Elijah Mak1, Maria-Eleni Dounavi2, Audrey Low2, Stephen F Carter2, Elizabeth McKiernan2, Guy B Williams3, P Simon Jones3, Isabelle Carriere4, Graciela Terrera Muniz4, Karen Ritchie5, Craig Ritchie4, Li Su2, John T O'Brien2. 1. Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0SP, UK. Electronic address: fkm24@medschl.cam.ac.uk. 2. Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0SP, UK. 3. Department of Clinical Neurosciences and Wolfson Brain Imaging Centre, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK. 4. Centre for Dementia Prevention, University of Edinburgh, Edinburgh, UK. 5. Centre for Dementia Prevention, University of Edinburgh, Edinburgh, UK; INSERM and University of Montpellier, Montpellier, France.
Abstract
BACKGROUND: First-degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer's disease (AD). Here, we investigate "estimated years to onset of dementia" (EYO) as a surrogate marker of preclinical disease progression and assess its associations with multi-modal neuroimaging biomarkers. METHODS: 89 FH+ participants in the PREVENT-Dementia study underwent longitudinal MR imaging over 2 years. EYO was calculated as the difference between the parental age of dementia diagnosis and the current age of the participant (mean EYO = 23.9 years). MPRAGE, ASL and DWI data were processed using Freesurfer, FSL-BASIL and DTI-TK. White matter lesion maps were segmented from FLAIR scans. The SPM Sandwich Estimator Toolbox was used to test for the main effects of EYO and interactions between EYO, Time, and APOE-ε4+. Threshold free cluster enhancement and family wise error rate correction (TFCE FWER) was performed on voxelwise statistical maps. RESULTS: There were no significant effects of EYO on regional grey matter atrophy or white matter hyperintensities. However, a shorter EYO was associated with lower white matter Fractional Anisotropy and elevated Mean/Radial Diffusivity, particularly in the corpus callosum (TFCEFWERp < 0.05). The influence of EYO on white matter deficits were significantly stronger compared to that of normal ageing. APOE-ε4 carriers exhibited hyperperfusion with nearer proximity to estimated onset in temporo-parietal regions. There were no interactions between EYO and time, suggesting that EYO was not associated with accelerated imaging changes in this sample. CONCLUSIONS: Amongst cognitively normal midlife adults with a family history of dementia, a shorter hypothetical proximity to dementia onset may be associated with incipient brain abnormalities, characterised by white matter disruptions and perfusion abnormalities, particularly amongst APOE-ε4 carriers. Our findings also confer biological validity to the construct of EYO as a potential stage marker of preclinical progression in the context of sporadic dementia. Further clinical follow-up of our longitudinal sample would provide critical validation of these findings.
BACKGROUND: First-degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer's disease (AD). Here, we investigate "estimated years to onset of dementia" (EYO) as a surrogate marker of preclinical disease progression and assess its associations with multi-modal neuroimaging biomarkers. METHODS: 89 FH+ participants in the PREVENT-Dementia study underwent longitudinal MR imaging over 2 years. EYO was calculated as the difference between the parental age of dementia diagnosis and the current age of the participant (mean EYO = 23.9 years). MPRAGE, ASL and DWI data were processed using Freesurfer, FSL-BASIL and DTI-TK. White matter lesion maps were segmented from FLAIR scans. The SPM Sandwich Estimator Toolbox was used to test for the main effects of EYO and interactions between EYO, Time, and APOE-ε4+. Threshold free cluster enhancement and family wise error rate correction (TFCE FWER) was performed on voxelwise statistical maps. RESULTS: There were no significant effects of EYO on regional grey matter atrophy or white matter hyperintensities. However, a shorter EYO was associated with lower white matter Fractional Anisotropy and elevated Mean/Radial Diffusivity, particularly in the corpus callosum (TFCEFWERp < 0.05). The influence of EYO on white matter deficits were significantly stronger compared to that of normal ageing. APOE-ε4 carriers exhibited hyperperfusion with nearer proximity to estimated onset in temporo-parietal regions. There were no interactions between EYO and time, suggesting that EYO was not associated with accelerated imaging changes in this sample. CONCLUSIONS: Amongst cognitively normal midlife adults with a family history of dementia, a shorter hypothetical proximity to dementia onset may be associated with incipient brain abnormalities, characterised by white matter disruptions and perfusion abnormalities, particularly amongst APOE-ε4 carriers. Our findings also confer biological validity to the construct of EYO as a potential stage marker of preclinical progression in the context of sporadic dementia. Further clinical follow-up of our longitudinal sample would provide critical validation of these findings.
Authors: Amanina Ahmad Safri; Che Mohd Nasril Che Mohd Nassir; Ismail Nurul Iman; Nur Hartini Mohd Taib; Anusha Achuthan; Muzaimi Mustapha Journal: World J Clin Cases Date: 2022-08-26 Impact factor: 1.534