Susceptibility to postmortem (co)-pathologies in antemortem atrophy-based subtypes of Alzheimer’s disease

ObjectivesTo investigate whether antemortem atrophy-based subtypes of Alzheimer’s disease (AD) may be differentially susceptible to individual or concomitance of AD and non-AD (co)-pathologies, assessed neuropathologically at postmortem.MethodsWe selected 31 individuals from the AD neuroimaging initiative with: an antemortem magnetic resonance imaging scan evaluating brain atrophy available within two years before death; an antemortem diagnosis of AD dementia or prodromal AD; and postmortem neuropathological confirmation of AD. Antemortem atrophy-based subtypes was modeled as a continuous phenomenon in terms of two recently proposed dimensions: typicality (ranging from limbic-predominant AD to hippocampal-sparing AD subtypes) and severity (ranging from typical AD to minimal atrophy AD subtypes). Postmortem neuropathological evaluation included global and regional outcomes: AD hallmark pathologies of amyloid-beta and tau; non-AD co-pathologies of alpha-synuclein Lewy body and TDP-43; and the overall concomitance across these four (co)-pathologies. Partial correlation and linear regression models were used to assess the association between antemortem atrophy-based subtypes and postmortem neuropathological outcomes.ResultsWe observed significant global and regional associations between antemortem typicality and postmortem (co)-pathologies including tau, alpha-synuclein Lewy bodies and TDP-43. Antemortem typicality demonstrated stronger regional associations with concomitance of multiple postmortem (co)-pathologies in comparison to antemortem severity. Our findings suggest the following susceptibilities of atrophy-based subtypes: limbic-predominant AD towards higher burden of tau and TDP-43 pathologies while hippocampal-sparing AD towards lower burdens; limbic-predominant AD and typical AD towards higher burden of alpha-synuclein Lewy body pathology while hippocampal-sparing AD and minimal-atrophy AD towards lower burdens.DiscussionThrough a direct antemortem-to-postmortem validation, our study highlights the importance of understanding heterogeneity in AD in relation to concomitance of AD and non-AD pathologies. Our findings provide a deeper understanding of both global and regional vulnerabilities of the biological subtypes of AD brain towards (co)-pathologies. Relative involvement of both AD hallmark and non-AD (co)-pathologies will enhance prevailing knowledge of biological heterogeneity in AD and could thus, contribute towards tracking disease progression and designing clinical trials in the future.

RADI-02. Hippocampal-sparing whole brain volumetric modulated arc therapy (VMAT) planning in Monaco: a “How-to” not pull your hair out

Purpose NRG-CC001 recently reported positive results on hippocampal-sparing IMRT (HS-IMRT) in conjunction with memantine for the reduction in cognitive decline compared to conventional whole brain radiation therapy. Herein, we report our experience in planning volumetric modulated arc therapy (VMAT) cases in Monaco® with the anticipation of increased utilization of the planning technique for delivery on Elekta linear accelerators. Methods and Materials Twelve patients previously treated with whole brain radiation therapy who would have been eligible for NRG-CC001 were replanned with VMAT HS-IMRT for to a dose of 30Gy/10fx using constraints from the trial. Results All twelve patients were able to be planned with VMAT and achieve NRG-CC001 dose constraints. Median maximum and D100% to the right and left hippocampi were: 13.37Gy and 13.43Gy, respectively and 8.76Gy and 8.86Gy, respectively. Median coverage of the brain minus the hippocampi with 30Gy was 96.53%. All cases passed quality assurance testing with 3%/3mm and 2%/2mm criterion. Conclusions Hippocampal-sparing IMRT whole brain radiation therapy can be feasibly planned with VMAT technique in Monaco® and delivered on Elekta linear accelerators.

Comparative Study Evaluating Cognitive Functions in Patients Receiving Conventional Whole Brain Radiotherapy vs Hippocampal Avoidance Whole Brain Radiotherapy

Background: Whole brain radiotherapy is the treatment of choice for patients with brain metastases. However, neurocognitive functions decline due to impaired hippocampal neurogenesis might occur thereafter. It is hypothesized that conformal hippocampal avoidance during the course of WBRT might provide meaningful neurocognitive functions preservation. Our study aims to demonstrate the impact of delivering HA‑WBRT on NCF changes in patients receiving WBRT. Methods: fifty patients who were referred for cranial irradiation were enrolled in the study. Before the HA‑WBRT course and randomly assigned to two equal groups, the first group will receive conventional whole brain palliative radiotherapy and the second group will receive hippocampal sparing whole brain radiotherapy, assigned to 30 Gy over 10 fractions over two weeks, all participants should receive baseline neurocognitive assessment, including memory, executive functions, and psychomotor speed,the primary endpoint was delayed recall, as determined by the change/decline in Hopkins Verbal Learning Test (HVLT-R) and The One Card Learning Test (OCLT) from the baseline assessment to 4 months after the start of HA‑WBRT. Results: Regarding neurocognitive outcomes, no statistically significant differences were found between various NCF scores obtained at baseline and at post‑radiotherapy intervals, in immediate verbal memory and non‑verbal memory, except for delayed recall memory on HVLT-R Hopkins Verbal Learning Test -Revised for delayed recall Learning, p =0.008. Conclusions: Functional preservation by hippocampal sparing during WBRT could largely be achieved in this study, which also suggests that HA‑WBRT should be a feasible technique preserving neurocognitive functions while maintaining intracranial control.