Longitudinal advanced MRI changes in relapse-free patients with AQP4-IgG+NMOSD

Recurrent inflammatory attacks in AQP4-antibody-seropositive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) can lead to devastating disabilities such as visual and motor dysfunction, pain, and cognitive impairment. However, the mechanisms driving the long-term effects of attacks and potential for subsequent recovery are still not well understood after patients enter a relapse-free disease phase. Here, we leveraged advanced structural and diffusion-weighted imaging analyses in a longitudinal cohort of patients with "stable" AQP4-IgG+NMOSD (retrospectively assessed, [≥]12 months without attack, n=33, 31/33 female, mean age 49.7 years (SD 14.2)). Brain changes over a median of 4 annual visits (range 2-6) were evaluated using FreeSurfer-based volumetry, regional damage profiles of white matter fibre bundles, cognitive testing (BRB-N), and neuropsychiatric self-reports. Our analysis revealed four key findings: (1) In the absence of new attacks, pre-existing symptoms persisted and contributed to motor impairment, fatigue, and lower visual function. By contrast, cognitive impairment - selective to higher attention and processing speed - improved over time (PASAT3s, PFDR=0.007). (2) On a macroscopic brain level, the continued decline of whole brain volumes (PFDR=0.037) was mainly driven by loss of cortical grey matter (PFDR=0.013) and linked to poorer motor outcomes (9-hole peg test: {rho}s=-0.55, PFDR=0.021) and higher pain levels (PD-Q: {rho}s=-0.51, PFDR=0.021) at last follow-up. Large-scale age- and sex-stratified reference curves (Braincharts) confirmed that cortical atrophy exceeded normal ageing. (3) Thalamic volumes, by contrast, were significantly higher compared to those of healthy participants (PFDR=0.044) throughout the entire follow-up period and predicted more favourable long-term attention (SDMT: {rho}s=0.63, PFDR=0.003) and spatial memory outcomes (SPART sum score: {rho}s=0.62, PFDR=0.029) as early as at the first MRI. Larger thalamic volumes were mainly seen in a subgroup of younger patients with lower disability burden, fewer comorbidities, and better integrity of thalamus-adjacent white matter tracts. (4) On a microstructural level, tract-specific longitudinal patterns emerged: decreasing regional fractional anisotropy (FA) in the optic radiation, thalamo-prefrontal and thalamo-occipital projections was linked to worse cognitive outcomes (e.g., SDMT: {rho}s=0.62, PFDR=0.012), while increasing FA, particularly in the corticospinal tract and inferior fronto-occipital fasciculus, predicted more favourable long-term cognitive and visual functions (e.g., NEI VFQ-25: {rho}s=0.64, PFDR=0.011). Collectively, our data suggest that even in relapse-free AQP4-IgG+NMOSD there is evidence for declining cortical volume, thalamic reserve in some patients, and white matter microstructural damage in distinct regions. Our clinically relevant findings elucidated in the "stable" disease phase highlight longitudinal mechanisms contributing to the long-term prognoses of patients with AQP4-IgG+NMOSD.