Quantitative Susceptibility Mapping to Assess Cerebral Vascular Compliance.

This study explored whether autoregulatory shifts in cerebral blood volume induce susceptibility changes large enough to be depicted by quantitative susceptibility mapping. Eight healthy subjects underwent fast quantitative susceptibility mapping at 3T while lying down to slowly decrease mean arterial pressure. A linear relationship between mean arterial pressure and susceptibility was observed in cortical and subcortical structures, likely representing vessels involved in autoregulation. The slope of this relationship is assumed to indicate the extent of cerebral vascular compliance.

Thalamic Iron Differentiates Primary-Progressive and Relapsing-Remitting Multiple Sclerosis.

BACKGROUND AND PURPOSE: Potential differences between primary progressive and relapsing remitting multiple sclerosis are the subject of ongoing controversial discussions. The aim of this work was to determine whether and how primary-progressive and relapsing-remitting multiple sclerosis subtypes differ regarding conventional MR imaging parameters, cerebral iron deposits, and their association with clinical status. MATERIALS AND METHODS: We analyzed 24 patients with primary-progressive MS, 80 with relapsing-remitting MS, and 20 healthy controls with 1.5T MR imaging for assessment of the conventional quantitative parameters: T2 lesion load, T1 lesion load, brain parenchymal fraction, and corpus callosum volume. Quantitative susceptibility mapping was performed to estimate iron concentration in the deep gray matter. RESULTS: Decreased susceptibility within the thalamus in relapsing-remitting MS compared with primary-progressive MS was the only significant MR imaging difference between these MS subtypes. In the relapsing-remitting MS subgroup, the Expanded Disability Status Scale score was positively associated with conventional parameters reflecting white matter lesions and brain atrophy and with iron in the putamen and caudate nucleus. A positive association with putaminal iron and the Expanded Disability Status Scale score was found in primary-progressive MS. CONCLUSIONS: Susceptibility in the thalamus might provide additional support for the differentiation between primary-progressive and relapsing-remitting MS. That the Expanded Disability Status Scale score was associated with conventional MR imaging parameters and iron concentrations in several deep gray matter regions in relapsing-remitting MS, while only a weak association with putaminal iron was observed in primary-progressive MS suggests different driving forces of disability in these MS subtypes.

Mechanical characterization of human brain tissue.

Mechanics are increasingly recognized to play an important role in modulating brain form and function. Computational simulations are a powerful tool to predict the mechanical behavior of the human brain in health and disease. The success of these simulations depends critically on the underlying constitutive model and on the reliable identification of its material parameters. Thus, there is an urgent need to thoroughly characterize the mechanical behavior of brain tissue and to identify mathematical models that capture the tissue response under arbitrary loading conditions. However, most constitutive models have only been calibrated for a single loading mode. Here, we perform a sequence of multiple loading modes on the same human brain specimen - simple shear in two orthogonal directions, compression, and tension - and characterize the loading-mode specific regional and directional behavior. We complement these three individual tests by combined multiaxial compression/tension-shear tests and discuss effects of conditioning and hysteresis. To explore to which extent the macrostructural response is a result of the underlying microstructural architecture, we supplement our biomechanical tests with diffusion tensor imaging and histology. We show that the heterogeneous microstructure leads to a regional but not directional dependence of the mechanical properties. Our experiments confirm that human brain tissue is nonlinear and viscoelastic, with a pronounced compression-tension asymmetry. Using our measurements, we compare the performance of five common constitutive models, neo-Hookean, Mooney-Rivlin, Demiray, Gent, and Ogden, and show that only the isotropic modified one-term Ogden model is capable of representing the hyperelastic behavior under combined shear, compression, and tension loadings: with a shear modulus of 0.4-1.4kPa and a negative nonlinearity parameter it captures the compression-tension asymmetry and the increase in shear stress under superimposed compression but not tension. Our results demonstrate that material parameters identified for a single loading mode fail to predict the response under arbitrary loading conditions. Our systematic characterization of human brain tissue will lead to more accurate computational simulations, which will allow us to determine criteria for injury, to develop smart protection systems, and to predict brain development and disease progression. STATEMENT OF SIGNIFICANCE: There is a pressing need to characterize the mechanical behavior of human brain tissue under multiple loading conditions, and to identify constitutive models that are able to capture the tissue response under these conditions. We perform a sequence of experimental tests on the same brain specimen to characterize the regional and directional behavior, and we supplement our tests with DTI and histology to explore to which extent the macrostructural response is a result of the underlying microstructure. Results demonstrate that human brain tissue is nonlinear and viscoelastic, with a pronounced compression-tension asymmetry, and we show that the multiaxial data can best be captured by a modified version of the one-term Ogden model.

