A generalizable deep voxel-guided morphometry algorithm for the detection of subtle lesion dynamics in multiple sclerosis

IntroductionMultiple sclerosis (MS) is a chronic neurological disorder characterized by the progressive loss of myelin and axonal structures in the central nervous system. Accurate detection and monitoring of MS-related changes in brain structures are crucial for disease management and treatment evaluation. We propose a deep learning algorithm for creating Voxel-Guided Morphometry (VGM) maps from longitudinal MRI brain volumes for analyzing MS disease activity. Our approach focuses on developing a generalizable model that can effectively be applied to unseen datasets.MethodsLongitudinal MS patient high-resolution 3D T1-weighted follow-up imaging from three different MRI systems were analyzed. We employed a 3D residual U-Net architecture with attention mechanisms. The U-Net serves as the backbone, enabling spatial feature extraction from MRI volumes. Attention mechanisms are integrated to enhance the model's ability to capture relevant information and highlight salient regions. Furthermore, we incorporate image normalization by histogram matching and resampling techniques to improve the networks' ability to generalize to unseen datasets from different MRI systems across imaging centers. This ensures robust performance across diverse data sources.ResultsNumerous experiments were conducted using a dataset of 71 longitudinal MRI brain volumes of MS patients. Our approach demonstrated a significant improvement of 4.3% in mean absolute error (MAE) against the state-of-the-art (SOTA) method. Furthermore, the algorithm's generalizability was evaluated on two unseen datasets (n = 116) with an average improvement of 4.2% in MAE over the SOTA approach.DiscussionResults confirm that the proposed approach is fast and robust and has the potential for broader clinical applicability

Characterizing 1-year development of cervical cord atrophy across different MS phenotypes: A voxel-wise, multicentre analysis

Background: Spatio-temporal evolution of cord atrophy in multiple sclerosis (MS) has not been investigated yet. Objective: To evaluate voxel-wise distribution and 1-year changes of cervical cord atrophy in a multicentre MS cohort. Methods: Baseline and 1-year 3D T1-weighted cervical cord scans and clinical evaluations of 54 healthy controls (HC) and 113 MS patients (14 clinically isolated syndromes (CIS), 77 relapsing-remitting (RR), 22 progressive (P)) were used to investigate voxel-wise cord volume loss in patients versus HC, 1-year volume changes and clinical correlations (SPM12). Results: MS patients exhibited baseline cord atrophy versus HC at anterior and posterior/lateral C1/C2 and C4–C6 (p < 0.05, corrected). While CIS patients showed baseline volume increase at C4 versus HC (p < 0.001, uncorrected), RRMS exhibited posterior/lateral C1/C2 atrophy versus CIS, and PMS showed widespread cord atrophy versus RRMS (p < 0.05, corrected). At 1 year, 13 patients had clinically worsened. Cord atrophy progressed in MS, driven by RRMS, at posterior/lateral C2 and C3–C6 (p < 0.05, corrected). CIS patients showed no volume changes, while PMS showed circumscribed atrophy progression. Baseline cord atrophy at posterior/lateral C1/C2 and C3–C6 correlated with concomitant and 1-year disability (r = −0.40/–0.62, p < 0.05, corrected). Conclusions: Voxel-wise analysis characterized spinal cord neurodegeneration over 1 year across MS phenotypes and helped to explain baseline and 1-year disability

Prominent microglial inclusions in transgenic mouse models of α-synucleinopathy that are distinct from neuronal lesions.

Alpha-synucleinopathies are a group of progressive neurodegenerative disorders, characterized by intracellular deposits of aggregated α-synuclein (αS). The clinical heterogeneity of these diseases is thought to be attributed to conformers (or strains) of αS but the contribution of inclusions in various cell types is unclear. The aim of the present work was to study αS conformers among different transgenic (TG) mouse models of α-synucleinopathies. To this end, four different TG mouse models were studied (Prnp-h[A53T]αS; Thy1-h[A53T]αS; Thy1-h[A30P]αS; Thy1-mαS) that overexpress human or murine αS and differed in their age-of-symptom onset and subsequent disease progression. Postmortem analysis of end-stage brains revealed robust neuronal αS pathology as evidenced by accumulation of αS serine 129 (p-αS) phosphorylation in the brainstem of all four TG mouse lines. Overall appearance of the pathology was similar and only modest differences were observed among additionally affected brain regions. To study αS conformers in these mice, we used pentameric formyl thiophene acetic acid (pFTAA), a fluorescent dye with amyloid conformation-dependent spectral properties. Unexpectedly, besides the neuronal αS pathology, we also found abundant pFTAA-positive inclusions in microglia of all four TG mouse lines. These microglial inclusions were also positive for Thioflavin S and showed immunoreactivity with antibodies recognizing the N-terminus of αS, but were largely p-αS-negative. In all four lines, spectral pFTAA analysis revealed conformational differences between microglia and neuronal inclusions but not among the different mouse models. Concomitant with neuronal lesions, microglial inclusions were already present at presymptomatic stages and could also be induced by seeded αS aggregation. Although nature and significance of microglial inclusions for human α-synucleinopathies remain to be clarified, the previously overlooked abundance of microglial inclusions in TG mouse models of α-synucleinopathy bears importance for mechanistic and preclinical-translational studies

Myeloid cell iron uptake pathways and paramagnetic rim formation in multiple sclerosis

