0000000000049473
AUTHOR
Julia Krämer
Early silent microstructural degeneration and atrophy of the thalamocortical network in multiple sclerosis
Recent studies on patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS) demonstrated thalamic atrophy. Here we addressed the following question: Is early thalamic atrophy in patients with CIS and relapsing-remitting MS (RRMS) mainly a direct consequence of white matter (WM) lesions-as frequently claimed-or is the atrophy stronger correlated to "silent" (nonlesional) microstructural thalamic alterations? One-hundred and ten patients with RRMS, 12 with CIS, and 30 healthy controls were admitted to 3 T magnetic resonance imaging. Fractional anisotropy (FA) was computed from diffusion tensor imaging (DTI) to assess thalamic and WM microstructure. The relative thalamic vol…
Translational value of choroid plexus imaging for tracking neuroinflammation in mice and humans.
Neuroinflammation is a pathophysiological hallmark of multiple sclerosis and has a close mechanistic link to neurodegeneration. Although this link is potentially targetable, robust translatable models to reliably quantify and track neuroinflammation in both mice and humans are lacking. The choroid plexus (ChP) plays a pivotal role in regulating the trafficking of immune cells from the brain parenchyma into the cerebrospinal fluid (CSF) and has recently attracted attention as a key structure in the initiation of inflammatory brain responses. In a translational framework, we here address the integrity and multidimensional characteristics of the ChP under inflammatory conditions and question w…
Sex-specific signatures of intrinsic hippocampal networks and regional integrity underlying cognitive status in multiple sclerosis
Abstract The hippocampus is an anatomically compartmentalized structure embedded in highly wired networks that are essential for cognitive functions. The hippocampal vulnerability has been postulated in acute and chronic neuroinflammation in multiple sclerosis, while the patterns of occurring inflammation, neurodegeneration or compensation have not yet been described. Besides focal damage to hippocampal tissue, network disruption is an important contributor to cognitive decline in multiple sclerosis patients. We postulate sex-specific trajectories in hippocampal network reorganization and regional integrity and address their relationship to markers of neuroinflammation, cognitive/memory per…
Gray matter integrity predicts white matter network reorganization in multiple sclerosis
Abstract Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease leading to gray matter atrophy and brain network reconfiguration as a response to increasing tissue damage. We evaluated whether white matter network reconfiguration appears subsequently to gray matter damage, or whether the gray matter degenerates following alterations in white matter networks. MRI data from 83 patients with clinically isolated syndrome and early relapsing–remitting MS were acquired at two time points with a follow‐up after 1 year. White matter network integrity was assessed based on probabilistic tractography performed on diffusion‐weighted data using graph theoretical analyses. We ev…
Increased cerebrospinal fluid albumin and immunoglobulin A fractions forecast cortical atrophy and longitudinal functional deterioration in relapsing-remitting multiple sclerosis.
