NfL and GFAP in serum are associated with microstructural brain damage in progressive multiple sclerosis.

BACKGROUND: The potential of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) as biomarkers of disease activity and severity in progressive forms of multiple sclerosis (MS) is unclear. OBJECTIVE: To investigate the relationship between serum concentrations of NfL, GFAP, and magnetic resonance imaging (MRI) in progressive MS. METHODS: Serum concentrations of NfL and GFAP were measured in 32 healthy controls and 32 patients with progressive MS from whom clinical and MRI data including diffusion tensor imaging (DTI) were obtained during three years of follow-up. RESULTS: Serum concentrations of NfL and GFAP at follow-up were higher in progressive MS patients than in healthy controls and serum NfL correlated with the EDSS score. Decreasing fractional anisotropy (FA) in normal-appearing white matter (NAWM) correlated with worsening EDSS scores and higher serum NfL. Higher serum NfL and increasing T2 lesion volume correlated with worsening paced autitory serial addition test scores. In multivariable regression analyses with serum GFAP and NfL as independent factors and DTI measures of NAWM as dependent factors, we showed that high serum NfL at follow-up was independently associated with decreasing FA and increasing MD in NAWM. Moreover, we found that high serum GFAP was independently associated with decreasing MD in NAWM and with decreasing MD and increasing FA in cortical gray matter. CONCLUSION: Serum concentrations of NfL and GFAP are increased in progressive MS and are associated with distinct microstructural changes in NAWM and CGM.

Uncovering a Role for the Dorsal Hippocampal Commissure in Recognition Memory.

The dorsal hippocampal commissure (DHC) is a white matter tract that provides interhemispheric connections between temporal lobe brain regions. Despite the importance of these regions for learning and memory, there is scant evidence of a role for the DHC in successful memory performance. We used diffusion-weighted magnetic resonance imaging (DW-MRI) and white matter tractography to reconstruct the DHC in both humans (in vivo) and nonhuman primates (ex vivo). Across species, our findings demonstrate a close consistency between the known anatomy and tract reconstructions of the DHC. Anterograde tract-tracer techniques also highlighted the parahippocampal origins of DHC fibers in nonhuman primates. Finally, we derived diffusion tensor MRI metrics from the DHC in a large sample of human subjects to investigate whether interindividual variation in DHC microstructure is predictive of memory performance. The mean diffusivity of the DHC correlated with performance in a standardized recognition memory task, an effect that was not reproduced in a comparison commissure tract-the anterior commissure. These findings highlight a potential role for the DHC in recognition memory, and our tract reconstruction approach has the potential to generate further novel insights into the role of this previously understudied white matter tract in both health and disease.

Multidimensional diffusion MRI with spectrally modulated gradients reveals unprecedented microstructural detail.

Characterization of porous media is essential in a wide range of biomedical and industrial applications. Microstructural features can be probed non-invasively by diffusion magnetic resonance imaging (dMRI). However, diffusion encoding in conventional dMRI may yield similar signatures for very different microstructures, which represents a significant limitation for disentangling individual microstructural features in heterogeneous materials. To solve this problem, we propose an augmented multidimensional diffusion encoding (MDE) framework, which unlocks a novel encoding dimension to assess time-dependent diffusion specific to structures with different microscopic anisotropies. Our approach relies on spectral analysis of complex but experimentally efficient MDE waveforms. Two independent contrasts to differentiate features such as cell shape and size can be generated directly by signal subtraction from only three types of measurements. Analytical calculations and simulations support our experimental observations. Proof-of-concept experiments were applied on samples with known and distinctly different microstructures. We further demonstrate substantially different contrasts in different tissue types of a post mortem brain. Our simultaneous assessment of restriction size and shape may be instrumental in studies of a wide range of porous materials, enable new insights into the microstructure of biological tissues or be of great value in diagnostics.

Thalamocortical Connectivity and Microstructural Changes in Congenital and Late Blindness.

There is ample evidence that the occipital cortex of congenitally blind individuals processes nonvisual information. It remains a debate whether the cross-modal activation of the occipital cortex is mediated through the modulation of preexisting corticocortical projections or the reorganisation of thalamocortical connectivity. Current knowledge on this topic largely stems from anatomical studies in animal models. The aim of this study was to test whether purported changes in thalamocortical connectivity in blindness can be revealed by tractography based on diffusion-weighted magnetic resonance imaging. To assess the thalamocortical network, we used a clustering method based on the thalamic white matter projections towards predefined cortical regions. Five thalamic clusters were obtained in each group representing their cortical projections. Although we did not find differences in the thalamocortical network between congenitally blind individuals, late blind individuals, and normal sighted controls, diffusion tensor imaging (DTI) indices revealed significant microstructural changes within thalamic clusters of both blind groups. Furthermore, we find a significant decrease in fractional anisotropy (FA) in occipital and temporal thalamocortical projections in both blind groups that were not captured at the network level. This suggests that plastic microstructural changes have taken place, but not in a degree to be reflected in the tractography-based thalamocortical network.

Spinal cord atrophy in anterior-posterior direction reflects impairment in multiple sclerosis.

