were determined in 124 non-obese subjects. RESULTS: We found highly significant increased MMP activity in migraine patients independent of aura symptoms, which was associated with migraine with an odds ratio of 7.57. Interestingly, none of the determined MMPs and TIMPs showed significant different serum levels between migraine patients and healthy controls. We found significant correlations between MMP activity and parameters of the insulin and lipid metabolism, like Homeostasis Model Assessment index (HOMA index), cholesterol, triglycerides, and oxidized LDL. CONCLUSION: We show here that increased MMP activity is tightly associated with migraine and migraine-related hyperinsulinemia and atherogenic lipid alterations. Our findings represent a new pathophysiological mechanism, which may be of clinical relevance, especially in regard to therapeutic approaches using MMP inhibitors.

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.

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.

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.

Quantitative assessment of brain iron by R(2)* 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 T(2)-weighted images. R(2)* 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 R(2)* relaxation rates and their correlations with age, disease duration, disability, T(2) lesion load, and normalized brain volumes. RESULTS: Basal ganglia R(2)* 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 R(2)* 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.