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Significance Many evolutionary–developmental models have attempted to relate development and aging, with one popular hypothesis proposing that healthy age-related brain decline mirrors developmental maturation. But this elegant hypothesis has so far lacked clear and direct data to support it. Here, we describe intrinsic, entirely data-driven evidence that healthy brain degeneration and developmental process mirror one another in certain brain regions. Specifically, a data-driven decomposition of structural brain images in 484 healthy participants reveals a network of mainly higher-order regions that develop relatively late during adolescence, demonstrate accelerated degeneration in old age, and show heightened vulnerability to disorders that impact on brain structure during adolescence and aging. These results provide a fundamental link between development, aging, and disease processes in the brain. Several theories link processes of development and aging in humans. In neuroscience, one model posits for instance that healthy age-related brain degeneration mirrors development, with the areas of the brain thought to develop later also degenerating earlier. However, intrinsic evidence for such a link between healthy aging and development in brain structure remains elusive. Here, we show that a data-driven analysis of brain structural variation across 484 healthy participants (8–85 y) reveals a largely—but not only—transmodal network whose lifespan pattern of age-related change intrinsically supports this model of mirroring development and aging. We further demonstrate that this network of brain regions, which develops relatively late during adolescence and shows accelerated degeneration in old age compared with the rest of the brain, characterizes areas of heightened vulnerability to unhealthy developmental and aging processes, as exemplified by schizophrenia and Alzheimer’s disease, respectively. Specifically, this network, while derived solely from healthy subjects, spatially recapitulates the pattern of brain abnormalities observed in both schizophrenia and Alzheimer’s disease. This network is further associated in our large-scale healthy population with intellectual ability and episodic memory, whose impairment contributes to key symptoms of schizophrenia and Alzheimer’s disease. Taken together, our results suggest that the common spatial pattern of abnormalities observed in these two disorders, which emerge at opposite ends of the life spectrum, might be influenced by the timing of their separate and distinct pathological processes in disrupting healthy cerebral development and aging, respectively.

Objectives In multiple sclerosis (MS), iron rim lesions (IRLs) are indicators of chronic low-grade inflammation and ongoing tissue destruction. The aim of this study was to assess the relationship of IRLs with clinical measures and magnetic resonance imaging (MRI) markers, in particular brain and cervical cord volume. Methods Clinical and MRI parameters from 102 relapsing MS patients (no relapses for at least 6 months, no contrast-enhancing lesions) were included; follow-up data obtained after 12 months was available in 49 patients. IRLs were identified on susceptibility-weighted images (SWIs). In addition to standard brain and spinal cord MRI parameters, normalised cross-sectional area (nCSA) of the upper cervical cord was calculated. Results Thirty-eight patients had at least one IRL on SWI MRI. At baseline, patients with IRLs had higher EDSS scores, higher lesion loads (brain and spinal cord), and lower cortical grey matter volumes and a lower nCSA. At follow-up, brain atrophy rates were higher in patients with IRLs. IRLs correlated spatially with T1-hypointense lesions. Conclusions Relapsing MS patients with IRLs showed more aggressive MRI disease characteristics in both the cross-sectional and longitudinal analyses. Key Points • Multiple sclerosis patients with iron rim lesions had higher EDSS scores, higher brain and spinal cord lesion loads, lower cortical grey matter volumes, and a lower normalised cross-sectional area of the upper cervical spinal cord. • Iron rim lesions are a new lesion descriptor obtained from susceptibility-weighted MRI. Our data suggests that further exploration of this lesion characteristic in regard to a poorer prognosis in multiple sclerosis patients is warranted.

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 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 ≥ 4 PRLs had higher sCD163 levels in the CSF than pwMS with ≤ 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.