OBJECTIVE: To investigate how atrophy is distributed over the cross section of the upper cervical spinal cord and how this relates to functional impairment in multiple sclerosis (MS). METHODS: We analysed the structural brain MRI scans of 54 patients with relapsing-remitting MS (n=22), primary progressive MS (n=9), secondary progressive MS (n=23) and 23 age- and sex-matched healthy controls. We measured the cross-sectional area (CSA), left-right width (LRW) and anterior-posterior width (APW) of the spinal cord at the segmental level C2. We tested for a nonparametric linear relationship between these atrophy measures and clinical impairments as reflected by the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impairment Scale (MSIS). RESULTS: In patients with MS, CSA and APW but not LRW were reduced compared to healthy controls (P<.02) and showed significant correlations with EDSS, MSIS and specific MSIS subscores. CONCLUSION: In patients with MS, atrophy of the upper cervical cord is most evident in the antero-posterior direction. As APW of the cervical cord can be readily derived from standard structural MRI of the brain, APW constitutes a clinically useful neuroimaging marker of disease-related neurodegeneration in MS.

Functional implications of corticospinal tract impairment on gait after spinal cord injury.

OBJECTIVE: Maximum toe elevation during walking is an objective measure of foot drop and reflects the impairment of the corticospinal tract (CST) in persons with spinal cord injury (SCI). To determine if this measurement is functionally relevant to ambulatory abilities, we correlated maximum toe elevation with clinical physiotherapy tests. SETTING: Cross-sectional study, laboratory and clinical settings. METHODS: A total of 24 individuals with SCI (American Spinal Injury Association (ASIA) Impairment Scale D) were recruited. Maximum toe elevation during the swing phase of treadmill gait was measured with a kinematic system. CST function was assessed in a sitting position by measuring the motor-evoked potentials (MEPs) induced in tibialis anterior muscle with transcranial magnetic stimulation over the motor cortex. Clinical tests performed were 10-m and 6-min walk test (6MWT), Timed-Up and Go (TUG), Walking Index for Spinal Cord Injury, Berg Balance Scale, Lower Extremity Motor Score (LEMS) and sensory score of the L4, L5 and S1 dermatomes. RESULTS: Participants with lower toe elevation during gait walked at a slower speed, took more time to perform the TUG test, and covered a shorter distance in the 6MWT. They also scored lower on the LEMS and showed impaired superficial sensitivity of the dermatomes around the ankles. Few correlations were observed between CST function and clinical tests, but the presence of MEP at rest was indicative of faster speed and longer distance in the 6MWT. CONCLUSION: These results indicate that maximum toe elevation, which is directly correlated with CST impairment, is functionally relevant as it also correlates with timed clinical tests, LEMS and sensory scores.

Independent spinal cord atrophy measures correlate to motor and sensory deficits in individuals with spinal cord injury.

STUDY DESIGN: Cross-sectional descriptive analysis of magnetic resonance imaging (MRI) and clinical outcome. OBJECTIVES: The aim of this study was to present anatomically consistent and independent spinal cord atrophy measures based on standard MRI material and analyze their specific relations to sensory and motor outcome in individuals with chronic incomplete spinal cord injury (SCI). SETTING: Danish study on human SCI. METHODS: We included 19 individuals with chronic incomplete SCI and 16 healthy controls. Participants underwent MRI and a neurological examination including sensory testing for light touch and pinprick, and muscle strength. Antero-posterior width (APW), left-right width (LRW) and cross-sectional spinal cord area (SCA) were extracted from MRI at the spinal level of C2. The angular variation of the spinal cord radius over the full circle was also extracted and compared with the clinical scores. RESULTS: The motor score was correlated to LRW and the sensory scores were correlated to APW. The scores correlated also well with decreases in spinal cord radius in oblique angles in coherent and non-overlapping sectors for the sensory and motor qualities respectively. CONCLUSION: APW and LRW can be used to assess sensory and motor function independently. The finding is corresponding well with the respective locations of the main sensory and motor pathways.

Cerebral activation is correlated to regional atrophy of the spinal cord and functional motor disability in spinal cord injured individuals.

Recovery of function following lesions in the nervous system requires adaptive changes in surviving circuitries. Here we investigate whether changes in cerebral activation are correlated to spinal cord atrophy and recovery of functionality in individuals with incomplete spinal cord injury (SCI). 19 chronic SCI individuals and 7 age-comparable controls underwent functional magnetic resonance imaging (fMRI) while performing rhythmic dorsiflexion of the ankle. A significant negative correlation was found between the activation in the ipsilateral motor (M1) and bilateral premotor cortex (PMC) on one hand and the functional ability of the SCI participants measured by the clinical motor score on the other. There was no significant correlation between activation in any other cerebral area and the motor score. Activation in ipsilateral somatosensory cortex (S1), M1 and PMC was negatively correlated to the width of the spinal cord in the left-right direction, where the corticospinal tract is located, but not in the antero-posterior direction. There was a tendency for a negative correlation between cerebral activation in ipsilateral S1, M1 and PMC and the amplitude of motor evoked potentials in the tibialis anterior muscle elicited by transcranial magnetic stimulation, but this did not reach statistical significance. There was no correlation between motor score or spinal cord dimensions and the volume of the cortical motor areas. The observations show that lesion of descending tracts in the lateral part of the spinal cord results in increased activation in ipsilateral motor and sensory areas, which may help to compensate for the functional deficit following SCI.