In multiple sclerosis (MS), sustained inflammatory activity can be visualized by iron-sensitive magnetic resonance imaging (MRI) at the edges of chronic lesions. These paramagnetic rim lesions (PRLs) are associated with clinical worsening, although the cell type-specific and molecular pathways of iron uptake and metabolism are not well known. We studied two postmortem cohorts: an exploratory formalin-fixed paraffin-embedded (FFPE) tissue cohort of 18 controls and 24 MS cases and a confirmatory snap-frozen cohort of 6 controls and 14 MS cases. Besides myelin and non-heme iron imaging, the haptoglobin-hemoglobin scavenger receptor CD163, the iron-metabolizing markers HMOX1 and HAMP as well as immune-related markers P2RY12, CD68, C1QA and IL10 were visualized in myeloid cell (MC) subtypes at RNA and protein levels across different MS lesion areas. In addition, we studied PRLs in vivo in a cohort of 98 people with MS (pwMS) via iron-sensitive 3&nbsp;T MRI and haptoglobin genotyping by PCR. CSF samples were available from 38 pwMS for soluble CD163 (sCD163) protein level measurements by ELISA. In postmortem tissues, we observed that iron uptake was linked to rim-associated C1QA-expressing MC subtypes, characterized by upregulation of CD163, HMOX1, HAMP and, conversely, downregulation of P2RY12. We found that pwMS with [Formula: see text] 4 PRLs had higher sCD163 levels in the CSF than pwMS with [Formula: see text] 3 PRLs with sCD163 correlating with the number of PRLs. The number of PRLs was associated with clinical worsening but not with age, sex or haptoglobin genotype of pwMS. However, pwMS with Hp2-1/Hp2-2 haplotypes had higher clinical disability scores than pwMS with Hp1-1. In summary, we observed upregulation of the CD163-HMOX1-HAMP axis in MC subtypes at chronic active lesion rims, suggesting haptoglobin-bound hemoglobin but not transferrin-bound iron as a critical source for MC-associated iron uptake in MS. The correlation of CSF-associated sCD163 with PRL counts in MS highlights the relevance of CD163-mediated iron uptake via haptoglobin-bound hemoglobin. Also, while Hp haplotypes had no noticeable influence on PRL counts, pwMS carriers of a Hp2 allele might have a higher risk to experience clinical worsening

Polygenic prediction of educational attainment within and between families from genome-wide association analyses in 3 million individuals

We conduct a genome-wide association study (GWAS) of educational attainment (EA) in a sample of ~3 million individuals and identify 3,952 approximately uncorrelated genome-wide-significant single-nucleotide polymorphisms (SNPs). A genome-wide polygenic predictor, or polygenic index (PGI), explains 12-16% of EA variance and contributes to risk prediction for ten diseases. Direct effects (i.e., controlling for parental PGIs) explain roughly half the PGI's magnitude of association with EA and other phenotypes. The correlation between mate-pair PGIs is far too large to be consistent with phenotypic assortment alone, implying additional assortment on PGI-associated factors. In an additional GWAS of dominance deviations from the additive model, we identify no genome-wide-significant SNPs, and a separate X-chromosome additive GWAS identifies 57

Genome-wide association study identifies 74 loci associated with educational attainment

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals1. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample1,2 of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases

Posttraumatische Gefahrenantwort nach experimentellem Polytrauma und hämorrhagischem Schock

Das Polytrauma ist heutzutage die häufigste Todesursache im jungen Erwachsenenalter und hat deshalb eine große individuelle, medizinische und wirtschaftliche Bedeutung. Auch bei Überleben führt es oft zu dauerhaften und schwerwiegenden Langzeitschäden. Bei einem Polytrauma ist der schwere Blutverlust oft wichtiger Bestandteil der Verletzungen, mit einem starken Einfluss auf den Verlauf. Immunologisch führt ein Schädelhirntrauma, Thoraxtrauma und eine Fraktur mit einem hämorrhagischen Schock zu einer komplexen molekularen und zellulären Gefahrenantwort, die noch nicht ausreichend verstanden ist. Daher sollte in der Arbeit ein experimentelles Polytraumamodell etabliert werden, welches die klinische Wirklichkeit dieser Gefahrenantwort, kurz nach einem Trauma, hinreichend zuverlässig darstellt. Dazu wurden Wildtyp-Mäusen der Linie C57BL/6J mit einem Alter von 8-12 Wochen einem Schädelhirntrauma durch weight-drop, einem Thoraxtrauma durch Luftdruck, einer geschlossenen Femurfraktur und einen druckkontrollierten hämorrhagischen Schock durch druckkontrollierte Blutabnahme zugeführt. Es sollte insbesondere der Effekt des hämorrhagischen Schocks auf, das schon früher etablierte hämodynamisch stabile Polytraumamodell untersucht werden. Nach einer Beobachtungsdauer von 4 Stunden wurde der Versuch terminiert und die Organe zur weiteren Beurteilung entnommen. Die Ergebnisse des kombinierten Polytraumas wurden mit denen der einzelnen Verletzungen verglichen. Bei der Kombination des Polytraumas mit einem hämorrhagischen Schock kam es zu einem signifikanten Anstieg von Interleukin 6, Club Cell Protein 16 und der Zahl der Granulozyten in der bronchoalveolären Lavage. Auch im Falle der Plasmakonzentrationen konnten signifikante Anstiege bei Interleukin-6, Club Cell Protein 16, neutrophilen gelatinase assoziiertes Lipocalin und glial fatty acidic protein nachgewiesen werden. Das durchgeführte Modell erlaubt Rückschlüsse auf die pathophysiologischen Abläufe und verstärkende Rolle des hämorrhagischen Schocks nach Polytrauma. Sowohl die systemische Entzündungsantwort als auch die organspezifischen Schädigungen wurden insgesamt durch den hämorrhagischen Schock nach Polytrauma aggraviert. Das etablierte hämodynamisch instabile Polytraumamodell kann für weitere Experimente zu Untersuchung klinisch relevanter Fragestellungen bezüglich des pathophysiologischen Ablaufs und möglicher therapeutischer Optionen genutzt werden