Cerebrospinal fluid lipocalin 2 in patients with clinically isolated syndromes and early multiple sclerosis.

BACKGROUND: Lipocalin 2 (LCN2) may be involved in the immunopathogenesis of multiple sclerosis (MS) and might further impact on iron homoeostasis. Brain iron accumulates in MS; however, the association to iron-related proteins is still unsolved. OBJECTIVE: To investigate cerebrospinal fluid (CSF) and serum LCN2, transferrin (Trf) and ferritin in early MS in relation to disease evolution and longitudinal brain iron accumulation. METHODS: We analysed CSF and serum LCN2 by enzyme-linked immunosorbent assay (ELISA) and Trf and ferritin by nephelometry in 55 patients (45 clinically isolated syndrome (CIS), 10 MS, median clinical follow-up 4.8 years) and 63 controls. In patients, we assessed sub-cortical grey matter iron by 3T magnetic resonance imaging (MRI) R2* relaxometry (median imaging follow-up 2.2 years). RESULTS: Compared to controls serum (p < 0.01), CSF (p < 0.001) LCN2 and CSF Trf (p < 0.001) levels were reduced in the patients. CSF LCN2 correlated with CSF Trf (r = 0.5, p < 0.001). In clinically stable patients, CSF LCN2 levels correlated with basal ganglia iron accumulation (r = 0.5, p < 0.05). In CIS, higher CSF LCN2 levels were associated with conversion to clinically definite MS (p < 0.05). CONCLUSION: We demonstrate altered LCN2 regulation in early MS and provide first evidence for this to be possibly linked to both clinical MS activity and iron accumulation in the basal ganglia.

Combined analysis of global and compartmental brain volume changes in early multiple sclerosis in clinical practice.

BACKGROUND: The extent and clinical significance of brain volume changes in different phases of multiple sclerosis (MS) is still under discussion. OBJECTIVE: To determine the rate of global and compartmental brain volume changes in patients with a clinically-isolated syndrome (CIS) compared to patients with definite MS, by long-term follow-up and as a predictor of conversion to MS in a routine clinical setting. METHODS: We investigated 120 patients (63 CIS and 57 MS) at baseline and after a mean follow-up period of 43 months, including detailed clinical examination and 3-Tesla magnetic resonance imaging (MRI). Our imaging analyses comprised the normalized brain volume (NBV), cortical grey matter (cGMV) and white matter (WMV) volumes using SIENA/X, the percentage of brain volume change (PBVC) using SIENA and the change in the volume of the thalami (TV) and basal ganglia (BGV). We also determined the amount and change of T2-lesion load (T2-LL). RESULTS: At baseline, all the brain volume metrics, except cGMV, were significantly lower; and the T2-LL was significantly higher, in patients with MS rather than CIS. During the follow-up, only the PBVC was higher in MS (p = 0.008) and this difference was driven by converters from CIS to MS. Quartiles of PBVC did not allow us to predict conversion to MS, but were associated with the degree of disability. CONCLUSIONS: PBVC is the most sensitive marker of progressing atrophy and a higher PBVC was generally associated with more active disease; however, it did not serve to predict the course of MS on an individual basis, in this study.

Cerebrospinal fluid transferrin levels are reduced in patients with early multiple sclerosis.

BACKGROUND: Previous magnetic resonance imaging (MRI) studies have demonstrated increased iron deposition in the basal ganglia of multiple sclerosis (MS) patients. However, it is not clear whether these alterations are associated with changes of iron metabolism in body fluids. OBJECTIVES: The purpose of this study was to investigate if iron metabolism markers in cerebrospinal fluid (CSF) and serum of clinically isolated syndrome (CIS) and MS patients differ from controls and how they relate to clinical and imaging parameters. METHODS: We analysed serum ferritin, transferrin and soluble transferrin-receptor and CSF ferritin and transferrin by nephelometry in non-anaemic CIS (n=60) or early MS (n=14) patients and 68 controls. In CIS/MS we additionally assessed the T2 lesion load. RESULTS: CSF transferrin was significantly decreased in CIS/MS compared to controls (p<0.001), while no significant differences were seen in serum. Higher CSF transferrin levels correlated with lower physical disability scores (r= -0.3, p<0.05). CSF transferrin levels did not correlate with other clinical data and the T2 lesion load. CONCLUSION: Our biochemical study provides evidence that altered iron homeostasis within the brain occurs in the very early phases of the disease, and suggests that the transporter protein transferrin may play a role in the increased iron deposition known to occur in the brain of MS patients.

Differences and similarities in the evolution of morphologic brain abnormalities between paediatric and adult-onset multiple sclerosis.

