Altered grey matter networks in young patients with MS at genetic risk for Alzheimer's disease [Abstract]

Background: The Apolipoprotein E (APOE) ε4 is the major susceptibility factor for cognitive impairment and Alzheimer’s disease. Cognitive decline is also a concern in patients with multiple sclerosis (MS). Whether APOE ε4 exerts an effect on brain structure and grey matter (GM) networks in MS patients that could potentiate the long-term cognitive disabilities is unclear. Moreover the description of the exact link between genetic markers and MR driven measures of brain integrity are of essential importance to study cognition in patients with MS and for interventions to prevent longitudinal deterioration. Methods: MS Patients with no immunomodulatory treatment were enrolled in the “Krankheitsbezogene Kompetenznetz Multiple Sclerosis (KKNMS)”. From this multicenter dataset 37 heterozygous APOE ε4 carriers (i.e. having the genotype ε3/ε4) and 37 non-carriers (ε3/ε3) were matched for demographics (mean age: 38.4±9.2 yrs, mean EDSS 1.23±0.99) from one site. A replication study was performed in a cohort (n=46) from a second site. Cortical thickness (CT) was derived from 3T MRI using FreeSurfer. GM connectivity networks were reconstructed from the CT correlation between the 68 regions of the Desikan-Killiany atlas. Cortical integrity and network connectivity -derived from graph theoretical approaches- were compared between the groups in both cohorts. Results corrected for multiple comparisons were considered (p< 0.05 FDR). Results: No regional or global cortical atrophy differences were attested between the two groups in both cohorts. In the network connectivity analysis a decreased local connectivity pattern (reduced transitivity, t=-3.24 p=0.008) was evident in APOE ε4 carriers. Regions with decreased connectivity were consistently seen in the medial part of the left temporal lobe. APOE ε4 status was further associated with raised whole brain connectivity, reflected by increased global efficiency (t=4.34 p=0.005) and reduced modularity (t=-2.84 p=0.02). This network pattern was shown in the frontal, parietal and lateral temporal associative cortices. The results were entirely replicated in the second cohort. Conclusion: We found that MS patients at genetic risk for cognitive decline have significant abnormalities of local GM networks and possibly compensatory increased long-range connectivity patterns. Chronic or focal neuroinflammation could lead to behaviourally relevant memory impairments in these patients through a specific break-down of the long-range paths

Disentangling Neurodegeneration From Aging in Multiple Sclerosis Using Deep Learning: The Brain-Predicted Disease Duration Gap

BACKGROUND AND OBJECTIVES: Disentangling brain aging from disease-related neurodegeneration in patients with multiple sclerosis (PwMS) is increasingly topical. The brain-age paradigm offers a window into this problem but may miss disease-specific effects. In this study, we investigated whether a disease-specific model might complement the brain-age gap (BAG) by capturing aspects unique to MS. METHODS: In this retrospective study, we collected 3D T1-weighted brain MRI scans of PwMS to build (1) a cross-sectional multicentric cohort for age and disease duration (DD) modeling and (2) a longitudinal single-center cohort of patients with early MS as a clinical use case. We trained and evaluated a 3D DenseNet architecture to predict DD from minimally preprocessed images while age predictions were obtained with the DeepBrainNet model. The brain-predicted DD gap (the difference between predicted and actual duration) was proposed as a DD-adjusted global measure of MS-specific brain damage. Model predictions were scrutinized to assess the influence of lesions and brain volumes while the DD gap was biologically and clinically validated within a linear model framework assessing its relationship with BAG and physical disability measured with the Expanded Disability Status Scale (EDSS). RESULTS: We gathered MRI scans of 4,392 PwMS (69.7% female, age: 42.8 ± 10.6 years, DD: 11.4 ± 9.3 years) from 15 centers while the early MS cohort included 749 sessions from 252 patients (64.7% female, age: 34.5 ± 8.3 years, DD: 0.7 ± 1.2 years). Our model predicted DD better than chance (mean absolute error = 5.63 years, R2 = 0.34) and was nearly orthogonal to the brain-age model (correlation between DD and BAGs: r = 0.06 [0.00-0.13], p = 0.07). Predictions were influenced by distributed variations in brain volume and, unlike brain-predicted age, were sensitive to MS lesions (difference between unfilled and filled scans: 0.55 years [0.51-0.59], p < 0.001). DD gap significantly explained EDSS changes (B = 0.060 [0.038-0.082], p < 0.001), adding to BAG (ΔR2 = 0.012, p < 0.001). Longitudinally, increasing DD gap was associated with greater annualized EDSS change (r = 0.50 [0.39-0.60], p < 0.001), with an incremental contribution in explaining disability worsening compared with changes in BAG alone (ΔR2 = 0.064, p < 0.001). DISCUSSION: The brain-predicted DD gap is sensitive to MS-related lesions and brain atrophy, adds to the brain-age paradigm in explaining physical disability both cross-sectionally and longitudinally, and may be used as an MS-specific biomarker of disease severity and progression