Objective To examine the temporal evolution of spinal cord (SC) atrophy in multiple sclerosis (MS), and its association with clinical progression in a large MS cohort. Methods A total of 352 patients from two centres with MS (relapsing remitting MS (RRMS): 256, secondary progressive MS (SPMS): 73, primary progressive MS (PPMS): 23) were included. Clinical and MRI parameters were obtained at baseline, after 12 months and 24 months of follow-up. In addition to conventional brain and SC MRI parameters, the annualised percentage brain volume change and the annualised percentage upper cervical cord cross-sectional area change (aUCCA) were quantified. Main outcome measure was disease progression, defined by expanded disability status scale increase after 24 months. Results UCCA was lower in SPMS and PPMS compared with RRMS for all time points. aUCCA over 24 months was highest in patients with SPMS (−2.2% per year) and was significantly higher in patients with disease progression (−2.3% per year) than in stable patients (−1.2% per year; p=0.003), while annualised percentage brain volume change did not differ between subtypes (RRMS: −0.42% per year; SPMS −0.6% per year; PPMS: −0.46% per year) nor between progressive and stable patients (p=0.055). Baseline UCCA and aUCCA over 24 months were found to be relevant contributors of expanded disability status scale at month-24, while baseline UCCA as well as number of SC segments involved by lesions at baseline but not aUCCA were relevant contributors of disease progression. Conclusions SC MRI parameters including baseline UCCA and SC lesions were significant MRI predictors of disease progression. Progressive 24-month upper SC atrophy occurred in all MS subtypes, and was faster in patients exhibiting disease progression at month-24.

The spinal cord is a clinically important site that is affected by pathological changes in most patients with multiple sclerosis; however, imaging of the spinal cord with conventional MRI can be difficult. Improvements in MRI provide a major advantage for spinal cord imaging, with better signal-to-noise ratio and improved spatial resolution. Through the use of multiplanar MRI, identification of diffuse and focal changes in the whole spinal cord is now routinely possible. Corroborated by related histopathological analyses, several new techniques, such as magnetisation transfer, diffusion tension imaging, functional MRI, and proton magnetic resonance spectroscopy, can detect non-focal, spinal cord pathological changes in patients with multiple sclerosis. Additionally, functional MRI can reveal changes in the response pattern to sensory stimulation in patients with multiple sclerosis. Through use of these techniques, findings of cord atrophy, intrinsic cord damage, and adaptation are shown to occur largely independently of focal spinal cord lesion load, which emphasises their relevance in depiction of the true burden of disease. Combinations of magnetisation transfer ratio or diffusion tension imaging indices with cord atrophy markers seem to be the most robust and meaningful biomarkers to monitor disease evolution in early multiple sclerosis.

Multiple 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. Longitudinal 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. Numerous 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 ( = 116) with an average improvement of 4.2% in MAE over the SOTA approach. Results confirm that the proposed approach is fast and robust and has the potential for broader clinical applicability.

Background: Cortical lesions (CLs) have been reported to be a better predictor for cognitive impairment than white matter (WM) lesions in relapsing–remitting multiple sclerosis (RRMS). Objectives: The objectives of this article are to investigate the contribution of CLs and WM lesions to cognitive impairment in 91 patients with MS and clinically isolated syndrome, and to test potential associations of CLs and WM lesions with fatigue and depression. Methods: Lesions were scored and segmented on 3D double inversion recovery sequences, according to their location (cortical, WM). Normalised grey matter volume was also determined. Cognitive performance was assessed with the SDMT and PASAT-3, fatigue with the FSMC and depression with the German version of the CES-D. Results: CL volume did not correlate with fatigue or depression, but correlated significantly with both neuropsychological outcome measures: PASAT-3 (r = −0.275, p = 0.009) and SDMT (r = −0.377, p < 0.001). Multiple regression analyses with age, WM lesions, CLs and GM volume as independent variables, however, did not reveal CL volume as a significant predictor of neuropsychological outcomes, whereas WM lesion volume significantly predicted SDMT and by trend PASAT performance. Conclusions: These findings suggest a role of WM lesions in the development of cognitive deficits, especially information-processing speed, which may be higher than previously assumed. Abbreviations: CES-D: Center for Epidemiologic Studies Depression scale (ADS-L: Allgemeine Depressions Skala-L, German version of CES-D), CIS: clinically isolated syndrome, CL: cortical lesion, DIR: double inversion recovery, EDSS: Expanded Disability Status Scale, FSMC: fatigue scale for motor and cognitive functions, GM: grey matter, MRI: magnetic resonance imaging, MS: multiple sclerosis, PASAT-3: paced auditory serial addition test 3s, PPMS: primary progressive multiple sclerosis, RRMS: relapsing–remitting multiple sclerosis, SDMT: symbol digit modalities test, SPM: statistical parametric mapping, SPMS: secondary progressive multiple sclerosis, WM: white matter

