Senjem, Matthew L.

AbstractAlzheimer's disease (AD) can present with atypical clinical forms where the prominent domain of deficit is not memory, that is, atypical AD. Atypical AD patients show cortical atrophy on MRI, hypometabolism on [18F]fluorodeoxyglucose (FDG) PET, tau uptake on [18F]AV‐1451 PET, and white matter tract degeneration on diffusion tensor imaging (DTI). How these disease processes relate to each other locally and distantly remains unclear. We aimed to examine multimodal neuroimaging relationships in individuals with atypical AD, using univariate and multivariate techniques at region‐ and voxel‐level. Forty atypical AD patients underwent MRI, FDG‐PET, tau‐PET, beta‐amyloid PET, and DTI. Patients were all beta‐amyloid positive. Partial Pearson's correlations were performed between tau and FDG standardized uptake value ratios, gray matter MRI‐volumes and white matter tract fractional anisotropy. Sparse canonical correlation analysis was applied to identify multivariate relationships between the same quantities. Voxel‐level associations across modalities were also assessed. Tau showed strong local negative correlations with FDG metabolism in the occipital and frontal lobes. Tau in frontal and parietal regions was negatively associated with temporoparietal gray matter MRI‐volume. Fractional anisotropy in a set of posterior white matter tracts, including the splenium of the corpus callosum, cingulum, and posterior thalamic radiation, was negatively correlated with parietal and occipital tau, atrophy and, predominantly, with hypometabolism. These results support the view that tau is the driving force behind neurodegeneration in atypical AD, and that a breakdown in structural connectivity is related to cortical neurodegeneration, particularly hypometabolism.

AbstractBackgroundElevated uptake of the [18F]AV‐1451 tau‐PET ligand has been observed cross‐sectionally in subjects with progressive supranuclear palsy (PSP). However, it is unknown how the ligand performs longitudinally in PSP. We aimed to determine how regional measures of change on [18F]AV‐1451 PET perform as longitudinal biomarkers of PSP compared with the more established biomarker of rate of midbrain atrophy.MethodsSixteen subjects with PSP underwent 2 serial [18F]AV‐1451 tau‐PET scans and 3‐Tesla MRI over 12 months and were age‐ and sex‐matched to 39 healthy controls with longitudinal [18F]AV‐1451 PET. Median [18F]AV‐1451 uptake was calculated for each scan for regions of interest across the brain and divided by uptake in cerebellar crus to create standard uptake value ratios. Midbrain volume on MRI was also calculated for each scan. Sample sizes required to power placebo‐controlled treatment trials were calculated.ResultsRate of midbrain atrophy was significantly increased in PSP compared with controls. [18F]AV‐1451 regional change measures were significantly increased in PSP compared with controls in the pallidum, precentral cortex, dentate nucleus of the cerebellum, and midbrain. Change over time in the PSP Rating Scale correlated with change in midbrain volume but did not correlate with change in the [18F]AV‐1451 measures. Smallest sample‐size estimates were obtained with rate of midbrain atrophy, followed by the PSP Rating Scale, with both outperforming [18F]AV‐1451 measures.Conclusions[18F]AV‐1451 tau‐PET measures increase over time in subjects with PSP, but longitudinal [18F]AV‐1451 measures may not perform as well as rate of midbrain atrophy as biomarkers for PSP clinical trials. © 2018 International Parkinson and Movement Disorder Society