Grey Matter Atrophy and its Relationship with White Matter Lesions in Patients with Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease, Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder, and Multiple Sclerosis

Objective: To evaluate: (1) the distribution of gray matter (GM) atrophy in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), and relapsing–remitting multiple sclerosis (RRMS); and (2) the relationship between GM volumes and white matter lesions in various brain regions within each disease. Methods: A retrospective, multicenter analysis of magnetic resonance imaging data included patients with MOGAD/AQP4+NMOSD/RRMS in non-acute disease stage. Voxel-wise analyses and general linear models were used to evaluate the relevance of regional GM atrophy. For significant results (p &lt; 0.05), volumes of atrophic areas are reported. Results: We studied 135 MOGAD patients, 135 AQP4+NMOSD, 175 RRMS, and 144 healthy controls (HC). Compared with HC, MOGAD showed lower GM volumes in the temporal lobes, deep GM, insula, and cingulate cortex (75.79 cm3); AQP4+NMOSD in the occipital cortex (32.83 cm3); and RRMS diffusely in the GM (260.61 cm3). MOGAD showed more pronounced temporal cortex atrophy than RRMS (6.71 cm3), whereas AQP4+NMOSD displayed greater occipital cortex atrophy than RRMS (19.82 cm3). RRMS demonstrated more pronounced deep GM atrophy in comparison with MOGAD (27.90 cm3) and AQP4+NMOSD (47.04 cm3). In MOGAD, higher periventricular and cortical/juxtacortical lesions were linked to reduced temporal cortex, deep GM, and insula volumes. In RRMS, the diffuse GM atrophy was associated with lesions in all locations. AQP4+NMOSD showed no lesion/GM volume correlation. Interpretation: GM atrophy is more widespread in RRMS compared with the other two conditions. MOGAD primarily affects the temporal cortex, whereas AQP4+NMOSD mainly involves the occipital cortex. In MOGAD and RRMS, lesion-related tract degeneration is associated with atrophy, but this link is absent in AQP4+NMOSD. ANN NEUROL 2024;96:276–288

Cervical cord and ventricle affection in neuromyelitis optica

Objectives: Cervical cord involvement is common in neuromyelitis optica (NMO) and multiple sclerosis (MS), but its impact on disability in NMO has rarely been studied. Recent publications on NMO examined the periventricular system, areas of high aquaporin-4 expression, but not yet by using ventricle volumetry. Purpose: To compare cervical cord atrophy, ventricular widening, and supra- and infratentorial brain measures between NMO and MS, and study their impact on clinical disability. Methods: Magnet resonance imaging-based volumetry of upper cervical cord, third and fourth lateral ventricles, grey matter, white matter, brainstem, cerebellum and clinical status of 18 NMO and 20 MS patients, was compared between the groups and with 26 healthy controls. Patterns of ventricular widening relative to healthy controls were inspected by voxel-based morphometry of the cerebrospinal fluid