Objective: The objective of this paper is to investigate the relationship between total and regional corpus callosum (CC) atrophy, neuropsychological test performance and fatigue in multiple sclerosis (MS) patients. Methods: We conducted a cross-sectional study in 113 MS patients: mean age 48±11 years, 75/113 women, 84/113 relapsing–remitting MS, mean disease duration 21±9 years, mean Expanded Disability Status Scale (EDSS) score 3.2±1.7. All patients underwent brain magnetic resonance imaging, standardised neurological assessment and comprehensive cognitive testing including assessments for fatigue and depression. Total and regional CC atrophy was assessed using the corpus callosum index (CCI). Results: CCI correlated more strongly with T2- and T1-lesion volume and whole brain volume than with disease duration or EDSS score. CCI correlated strongly with the verbal fluency test (VFT), Symbol Digit Modalities Test (SDMT) and Paced Auditory Serial Addition Test (PASAT). Multivariate regression analysis revealed that atrophy of the posterior CC segment was significantly associated with poor outcome in the PASAT, VFT and SDMT. In contrast, atrophy of the anterior CC segment was significantly associated with fatigue severity and poor outcome in the long-term memory test. Conclusions: Atrophy of the CC is associated with cognitive impairment and fatigue. Regional CCI results indicate that these associations are partially spatially segregated.

IgG4‐related disease (IgG4‐RD) is a fibroinflammatory disorder signified by aberrant infiltration of IgG4‐restricted plasma cells into a variety of organs. Clinical presentation is heterogeneous, and pathophysiological mechanisms of IgG4‐RD remain elusive. There are very few cases of IgG4‐RD with isolated central nervous system manifestation. By leveraging single‐cell sequencing of the cerebrospinal fluid (CSF) of a patient with an inflammatory intracranial pseudotumor, we provide novel insights into the immunopathophysiology of IgG4‐RD. Our data illustrate an IgG4‐RD‐associated polyclonal T‐cell response in the CSF and an oligoclonal T‐cell response in the parenchymal lesions, the latter being the result of a multifaceted cell–cell interaction between immune cell subsets and pathogenic B cells. We demonstrate that CD8 + T effector memory cells might drive and sustain autoimmunity via macrophage migration inhibitory factor (MIF)‐CD74 signaling to immature B cells and CC‐chemokine ligand 5 (CCL5)‐mediated recruitment of cytotoxic CD4 + T cells. These findings highlight the central role of T cells in sustaining IgG4‐RD and open novel avenues for targeted therapies. SYNOPSIS This translational study demonstrates the potential of single‐cell profiling technologies to support clinicians in the diagnosis of rare autoimmune disorders while shedding new light into potential molecular pathomechanisms of intercellular communication in IgG4‐related disease. T‐cell ‐ T‐cell crosstalk facilitates recruitment of helper and cytotoxic CD4 + T‐cells to manifestation sites of IgG4‐related disease. T‐cell‐derived CXCL13 might regulate pathogenic B cell migration into the CNS and promote intrathecal accumulation of B‐cells. Recurrent IgG4‐RD in three intracranial manifestation sites is driven by a clonal T‐cell response. Graphical Abstract This translational study demonstrates the potential of single‐cell profiling technologies to support clinicians in the diagnosis of rare autoimmune disorders while shedding new light into potential molecular pathomechanisms of intercellular communication in IgG4‐related disease.

Objective: To investigate the entire spinal cord (SC) of multiple sclerosis (MS) patients with biplanar MRI and to relate these MRI findings to clinical functional scores. Methods: Two hundred and two patients (140 women, 62 men 24–74 years, Expanded Disability Status Scale (EDSS) scores 0–7.5) were investigated clinically and with biplanar MRI. Sagittal and axial proton density weighted (PDw) and T2 weighted (T2w) images of the whole SC were obtained employing parallel imaging. Data were analyzed by consensus reading using a standardized reporting scheme. Different combinations of findings were compared to EDSS scores with Spearman’s rank correlation coefficient (ρ). Results: The combined analysis of sagittal and axial planes demonstrated slightly differing results in 97/202 (48%) patients. There were 9% additional lesions identified, leading to a higher lesion count in 28% of these patients, but also rejection of equivocal abnormality leading to a lower lesion count in 11% of patients. Considering both sagittal and axial images, SC abnormalities were found in 167/202 (83%) patients. When compared with EDSS scores, the combination of focal lesions, signs of atrophy and diffuse abnormalities showed a moderate correlation (ρ=0.52), that precludes its use for individual patient assessment. Conclusion: Biplanar MRI facilitates a comprehensive identification, localization, and grading of pathological SC findings in MS patients. This improves the confidence and utility of SC imaging.