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Background: The role of white matter (WM) neurodegeneration in Alzheimer's disease (AD) is poorly understood. Fine‐grained sequencing of WM neurodegeneration could provide new avenues for early diagnosis and novel disease‐modifying therapies to slow or halt AD progression. Previous approaches are limited by their coarse granularity and incomplete disease coverage. In this study, we apply event‐based disease progression modelling (DPM) (Fonteijn et al, Neuroimage, 2012), which can provide fine‐grained ordering, to estimate progression of regional WM abnormality in AD. Method: Diffusion tensor imaging (DTI) markers of WM abnormality and Freesurfer volumetric markers of grey matter (GM) atrophy were obtained from ADNI. DTI markers were hemisphere‐averaged and GM volumes were normalised by head size. Eleven WM ROIs with reported AD abnormality and 4 reference GM ROIs were selected for sequencing (abbreviations in Table 1), yielding complete data for 83 cognitively normal subjects, 40 AD patients and 102 MCI subjects. Event‐based DPM (github.com/ucl‐pond/kde_ebm) was used to estimate a data‐driven sequence of neurodegeneration and its uncertainty (positional variance), and individuals were assigned to their most likely stage (Young et al., Brain, 2014). Resampling analysis assessed the robustness of the estimated sequence. Result: Fig. 1 shows the first data‐driven sequence of WM abnormalities in AD, including positional variance, with GM abnormality events for reference. The earliest WM events are increases in mean diffusivity (MD) in CGH and axial diffusivity (AxD) in FX and BCC. Subsequently, a cascade of AxD events in corpus callosum regions precedes abnormality in other medial temporal lobe WM structures. Fig. 2 shows the sequence is relatively robust under resampling, with low positional variance and similar median positions for most ROIs. Subject staging (Fig. 3, 4) shows that the fine‐grained approach splits MCI subjects with hippocampal atrophy into those with hippocampal atrophy and those with additional increased MD in CGH. Conclusion: This study finds WM microstructural abnormality among the earliest events in AD. Early hippocampal WM abnormality and corpus callosum ordering are consistent with early memory deficits in AD and inferences from cruder group‐based comparisons. The order suggests Wallerian degeneration rather than retrogenesis is the primary driver of WM neurodegeneration in AD. [ABSTRACT FROM AUTHOR]

Patients with medically-refractory focal epilepsy may be candidates for neurosurgery and some may require placement of intracranial EEG electrodes to localise seizure onset. Assessing cerebral responses to single pulse electrical stimulation (SPES) may give diagnostically useful data. SPES produces cortico-cortical evoked potentials (CCEPs), which infer effective brain connectivity. Diffusion-weighted images and tractography may be used to estimate structural brain connectivity. This combination provides the opportunity to observe seizure onset and its propagation throughout the brain, spreading contiguously along the cortex explored with electrodes, or non-contiguously. We analysed CCEPs and diffusion tractography in seven focal epilepsy patients and reconstructed the effective and structural brain networks. We aimed to assess the inter-modal similarity of the networks at a large scale across the cortex, the effective and structural connectivity of the ictal-onset zone, and investigate potential mechanisms of non-contiguous seizure spread. We found a significant overlap between structural and effective networks. Effective network CCEP amplitude, baseline variation, and outward connectivity was higher at ictal-onset zones, while structural connection strength within the ictal-onset zone tended to be higher. These findings support the concept of hyperexcitable cortex being associated with seizure generation. The high prevalence of structural and effective connections from the ictal-onset zone to sites of non-contiguous spread suggests that macroscopic structural and effective connections are plausible routes for non-contiguous seizure spread.