Background: Currently, no unequivocal predictors of disease evolution exist in patients with multiple sclerosis (MS). Cortical atrophy measurements are, however, closely associated with cumulative disability. Objective: Here, we aim to forecast longitudinal magnetic resonance imaging (MRI)-driven cortical atrophy and clinical disability from cerebrospinal fluid (CSF) markers. Methods: We analyzed CSF fractions of albumin and immunoglobulins (Ig) A, G, and M and their CSF to serum quotients. Results: Widespread atrophy was highly associated with increased baseline CSF concentrations and quotients of albumin and IgA. Patients with increased CSFIgA and CSFIgM showed higher functional disabilit…
Linking Microstructural Integrity and Motor Cortex Excitability in Multiple Sclerosis
Motor skills are frequently impaired in multiple sclerosis (MS) patients following grey and white matter damage with cortical excitability abnormalities. We applied advanced diffusion imaging with 3T magnetic resonance tomography for neurite orientation dispersion and density imaging (NODDI), as well as diffusion tensor imaging (DTI) in 50 MS patients and 49 age-matched healthy controls to quantify microstructural integrity of the motor system. To assess excitability, we determined resting motor thresholds using non-invasive transcranial magnetic stimulation. As measures of cognitive-motor performance, we conducted neuropsychological assessments including the Nine-Hole Peg Test, Trail Makin…
Imaging in mice and men: Pathophysiological insights into multiple sclerosis from conventional and advanced MRI techniques
Abstract Magnetic resonance imaging (MRI) is the most important tool for diagnosing multiple sclerosis (MS). However, MRI is still unable to precisely quantify the specific pathophysiological processes that underlie imaging findings in MS. Because autopsy and biopsy samples of MS patients are rare and biased towards a chronic burnt-out end or fulminant acute early stage, the only available methods to identify human disease pathology are to apply MRI techniques in combination with subsequent histopathological examination to small animal models of MS and to transfer these insights to MS patients. This review summarizes the existing combined imaging and histopathological studies performed in M…
Evidence for early, non-lesional cerebellar damage in patients with multiple sclerosis: DTI measures correlate with disability, atrophy, and disease duration
Background: Common symptoms of multiple sclerosis (MS) such as gait ataxia, poor coordination of the hands, and intention tremor are usually the result of dysfunctionality in the cerebellum. Magnetic resonance imaging (MRI) has frequently failed to detect cerebellar damage in the form of inflammatory lesions in patients presenting with symptoms of cerebellar dysfunction. Objective: To detect microstructural cerebellar tissue alterations in early MS patients with a “normal appearing” cerebellum using diffusion tensor imaging (DTI). Methods: A total of 68 patients with relapsing–remitting MS (RRMS) and without cerebellar lesions and 26 age-matched healthy controls were admitted to high-resolu…
Selective Brain Network and Cellular Responses Upon Dimethyl Fumarate Immunomodulation in Multiple Sclerosis
Background: Efficient personalized therapy paradigms are needed to modify the disease course and halt gray (GM) and white matter (WM) damage in patients with multiple sclerosis (MS). Presently, promising disease-modifying drugs show impressive efficiency, however, tailored markers of therapy responses are required. Here, we aimed to detect in a real-world setting patients with a more favorable brain network response and immune cell dynamics upon dimethyl fumarate (DMF) treatment. Methods: In a cohort of 78 MS patients we identified two thoroughly matched groups, based on age, disease duration, disability status and lesion volume, receiving DMF (n = 42) and NAT (n = 36) and followed them ove…
Serum neurofilament levels reflect outer retinal layer changes in multiple sclerosis
Background: Serum neurofilament light chain (sNfL) and distinct intra-retinal layers are both promising biomarkers of neuro-axonal injury in multiple sclerosis (MS). We aimed to unravel the association of both markers in early MS, having identified that neurofilament has a distinct immunohistochemical expression pattern among intra-retinal layers. Methods: Three-dimensional (3D) spectral domain macular optical coherence tomography scans and sNfL levels were investigated in 156 early MS patients (female/male: 109/47, mean age: 33.3 ± 9.5 years, mean disease duration: 2.0 ± 3.3 years). Out of the whole cohort, 110 patients had no history of optic neuritis (NHON) and 46 patients had a previous…
Increased cortical curvature reflects white matter atrophy in individual patients with early multiple sclerosis
Objective White matter atrophy occurs independently of lesions in multiple sclerosis. In contrast to lesion detection, the quantitative assessment of white matter atrophy in individual patients has been regarded as a major challenge. We therefore tested the hypothesis that white matter atrophy (WMA) is present at the very beginning of multiple sclerosis (MS) and in virtually each individual patient. To find a new sensitive and robust marker for WMA we investigated the relationship between cortical surface area, white matter volume (WMV), and whole-brain-surface-averaged rectified cortical extrinsic curvature. Based on geometrical considerations we hypothesized that cortical curvature increa…