Widespread brain tau and its association with ageing, Braak stage and Alzheimer’s dementia

Abstract

See Herholz (doi:10.1093/brain/awx340) for a scientific commentary on this article.Autopsy data have proposed that a topographical pattern of tauopathy occurs in the brain with the development of dementia due to Alzheimer's disease. We evaluated the findings of tau-PET to better understand neurofibrillary tangle development as it is seen in cognitively unimpaired and impaired individuals. The evolution of Alzheimer's disease tauopathy in cognitively unimpaired individuals needs to be examined to better understand disease pathogenesis. Tau-PET was performed in 86 cognitively impaired individuals who all had abnormal amyloid levels and 601 cognitively unimpaired individuals. Tau-PET findings were assessed for relationships with clinical diagnosis, age, and regional uptake patterns relative to Braak stage. Regional and voxel-wise analyses were performed. Topographical findings from tau-PET were characterized using hierarchical clustering and clinical characteristic-based subcategorization. In older cognitively unimpaired individuals (≥50 years), widespread, age-related elevated tau signal was seen among those with normal or abnormal amyloid status as compared to younger cognitively unimpaired individuals (30-49 years). More frequent regional tau signal elevation throughout the brain was seen in cognitively unimpaired individuals with abnormal versus normal amyloid. Elevated tau signal was seen in regions that are considered high Braak Stage in cognitively unimpaired and cognitively impaired individuals. Hierarchical clustering and clinical characteristic-based categorizations both showed different patterns of tau signal between groups such as greater tau signal in frontal regions in younger onset Alzheimer's disease dementia participants (most of whom had a dysexecutive clinical presentation). Tau-PET signal increases modestly with age throughout the brain in cognitively unimpaired individuals and elevated tau is seen more often when amyloid brain accumulation is present. Tau signal patterns in cognitively unimpaired correspond to early Braak stage but also suggest tangle involvement in extra-medial temporal and extra-temporal regions that are considered more advanced in the Braak scheme even when amyloid negative. Our findings also suggest the possibility of widespread development of early tangle pathology rather than a pattern defined exclusively by adjacent, region-to-region spread, prior to onset of clinical symptoms. Distinct patterns of neurofibrillary tangle deposition in younger-onset Alzheimer's disease dementia versus older-onset Alzheimer's disease dementia provide evidence for variability in regional tangle deposition patterns and demonstrate that different disease phenotypes have different patterns of tauopathy. Pathological correlation with imaging is needed to assess the implications of these observations.

The impact of amyloid‐beta and tau on prospective cognitive decline in older individuals

“…1,7,37,38 Furthermore, we show that it is only a subset of Aβ + , with higher levels of tau detected by PET imaging, who demonstrate prospective memory decline. 1,7,37,38 Furthermore, we show that it is only a subset of Aβ + , with higher levels of tau detected by PET imaging, who demonstrate prospective memory decline.…”

Tau‐positron emission tomography correlates with neuropathology findings

“…Analysis of entorhinal cortex as a single ROI was also performed. The FTP‐PET ROI median values were normalized to cerebellar crus (bilateral crus, 1‐2) to calculate regional standardized uptake value ratios (SUVRs) . Data with and without PVC were evaluated.…”

“…The FTP-PET ROI median values were normalized to cerebellar crus (bilateral crus, 1-2) to calculate regional standardized uptake value ratios (SUVRs). 13 Data with and without PVC were evaluated. Correlative analysis of quantitative immunohistochemistry (IHC) and regional FTP-PET signal was performed in three ROIs defined by the MRI brain atlas (hippocampus, middle temporal, and superior temporal) that were sites of probable early tau involvement, were all sampled at autopsy, and were included in an automated image/autopsy-tissue correlation program we previously developed.…”

“…7,8 Tau-positron emission tomography (tau-PET) imaging allows study of tau neuropathology in vivo [9][10][11] and initial studies have shown that tau-PET correlates with AD neurofibrillary tangles in vitro. 12 In aging, tau-PET signal has been described to occur in the medial temporal lobe as well as in extratemporal areas of the brain 13 and increases in these regions in longitudinal studies. 14 The composition of fibrillar tau differs across tauopathies, 15 engendering challenges for tau-PET imaging.…”

Imaging Biomarkers of Alzheimer Disease in Multiple Sclerosis

“…The AD signature PiB SUVr was obtained from the bilateral prefrontal, orbitofrontal, temporal, anterior cingulate, and parietal (including precuneus and posterior cingulate) gray matter regions as previously described . The (median) AD signature AV1451 SUVr was obtained from the entorhinal, amygdala, parahippocampal, fusiform, inferior, and middle temporal gray matter regions as previously described . AD signature PiB SUVr was used to classify participants as PiB positive or negative using a cutoff point of 1.48, and AD signature AV1451 SUVr was used to classify participants as AV1451 positive or negative using a cutoff point of 1.25 as previously operationalized .…”