Kramberger, Milica G.

AbstractBackgroundPatterns of regional atrophy and hypometabolism have been observed in dementia with Lewy bodies (DLB). However, determinants of regional vulnerability to structural and functional neurodegeneration remain largely unexplored. First, we investigated the association between regional gene expression and grey matter volumes in probable DLB patients. Since hypometabolism presumably precedes overt brain atrophy, we additionally investigate the association between regional gene expression and hypometabolism in DLB.MethodTo investigate the association between gene expression and regional volumes, 165 DLB patients along with 165 age‐ and sex‐matched healthy controls from three European centres and the Mayo Clinic (USA) were included. Regional volumes were quantified from MRI using SPM12 in 112 cortical, subcortical, and cerebellar brain regions, and compared between groups, using w‐scores. Regional expression data of seven genes involved in the formation and degradation of pathological protein aggregates (APOE, APP, BIN1, GBA, MAPT, SNCA, TMEM175) was extracted from six healthy donors from the Allen Human Brain Atlas and correlated with regional volumetric w‐scores. To assess the predictive value of regional gene expression on regional volumes we used Gaussian stepwise backwards linear regression including all seven genes as predictors. To investigate the association between gene expression and hypometabolism, we are currently applying the same analysis pipeline to FDG‐PET data of 139 DLB patients from 8 European centres.ResultMost brain regions showed lower volumes in DLB patients compared to healthy controls, with differences being most pronounced in occipital and parietal lobes. Regional expression of APOE correlated positively with regional volumes in DLB. Conversely, regional expression of MAPT correlated negatively with regional volumes. Both APOE and MAPT gene expression were significant predictors of regional volumes in the regression analysis. None of the other gene expression values was significantly associated with regional volumes in DLB.ConclusionOur findings show that regional expression of genes associated with the abnormal accumulation of amyloid and tau, common co‐pathologies in DLB, partially account for the brain atrophy pattern observed in DLB patients. Analyses are ongoing for the hypometabolism pattern. Our finding emphasises the relevance of co‐pathologies in predicting atrophy progression and identifying potential targets for future disease‐modifying treatments.

Abstract INTRODUCTION Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). METHODS We included 436 patients from the European‐DLB consortium and the Mayo Clinic. Sex differences and sex‐by‐age interactions were assessed through visual atrophy rating scales ( n = 327; 73 ± 8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness ( n = 165; 69 ± 9 years, 72% males). RESULTS We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex‐by‐age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. DISCUSSION We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. Highlights Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales. Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods. Sex differences in gray matter measures in DLB tended to disappear with increasing age.

Abstract Background and objectives. Sex is an important contributing factor to neuroimaging phenotypes in brain disorders. However, little is known about the contribution of sex differences to the neurodegeneration in dementia with Lewy bodies (DLB). We investigated sex differences in probable DLB patients by using both visual rating scales of lobar atrophy and automated estimations of regional atrophy. Methods. We included 442 probable DLB patients from the European-DLB consortium and the Mayo Clinic who have magnetic resonance imaging (MRI) data available. We assessed sex differences and the sex-by-age interaction in two largely independent samples through visual rating scales of lobar atrophy (n = 333; mean age 73 ± 8 years, 62% males) and automated regional estimations of gray matter (GM) volume and mean cortical thickness (CTh) (n = 165; mean age 69 ± 9 years, 72% males). We used binary logistic regression and ANOVA for statistical analysis. Results. We found a statistically significantly higher likelihood of frontal atrophy measured by the global cortical atrophy-frontal subscale (GCA-F) in males (40% of males had an abnormal GCA-F score versus 29% of females, P-value = 0.006). Using automated estimations, we found smaller GM volumes in 6 cortical regions in males compared with females, as well as smaller GM volume in the entorhinal cortex and thinner olfactory cortices in females, compared with males. The sex-by-age interaction showed statistically significant results in 6 cortical volumes and 7 mean CTh estimations (P-value ≤ 0.05), accentuated in the right middle frontal gyrus (FDR-adjusted P-value = 0.047). These cross-sectional interactions indicated that while females have statistically significantly less atrophy than males at younger ages, differences become non-significant at older ages, with females showing the same level of atrophy than males around the age of 75. Conclusions. This study demonstrates sex differences on brain atrophy in probable DLB. While male DLB patients have a more widespread pattern of cortical atrophy at younger ages, these sex differences tend to disappear with increasing age. Longitudinal studies will help establish these cross-sectional findings and inform on sex and age considerations to the use of MRI in clinical routine, as the field moves towards precision medicine.