Cortical microstructure in the behavioural variant of frontotemporal dementia: looking beyond atrophy.

Cortical mean diffusivity has been proposed as a novel biomarker for the study of the cortical microstructure in Alzheimer's disease. In this multicentre study, we aimed to assess the cortical microstructural changes in the behavioural variant of frontotemporal dementia (bvFTD); and to correlate cortical mean diffusivity with clinical measures of disease severity and CSF biomarkers (neurofilament light and the soluble fraction beta of the amyloid precursor protein). We included 148 participants with a 3 T MRI and appropriate structural and diffusion weighted imaging sequences: 70 patients with bvFTD and 78 age-matched cognitively healthy controls. The modified frontotemporal lobar degeneration clinical dementia rating was obtained as a measure of disease severity. A subset of patients also underwent a lumbar puncture for CSF biomarker analysis. Two independent raters blind to the clinical data determined the presence of significant frontotemporal atrophy to dichotomize the participants into possible or probable bvFTD. Cortical thickness and cortical mean diffusivity were computed using a surface-based approach. We compared cortical thickness and cortical mean diffusivity between bvFTD (both using the whole sample and probable and possible bvFTD subgroups) and controls. Then we computed the Cohen's d effect size for both cortical thickness and cortical mean diffusivity. We also performed correlation analyses with the modified frontotemporal lobar degeneration clinical dementia rating score and CSF neuronal biomarkers. The cortical mean diffusivity maps, in the whole cohort and in the probable bvFTD subgroup, showed widespread areas with increased cortical mean diffusivity that partially overlapped with cortical thickness, but further expanded to other bvFTD-related regions. In the possible bvFTD subgroup, we found increased cortical mean diffusivity in frontotemporal regions, but only minimal loss of cortical thickness. The effect sizes of cortical mean diffusivity were notably higher than the effect sizes of cortical thickness in the areas that are typically involved in bvFTD. In the whole bvFTD group, both cortical mean diffusivity and cortical thickness correlated with measures of disease severity and CSF biomarkers. However, the areas of correlation with cortical mean diffusivity were more extensive. In the possible bvFTD subgroup, only cortical mean diffusivity correlated with the modified frontotemporal lobar degeneration clinical dementia rating. Our data suggest that cortical mean diffusivity could be a sensitive biomarker for the study of the neurodegeneration-related microstructural changes in bvFTD. Further longitudinal studies should determine the diagnostic and prognostic utility of this novel neuroimaging biomarker.

Reelin signaling pathway genotypes and Alzheimer disease in a Spanish population.

BACKGROUND: Several reports suggest that the reelin protein could play a role in Alzheimer pathophysiology. This led us to ask whether genetic variability in the reelin pathway may increase the risk of developing Alzheimer disease (AD) or mild cognitive impairment (MCI). METHODS: This was a case-control study in which neuropsychological tests were administered and peripheral blood samples taken. The study included 121 patients with AD, 94 with MCI, and 198 controls. Forty biallelic variants single nucleotide polimorphisms were genotyped in 8 genes related to reelin signaling pathway using a SNPlex genotyping system, and allele frequencies were compared between patients and controls using χ tests and obtaining odds ratios (OR). RESULTS: A total of 413 subjects with complete neuropsychological data were analyzed. A significant association between the genotypes RELN (rs528528 and rs2299356), PLK2 (rs15009 and rs702723), and CAMK2A (rs3756577 and rs3822606) and AD or MCI was found. A significant association also was found between the GG genotype at the RELN-rs2299356 and the risk of AD (OR=2.68, P=0.003) and between the AG genotype at the CAMK2A-rs3822606 (OR=2.13, P=0.004). We found a protective effect of the RELN-rs528528 CT genotype and MCI (OR=0.36, P=0.002), and the PLK2-rs15009 CC and GG genotypes and CC genotype at PLK2-rs702723 with OR ranging from 0.40 to 0.57 on AD. These data suggest that TT or CT genotypes at CAMK2A-rs3756577 is associated with risk reduction for AD and MCI ranging from 2 to nearly 8 times. CONCLUSIONS: Our data suggest a possible relation between certain reelin signaling pathway genotypes and cognitive impairment related to AD.