BACKGROUND: Paediatric-onset multiple sclerosis (pMS) is multiple sclerosis (MS) occurring before the age of 18 years and may present and develop differently from adult-onset MS (aMS). Whether there are also differences regarding the accrual of brain changes is largely unknown. METHODS: We compared the evolution of the T2- and T1-lesion load (LL), the black hole ratio (BHR), and annualised brain volume change (aBVC) between 21 pMS patients (age at onset: 14.4±2.3 years) and 21 aMS patients (age at onset: 29.4±6.5 years) matched for disease duration (pMS: 1.0±1.8 years; aMS: 1.6±1.7 years, p=0.27). Follow-up was for 4.2±3.7 years in pMS and 3.1±0.6 years in aMS. Clinical comparisons included the course of disability assessed with the Expanded Disability Status Scale (EDSS) score and annualised relapse rate (ARR). RESULTS: At baseline, pMS and aMS had similar EDSS, T1-LL, BHR, whereas T2-LL was higher in aMS (aMS: 9.2±11.6 ccm; pMS: 4.1±6.2 ccm, p=0.02). The change of T2-LL and T1-LL during the observation period was similar in both groups. At follow-up, disability was lower in pMS (EDSS score in pMS: 0.9±0.9; aMS: 1.7±1.3, p=0.04), despite a significantly higher accrual of destructive brain lesions (BHR in pMS: 23.7±23.7%; aMS: 5.9±4.0%, p=0.02) and a similar rate of brain volume loss. CONCLUSION: Our observation of a morphologically more aggressive disease evolution paralleled by less disability in pMS than in aMS (defined using EDSS) suggests a higher compensatory capacity in pMS. This fact may obscure the need for treatment of pMS patients with disease modifying treatments (DMTs) based solely on clinical observation.

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.

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.

The functional correlates of face perception and recognition of emotional facial expressions as evidenced by fMRI.

Recognition and processing of emotional facial expression are crucial for social behavior and employ higher-order cognitive and visual working processes. In neuropsychiatric disorders, impaired emotion recognition most frequently concerned three specific emotions, i.e., anger, fear, and disgust. As incorrect processing of (neutral) facial stimuli per se might also underlie deficits in the recognition of emotional facial expressions, we aimed to assess all these aspects in one experiment. We therefore report here a functional magnetic resonance imaging (fMRI) paradigm for parallel assessment of the neural correlates of both the recognition of neutral faces and the three clinically most relevant emotions for future use in patients with neuropsychiatric disorders. FMRI analyses were expanded through comparisons of the emotional conditions with each other. The differential insights resulting from these two analyses strategies are compared and discussed. 30 healthy participants (21 F/9 M; age 36.3 ± 14.3, 17-66 years) underwent fMRI and behavioral testing for non-emotional and emotional face recognition. Recognition of neutral faces elicited activation in the fusiform gyri. Processing angry faces led to activation in left middle and superior frontal gyri and the anterior cingulate cortex. There was considerable heterogeneity regarding the fear versus neutral contrast, resulting in null effects for this contrast. Upon recognition of disgust, activation was noted in bilateral occipital, in the fronto-orbital cortex and in the insula. Analyzing contrasts between emotional conditions showed similar results (to those of contrasting with reference conditions) for separated emotional network patterns. We demonstrate here that our paradigm reproduces single aspects of separate previous studies across a cohort of healthy subjects, irrespective of age. Our approach might prove useful in future studies of patients with neurologic disorders with potential effect on emotion recognition.

Fast bound pool fraction mapping using stimulated echoes.

Magnetization transfer imaging advanced to an indispensible tool for investigating white matter changes. Quantitative magnetization transfer imaging methods allow the determination of the bound pool fraction (BPF), which is thought to be directly linked to myelin integrity. Long acquisition times and high specific absorption rates are still inhibiting broad in vivo utilization of currently available BPF mapping techniques. Herewith, a stimulated echoes amplitude modulation-based, single-shot echo planar imaging technique for BPF and T(1) quantification is presented at 3T. It allows whole brain mapping in 10-15 min and is low in specific absorption rates. The method was validated with different concentrations of bovine serum albumin (BSA) phantoms. Intra- and inter-subject variability was assessed in vivo. Phantom measurements verified linearity between bovine serum albumin concentrations and measured BPF, which was independent of T(1) variations. T(1) values in the phantoms correlated well with values provided by standard T(1) mapping methods. Intrasubject variability was minimal and mean regional BPFs of 10 volunteers (e.g., left frontal white matter=0.135 ± 0.003, right frontal white matter=0.129 ± 0.006) were in line with previously published data. Assessment of interhemispheric BPF differences revealed significantly higher BPF for the left brain hemisphere. To sum up, these results suggest the proposed method useful for cross-sectional and longitudinal studies of white matter changes in the human brain.

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.

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.

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.