Postmortem brain MRI reveals differential associations of subcortical and limbic volumes with cortical thinning and neurodegenerative pathologies

The impact of different neuropathologies on deep brain structures remains to be understood. We examine subcortical and limbic volumetry in neurodegenerative diseases involving p-tau, α-synuclein and TDP-43.

We acquired neuropathological measures and brain segmentations from postmortem analysis of 132 donors with Alzheimer’s disease (AD), Lewy body disease (LBD), Frontotemporal Lobar Degeneration with TDP-43 (FTLD-TDP) and FTLD-Tau.

LBD had the least subcortical, limbic and cortical atrophy compared to AD, FTLD-TDP and FTLD-Tau. In donors with both AD and LBD pathologies, primary LBD was associated with less atrophy than primary AD. While AD had cortico-subcortical and cortico-limbic morphometric associations, LBD had more limited parieto-occipital cortico-limbic associations. FTLD-TDP had cortico-subcortical while FTLD-Tau had cortico-subcortical and cortico-limbic associations. In AD and FTLD-Tau, hippocampal volumes correlated with p-tau burden, neuron loss and gliosis. In LBD, thalamic α-synuclein severity was associated with subcortical/limbic volumes.

Postmortem neuroimaging reveals disease- and region-specific structure-pathology relationships. Competing Interest Statement J.A.V. reports honoraria/fees from the International Parkinson and Movement Disorder Society and the University City Science Center outside this work. I.M.N. reports fees from Biogen and Eisai outside this work. S.R.D. reports grants/fees from Nia Therapeutics and Rancho Biosciences outside this work. D.J.I. receives funding to the institution for clinical trials by Alector, CervoMed, Denali, PassageBio and Prevail outside this work. D.A.W. reports grants/fees from Beckman Coulter, Biogen, Eli Lilly, Functional Neuromodulation, GE Healthcare, GSK and Qynapse outside of this work. No additional disclosures. Footnotes The manuscript was revised to include new analyses including antemortem MRI comparisons, postmortem cortical thickness group comparisons, AD primary versus LBD primary mixed pathology analyses, and expanded polypathology models including neuronal loss and gliosis.